Beta-hairpin peptidomimetics

Abstract

Beta-hairpin peptidomimetics of the general formula (I), and pharmaceutically acceptable salts thereof, with P, X, Q., and optionally L being elements as defined in the description and the claims, have Gram-negative antimicrobial activity to e.g. inhibit the growth or to kill microorganisms such as Klebsiella pneumoniae and/or Acinetobacter baumannii and/or Escherichia coli and/or Pseudomonas aeruginosa and/or Enterobacter cloacae. They can be used as medicaments to treat or prevent infections or as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials. These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

Claims

1. A β-hairpin peptidomimetic selected from the group consisting of Ex. 1 to 385, the sequences of which are shown in the following Table below: TABLE-US-00009 Ex. No. Sequence Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ex. 17 Ex. 18 Ex. 19 Ex. 20 Ex. 21 Ex. 22 Ex. 23 Ex. 24 Ex. 25 Ex. 26 Ex. 27 Ex. 28 Ex. 29 Ex. 30 Ex. 31 Ex. 32 Ex. 33 Ex. 34 Ex. 35 Ex. 36 Ex. 37 Ex. 38 Ex. 39 Ex. 40 Ex. 41 Ex. 42 Ex. 43 Ex. 44 Ex. 45 Ex. 46 Ex. 47 Ex. 48 Ex. 49 Ex. 50 Ex. 51 Ex. 52 Ex. 53 Ex. 54 Ex. 55 Ex. 56 Ex. 57 Ex. 58 Ex. 59 Ex. 60 Ex. 61 Ex. 62 Ex. 63 Ex. 64 Ex. 65 Ex. 66 Ex. 67 Ex. 68 Ex. 69 Ex. 70 Ex. 71 Ex. 72 Ex. 73 Ex. 74 Ex. 75 Ex. 76 Ex. 77 Ex. 78 Ex. 79 Ex. 80 Ex. 81 Ex. 82 Ex. 83 Ex. 84 Ex. 85 Ex. 86 Ex. 87 Ex. 88 Ex. 89 Ex. 90 Ex. 91 Ex. 92 Ex. 93 Ex. 94 Ex. 95 Ex. 96 Ex. 97 Ex. 98 Ex. 99 Ex. 100 Ex. 101 Ex. 102 Ex. 103 Ex. 104 Ex. 105 Ex. 106 Ex. 107 Ex. 108 Ex. 109 Ex. 110 Ex. 111 Ex. 112 Ex. 113 Ex. 114 Ex. 115 Ex. 116 Ex. 117 Ex. 119 Ex. 120 Ex. 121 Ex. 122 Ex. 123 Ex. 124 Ex. 125 Ex. 126 Ex. 127 Ex. 128 Ex. 129 Ex. 130 Ex. 131 Ex. 132 Ex. 133 Ex. 134 Ex. 135 Ex. 136 Ex. 137 Ex. 138 Ex. 139 Ex. 140 Ex. 141 Ex. 142 Ex. 143 Ex. 144 Ex. 145 Ex. 146 Ex. 147 Ex. 148 Ex. 149 Ex. 150 Ex. 151 Ex. 152 Ex. 153 Ex. 154 Ex. 155 Ex. 156 Ex. 157 Ex. 158 Ex. 159 Ex. 160 Ex. 161 Ex. 162 Ex. 163 Ex. 164 Ex. 165 Ex. 166 Ex. 167 Ex. 168 Ex. 169 Ex. 170 Ex. 171 Ex. 172 Ex. 173 Ex. 174 Ex. 175 Ex. 176 Ex. 177 Ex. 178 Ex. 179 Ex. 180 Ex. 181 Ex. 182 Ex. 183 Ex. 184 Ex. 185 Ex. 186 Ex. 187 Ex. 188 Ex. 189 Ex. 190 Ex. 191 Ex. 192 Ex. 193 Ex. 194 Ex. 195 Ex. 196 Ex. 197 Ex. 198 Ex. 199 Ex. 200 Ex. 201 Ex. 202 Ex. 203 Ex. 204 Ex. 205 Ex. 206 Ex. 207 Ex. 208 Ex. 209 Ex. 210 Ex. 211 Ex. 212 Ex. 213 Ex. 214 Ex. 215 Ex. 216 Ex. 217 Ex. 218 Ex. 219 Ex. 220 Ex. 221 Ex. 222 Ex. 223 Ex. 224 Ex. 225 Ex. 226 Ex. 227 Ex. 228 Ex. 229 Ex. 230 Ex. 232 Ex. 233 Ex. 234 Ex. 235 Ex. 236 Ex. 237 Ex. 238 Ex. 239 Ex. 240 Ex. 241 Ex. 242 Ex. 243 Ex. 244 Ex. 245 Ex. 246 Ex. 247 Ex. 248 Ex. 249 Ex. 250 Ex. 251 Ex. 252 Ex. 253 Ex. 254 Ex. 255 Ex. 256 Ex. 257 Ex. 258 Ex. 259 Ex. 260 Ex. 261 Ex. 262 Ex. 263 Ex. 264 Ex. 265 Ex. 266 Ex. 267 Ex. 268 Ex. 269 Ex. 270 Ex. 271 Ex. 272 Ex. 273 Ex. 274 Ex. 275 Ex. 276 Ex. 277 Ex. 278 Ex. 279 Ex. 280 Ex. 281 Ex. 282 Ex. 283 Ex. 284 Ex. 285 Ex. 286 Ex. 287 Ex. 288 Ex. 289 Ex. 290 Ex. 291 Ex. 292 Ex. 293 Ex. 294 Ex. 295 Ex. 296 Ex. 297 Ex. 298 Ex. 299 Ex. 300 Ex. 301 Ex. 302 Ex. 303 Ex. 304 Ex. 305 Ex. 306 Ex. 307 Ex. 308 Ex. 309 Ex. 310 Ex. 311 Ex. 312 Ex. 313 Ex. 314 Ex. 315 Ex. 316 Ex. 317 Ex. 318 Ex. 319 Ex. 320 Ex. 321 Ex. 322 Ex. 323 Ex. 324 Ex. 325 Ex. 326 Ex. 327 Ex. 328 Ex. 329 Ex. 330 Ex. 331 Ex. 332 Ex. 333 Ex. 334 Ex. 335 Ex. 336 Ex. 337 Ex. 338 Ex. 339 Ex. 340 Ex. 341 Ex. 342 Ex. 343 Ex. 344 Ex. 345 Ex. 346 Ex. 347 Ex. 348 Ex. 349 Ex. 350 Ex. 351 Ex. 352 Ex. 353 Ex. 354 Ex. 355 Ex. 356 Ex. 357 Ex. 358 Ex. 359 Ex. 360 Ex. 361 Ex. 362 Ex. 363 Ex. 364 Ex. 365 Ex. 366 Ex. 367 Ex. 368 Ex. 369 Ex. 370 Ex. 371 Ex. 372 Ex. 373 Ex. 374 Ex. 375 Ex. 376 Ex. 377 Ex. 378 Ex. 379 Ex. 380 Ex. 381 Ex. 382 Ex. 383 Ex. 384 Ex. 385 or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition containing a β-hairpin peptidomimetic or a mixture thereof according to claim 1 and at least one pharmaceutically inert carrier.

3. A pharmaceutical composition according to claim 2 is in a form suitable for oral, topical, injection, pulmonary or inhalation or transdermal administration.

Description

EXAMPLES

(1) 1. Peptide Synthesis

(2) 1.1 Synthetic Procedures

(3) A method for the synthesis of the peptidomimetics of the present invention is exemplified in the following. This is to demonstrate the principal concept and does not limit or restrict the present invention in any way. A person skilled in the art is easily able to modify these procedures, especially, but not limited to, choosing a different strategy for formation of a disulfide interstrand linkage and a different fragment coupling strategy, to still achieve the preparation of the claimed cyclic peptidomimetic compounds of the present invention.

(4) 1.1.1 Coupling of the First Protected Residue to the Resin

(5) 1.1.1.1 Coupling of an Fmoc-Protected Amino Acid to the Resin Via a Side Chain Hydroxyl Group

(6) In a dried flask, 2-chlorotritylchloride resin (polystyrene, 1% crosslinked; loading: 1.4 mMol/g) was swollen in dry 1,2 dichloroethane for 30 min (4.5 mL 1,2 dichloroethane per g resin). A suspension of 3.2 eq of the Fmoc-protected amino acid and 2 eq of NMM in dry 1,2-dichloroethane (10 mL per g resin) was added. After stirring under reflux for 1-2 h the resin was filtered off and washed with 1,2 dichloroethane (3×) and with CH.sub.2Cl.sub.2. Then a solution of dry CH.sub.2Cl.sub.2/MeOH/DIPEA (17:2:1, v/v/v) was added (10 mL per g resin). After shaking for 3×30 min the resin was filtered off in a pre-weighed sintered funnel and washed successively with CH.sub.2Cl.sub.2, DMF, CH.sub.2Cl.sub.2, MeOH, CH.sub.2Cl.sub.2, MeOH, CH.sub.2Cl.sub.2 (2×) and Et.sub.2O (2×). The resin was dried under high vacuum overnight. The final mass of resin was calculated before the qualitative control.

(7) Loading was typically 0.2-0.3 mMol/g.

(8) The following preloaded resin was prepared: Fmoc-Thr(-2-chlorotrityl resin)-allyl.

(9) 1.1.1.2 Coupling of an Fmoc-Protected Amino Alcohol to the Resin Via a Hydroxyl Group

(10) In a dried flask, 2-chlorotritylchloride resin (polystyrene, 1% crosslinked; loading: 1.4 mMol/g) was swollen in dry 1,2 dichloroethane for 30 min (4.5 mL 1,2 dichloroethane per g resin). A suspension of 3.2 eq of the Fmoc-protected amino alcohol and 2 eq of NMM in dry 1,2-dichloroethane (10 mL per g resin) was added. After stirring under reflux for 1-2 h the resin was filtered off and washed with 1,2 dichloroethane (3×) and with CH.sub.2Cl.sub.2. Then a solution of dry CH.sub.2Cl.sub.2/MeOH/DIPEA (17:2:1, v/v/v) was added (10 mL per g resin). After shaking for 3×30 min the resin was filtered off in a pre-weighed sintered funnel and washed successively with CH.sub.2Cl.sub.2, DMF, CH.sub.2Cl.sub.2, MeOH, CH.sub.2Cl.sub.2, MeOH, CH.sub.2Cl.sub.2 (2×) and Et.sub.2O (2×). The resin was dried under high vacuum overnight. The final mass of resin was calculated before the qualitative control.

(11) Loading was typically 0.2-0.3 mMol/g.

(12) The following preloaded resins were prepared: Fmoc-Glyol-2-chlorotrityl resin, Fmoc-Serol(tBu)-2-chlorotrityl resin, Fmoc-Throl(tBu)-2-chlorotrityl resin, Fmoc-.sup.DThrol(tBu)-2-chlorotrityl resin, and Fmoc-Tyrol(tBu)-2-chlorotrityl resin.

(13) 1.1.1.3 Coupling of an Fmoc-Protected Amino Acid to the Resin Via a Carboxyl Group

(14) In a dried flask, 2-chlorotritylchloride resin (polystyrene, 1% crosslinked; loading: 1.4 mMol/g) was swollen in dry CH.sub.2Cl.sub.2 for 30 min (7 mL CH.sub.2Cl.sub.2 per g resin). A solution of 0.8 eq of the Fmoc-protected amino acid and 6 eq of DIPEA in dry CH.sub.2Cl.sub.2/DMF (4/1, v/v) (10 mL per g resin) was added. After shaking for 2-4 h at rt the resin was filtered off and washed successively with CH.sub.2Cl.sub.2, DMF, CH.sub.2Cl.sub.2, DMF and CH.sub.2Cl.sub.2. Then a solution of dry CH.sub.2Cl.sub.2/MeOH/DIPEA (17:2:1, v/v/v) was added (10 mL per g resin). After shaking for 3×30 min the resin was filtered off in a pre-weighed sintered funnel and washed successively with CH.sub.2Cl.sub.2, DMF, CH.sub.2Cl.sub.2, MeOH, CH.sub.2Cl.sub.2, MeOH, CH.sub.2Cl.sub.2 (2×) and Et.sub.2O (2×). The resin was dried under high vacuum overnight. The final mass of resin was calculated before the qualitative control.

(15) Loading was typically 0.6-0.7 mMol/g.

(16) The following preloaded resins were prepared: Fmoc-.sup.DAla-2-chlorotrityl resin, Fmoc-.sup.DAsn(Trityl)-2-chlorotrityl resin, Fmoc-Cys(Trityl)-2-chlorotrityl resin, Fmoc-.sup.DDab(Boc)-2-chlorotrityl resin, Fmoc-.sup.DGln(Trityl)-2-chlorotrityl resin, Fmoc-.sup.DGlu(tBu)-2-chlorotrityl resin, Fmoc-.sup.DHse(tBu)-2-chlorotrityl resin, Fmoc-Leu(3R)OtBu-2-chlorotrityl resin, Fmoc-.sup.DLys(Boc)-2-chlorotrityl resin, Fmoc-Ser(tBu)-2-chlorotrityl resin, Fmoc-.sup.DSer(tBu)-2-chlorotrityl resin, Fmoc-Thr(tBu)-2-chlorotrityl resin, Fmoc-.sup.DThr(tBu)-2-chlorotrityl resin, Fmoc-.sup.DVal-2-chlorotrityl resin and Fmoc-.sup.DTyr(tBu)-2-chlorotrityl resin.

(17) 1.1.2 Methods for Synthesis on Solid Support of the Fully Protected Peptide and of the Fully Protected Peptide Fragment for Fragment Coupling

(18) The synthesis was carried out on a Syro-peptide synthesizer (MultiSynTech GmbH) using 24 to 96 reaction vessels. Unless otherwise indicated, in each vessel were placed 0.05 mMol of the resin, obtained from procedures 1.1.1.1, 1.1.1.2, or 1.1.1.3, as described above, or 0.05 mMol of Sieber amide resin, as described below, and the resin was swelled in CH.sub.2Cl.sub.2 and DMF for 15 min, respectively.

(19) The following reaction cycles were programmed and carried out as described in the methods A-K, as described herein below:

(20) TABLE-US-00001 Step Reagent Time  1 CH.sub.2Cl.sub.2, wash and swell (manual) 1 × 3 min  2 DMF, wash and swell 2 × 30 min  3 20% piperidine/DMF 1 × 5 min and 1 × 15 min  4 DMF, wash 5 × 1 min    5.sup.a) 3.6 eq appropriately protected amino acid and 3.6 eq HOAt in DMF or NMP + 3.6 eq DIC in DMF 1 × 40 min  6 3.6 eq appropriately protected amino acid and 3.6 eq HOAt in DMF or NMP + 3.6 eq HATU + 7.2 eq DIPEA in NMP 1 × 40 min  7 DMF, wash 5 × 1 min  8 20% piperidine/DMF 1 × 5 min and 1 × 15 min or 2 × 2 min.sup.b)  9 DMF, wash 5 × 1 min 10 CH.sub.2Cl.sub.2, wash (at the end of the synthesis) 3 × 1 min .sup.a)In the coupling cycle following coupling of an N-alkyl amino acid residue and for coupling of the first protected amino acid residue to Sieber amide resin, step 5 was omitted and step 6 was performed twice instead. .sup.b)Reduced times were used for Fmoc deprotection of an amino acid residue having a carboxyl group protected as allyl ester, and for the Fmoc deprotection step of the following coupling cycle.

(21) The term “macrolactam cycle”, as used herein below, refers to a cyclic peptide moiety that is generated through formation of an amide bond between two amino acid residues of module B, involving an α-carboxyl group and a side-chain amino group.

(22) The term “lactam interstrand linkage”, as used herein, refers to a linkage of two amino acid residues of module A by an amide bond, involving a side-chain carboxyl group and a side-chain amino group; or, an α-carboxyl group and a side-chain amino group.

(23) 1.1.2.1 Method A

(24) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide fragment (module B and linker L) using 0.05 mMol of the resin obtained from procedure 1.1.1.1 and appropriately protected Fmoc amino acid building blocks.

(25) In a first part, a fully protected peptide fragment encompassing amino acid residues of module B was prepared. Steps 5 to 9 are repeated to add each amino acid residue of module B, except for the last amino acid residue of this peptide fragment, which was added by steps 5 to 7. Subsequently, allyl and alloc deprotection (module B) and macrolactam cycle formation (module B) were performed as described in the corresponding section of procedure A herein below, followed by steps 8 to 9 for Fmoc deprotection and washing.

(26) Assembly of the fully protected peptide fragment was then continued. Steps 5 to 9 were repeated to add each amino acid residue of linker L.

(27) 1.1.2.2 Method B

(28) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of the resin obtained from procedure 1.1.1.2 and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L) and the last coupling, as described herein below. For the latter, an appropriately protected Boc-amino acid building block was used.

(29) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with the amino acid residue at position 12 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(30) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A, except for the last amino acid residue, which was added by steps 5 to 7, followed by step 10.

(31) 1.1.2.3 Method C

(32) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of the resin obtained from procedure 1.1.1.2 and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L), as described herein below.

(33) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with amino acid residue at position L.sup.1 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed. Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A.

(34) 1.1.2.4 Method D

(35) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of the resin obtained from procedure 1.1.1.2 and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L) and the last coupling, as described herein below. For the latter, an acid building block was used.

(36) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with amino acid residue at position L.sup.1 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(37) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A, except for the acid residue, which was added by steps 5 to 7, followed by step 10.

(38) 1.1.2.5 Method E

(39) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of the resin obtained from procedure 1.1.1.2 and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L) and the last coupling, as described herein below. For the latter, an appropriately protected hydroxy acid building block was used.

(40) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with the amino acid residue at position 12 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(41) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A, except for the hydroxy acid residue, which was added by steps 5 to 7, followed by step 10.

(42) 1.1.2.6 Method F

(43) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of the resin obtained from procedure 1.1.1.3 and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L) and the last coupling, as described herein below. For the latter, an appropriately protected Boc-amino acid building block was used.

(44) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with the amino acid residue at position 12 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(45) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A, except for the last amino acid residue, which was added by steps 5 to 7, followed by step 10.

(46) 1.1.2.7 Method G

(47) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of the resin obtained from procedure 1.1.1.3 and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L), as described herein below.

(48) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with the amino acid residue at position 12 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(49) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A.

(50) 1.1.2.8 Method H

(51) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of the resin obtained from procedure 1.1.1.3 and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L) and the last coupling, as described herein below. For the latter, an appropriately protected hydroxy acid building block was used.

(52) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with the amino acid residue at position 12 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding section of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(53) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A, except for the hydroxy acid residue, which was added by steps 5 to 7, followed by step 10.

(54) 1.1.2.9 Method I

(55) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of Sieber amide resin (polystyrene, 1% crosslinked; loading: 0.65 mMol/g) and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L), and the last coupling, as described herein below. For the latter, an appropriately protected Boc-amino acid building block was used.

(56) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with the amino acid residue at position 12 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(57) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A, except for the last amino acid residue, which was added by steps 5 to 7, followed by step 10.

(58) 1.1.2.10 Method J

(59) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of Sieber amide resin (polystyrene, 1% crosslinked; loading: 0.65 mMol/g) and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L), as described herein below.

(60) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with the amino acid residue at position 12 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(61) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A.

(62) 1.1.2.11 Method K

(63) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of Sieber amide resin (polystyrene, 1% crosslinked; loading: 0.65 mMol/g) and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L) and the last coupling, as described herein below. For the latter, an appropriately protected hydroxy acid building block was used. In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with the amino acid residue at position 12 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(64) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A, except for the hydroxy acid residue, which was added by steps 5 to 7, followed by step 10.

(65) 1.1.2.12 Method L

(66) The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide (module A, module B and linker L), using 0.05 mMol of Sieber amide resin (polystyrene, 1% crosslinked; loading: 0.65 mMol/g) and appropriately protected Fmoc amino acid building blocks, except for coupling of the protected peptide fragment (module B and linker L) and the last coupling, as described herein below. For the latter, an acid building block was used.

(67) In a first part, steps 5 to 9 are repeated to add each amino acid residue of module A, except for the case, where the carboxyl group-bearing side chain of the added amino acid residue of module A is connected with the amino acid residue at position 12 of linker L. In this case, coupling of the allyl protected Fmoc amino acid by steps 5 to 7 was followed by allyl deprotection and coupling of the protected peptide fragment (module B and linker L) as described in the corresponding sections of procedure A herein below. Subsequently, steps 8 to 9 for Fmoc protection and washing were performed.

(68) Assembly of the fully protected peptide was then continued. Steps 5 to 9 were repeated to add each remaining amino acid residue of module A, except for the acid residue, which was added by steps 5 to 7, followed by step 10.

(69) 1.1.3 Procedures for the Preparation of the Peptides

(70) One of the procedures A Q, as described herein below, was adopted for preparation of the peptides.

(71) 1.1.3.1 Procedure A:

(72) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A Having an Amino Alcohol Residue Attached to the C-Terminal Amino Acid Residue and Having a Free N-Terminal Amino Group

(73) The peptide was prepared based on an on-resin fragment coupling strategy.

(74) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(75) The appropriately protected peptide fragment encompassing amino acid residues of module B and linker L was assembled on solid support according to Method A as described above. Allyl and alloc deprotection, and macrolactam cycle formation were performed as follows:

(76) Allyl and Alloc Deprotection (Module B)

(77) For selective removal of the allyl and alloc protecting groups from carboxyl and amino functions present in the resin bound peptide, the latter (0.05 mMol) was swollen in 1 mL dry CH.sub.2Cl.sub.2 for at least 10 min, washed twice with iPrOH and twice with iPr.sub.2O, followed by addition of 40 eq triphenylsilane in 0.5 mL NMP, shaking of the mixture for 1 minute, and addition of 0.2 eq tetrakis(triphenylphosphine)palladium(0) in 0.5 mL dry CH.sub.2Cl.sub.2. After shaking the reaction mixture for 5 min at rt, the resin was filtered off and washed three times with 1 mL dry CH.sub.2Cl.sub.2. The deprotection procedure was repeated with fresh solutions of reagents, applying a shaking time of 15 min after addition of the palladium catalyst. LC-MS was used to monitor the deprotection reaction and, if required, the deprotection procedure was repeated. Subsequently the resin was thoroughly washed with CH.sub.2Cl.sub.2, DMF, iPrOH, and finally again with CH.sub.2Cl.sub.2.

(78) Macrolactam Cycle Formation (Module B)

(79) 1 eq OxymaPure in 0.4 mL CH.sub.2Cl.sub.2 and 2 eq DIC in 0.6 mL CH.sub.2Cl.sub.2 were added to the resin in CH.sub.2Cl.sub.2. After stirring the reaction mixture for approximately 2-3 h, the resin was filtered, and fresh solutions of reagents were added to repeat the procedure. The resin was subsequently filtered and washed with CH.sub.2Cl.sub.2, DMF, iPrOH, and finally again with CH.sub.2Cl.sub.2.

(80) Subsequently the following steps were performed:

(81) Cleavage of Peptide Fragment from Resin (Module B and Linker L)

(82) The resin was swollen in 1 mL CH.sub.2Cl.sub.2 (2×10 min). After filtration, the resin was suspended in 1 mL of 1% TFA in CH.sub.2Cl.sub.2 (v/v) for 5 min. The resin was then filtered and washed three times with 1 mL of CH.sub.2Cl.sub.2, and a solution of 1 mL of 40% DIPEA in CH.sub.2Cl.sub.2 (v/v) was added to the combined filtrate and washings. The cleavage procedure was repeated 6 times. LC-MS was used to monitor the cleavage and, if required, the cleavage procedure was repeated further.

(83) The combined filtrate and washings were evaporated to dryness.

(84) Preparation of Free Base Peptide Fragment (Module B and Linker L)

(85) The obtained protected peptide fragment was then dissolved in 4 mL of MeOH/CH.sub.2Cl.sub.2 (1:4, v/v) and washed twice with 2 mL of aq. Na.sub.2CO.sub.3 (0.1 M). The organic layer was dried (Na.sub.2SO.sub.4), filtered, and evaporated to dryness.

(86) (II) Preparation of the Peptide (Module A, Module B and Linker L)

(87) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method B as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as follows:

(88) Allyl Deprotection

(89) Selective removal of the allyl protecting group from a carboxyl function was performed as described in the corresponding section above for allyl and alloc deprotection (module B).

(90) Coupling of Protected Peptide Fragment (Module B and Linker L)

(91) The resin was swollen in 1 mL DMF for 10 min and then filtered off. The swelling procedure was repeated once with fresh DMF. Subsequently, 1 eq OxymaPure in 0.4 mL CH.sub.2Cl.sub.2/DMSO (1:1, v/v) and 2 eq DIC in 0.6 mL CH.sub.2Cl.sub.2 were added to the resin in DMF. After stirring the reaction mixture for approximately 5-10 minutes, 1.2 eq protected peptide fragment (module B and linker L) in 0.5 mL CH.sub.2Cl.sub.2/DMSO (1:1, v/v) were added. The reaction mixture was then stirred for approximately 16 h. Afterwards, the resin was filtered and washed three times with CH.sub.2Cl.sub.2/DMSO (1:1, v/v), and finally with DMF.

(92) Subsequently, cleavage of the peptide from the resin and disulfide bridge formation were performed as follows:

(93) Cleavage of Peptide from Resin

(94) The resin was swollen in 1 mL CH.sub.2Cl.sub.2 (2×10 min). After filtration, the resin was suspended in 1 mL of 1% TFA in CH.sub.2Cl.sub.2 (v/v) for 5 min. The resin was then filtered and washed three times with 1 mL of CH.sub.2Cl.sub.2, and a solution of 1 mL of 40% DIPEA in CH.sub.2Cl.sub.2 (v/v) was added to the combined filtrate and washings. The cleavage procedure was repeated 6 times. LC-MS was used to monitor the cleavage and, if required, the cleavage procedure was repeated further.

(95) The combined filtrate and washings were evaporated to dryness.

(96) Formation of Disulfide Interstrand Linkage(s) (Module A)

(97) The protected peptide was dissolved in 8 mL of HFIP/CH.sub.2Cl.sub.2 (1:4, v/v) and 2 eq iodine in 2 mL of HFIP/CH.sub.2Cl.sub.2 (1:4, v/v) were added. After shaking for 20-45 minutes, 3 mL of a 1 M aqueous solution of ascorbic acid were added to quench excess reagent, and the mixture was further shaken for 10 min. The aqueous phase was discarded, optionally applying a centrifugation step for phase separation. The organic phase was washed with 4 mL of H.sub.2O, and concentrated to dryness.

(98) Full Deprotection

(99) To fully deprotect the peptide, 7 mL of cleavage cocktail TFA/TIS/H.sub.2O (95:2.5:2.5, v/v/v) were added, and the mixture was kept for 2.5-4 h at room temperature. The reaction mixture was evaporated close to dryness, the peptide precipitated with 7 mL of cold Et.sub.2O/pentane (1:1, v/v) and finally washed three times with 3 mL of cold Et.sub.2O/pentane (1:1, v/v).

(100) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(101) 1.1.3.2 Procedure B

(102) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A Having an Amino Alcohol Residue Attached to the C-Terminal Amino Acid Residue and being Acylated at the N-Terminal Amino Group

(103) The peptide was prepared based on an on-resin fragment coupling strategy.

(104) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(105) The appropriately protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(106) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(107) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method C as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(108) Acylation of the N-terminal amino group was then carried out as follows:

(109) Acylation

(110) After assembly of the peptide on the resin, steps 5 to 7 of the programmed reaction cycles were performed using 3.6 eq appropriate acid instead of 3.6 eq protected amino acid, followed by step 10.

(111) Subsequently, cleavage of the peptide from the resin, formation of a disulfide interstrand linkage(s), and full deprotection were performed as indicated in the corresponding sections of procedure A, following the same order.

(112) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(113) 1.1.3.3 Procedure C

(114) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A Having an Amino Alcohol Residue Attached to the C-Terminal Amino Acid Residue and Having an Acid Residue Attached to the N-Terminal Amino Acid Residue

(115) The peptide was prepared based on an on-resin fragment coupling strategy.

(116) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(117) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(118) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(119) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method D as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(120) Subsequently, cleavage of the peptide from the resin, formation of a disulfide interstrand linkage(s), and full deprotection were performed as indicated in the corresponding sections of procedure A, following the same order.

(121) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(122) 1.1.3.4 Procedure D:

(123) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module a Having an Amino Alcohol Residue Attached to the C-Terminal Amino Acid Residue and Having an α-Hydroxy Acid Residue Attached to the N-Terminal Amino Acid Residue

(124) The peptide was prepared based on an on-resin fragment coupling strategy.

(125) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(126) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(127) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(128) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method E as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(129) Subsequently, cleavage of the peptide from the resin, formation of a disulfide interstrand linkage(s), and full deprotection were performed as indicated in the corresponding sections of procedure A, following the same order.

(130) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(131) 1.1.3.5 Procedure E:

(132) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A Having a Free C-Terminal Carboxyl Group and Having a Free N-Terminal Amino Group

(133) The peptide was prepared based on an on-resin fragment coupling strategy.

(134) (I) Preparation of a protected peptide fragment (module B and linker L)

(135) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(136) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(137) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method F as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(138) Subsequently, cleavage of the peptide from the resin, formation of a disulfide interstrand linkage(s), and full deprotection were performed as indicated in the corresponding sections of procedure A, following the same order.

(139) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(140) 1.1.3.6 Procedure F:

(141) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module a Having a Free C-Terminal Carboxyl Group and being Acylated at the N-Terminal Amino Group

(142) The peptide was prepared based on an on-resin fragment coupling strategy.

(143) (I) Preparation of a Protected Peptide Fragment (Module 13 and Linker L)

(144) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(145) (II) Preparation of a Peptide (Module a, Module 13 and Linker L)

(146) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method G as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(147) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B.

(148) Subsequently, cleavage of the peptide from the resin, formation of a disulfide interstrand linkage(s), and full deprotection were performed as indicated in the corresponding sections of procedure A, following the same order.

(149) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(150) 1.1.3.7 Procedure G

(151) Preparation of a Peptide Having a Lactam Interstrand Linkage Between a Side-Chain Carboxyl Group and a Side-Chain Amino Group in Module a Having a Free C-Terminal Carboxyl Group and Having a Free N-Terminal Amino Group

(152) The peptide was prepared based on an on-resin fragment coupling strategy.

(153) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(154) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(155) (II Preparation of a Peptide (Module a, Module B and Linker L)

(156) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method F as described above. Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(157) Subsequently, the following steps were performed:

(158) Allyl Deprotection

(159) Selective removal of the allyl protecting group from the carboxyl function was performed as described in the corresponding section for allyl and alloc deprotection (module B) in procedure A.

(160) ivDde Deprotection

(161) The resin was swollen in 1 mL DMF for 10 min and subsequently filtered off. For deprotection, 1 mL of a 5% solution of hydrazine monohydrate in DMF (v/v) was added and the reaction mixture was shaken for 30 min. The reaction mixture was then filtered off and washed with 1 mL DMF. The deprotection step was repeated by employing the same amount of reagents. LC-MS was used to monitor the deprotection reaction and, if required, the deprotection procedure was repeated again. Finally, the resin was thoroughly washed with DMF, CH.sub.2Cl.sub.2, DMF, and iPrOH, and finally washed with CH.sub.2Cl.sub.2.

(162) Formation of Lactam Interstrand Linkage

(163) To the resin swollen in CH.sub.2Cl.sub.2, 2 eq FDPP in 0.5 mL DMF and 2 eq DIPEA in 0.5 mL CH.sub.2Cl.sub.2 were added. After stirring the reaction mixture for approximately 16 h at rt, the resin was filtered off, and fresh solutions of reagents were added to repeat the procedure. Subsequently, the resin was washed three times with DMF.

(164) Cleavage of peptide from resin and full deprotection were then performed as indicated in the corresponding sections of procedure A.

(165) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below

(166) 1.1.3.8 Procedure H:

(167) Preparation of a Peptide Having a Disulfide Interstrand Linkage in Module A Having a Carboxy Methylamide Group at the C-Terminus and being Acylated at the N-Terminal Amino Group

(168) The peptide was prepared based on an on-resin fragment coupling strategy.

(169) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(170) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(171) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(172) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method G as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(173) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B. Subsequently, cleavage of the peptide from the resin was performed as indicated in the corresponding section of procedure A.

(174) Afterwards the following step was performed:

(175) Formation of the Carboxy Methylamide Group

(176) The protected peptide was solubilized in 0.5 mL CH.sub.2Cl.sub.2, followed by the addition of 1 mL DMF and of 4 eq. CH.sub.3NH.sub.2 (100 μl, 2M CH.sub.3NH.sub.2 in THF). Then 2 eq NMM in 2 mL DMF, and 2 eq HATU and 1 eq HOAt in 2 mL DMF were added, and the reaction mixture was stirred for approximately 16 h. The volatiles were removed by evaporation. The crude cyclic peptide was dissolved in 7 mL of CH.sub.2Cl.sub.2 and washed three times with 4.5 mL 10% acetonitrile in water (v/v). The CH.sub.2Cl.sub.2 layer was then evaporated to dryness.

(177) Subsequently, formation of a disulfide interstrand linkage(s) and full deprotection were performed as indicated in the corresponding sections of procedure A.

(178) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below

(179) 1.1.3.9 Procedure I:

(180) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A

(181) Having a Carboxyisopropyl Ester Group at the C-Terminus and being Acylated at the N-Terminal Amino Group

(182) The peptide was prepared based on an on-resin fragment coupling strategy.

(183) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(184) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(185) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(186) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method G as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(187) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B.

(188) Subsequently, the following step was performed:

(189) Cleavage of Peptide from Resin and Formation of the Carboxyisopropyl Ester Group

(190) The resin (0.05 mMol) was swollen in 1 mL CH.sub.2Cl.sub.2 (2×10 min). To the resin in 0.6 mL CH.sub.2Cl.sub.2, 108 eq. acetyl chloride (1.8 mL, freshly prepared solution of 3M acetyl chloride in iPrOH at 0° C.) were added. After shaking the reaction mixture for 24 hours, the resin was filtered off and washed with three times 1 ml CH.sub.2Cl.sub.2, and the combined filtrate and washings were evaporated to dryness.

(191) Subsequently, full deprotection and formation of a disulfide interstrand linkage(s) were performed as indicated in the corresponding sections of procedure M2.

(192) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(193) 1.1.3.10 Procedure J:

(194) Preparation of a Peptide Having a Lactam Interstrand Linkage Between a Side-Chain Amino Group and the C-Terminal Carboxyl Group in Module A and being Acylated at the N-Terminal Amino Group

(195) The peptide was prepared based on an on-resin fragment coupling strategy.

(196) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(197) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(198) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(199) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method G as described above. Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(200) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B.

(201) Subsequently, removal of the alloc protecting group from the amino function and cleavage of the peptide from the resin, in this order, were performed as described for allyl and alloc deprotection (module B), and cleavage of peptide from resin in the corresponding sections of procedure A.

(202) Formation of a lactam interstrand linkage was then carried out as follows:

(203) Lactam Interstrand Linkage Formation

(204) The protected peptide was first solubilized in 0.5 mL CH.sub.2Cl.sub.2, followed by the addition of 8 mL DMF. Then 6 eq NMM in 2 mL DMF, and 2 eq HATU and 1 eq HOAt in 2 mL DMF were added, and the reaction mixture was stirred for approximately 16 h. The volatiles were removed by evaporation. The crude cyclic peptide was dissolved in 7 mL of CH.sub.2Cl.sub.2 and washed three times with 4.5 mL 10% acetonitrile in water (v/v). The CH.sub.2Cl.sub.2 layer was then evaporated to dryness.

(205) Full deprotection was afterwards performed as indicated in the corresponding section of procedure A.

(206) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(207) 1.1.3.11 Procedure K:

(208) Preparation of a Peptide Having a Lactam Interstrand Linkage Between a Side-Chain Amino Group and the C-Terminal Carboxyl Group in Module A and Having an α-Hydroxy Acid at the N-Terminus

(209) The peptide was prepared based on an on-resin fragment coupling strategy.

(210) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(211) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(212) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(213) The fully protected peptide fragment was assembled on solid support according to Method H as described above. Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(214) Subsequently, removal of the alloc protecting group from the amino function, cleavage of the peptide from the resin, formation of a lactam interstrand linkage, and full deprotection, in this order, were then performed as indicated in procedure J.

(215) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(216) 1.1.3.12 Procedure L:

(217) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A Having a Carboxylamide Group at the C-Terminus and Having a Free N-Terminal Amino Group

(218) The peptide was prepared based on an on-resin fragment coupling strategy.

(219) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(220) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(221) (II) Preparation of a Peptide (Module A, Module B and Linker L)

(222) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method I as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(223) Subsequently, cleavage of the peptide from the resin was carried out as follows:

(224) Cleavage of Peptide from Resin

(225) The resin was swollen in 1 mL CH.sub.2Cl.sub.2 (2×10 min). After filtration, the resin was suspended in 1 mL of 1% TFA in CH.sub.2Cl.sub.2 (v/v) for 10-30 min. The resin was then filtered and washed three times with 1 mL of CH.sub.2Cl.sub.2, and a solution of 1 mL of 40% DIPEA in CH.sub.2Cl.sub.2 (v/v) was added to the combined filtrate and washings. LC-MS was used to monitor the cleavage and, if required, the cleavage procedure was repeated 3-5 times. The combined filtrate and washings were evaporated to dryness.

(226) Formation of a disulfide interstrand linkage(s) and full deprotection were performed as indicated in the corresponding sections of procedure A.

(227) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(228) 1.1.3.13 Procedure M1:

(229) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A Having a Carboxylamide Group at the C-Terminus and being Acylated at the N-Terminal Amino Group

(230) The peptide was prepared based on an on-resin fragment coupling strategy.

(231) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(232) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(233) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(234) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method J as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(235) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B.

(236) Subsequently, cleavage of the peptide from the resin, formation of a disulfide interstrand linkage(s), and full deprotection were performed as indicated in the corresponding sections of procedure L, following the same order.

(237) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(238) 1.1.3.14 Procedure M2:

(239) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A Having a Carboxylamide Group at the C-Terminus and being Acylated at the N-Terminal Amino Group

(240) The peptide was prepared based on an on-resin fragment coupling strategy.

(241) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(242) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(243) (I) Preparation of a Peptide (Module a, Module B and Linker L)

(244) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method J as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(245) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B.

(246) Subsequently, cleavage of the peptide from the resin was performed as indicated in the corresponding section of procedure L.

(247) Afterwards full deprotection and formation of a disulfide interstrand linkage(s) were performed as follows:

(248) Full Deprotection

(249) To fully deprotect the peptide, 7 mL of cleavage cocktail TFA/TIS/thioanisole/anisole/water (82.5:2.5:5:5:5, v/v/v/v/v) were added, and the mixture was kept for 2.5-4 h at room temperature. The reaction mixture was evaporated close to dryness, the peptide precipitated with 7 mL of cold Et.sub.2O/pentane (1:1, v/v) and finally washed 3 times with 4 mL of cold Et.sub.2O/pentane.

(250) Formation of a Disulfide Interstrand Linkage(s)

(251) The deprotected peptide was dissolved in 0.8 mL DMSO, 7.2 mL aq. NH.sub.4OAc (0.5 M, adjusted to pH 8 with aq. NH.sub.4OH (28% in water, w/v)) were added, and the reaction mixture was then stirred for 24 h at rt. LC-MS was used to monitor the formation of the disulfide interstrand linkages and, if required, the reaction mixture was stirred for further 24 h at rt, followed again by LC-MS monitoring.

(252) Thereafter, the reaction mixture was adjusted to pH 5-6 by addition of acetic acid and evaporated to dryness.

(253) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(254) 1.1.3.15 Procedure N1:

(255) Preparation of a Peptide Having a Lactam Interstrand Linkage Between a Side-Chain Carboxyl Group and a Side-Chain Amino Group in Module a Having a Carboxylamide Group at the C-Terminus and being Acylated at the N-Terminal Amino Group

(256) The peptide was prepared based on an on-resin fragment coupling strategy.

(257) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(258) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(259) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(260) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method J as described above. Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(261) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B.

(262) Subsequently, removal of the alloc protecting group from the amino function was performed as described for allyl and alloc deprotection (module B) in the corresponding section of procedure A.

(263) Thereafter, the following steps was carried out:

(264) Cleavage of Peptide from Resin and Removal of the 2-Phenyl-Isopropyl Protecting Group from the Carboxyl Function

(265) The resin was swollen in 1 mL CH.sub.2Cl.sub.2 (2×10 min). After filtration, the resin was suspended in 1 mL of 1% TFA in CH.sub.2Cl.sub.2 (v/v) for 10-30 min. The resin was then filtered and washed three times with 1 mL of CH.sub.2Cl.sub.2, and a solution of 1 mL of 40% DIPEA in CH.sub.2Cl.sub.2 (v/v) was added to the combined filtrate and washings. LC-MS was used to monitor the cleavage and, if required, the cleavage procedure was repeated 3-5 times. The combined filtrate and washings were evaporated to dryness.

(266) Lactam Interstrand Linkage Formation

(267) The protected peptide was first solubilized in 0.5 mL CH.sub.2Cl.sub.2, followed by the addition of 8 mL DMF. Then 6 eq NMM in 2 mL DMF, and 2 eq HATU and 1 eq HOAt in 2 mL DMF were added, and the reaction mixture was stirred for approximately 16 h. The volatiles were removed by evaporation. The crude cyclic peptide was dissolved in 7 mL of CH.sub.2Cl.sub.2 and washed three times with 4.5 mL 10% acetonitrile in water (v/v). The CH.sub.2Cl.sub.2 layer was then evaporated to dryness.

(268) Full deprotection was then performed as indicated in the corresponding section of procedure A.

(269) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(270) 1.1.3.16 Procedure N2:

(271) Preparation of a Peptide Having a Lactam Interstrand Linkage Between a Side-Chain Carboxyl Group and a Side-Chain Amino Group in Module A Having a Carboxylamide Group at the C-Terminus and being Acylated at the N-Terminal Amino Group

(272) The peptide was prepared based on an on-resin fragment coupling strategy.

(273) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(274) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(275) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(276) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method J as described above. Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(277) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B.

(278) Subsequently, the following step was performed:

(279) ivDde Deprotection

(280) The resin was swollen in 1 mL DMF for 10 min and subsequently filtered off. For deprotection, 1 mL of a 5% solution of hydrazine monohydrate in DMF (v/v) was added and the reaction mixture was shaken for 30 min. The reaction mixture was then filtered off and washed with 1 mL DMF. The deprotection step was repeated by employing the same amount of reagents. LC-MS was used to monitor the deprotection reaction and, if required, the deprotection procedure was repeated again. Finally, the resin was thoroughly washed with DMF, CH.sub.2Cl.sub.2, DMF, and iPrOH, and finally washed again with CH.sub.2Cl.sub.2.

(281) Cleavage of peptide from resin and removal of the 2-phenyl-isopropyl protecting group from the carboxyl function, formation of the lactam interstrand linkage and full deprotection were then performed as indicated in the corresponding section of procedure N1, in the same order.

(282) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(283) 1.1.3.17 Procedure O:

(284) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A Having a Carboxylamide Group at the C-Terminus and Having an α-Hydroxy Acid Residue Attached to the N-Terminal Amino Acid Residue

(285) The peptide was prepared based on an on-resin fragment coupling strategy.

(286) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(287) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(288) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(289) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method K as described above. Appropriately protected Fmoc amino acid building blocks with a thiol group protected as trityl thioether were used for the addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(290) Subsequently, cleavage of the peptide from the resin, formation of a disulfide interstrand linkage(s), and full deprotection were performed as indicated in the corresponding sections of procedure L, following the same order.

(291) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(292) 1.1.3.18 Procedure P:

(293) Preparation of a Peptide Having a Disulfide Interstrand Linkage(s) in Module A Having a Carboxylamide Group at the C-Terminus and Having a Thiol-Substituted Acid Residue Attached to the N-Terminal Amino Acid Residue

(294) The peptide was prepared based on an on-resin fragment coupling strategy.

(295) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(296) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(297) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(298) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method L as described above. An appropriately protected Fmoc amino acid building block(s) with a thiol group protected as trityl thioether and an appropriately protected acid building block with a thiol group protected as trityl thioether were used for the addition of the residues that are involved in the formation of a disulfide interstrand linkage(s). Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(299) Subsequently, cleavage of the peptide from the resin, formation of a disulfide interstrand linkage(s), and full deprotection were performed as indicated in the corresponding sections of procedure L, following the same order.

(300) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(301) 1.1.3.19 Procedure Q:

(302) Preparation of a Peptide Having a Salt Bridge(s) in Module A Having a Carboxylamide Group at the C-Terminus and being Acylated at the N-Terminal Amino Group

(303) The peptide was prepared based on an on-resin fragment coupling strategy.

(304) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(305) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(306) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(307) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method J as described above. Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(308) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B.

(309) Subsequently, cleavage of the peptide from the resin and full deprotection were performed as indicated in the corresponding sections of procedure L.

(310) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(311) 1.1.3.20 Procedure R:

(312) Preparation of a Peptide Having a Lactam Interstrand Linkage Between a Side-Chain Carboxyl Group and a Side-Chain Amino Group in Module A Having a Carboxylamide Group at the C-Terminus and being Acetylated at the N-Terminal Amino Group

(313) The peptide was prepared based on an on-resin fragment coupling strategy.

(314) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(315) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(316) (II Preparation of a Peptide (Module a, Module B and Linker L)

(317) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method J as described above. Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(318) Acylation of the N-terminal amino group was then carried out as indicated in the corresponding section of procedure B.

(319) Subsequently, allyl-deprotection, ivDde deprotection, and formation of lactam interstrand linkage were performed as indicated in the corresponding section of procedure G, following the same order.

(320) Cleavage of peptide from resin and full deprotection were then performed as indicated in the corresponding sections of procedure A.

(321) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(322) 1.1.3.21 Procedure S:

(323) Preparation of a Peptide Having a Lactam Interstrand Linkage Between a Side-Chain Carboxyl Group and a Side-Chain Amino Group in Module A Having a Carboxylamide Group at the C-Terminus and Having an α-Hydroxy Acid at the N-Terminus

(324) The peptide was prepared based on an on-resin fragment coupling strategy.

(325) (I) Preparation of a Protected Peptide Fragment (Module B and Linker L)

(326) The protected peptide fragment encompassing amino acid residues of module B and linker L was prepared as described in the corresponding section of procedure A.

(327) (II) Preparation of a Peptide (Module a, Module B and Linker L)

(328) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to Method K as described above. Allyl deprotection and coupling of the protected peptide fragment (module B and linker L) were performed as indicated in the corresponding sections of procedure A.

(329) Subsequently, removal of the alloc protecting group from the amino function was performed as described for allyl and alloc deprotection (module B) in the corresponding section of procedure A.

(330) Thereafter, the following steps was carried out:

(331) Cleavage of Peptide from Resin and Removal of the 2-Phenyl-Isopropyl Protecting Group from the Carboxyl Function

(332) The resin was swollen in 1 mL CH.sub.2Cl.sub.2 (2×10 min). After filtration, the resin was suspended in 1 mL of 1% TFA in CH.sub.2Cl.sub.2 (v/v) for 10-30 min. The resin was then filtered and washed three times with 1 mL of CH.sub.2Cl.sub.2, and a solution of 1 mL of 40% DIPEA in CH.sub.2Cl.sub.2 (v/v) was added to the combined filtrate and washings. LC-MS was used to monitor the cleavage and, if required, the cleavage procedure was repeated 3-5 times. The combined filtrate and washings were evaporated to dryness.

(333) Lactam Interstrand Linkage Formation

(334) The protected peptide was first solubilized in 0.5 mL CH.sub.2Cl.sub.2, followed by the addition of 8 mL DMF. Then 6 eq NMM in 2 mL DMF, and 2 eq HATU and 1 eq HOAt in 2 mL DMF were added, and the reaction mixture was stirred for approximately 16 h. The volatiles were removed by evaporation. The crude cyclic peptide was dissolved in 7 mL of CH.sub.2Cl.sub.2 and washed three times with 4.5 mL 10% acetonitrile in water (v/v). The CH.sub.2Cl.sub.2 layer was then evaporated to dryness.

(335) Full deprotection was then performed as indicated in the corresponding section of procedure A.

(336) Finally, the peptide was purified by preparative reverse phase LC-MS, as described herein below.

(337) 1.1.4 Purification Procedure (Preparative Reverse Phase LC-MS)

(338) Compounds were purified by reverse phase chromatography using a Waters XBridge C8 OBD column, 30×150 mm, 5 μm (Cat No. 186003083), a Waters XSelect C18 OBD column, 30×150 mm, 5 μm (Cat. 186005426), or a Waters CSH XSelect Phenyl Hexyl column, 50×300 mm, 5 μm.

(339) Mobile phases used were:

(340) A: 0.1% TFA in Water/Acetonitrile 98/2 v/v

(341) B: 0.1% TFA in Acetonitrile

(342) Gradient slopes in the preparative runs were adapted each time based on analytical LC-MS analysis of the crude product. As an example, a typical run (purification of Ex. 204) was executed using two Waters CSH XSelect Phenyl Hexyl columns in series with a flow rate of 130 mL/min and at a column temperature of 50° C., running a gradient from 0-2.1 min 0% B, at 2.2 min 14% B to 38.2 min 18% B, and finally 48.0-55.0 min 100% B (retention time: 20.7 min in this case).

(343) Detection: MS and UV @ 220 nm

(344) Fractions collected were evaporated using a Genevac HT4/HT12 evaporator a Buchi system.

(345) Alternatively for larger amounts the following LC-purification system was used:

(346) Column: Waters XBridge C18 OBD column, 50×250 mm, 10 μm (Cat No. 186003900)

(347) Mobile phase A: 0.1% TFA in Water/Acetonitrile 98/2 v/v

(348) Mobile phase B: 0.1% TFA in Acetonitrile

(349) Flow rate: 150 mL/min

(350) Detection: UV @ 220 nm

(351) After lyophilisation the products were obtained typically as white to off-white powders. Unless otherwise indicated the obtained products as TFA salts were analysed by HPLC-ESI-MS methods as described below. Salt exchange to obtain the corresponding products as acetate salts or chloride salts was performed using procedures described under 1.1.5, and obtained products as acetate salts or chloride salts were analysed by HPLC-ESI-MS methods as described below.

(352) 1.1.5 Salt Exchange Procedure

(353) Purification of compounds according to procedure 1.1.4 above provided the products as TFA salts. Conversion of the products to the corresponding acetate salts was performed using AG® 1-X2 Resin (acetate form, 2% crosslinkage, 200-400 dry mesh size; Bio-Rad, 140-1253). For the conversion of the products to the corresponding chloride salts AG® 1-X2 Resin (chloride form, 2% crosslinkage, 200-400 dry mesh; Bio-Rad, 140-1251) was used. Salt exchanges were carried out based on the corresponding instruction manual of the supplier.

(354) After lyophilisation the products were obtained typically as white to off-white powders and analysed by HPLC-ESI-MS methods as described below.

(355) 1.2 Analytical Methods

(356) 1.2.1 Analytical Method A

(357) Analytical HPLC retention times (rt, in minutes) were determined using an Ascentis Express C8 column 100×3 mm, 2.7 μm (Supelco, 53852-U) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 7 min: 45% A, 55% B; 7.02-7.5 min: 3% A, 97% B; 7.52-7.8 min: 95% A, 5% B. Flow rate=1.4 mL/min at 55° C.

(358) 1.2.2 Analytical Method B

(359) Analytical HPLC retention times (rt, in minutes) were determined using a Poroshell Bonus RP 100×3 mm, 2.7 μm (Agilent technologies, 695968-301) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 7 min: 45% A, 55% B; 7.02-7.5 min: 3% A, 97% B; 7.52-7.8 min: 95% A, 5% B. Flow rate=1.4 mL/min at 55° C.

(360) 1.2.3 Analytical Method C

(361) Analytical HPLC retention times (rt, in minutes) were determined using an Ascentis Express C8 column, 100×3 mm, 2.7 μm (Supelco, 53852-U) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 7 min: 15% A, 85% B; 7.02-7.5 min: 3% A, 97% B; 7.52-7.8 min: 95% A, 5% B. Flow rate=1.4 mL/min at 55° C.

(362) 1.2.4 Analytical Method D

(363) Analytical HPLC retention times (rt, in minutes) were determined using an Ascentis Express C8 column 100×3 mm, 2.7 μm (Supelco, 53852-U) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 7 min: 45% A, 55% B; 7.02-7.5 min: 3% A, 97% B; 7.52-7.8 min: 95% A, 5% B. Flow rate=1.4 mL/min at 70° C.

(364) 1.2.5 Analytical Method E

(365) Analytical HPLC retention times (rt, in minutes) were determined using an Ascentis Express C8 column 100×3 mm, 2.7 μm (Supelco, 53852-U) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 11 min: 45% A, 55% B; 11.02-12.5 min: 3% A, 97% B; 12.55-13.5 min: 95% A, 5% B. Flow rate=1.4 mL/min at 55° C.

(366) 1.2.6 Analytical Method F

(367) Analytical HPLC retention times (rt, in minutes) were determined using a Poroshell Bonus RP 100×3 mm, 2.7 μm (Agilent technologies, 695968-301) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 7 min: 45% A, 55% B; 7.02-7.5 min: 3% A, 97% B; 7.52-7.8 min: 95% A, 5% B. Flow rate=1.4 mL/min at 70° C.

(368) 1.2.7 Analytical Method G

(369) Analytical HPLC retention times (rt, in minutes) were determined using a XSelect CSH Phenyl-Hexyl 150×3 mm, 2.5 μm (Waters, 186006734) with the following solvents A (H2O 2O+0.1% TFA) and B (CH3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 7 min: 45% A, 55% B; 7.02-7.7 min: 3% A, 97% B; 7.72-9.95 min: 95% A, 5% B. Flow rate=1.3 mL/min at 55° C.

(370) 1.2.8 Analytical Method H

(371) Analytical HPLC retention times (rt, in minutes) were determined using a Ascentis Express C8 100×3 mm, 2.7 μm (Supelco, 53852-U) with the following solvents A (H2O 2O+0.1% TFA) and B (CH3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 12.1 min: 45% A, 55% B; 12.12-13.1 min: 3% A, 97% B; 13.12-14.8 min: 95% A, 5% B. Flow rate=0.750 mL/min at 55° C.

(372) 1.2.8 Analytical Method I

(373) Analytical HPLC retention times (rt, in minutes) were determined using a Poroshell Bonus RP 100×3 mm, 2.7 μm (Agilent technologies, 695968-301) with the following solvents A (H2O 2O+0.1% TFA) and B (CH3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 12.1 min: 45% A, 55% B; 12.12-13.1 min: 3% A, 97% B; 13.12-15.2 min: 95% A, 5% B. Flow rate=0.750 mL/min at 55° C.

(374) 1.3 Synthesis of Peptide Sequences

(375) Example 1 is shown in Table 1.

(376) Procedure C, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(377) (I) The protected peptide fragment (module B and linker L) was synthesized starting with the amino acid Fmoc-Thr-allyl ester, which was grafted to the resin (Fmoc-Thr(-2-chlorotrityl resin)-allyl). The peptide fragment was synthesized on solid support according to method A as described above. Following coupling of Fmoc-Dab(Alloc)-OH for addition of the amino acid residue at Q.sup.1, allyl and alloc deprotection (module B), and macrolactam cycle formation (module B) by an amide bond between the liberated α-carboxyl group of Thr at Q.sup.7 and the liberated γ-amino group of Dab at Q.sup.1 was performed as indicated in the corresponding sections of procedure A above. Assembly of the peptide fragment was in the following sequence:

(378) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(379) Subsequently, cleavage of the protected peptide fragment from the resin and preparation of the free base of the protected peptide fragment were performed as indicated in procedure A above.

(380) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method D as described above.

(381) The peptide was synthesized starting with the amino alcohol Fmoc-Glyol, which was grafted to the resin (Fmoc-Glyol-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at at P.sup.5 and using 3-methyl-butanoic acid for addition of the acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(382) Resin-Glyol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(383) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure C above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 1 in Table 2.

(384) Examples 2 and 4 are shown in Table 1.

(385) Procedure C, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(386) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1. Assembly of the peptide fragment was in the following sequence:

(387) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(388) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method D as described above.

(389) The peptides were synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5 and using 3-methyl-butanoic acid for addition of the acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(390) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(391) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure C above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 2 and 4 in Table 2. Example 3 is shown in Table 1.

(392) Procedure C, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(393) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1. Assembly of the peptide fragment was in the following sequence:

(394) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(395) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method D as described above.

(396) The peptide was synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5 and using isobutyric acid for addition of the acid residue at P.sup.1. Coupling of the protected fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(397) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(398) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure C above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 3 in Table 2.

(399) Example 5 is shown in Table 1.

(400) Procedure C, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(401) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(402) Assembly of the peptide fragment was in the following sequence:

(403) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(404) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method D as described above.

(405) The peptide was synthesized starting with the amino alcohol Fmoc-Serol(tBu), which was grafted to the resin (Fmoc-Serol(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5 and using 3-methyl-butanoic acid for addition of the acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(406) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(407) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure C above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 5 in Table 2.

(408) Examples 6, 8 and 10 are shown in Table 1.

(409) Procedure M1, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(410) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(411) Assembly of the peptide fragment was in the following sequence:

(412) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(413) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J.

(414) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at P.sup.11 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(415) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(416) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 6, 8 and 10 in Table 2.

(417) Example 7 is shown in Table 1.

(418) Procedure O, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(419) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1. Assembly of the peptide fragment was in the following sequence:

(420) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1

(421) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method K as described above.

(422) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at P.sup.11 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(423) Resin-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(424) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure O above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 7 in Table 2.

(425) Examples 9 and 57 are shown in Table 1.

(426) Procedure L, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(427) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(428) Assembly of the peptide fragments was in the following sequence:

(429) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(430) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method I as described above.

(431) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at P.sup.11 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(432) Resin-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(433) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure L above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 9 and 57 in Table 2.

(434) Example 11 is shown in Table 1.

(435) Procedure M1, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(436) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(437) Assembly of the peptide fragment was in the following sequence:

(438) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(439) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(440) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at P.sup.11 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(441) Resin-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(442) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 11 in Table 2.

(443) Example 12 is shown in Table 1.

(444) Procedure L, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(445) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1. Assembly of the peptide fragment was in the following sequence:

(446) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(447) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method I as described above.

(448) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at P.sup.11 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(449) Resin-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(450) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure L above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 12 in Table 2.

(451) Examples 13 and 14 are shown in Table 1.

(452) Procedure M1, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(453) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(454) Assembly of the peptide fragment was in the following sequence:

(455) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(456) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J.

(457) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at P.sup.10 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(458) Resin-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(459) Subsequently, acylation with acetic acid at X.sup.14, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 13 and 14 in Table 2.

(460) Examples 15 to 18, 23, 25 and 31 to 38 are shown in Table 1.

(461) Procedure J, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(462) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1. Assembly of the peptide fragments was in the following sequence:

(463) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(464) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method G as described above.

(465) The peptides were synthesized starting with the amino acid Fmoc-.sup.DThr(tBu)-OH, which was grafted to the resin (Fmoc-.sup.DThr(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(466) Resin-.sup.DThr-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(467) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptides from the resin, formation of the lactam interstrand linkage by an amide bond between the liberated side-chain amino group of the amino acid residue at P.sup.2 and the liberated α-carboxyl group of .sup.DThr at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 15 to 18, 23, 25 and 31 to 38 in Table 2.

(468) Example 19 is shown in Table 1.

(469) Procedure J, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(470) (l) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(471) Assembly of the peptide fragment was in the following sequence:

(472) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(473) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(474) The peptide was synthesized starting with the amino acid Fmoc-.sup.DAsn(Trityl)-OH, which was grafted to the resin (Fmoc-.sup.DAsn(Trityl)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(475) Resin-.sup.DAsn-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(476) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DAsn at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 19 in Table 2.

(477) Example 20 is shown in Table 1.

(478) Procedure J, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(479) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(480) Assembly of the peptide fragment was in the following sequence:

(481) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(482) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(483) The peptide was synthesized starting with the amino acid Fmoc-.sup.DGln(Trityl)-OH, which was grafted to the resin (Fmoc-.sup.DGln(Trityl)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(484) Resin-.sup.DGln-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(485) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DGln at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 20 in Table 2.

(486) Example 21 is shown in Table 1.

(487) Procedure J, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(488) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(489) Assembly of the peptide fragment was in the following sequence:

(490) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(491) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(492) The peptide was synthesized starting with the amino acid Fmoc-.sup.DGlu(tBu)-OH, which was grafted to the resin (Fmoc-.sup.DGlu(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(493) Resin-.sup.DGlu-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(494) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DGlu at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 21 in Table 2.

(495) Example 22 is shown in Table 1.

(496) Procedure J, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(497) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(498) Assembly of the peptide fragment was in the following sequence:

(499) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(500) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(501) The peptide was synthesized starting with the amino acid Fmoc-.sup.DHse(tBu)-OH, which was grafted to the resin (Fmoc-.sup.DHse(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(502) Resin-.sup.DHse-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(503) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DHse at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 22 in Table 2.

(504) Example 24 is shown in Table 1.

(505) Procedure K, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(506) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(507) Assembly of the peptide fragment was in the following sequence:

(508) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(509) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method H as described above.

(510) The peptide was synthesized starting with the amino acid Fmoc-.sup.DThr(tBu)-OH, which was grafted to the resin (Fmoc-.sup.DThr(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(511) Resin-.sup.DThr-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(512) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DThr at P.sup.11, and full deprotection were performed as indicated in procedure K above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 24 in Table 2.

(513) Example 26 is shown in Table 1.

(514) Procedure J, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(515) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(516) Assembly of the peptide fragment was in the following sequence:

(517) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(518) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(519) The peptide was synthesized starting with the amino acid Fmoc-.sup.DTyr(tBu)-OH, which was grafted to the resin (Fmoc-.sup.DTyr(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(520) Resin-.sup.DTyr-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(521) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DTyr at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 26 in Table 2.

(522) Example 27 is shown in Table 1.

(523) Procedure J, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(524) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(525) Assembly of the peptide fragment was in the following sequence:

(526) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(527) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(528) The peptide was synthesized starting with the amino acid Fmoc-.sup.DVal-OH, which was grafted to the resin (Fmoc-.sup.DVal-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(529) Resin-.sup.DVal-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(530) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DVal at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 27 in Table 2.

(531) Example 28 is shown in Table 1.

(532) Procedure J, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(533) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(534) Assembly of the peptide fragment was in the following sequence:

(535) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(536) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(537) The peptide was synthesized starting with the amino acid Fmoc-.sup.DDab(Boc)-OH, which was grafted to the resin (Fmoc-.sup.DDab(Boc)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(538) Resin-.sup.DDab-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(539) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DDab at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 28 in Table 2.

(540) Example 29 is shown in Table 1.

(541) Procedure J, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(542) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(543) Assembly of the peptide fragment was in the following sequence:

(544) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(545) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(546) The peptide was synthesized starting with the amino acid Fmoc-.sup.DOrn(Boc)-OH, which was grafted to the resin (Fmoc-.sup.DOrn(Boc)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(547) Resin-.sup.DOrn-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3P.sup.2-P.sup.1.

(548) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DOrn at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 29 in Table 2.

(549) Example 30 is shown in Table 1.

(550) Procedure J, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(551) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(552) Assembly of the peptide fragment was in the following sequence:

(553) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(554) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(555) The peptide was synthesized starting with the amino acid Fmoc-.sup.DLys(Boc)-OH, which was grafted to the resin (Fmoc-.sup.DLys(Boc)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(556) Resin-.sup.DLys-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(557) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptide from the resin, formation of the lactam interstrand linkage by an amide bond between the δ-amino group of Orn at P.sup.2 and the liberated α-carboxyl group of .sup.DLys at P.sup.11, and full deprotection were performed as indicated in procedure J above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 30 in Table 2.

(558) Examples 39 to 41, 44 to 46, 49, 62 to 68, 119 and 144 are shown in Table 1.

(559) Procedure M1, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(560) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(561) Assembly of the peptide fragments was in the following sequence:

(562) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(563) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(564) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at C. Assembly of the peptides was in the following sequence, showing only residues of module A:

(565) Resin-X.sup.11-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(566) Subsequently, acylation with acetic acid at P.sup.1 (Ex. 39, 41, 44 to 46, 49, and 62 to 68) or acylation with 6-methly heptanoic acid at P.sup.1 (Ex. 40) or acylation with propionic acid at P.sup.1 (Ex. 119 and 144), cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 39 to 41, 44 to 46, 49, 62 to 68, 119 and 144 in Table 2.

(567) Examples 100, 113, 114, 117, 120, 121, 128, 130 to 143, 150 to 156, 158, 159, 251 to 264, 267 to 269, 272, 275, 276, 278, 280 to 284, 289, 294 to 300, 305 to 318, 328 to 339, 342, 343, 345, 350, 352 and 353 are shown in Table 1.

(568) Procedure M2, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(569) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(570) Assembly of the peptide fragments was in the following sequence:

(571) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(572) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(573) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(574) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(575) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, full deprotection, and formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11 were performed as indicated in procedure M2 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 100, 113, 114, 117, 120, 121, 128, 130 to 143, 150 to 156, 158, 159, 251 to 264, 267 to 269, 272, 275, 276, 278, 280 to 284, 289, 294 to 300, 305 to 318, 328 to 339, 342, 343, 345, 350, 352 and 353 in Table 2.

(576) Example 42 is shown in Table 1.

(577) Procedure E, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(578) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(579) Assembly of the peptide fragment was in the following sequence:

(580) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(581) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method F as described above.

(582) The peptide was synthesized starting with the amino acid Fmoc-Ser(tBu)-OH, which was grafted to the resin (Fmoc-Ser(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(583) Resin-Ser-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(584) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure E above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 42 in Table 2.

(585) Examples 43, 47, 48, 50 and 51 are shown in Table 1.

(586) Procedure L, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(587) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(588) Assembly of the peptide fragment was in the following sequence:

(589) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(590) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method I as described above.

(591) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at C. Assembly of the peptides was in the following sequence, showing only residues of module A:

(592) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(593) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure L above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 43, 47, 48, 50 and 51 in Table 2.

(594) Example 52 is shown in Table 1.

(595) Procedure F, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(596) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(597) Assembly of the peptide fragment was in the following sequence:

(598) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(599) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(600) The peptide was synthesized starting with the amino acid Fmoc-Ser(tBu)-OH, which was grafted to the resin (Fmoc-Ser(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(601) Resin-Ser-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(602) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure F above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 52 in Table 2.

(603) Examples 53 and 54 are shown in Table 1.

(604) Procedure E, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(605) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(606) Assembly of the peptide fragment was in the following sequence:

(607) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(608) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method F as described above.

(609) The peptides were synthesized starting with the amino acid Fmoc-Ser(tBu)-OH, which was grafted to the resin (Fmoc-Ser(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(610) Resin-Ser-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(611) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure E above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 53 and 54 in Table 2.

(612) Examples 55 and 56 are shown in Table 1.

(613) Procedure G, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(614) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(615) Assembly of the peptide fragment was in the following sequence:

(616) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(617) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method F as described above.

(618) The peptides were synthesized starting with the amino acid Fmoc-Ser(tBu)-OH, which was grafted to the resin (Fmoc-Ser(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(619) Resin-Ser-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(620) Subsequently, allyl deprotection at P.sup.2, ivDde deprotection at P.sup.11, and formation of the lactam interstrand linkage by an amide bond between the liberated side-chain functional groups of the amino acid residue at P.sup.2 and Dab at P.sup.11, cleavage of the peptides from the resin, and full deprotection were performed as indicated in procedure G above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 55 and 56 in Table 2.

(621) Examples 58, 60, 61, 74 to 76, 78 to 85, 87 to 91 and 104 to 112 are shown in Table 1. Procedure D, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(622) (I) The protected peptide fragments (module B and linker L) were synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(623) Assembly of the peptide fragment was in the following sequence:

(624) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(625) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method E as described above.

(626) The peptides were synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(627) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(628) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 58, 60, 61, 74 to 76, 78 to 85, 87 to 91 and 104 to 112 in Table 2.

(629) Examples 59, 72 and 73 are shown in Table 1.

(630) Procedure D, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(631) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(632) Assembly of the peptide fragment was in the following sequence:

(633) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(634) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method E as described above.

(635) The peptides were synthesized starting with the amino alcohol Fmoc-Glyol, which was grafted to the resin (Fmoc-Glyol-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(636) Resin-Glyol-P.sup.11; P.sup.10; P.sup.9; P.sup.8; P.sup.7; P.sup.6; P.sup.5; P.sup.4; P.sup.3; P.sup.2-Hiv.

(637) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 59, 72 and 73 in Table 2.

(638) Examples 69 and 70 are shown in Table 1.

(639) Procedure D, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(640) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(641) Assembly of the peptide fragment was in the following sequence:

(642) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(643) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method E as described above.

(644) The peptides were synthesized starting with the amino alcohol Fmoc-Glyol, which was grafted to the resin (Fmoc-Glyol-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(645) Resin-Glyol-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-Hiv.

(646) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 69 and 70 in Table 2.

(647) Example 71 is shown in Table 1.

(648) Procedure B, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(649) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(650) Assembly of the peptide fragment was in the following sequence:

(651) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(652) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method C as described above.

(653) The peptide was synthesized starting with the amino alcohol Fmoc-Glyol, which was grafted to the resin (Fmoc-Glyol-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at C. Assembly of the peptide was in the following sequence, showing only residues of module A:

(654) Resin-Glyol-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(655) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure B above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 71 in Table 2.

(656) Example 77 is shown in Table 1.

(657) Procedure A, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(658) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(659) Assembly of the peptide fragment was in the following sequence:

(660) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(661) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method B as described above.

(662) The peptide was synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(663) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(664) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure A above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 77 in Table 2.

(665) Examples 86, 123 and 129 are shown in Table 1.

(666) Procedure B, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(667) (I) The protected peptide fragments (module B and linker L) were synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(668) Assembly of the peptide fragments was in the following sequence:

(669) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(670) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method C as described above.

(671) The peptides were synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(672) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(673) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure B above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 86, 123 and 129 in Table 2.

(674) Examples 92 and 93 are shown in Table 1.

(675) Procedure D, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(676) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(677) Assembly of the peptide fragment was in the following sequence:

(678) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(679) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method E as described above.

(680) The peptides were synthesized starting with the amino alcohol Fmoc-Tyrol(tBu), which was grafted to the resin (Fmoc-Tyrol(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(681) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(682) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 92 and 93 in Table 2.

(683) Example 94 is shown in Table 1.

(684) Procedure B, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(685) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(686) Assembly of the peptide fragment was in the following sequence:

(687) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(688) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method C as described above.

(689) The peptide was synthesized starting with the amino alcohol Fmoc-Tyrol(tBu), which was grafted to the resin (Fmoc-Tyrol(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(690) Resin-Tyrol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(691) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure B above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 94 in Table 2.

(692) Examples 95, 97 and 101 to 103 are shown in Table 1.

(693) Procedure D, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(694) (I) The protected peptide fragments (module B and linker L) were synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(695) Assembly of the peptide fragments were in the following sequence:

(696) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(697) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method E as described above.

(698) The peptides were synthesized starting with the amino alcohol Fmoc-Serol(tBu), which was grafted to the resin (Fmoc-Serol(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(699) Resin-Serol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(700) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 95, 97 and 101 to 103 in Table 2.

(701) Examples 96, 98 and 116 are shown in Table 1.

(702) Procedure B, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(703) (I) The protected peptide fragments (module B and linker L) were synthesized as indicated above in the corresponding section in the synthesis of Ex. 1. Assembly of the peptide fragments was in the following sequence:

(704) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(705) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method C as described above.

(706) The peptides were synthesized starting with the amino alcohol Fmoc-Serol(tBu), which was grafted to the resin (Fmoc-Serol(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(707) Resin-Serol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(708) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure B above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 96, 98 and 116 in Table 2.

(709) Example 99, 115, 157, 270, 271, 274, 277, 301, 340, and 344 are shown in Table 1. Procedure O, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(710) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(711) Assembly of the peptide fragment was in the following sequence:

(712) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(713) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method K as described above.

(714) The peptides were synthesized starting with an appropriately protected Fmoc amino acid which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(715) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(716) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure O above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 99, 115, 157, 270, 271, 274, 277, 301, 340, and 344 in Table 2.

(717) Example 122 is shown in Table 1.

(718) Procedure I, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(719) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(720) Assembly of the peptide fragment was in the following sequence:

(721) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(722) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(723) The peptide was synthesized starting with the amino acid Fmoc-Ser(tBu)-OH, which was grafted to the resin (Fmoc-Ser(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(724) Resin-Ser-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(725) Subsequently, cleavage of the peptide from resin and formation of the isopropyl ester of the liberated α-carboxyl group of Ser at X.sup.12, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure I above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 122 in Table 2.

(726) Example 124 is shown in Table 1.

(727) Procedure B, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(728) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(729) Assembly of the peptide fragment was in the following sequence:

(730) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(731) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method C as described above.

(732) The peptide was synthesized starting with the amino alcohol Fmoc-.sup.DThrol(tBu), which was grafted to the resin (Fmoc-.sup.DThrol(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(733) Resin-.sup.DThrol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(734) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure B above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 124 in Table 2.

(735) Examples 125 and 126 are shown in Table 1.

(736) Procedure M1, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(737) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(738) Assembly of the peptide fragment was in the following sequence:

(739) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(740) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(741) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at P.sup.11 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(742) Resin-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(743) Subsequently, acylation with acetic acid at X.sup.14, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 125 and 126 in Table 2.

(744) Example 127 is shown in Table 1.

(745) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(746) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(747) Assembly of the peptide fragment was in the following sequence:

(748) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.1.

(749) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(750) The peptide was synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(751) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(752) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 127 in Table 2.

(753) Example 145 is shown in Table 1.

(754) Procedure H, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(755) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(756) Assembly of the peptide fragment was in the following sequence:

(757) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(758) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(759) The peptide was synthesized starting with the amino acid Fmoc-Ser(tBu)-OH, which was grafted to the resin (Fmoc-Ser(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(760) Resin-Ser-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(761) Subsequently, cleavage of the peptide from resin, formation of the N-methlyamide of the liberated α-carboxyl group of Ser at X.sup.12, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure H above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 145 in Table 2.

(762) Examples 146 and 147 are shown in Table 1.

(763) Procedure N1, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(764) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(765) Assembly of the peptides fragment was in the following sequence:

(766) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(767) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(768) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-Glu(2-PhiPr)-OH for addition of the amino acid residue at P.sup.11 and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at C. Assembly of the peptide was in the following sequence, showing only residues of module A:

(769) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(770) Subsequently, acylation with acetic acid at P.sup.1, removal of the alloc protecting group at P.sup.2, cleavage of the peptides from resin and removal of the 2-phenyl-isopropyl protecting group at P.sup.11, formation of the lactam interstrand linkage by an amide bond between the liberated side-chain functional groups of the residues at P.sup.2 and at P.sup.11, and full deprotection were performed as indicated in procedure N1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 146 and 147 in Table 2.

(771) Examples 148, 149, 265, 273, 279, 287, 290, 291, 293, 302, 303, 319 to 327, 341, 346, 348, 349 and 351 are shown in Table 1.

(772) Procedure N1, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(773) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(774) Assembly of the peptide fragments was in the following sequence:

(775) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(776) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(777) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5 and using Fmoc-Asp(2-PhiPr)-OH for addition of the amino acid residue at P.sup.11. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at C. Assembly of the peptides was in the following sequence, showing only residues of module A:

(778) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(779) Subsequently, acylation with acetic acid at P.sup.1, removal of the alloc protecting group at P.sup.2, cleavage of the peptides from the resin and removal of the 2-phenyl-isopropyl protecting group at P.sup.11, formation of the lactam interstrand linkage by an amide bond between the liberated side-chain functional groups of the residues at P.sup.2 and at P.sup.11, and full deprotection were performed as indicated in procedure N1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 148, 149, 265, 273, 279, 287, 290, 291, 293, 302, 303, 319 to 327, 341, 346, 348, 349 and 351 in Table 2.

(780) Example 160 is shown in Table 1.

(781) Procedure O, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(782) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(783) Assembly of the peptide fragment was in the following sequence:

(784) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(785) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method K as described above.

(786) The peptide was synthesized starting with an appropriately protected Fmoc amino acid which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(787) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(788) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure O above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 160 in Table 2.

(789) Example 161 is shown in Table 1.

(790) Procedure O, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(791) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(792) Assembly of the peptide fragment was in the following sequence:

(793) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(794) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method K as described above.

(795) The peptide was synthesized starting with an appropriately protected Fmoc amino acid which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-.sup.DGlu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of .sup.DGlu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(796) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(797) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure O above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 161 in Table 2.

(798) Example 162 is shown in Table 1.

(799) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(800) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(801) Assembly of the peptide fragment was in the following sequence:

(802) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(803) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(804) The peptide was synthesized starting with the amino alcohol Fmoc-Serol(tBu), which was grafted to the resin (Fmoc-Serol(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(805) Resin-Serol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(806) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 162 in Table 2.

(807) Example 163 is shown in Table 1.

(808) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(809) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(810) Assembly of the peptide fragment was in the following sequence:

(811) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(812) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(813) The peptide was synthesized starting with the amino alcohol Fmoc-Serol(tBu), which was grafted to the resin (Fmoc-Serol(tBu)-2-chlorotrityl resin), using Fmoc-.sup.DGlu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of .sup.DGlu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(814) Resin-Serol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(815) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 163 in Table 2.

(816) Example 164 is shown in Table 1.

(817) Procedure O, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(818) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(819) Assembly of the peptide fragment was in the following sequence:

(820) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.1.

(821) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method K as described above.

(822) The peptide was synthesized starting with an appropriately protected Fmoc amino acid which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(823) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(824) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure O above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 164 in Table 2.

(825) Example 165 is shown in Table 1.

(826) Procedure O, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(827) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(828) Assembly of the peptide fragment was in the following sequence:

(829) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.1.

(830) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method K as described above.

(831) The peptide was synthesized starting with an appropriately protected Fmoc amino acid which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-.sup.DGlu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of .sup.DGlu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence:

(832) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(833) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure O above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 165 in Table 2.

(834) Examples 166, 167 and 168 are shown in Table 1.

(835) Procedure O, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(836) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(837) Assembly of the peptide fragment was in the following sequence:

(838) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(839) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method K as described above.

(840) The peptides were synthesized starting with an appropriately protected Fmoc amino acid which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.7, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.7 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(841) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(842) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure O above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 166, 167 and 168 in Table 2.

(843) Examples 169, 170 and 171 are shown in Table 1.

(844) Procedure O, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(845) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(846) Assembly of the peptide fragment was in the following sequence:

(847) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(848) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method K as described above.

(849) The peptides were synthesized starting with an appropriately protected Fmoc amino acid which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-.sup.DGlu(Allyl)-OH for addition of the amino acid residue at P.sup.7, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of .sup.DGlu at P.sup.7 and the α-amino group of Dab at C. Assembly of the peptides was in the following sequence, showing only residues of module A:

(850) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(851) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure O above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 169, 170 and 171 in Table 2.

(852) Examples 172, 173 and 174 are shown in Table 1.

(853) Procedure D, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(854) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(855) Assembly of the peptide fragment was in the following sequence:

(856) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(857) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method E as described above.

(858) The peptides were synthesized starting with the amino alcohol Fmoc-Serol(tBu), which was grafted to the resin (Fmoc-Serol(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.7, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.7 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(859) Resin-Serol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(860) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 172, 173 and 174 in Table 2.

(861) Example 175 is shown in Table 1.

(862) Procedure M1, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(863) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(864) Assembly of the peptide fragments was in the following sequence:

(865) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1.

(866) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(867) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(868) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(869) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, formation of the disulfide interstrand linkages between P.sup.2 and P.sup.11 and between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 175 in Table 2.

(870) Examples 176 and 177 are shown in Table 1.

(871) Procedure L, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(872) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(873) Assembly of the peptide fragment was in the following sequence:

(874) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(875) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method I as described above.

(876) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(877) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(878) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkages between P.sup.2 and P.sup.11 and between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure L above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 176 and 177 in Table 2.

(879) Examples 178, 179, 205 to 208 and 215 are shown in Table 1.

(880) Procedure M1, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(881) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(882) Assembly of the peptide fragments was in the following sequence:

(883) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(884) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(885) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at C. Assembly of the peptide was in the following sequence, showing only residues of module A:

(886) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(887) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 178, 179, 205 to 208 and 215 in Table 2.

(888) Examples 219 to 227 and 266 are shown in Table 1.

(889) Procedure M2, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(890) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(891) Assembly of the peptide fragments was in the following sequence:

(892) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1

(893) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(894) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at C. Assembly of the peptide was in the following sequence, showing only residues of module A:

(895) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(896) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, full deprotection and formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9 were performed as indicated in procedure M2 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 219 to 227 and 266 in Table 2.

(897) Examples 180 to 185 are shown in Table 1.

(898) Procedure L, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(899) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(900) Assembly of the peptide fragments was in the following sequence:

(901) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(902) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method I as described above.

(903) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(904) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(905) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure L above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 180 to 185 in Table 2.

(906) Example 186 is shown in Table 1.

(907) Procedure E, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(908) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(909) Assembly of the peptide fragment was in the following sequence:

(910) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1.

(911) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method F as described above.

(912) The peptide was synthesized starting with the amino acid Fmoc-Ser(tBu)-OH, which was grafted to the resin (Fmoc-Ser(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(913) Resin-Ser-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(914) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure E above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 186 in Table 2.

(915) Example 187 is shown in Table 1.

(916) Procedure N2, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(917) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(918) Assembly of the peptide fragment was in the following sequence:

(919) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(920) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(921) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at) X.sup.12 to Sieber amide resin, using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using Fmoc-Asp(2-PhiPr)-OH for addition of the amino acid residue at P.sup.4. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(922) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(923) Subsequently, acylation with acetic acid at P.sup.1, ivDde deprotection at P.sup.9, cleavage of the peptide from the resin and removal of the 2-phenyl-isopropyl protecting group at P.sup.4, formation of a lactam interstrand linkage by an amide bond between the liberated β-carboxyl group of Asp at P.sup.4 and the γ-amino group of Dab at P.sup.9, and full deprotection were performed as indicated in procedure N2 above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 187 in Table 2.

(924) Example 188 to 195, 198 to 202 and 204 are shown in Table 1.

(925) Procedure D, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(926) (I) The protected peptide fragments (module B and linker L) were synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(927) Assembly of the peptide fragments was in the following sequence:

(928) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(929) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method E as described above.

(930) The peptides were synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(931) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(932) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 188 to 195, 198 to 202 and 204 in Table 2.

(933) Example 196 is shown in Table 1.

(934) Procedure B, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(935) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(936) Assembly of the peptide fragment was in the following sequence:

(937) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(938) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method C as described above.

(939) The peptide was synthesized starting with the amino alcohol Fmoc-Serol(tBu), which was grafted to the resin (Fmoc-Serol(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(940) Resin-Serol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(941) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure B above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 196 in Table 2.

(942) Example 197 is shown in Table 1.

(943) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(944) (I) The protected peptide fragment (module B and linker L) were synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(945) Assembly of the peptide fragment was in the following sequence:

(946) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(947) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(948) The peptide was synthesized starting with the amino alcohol Fmoc-Serol(tBu), which was grafted to the resin (Fmoc-Serol(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(949) Resin-Serol-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-Hiv.

(950) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 197 in Table 2.

(951) Example 203 is shown in Table 1.

(952) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(953) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(954) Assembly of the peptide fragment was in the following sequence:

(955) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(956) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(957) The peptide was synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.7, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.7 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(958) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-Hiv.

(959) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 203 in Table 2.

(960) Example 209 is shown in Table 1.

(961) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(962) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(963) Assembly of the peptide fragment was in the following sequence:

(964) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(965) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(966) The peptide was synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(967) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(968) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 209 in Table 2.

(969) Example 210 is shown in Table 1.

(970) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(971) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1. Assembly of the peptide fragment was in the following sequence:

(972) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(973) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(974) The peptide was synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-.sup.DGlu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of .sup.DGlu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(975) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-Hiv.

(976) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 210 in Table 2.

(977) Example 211, 212 and 213 are shown in Table 1.

(978) Procedure D, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(979) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(980) Assembly of the peptide fragment was in the following sequence:

(981) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(982) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method E as described above.

(983) The peptides were synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.7, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.7 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(984) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-Hiv.

(985) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 211, 212 and 213 in Table 2.

(986) Example 214 is shown in Table 1.

(987) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(988) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(989) Assembly of the peptide fragment was in the following sequence:

(990) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(991) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(992) The peptide was synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-.sup.DGlu(Allyl)-OH for addition of the amino acid residue at P.sup.7, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of .sup.DGlu at P.sup.7 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(993) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-Hiv.

(994) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 214 in Table 2.

(995) Example 216 is shown in Table 1.

(996) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(997) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(998) Assembly of the peptide fragment was in the following sequence:

(999) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.1.

(1000) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(1001) The peptide was synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1002) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1003) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 216 in Table 2.

(1004) Example 217 is shown in Table 1.

(1005) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1006) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(1007) Assembly of the peptide fragment was in the following sequence:

(1008) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.1.

(1009) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(1010) The peptide was synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin), using Fmoc-.sup.DGlu(Allyl)-OH for addition of the amino acid residue at P.sup.6, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of .sup.DGlu at P.sup.6 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1011) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-Hiv.

(1012) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 217 in Table 2.

(1013) Example 218 is shown in Table 1.

(1014) Procedure M1, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1015) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1016) Assembly of the peptide fragment was in the following sequence:

(1017) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1018) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(1019) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at P.sup.11 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at C. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1020) Resin-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1021) Subsequently, acylation with acetic acid at X.sup.14, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 218 in Table 2.

(1022) Example 228 is shown in Table 1.

(1023) Procedure M1, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1024) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1025) Assembly of the peptide fragment was in the following sequence:

(1026) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1027) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(1028) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at C. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1029) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1030) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.1 and X.sup.12, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 228 in Table 2.

(1031) Examples 229, and 230 are shown in Table 1.

(1032) Procedure Q, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1033) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1034) Assembly of the peptide fragment was in the following sequence:

(1035) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1036) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(1037) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1038) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1039) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, and full deprotection were performed as indicated in procedure Q above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 229, and 230 in Table 2.

(1040) Examples 232 and 233 are shown in Table 1.

(1041) Procedure A, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1042) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(1043) Assembly of the peptide fragment was in the following sequence:

(1044) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1.

(1045) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method B as described above.

(1046) The peptides were synthesized starting with the amino alcohol Fmoc-Throl(tBu), which was grafted to the resin (Fmoc-Throl(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1047) Resin-Throl-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1048) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure A above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 232 and 233 in Table 2.

(1049) Examples 234 and 235 are shown in Table 1.

(1050) Procedure M1, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1051) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1052) Assembly of the peptide fragment was in the following sequence:

(1053) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1054) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(1055) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1056) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1057) Subsequently, acylation with acetic acid at X.sup.14, cleavage of the peptides from the resin, formation of the disulfide interstrand linkages between P.sup.2 and P.sup.11 and between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 234 and 235 in Table 2.

(1058) Example 236 is shown in Table 1.

(1059) Procedure D, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1060) (I) The protected peptide fragment (module B and linker L) was synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(1061) Assembly of the peptide fragment was in the following sequence:

(1062) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1063) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method E as described above.

(1064) The peptide was synthesized starting with the amino alcohol Fmoc-Glyol, which was grafted to the resin (Fmoc-Glyol-2-chlorotrityl resin), using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1065) Resin-Glyol-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-Hiv.

(1066) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure D above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 236 in Table 2.

(1067) Examples 237 to 240 are shown in Table 1.

(1068) Procedure M1, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1069) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1070) Assembly of the peptide fragment was in the following sequence:

(1071) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1072) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(1073) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1074) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1075) Subsequently, acylation with acetic acid at X.sup.14, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.4 and P.sup.9, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 237 to 240 in Table 2.

(1076) Example 243 is shown in Table 1.

(1077) Procedure M1, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1078) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1079) Assembly of the peptide fragment was in the following sequence:

(1080) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1081) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(1082) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.13 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1083) Resin-X.sup.13-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1084) Subsequently, acylation with acetic acid at X.sup.14, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 243 in Table 2.

(1085) Example 241 is shown in Table 1.

(1086) Procedure E, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1087) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1088) Assembly of the peptide fragment was in the following sequence:

(1089) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1090) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method F as described above.

(1091) The peptide was synthesized starting with the amino acid Fmoc-.sup.DAla-OH, which was grafted to the resin (Fmoc-.sup.DAla-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1092) Resin-.sup.DAla-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1093) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure E above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 241 in Table 2.

(1094) Example 242 is shown in Table 1.

(1095) Procedure E, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1096) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1097) Assembly of the peptide fragment was in the following sequence:

(1098) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1099) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method F as described above.

(1100) The peptide was synthesized starting with the amino acid Fmoc-.sup.DSer(tBu)-OH, which was grafted to the resin (Fmoc-.sup.DSer(tBu)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1101) Resin-.sup.DSer-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1102) Subsequently, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure E above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 242 in Table 2.

(1103) Example 244 is shown in Table 1.

(1104) Procedure M1, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1105) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1106) Assembly of the peptide fragment was in the following sequence:

(1107) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1108) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(1109) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.13 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1110) Resin-X.sup.13-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1111) Subsequently, acylation with acetic acid at X.sup.14, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between X.sup.13 and X.sup.14, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 244 in Table 2.

(1112) Examples 245, 250, and 383 are shown in Table 1.

(1113) Procedure P, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1114) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1115) Assembly of the peptide fragment was in the following sequence:

(1116) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1117) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method L as described above.

(1118) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.13 to Sieber amide resin, using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5 and using 3-(tritylthio)propionic acid for addition of the thiol-substituted acyl residue at X.sup.14. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1119) Resin-X.sup.13-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1120) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between X.sup.13 and X.sup.14, and full deprotection were performed as indicated in procedure P above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 245, 250, and 383 in Table 2.

(1121) Example 246 is shown in Table 1.

(1122) Procedure M1, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1123) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1124) Assembly of the peptide fragment was in the following sequence:

(1125) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1126) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(1127) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.13 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1128) Resin-X.sup.13-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1129) Subsequently, acylation with acetic acid at X.sup.14, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.9, and full deprotection were performed as indicated in procedure M1 above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 246 in Table 2.

(1130) Example 247, 248 and 249 are shown in Table 1.

(1131) Procedure Q, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1132) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1133) Assembly of the peptide fragment was in the following sequence:

(1134) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1135) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(1136) The peptide was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1137) Resin-X.sup.13-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1138) Subsequently, acylation with acetic acid at X.sup.14, cleavage of the peptides from the resin, and full deprotection were performed as indicated in procedure Q above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 247, 248 and 249 in Table 2.

(1139) Examples 367 to 371, 373, 374, 375, 377, 378, and 380 are shown in Table 1. Procedure M2, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1140) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1141) Assembly of the peptide fragments was in the following sequence:

(1142) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1143) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(1144) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.13 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1145) Resin-X.sup.13-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1146) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, full deprotection, and formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11 were performed as indicated in procedure M2 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 367 to 371, 373, 374, 375, 377, 378, and 380 in Table 2.

(1147) Example 372, 376, 379, 381, and 382 are shown in Table 1.

(1148) Procedure O, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1149) (I) The protected peptide fragments (module B and linker L) were synthesized as indicated above in the corresponding section in the synthesis of Ex. 1.

(1150) Assembly of the peptide fragments was in the following sequence:

(1151) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1152) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method K as described above.

(1153) The peptides were synthesized starting with an appropriately protected Fmoc amino acid which was used in the first coupling cycle for grafting the amino acid residue at X.sup.13 to Sieber amide resin, using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1154) Resin-X.sup.13-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1-X.sup.14.

(1155) Subsequently, cleavage of the peptides from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure O above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 372, 376, 379, 381, and 382 in Table 2.

(1156) Examples 285, 286, 288 and 292 are shown in Table 1.

(1157) Procedure R as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1158) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1159) Assembly of the peptide fragments was in the following sequence:

(1160) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1161) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(1162) The peptides were synthesized starting with the amino acid Fmoc-Ser(tBu)-OH, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1.

(1163) Assembly of the peptide was in the following sequence, showing only residues of module A:

(1164) Resin-Ser-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1165) Subsequently, acylation with acetic acid at P.sup.1, allyl deprotection at P.sup.2, ivDde deprotection at P.sup.11, and formation of the lactam interstrand linkage by an amide bond between the liberated side-chain functional groups of the amino acid residue at P.sup.2 and Dab at P.sup.11, cleavage of the peptides from the resin, and full deprotection were performed as indicated in procedure P above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 285, 286, 288 and 292 in Table 2.

(1166) Examples 304 and 347 are shown in Table 1.

(1167) Procedure S, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1168) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1169) Assembly of the peptide fragments was in the following sequence:

(1170) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1171) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(1172) The peptides were synthesized starting with the amino acid Fmoc-Ser(tBu)-OH, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5, using Fmoc-Asp(2-PhiPr)-OH for addition of the amino acid residue at P.sup.11, and using alpha-hydroxyisovaleric acid (Hiv) for addition of the hydroxy acid residue at P.sup.1. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1173) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1174) Subsequently, removal of the alloc protecting group at P.sup.2, cleavage of the peptides from the resin and removal of the 2-phenyl-isopropyl protecting group at P.sup.11, formation of the lactam interstrand linkage by an amide bond between the liberated side-chain functional groups of the residues at P.sup.2 and at P.sup.11, and full deprotection were performed as indicated in procedure Q above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 304 and 347, in Table 2.

(1175) Examples 366 is shown in Table 1.

(1176) Procedure M2, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1177) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1178) Assembly of the peptide fragment was in the following sequence:

(1179) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1180) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method J as described above.

(1181) The peptides was synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-.sup.DGlu(Allyl)-OH for addition of the amino acid residue at P.sup.7. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of .sup.DGlu at P.sup.7 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1182) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1183) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, full deprotection, and formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11 were performed as indicated in procedure M2 above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 366 in Table 2.

(1184) Examples 354 to 365 are shown in Table 1.

(1185) Procedure M2, as described above, was used for the preparation of the peptides, applying an on-resin fragment coupling strategy.

(1186) (I) The protected peptide fragments (module B and linker L) were synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1187) Assembly of the peptide fragments was in the following sequence:

(1188) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1189) (II) The fully protected peptides (module A, module B and linker L) were assembled on solid support according to method J as described above.

(1190) The peptides were synthesized starting with an appropriately protected Fmoc-amino acid, which was used in the first coupling cycle for grafting the amino acid residue at X.sup.12 to Sieber amide resin, and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.7. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.7 and the α-amino group of Dab at L.sup.1. Assembly of the peptides was in the following sequence, showing only residues of module A:

(1191) Resin-X.sup.12-P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1192) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptides from the resin, full deprotection, and formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11 were performed as indicated in procedure M2 above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 354 to 365 in Table 2.

(1193) Example 384 is shown in Table 1.

(1194) Procedure F, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1195) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1196) Assembly of the peptide fragment was in the following sequence:

(1197) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1198) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(1199) The peptide was synthesized starting with the amino acid Fmoc-Cys(Trityl)-OH, which was grafted to the resin (Fmoc-Cys(Trityl)-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1200) Resin-Cys-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1201) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure F above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see 384 in Table 2.

(1202) Example 385 is shown in Table 1.

(1203) Procedure F, as described above, was used for the preparation of the peptide, applying an on-resin fragment coupling strategy.

(1204) (I) The protected peptide fragment (module B and linker L) was synthesized as described above in the corresponding section in the synthesis of Ex. 1.

(1205) Assembly of the peptide fragment was in the following sequence:

(1206) Resin-Thr-Q.sup.6-Q.sup.5-Q.sup.4-Q.sup.3-Q.sup.2-Q.sup.1-L.sup.3-L.sup.2-L.sup.1.

(1207) (II) The fully protected peptide (module A, module B and linker L) was assembled on solid support according to method G as described above.

(1208) The peptide was synthesized starting with the amino acid Fmoc-Leu(3R)OtBu-OH, which was grafted to the resin (Fmoc-Leu(3R)OtBu-2-chlorotrityl resin) and using Fmoc-Glu(Allyl)-OH for addition of the amino acid residue at P.sup.5. Coupling of the protected peptide fragment (module B and linker L) was performed as indicated in the corresponding section of procedure A above by formation of an amide bond between the γ-carboxyl group of Glu at P.sup.5 and the α-amino group of Dab at L.sup.1. Assembly of the peptide was in the following sequence, showing only residues of module A:

(1209) Resin-Leu(3R)OH—P.sup.11-P.sup.10-P.sup.9-P.sup.8-P.sup.7-P.sup.6-P.sup.5-P.sup.4-P.sup.3-P.sup.2-P.sup.1.

(1210) Subsequently, acylation with acetic acid at P.sup.1, cleavage of the peptide from the resin, formation of the disulfide interstrand linkage between P.sup.2 and P.sup.11, and full deprotection were performed as indicated in procedure F above. Finally, the peptide was purified, as described above, and characterized by HPLC-MS. For analytical data, see 385 in Table 2.

(1211) TABLE-US-00002 TABLE 1 Examples (Ex.) In the below-mentioned examples, amino acid residues are connected in either direction from the α carbonyl (C═O) point of attachment to the α nitrogen (N) of the next element, unless otherwise indicated. Other linkages, residues, connection of residues and modifications are as specified. Ex. No. Sequence Ex. 1.sup.a) b) c) Ex. 2.sup.a) b) c) 0 Ex. 3.sup.a) b) c) Ex. 4.sup.a) b) c) Ex. 5.sup.a) b) c) Ex. 6.sup.a) Ex. 7.sup.a) e) Ex. 8.sup.a) Ex. 9.sup.a) Ex. 10.sup.a) Ex. 11.sup.a) Ex. 12.sup.a) 0 Ex. 13.sup.a) Ex. 14.sup.a) Ex. 15.sup.f) Ex. 16.sup.f) Ex. 17.sup.f) Ex. 18.sup.f) Ex. 19.sup.f) Ex. 20.sup.f) Ex. 21.sup.f) Ex. 22.sup.f) 0 Ex. 23.sup.f) Ex. 24.sup.e) f) Ex. 25.sup.f) Ex. 26.sup.f) Ex. 27.sup.f) Ex. 28.sup.f) Ex. 29.sup.f) Ex. 30.sup.f) Ex. 31.sup.f) Ex. 32.sup.f) 00 Ex. 33.sup.f) 01 Ex. 34.sup.f) 02 Ex. 35.sup.f) 03 Ex. 36.sup.f) 04 Ex. 37.sup.f) 05 Ex. 38.sup.f) 06 Ex. 39.sup.a) 07 Ex. 40.sup.a) 08 Ex. 41.sup.a) 09 Ex. 42.sup.a) 0 Ex. 43.sup.a) Ex. 44.sup.a) Ex. 45.sup.a) Ex. 46.sup.a) Ex. 47.sup.a) Ex. 48.sup.a) Ex. 49.sup.a) Ex. 50.sup.a) Ex. 51.sup.a) Ex. 52.sup.a) 0 Ex. 53.sup.a) Ex. 54.sup.a) Ex. 55.sup.g) Ex. 56.sup.g) Ex. 57.sup.a) Ex. 58.sup.a) h) Ex. 59.sup.a) h) Ex. 60.sup.a) h) Ex. 61.sup.a) h) Ex. 62.sup.a) 0 Ex. 63.sup.a) Ex. 64.sup.a) Ex. 65.sup.a) Ex. 66.sup.a) Ex. 67.sup.a) Ex. 68.sup.a) Ex. 69.sup.a) h) Ex. 70.sup.a) h) Ex. 71.sup.a) b) Ex. 72.sup.a) h) 0 Ex. 73.sup.a) h) Ex. 74.sup.a) h) Ex. 75.sup.a) h) Ex. 76.sup.a) h) Ex. 77.sup.a) b) Ex. 78.sup.a) h) Ex. 79.sup.a) h) Ex. 80.sup.a) h) Ex. 81.sup.a) h) Ex. 82.sup.a) h) 0 Ex. 83.sup.a) h) Ex. 84.sup.a) h) Ex. 85.sup.a) h) Ex. 86.sup.a) b) Ex. 87.sup.a) h) Ex. 88.sup.a) h) Ex. 89.sup.a) h) Ex. 90.sup.a) h) Ex. 91.sup.a) h) Ex. 92.sup.a) h) 0 Ex. 93.sup.a) h) Ex. 94.sup.a) b) Ex. 95.sup.a) h) Ex. 96.sup.a) b) Ex. 97.sup.a) h) Ex. 98.sup.a) b) Ex. 99.sup.a) e) Ex. 100.sup.a) Ex. 101.sup.a) h) Ex. 102.sup.a) h) 0 Ex. 103.sup.a) h) Ex. 104.sup.a) h) Ex. 105.sup.a) h) Ex. 106.sup.a) h) Ex. 107.sup.a) h) Ex. 108.sup.a) h) Ex. 109.sup.a) h) Ex. 110.sup.a) h) Ex. 111.sup.a) h) Ex. 112.sup.a) h) 0 Ex. 113.sup.a) Ex. 114.sup.a) Ex. 115.sup.a) e) Ex. 116.sup.a) b) Ex. 117.sup.a) Ex. 119.sup.a) Ex. 120.sup.a) Ex. 121.sup.a) Ex. 122.sup.a) Ex. 123.sup.a) b) 0 Ex. 124.sup.a) b) Ex. 125.sup.a) Ex. 126.sup.a) Ex. 127.sup.a) h) Ex. 128.sup.a) Ex. 129.sup.a) b) Ex. 130.sup.a) Ex. 131.sup.a) Ex. 132.sup.a) Ex. 133.sup.a) 00 Ex. 134.sup.a) 01 Ex. 135.sup.a) 02 Ex. 136.sup.a) 03 Ex. 137.sup.a) 04 Ex. 138.sup.a) 05 Ex. 139.sup.a) 06 Ex. 140.sup.a) 07 Ex. 141.sup.a) 08 Ex. 142.sup.a) 09 Ex. 143.sup.a) 0 Ex. 144.sup.a) Ex. 145.sup.a) Ex. 146.sup.g) Ex. 147.sup.g) Ex. 148.sup.g) Ex. 149.sup.g) Ex. 150.sup.a) Ex. 151.sup.a) Ex. 152.sup.a) Ex. 153.sup.a) 0 Ex. 154.sup.a) Ex. 155.sup.a) Ex. 156.sup.a) Ex. 157.sup.a) e) Ex. 158.sup.a) Ex. 159.sup.a) Ex. 160.sup.a) e) Ex. 161.sup.a) e) Ex. 162.sup.a) h) Ex. 163.sup.a) h) 0 Ex. 164.sup.a) e) Ex. 165.sup.a) e) Ex. 166.sup.a) e) Ex. 167.sup.a) e) Ex. 168.sup.a) e) Ex. 169.sup.a) e) Ex. 170.sup.a) e) Ex. 171.sup.a) e) Ex. 172.sup.a) h) Ex. 173.sup.a) h) 0 Ex. 174.sup.a) h) Ex. 175.sup.a) Ex. 176.sup.a) Ex. 177.sup.a) Ex. 178.sup.a) Ex. 179.sup.a) Ex. 180.sup.a) Ex. 181.sup.a) Ex. 182.sup.a) Ex. 183.sup.a) 0 Ex. 184.sup.a) Ex. 185.sup.a) Ex. 186.sup.a) Ex. 187.sup.g) Ex. 188.sup.a) h) Ex. 189.sup.a) h) Ex. 190.sup.a) h) Ex. 191.sup.a) h) Ex. 192.sup.a) h) Ex. 193.sup.a) h) 0 Ex. 194.sup.a) h) Ex. 195.sup.a) h) Ex. 196.sup.a) b) Ex. 197.sup.a) h) Ex. 198.sup.a) h) Ex. 199.sup.a) h) Ex. 200.sup.a) h) Ex. 201.sup.a) h) Ex. 202.sup.a) h) Ex. 203.sup.a) h) 0 Ex. 204.sup.a) h) Ex. 205.sup.a) Ex. 206.sup.a) Ex. 207.sup.a) Ex. 208.sup.a) Ex. 209.sup.a) h) Ex. 210.sup.a) h) Ex. 211.sup.a) h) Ex. 212.sup.a) h) Ex. 213.sup.a) h) 0 Ex. 214.sup.a) h) Ex. 215.sup.a) Ex. 216.sup.a) h) Ex. 217.sup.a) h) Ex. 218.sup.a) Ex. 219.sup.a) Ex. 220.sup.a) Ex. 221.sup.a) Ex. 222.sup.a) Ex. 223.sup.a) 0 Ex. 224.sup.a) Ex. 225.sup.a) Ex. 226.sup.a) Ex. 227.sup.a) Ex. 228.sup.a) Ex. 229 Ex. 230 Ex. 232.sup.a) b) Ex. 233.sup.a) b) Ex. 234.sup.a) 00 Ex. 235.sup.a) 01 Ex. 236.sup.a) h) 02 Ex. 237.sup.a) 03 Ex. 238.sup.a) 04 Ex. 239.sup.a) 05 Ex. 240.sup.a) 06 Ex. 241.sup.a) 07 Ex. 242.sup.a) 08 Ex. 243.sup.a) 09 Ex. 244.sup.a) 0 Ex. 245.sup.a) c) i) Ex. 246.sup.a) Ex. 247 Ex. 248 Ex. 249 Ex. 250.sup.a) c) i) Ex. 251.sup.a) Ex. 252.sup.a) Ex. 253.sup.a) Ex. 254.sup.a) 0 Ex. 255.sup.a) Ex. 256.sup.a) Ex. 257.sup.a) Ex. 258.sup.a) Ex. 259.sup.a) Ex. 260.sup.a) Ex. 261.sup.a) Ex. 262.sup.a) Ex. 263.sup.a) Ex. 264.sup.a) 0 Ex. 265.sup.g) Ex. 266.sup.a) Ex. 267.sup.a) Ex. 268.sup.a) Ex. 269.sup.a) Ex. 270.sup.a) e) Ex. 271.sup.a) e) Ex. 272.sup.a) Ex. 273.sup.g) Ex. 274.sup.a) e) 0 Ex. 275.sup.a) Ex. 276.sup.a) Ex. 277.sup.a) e) Ex. 278.sup.a) Ex. 279.sup.g) Ex. 280.sup.a) Ex. 281.sup.a) Ex. 282.sup.a) Ex. 283.sup.a) Ex. 284.sup.a) 0 Ex. 285.sup.g) Ex. 286.sup.g) Ex. 287.sup.g) Ex. 288.sup.g) Ex. 289.sup.a) Ex. 290.sup.g) Ex. 291.sup.g) Ex. 292.sup.g) Ex. 293.sup.g) Ex. 294.sup.a) 0 Ex. 295.sup.a) Ex. 296.sup.a) Ex. 297.sup.a) Ex. 298.sup.a) Ex. 299.sup.a) Ex. 300.sup.a) Ex. 301.sup.a) e) Ex. 302.sup.g) Ex. 303.sup.g) Ex. 304.sup.g) e) 0 Ex. 305.sup.a) Ex. 306.sup.a) Ex. 307.sup.a) Ex. 308.sup.a) Ex. 309.sup.a) Ex. 310.sup.a) Ex. 311.sup.a) Ex. 312.sup.a) Ex. 313.sup.a) Ex. 314.sup.a) 0 Ex. 315.sup.a) Ex. 316.sup.a) Ex. 317.sup.a) Ex. 318.sup.a) Ex. 319.sup.g) Ex. 320.sup.g) Ex. 321.sup.g) Ex. 322.sup.g) Ex. 323.sup.g) Ex. 324.sup.g) 0 Ex. 325.sup.g) Ex. 326.sup.g) Ex. 327.sup.g) Ex. 328.sup.a) Ex. 329.sup.a) Ex. 330.sup.a) Ex. 331.sup.a) Ex. 332.sup.a) Ex. 333.sup.a) Ex. 334.sup.a) 00 Ex. 335.sup.a) 01 Ex. 336.sup.a) 02 Ex. 337.sup.a) 03 Ex. 338.sup.a) 04 Ex. 339.sup.a) 05 Ex. 340.sup.a) e) 06 Ex. 341.sup.g) 07 Ex. 342.sup.a) 08 Ex. 343.sup.a) 09 Ex. 344.sup.a) e) 0 Ex. 345.sup.a) Ex. 346.sup.g) Ex. 347.sup.g) e) Ex. 348.sup.g) Ex. 349.sup.g) Ex. 350.sup.a) Ex. 351.sup.g) Ex. 352.sup.a) Ex. 353.sup.a) Ex. 354.sup.a) 0 Ex. 355.sup.a) Ex. 356.sup.a) Ex. 357.sup.a) Ex. 358.sup.a) Ex. 359.sup.a) Ex. 360.sup.a) Ex. 361.sup.a) Ex. 362.sup.a) Ex. 363.sup.a) Ex. 364.sup.a) 0 Ex. 365.sup.a) Ex. 366.sup.a) Ex. 367.sup.a) Ex. 368.sup.a) Ex. 369.sup.a) Ex. 370.sup.a) Ex. 371.sup.a) Ex. 372.sup.a) e) Ex. 373.sup.a) Ex. 374.sup.a) 0 Ex. 375.sup.a) Ex. 376.sup.a) e) Ex. 377.sup.a) Ex. 378.sup.a) Ex. 379.sup.a) e) Ex. 380.sup.a) Ex. 381.sup.a) e) Ex. 382.sup.a) e) Ex. 383.sup.a) Ex. 384.sup.a) 0 Ex. 385.sup.a) .sup.a)Disulfide interstrand linkage(s) between indicated amino acid residues in module A, involving disulfide bond(s) between a pair(s) of side-chain thiol groups as specified. .sup.b)1,2-amino alcohol residue attached to the C-terinal amino acid residue of module A, involving an amide bond between the α-carboxyl group of the C-terminal amino acid residue and the amino group of the amino alcohol residue. .sup.c)Acid residue attached to the N-terminal amino acid residue of a module A, involving an amide bond between the carboxy group of the acid residue and the α-amino group of the N-terminal amino acid residue. .sup.e)α-hydroxy acid residue attached to the N-terminal amino acid residue of module A, involving an amide bond between the carboxyl group of the hydroxy acid residue and the α-amino group of the N-terminal amino acid residue. .sup.f)Lactam linkage between the two indicated amino acid residues in a module A, involving an amide bond between the side-chain amino group of the residue at P.sup.2 and the α-carboxyl group of the residue at P.sup.11. .sup.g)Lactam interstrand linkage between the two indicated amino acid residues in module A, involving an amide bond between a side-chain amino group and a side-chain carboxyl group. .sup.h)1,2-amino alcohol residue attached to the C-terminal amino acid residue of module A, involving an amide bond between and the α-carboxyl group of the C-terminal amino acid residue and the amino group of the amino alcohol residue, and α-hydroxy acid residue attached to the N-terminal amino acid residue of module A, involving an amide bond between the carboxyl group of the hydroxy acid residue and the α-amino group of the N-terminal amino acid residue. .sup.i)Disulfide interstrand linkage between the indicated amino acid residue and the indicated acid residue in module A, involving a disulfide bond between a pair of side-chain thiol groups as specified.

(1212) TABLE-US-00003 TABLE 2 Analytical data Ex. Meth. .sup.a) MS RT .sup.b) Pur. .sup.c)   1 A  776.7 .sup.g) 4.11 87   2 A  795.8 .sup.g) 3.98 83   3 B  791.3 .sup.g) 3.55 80   4 B  791.3 .sup.g) 3.69 90   5 A  589.9 .sup.h) 3.93 91   6 A  785.4 .sup.g) 3.81 92   7 A  771.8 .sup.g) 3.96 92   8 A  771.4 .sup.g) 3.95 90   9 A  766.4 .sup.g) 3.52 88  10 A  775.8 .sup.g) 3.89 91  11 A  780.9 .sup.g) 3.75 79  12 A  771.9 .sup.g) 3.45 92  13 A  775.7 .sup.g) 3.69 77  14 A  780.0 .sup.g) 3.62 85  15 B  783.3 .sup.g) 3.62 94  16 .sup.d) A  778.8 .sup.g) 4.12 95  17 B  779.2 .sup.g) 3.99 74  18 A  774.3 .sup.g) 4.37 82  19 A  778.5 .sup.g) 4.11 83  20 B  783.5 .sup.g) 3.75 76  21 A  783.5 .sup.g) 4.29 77  22 A  774.3 .sup.g) 4.22 75  23 A  769.5 .sup.g) 4.37 71  24 B  760.5 .sup.g) 3.80 70  25 A  773.9 .sup.g) 4.34 84  26 A  795.2 .sup.g) 4.51 83  27 A  773.9 .sup.g) 4.85 83  28 A  773.9 .sup.g) 3.92 77  29 B  778.7 .sup.g) 3.55 75  30 A  783.2 .sup.g) 3.96 80  31 .sup.d) E  774.3 .sup.g) 6.84 95  32 B  778.5 .sup.g) 3.90 73  33 A  778.8 .sup.g) 4.35 81  34 A  778.5 .sup.g) 4.31 82  35 B  769.2 .sup.g) 3.82 77  36 A  790.2 .sup.g) 4.34 80  37 A  768.9 .sup.g) 3.92 76  38 A  773.8 .sup.g) 4.09 80  39 .sup.d) A  814.7 .sup.g) 3.64 95  40 A  842.3 .sup.g) 4.76 92  41 .sup.d) B  809.7 .sup.g) 3.28 92  42 .sup.d) B  800.7 .sup.g) 3.21 95  43 .sup.d) B  600.5 .sup.h) 3.03 92  44 C  814.4 .sup.g) 2.83 93  45 C  809.7 .sup.g) 2.79 95  46 C  810.3 .sup.g) 2.94 93  47 C  600.7 .sup.h) 2.62 95  48 C  600.4 .sup.h) 2.55 94  49 C  819.0 .sup.g) 2.78 92  50 A  603.9 .sup.h) 3.34 90  51 C  607.4 .sup.h) 2.62 84  52 A  814.5 .sup.g) 3.86 81  53 C  600.9 .sup.h) 2.70 92  54 C  607.9 .sup.h) 2.70 91  55 A  798.4 .sup.g) 3.54 93  56 A  803.0 .sup.g) 3.40 83  57 A  776.0 .sup.g) 3.40 88  58 .sup.d) B  796.5 .sup.g) 3.59 95  59 A  777.0 .sup.g) 3.97 80  60 A  796.5 .sup.g) 3.88 84  61 A  812.4 .sup.g) 3.92 81  62 A  809.9 .sup.g) 3.74 88  63 A  809.8 .sup.g) 3.57 89  64 A  809.8 .sup.g) 3.57 84  65 A  607.5 .sup.h) 3.82 93  66 A  809.7 .sup.g) 3.53 92  67 A  809.7 .sup.g) 3.81 89  68 A  809.9 .sup.g) 3.72 71  69 A  819.4 .sup.g) 3.90 92  70 A  820.0 .sup.g) 3.85 85  71 A  829.2 .sup.g) 3.87 92  72 A  786.4 .sup.g) 3.93 80  73 A  781.9 .sup.g) 3.97 78  74 A  801.3 .sup.g) 3.86 80  75 A  819.8 .sup.g) 3.85 79  76 A  806.0 .sup.g) 3.86 90  77 A  804.9 .sup.g) 3.57 93  78 A  796.7 .sup.g) 3.79 87  79 A  796.5 .sup.g) 3.89 86  80 A  796.5 .sup.g) 3.84 82  81 A  805.8 .sup.g) 3.84 87  82 A  806.0 .sup.g) 3.83 84  83 A  801.0 .sup.g) 3.82 85  84 A  607.9 .sup.h) 3.98 78  85 B  810.4 .sup.g) 3.77 78  86 A  815.0 .sup.g) 3.87 92  87 A  593.4 .sup.h) 3.98 84  88 A  796.7 .sup.g) 3.98 87  89 A  796.4 .sup.g) 3.69 81  90 B  810.4 .sup.g) 3.59 81  91 A  810.4 .sup.g) 3.87 87  92 .sup.d) A  800.5 .sup.g) 4.05 95  93 B  801.3 .sup.g) 3.72 82  94 A  810.0 .sup.g) 3.96 91  95 A  796.4 .sup.g) 3.78 88  96 .sup.d) A  810.2 .sup.g) 3.67 95  97 A  791.8 .sup.g) 3.62 82  98 A  805.4 .sup.g) 3.57 88  99 A  796.3 .sup.g) 3.83 90 100 A  800.4 .sup.g) 3.68 93 101 A  801.0 .sup.g) 3.82 73 102 A  801.0 .sup.g) 3.79 88 103 A  787.0 .sup.g) 3.77 82 104 A  796.4 .sup.g) 3.88 84 105 .sup.d) A  815.2 .sup.g) 3.85 95 106 .sup.d) B  791.8 .sup.g) 3.57 95 107 .sup.d) B  791.8 .sup.g) 3.59 95 108 .sup.d) A  791.8 .sup.g) 3.90 95 109 .sup.d) A  782.4 .sup.g) 3.60 95 110 .sup.d) A  797.2 .sup.g) 3.79 95 111 .sup.d) A  791.5 .sup.g) 3.82 95 112 .sup.d) A  791.8 .sup.g) 3.91 95 113 .sup.d) A  814.4 .sup.g) 3.55 95 114 .sup.d) A  805.0 .sup.g) 3.76 95 115 .sup.d) A  786.7 .sup.g) 3.68 95 116 .sup.d) A  796.0 .sup.g) 3.71 95 117 .sup.d) A  800.7 .sup.g) 3.78 95 119 A  805.0 .sup.g) 3.91 87 120 A  804.7 .sup.g) 3.72 81 121 A  805.2 .sup.g) 3.97 81 122 A  814.7 .sup.g) 4.51 78 123 A  800.8 .sup.g) 3.92 87 124 A  800.7 .sup.g) 3.91 75 125 A  805.2 .sup.g) 3.69 82 126 A  809.0 .sup.g) 3.62 79 127 A  738.3 .sup.g) 4.25 85 128 .sup.d) A  805.2 .sup.g) 3.74 95 129 .sup.d) E  814.9 .sup.g) 6.50 95 130 .sup.d) E 1193.2 .sup.f) 6.01 95 131 .sup.d) E  819.3 .sup.g) 6.28 95 132 .sup.d) A  800.8 .sup.g) 3.90 95 133 .sup.d) A  805.2 .sup.g) 3.87 95 134 .sup.d) A  829.0 .sup.g) 3.71 95 135 .sup.d) A  823.8 .sup.g) 3.72 95 136 .sup.d) A  795.8 .sup.g) 3.41 95 137 .sup.d) B  790.8 .sup.g) 3.03 95 138 .sup.d) D  814.9 .sup.g) 3.55 94 139 .sup.d) A  805.5 .sup.g) 3.41 95 140 .sup.d) D  805.5 .sup.g) 3.25 95 141 .sup.d) A  805.2 .sup.g) 3.68 95 142 .sup.d) A  805.2 .sup.g) 3.75 95 143 .sup.d) A  800.3 .sup.g) 3.57 94 144 .sup.d) A  809.8 .sup.g) 3.89 95 145 .sup.d) A  809.8 .sup.g) 3.86 95 146 A  802.8 .sup.g) 3.70 89 147 A 1196.8 .sup.f) 3.56 84 148 A  798.2 .sup.g) 3.74 88 149 A  793.3 .sup.g) 3.63 82 150 .sup.d) A  814.4 .sup.g) 3.66 95 151 .sup.d) A  823.9 .sup.g) 3.64 95 152 .sup.d) A  819.3 .sup.g) 3.67 95 153 .sup.d) A  818.8 .sup.g) 3.63 95 154 .sup.d) A  819.2 .sup.g) 3.72 94 155 B  819.2 .sup.g) 3.38 80 156 A  823.9 .sup.g) 3.74 82 157 B  805.5 .sup.g) 3.40 76 158 A  828.5 .sup.g) 3.67 89 159 A  833.2 .sup.g) 3.75 90 160 A  604.4 .sup.h) 3.98 87 161 B  604.3 .sup.h) 3.64 90 162 A  597.5 .sup.h) 3.97 88 163 A  796.4 .sup.g) 3.88 82 164 A  747.3 .sup.g) 4.37 88 165 A  746.9 .sup.g) 4.24 91 166 A  604.0 .sup.h) 3.79 90 167 A  593.3 .sup.h) 3.88 91 168 A  589.8 .sup.h) 4.04 89 169 A  604.2 .sup.h) 3.86 85 170 A  593.2 .sup.h) 3.92 87 171 A  786.3 .sup.g) 4.01 83 172 A  597.3 .sup.h) 3.76 91 173 A  781.8 .sup.g) 3.86 82 174 A  776.9 .sup.g) 3.97 79 175 A  815.3 .sup.g) 3.82 89 176 C  601.3 .sup.h) 2.71 84 177 C  604.5 .sup.h) 2.74 82 178 C  809.4 .sup.g) 2.88 95 179 C  804.4 .sup.g) 2.82 95 180 A  795.0 .sup.g) 3.54 79 181 A  804.4 .sup.g) 3.51 82 182 C  795.4 .sup.g) 2.68 94 183 A  795.4 .sup.g) 3.49 76 184 C  593.2 .sup.h) 2.62 82 185 A  800.0 .sup.g) 3.59 76 186 C  795.7 .sup.g) 2.74 92 187 A  802.3 .sup.g) 3.74 85 188 .sup.d) B  796.3 .sup.g) 3.63 95 189 A  824.4 .sup.g) 3.64 89 190 A  611.5 .sup.h) 3.64 94 191 .sup.d) A  815.0 .sup.g) 3.76 95 192 B  614.9 .sup.h) 3.41 81 193 B  796.0 .sup.g) 3.68 75 194 A  805.4 .sup.g) 4.00 88 195 A 1208.8 .sup.f) 4.05 84 196 A  805.2 .sup.g) 3.81 82 197 B  782.0 .sup.g) 3.60 78 198 A  791.4 .sup.g) 3.98 90 199 .sup.d) B  791.3 .sup.g) 3.66 95 200 .sup.d) B  791.4 .sup.g) 3.65 95 201 .sup.d) A  781.2 .sup.g) 3.89 95 202 .sup.d) B  790.8 .sup.g) 3.90 95 203 .sup.d) A  795.8 .sup.g) 3.95 95 204 .sup.d) A  811.2 .sup.g) 3.96 94 205 A  799.4 .sup.g) 3.58 82 206 A  813.7 .sup.g) 4.00 80 207 A  804.2 .sup.g) 4.03 81 208 A  808.4 .sup.g) 4.29 91 209 A  796.0 .sup.g) 4.13 74 210 A  796.4 .sup.g) 4.07 80 211 B  597.0 .sup.h) 3.64 76 212 A  781.7 .sup.g) 4.03 82 213 B  582.8 .sup.h) 3.75 74 214 A  582.9 .sup.h) 4.02 71 215 .sup.d) A  804.8 .sup.g) 3.76 95 216 A  737.7 .sup.g) 4.54 83 217 A  737.5 .sup.g) 4.40 83 218 A  610.7 .sup.h) 3.51 74 219 .sup.d) E  800.3 .sup.g) 6.60 95 220 .sup.d) E 1206.7 .sup.f) 6.75 95 221 .sup.d) A  824.2 .sup.g) 3.91 95 222 .sup.d) A  819.4 .sup.g) 3.76 95 223 .sup.d) A  824.8 .sup.g) 3.95 95 224 .sup.d) A  819.8 .sup.g) 3.49 95 225 .sup.d) A  843.0 .sup.g) 3.64 95 226 .sup.d) A  824.8 .sup.g) 3.78 95 227 .sup.d) E  814.5 .sup.g) 6.52 95 228 A  828.2 .sup.g) 3.97 92 229 A  808.8 .sup.g) 3.57 73 230 A  813.0 .sup.g) 3.73 76 232 A  828.4 .sup.g) 3.82 90 233 A  621.5 .sup.h) 3.87 81 234 A  857.1 .sup.g) 4.31 83 235 A  853.7 .sup.g) 4.09 82 236 A  810.4 .sup.g) 4.05 88 237 A  833.4 .sup.g) 3.62 78 238 A  837.4 .sup.g) 3.94 82 239 A  846.4 .sup.g) 4.01 73 240 A  851.8 .sup.g) 3.84 80 241 A  640.4 .sup.h) 3.59 72 242 C  644.3 .sup.h) 2.65 90 243 .sup.d) A  881.6 .sup.g) 3.62 95 244 A  857.8 .sup.g) 3.91 83 245 A  839.0 .sup.g) 4.04 74 246 A  875.4 .sup.g) 3.78 88 247 A  870.6 .sup.g) 3.45 73 248 A  870.6 .sup.g) 3.46 74 249 A  875.4 .sup.g) 3.81 92 250 .sup.d) A  862.2 .sup.g) 4.16 95 251 .sup.d) A  800.2 .sup.g) 3.78 95 252 .sup.d) B  809.8 .sup.g) 3.60 95 253 .sup.d) A  805.0 .sup.g) 3.93 95 254 .sup.d) A  795.5 .sup.g) 3.58 95 255 .sup.d) B  800.2 .sup.g) 3.36 95 256 .sup.d) A  800.4 .sup.g) 3.65 95 257 .sup.d) A  795.7 .sup.g) 3.66 95 258 .sup.d) B  800.2 .sup.g) 3.42 95 259 .sup.d) B  805.0 .sup.g) 3.64 95 260 .sup.d) A  791.4 .sup.g) 3.66 95 261 .sup.d) A  801.0 .sup.g) 3.48 95 262 .sup.d) A  805.4 .sup.g) 3.49 95 263 .sup.d) A  810.4 .sup.g) 3.58 95 264 .sup.e) A  800.2 .sup.g) 3.82 94 265 .sup.e) B  802.8 .sup.g) 3.49 90 266 .sup.d) B  814.5 .sup.g) 3.17 95 267 .sup.e) A  804.9 .sup.g) 3.84 97 268 .sup.e) A  814.3 .sup.g) 3.75 97 269 .sup.e) B  795.5 .sup.g) 3.44 96 270 .sup.e) A  786.4 .sup.g) 3.72 97 271 .sup.e) B  791.3 .sup.g) 3.48 98 272 .sup.e) A  805 .sup.g) 3.76 96 273 .sup.e) A  797.9 .sup.g) 3.70 98 274 .sup.e) A  772.5 .sup.g) 3.35 96 275 .sup.e) H  790.3 .sup.g) 6.69 96 276 .sup.e) B  795.7 .sup.g) 3.54 97 277 .sup.e) B  782.2 .sup.g) 3.52 95 278 .sup.e) A  800.4 .sup.g) 3.79 96 279 .sup.e) B  793.5 .sup.g) 3.40 92 280 .sup.e) I  800.5 .sup.g) 6.08 92 281 .sup.e) H  790.7 .sup.g) 6.57 96 282 .sup.e) A  800.5 .sup.g) 3.78 89 283 .sup.e) A  791.9 .sup.g) 3.36 93 284 .sup.e) A  796.7 .sup.g) 3.39 86 285 .sup.e) G  793.7 .sup.g) 3.38 98 286 .sup.e) A  798.3 .sup.g) 3.49 96 287 .sup.e) G  798.3 .sup.g) 3.25 98 288 .sup.e) G  798.3 .sup.g) 3.36 99 289 .sup.e) G  785.8 .sup.g) 3.51 98 290 .sup.e) G  783.7 .sup.g) 3.38 96 291 .sup.e) G  788.3 .sup.g) 3.36 99 292 .sup.e) G  783.5 .sup.g) 3.40 99 293 .sup.e) G  788.3 .sup.g) 3.29 98 294 .sup.d) A  795.5 .sup.g) 3.41 97 295 .sup.e) 1  597.2 .sup.g) 6.08 97 296 .sup.e) H  800.5 .sup.g) 6.29 96 297 .sup.e) 1  800.5 .sup.g) 5.91 97 298 .sup.d) A  785.5 .sup.g) 3.48 98 299 .sup.e) H  785.7 .sup.g) 6.61 96 300 .sup.e) A  795.3 .sup.g) 3.24 96 301 .sup.e) G  796 .sup.g) 3.40 97 302 .sup.e) G  802.9 .sup.g) 3.24 95 303 .sup.e) A  807.5 .sup.g) 3.66 99 304 .sup.e) G  789 .sup.g) 3.17 93 305 .sup.e) A  800.3 .sup.g) 3.87 96 306 .sup.e) A  805.3 .sup.g) 3.62 95 307 .sup.e) A  785.7 .sup.g) 3.66 95 308 .sup.e) G  800.7 .sup.g) 3.26 95 309 .sup.e) G  805.3 .sup.g) 3.31 98 310 .sup.e) A  800.5 .sup.g) 3.68 97 311 .sup.e) G  805 .sup.g) 3.30 95 312 G  795.5 .sup.g) 3.07 90 313 G  795.7 .sup.g) 3.13 90 314 A  804.9 .sup.g) 3.84 98 315 .sup.e) A  805 .sup.g) 3.76 95 316 .sup.d) A  805 .sup.g) 3.84 97 317 .sup.e) A  800.4 .sup.g) 3.67 94 318 .sup.e) A  795.9 .sup.g) 3.65 93 319 .sup.e) A  802.8 .sup.g) 3.62 95 320 .sup.e) G  798.3 .sup.g) 3.15 95 321 .sup.e) A  807.5 .sup.g) 3.41 94 322 .sup.e) A  802.8 .sup.g) 3.59 95 323 .sup.e) A  802.9 .sup.g) 3.67 97 324 .sup.e) A  807.3 .sup.g) 3.54 96 325 .sup.e) G  802.9 .sup.g) 3.32 95 326 .sup.e) A  807.4 .sup.g) 3.59 96 327 .sup.e) A  807.5 .sup.g) 3.59 97 328 .sup.e) A  812.8 .sup.g) 3.65 95 329 .sup.e) A  816.8 .sup.g) 3.53 95 330 A  809.3 .sup.g) 3.74 98 331 .sup.e) H  796.7 .sup.g) 5.64 96 332 .sup.e) 1  795.9 .sup.g) 5.43 94 333 .sup.e) H  801.3 .sup.g) 5.60 92 334 .sup.e) H  805.3 .sup.g) 6.32 96 335 .sup.e) H  790.5 .sup.g) 6.60 97 336 .sup.e) 1  809.5 .sup.g) 5.80 95 337 .sup.e) 1  786.4 .sup.g) 6.36 96 338 .sup.e) H  795.9 .sup.g) 6.06 95 339 .sup.e) H  786.5 .sup.g) 5.68 97 340 .sup.e) G  795.9 .sup.g) 3.38 99 341 .sup.e) G  797.9 .sup.g) 3.16 99 342 .sup.e) A  800.5 .sup.g) 3.57 97 343 .sup.e) A  800.8 .sup.g) 3.21 92 344 .sup.e) A  786.5 .sup.g) 3.69 98 345 .sup.e) 1  790.7 .sup.g) 6.30 96 346 .sup.e) G  783.3 .sup.g) 3.24 95 347 .sup.e) G  774.4 .sup.g) 3.14 95 348 .sup.e) A  792.9 .sup.g) 3.76 95 349 .sup.e) G  792.9 .sup.g) 2.75 96 350 .sup.e) H  790.7 .sup.g) 6.53 96 351 .sup.e) G  788 .sup.g) 3.25 97 352 A  823.2 .sup.g) 3.77 97 353 A  813.7 .sup.g) 3.72 96 354 .sup.e) G  804.9 .sup.g) 3.34 98 355 .sup.e) G  809.7 .sup.g) 3.36 96 356 .sup.e) A  800.5 .sup.g) 3.74 96 357 .sup.e) G  785.9 .sup.g) 3.59 97 358 .sup.e) G  812.9 .sup.g) 3.37 96 359 .sup.e) 1  809.5 .sup.g) 5.94 97 360 .sup.e) G  790.5 .sup.g) 3.41 97 361 .sup.e) A  794.9 .sup.g) 3.91 96 362 .sup.e) G  804.5 .sup.g) 3.79 96 363 .sup.e) A  799.7 .sup.g) 4.01 96 364 .sup.e) G  805 .sup.g) 3.42 96 365 .sup.e) G  816.9 .sup.g) 3.30 98 366 .sup.e) G  804.9 .sup.g) 3.30 98 367 .sup.e) B  823.9 .sup.g) 3.39 98 368 .sup.e) A  828.8 .sup.g) 3.79 97 369 .sup.e) A  819.3 .sup.g) 3.58 96 370 .sup.e) F  824 .sup.g) 3.17 94 371 .sup.e) B  838.9 .sup.g) 3.46 96 372 .sup.e) B  829.5 .sup.g) 3.39 94 373 .sup.e) B  838.4 .sup.g) 3.40 97 374 .sup.e) A  838.9 .sup.g) 3.61 91 375 .sup.e) A  829.3 .sup.g) 3.59 97 376 .sup.e) A  801.2 .sup.g) 3.52 93 377 .sup.e) A  819.5 .sup.g) 3.65 98 378 .sup.e) A  823.9 .sup.g) 3.66 95 379 .sup.e) A  810.3 .sup.g) 3.69 94 380 .sup.e) A  824.9 .sup.g) 3.45 94 381.sup.e) A  806.5 .sup.g) 3.33 95 382 .sup.e) A  795.9 .sup.g) 3.65 95 383 .sup.e) H  643.4 .sup.g) 6.95 92 384 .sup.e) G  771.5 .sup.g) 3.45 97 385 .sup.e) A  824.5 .sup.g) 3.91 95 .sup.a) Analytical method .sup.b) Retention time in [min] .sup.c) Purity in [%] .sup.d) Acetate salt .sup.e) Chloride salt .sup.f) MS: m/z for [M + 2H].sup.2+ .sup.g) MS: m/z for [M + 3H].sup.3+ .sup.h) MS: m/z for [M + 4H].sup.4+

(1213) 2. Biological Methods

(1214) 2.1 Preparation of the Peptides

(1215) Lyophilized peptides were weighed on a Microbalance (Mettler MT5) and dissolved in sterile water to a final concentration of 1 mg/mL. Stock solutions were kept at +4° C., light protected.

(1216) 2.2 Antimicrobial Activity of the Peptides

(1217) The in vitro antimicrobial activities of the peptides were determined in 96-well plates (Greiner, polystyrene) by the standard CLSI broth microdilution method (Clinical and Laboratory Standards Institute 2014. Performance standards for antimicrobial susceptibility testing, 24th informational supplement. Approved standard CLSI M100-S24; Clinical and Laboratory Standards Institute, Wayne, Pa.). The following microorganisms were used to determine antibiotic activity of the peptides: Escherichia coli ATCC 25922, Klebsiella pneumoniae SSI #3010.sup.a), Acinetobacter baumannii DSM 30008, Pseudomonas aeruginosa ATCC 27853 and the clinical isolates Escherichia coli 926415.sup.b), Klebsiella pneumoniae 968733.sup.b), Acinetobacter baumannii 872842.sup.b), Enterobacter cloacae 848840.sup.b) and Escherichia coli MCR-1 Af45.sup.c). Before preparation of inocula, Escherichia coli MCR-1 Af45 was subcultured on Mueller-Hinton II (MH-cation adjusted) agar containing 2 μg/mL colistin. .sup.a) Obtained from Statens Serum Institut (SSI), Copenhagen, Denmark.sup.b) Obtained from International Health Management Associates, Inc. (IHMA Europe Sàrl), Epalinges, Switzerland.sup.c) Obtained from Prof. Patrice Nordmann, University of Fribourg, Fribourg, Switzerland

(1218) Inocula of the microorganisms were diluted into Mueller-Hinton II (MH-cation adjusted) broth and compared with a 0.5 McFarland standard to give appr. 10.sup.6 colony forming units (CFU)/mL. Aliquots (90 μL) of inoculum were added to 10 μL of MH-II broth+P-80 (Polysorbate 80, 0.002% final concentration, v/v) containing the peptide in serial two-fold dilutions. Antimicrobial activities of the peptides were expressed as the minimal inhibitory concentration (MIC) in μg/mL at which no visible growth was observed after 18-20 hours of incubation at 35° C.

(1219) 2.3 Hemolysis

(1220) The peptides were tested for their hemolytic activity against human red blood cells (hRBC). Fresh hRBC were washed four times with phosphate buffered saline (PBS) and centrifuged for 10 min at 3000×g. Compounds (200 μg/mL) were incubated with 20% hRBC (v/v) for 1 h at 37° C. and shaking at 300 rpm. A value of 0% and 100% cell lysis, respectively, was determined by incubation of hRBC in the presence of PBS containing 10% water and 2% Triton X-100 in H.sub.2O, respectively. The samples were centrifuged, the supernatants were ˜7.5-fold diluted in PBS buffer and the optical densities (OD) were measured at 540 nm and blank corrected. The 100% lysis value (OD.sub.540Triton X-100) gave an OD.sub.540 of approximately 0.5-1.0.

(1221) Percent hemolysis was calculated as follows: (OD.sub.540peptide/OD.sub.540Triton X-100)×100%.

(1222) 2.4 Tolerability in a Mouse Model

(1223) The tolerability of the peptides was tested in a mouse model at Pharmacology Discovery Services Taiwan Ltd, Taipei, Taiwan. The peptides were administered subcutaneously (s.c.) at 30 mg/kg or 40 mg/kg, respectively; twice at a 12-hr interval, for assessment of possible adverse effects in the Maximum Tolerated Dose (MTD) assay in male ICR (Institute of Cancer Research) mice. The peptides were dissolved in 0.9% NaCl at the concentrations either of 6 or 8 mg/mL, respectively, based on the free base molecular weight. The pH values of dosing solutions were adjusted to 6.5-7.6 before s.c. administration. A dosing volume at 5 mL/kg and a concentration of 6 or 8 mg/mL, respectively, was applied. The fresh prepared stock solution were stored at 4° C. during the study. Male ICR mice weighing 23±3 g were provided by BioLasco Taiwan (under Charles River Laboratories Licensee). Animals were acclimated for 3 days prior to use and were confirmed to be in good health. The peptides were administered s.c. at 30 mg/kg or 40 mg/kg, respectively, twice at a 12-hr interval, to groups of 3 ICR male mice and observed for the presence of acute toxic symptoms (mortality, convulsions, tremors, muscle relaxation, sedation, etc.) and autonomic effects (diarrhea, salivation, lacrimation, vasodilation, piloerection, etc.) during the first 30 min. The peptides were administered again at a 12-hr (two total doses) interval, following the first dose. The animals were then observed again for the presence of acute toxic symptoms and autonomic effects during the first 30 min. Mortality was observed at 0.5 and 12 hr following the first dose and again at 0.5, 1, 3, 24, 48, and 72 hr after the second dose of test articles.

(1224) 2.5 Nephrotoxicity in a Mouse Model

(1225) The nephrotoxicity of the peptides was tested in a mouse model at Fidelta Ltd, Zagreb, Croatia. Colistin B (polymyxin E2, acetate salt, individually synthesized, 95% purity) was provided by Polyphor Ltd (Allschwil, Switzerland). The purpose of the study was to evaluate the toxic potential of the peptides in male CD1 mice after 1 day of subcutaneous dosing (72 mg/kg/day), divided into 6 administrations (12 mg/kg). Stock solutions of the peptides were prepared in saline (7.2 mg/ml), pH adjusted if required to pH 6.5-7.6 before s.c. administration. The peptides were administered to the animals subcutaneously 6 times a day (every 2 hours). The study involved 7 groups of 5 males in control and dose groups. After 24 h from start of the first dosing the animals were euthanized (isoflurane anesthesia-Abbott, Netherlands and exsanguination). All animals were subjected to gross necropsy as rapidly as possible and their main tissues examined macroscopically. The kidneys were fixed in an appropriate fixative and preserved in 10% buffered formaldehyde for histopathological examination. After dehydration and embedding in paraffin wax, sections of the tissues were cut at 5 micrometer thickness and stained with haematoxylin and eosin.

(1226) Semi-quantitative scoring of the kidneys was performed according to the following method:

(1227) Lesions were rated as follows: mild acute tubular damage with tubular dilation, prominent nuclei and a few pale tubular casts (Grade 1); severe acute tubular damage with necrosis of tubular epithelial cells and numerous tubular casts (Grade 2); necrosis/infarction of tubules and glomeruli with or without papillary necrosis (Grade 3). The grades were given the following scores: grade 1=1, grade 2=4 and grade 3=10. Moreover, the percentages of kidney slides affected were scored as follows:

(1228) <1%=0; 1 to 5%=1; 5 to <10%=2; 10 to <20%=3; 20 to <30%=4; 30 to <40%=5; and >40%=6.

(1229) Subsequently, the overall kidney histology score was calculated as the product of percentage score and grade score. These scores were then expressed as a semi-quantitative score (SQS) on a scale of 0 to +5 for renal histological changes. These scores were assigned as follows: SQS 0=no significant change (overall score, <1) SQS +1=mild damage (overall score, 1 to <15) SQS +2=mild to moderate damage (overall score, 15 to <30) SQS +3=moderate damage (overall score, 30 to <45) SQS +4=moderate to severe damage (overall score, 45 to <60) SQS +5=severe damage (overall score, >60)

(1230) (Yousef, J., Chen, G., Hill, P., Nation, R., Li, J., Antimicrobial Agents And Chemotherapy [P], 2011, Vol 55, issue 9, American Society for Microbiology, USA, pp. 4044-4049).

(1231) The results of the experiments described in 2.2-2.5 are indicated in Tables 3, 4, 5, 6 and 7 herein below.

(1232) TABLE-US-00004 TABLE 3 Minimal inhibitory concentrations (MIC) in Mueller-Hinton II broth and Hemolysis Klebsiella Acinetobacter Pseudomonas Escherichia coli pneumoniae baumannii aeruginosa ATCC 25922 SSI #3010 DSM 30008 ATCC 27853 MIC MIC MIC MIC Hemolysis at Ex. [μg/mL] [μg/mL] [μg/mL] [μg/mL] 200 μg/mL [%] 1 0.125 0.5 0.125 0.125 <1 2 0.125 0.5 0.125 0.25 <1 3 0.125 0.125 0.0625 0.125 <1 4 0.125 0.125 0.0625 0.125 1 5 0.0625 0.125 0.0625 0.125 <1 6 0.125 0.25 0.125 0.125 2 7 0.125 0.125 0.0625 0.125 <1 8 0.0625 0.125 0.125 0.125 <1 9 0.125 0.125 0.125 0.125 <1 10 0.25 0.25 0.125 0.125 <1 11 0.125 0.125 0.125 0.25 1 12 0.0625 0.25 0.125 0.125 2 13 0.125 0.125 0.125 0.125 <1 14 0.25 0.5 0.5 0.25 <1 15 0.0625 0.125 0.125 0.25 <1 16 0.0625 0.0625 0.0625 0.25 <1 17 0.0625 0.125 0.0625 0.25 <1 18 0.0625 0.125 0.0625 0.25 1 19 0.125 0.125 0.125 0.25 <1 20 0.125 0.125 0.125 0.25 <1 21 0.25 0.5 0.5 0.5 <1 22 0.0625 0.125 0.0625 0.5 <1 23 0.0625 0.125 0.0625 0.25 <1 24 0.125 0.125 0.125 0.25 <1 25 0.0625 0.125 0.0625 0.25 <1 26 0.0625 0.125 0.03125 0.25 1 27 0.0625 0.25 0.0625 0.5 <1 28 0.125 0.125 0.125 0.25 <1 29 0.0625 0.125 0.125 0.25 1 30 0.0625 0.125 0.125 0.25 <1 31 0.03125 0.0625 0.03125 0.25 <1 32 0.0625 0.125 0.0625 0.25 <1 33 0.0625 0.125 0.0625 0.25 <1 34 0.0625 0.125 0.03125 0.25 <1 35 0.125 0.25 0.125 0.25 <1 36 0.0625 0.125 0.0625 0.25 <1 37 0.25 0.25 0.125 0.5 1 38 0.0625 0.125 0.125 0.25 n.d. 39 0.0625 0.0625 0.0625 0.125 <1 40 0.125 0.5 1 0.25 2 41 0.0625 0.125 0.0625 0.25 <1 42 0.125 0.25 0.5 0.25 <1 43 0.25 0.25 0.5 0.5 <1 44 0.0625 0.125 0.125 0.125 <1 45 0.0625 0.125 0.0625 0.125 <1 46 0.0625 0.125 0.0625 0.125 2 47 0.0625 0.125 0.125 0.125 <1 48 0.25 0.25 0.25 0.125 <1 49 0.125 0.125 0.0625 0.125 <1 50 0.125 0.125 0.25 0.25 <1 51 0.25 0.125 0.5 0.125 <1 52 0.25 0.25 1 0.25 <1 53 0.125 0.125 0.25 0.125 <1 54 0.0625 0.25 0.25 0.25 <1 55 0.25 0.5 0.5 0.25 2 56 0.5 1 1 0.5 <1 57 0.125 0.25 0.125 0.25 3 58 0.0625 0.125 0.0625 0.25 1 59 0.125 0.125 0.125 0.125 <1 60 0.0625 0.125 0.0625 0.125 <1 61 0.125 0.0625 0.0625 0.125 3 62 0.125 0.0625 0.0625 0.125 <1 63 0.125 0.125 0.125 0.125 <1 64 0.125 0.125 0.0625 0.125 <1 65 0.125 0.25 0.125 0.125 <1 66 0.0625 0.125 0.25 0.25 <1 67 0.125 0.5 0.25 0.25 <1 68 0.25 0.125 0.25 0.5 <1 69 0.0625 0.0625 0.0625 0.125 2 70 0.125 0.125 0.0625 0.125 <1 71 0.0625 0.125 0.0625 0.125 1 72 0.0625 0.125 0.0625 0.125 <1 73 0.0625 0.125 0.0625 0.25 <1 74 0.0625 0.0625 0.0625 0.25 <1 75 0.0625 0.125 0.0625 0.125 <1 76 0.0625 0.125 0.0625 0.25 1 77 0.125 0.125 0.125 0.125 <1 78 0.03125 0.25 0.0625 0.125 <1 79 0.0625 0.0625 0.03125 0.125 <1 80 0.03125 0.125 0.125 0.125 <1 81 0.0625 0.0625 0.125 0.125 <1 82 0.0625 0.0625 0.125 0.25 <1 83 0.0625 0.0625 0.0625 0.125 <1 84 0.0625 0.125 0.125 0.25 <1 85 0.0625 0.125 0.25 0.25 1 86 0.125 0.125 0.0625 0.125 <1 87 0.0625 0.125 0.0625 0.125 <1 88 0.0625 0.125 0.03125 0.125 <1 89 0.125 0.125 0.0625 0.25 <1 90 0.0625 0.125 0.125 0.25 <1 91 0.0625 0.25 0.125 0.25 <1 92 0.0625 0.0625 0.125 0.125 <1 93 0.125 0.125 0.25 0.25 <1 94 0.0625 0.0625 0.125 0.25 <1 95 0.03125 0.125 0.0625 0.125 <1 96 0.0625 0.125 0.125 0.125 <1 97 0.25 0.125 0.25 0.25 <1 98 0.125 0.25 0.25 0.25 <1 99 0.0625 0.125 0.0625 0.125 1 100 0.03125 0.125 0.0625 0.125 <1 101 0.0625 0.125 0.0625 0.125 <1 102 0.0625 0.25 0.0625 0.25 <1 103 0.0625 0.125 0.0625 0.125 1 104 0.0625 0.125 0.125 0.25 1 105 0.0625 0.0625 0.03125 0.125 <1 106 0.0625 0.125 0.0625 0.125 <1 107 0.0625 0.125 0.0625 0.125 <1 108 0.0625 0.0625 0.03125 0.125 2 109 0.03125 0.0625 0.03125 0.125 <1 110 0.0625 0.0625 0.0625 0.125 2 111 0.125 0.125 0.03125 0.25 <1 112 0.0625 0.0625 0.0625 0.125 <1 113 0.0625 0.0625 0.125 0.125 <1 114 0.03125 0.0625 0.0625 0.125 <1 115 0.0625 0.0625 0.0625 0.125 <1 116 0.03125 0.03125 0.03125 0.125 <1 117 0.0625 0.0625 0.015625 0.125 2 119 0.0625 0.0625 0.0625 0.125 <1 120 0.125 0.0625 0.0625 0.125 1 121 0.0625 0.125 0.0625 0.125 <1 122 0.25 0.5 0.25 0.5 1 123 0.015625 0.0625 0.015625 0.0625 <1 124 0.0625 0.125 0.0625 0.125 2 125 0.0625 0.0625 0.125 0.125 2 126 0.125 0.125 0.125 0.25 <1 127 0.0625 0.25 0.0625 0.5 2 128 0.03125 0.0625 0.03125 0.125 <1 129 0.03125 0.0625 0.0625 0.25 <1 130 0.03125 0.0625 0.015625 0.125 1 131 0.0625 0.125 0.25 0.25 <1 132 0.03125 0.125 0.03125 0.125 2 133 0.03125 0.125 0.0625 0.25 2 134 0.03125 0.03125 0.03125 0.125 3 135 0.03125 0.0625 0.03125 0.125 <1 136 0.03125 0.0625 0.03125 0.25 3 137 0.03125 0.0625 0.0625 0.125 1 138 0.03125 0.03125 0.03125 0.125 <1 139 0.0625 0.0625 0.0625 0.25 2 140 0.125 0.125 0.125 0.25 <1 141 0.03125 0.03125 0.03125 0.125 2 142 0.0625 0.03125 0.03125 0.125 <1 143 0.03125 0.0625 0.0625 0.125 2 144 0.03125 0.0625 0.0625 0.125 <1 145 0.0625 0.125 0.0625 0.125 2 146 0.0625 0.0625 0.0625 0.125 <1 147 0.0625 0.0625 0.0625 0.125 <1 148 0.03125 0.0625 0.03125 0.125 <1 149 0.0625 0.125 0.0625 0.125 <1 150 0.03125 0.125 0.0625 0.125 <1 151 0.03125 0.0625 0.0625 0.125 <1 152 0.125 0.25 0.125 0.25 <1 153 0.0625 0.0625 0.03125 0.125 <1 154 0.03125 0.0625 0.015625 0.125 <1 155 0.0625 0.125 0.0625 0.125 1 156 0.03125 0.125 0.0625 0.125 <1 157 0.0625 0.125 0.125 0.25 <1 158 0.0625 0.125 0.0625 0.25 <1 159 0.0625 0.125 0.0625 0.125 <1 160 0.125 0.25 0.125 0.25 <1 161 0.125 0.125 0.125 0.25 1 162 0.125 0.5 0.25 0.25 <1 163 0.125 0.25 0.125 0.25 1 164 0.5 0.5 0.5 1 <1 165 0.25 0.25 1 0.5 <1 166 0.125 0.125 0.0625 0.25 <1 167 0.0625 0.125 0.0625 0.25 <1 168 0.0625 0.125 0.125 0.25 <1 169 0.25 0.5 0.25 0.25 <1 170 0.125 0.5 0.25 0.5 <1 171 0.125 0.125 0.0625 0.25 <1 172 0.125 0.125 0.125 0.25 <1 173 0.125 0.125 0.0625 0.5 <1 174 0.0625 0.0625 0.0625 0.125 <1 175 0.0625 0.125 0.125 0.125 1 176 0.0625 0.125 0.125 0.125 <1 177 0.0625 0.25 0.0625 0.125 <1 178 0.125 0.125 0.0625 0.125 <1 179 0.125 0.25 0.0625 0.25 <1 180 0.125 0.5 0.25 0.125 <1 181 0.25 0.5 0.25 0.5 <1 182 0.03125 0.125 0.0625 0.125 <1 183 0.125 0.25 0.25 0.125 <1 184 0.125 0.25 0.125 0.25 <1 185 0.125 0.125 0.125 0.125 <1 186 0.125 0.125 0.0625 0.125 <1 187 0.125 0.25 0.5 0.5 <1 188 0.0625 0.25 0.125 0.5 <1 189 0.125 0.125 0.125 0.25 <1 190 0.0625 0.125 0.0625 0.25 <1 191 0.125 0.25 0.125 0.25 1 192 0.25 0.5 0.5 0.5 <1 193 0.125 0.25 0.0625 0.25 <1 194 0.0625 0.0625 0.0625 0.125 <1 195 0.0625 0.125 0.0625 0.125 <1 196 0.25 0.25 0.125 0.25 <1 197 0.0625 0.125 0.0625 0.125 <1 198 0.0625 0.125 0.0625 0.25 <1 199 0.125 0.125 0.0625 0.25 <1 200 0.125 0.5 0.25 0.25 <1 201 0.0625 0.125 0.125 0.125 <1 202 0.125 0.125 0.125 0.125 <1 203 0.0625 0.125 0.0625 0.25 <1 204 0.0625 0.125 0.0625 0.125 1 205 0.25 0.25 0.25 0.25 <1 206 0.03125 0.0625 0.0625 0.125 1 207 0.125 0.125 0.0625 0.125 1 208 0.125 0.125 0.125 0.125 2 209 0.125 0.25 0.25 0.5 <1 210 0.125 0.25 0.25 0.25 <1 211 0.0625 0.0625 0.03125 0.125 <1 212 0.0625 0.25 0.125 0.25 1 213 0.125 0.125 0.0625 0.25 <1 214 0.0625 0.25 0.125 0.5 <1 215 0.125 0.25 0.125 0.25 3 216 0.5 1 1 2 <1 217 0.25 0.5 2 2 <1 218 0.125 0.125 0.125 0.125 <1 219 0.03125 0.0625 0.03125 0.125 <1 220 0.03125 0.0625 0.03125 0.125 <1 221 0.0625 0.125 0.0625 0.125 2 222 0.03125 0.0625 0.0625 0.125 1 223 0.03125 0.0625 0.03125 0.125 <1 224 0.03125 0.125 0.0625 0.125 1 225 0.0625 0.0625 0.125 0.125 <1 226 0.03125 0.125 0.03125 0.125 1 227 0.03125 0.125 0.03125 0.125 <1 228 0.5 0.25 1 0.25 <1 229 0.125 0.125 0.5 0.5 2 230 0.25 0.5 1 1 <1 232 0.0625 0.125 0.0625 0.125 <1 233 0.03125 0.0625 0.0625 0.125 <1 234 0.125 0.25 0.25 0.5 9 235 0.0625 0.25 0.0625 0.25 4 236 0.25 0.25 0.25 0.25 <1 237 0.0625 0.0625 0.03125 0.125 <1 238 0.0625 0.125 0.03125 0.125 2 239 0.125 0.125 0.0625 0.25 1 240 0.0625 0.125 0.03125 0.25 1 241 0.125 0.125 0.125 0.25 <1 242 0.0625 0.125 0.125 0.125 <1 243 0.0625 0.0625 0.0625 0.25 <1 244 0.03125 0.0625 0.03125 0.25 1 245 0.0625 0.125 0.03125 0.25 1 246 0.25 0.25 0.5 0.25 <1 247 0.125 0.25 0.125 0.25 <1 248 0.125 0.125 0.5 0.25 <1 249 0.03125 0.0625 0.03125 0.125 2 250 0.03125 0.0625 0.03125 0.125 1 251 0.03125 0.03125 0.015625 0.0625 1 252 0.0625 0.03125 0.0625 0.0625 2 253 0.03125 0.0625 0.03125 0.0625 2 254 0.03125 0.03125 0.03125 0.0625 1 255 0.0625 0.03125 0.03125 0.0625 1 256 0.03125 0.03125 0.03125 0.0625 1 257 0.03125 0.03125 0.03125 0.0625 1 258 0.0625 0.03125 0.03125 0.0625 2 259 0.015625 0.03125 0.015625 0.0625 2 260 0.015625 0.0625 0.015625 0.0625 <1 261 0.03125 0.0625 0.03125 0.125 1 262 0.03125 0.03125 0.0625 0.125 1 263 0.03125 0.03125 0.03125 0.125 1 264 0.03125 0.125 0.0625 0.25 <1 265 0.0625 0.0625 0.0625 0.125 <1 266 0.03125 0.0625 0.0625 0.125 1 267 0.03125 0.0625 0.0625 0.0625 <1 268 0.0625 0.0625 0.03125 0.125 <1 269 0.015625 0.0625 0.015625 0.0625 <1 270 0.0625 0.0625 0.0625 0.125 <1 271 0.03125 0.0625 0.03125 0.0625 <1 272 0.0625 0.0625 0.0625 0.125 <1 273 0.0625 0.125 0.0625 0.0625 <1 274 0.015625 0.03125 0.03125 0.0625 <1 275 0.0625 0.0625 0.0625 0.125 <1 276 0.03125 0.0625 0.03125 0.0625 <1 277 0.0625 0.125 0.0625 0.125 <1 278 0.03125 0.125 0.0625 0.0625 1 279 0.0625 0.125 0.125 0.125 <1 280 0.03125 0.0625 0.0625 0.125 <1 281 0.03125 0.125 0.0625 0.125 <1 282 0.03125 0.0625 0.015625 0.0625 <1 283 0.0625 0.0625 0.0625 0.125 <1 284 0.0625 0.0625 0.0625 0.125 <1 285 0.0625 0.0625 0.125 0.25 <1 286 0.0625 0.0625 0.125 0.25 <1 287 0.0625 0.0625 0.0625 0.25 <1 288 0.0625 0.125 0.25 0.25 <1 289 0.03125 0.0625 0.03125 0.125 <1 290 0.0625 0.125 0.125 0.25 <1 291 0.0625 0.125 0.25 0.25 <1 292 0.0625 0.25 0.125 0.125 <1 293 0.0625 0.0625 0.0625 0.25 <1 294 0.0625 0.0625 0.0625 0.25 <1 295 0.0625 0.0625 0.0625 0.125 <1 296 0.125 0.0625 0.125 0.25 <1 297 0.03125 0.0625 0.03125 0.125 <1 298 0.03125 0.0625 0.0625 0.25 <1 299 0.0625 0.0625 0.0625 0.25 <1 300 0.125 0.0625 0.125 0.125 <1 301 0.0625 0.125 0.0625 0.125 2 302 0.0625 0.125 0.125 0.125 3 303 0.0625 0.0625 0.25 0.25 <1 304 0.125 0.0625 0.25 0.25 <1 305 0.0625 0.0625 0.0625 0.125 3 306 0.03125 0.0625 0.0625 0.0625 <1 307 0.125 0.125 0.25 0.125 <1 308 0.0625 0.25 0.125 0.125 <1 309 0.015625 0.0625 0.0625 0.125 <1 310 0.03125 0.0625 0.0625 0.125 <1 311 0.0625 0.0625 0.0625 0.25 <1 312 0.03125 0.0625 0.03125 0.125 <1 313 0.015625 0.0625 0.03125 0.125 <1 314 0.015625 0.125 0.015625 0.25 2 315 0.015625 0.0625 0.015625 0.0625 2 316 0.015625 0.0625 0.015625 0.0625 <1 317 0.015625 0.125 0.015625 0.125 <1 318 0.015625 0.0625 0.03125 0.125 1 319 0.0625 0.25 0.125 0.125 <1 320 0.0625 0.125 0.5 0.25 <1 321 0.0625 0.125 0.125 0.125 0 322 0.0625 0.125 0.0625 0.125 <1 323 0.0625 0.125 0.0625 0.125 <1 324 0.0625 0.0625 0.0625 0.0625 <1 325 0.0625 0.0625 0.0625 0.125 <1 326 0.0625 0.0625 0.0625 0.0625 <1 327 0.0625 0.0625 0.0625 0.125 <1 328 0.015625 0.125 0.015625 0.0625 1 329 0.0625 0.125 0.0625 0.125 <1 330 0.0625 0.0625 0.25 0.25 1 331 0.0625 0.0625 0.125 0.125 <1 332 0.03125 0.0625 0.0625 0.25 2 333 0.0625 0.0625 0.125 0.25 2 334 0.03125 0.0625 0.03125 0.125 <1 335 0.0625 0.0625 0.0625 0.125 <1 336 0.0625 0.25 0.0625 0.125 <1 337 0.0625 0.125 0.125 0.25 2 338 0.03125 0.03125 0.03125 0.125 <1 339 0.0625 0.0625 0.0625 0.125 <1 340 0.03125 0.0625 0.0625 0.25 <1 341 0.0625 0.0625 0.0625 0.125 <1 342 0.0625 0.0625 n.d. 0.0625 n.d. 343 0.03125 0.0625 0.0625 0.125 <1 344 0.0625 0.0625 0.125 0.125 <1 345 0.0625 0.0625 0.0625 0.125 <1 346 0.0625 0.0625 0.0625 0.125 <1 347 0.0625 0.0625 0.125 0.125 <1 348 0.0625 0.0625 0.125 0.125 <1 349 0.0625 0.125 0.0625 0.125 <1 350 0.03125 0.125 0.03125 0.125 <1 351 0.0625 0.0625 0.0625 0.125 <1 352 0.125 0.125 1 0.25 <1 353 0.125 0.125 1 0.25 <1 354 0.0625 0.0625 0.03125 0.125 1 355 0.03125 0.0625 0.03125 0.125 6 356 0.0625 0.0625 0.0625 0.125 2 357 0.0625 0.125 0.0625 0.25 <1 358 0.03125 0.125 0.03125 0.125 1 359 0.0625 0.125 0.0625 0.125 1 360 0.0625 0.0625 0.0625 0.125 2 361 0.0625 0.0625 0.0625 0.125 <1 362 0.0625 0.0625 0.0625 0.125 2 363 0.0625 0.0625 0.0625 0.125 2 364 0.0625 0.0625 0.0625 0.125 <1 365 0.03125 0.0625 0.0625 0.125 <1 366 0.125 0.25 0.25 0.25 4 367 0.015625 0.03125 0.007813 0.0625 <1 368 0.015625 0.03125 0.007813 0.0625 1 369 0.015625 0.03125 0.007813 0.0625 <1 370 0.0625 0.0625 0.0625 0.125 2 371 0.0625 0.0625 0.0625 0.0625 0 372 0.0625 0.0625 0.03125 0.0625 <1 373 0.0625 0.0625 0.03125 0.0625 <1 374 0.0625 0.0625 0.0625 0.125 <1 375 0.03125 0.0625 0.03125 0.125 <1 376 0.0625 0.0625 0.0625 0.125 <1 377 0.015625 0.03125 0.015625 0.0625 <1 378 0.0625 0.0625 0.03125 0.0625 <1 379 0.03125 0.0625 0.0625 0.125 <1 380 0.03125 0.0625 0.0625 0.125 <1 381 0.0625 0.0625 0.0625 0.125 <1 382 0.0625 0.0625 0.0625 0.125 <1 383 0.03125 0.0625 0.0625 0.125 <1 384 0.125 0.25 1 0.5 <1 385 0.015625 0.0625 0.03125 0.125 <1 n.d.: not determined

(1233) TABLE-US-00005 TABLE 4 Minimal inhibitory concentrations (MIC) of selected clinical isolates of Escherichia coli, Klebsiella pneumonia, Acintobacter baumannii and Enterobacter cloacae in Mueller-Hinton II broth Escherichia Klebsiella Acinetobacter Enterobacter coli pneumoniae baumannii cloacae 926415 968733 872842 848840 MIC MIC MIC MIC Ex. [μg/mL] [μg/mL] [μg/mL] [μg/mL] 1 1 2 1 4 2 0.125 0.25 0.125 0.5 3 0.25 0.25 0.125 2 4 0.25 0.5 0.125 0.25 5 0.125 0.25 0.125 0.125 6 0.5 0.5 4 4 7 0.5 0.25 1 2 8 0.5 0.25 0.0625 0.25 9 1 0.5 0.125 0.25 10 8 0.5 0.125 0.25 11 4 4 8 2 12 1 4 1 0.5 15 0.25 0.25 0.25 0.125 16 0.25 0.125 0.25 0.25 17 0.5 0.5 0.125 0.25 18 0.25 0.5 0.25 0.125 20 1 2 0.5 0.25 21 8 8 2 0.5 22 0.5 1 0.25 0.125 23 0.5 0.5 0.25 0.125 24 2 0.5 1 0.25 25 0.25 0.25 0.25 0.125 26 0.125 0.25 0.125 0.25 27 1 1 0.125 0.25 28 8 8 4 0.125 29 4 8 1 0.0625 31 0.5 0.125 0.125 0.125 32 0.0625 0.25 0.0625 0.125 33 0.125 0.25 0.0625 0.125 34 0.0625 0.125 0.0625 0.125 35 1 0.25 0.25 0.25 36 0.125 0.25 0.0625 0.125 37 0.5 2 1 0.25 38 0.5 0.25 0.25 0.5 39 0.25 0.5 0.25 0.5 40 1 0.25 0.5 0.5 41 0.25 0.125 0.125 0.25 42 0.5 2 1 4 43 0.5 2 0.125 2 44 0.125 0.25 0.125 0.125 45 0.5 0.5 0.25 0.25 46 0.125 0.5 0.125 0.125 47 0.25 1 0.125 4 48 1 8 0.5 4 49 0.25 0.125 0.25 0.25 50 0.5 4 1 8 51 0.5 1 0.25 0.5 52 2 4 2 2 53 0.5 4 0.5 8 54 0.5 4 0.5 4 55 1 8 1 8 57 0.5 4 0.5 0.25 58 0.125 0.25 0.0625 0.125 59 0.125 0.25 0.25 1 60 0.125 0.125 0.125 4 61 0.25 0.125 0.125 0.125 62 0.25 0.125 0.125 4 63 0.5 0.25 0.25 4 64 0.5 1 0.5 4 65 0.5 0.5 0.25 4 66 1 4 0.5 0.5 67 2 2 2 2 68 2 1 8 n.d. 69 0.0625 0.125 0.0625 0.125 70 0.5 0.25 0.25 0.125 71 0.25 0.25 0.125 0.25 72 0.125 0.125 0.0625 0.25 73 0.125 0.125 0.0625 0.125 74 0.25 0.0625 0.0625 0.125 75 0.125 0.125 0.0625 0.125 76 0.125 0.125 0.25 0.125 77 0.25 0.25 0.25 0.25 78 0.125 0.0625 0.125 2 79 0.0625 0.0625 0.0625 0.0625 80 0.0625 0.125 0.0625 0.125 81 0.125 0.125 0.25 0.125 82 0.5 0.25 0.25 0.25 83 0.25 0.25 0.125 0.125 84 0.125 0.125 0.125 0.25 85 0.25 0.25 0.25 0.125 86 0.25 0.125 0.25 1 87 0.0625 0.125 0.25 2 88 0.125 0.125 0.125 0.125 89 0.5 1 0.5 0.5 90 0.5 0.25 0.125 0.25 91 2 2 0.5 1 92 0.0625 0.125 0.125 0.25 93 0.25 0.5 0.5 0.25 94 0.25 0.25 0.25 1 95 0.125 0.125 0.125 4 96 0.5 0.125 0.5 8 97 2 8 2 n.d. 98 2 4 2 2 99 0.125 0.0625 0.0625 0.125 100 0.25 0.0625 0.125 0.125 101 0.5 0.5 0.125 0.25 102 2 4 0.5 0.5 103 0.125 0.25 0.0625 0.125 104 0.0625 0.0625 0.0625 0.125 105 0.25 0.25 0.125 0.125 106 0.125 0.25 0.25 0.25 107 0.125 0.125 0.0625 0.0625 108 0.125 0.125 0.0625 0.125 109 0.0625 0.125 0.0625 0.125 110 0.125 0.125 0.0625 0.0625 111 0.0625 0.125 0.0625 0.125 112 0.0625 0.125 0.0625 0.125 113 0.25 0.5 0.25 0.125 114 0.0625 0.0625 0.03125 0.0625 115 0.125 0.25 0.125 0.0625 116 0.125 0.25 0.0625 0.03125 117 0.0625 0.0625 0.015625 0.0625 119 0.0625 0.125 0.03125 0.0625 120 0.0625 0.125 0.0625 0.25 121 0.125 0.25 0.0625 0.125 122 4 2 1 2 123 0.03125 0.0625 0.03125 0.0625 124 0.25 0.25 0.0625 0.125 125 0.0625 0.125 0.125 0.125 126 0.125 0.25 0.25 0.5 127 0.125 0.5 0.0625 0.125 128 0.125 0.0625 0.0625 0.0625 129 0.25 0.125 0.125 0.125 130 0.125 0.125 0.125 0.0625 131 0.5 1 1 0.25 132 0.0625 0.125 0.0625 0.125 133 0.0625 0.125 0.03125 0.25 134 0.125 0.125 0.0625 0.125 135 0.0625 0.125 0.03125 0.0625 136 0.0625 0.0625 0.03125 0.0625 137 0.125 0.125 0.125 0.0625 138 0.03125 0.0625 0.03125 0.125 139 0.125 0.25 0.0625 0.125 140 0.25 0.5 0.5 0.25 141 0.03125 0.03125 0.0625 0.0625 142 0.03125 0.0625 0.03125 0.125 143 0.125 0.0625 0.03125 0.0625 144 0.0625 0.0625 0.0625 0.125 145 0.0625 0.125 0.03125 0.125 146 0.25 0.25 0.125 0.25 147 0.25 0.5 0.25 0.125 148 0.125 0.25 0.0625 0.0625 149 0.25 0.5 0.125 0.125 150 0.25 0.5 0.125 0.125 151 0.5 1 0.25 0.125 152 2 8 1 0.5 153 0.125 0.25 0.0625 0.125 154 0.125 0.25 0.0625 0.125 155 0.5 0.5 0.125 0.125 156 0.125 0.25 0.125 0.125 157 1 1 0.5 0.25 158 0.5 1 0.25 0.125 159 0.25 0.5 0.25 0.125 160 0.5 0.5 0.5 2 161 0.5 0.25 0.25 1 162 1 8 0.5 n.d. 163 0.5 0.5 0.25 4 164 0.25 1 2 n.d. 165 0.125 0.5 1 4 166 0.25 0.125 0.25 0.25 167 0.25 0.25 0.125 2 168 0.125 0.5 0.125 0.25 169 0.5 4 1 n.d. 170 0.5 2 2 n.d. 171 0.125 0.5 0.0625 0.5 172 0.25 0.5 0.125 0.25 173 0.25 2 0.125 4 174 0.125 0.25 0.125 0.25 175 0.25 0.5 0.0625 0.25 176 0.25 0.25 0.125 0.5 177 0.25 0.5 0.125 1 178 0.5 2 0.25 0.25 179 0.5 4 0.25 0.5 181 2 8 2 1 182 0.5 1 0.125 0.125 184 2 8 1 1 185 0.25 1 0.25 0.25 186 1 8 0.25 0.25 188 0.5 1 0.5 0.5 189 1 4 0.5 0.25 190 1 4 0.5 0.5 191 1 2 0.5 0.5 193 0.5 0.5 0.5 0.5 194 0.5 0.25 0.25 0.125 195 0.5 0.5 0.25 0.25 196 2 2 1 1 197 0.5 0.5 0.25 0.25 198 0.25 0.5 0.125 0.25 199 0.5 0.5 0.25 0.25 200 2 2 1 2 201 0.25 0.25 0.125 0.125 202 0.25 0.25 0.25 0.125 203 0.5 0.25 0.125 0.5 204 0.5 0.5 0.25 0.125 206 0.0625 0.5 0.0625 0.125 207 0.5 1 0.25 0.5 208 0.25 0.5 0.125 0.25 209 1 4 2 n.d. 210 2 2 0.5 2 211 0.25 0.25 0.0625 2 212 1 2 0.5 0.5 213 0.5 0.5 0.125 1 214 0.5 0.5 0.5 8 215 2 2 0.5 0.5 216 1 4 2 n.d. 217 1 2 4 n.d. 219 0.25 0.5 0.125 0.125 220 0.125 0.125 0.0625 0.125 221 0.125 0.25 0.0625 0.125 222 0.25 0.25 0.0625 0.125 223 0.125 0.25 0.03125 0.0625 224 0.125 0.25 0.0625 0.125 225 0.25 1 0.25 0.125 226 0.0625 0.25 0.0625 0.0625 227 0.125 0.5 0.125 0.125 228 1 1 4 8 232 0.0625 0.125 0.0625 0.125 233 0.0625 0.0625 0.0625 0.125 234 0.25 1 0.25 0.5 235 0.125 0.25 0.0625 0.25 236 2 8 2 1 237 0.25 0.5 0.125 0.125 238 0.125 0.25 0.0625 0.125 239 0.0625 0.25 0.125 0.25 240 0.0625 0.5 0.0625 0.125 241 1 1 0.125 2 242 0.25 1 0.125 4 243 0.125 0.125 0.0625 0.25 244 0.125 0.0625 0.0625 0.0625 245 0.125 0.25 0.0625 0.125 246 2 4 4 2 247 0.5 8 0.5 0.25 248 0.25 4 1 4 249 0.125 0.25 0.03125 0.125 250 0.0625 0.125 0.03125 0.0625 251 0.125 0.0625 0.03125 0.125 252 0.125 0.125 0.0625 0.125 253 0.0625 0.0625 0.03125 0.125 254 0.125 0.125 0.03125 0.0625 255 0.0625 0.25 0.125 0.0625 256 0.0625 0.0625 0.03125 0.0625 257 0.0625 0.125 0.03125 0.0625 258 0.25 0.125 0.03125 0.0625 259 0.125 0.0625 0.03125 0.0625 260 0.5 0.5 0.0625 0.0625 261 0.125 0.25 0.0625 0.125 262 0.25 0.25 0.0625 0.0625 263 0.125 0.25 0.0625 0.125 264 0.125 0.125 0.0625 0.5 265 0.125 0.25 0.125 0.5 266 0.5 1 0.5 0.25 267 0.0625 0.125 0.0625 0.125 268 0.5 0.5 0.125 0.25 269 0.0625 0.0625 0.03125 0.125 270 0.125 0.125 0.0625 0.25 271 0.0625 0.0625 0.0625 0.25 272 0.125 0.125 0.0625 0.25 273 0.5 0.5 0.0625 0.25 274 0.125 0.125 0.125 0.25 275 0.125 0.25 0.125 1 276 0.25 0.25 0.0625 0.125 277 0.25 0.25 0.125 0.125 278 0.25 0.25 0.125 0.125 279 1 2 0.5 0.25 280 0.25 0.5 0.125 0.0625 281 0.25 0.25 0.25 0.125 282 0.125 0.25 0.125 0.0625 283 0.5 2 0.5 0.125 284 1 2 0.5 0.125 285 2 4 0.5 0.25 286 1 2 0.5 0.25 287 1 2 0.25 0.125 288 4 8 1 1 289 0.25 0.25 0.0625 0.125 290 1 4 0.25 0.25 291 2 8 1 1 292 1 4 0.5 1 293 0.5 2 0.5 0.5 294 0.25 1 0.5 0.125 295 0.5 0.5 0.125 0.25 296 0.5 4 0.25 0.5 297 0.125 0.125 0.0625 0.125 298 0.5 1 0.25 0.25 299 0.25 0.5 0.125 0.125 300 0.25 2 1 0.125 301 0.125 0.5 0.25 0.125 302 2 2 0.5 0.5 303 1 1 0.5 1 304 2 4 1 2 305 0.25 0.25 0.125 0.25 306 0.0625 0.125 0.0625 0.0625 307 0.5 1 0.5 4 308 0.5 1 0.5 1 309 0.0625 0.125 0.03125 0.0625 310 0.0625 0.0625 0.0625 0.0625 311 0.25 0.125 0.125 0.125 312 0.25 0.125 0.0625 0.0625 313 0.125 0.125 0.125 0.0625 314 0.0625 0.125 0.0625 0.125 315 0.0625 0.0625 0.0625 0.125 316 0.0625 0.0625 0.03125 0.0625 317 0.0625 0.125 0.03125 0.0625 318 0.125 0.125 0.0625 0.125 319 1 4 0.5 1 320 4 8 1 2 321 0.5 1 0.25 0.25 322 0.125 0.25 0.0625 0.0625 323 0.25 0.5 0.0625 0.125 324 0.125 0.5 0.125 0.125 325 0.125 0.5 0.125 0.0625 326 0.125 0.5 0.125 0.0625 327 0.25 0.5 0.125 0.125 328 0.125 0.25 0.0625 0.0625 329 0.125 0.25 0.125 0.125 330 0.25 2 1 0.125 331 0.5 0.5 0.25 0.25 332 0.25 0.5 0.25 0.125 333 0.5 1 0.5 0.25 334 0.25 0.25 0.125 0.125 335 0.25 0.5 0.25 0.25 336 0.5 0.5 0.125 0.125 337 1 2 0.25 0.25 338 0.0625 0.125 0.0625 0.0625 339 0.5 0.5 0.125 0.125 340 0.125 0.25 0.0625 0.125 341 0.5 1 0.25 2 342 0.125 0.25 0.0625 343 0.25 0.5 0.25 0.125 344 0.125 0.25 0.25 1 345 0.125 0.25 0.125 0.125 346 0.25 0.5 0.125 0.125 347 0.25 1 0.25 0.5 348 0.5 2 0.5 0.5 349 0.25 0.25 0.25 0.25 350 0.125 0.125 0.0625 0.125 351 0.5 1 0.25 0.25 352 0.25 0.5 4 8 353 0.25 4 4 8 354 0.5 0.25 0.0625 0.125 355 0.25 0.25 0.0625 0.125 356 0.25 0.25 0.125 0.125 357 0.5 0.5 0.25 0.125 358 0.25 0.25 0.0625 0.125 359 0.25 0.5 0.125 0.125 360 0.25 0.5 0.125 0.125 361 0.125 0.125 0.0625 0.0625 362 0.0625 0.125 0.0625 0.0625 363 0.125 0.125 0.0625 0.0625 364 0.25 0.125 0.125 0.125 365 0.125 0.125 0.0625 0.0625 366 0.5 2 0.5 8 367 0.0625 0.0625 0.03125 0.0625 368 0.015625 0.0625 0.03125 0.03125 369 0.0625 0.0625 0.03125 0.03125 370 0.5 1 0.5 0.125 371 0.25 0.5 0.0625 0.5 372 0.125 0.25 0.125 0.25 373 0.125 0.125 0.0625 0.25 374 0.5 1 0.25 0.25 375 0.125 0.125 0.0625 0.25 376 0.25 0.5 0.25 0.0625 377 0.125 0.0625 0.0625 0.0625 378 0.0625 0.125 0.0625 0.0625 379 0.25 0.25 0.125 1 380 0.125 0.5 0.25 0.125 381 0.5 1 0.25 0.5 382 0.125 0.25 0.25 0.125 383 0.25 1 0.125 0.125 384 4 >8 2 2 385 0.0625 0.125 0.0625 0.0625 Colistin.sup.1) 3) 16 16 64 >8 Colistin .sup.2) 3) 8 >8 >8 >8 .sup.1) measured in absence of P-80 2) measured in presence of P-80 .sup.3) Colistin (Colistin sulfate salt, Cat-Nr. C4461, Lot-Nr. SLBK0713V) obtained from Sigma Aldrich, Buchs; Switzerland

(1234) TABLE-US-00006 TABLE 5 Minimal inhibitory concentrations (MIC) of Escherichia coli MCR-1 Af45 in Mueller-Hinton II broth Escherichia coli Escherichia coli MCR-1 Af45 MCR-1 Af45 MIC MIC Ex. [μg/mL] Ex. [μg/mL] 3 0.125 132 0.125 41 0.125 133 0.125 72 0.125 134 0.25 73 0.125 135 0.125 79 0.125 136 0.125 84 0.125 137 0.25 88 0.25 138 0.125 92 0.25 139 0.25 96 0.25 140 0.25 99 0.0625 141 0.0625 100 0.125 142 0.125 103 0.0625 143 0.5 104 0.125 144 0.125 105 0.5 145 0.25 106 0.25 147 0.5 107 0.125 148 0.25 108 0.0625 150 0.25 109 0.125 151 0.5 110 0.125 153 0.25 111 0.125 154 0.125 112 0.125 156 0.25 113 0.5 159 0.25 114 0.0625 161 0.25 115 0.25 166 0.25 116 0.25 168 0.25 117 0.125 172 0.125 119 0.125 185 0.5 120 0.25 193 0.5 126 0.5 199 0.5 128 0.25 201 0.125 129 0.125 202 0.25 203 0.25 282 0.25 204 0.25 289 0.25 206 0.25 297 0.125 219 0.25 310 0.0625 221 0.25 334 0.125 222 0.5 340 0.0625 223 0.25 341 0.5 224 0.5 350 0.25 225 0.25 351 0.25 226 0.25 359 0.125 232 0.0625 365 0.0625 233 0.125 375 0.125 250 0.125 379 0.125 276 0.25 Colistin .sup.1) 3) 4 281 0.125 Colistin .sup.2) 3) 2 .sup.1) measured in absence of P-80 .sup.2) measured in presence of P-80 .sup.3) Colistin (Colistin sulfate salt, Cat-Nr. C4461, Lot-Nr. SLBK0713V) obtained from Sigma Aldrich, Buchs; Switzerland

(1235) TABLE-US-00007 TABLE 6 Tolerability in a mouse model Ex. Mortality and dose Ex. Mortality and dose 39 0/3 died at 2 × 30 mg/kg 284 0/3 died at 2 × 40 mg/kg 41 0/3 died at 2 × 30 mg/kg 289 0/3 died at 2 × 40 mg/kg 42 0/3 died at 2 × 30 mg/kg 293 0/3 died at 2 × 40 mg/kg 43 0/3 died at 2 × 30 mg/kg 294 0/3 died at 2 × 40 mg/kg 58 0/3 died at 2 × 30 mg/kg 295 0/3 died at 2 × 40 mg/kg 65 0/3 died at 2 × 30 mg/kg 296 0/3 died at 2 × 40 mg/kg 92 0/3 died at 2 × 30 mg/kg 297 0/3 died at 2 × 40 mg/kg 96 0/3 died at 2 × 30 mg/kg 298 0/3 died at 2 × 40 mg/kg 100 0/3 died at 2 × 30 mg/kg 299 0/3 died at 2 × 40 mg/kg 114 0/3 died at 2 × 30 mg/kg 300 0/3 died at 2 × 40 mg/kg 115 0/3 died at 2 × 30 mg/kg 306 0/3 died at 2 × 40 mg/kg 116 0/3 died at 2 × 30 mg/kg 309 0/3 died at 2 × 40 mg/kg 137 0/3 died at 2 × 30 mg/kg 310 0/3 died at 2 × 40 mg/kg 150 0/3 died at 2 × 30 mg/kg 311 0/3 died at 2 × 40 mg/kg 161 0/3 died at 2 × 30 mg/kg 331 0/3 died at 2 × 40 mg/kg 188 0/3 died at 2 × 30 mg/kg 332 0/3 died at 2 × 40 mg/kg 215 0/3 died at 2 × 30 mg/kg 333 0/3 died at 2 × 40 mg/kg 219 0/3 died at 2 × 30 mg/kg 334 0/3 died at 2 × 40 mg/kg 257 0/3 died at 2 × 30 mg/kg 335 0/3 died at 2 × 40 mg/kg 258 0/3 died at 2 × 30 mg/kg 336 0/3 died at 2 × 40 mg/kg 259 0/3 died at 2 × 30 mg/kg 337 0/3 died at 2 × 40 mg/kg 260 0/3 died at 2 × 30 mg/kg 338 0/3 died at 2 × 40 mg/kg 261 0/3 died at 2 × 30 mg/kg 339 0/3 died at 2 × 40 mg/kg 266 0/3 died at 2 × 30 mg/kg 340 0/3 died at 2 × 40 mg/kg 270 0/3 died at 2 × 40 mg/kg 341 0/3 died at 2 × 40 mg/kg 274 0/3 died at 2 × 40 mg/kg 343 0/3 died at 2 × 40 mg/kg 275 0/3 died at 2 × 40 mg/kg 344 0/3 died at 2 × 40 mg/kg 276 0/3 died at 2 × 40 mg/kg 345 0/3 died at 2 × 40 mg/kg 277 0/3 died at 2 × 40 mg/kg 350 0/3 died at 2 × 40 mg/kg 278 0/3 died at 2 × 40 mg/kg 351 0/3 died at 2 × 40 mg/kg 279 0/3 died at 2 × 40 mg/kg 358 0/3 died at 2 × 40 mg/kg 280 0/3 died at 2 × 40 mg/kg 359 0/3 died at 2 × 40 mg/kg 281 0/3 died at 2 × 40 mg/kg 361 0/3 died at 2 × 40 mg/kg 282 0/3 died at 2 × 40 mg/kg 362 0/3 died at 2 × 40 mg/kg 283 0/3 died at 2 × 40 mg/kg 363 0/3 died at 2 × 40 mg/kg 364 0/3 died at 2 × 40 mg/kg 365 0/3 died at 2 × 40 mg/kg 370 0/3 died at 2 × 40 mg/kg 375 0/3 died at 2 × 40 mg/kg 376 0/3 died at 2 × 40 mg/kg 379 0/3 died at 2 × 40 mg/kg 380 0/3 died at 2 × 40 mg/kg 381 0/3 died at 2 × 40 mg/kg 382 0/3 died at 2 × 40 mg/kg 383 0/3 died at 2 × 40 mg/kg

(1236) TABLE-US-00008 TABLE 7 Nephrotoxicity in a mouse model Max Overall Kidney Histology Semi-Quantiative Ex. Score Score (SQS) 39 1 +1 100 2 +1 113 3 +1 114 6 +1 115 4 +1 128 12 +1 132 12 +1 137 1 +1 260 3 +1 276 2 +1 277 2 +1 278 2 +1 279 1 +1 281 2 +1 282 2 +1 289 0 0 293 1 +1 297 1 +1 306 3 +1 310 2 +1 334 2 +1 340 3 +1 341 2 +1 350 8 +1 351 3 +1 Colistin B 24 +2