BISPIDINE DERIVATIVES AND THE USE THEREOF

Abstract

A compound of general formula I

##STR00001##

Also, the use of the compound for the complexation of a metal ion, including lutetium ions or actinium ions, and the method for the complexation of a metal ion in which the compound is contacted with the metal ion at a reaction temperature in the range of from 20 to 50? C.

Claims

1-15. (canceled)

16. A compound of general formula I ##STR00053## in which X is selected from a first group or a second group or third group, wherein the first group consists of ##STR00054## the second group consists of ##STR00055## and the third group consists of ##STR00056## Y is a group of general formula II or of general formula III ##STR00057## if X is selected from the first group, Z is selected from a first group consisting of ##STR00058## if X is selected from the second group, Z is selected from a second group consisting of ##STR00059## if X is selected from the third group, Z is selected from a third group consisting of ##STR00060## R.sup.1 and R.sup.2 independently are selected from the group consisting of a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, a substituted or unsubstituted C.sub.1-C.sub.6 heteroalkyl group, C(O)O.sup.eR.sup.a, C(O)NR.sup.bR.sup.e, C(O)C(R.sup.a).sub.2NR.sup.bR.sup.c, and C(O)NR.sup.b(CH.sub.2).sub.nC(O)OR.sup.a, wherein R.sup.a, R.sup.b and R.sup.e each independently are selected from the group consisting of hydrogen, a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, a substituted or unsubstituted C.sub.1-C.sub.6 heteroalkyl group, a substituted or unsubstituted aryl group, a group -A-L and a group L and n is an integer from 1 to 10; R.sup.3 is selected from the group consisting of oxygen, sulfur, ?NR.sup.d, and ?CHR.sup.d, wherein R.sup.d is selected from the group consisting of hydrogen, a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, a substituted or unsubstituted C.sub.1-C.sub.6 heteroalkyl group, a substituted or unsubstituted aryl group, OR.sup.e, C(O)OR.sup.e, C(O)NR.sup.fR.sup.g, a group -A-L and a group L, R.sup.e is hydrogen or a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, and R.sup.f and R.sup.g each independently are hydrogen or a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group; and R.sup.4 is selected from the group consisting of OR.sup.h, SR.sup.h, NHR.sup.h and CH.sub.2R.sup.h, wherein R.sup.h is selected from the group consisting of hydrogen, a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, a substituted or unsubstituted C.sub.1-C.sub.6 alkenyl group, a substituted or unsubstituted C.sub.1-C.sub.6 alkynyl group, a substituted or unsubstituted C.sub.1-C.sub.6 heteroalkyl group, a substituted or unsubstituted aryl group, C(O)(CH.sub.2).sub.mR.sup.k, C(O)(CH.sub.2).sub.mNR.sup.nR.sup.n, a group -A-L and a group L, R.sup.k is selected from the group consisting of a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, a substituted or unsubstituted C.sub.1-C.sub.6 heteroalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted carboxy group, R.sup.m and R.sup.n each independently are hydrogen or a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, and m is 0 or an integer from 1 to 10; R.sup.5 and R.sup.6 independently are selected from the group consisting of hydrogen, chloro, bromo, iodo, and OR.sup.o, wherein R.sup.o is a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group; A is a linker group and L is an amino acid residue or a peptide.

17. The compound according to claim 16, wherein R.sup.1 and R.sup.2 independently are C(O)OR.sup.a, wherein R.sup.a has the meaning given as above.

18. The compound according to claim 16, wherein R.sup.3 is selected from the group consisting of oxygen and ?NR.sup.d, wherein R.sup.d has the meaning as above.

19. The compound according to claim 16, wherein R.sup.4 is a hydroxy group or OR.sup.4, wherein R.sup.h has the meaning given above.

20. The compound according to claim 16, wherein X is a group of formula ##STR00061## and Z is a group of formula ##STR00062##

21. The compound according to claim 16, wherein X is a group of formula ##STR00063## and Z is a group of formula ##STR00064##

22. The compound according to claim 16, wherein the compound is a compound of formula A1, A2, or A3: ##STR00065##

23. The compound according to claim 16, wherein the group -A-L is a group of formula L1 ##STR00066##

24. The compound according to claim 16, wherein the compound is a compound of formula A4: ##STR00067## in which the designation py indicates a pyridyl group.

25. A method for the complexation of a metal ion, comprising contacting the compound according to claim 16 with a metal ion.

26. The method according to claim 25, the metal ion is a lutetium ion or an actinium ion.

27. A method for the complexation of a metal ion, wherein the compound according to claim 16 is contacted with the metal ion at a reaction temperature in the range of from 20 to 50? C.

28. The method according to claim 27, wherein the compound is reacted with a metal salt at ambient pressure.

29. A complex of a compound according to claim 16 as ligands and a metal ion.

30. The complex according to claim 29, wherein the ligand is a nonadentate or decadentate ligand.

Description

GENERAL SYNTHESIS METHODS FOR THE COMPOUNDS OF GENERAL FORMULA I

a) General Procedure 1 (GP1): Alkylation of the Free Amine of a Bispidine Precursor

[0092] A bispidine precursor (1.0 eq.) was suspended in acetonitrile (MeCN). After addition of base (1.0-6.0 eq.) and the respective alkylation agent (1.0-1.1 eq.) over a given time, the reaction mixture was stirred under reflux (30 min -16 h). Leftover base was filtered and the solvent of the filtrate was removed under reduced pressure. The leftover solid was dissolved in dichloromethane (DCM) and water and the organic phase collected, followed by extraction of the aqueous phase with DCM. The combined organic phases were dried over Na.sub.2SO.sub.4 and the solvent removed in-vacuo. The compounds, comprising the protected bispidine derivative, were purified as described in each procedure.

General Procedure 2 (GP2): Deprotection of DMB- or tBu-Protective Group

[0093] The protected bispidine derviative was dissolved in DCM and equivalent amounts of trifluoroacetic acid was added to the solution. The reaction mixture was stirred under reflux for 16 h, the solvent was removed in-vacuo using a separate cooling trap and the crude product was purified as described in each procedure. DMB indicates 2,4-dimethoxybenzyl, tBu a tert-butyl group.

General Procedure 3 (GP3): Deprotection of Benzylic Protective Group

[0094] The protected bispidine derivative was placed in a three necked flask, suspended in EtOAc and 10 wt % of Pd/C was added. The flask was equipped with two adapters with stopcock and a reflux condenser attached to a balloon. The apparatus was flushed with nitrogen and put under vacuum using a water pump. This step was conducted three times, before the same was done using H.sub.2, leaving the apparatus under hydrogen the third time. The reaction mixture was stirred under reflux for at least 16 h until reaction control showed full conversion of the reactant. After filtration over Celite? the solvent was removed under reduced pressure. The product was obtained by ether diffusion into ethanolic solution.

EXAMPLE 1

Synthesis of Compound A1

[0095] The method for preparing compound A1 is shown in scheme B1-1. The synthesis of the bispidine fragment 1 follows the process mode described in AF. Bruchertseifer, P. Comba, B. Martin, A. Morgenstern, J. Notni, M. Starke, H. Wadepohl, ChemMedChem 2020; BP. Comba, M. Starke, H. Wadepohl, ChemPlusChem 2018, 83, 597-604.

##STR00041##

[0096] The method for preparing compound 2 needed for preparing compound A1 is shown in scheme B1-2. The alkylation agent 2 was synthesized from literature known compound 5. Compound 5 is described in Y. Yamamoto, A. Miura, A. Kawamata, M. Miura, S. Takei, Bull. Chem. Soc. Jpn. 1978, 51, 3489-3495.

##STR00042##

a) Synthesis of Compound 6

[0097] 2.00 g of 5 (6.62 mmol, 1.0 eq.) was placed in a flame dried Schlenck tube under N.sub.2, 6.3 ml of acetic anhydride (Ac.sub.2O) (6.75 g, 66.2 mmol, 10.0 eq.) was added and the resulting slurry was stirred at room temperature (RT) for 30 min. Leftover acetic anhydride was removed in-vacuo with low heating (50? C.). The product 6 was obtained as yellow solid and was used in the next reaction without further purification.

b) Synthesis of Compound 2

[0098] The crude product of 6 (2.56 g, 6.62 mmol, 1.0 eq.) was suspended in CCl.sub.4 (65 ml) and 1.18 g of N-bromosuccinimide (NBS) (6.62 mmol, 1.0 eq.) was added. The reaction mixture was refluxed for 30 min and after cooling to room temperature the precipitated solids were removed by filtration. The solvent of the filtrate was removed in-vacuo and the leftover solids dissolved in dichloromethane (DCM). The organic phase was washed with first water and then brine and then was dried over Na.sub.2SO.sub.4, filtrated and the solvent removed under reduced pressure. Compound 2 was obtained in quantitative yield as yellow solid (3.08 g, 6.62 mmol, 99%).

[0099] .sup.1H-NMR (200 MHz, 300K, CDCl.sub.3): ?=8.18 (d, J=8.6 Hz, 2H, H.sub.ar), 7.85 (d, J=8.6 Hz, 2H, H.sub.ar), 7.71 (dd, J=8.1, 1.6 Hz, 2H, H.sub.ar), 7.53 (dd, J=8.1, 7.5 Hz, 2H, H.sub.ar), 7.43 (dd, J=7.5, 1.6 Hz, 2H, H.sub.ar), 6.59 (s, 1H, CHBr), 2.36 (s, 6H, OAc).

c) Synthesis of Compound 3

[0100] The general procedure GP1 was conducted using following amounts: 500 mg of 1 (993 ?mol, 1.0 eq.), 647 mg of Cs.sub.2CO.sub.3 (1.99 mmol, 2.0 eq.) and 462 mg of 2 (993 ?mol, 1.0 eq.) in 20 ml of acetonitrile (MeCN) and 30 min reaction time. Compound 2 was added over time (10 min). The product was obtained as white solid after crystallization from acetone (390 mg, 437 ?mol, 44%).

[0101] 2?0.25 Cs.sub.2CO.sub.3.Math.1.5 H.sub.2O, [C.sub.52.25H.sub.53Cs.sub.0.5N.sub.7O.sub.11.5]: .sup.1H-NMR (600 MHz, 295K, CDCl.sub.3): ?=8.44 {8.41 (m, 1H, H.sub.ar), 8.41 {8.37 (m, 2H, H.sub.py), 8.04 (d, J=8.6 Hz, 2H, H.sub.py), 7.70 (d, J=8.5 Hz, 3H, H.sub.ar), 7.64 (dd, J=8.2, 1.4 Hz, 2H, H.sub.ar), 7.47 (t, J=7.8 Hz, 2H, H.sub.ar), 7.41 (dd, J=7.5, 1.4 Hz, 2H, H.sub.py), 7.35 (td, J=7.7, 1.9 Hz, 1H, H.sub.ar), 7.19 {7.14 (m, 2H, H.sub.py), 6.98 {6.92 (m, 3H, H.sub.ar), 6.65 (d, J=7.8 Hz, 1H, H.sub.ar), 5.32 (s, 1H, CH.sub.N7), 4.74 {4.70 (m, 3H, CH.sub.py/CHOH), 3.66 (s, 2H, CH.sub.2,py), 3.56 (s, 6H, CO.sub.2Me), 3.30 (d, J=12.5 Hz, 2H, CH.sub.2,ax/eq), 3.08 (m, 2H, CH.sub.2,ax/eq), 2.48 (s, 6H, OAc) ppm. .sup.13C-NMR (101 MHz, 295K, CDCl.sub.3): ?=172.78, 169.91, 159.73, 149.12, 148.71, 147.65, 140.79, 136.28, 135.67, 135.54, 128.85, 126.15, 125.77, 124.58, 124.31, 123.28, 122.52, 121.58, 121.50, 78.32, 71.50, 65.99, 53.76, 52.22, 21.17, 15.41 ppm. ESI-HRMS (pos. DCM/MeOH): m/z [C.sub.50H.sub.46N.sub.7O9].sup.+ ([M+H].sup.+): calc.: 888.3352, exp.: 888.3370; m/z [C.sub.50H.sub.45N.sub.7NaO.sub.9].sup.+ ([M+Na].sup.+): calc.: 910.3171, exp.: 910.3189; elemental analysis (Nr.: 45315): calc.: C 60.57, H 4.86, N 9.84; exp.: C 60.66, H 4.83, N 9.96.

c) Synthesis of Compound A1

[0102] To a solution of 3 (212 mg, 238 ?mol, 1.0 eq) in Methanol (MeOH) (10 ml) was added 75.9 mg Na.sub.2CO.sub.3 (716 ?mol, 3.0 eq.) and the mixture was let to stir for 1 h at room temperature (RT). The solvent was removed under reduced pressure and the leftover solids dissolved in same amounts of dichloromethane (DCM) and water (20 ml). The phases were separated, the aqueous phase extracted with DCM (3?20 ml) and the combined organic phases dried over Na.sub.2SO.sub.4. After filtration the solvent was removed under reduced pressure. To remove coordination cations, the crude product was treated with trifluoroacetic acid (TFA). The TFA salt was obtained by crystallization from ethyl acetate (EtOAc). Compound A1 was neutralized using pH 7 buffer solution. After DCM extraction (3?50 ml) the combined organic phases were dried over Na.sub.2SO.sub.4 and the solvent was removed in-vacuo to furnish A1 as light-red solid (122 mg, 152 ?mol, 64%).

[0103] A1?2 MeOH, [C.sub.48H.sub.49N.sub.7O.sub.9]: .sup.1H-NMR (400 MHz, 295K, CD.sub.3CN): ?=8.68 -8.61 (m, 1H, H.sub.py), 8.48 (d, J=8.7 Hz, 2H, H.sub.py), 7.94 (d, J=8.7 Hz, 2H, H.sub.py), 7.73 (d, J=4.8 Hz, 2H, H.sub.ar), 7.65-7.53 (m, 6H, H.sub.py,ar), 7.48 (td, J=7.7, 1.8 Hz, 1H, H.sub.py), 7.24 (dd, J=7.5, 1.4 Hz, 3H, H.sub.py), 7.14-7.05 (m, 4H, H.sub.ar), 6.30 (d, J=7.8 Hz, 1H, H.sub.py), 6.26 (s, 1H, CH.sub.N7), 5.02 (s, 2H, CH.sub.py), 4.75 (s, 1H, CHOH), 4.02-3.93 (m, 4H, CH.sub.2,ax/eq), 3.55 (s, 2H, CH.sub.2,py), 3.49 (s, 6H, CO.sub.2Me). .sup.13C-NMR (101 MHz, 295K, CD.sub.3CN):=169.95, 155.74, 153.74, 150.60, 150.16,139.23, 138.61, 138.48, 138.04, 130.43, 129.54, 126.71, 124.89, 123.59, 123.46, 119.13, 112.51, 77.93, 71.78, 70.47, 66.22, 53.64, 53.40, 49.81, 15.56 ppm. ESI-HRMS (pos. DCM/MeOH): m/z [C.sub.46H.sub.42N.sub.7O.sub.7].sup.+ ([M+H].sup.+): calc.: 804.3140, exp.: 804.3155; m/z [C.sub.46H.sub.41N.sub.7NaO.sub.7].sup.+ ([M+Na].sup.+): calc.: 826.2960, exp.: 826.2977; m/z [C.sub.46H.sub.41KN.sub.7O.sub.7].sup.+ ([M+K].sup.+): calc.: 842.2699, exp.: 842.2624; elemental analysis (Nr.: 45429): calc.: C 66.42, H 5.69, N 11.30, exp.: C 66.26, H 5.70, N 11.03.

EXAMPLE 2

Synthesis of Compound A2

[0104] The method for preparing compound A2 is shown in scheme B2-1. Piperidone 7, tert-butyl 6-(bromomethyl)picolinate 11, and 6-methyl-2,2-bipyridin carboxylic acid 17 were synthesized according to literature procedure. Compound 7 was synthesized as described in P. Barman, A. K. Vardhaman, B. Martin, S. J. Worner, C. V. Sastri, P. Comba, Angew. Chem. Int. Ed. Engl. 2015, 54, 2095-2099. Compound 11 was synthesized as described in P. Comba, U. Jermilova, C. Orvig, B. O. Patrick, C. F. Ramogida, K. Ruck, C. Schneider, M. Starke, Chem. Eur. J. 2017, 23, 15945-15956. Compound 17 was synthesized as described in M. H. Al-Sayah, R. McDonald, N. R. Branda, Eur. J. Org. Chem. 2004, 2004, 173-182.

##STR00043## ##STR00044##

[0105] The method for preparing compound 14 needed for preparing compound A1 is shown in scheme B2-2.

##STR00045##

a) Synthesis of Compound 8

[0106] Piperidone 7 (10.2 g, 21.8 mmol, 1.0 equiv.) was suspended in ethanol (EtOH) (130 ml) and heated to 50? C. To this suspension, 2,4-dimethoxybenzylamine (3.80 ml, 4.20 g, 25.1 mmol, 1.2 equiv.) and formaldehyde (3.70 ml, 37% in water, 1.61 g, 50.1 mmol, 2.3 equiv.) were added dropwise and simultaneously by syringe in a period of 5 min. The reaction mixture was refluxed for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure, the remaining solid was dissolved in EtOH (15 ml). Layering with diethyl ether yielded 8 as colorless solid (6.87 g, 10.6 mmol, 48%).

[0107] .sup.1H-NMR (200 MHz, CDCl.sub.3): ?=8.49 (ddd, J=4.9, 1.8, 0.8 Hz, 2H, H.sub.py), 8.13 (d, J=7.9 Hz, 2H, H.sub.py), 7.43 (td, J=7.7, 1.8 Hz, 2H, H.sub.py), 7.21-7.00 (m, 4H, H.sub.py,Bn), 6.84 (dd, J=7.0, 2.6 Hz, 2H, H.sub.py), 6.63 (d, J=2.4 Hz, 1H, H.sub.Bn), 6.44 (dd, J=8.2, 2.4 Hz, 1H, H.sub.Bn), 5.08 (s, 2H, CH.sub.py), 4.01 (s, 2H, CH.sub.2), 3.87 (s, 2H, CH.sub.2), 3.75 (s, 6H, CO2Me), 3.46 (s, 2H, CH2.sub.Bn/DMB), 3.39 (s, 2H, CH2.sub.Bn/DMB), 3.10 (d, J=12.9 Hz, 2H, CH2.sub.ax,eq), 2.43 (d, J=12.3 Hz, 2H, CH2.sub.ax,eq) ppm.

b) Synthesis of Compound 9

[0108] Compound 8 (6.87 g, 10.6 mmol, 1.0 equiv.) was suspended in 180 ml of a 1,4-dioxane-water mixture (3:1) and cooled to ?5? C. A solution of sodium borohydride (201 mg, 5.30 mmol, 0.5 equiv.) in 90 ml of the same solvent mixture was added with a dropping funnel in a period of 20 min. The reaction mixture was allowed to warm up to 0? C. and stir at this temperature for 16 h. The pH value was set to 1 by adding concentrated sulfuric acid and the solution was stirred for 20 min. The volume was reduced to 50 ml under reduced pressure and an aqueous solution of sodium hydroxide (20 wt %) was added to adjust the pH value to 9. The resulting slurry was stirred for 1 h at room temperature before adding DCM (100 ml). The leftover solid was filtered off and the liquid layers separated. Afterwards the aqueous phase was extracted with DCM (3?50 ml), the combined organic layers were dried over anhydrous Na.sub.2SO.sub.4. filtrated and the solvent removed under reduced pressure. Compound 9 was used in the next step without further purification.

[0109] 9?1.5 1,4-dioxane: HRMS (ESI): m/z calcd for C.sub.37H.sub.41N.sub.4O.sub.7.sup.+: 653.2970 [M+H].sup.+; found: 653.2971; elemental analysis calcd (%) for C.sub.43H.sub.52N.sub.4O.sub.10: C 65.80, H 6.68, N 7.14; found: C 66.01, H 6.64, N 7.36.

c) Synthesis of Compound 10

[0110] The general procedure 2 (GP2) was conducted using following approach: Crude of 9 (6.82 g) was reacted in 25 ml of DCM with 25 ml of trifluoroacetic acid (TFA). The product was obtained by ether diffusion into methanolic solution resulted in colorless crystals of 10 as TFA salt (3.24 g, 5.25 mmol, 24% over two steps).

[0111] 10?TFA: .sup.1H-NMR (600 MHz, CDCl.sub.3): ?=8.67 (s, 2H, H.sub.py), 7.76-7.55 (m, 2H, H.sub.py), 7.25-7.22 (m, 2H, H.sub.py), 7.20-7.15 (m, 1H, H.sub.Bn), 7.12 (t, J=7.3 Hz, 2H, H.sub.py), 7.06 (s, 2H, H.sub.Bn), 6.61 (d, J=7.4 Hz, 2H, H.sub.Bn), 4.75 (s, 1H, CH.sub.OH), 4.53 (d, J=7.8 Hz, 2H, CH.sub.py), 3.70 (d, J=3.2 Hz, 2H, CH2.sub.ax,eq), 3.66-3.56 (m, 2H, CH2.sub.Bn), 3.54 (s, 6H, CO2Me) 3.32 (s, 2H, CH2.sub.ax,eq) ppm; HRMS (ESI): m/z calcd for C.sub.28H.sub.31N.sub.4O.sub.5.sup.+: 503.2289 [M+H].sup.+; found: 503.2286; elemental analysis calcd (%) for C.sub.30H.sub.31F.sub.3N.sub.4O.sub.7: C 58.44, H 5.07, N 9.09; found: C 58.52, H 5.19, N 9.22.

d) Synthesis of Compound 12

[0112] The general procedure 1 (GP1) was conducted using following approach: 3.24 g of 10 (5.25 mmol, 1.0 equiv.), 3.34 g of Na.sub.2CO.sub.3 (31.5 mmol, 6.0 equiv.) and 1.64 g of tert-butyl 6-(bromomethyl)-picolinate 11 (6.04 mmol, 1.2 equiv.) were reacted in 100 ml of MeCN. 12 was recrystallized from hot ethanol (EtOH), yielding the pure compound as colorless solid (2.22 g, 3.20 mmol, 61%).

[0113] .sup.1H-NMR (200 MHz, CDCl.sub.3): ?=8.49 (ddd, J=4.9, 1.8, 0.9 Hz, 2H, H.sub.py), 8.14 (d, J=7.9 Hz, 2H, H.sub.py), 8.07 (dd, J=7.8, 1.1 Hz, 1H, H.sub.pa), 7.78 (t, J=7.7 Hz, 1H, H.sub.pa), 7.57-7.37 (m, 3H, H.sub.py,pa), 7.25-7.14 (m, 2H, H.sub.py), 7.11 (ddd, J=7.4, 4.9, 1.2 Hz, 2H, H.sub.py), 6.85 (dd, J=7.4, 1.9 Hz, 2H, H.sub.py), 4.53 (s, 2H, CH.sub.py), 4.49 (d, J=5.4 Hz, 1H, CHOH), 3.60 (s, 6H, CO.sub.2Me), 3.58 (s, 2H, CH2.sub.pa,Bn), 3.43 (s, 2H, CH2.sub.pa,Bn), 2.66-2.46 (m, 4H, CH2.sub.ax,eq), 1.64 (s, 9H, tBu) ppm.

e) Synthesis of Compound 13

[0114] The general procedure 3 (GP3) was conducted using following approach: Compound 12 (2.22 g, 3.20 mmol, 1.0 equiv.) and Pd/C (222 mg, 10 wt %) were reacted in 140 ml EtOAc. The crude product was dissolved in EtOH (10 ml). Layering with diethyl ether (Et.sub.2O) yielded 13 as colorless solid (1.52 g, 2.53 mmol, 79%).

[0115] 13?0.75MeOH: .sup.1H-NMR (200 MHz, CDCl.sub.3): ?=8.36 (d, J=4.9 Hz, 2H, H.sub.py), 8.24 (d, J=7.1 Hz, 1H, H.sub.pa), 8.12-7.85 (m, 2H, H.sub.py,pa), 7.71-7.52 (m, 2H, H.sub.py,pa), 7.28-7.24 (m, 2H, H.sub.py), 7.19 (dd, J=7.6, 4.8 Hz, 2H, H.sub.py), 5.03 (s, 2H, CH.sub.py), 3.83 (s, 2H, CH2.sub.pa), 3.73 (d, J=1.0 Hz, 1H, CHOH), 3.66 (s, 6H, CO2Me), 3.01 (d, J=5.4 Hz, 4H, CH2.sub.ax,eq), 1.61 (s, 9H, tBu) ppm; HRMS (ESI): m/z calcd for C.sub.32H.sub.38N.sub.5O.sub.7.sup.+: 604.2766 [M+H].sup.+; found: 604.2727; m/z calc. for C.sub.32H.sub.37N.sub.5NaO.sub.7.sup.+: 626.2585 [M+Na].sup.+; found: 626.2587; elemental analysis calcd (%) for C.sub.32.75H.sub.40N.sub.5O.sub.7.75: C 62.67, H 6.42, N 11.16; found: C 62.40, H 6.38, N 11.33.

f) Synthesis of Compound 15

[0116] General procedure 1 (GP1) was followed with following approach: 927 mg of 13 (1.54 mmol, 1.0 equiv), 976 mg of Na.sub.2CO.sub.3 (9.21 mmol, 6.0 equiv.) and 536 mg of tert-butyl 6-(bromomethyl)-[2,2-bipyridine] carboxylate 14 (1.54 mmol, 1.0 equiv.) were reacted in 30 ml of MeCN. The crude product was used in the next step without further purification.

[0117] UPLC-MS (APCI): m/z calcd for C.sub.48H.sub.54N.sub.7O.sub.9.sup.+: 872.399 [M+H].sup.+; found: 872.530 (peak intensity 100%; retention time: 4.00 min). HRMS (ESI): m/z calcd for C.sub.48H.sub.54N.sub.7O.sub.9.sup.+: 872.3978 [M+H].sup.+; found: 872.3968; m/z calc. for C.sub.48H.sub.53N.sub.7NaO.sub.9.sup.+: 894.3797 [M+Na].sup.+; found: 894.3787.

g) Synthesis of Compound A2

[0118] The general procedure 2 (GP2) was conducted with following approach: The crude of 15 (1.42 g, 1.0 equiv.) was reacted in 15 ml of DCM and 15 ml of trifluoroacetic acid (TFA). EtOH (10 ml) and 10 ml of diethyl ether were added to the crude solid. The formed precipitate was collected via filtration and the TFA salt of A2 was obtained as colorless solid (679 mg, 688 ?mol, 45% over two steps).

[0119] 16?1.25TFA.Math.2MeOH.Math.0.5MeCN: .sup.1H-NMR (600 MHz, CD.sub.3OD): ?=8.70 (s, 1H, H.sub.arom), 8.43 (t, J=7.8 Hz, 2H, H.sub.arom), 8.33-8.25 (m, 3H, H.sub.arom), 8.27-8.23 (m, 2H, H.sub.arom), 8.07 (s, 1H, H.sub.arom), 7.76-7.61 (m, 3H, H.sub.arom), 7.33-7.19 (m, 2H, H.sub.arom), 7.07 (s, 2H, H.sub.arom), 6.57 (s, 1H, H.sub.arom), 5.39-5.36 (m, 2H, CH.sub.py), 4.85 (s, 1H, CHOH), 4.75 (s, 2H, CH.sub.2bpic), 4.17 (s, 2H, CH2.sub.ax/eq), 3.78 (d, J=12.5 Hz, 2H, CH.sub.2pic), 3.59 (s, 6H, CO.sub.2Me), 3.52-3.46 (m, 2H, CH2.sub.ax/eq) ppm; .sup.13C-NMR (151 MHz, CD.sub.3OD): ?=208.86, 200.12, 170.61, 168.18, 167.38, 162.85, 157.35, 156.32, 155.53, 151.58, 150.98, 150.91, 149.42, 140.73, 139.76, 138.97, 138.90, 138.71, 126.59, 126.14, 125.28, 121.31, 72.36, 70.79, 62.73, 55.09, 53.98, 53.29, 51.28 ppm;, HRMS (ESI): m/z calcd for C.sub.40H.sub.36N.sub.7O.sub.9: 758.2580 [M?H].sup.?; found: 758.2580; m/z calcd for C.sub.42H.sub.37F.sub.3N.sub.7O.sub.11.sup.?: 872.2509 [M+TFA?H].sup.?; found: 872.2506. elemental analysis calcd (%) for C.sub.45.5H.sub.47.75F.sub.3.75N.sub.7.5O.sub.13.5: C 55.37, H 4.88, N 10.64; found: C 55.28, H 4.73, N 10.65.

h) Synthesis of Tert-butyl 6-methyl-2,2bipyridine Carboxylate (Compound 18)

[0120] 6-Methyl-2,2-bipyridine carboxylic acid 17 (2.52 g, 11.8 mmol, 1.0 equiv.) was dissolved in 100 ml of DCM. To this solution were added 4.22 ml of tert-butyl 2,2,2-trichloroacetimidate (5.15 g, 23.6 mmol, 2.0 equiv.) and a catalytic amount of Boron trifluoride diethyl etherate (BF.sub.3(Et.sub.2O)) (0.24 ml, 276 mg, 1.97 mmol, 20 pl/mmol acid) and the mixture was let to stir for 16 h at room temperature. Sodium carbonate (approx. 150 mg) was added to quench the reaction, the solvent was removed in vacuo and the remaining solid extracted with 200 ml of n-hexane. The extraction process was repeated three times, before removing the solvent in vacuo yielded 18 as colorless solid (1.36 g, 5.00 mmol, 43%).

[0121] .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=8.64 (d, J=8.8 Hz, 1H, C.sub.ar), 8.40 (d, J=7.9 Hz, 1H, C.sub.ar), 8.03 (dt, J=7.8, 1.0 Hz, 1H, C.sub.ar), 7.91 (td, J=7.8, 1.0 Hz, 1H, C.sub.ar), 7.73 (dd, J=8.7, 6.8 Hz, 1H, C.sub.ar), 7.20 (d, J=7.6 Hz, 1H, C.sub.ar), 2.65 (s, 3H, CH.sub.3), 1.66 (s, 9H, tBu) ppm; .sup.13C-NMR (101 MHz, CDCl.sub.3): ?=164.28, 157.87, 154.65, 148.88, 137.80, 137.54, 124.71, 124.00, 118.99, 82.22, 28.28, 27.83 ppm.

i) Synthesis of Tert-butyl 6-(bromomethyl)-[2,2-bipyridine]-6-carboxylate (Compound 14)

[0122] To a solution of 18 (1.99 g, 7.34 mmol, 1.0 equiv.) in CCl.sub.4 (80 ml) was added N-bromosuccinimide (NBS) (1.31 g, 7.34 mmol, 1.0 equiv.) and azobisisobutyronitrile (AIBN) (199 mg, 1.22 mmol, 10 wt %). The resulting suspension was refluxed for 6 h, cooled to room temperature, filtrated and the solvent removed in vacuo. Compound 14 was obtained as colorless solid after purification with column chromatography (SiO.sub.2, gradient from 100% petroleum ether to 15% ethyl acetate) in 30% yield (777 mg, 2.22 mmol).

[0123] 14: .sup.1H-NMR (200 MHz, CDCl.sub.3): ?=8.64 (dd, J=7.8, 1.3 Hz, 1H, C.sub.ar), 8.52 (dd, J=7.9, 1.0 Hz, 1H, C.sub.ar), 8.06 (dd, J=7.7, 1.3 Hz, 1H, C.sub.ar), 7.93 (t, J=7.7 Hz, 1H, C.sub.ar), 7.84 (t, J=7.8 Hz, 1H, C.sub.ar), 7.48 (dd, J=7.7, 1.0 Hz, 1H, C.sub.ar), 4.63 (s, 2H, CH.sub.2), 1.67 (s, 9H, tBu) ppm; .sup.13C-NMR (151 MHz, CDCl.sub.3): ?=164.06, 156.19, 148.82, 138.54, 138.13, 138.11, 125.13, 124.32, 124.21, 123.49, 121.24, 82.47, 33.79, 28.28 ppm; HRMS (ESI): m/z calcd for C.sub.16H.sub.17BrN.sub.2NaO.sub.2.sup.+: 371.0366 [M+Na].sup.+; found: 371.0363; elemental analysis calcd (%) for C.sub.16H.sub.17BrN.sub.2O.sub.2: C 55.03, H 4.91, N 8.02; found: C 54.73, H 4.85, N 8.55.

EXAMPLE 3

Synthesis of Compound 21

[0124] Compound 15 prepared in example 2, step f can be used for preparing compound 21. Here, the OH group forming residue R.sup.4 is subjected to a functionalization. The preparation of compound 21 is shown in scheme B3-1. Compound 21 can be converted into a compound according to the invention by cleavage of the tert-butyl protective group.

##STR00046## ##STR00047##

a) Synthesis of Compound 19

[0125] Under nitrogen and in a flame dried Schlenck flask, 15 (200 mg, 229 ?mol, 1.0 eq.) was dissolved in dry tetrahydrofuran (THF). After addition of sodium hydride (NaH) (60 wtf %, 7.20 mg, 298 ?mol, 1.3 eq.) the reaction mixture was stirred for 1 h at 50? C., until gas evolution stopped. 64.4 mg of 4-nitrobenzylbromide (298 ?mol, 1.3 eq.) was added and the mixture was stirred at 50? C. for 24 h. The reaction was stopped by adding water (5 ml), followed by extraction with DCM (3?50 ml). The combined organic phases were dried over Na.sub.2SO.sub.4, filtrated and the solvent removed under reduced pressure. The product 19 was obtained by column chromatography (C.sub.18-SiO.sub.2, gradient from 80% water to 100% MeOH) as orange solid (75.2 mg, 74.7 ?mol, 32%).

[0126] .sup.1H-NMR (400 MHz, 295K, CDCl.sub.3):=9.06 (d, J=7.8 Hz, 1H, H.sub.py), 8.52-8.40 (m, 3H, H.sub.pa,bpa), 8.17 (d, J=7.8 Hz, 2H, H.sub.pa,bpa), 8.11 (d, J=8.7 Hz, 2H, H.sub.Bn-NO2), 8.05 (td, J=7.4, 1.1 Hz, 2H, H.sub.pa,bpa), 7.98 (t, J=7.8 Hz, 1H, Hp.sub.a/bpa), 7.74 (t, J=7.7 Hz, 1H, H.sub.py), 7.68 (t, J=7.7 Hz, 1H, H.sub.py), 7.47 (td, J=7.6, 1.8 Hz, 3H, H.sub.py,pa/bpa), 7.28 (d, J=8.7 Hz, 2H, H.sub.Bn-NO2), 7.09 (ddd, J=7.5, 4.8, 1.2 Hz, 2H, H.sub.py), 6.77 (d, J=7.5 Hz, 1H, H.sub.py), 5.08 (s, 2H, CH.sub.2,Bn-NO2), 4.65 (s, 2H, CH.sub.py), 4.53 (s, 1H, CHOH), 3.66 (s, 2H, CH.sub.2,bpa), 3.57 (s, 2H, CH.sub.2,pa), 3.47 (s, 6H, CO.sub.2Me), 2.58 (s, 4H, CH.sub.2,ax/eq), 1.68 (s, 9H, (Bu), 1.65 (s, 9H, tBu). .sup.13C-NMR (101 MHz, 295K, CDCl.sub.3):=172.64, 164.94, 164.32, 160.21, 159.69, 158.52, 156.77, 154.76, 154.67, 148.58, 147.40, 147.18, 146.73, 146.54, 137.24, 137.22, 137.00, 136.95, 136.41, 135.96, 128.46, 127.48, 126.95, 125.76, 124.41, 123.58, 122.66, 119.77, 82.28, 82.19, 81.71, 77.48, 76.84, 73.77, 70.09, 65.37, 53.57, 52.67, 51.95, 50.31, 28.41, 28.31. ESI-HRMS (pos. DCM/MeOH): m/z [C.sub.55H.sub.59N.sub.8O11].sup.+ ([M+H].sup.+): calc.: 1007.4298, exp.: 1007.4361; m/z [C.sub.55H.sub.58NgNaO.sub.11].sup.+([M+Na].sup.+): calc.: 1029.4117, exp.: 1029.4171.

b) Synthesis of Compound 20

[0127] 128 mg of 19 (127 ?mol, 1.0 eq.) was placed into a three necked flask and suspended in 40 ml of ethanol (EtOH), Pd/C (26.0 mg, 20wt %) was added and the flask equipped with two valves with stopcock and a reflux condenser attached to a balloon. The apparatus was flushed three times with N.sub.2 and put under vacuum using a water pump. The same procedure was done using H.sub.2, leaving the apparatus under hydrogen the third time. The reaction mixture was let to stir for 48 h at room temperature, before it was filtrated through Celite?. The solvent was removed under reduced pressure and the solids extracted with Et.sub.2O, yielding the product 20 as pale-yellow solid (83.6 mg, 85.6 ?mol, 67%).

[0128] .sup.1H-NMR (600 MHz, 295K, CDCl.sub.3): ?=9.08 (d, J=7.4 Hz, 1H, H.sub.py), 8.47 -8.44 (m, 2H, H.sub.pa,bpa), 8.37 (d, J=8.0 Hz, 1H, H.sub.pa/bpa), 8.16 (d, J=7.6 Hz, 2H, H.sub.pa,bpa), 8.07-8.01 (m, 3H, H.sub.pa,bpa), 7.76 (t, J=7.8 Hz, 1H, H.sub.py), 7.70 (t, J=7.7 Hz, 1H, H.sub.py), 7.47 (td, J=7.6, 1.7 Hz, 2H, H.sub.py), 7.10 (dd, J=7.2, 5.0 Hz, 2H, H.sub.py), 6.89 (d, J=8.3 Hz, 2H, H.sub.Bn-NH2), 6.74 (d, J=7.9 Hz, 1H, H.sub.py), 6.56 (d, J=8.3 Hz, 2H, H.sub.Bn-NH2), 5.12 (d, J=3.8 Hz, 2H, CH.sub.2,Bn-NH2), 4.53 (s, 1H, CHOH), 4.34 (s, 2H, CH.sub.py), 3.64 (s, 2H, CH.sub.2,bpa), 3.56 (s, 6H, CO.sub.2Me), 3.48 (s, 2H, CH.sub.2,pa), 2.53-2.45 (m, 4H, CH.sub.2,ax/eq), 1.66 (s, 9H, tBu), 1.63 (s, 9H, tBu). ESI-HRMS (pos. DCM/MeOH): m/z [C.sub.55H.sub.60N.sub.8NaO.sub.9].sup.+ ([M+Na].sup.+): calc.: 999.4375, exp.: 999.4403.

Synthesis of Compound 21

[0129] 20 mg (20.5 ?mol, 1 eq.) of 20 and 4.8 mg (20.5 ?mol, 1 eq.) of 1,1-thio-carbonyldi-2-(1H)-pyridone were place into an oven dried round-bottom flask and dissolved in dry DCM. The reaction mixture was stirred for 24 h at room temperature.

[0130] The solvent was removed under reduced pressure and purified by preparative HPLC using a Jupiter Proteo (250 mm?21.2 mm, 4 ?m, 90 ?) with a flow rate of 10 mL/min. The solvents used were H.sub.2O+0.1% TFA (A) and acetonitrile+0.1% TFA (B). The gradient was applied as follows: 5 min 50% B, 50% to 90% B in 20 min, 90 to 95% B in 1 min, 5 min 95% B. The retention time is 22.8 min. The fractions were combined and lyophilized to yield product 21 as a colorless powder (14 mg, 13.8 ?mol, 67%).

[0131] ESI-MS (pos. H.sub.2O/CH.sub.3CN): m/z ([M+H].sup.+): calc.: 1019.41, exp.: 1019.06; ([M+Na].sup.+): calc.: 1041.4, exp.: 1041.00; ([M+H?tBu].sup.+): calc.: 963.07, exp.: 963.07; ([M+2H?2+tBu].sup.+): calc.: 906.98, exp.: 906.98. IR (diamond, ATR): ? (-NCS)=2095 cm.sup.?1.

EXAMPLE 4

Synthesis of Compound A3

[0132] The method for preparing compound A3 is shown in scheme B4-1. Compound 22 was synthesized as described in AR. Haller, H. Unholzer, Arch. Pharm. 1971, 304, 654-659, and BA. Samhammer, U. Holzgrabe, R. Haller, Arch. Pharm. 1989, 322, 551-555.

##STR00048## ##STR00049##

a) Synthesis of Compound 22

[0133] General procedure 1 (GP1) was conducted with the following approach: 1.00 g of 22 (1.99 mmol, 1.0 eq.), 1.27 g Na.sub.2CO.sub.3 (11.9 mmol, 6.0 eq.) and 542 mg 11 (1.99 mmol, 1.0 eq.) were reacted for 16 h in 40 ml acetonitrile (MeCN). The product was obtained by crystallization from acetone as colorless solid (888 mg, 1.28 mmol, 64%).

[0134] [C.sub.39H.sub.43NsO.sub.7]: .sup.1H-NMR (600 MHz, 295K, CDCl.sub.3): ?=8.35 (dd, J=5.0, 1.8 Hz, 2H, H.sub.py), 7.84-7.81 (m, 2H, H.sub.py), 7.68 (d, J=7.7 Hz, 1H, H.sub.pa), 7.43-7.40 (m, 2H, H.sub.Bn), 7.39 -7.36 (m, 2H, H.sub.Bn), 7.35-7.32 (m, 2H, H.sub.pa,Bn), 7.29 (td, J=7.7, 1.9 Hz, 2H, H.sub.py), 6.99 (ddd, J=7.5, 4.8, 1.2 Hz, 2H, H.sub.py), 6.67 (d, J=7.8 Hz, 1H, H.sub.pa), 4.91-4.88 (m, 1H, CHOH), 4.77 (s, 2H, CH.sub.py), 3.64 (d, J=1.7 Hz, 2H, CH.sub.2,pa), 3.62 (s, 6H, CO.sub.2Me), 3.36 (s, 2H, CH.sub.2,Bn), 2.64 (s, 2H, CH.sub.2,ax/eq), 2.45 (s, 2H, CH.sub.2,ax/eq), 1.70 (s, 9H, tBu) ppm. .sup.13C-NMR (151 MHz, 295K, CDCl.sub.3):=172.67, 164.49, 159.13, 157.92, 148.96, 148.92, 148.26, 137.85, 136.20, 135.49, 130.65, 129.94, 128.30, 128.18, 127.29, 126.52, 124.78, 122.55, 122.51, 121.70, 81.74, 72.46, 66.77, 64.01, 53.24, 52.21, 52.02, 51.74, 49.33, 49.10, 28.33 ppm. ESI-HRMS (pos. DCM/MeOH): m/z [C.sub.39H.sub.43N.sub.5O.sub.7].sup.+ ([M+H].sup.+): calc.: 694.3244, exp.: 694.3244; elemental analysis (Nr.: 45409): calc.: C 67.52, H 6.25, N 10.09; exp.: C 67.31, H 6.21, N 10.11.

b) Synthesis of Compound 24

[0135] General procedure 3 (GP3) was conducted using following approach: 888 mg of 23 (1.28 mmol) and 88.8 mg of Pd/C were reacted in 60 ml ethyl acetate (EtOAc). The crude product was purified by washing with Et.sub.2O using an ultrasonic bath (10 min) and subsequent filtration. After drying in-vacuo the product 24 was obtained as colorless solid (488 mg, 808 ?mol, 63%).

[0136] 24.0.5 H.sub.2O, [C.sub.32H.sub.38N.sub.507.5]: .sup.1H-NMR (600 MHz, 295K, CDCl.sub.3): ?=8.55 (s, 2H, H.sub.py), 7.78 (d, J=7.2 Hz, 1H, H.sub.ar), 7.58 (d, J=47.8 Hz, 4H, H.sub.ar), 7.15 (d, J=6.4 Hz, 2H, H.sub.ar), 6.87 (s, 1H, H.sub.ar), 4.95-4.44 (m, 3H, CH.sub.py/CHOH), 3.58 (s, 2H, CH.sub.2,pa), 3.47 (s, 6H, CO.sub.2Me), 3.20-3.04 (m, 4H, CH.sub.2,ax/eq), 1.65 (s, 9H, tBu) ppm. .sup.13C-NMR (101 MHz, 295K, CDCl.sub.3): ?=172.93, 164.37, 157.75, 149.47, 148.82, 136.59, 136.22, 123.02, 81.95, 73.60, 70.93, 65.98, 51.94, 51.64, 42.34, 37.44, 28.34 ppm. ESI-HRMS (pos. DCM/MeOH): m/z [C.sub.32H.sub.38N.sub.5O.sub.7].sup.+ ([M+H].sup.+): calc.: 604.2766, exp.: 604.2768 elemental analysis (Nr.: 45330): calc.: C 62.73, H 6.25, N 11.43; exp.: C 62.62, H 6.04, N 11.33.

c) Synthesis of Compound 25

[0137] General procedure 1 (GP1) was followed with the following approach: 431 mg of 24 (713 ?mol, 1.0 eq.), 232 mg Cs.sub.2CO.sub.3 (713 ?mol, 1.0 eq.) and 332 mg of 2 (713 ?mol, 1.0 eq.) were reacted for 30 min in 20 ml MeCN. The bromide 2 was added over a time period of 10 min. The crude product was purified by use of column chromatography (C.sub.18-SiO.sub.2, gradient from 80% water to 100% MeOH) and yielded the 25 as yellow solid (290 mg, 293 ?mol, 41%).

[0138] 25?5 H.sub.2O.Math.0.25 MeCN, [C.sub.55.5H.sub.63.75N.sub.7.25O.sub.16]: .sup.1H-NMR (600 MHz, 295K, CDCl.sub.3): ?=8.36 (d, J=8.5 Hz, 2H, H.sub.py), 7.99 (s, 2H, H.sub.ar), 7.93 (d, J=6.8 Hz, 1H, H.sub.ar), 7.83 (d, J=7.7 Hz, 2H, H.sub.py), 7.67 (t, J=7.9 Hz, 1H, H.sub.ar), 7.62-7.44 (m, 7H, H.sub.ar), 7.22 (s, 2H, H.sub.py), 7.04 (s, 2H, H.sub.py), 6.25 (s, 1H, H.sub.ar), 6.13 (s, 1H, CH.sub.N7), 5.03 (s, 3H, CH.sub.py/CHOH), 4.41 (s, 2H, CH.sub.2,ax/eq), 4.07 (s, 2H, CH.sub.2,ax/eq), 3.63 (s, 6H, CO.sub.2Me), 3.60 (s, 2H, CH.sub.2,pa), 2.38 (s, 6H, OAc), 1.74 (s, 9H, tBu) ppm. .sup.13C-NMR (151 MHz, 295K, CD.sub.2Cl.sub.2): ?=169.97, 169.09, 163.93, 148.92, 148.69, 147.79, 147.65, 141.21, 137.96, 136.95, 129.28, 128.07, 126.00, 123.77, 123.26, 122.92, 117.65, 103.49, 82.67, 66.00, 53.09, 52.73, 49.30, 28.48, 26.81, 21.28 ppm. ESI-HRMS (pos. DCM/MeOH): m/z [C.sub.55H.sub.54N.sub.7O.sub.11].sup.+ ([M+H].sup.+): calc.: 988.3876, exp.: 988.3880; m/z [C.sub.55H.sub.53N.sub.7NaO.sub.11].sup.+ ([M+Na].sup.+): calc.: 1010.3695, exp.: 1010.3703; elemental analysis (Nr.: 45337): calc.: C 61.25, H 5.90, N 9.33; exp.: C 61.07, H 5.75, N 9.30.

d) Synthesis of Compound 26

[0139] To a solution of 25 (1.20 g, 1.21 mmol, 1.0 eq) in methanol (MeOH) (50 ml) was added 386 mg Na.sub.2CO.sub.3 (3.64 mmol, 3.0 eq.) and the mixture was let to stir for 1 h at room temperature (RT). The solvent was removed under reduced pressure and the leftover solids dissolved in same amounts of DCM and water (20 ml). The phases were separated, the aqueous phase extracted with DCM (3?20 ml) and the combined organic phases dried over Na.sub.2SO.sub.4. After filtration the solvent was removed under reduced pressure and the crude product of 26 was used in the next reaction without further purification.

[0140] 26?2 H.sub.2O, [C.sub.51H.sub.53N.sub.7O.sub.11]: .sup.1H-NMR (200 MHz, 300K, CDCl.sub.3): ?=8.30-8.19 (m, 3H, H.sub.ar,py), 7.96 (d, J=8.5 Hz, 2H, H.sub.py), 7.87-7.77 (m, 2H, H.sub.ar), 7.69 (d, J=7.0 Hz, 2H, H.sub.ar), 7.51 -7.34 (m, 5H, H.sub.ar), 7.32-7.20 (m, 2H, H.sub.ar), 7.12 (dd, J=7.3, 1.6 Hz, 2H, H.sub.py), 6.98-6.86 (m, 2H, H.sub.py), 6.73 (d, J=8.0 Hz, 1H, H.sub.ar), 5.20 (s, 1H, CH.sub.N7), 4.73 (s, 1H, CHOH), 4.66 (s, 2H, CH.sub.py), 3.59 (s, 2H, CH.sub.2,pa), 3.50 (s, 6H, CO.sub.2Me), 3.15 (d, J=11.9 Hz, 2H, CH.sub.2,ax/eq), 2.90 (s, 2H, CH.sub.2,ax/eq), 1.66 (s, 9H, tBu) ppm. ESI-HRMS (pos. DCM/MeOH): m/z [C.sub.51H.sub.50N.sub.7O.sub.9].sup.+ ([M+H].sup.+): calc.: 904.3670, exp.: 904.3705; m/z [C.sub.51H.sub.49N.sub.7NaO.sub.9].sup.+ ([M+Na].sup.+): calc.: 926.3489, exp.: 926.3520; elemental analysis (Nr.: 45355): calc.: C 65.16, H 5.68, N 10.43, exp.: C 65.26, H 5.46, N 10.56.

e) Synthesis of Compound 27

[0141] General procedure 2 (GP2) was conducted using following approach: 240 mg of 26 (265 ?mol) was reacted in 10 ml of DCM and 10 ml of trifluoroacetic acid. Product 27 was obtained by precipitation with diethyl ether (Et.sub.2O) from acetonic solution (128 mg, 133 ?mol, 50%).

[0142] 27?1.5 H.sub.2O.Math.HOAc, [C.sub.49H.sub.48N.sub.7O.sub.12,5]: .sup.1H-NMR (400 MHz, 295K, CD.sub.3CN): ?=8.47 (d, J=8.8 Hz, 2H, H.sub.py), 7.97 (d, J=7.7 Hz, 2H, H.sub.py), 7.94-7.87 (m, 2H, H.sub.ar), 7.86-7.79 (m, 1H, H.sub.ar), 7.74-7.67 (m, 2H, H.sub.ar), 7.67-7.59 (m, 3H, H.sub.ar), 7.58-7.51 (m, 2H, H.sub.ar), 7.24 (d, J=7.5 Hz, 4H, H.sub.py), 7.16 (s, 2H, H.sub.ar), 6.57 (s, 1H, H.sub.ar), 6.30 (s, 1H, CH.sub.N7), 5.13 (s, 2H, CH.sub.py), 4.73 (s, 1H, CHOH), 4.05-3.92 (m, 2H, CH.sub.2,ax/eq), 3.86-3.72 (m, 2H, CH.sub.2,ax/eq), 3.59 (s, 2H, CH.sub.2,pa), 3.50 (s, 6H CO.sub.2Me) ppm. .sup.13C-NMR (101 MHz, 295K, CD.sub.3CN): ?=166.64, 156.07, 153.70, 150.29, 146.56, 139.32, 138.57, 130.43, 124.86, 123.65, 119.12, 112.52, 53.64, 49.89 ppm. ESI-HRMS (pos. DCM/MeOH). m/z [C.sub.47H.sub.41KN.sub.7O.sub.9].sup.+ ([M+K].sup.+): calc.: 886.2597, exp.: 886.2528 m/z [C.sub.47H.sub.41N.sub.7NaO.sub.9].sup.+ ([M+Na].sup.+): calc.: 870.2858, exp.: 870.2755; elemental analysis (Nr.: 45315): calc.: C 62.95, H 5.17, N 10.49; exp.: C 63.12, H 5.17, N 10.69.

EXAMPLE 5

Synthesis of Compound A4

[0143] The synthesis of compound A4 illustrates the introduction of an amino acid derivative as residue R.sup.4. The synthesis of compound A4 is shown in scheme B5-1. The synthesis starts with compound 21 that is shown in scheme B5-1 in a varied form. Here, picture A and picture B both are the reproduction of compound 21.

##STR00050##

In picture B the designation py indicates a pyridyl group.

##STR00051## ##STR00052##

The designation Wang used in compounds 28 and 29 indicates a resin for attaching carboxylic acids for further functionalization (S. S. Wang, J. Am. Chem. Soc., 1973, 95, 1328).

[0144] Compound 28 and compound A4 were conducted using SPPS (solid-phase peptide synthesis) approach: All solid-phase peptide synthesis (SPPS) was performed in syringes fitted with internal frits and removable caps on the needle end. The resin remains stuck in the syringe during washing and reagent switching steps. The peptide on the Wang resin 28 was swelled in 1 mL DCM for 30 min and then the solvent was removed. 5.3 mg of 21 (4.7 ?mol) was dissolved in 1 mL DCM, treated with 0.9 ?L (5.2 ?mol) of N,N-diisopropylethylamine (DIPEA) and was added to the pre-swollen 28 (21.8 mg, loading capacity: 0.055 mmol/g). The reaction mixture was then agitated for 2 h at 40? C. The resin was washed thoroughly with DCM (2?1 mL), MeOH (2?1 mL) and Et.sub.2O (2?1 mL). Then, the resin was dried in an oven at 60 ? C.for 15 min. To cleave the synthesized conjugate 29 from the resin and remove the protecting groups, a cleavage cocktail was added to the resin. This mixture consisted of 95% trifluoracetic acid (TFA), 2.5% H.sub.2O, and 2.5% triisopropylsilane (TIPS). The resin was then agitated for 2 h at room temperature (RT). The cleavage cocktail was collected, and the resin was washed with minimal amounts of DMF (?1 mL). The filtrate was concentrated under a stream of nitrogen and the residue was dissolved in CH.sub.3CN/H.sub.2O (1:4, v/v). The pH of the solution was adjusted between 7-8 with 10% ammonia. Finally, 10% (v/v) DMSO was added to the final solution (1 mL per mg) of crude 30 dissolved. The reaction mixture was stirred for 72 h and lyophilized. The crude was purified by semi-preparative HPLC using Gemini C18 (250?10 mm, 5?, 110 ?, Phenomenex), A: H.sub.2O, 0.1% (TFA), B: CH.sub.3CN, 0.1% (TFA), gradient 30-65% B in 25 min, flow rate: 3 mL/min, t.sub.R=17.1 min. The fractions were combined and lyophilized to yield the product A4 as TFA salt: 2.8 mg (1.26 ?mol, 27%)

[0145] A4?TFA: ESI-MS (pos. CH.sub.3CN/H.sub.2O) m/z: [M+H+Fe.sup.3+].sup.2+ calc.: 1078.36, exp.: 1078.26; [M+H+Fe.sup.3+].sup.3+ calc.: 718.90, exp.: 718.99.

EXAMPLE 6

Synthesis of [.SUP.177.Lu]Lu-A1 and [.SUP.177.Lu]Lu-A2

[0146] To prove the high stability of the complexes according to the invention and the ability of fast radiolabeling compounds A1 and A2 according to the invention have been reacted with [.sup.177Lu]LuCl.sub.3 to the complexes [.sup.177Lu]Lu-A1 and [.sup.177Lu]Lu-A2, respectively.

[0147] Different concentrations of [.sup.177Lu]Lu-A1 and [.sup.177Lu]Lu-A2 were prepared by adding 20 ?L (to reach final concentration of 10.sup.?4 M or 10.sup.?6 M) or 2 ?L (to reach final concentration of 10.sup.?5 M or 10.sup.?7 M) of A1 or A2 (10.sup.?3 M or 10.sup.?5 stock solution in ddH.sub.2O) to [.sup.177Lu]LuCl.sub.3 (?5 MBq) diluted in 0.15 M ammonium acetate buffer (0.2 mL, pH 6 or pH 7) at 40 ? C. The formation of the radiolutetium complex was verified by radio-TLC and radio-HPLC. A radiochemical yield >98% was achieved for [.sup.177Lu]Lu-A1 and [.sup.177Lu]Lu-A2 (up to 10.sup.?6 M) at 40? C. and pH 6 within 1 h.

Radio-TLC

[0148] The degree of radiolabeling was assessed by radio-TLC analysis using system 1: Al.sub.2O.sub.3 (neutral) TLC plates (Merck) and 1:1 (v/v) 1M NH.sub.4OAc/MeOH as eluent system, and system 2: iTLC-SA and an aqueous solution of 0.05 M Na-EDTA (pH 7). Plates were scanned using a BAS-1800II system (Raytest).

System 1

[0149] R.sub.f value ([.sup.177Lu]Lu-A1): 0.85 [0150] R.sub.f value ([.sup.177Lu]Lu-A2): 0.85 [0151] R.sub.f value ([.sup.177Lu]Lu3+): 0

System 2

[0152] R.sub.f value ([.sup.177Lu]Lu-A1): 0 [0153] R.sub.f value ([.sup.177Lu]Lu-A2): 0 [0154] R.sub.f value ([.sup.177Lu]Lu3+): 0.9

Radio-HPLC

[0155] The radiochemical purity and yield was monitored by radio-HPLC of [.sup.177Lu]Lu-A1 and [.sup.177Lu]Lu-A2 was performed on a Knauer Smartline System, consisting of a Smartline 1000 pump, a K-2501 UV detector, a Raytest Gabi Star activity detector, Chromgate 2.8 software, and a Smartline 5000 manager using a Phenomenex Aqua C18 column (4.6 mm?250mm, 125 ?, 5 ?m). The flow rate was 1 mL/min and the injection volume 10 ?L. The solvents used were H.sub.2O+0.1% TFA (A) and CH.sub.3CN+0.1% TFA (B). The gradient applied was as follows: 20 min 0% B to 100% B.

[00001]$\begin{array}{c}{t}_R=4.3\min \mathrm{of}{[}^{177}\mathrm{Lu}]{\mathrm{Lu}}^{3+}\\ t_R=16.3\min \mathrm{of}{[}^{177}\mathrm{Lu}]\mathrm{Lu}-A1\\ t_R=11.5\min \mathrm{of}{[}^{177}\mathrm{Lu}]\mathrm{Lu}-A2\end{array}$

EXAMPLE 7

Determination of Partition Coefficients for [.SUP.177.Lu]Lu-A1 and [.SUP.177.Lu]Lu-A2

[0156] Partition Experiments (log D.sub.O/W) have been carried out to determine the distribution ratios of [.sup.177Lu]Lu-A1 or [.sup.177Lu]Lu-A2 in a two-phase system consisting of n-octanol and water at different pH values. The results are shown in table 3. Two replicates have been made.

TABLE-US-00003 TABLE 3 Partition Coefficients (log D.sub.O/W) of the [.sup.177Lu] Lu-bispidine at different pH pH 7.2 7.4 7.6 [.sup.177Lu]Lu-A1 0.77 ? 0.01 0.80 ? 0.01 0.80 ? 0.00 [.sup.177Lu]Lu-A2 ?3.02 ? 0.01 ?3.01 ? 0.01 ?2.98 ? 0.01

[0157] The determination of distribution ratio log D.sub.o/w at 25+1? C. followed the standard method used for copper-64. Information about the lipophilicity of the .sup.177Lu-labeled bispidine ligand A1 or A2 was obtained using water/1-octanol mixtures. An aqueous ammonium acetate buffer solution (0.15 M, 380 ?L, pH 6) containing A1 or A2 (1 mM, 50 ?L) and LuCl.sub.3 (100 M, 50 ?L in 0.01 M HCl) spiked with [.sup.177Lu]LuCl.sub.3 (3-4 MBq , 20 ?L) was prepared. Full complexation was checked by radio-HPLC and radio-TLC, which gave no evidence of free .sup.177Lu3+ in the aqueous phase. Then, 50 ?L of this solution was added to 450 ?L of 0.05 M 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES)-NaOH buffer (pH of 7.2, 7.4, 7.6). The distribution experiments were carried out at room temperature in microcentrifuge tubes (2 cm.sup.3) with mechanical shaking for 30 min. The phase ratio V.sub.(1-octanol):V.sub.(aq) was 1:1 (0.5 mL each). All samples were centrifuged and the phases then separated. The lutetium complex concentration in both phases was determined radiometrically using ?-radiation [.sup.177Lu, NaI(Tl) scintillation counter, Hidex AMG, automatic gamma counter].

EXAMPLE 8

Stability of [.SUP.177.Lu]Lu-A1 and [.SUP.177.Lu]Lu-A2 in the Presence of Human Serum

[0158] The stability of the complexes in the presence of human serum (Sigma, product number: H6914, batch number: SLBS2266V) was investigated by radio-SEC. To 10.sup.?4 M solution of A1 or A2 in 0.15 M NH.sub.4OAc-buffer pH 6, total volume 0.2 mL) was added 100 MBq [.sup.177Lu]LuCl.sub.3 (in 0.01 M HCl). The reaction mixture was incubated for 5 min at 40? C. After complete complexation (radio-TLC), 100 ?L of the [.sup.177Lu]Lu-A1 or [.sup.177Lu]Lu-A2 solution, respectively, was transferred to 250 ?L of human serum and 50 ?L of 1 M HEPES buffer (pH 7.4) was added. The mixture was incubated at 37 ? C. for 7 d. Time points taken for analysis were 1 h, 1 d, 3 d and 7 d using radio-TLC (system 2).

TABLE-US-00004 TABLE 4 Stability of [.sup.177Lu]Lu-A1 and [.sup.177Lu]Lu-A2 monitored intact complex [%]* dependent on time complex by 1 h 1 d 3 d 7 d [.sup.177Lu]Lu-A1 radio-TLC 94 94 83 76 [.sup.177Lu]Lu-A2 radio-TLC 97 96 96 94 *absolute value which is not bound/dissociated to human serum

EXAMPLE 9

Synthesis of [.SUP.225.Ac]Ac-A1 and [.SUP.225.Ac]Ac-A2

[0159] To prove the high stability of the complexes according to the invention and the ability of fast radiolabeling compounds A1 and A2 according to the invention have been reacted with [.sup.225Ac]AcNO.sub.3 to the complexes [.sup.225Ac]Ac-A1 and [.sup.225Ac]Ac-A2, respectively.

[0160] Different concentrations of [.sup.225Ac]Ac-A1 and [.sup.225Ac]Ac-A2 were prepared by adding 20 ?L (to reach final concentration of 10.sup.?4 M or 10.sup.?6 M) or 2 ?L (to reach final concentration of 10.sup.?5 M or 10.sup.?7 M) of A1 or A2 (10.sup.?3 M or 10.sup.?5 stock solution in ddH.sub.2O) to [.sup.225Ac]AcNO.sub.3 (40-100 kBq) diluted in 0.15 M ammonium acetate buffer (0.2 mL, pH 6 or pH 7) at 40 and 80? C. The formation of the radio complex was verified by radio-TLC. A radiochemical yield >98% was achieved up to 10.sup.?6 M at pH 6 for [.sup.225Ac]Ac-A2 at 40? C. and for [.sup.225Ac]Ac-A1 at 80? C. up to 10.sup.?5 M within 5 min.

System 2

[0161] R.sub.f value ([.sup.225Ac]Ac-A1): 0 [0162] R.sub.f value ([.sup.225Ac]Ac-A2): 0 [0163] R.sub.f value (([.sup.225Ac]Ac 3+): 0.85

EXAMPLE 19

Stability of [.SUP.225.Ac]Ac-A1 and [.SUP.225.Ac]Ac-A2 in the Presence of Human Serum

[0164] The stability of the complexes in the presence of human serum (Sigma, product number: H6914, batch number: SLBS2266V) was investigated by radio-TLC (system 2). To 10.sup.?4 M solution of A1 or A2 in 0.15 M NH.sub.4OAc-buffer pH 6, total volume 0.2 mL) was added 600 kBq [.sup.225Ac]AcNO.sub.3 (in 0.01 M HCl). The reaction mixture was incubated for 60 min at 40? C. (for A2) or 80? C. (for A1). After complete complexation (radio-TLC), 100 ?L of the [.sup.225Ac]Ac-A1 or [.sup.225Ac]Ac-A2, respectively, (?300 kBq) solution was transferred to 250 ?L of human serum and 50 L of 1 M HEPES buffer (pH 7.4) was added. The mixture was incubated at 37 ? C.for 10 d. Time points taken for analysis were 1 h, 1 d, 3 d, 7 d and 10 d using radio-TLC (system 2).

TABLE-US-00005 TABLE 5 Stability [%] of [.sup.225Ac]Ac-A1 and [.sup.225Ac]Ac-A2 intact complex [%]* dependent on time complex monitored by 1 h 1 d 3 d 7 d 10 d [.sup.225Ac]Ac-A1 radio-TLC 98 97 83 73 66 [.sup.225Ac]Ac-A2 radio-TLC 99 98 95 94 93 *absolute value which is not bound/dissociated to human serum