Selective inhibitors of carbonic anhydrase

Abstract

Disclosed are novel compounds—benzenesulfonamides of general formulas (I) and (II) ##STR00001## The compounds can be used in biomedicine as active ingredients in pharmaceutical formulations, because they inhibit enzymes which participate in disease progression. Also disclosed are method of treatment using such compounds.

Claims

1. A compound of formula (I): ##STR00013## where A is F, Cl, Br, or I; B is SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1, NHR.sup.1, or N(R.sup.1).sub.2; X is O; Y is OR.sup.2, SR.sup.2, S(O)R.sup.2, SO.sub.2R.sup.2, NHR.sup.2, or N(R.sup.2).sub.2; R.sup.1 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene, and each phenyl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, or heterocycloalkenyl and benzene is unsubstituted or substituted by one or more identical or different groups R.sup.3; R.sup.2 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl or heterocycloalkynyl, each of which is unfused or fused with benzene and each of phenyl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, or heterocycloalkenyl and benzene is unsubstituted or substituted by one or more identical or different groups R.sup.3, or R.sup.2 is linear or branched alkyl each of which is unsubstituted or substituted by one or more identical or different groups R.sup.3; R.sup.3 is R.sup.5, OH, OR.sup.5, SH, SR.sup.5, S(O)R.sup.5, SO.sub.2R.sup.5, C(O)R.sup.5, C(O)OR.sup.5, OC(O)R.sup.5, NHR.sup.5, N(R.sup.5).sub.2, C(O)NHR.sup.5, C(O)N(R.sup.5).sub.2, NHC(O)R.sup.5, NR.sup.5C(O)R.sup.5, NHC(O)OR.sup.5, NR.sup.5C(O)OR.sup.5, NHC(O)NH.sub.2, NHC(O)NHR.sup.5, NHC(O)N(R.sup.5).sub.2, NR.sup.5C(O)NHR.sup.5, NR.sup.5C(O)N(R.sup.5).sub.2, SO.sub.2NHR.sup.5, SO.sub.2N(R.sup.5).sub.2, NHSO.sub.2R.sup.5, NR.sup.5SO.sub.2R.sup.5, NHSO.sub.2NHR.sup.5, NHSO.sub.2N(R.sup.5).sub.2, NR.sup.5SO.sub.2NHR.sup.5, NR.sup.5SO.sub.2N(R.sup.5).sub.2, C(O)NHNOH, C(O)NHNOR.sup.5, C(O)NHSO.sub.2R.sup.5, C(NH)NH.sub.2, C(NH)NHR.sup.5, C(NH)N(R.sup.5).sub.2, NHSO.sub.2NHR.sup.5, NHSO.sub.2N(CH.sub.3)R.sup.5, N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.5, F, Cl, Br, I, CN, NO.sub.2, N.sub.3, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, C(O)OH, C(O)NH.sub.2; R.sup.5 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene and each of phenyl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, or heterocycloalkenyl and benzene is unsubstituted or substituted by one or more identical or different groups R.sup.7; or R.sup.5 is linear or branched alkyl each of which is unsubstituted or substituted by one or more identical or different groups R.sup.7; R.sup.7 is selected from NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, SH, SCH.sub.3, C(O)NH.sub.2, C(O)NHOH, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, C(O)H, C(O)OH, C(O)OCH.sub.3, C(O)OC.sub.2H.sub.5, OH, OCH.sub.3, OC.sub.2H.sub.5, CH.sub.3, C.sub.2H.sub.5, CH(CH.sub.3).sub.2, CN, N.sub.3, NO.sub.2, F, Cl, Br, I, pharmaceutically acceptable salts thereof, or single stereoisomer or mixtures of stereoisomers thereof; with the proviso that when A is Cl then B is not cyclohexylamino; with the proviso that compounds according to formula I exclude 4-chloro-2-(3-methylanilino)-N-(2-methylindolin-1-yl)-5-sulfamoyl-benzamide.

2. A compound, wherein the compound is: 2,4-dichloro-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide, methyl 4-[(2,4-dichloro-5-sulfamoyl-benzoyl)amino]butanoate, N-benzyl-2,4-dichloro-5-sulfamoyl-benzamide, 2,4-dibromo-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 2,4-dibromo-N-butyl-5-sulfamoyl-benzamide, 3-[(2,4-dichloro-5-sulfamoyl-benzoyl)amino]propyl acetate, 2-benzylsulfinyl-4-chloro-N-cyclohexyl-5-sulfamoyl-benzamide, 2-(benzenesulfinyl)-4-bromo-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 4-[(2,4-dichloro-5-sulfamoyl-benzoyl)amino]butanoic acid, 4-[(4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzoyl)amino]butanoic acid, 4-[(2-benzylsulfonyl-4-chloro-5-sulfamoyl-benzoyl)amino]butanoic acid, 4-chloro-N-(2-hydroxyethyl)-2-phenylsulfanyl-5-sulfamoyl-benzamide, 4-chloro-N-(3-hydroxypropyl)-2-phenylsulfanyl-5-sulfamoyl-benzamide, N-butyl-4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzamide, 4-chloro-N-(2-methoxyethyl)-2-phenylsulfanyl-5-sulfamoyl-benzamide, 2-chloro-5-(morpholine-4-carbonyl)-4-phenylsulfanyl-benzenesulfonamide, 4-chloro-N-cyclohexyl-2-phenylsulfanyl-5-sulfamoyl-benzamide, N-benzyl-4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzamide, 4-bromo-N-(2-hydroxyethyl)-2-phenylsulfanyl-5-sulfamoyl-benzamide, 4-bromo-N-butyl-2-phenylsulfanyl-5-sulfamoyl-benzamide, 3-[(4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzoyl)amino]propyl acetate, methyl 4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzoate, 2-methoxyethyl 4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzoate, methyl 4-bromo-2-phenylsulfanyl-5-sulfamoyl-benzoate, 2-(benzenesulfonyl)-4-chloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 2-(benzenesulfonyl)-4-chloro-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide, 2-(benzenesulfonyl)-N-butyl-4-chloro-5-sulfamoyl-benzamide, 2-(benzenesulfonyl)-4-chloro-N-(2-methoxyethyl)-5-sulfamoyl-benzamide, 2-(benzenesulfonyl)-4-chloro-N-cyclohexyl-5-sulfamoyl-benzamide, 2-(benzenesulfonyl)-N-benzyl-4-chloro-5-sulfamoyl-benzamide, 2-(benzenesulfonyl)-4-bromo-N-butyl-5-sulfamoyl-benzamide, methyl 2-(benzenesulfonyl)-4-chloro-5-sulfamoyl-benzoate, methyl 2-(benzenesulfonyl)-4-bromo-5-sulfamoyl-benzoate, 4-chloro-2-cyclohexylsulfanyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 4-chloro-2-cyclohexylsulfanyl-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide, N-butyl-4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzamide, 4-chloro-2-cyclohexylsulfanyl-N-(2-methoxyethyl)-5-sulfamoyl-benzamide, methyl 4-[(4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzoyl)amino]butanoate, 4-chloro-N-cyclohexyl-2-cyclohexylsulfanyl-5-sulfamoyl-benzamide, N-benzyl-4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzamide, 4-bromo-2-cyclohexylsulfanyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 4-bromo-N-butyl-2-cyclohexylsulfanyl-5-sulfamoyl-benzamide, methyl 4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzoate, methyl 4-bromo-2-cyclohexylsulfanyl-5-sulfamoyl-benzoate, 4-chloro-2-cyclohexylsulfonyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 4-chloro-2-cyclohexylsulfonyl-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide, N-butyl-4-chloro-2-cyclohexylsulfonyl-5-sulfamoyl-benzamide, 4-chloro-2-cyclohexylsulfonyl-N-(2-methoxyethyl)-5-sulfamoyl-benzamide, methyl 4-[(4-chloro-2-cyclohexylsulfonyl-5-sulfamoyl-benzoyl)amino]butanoate, 4-chloro-N-cyclohexyl-2-cyclohexylsulfonyl-5-sulfamoyl-benzamide, N-benzyl-4-chloro-2-cyclohexylsulfonyl-5-sulfamoyl-benzamide, 4-bromo-2-cyclohexylsulfonyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 4-bromo-N-butyl-2-cyclohexylsulfonyl-5-sulfamoyl-benzamide, methyl 4-chloro-2-cyclohexylsulfonyl-5-sulfamoyl-benzoate, methyl 4-bromo-2-cyclohexylsulfonyl-5-sulfamoyl-benzoate, 2-benzylsulfanyl-4-chloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 2-benzylsulfanyl-N-butyl-4-chloro-5-sulfamoyl-benzamide, methyl 4-[(2-benzylsulfanyl-4-chloro-5-sulfamoyl-benzoyl)amino]butanoate, 2-benzylsulfanyl-4-chloro-N-cyclohexyl-5-sulfamoyl-benzamide, 2-benzylsulfanyl-4-bromo-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 2-benzylsulfanyl-4-bromo-N-butyl-5-sulfamoyl-benzamide, methyl 2-benzylsulfanyl-4-chloro-5-sulfamoyl-benzoate, 2-benzylsulfonyl-4-chloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, methyl 4-[(2-benzylsulfonyl-4-chloro-5-sulfamoyl-benzoyl)amino]butanoate, 2-benzylsulfonyl-4-chloro-N-cyclohexyl-5-sulfamoyl-benzamide, 2-benzylsulfonyl-4-bromo-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, methyl 2-benzylsulfonyl-4-chloro-5-sulfamoyl-benzoate, N-butyl-4-chloro-2-phenethylsulfanyl-5-sulfamoyl-benzamide, 4-bromo-N-(2-hydroxyethyl)-2-phenethylsulfanyl-5-sulfamoyl-benzamide, 4-bromo-N-butyl-2-phenethylsulfanyl-5-sulfamoyl-benzamide, methyl 4-chloro-2-phenethylsulfanyl-5-sulfamoyl-benzoate, 4-chloro-N-cyclohexyl-2-(2-hydroxyethylsulfanyl)-5-sulfamoyl-benzamide, 4-bromo-N-butyl-2-(2-hydroxyethylsulfanyl)-5-sulfamoyl-benzamide, 4-chloro-N-cyclohexyl-2-(2-hydroxyethylsulfonyl)-5-sulfamoyl-benzamide, 4-chloro-2-(cyclohexylamino)-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide, N-butyl-4-chloro-2-(cyclohexylamino)-5-sulfamoyl-benzamide, 4-chloro-2-(cyclohexylamino)-N-(2-methoxyethyl)-5-sulfamoyl-benzamide, 4-bromo-N-butyl-2-(cyclohexylamino)-5-sulfamoyl-benzamide, methyl 4-chloro-2-(cyclohexylamino)-5-sulfamoyl-benzoate, 2-(benzylamino)-4-chloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide, 2-(benzylamino)-4-chloro-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide, 2-(benzylamino)-N-butyl-4-chloro-5-sulfamoyl-benzamide, 2-(benzylamino)-4-chloro-N-(2-methoxyethyl)-5-sulfamoyl-benzamide, N-benzyl-2-(benzylamino)-4-chloro-5-sulfamoyl-benzamide, 2-(benzylamino)-4-bromo-N-butyl-5-sulfamoyl-benzamide, or N-butyl-4-chloro-2-(cyclooctylamino)-5-sulfamoyl-benzamide.

3. A pharmaceutical composition comprising the compound according to claim 1 and pharmaceutically acceptable diluents, an excipient or a carrier.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1. FTSA data of compounds 19 and 31 binding to CA VA. Top panel shows raw data of 19 binding to CA VA. Panel on the bottom shows the dependence of the protein melting temperatures on ligands concentrations. The curves in this panel show the simulation according to the model.

(2) FIG. 2. Compound 13a binding to CA IX observed by ITC at pH 7.0, 37° C. Panel on the top shows raw data, panel on the bottom shows integrated ITC curve. Experiment was performed in sodium phosphate buffer at pH 7.0, 37° C.

(3) FIG. 3. ITC data of compound 13a binding to CA I, II, IX and XII. Experiments were performed in phosphate buffer at pH 7.0, 37° C.

(4) New compounds of the vention are obtained according to general synthesis schemes A-G.

(5) ##STR00005##

(6) ##STR00006##

(7) ##STR00007##

(8) ##STR00008##

(9) ##STR00009##

(10) ##STR00010##

(11) ##STR00011##

EMBODIMENTS OF THE INVENTION

(12) Represented below are specific examples of invention compounds' synthesis. These examples are presented only for illustrative purpose of the invention; they do not limit the scope of the invention.

Example 1

Preparation of 2,4-dichloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 3), 2,4-dichloro-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide (Compound 4), N-butyl-2,4-dichloro-5-sulfamoyl-benzamide (Compound 5), 2,4-dichloro-N-(2-methoxyethyl)-5-sulfamoyl-benzamide (Compound 6), methyl 4-[(2,4-dichloro-5-sulfamoyl-benzoyl)amino]butanoate (Compound 7), 2,4-dichloro-5-(morpholine-4-carbonyl)benzenesulfonamide (Compound 8), 2,4-dichloro-N-cyclohexyl-5-sulfamoyl-benzamide (Compound 9), N-benzyl-2,4-dichloro-5-sulfamoyl-benzamide (Compound 10), 2,4-dibromo-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 11), 2,4-dibromo-N-butyl-5-sulfamoyl-benzamide (Compound 12)

(13) The mixture of appropriate 2,4-dichloro-5-sulfamoylbenzoic acid (compound 1) or 2,4-dibromo-5-sulfamoylbenzoic acid (compound 2) (10.0 mmol), SOCl.sub.2 (2-3 eq), and 1 drop DMF in toluene (5 ml) was refluxed for 4 h. Excess SOCl.sub.2 and toluene were removed by distillation under reduced pressure, and the crude acid chloride was used directly in the next step.

(14) The solution of 2,4-dihalogeno-N-substituted-5-sulfamoylbenzoyl chloride in THF (30 ml) was added dropwise to a solution of appropriate amine (30.0 mmol) in THF (20 ml) at 0° C. and allowed stirring for 1 h (for compound 7 used methyl 4-aminobutanoate hydrochloride (1.3 eq), Et.sub.3N (2 eq)). The mixture was warmed to room temperature and stirred for another 1-2 h. THF was removed under reduced pressure. Water was added to the residue and product was extracted with EtOAc. The organic layer was washed with 5% HCl (aq), dried over anhydrous MgSO.sub.4, filtered and concentrated.

(15) The compound 3. Recrystallization was accomplished from EtOAc. Yield: 1.69 g, 54%, mp 182-183° C.

(16) .sup.1H NMR δ ppm: 3.31 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.51 (2H, J=6.0 Hz, CH.sub.2OH), 4.77 (1H, br s, OH), 7.81 (2H, s, SO.sub.2NH.sub.2), 7.93 (1H, s, C.sub.3—H), 7.95 (1H, s, C.sub.6—H), 8.67 (1H, t, J=5.6 Hz, NH).

(17) .sup.13C NMR δ ppm: 42.5, 60.0, 129.3, 132.1, 132.5, 134.5, 136.4, 140.3, 165.0.

(18) HRMS calcd. for C.sub.9H.sub.10Cl.sub.2N.sub.2O.sub.4S[(M+H).sup.+]: 312.9811, found: 312.9814.

(19) The compound 4. Recrystallization was accomplished from H.sub.2O. Yield 1.96 g, 60%, mp 153-155° C.

(20) .sup.1H NMR δ ppm: 1.67 (2H, quint, J=6.4 Hz, CH.sub.2), 3.30 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.48 (2H, t, J=6.4 Hz, CH.sub.2OH), 4.49 (1H, br s, OH), 7.83 (2H, s, SO.sub.2NH.sub.2), 7.92 (1H, s, C.sub.3—H), 7.94 (1H, s, C.sub.6—H), 8.65 (1H, t, J=5.6 Hz, NH).

(21) .sup.13C NMR δ ppm: 32.6, 36.9, 58.9, 129.2, 132.1, 132.5, 134.4, 136.4, 140.4, 164.9.

(22) HRMS calcd. for C.sub.10H.sub.12Cl.sub.2N.sub.2O.sub.4S[(M+H).sup.+]: 326.9968, found: 326.9971.

(23) The compound 5. Recrystallization was accomplished from toluene:MeOH (5:1). Yield: 3.03 g, 93%, mp 184-186° C.

(24) .sup.1H NMR δ ppm: 0.91 (3H, t, J=7.2 Hz, CH.sub.3), 1.36 (2H, sext, J=7.2 Hz, CH.sub.2), 1.50 (2H, quint, J=7.2 Hz, CH.sub.2), 3.24 (2H, q, J=6.8 Hz, NHCH.sub.2), 7.81 (2H, s, SO.sub.2NH.sub.2), 7.90 (1H, s, C.sub.3—H), 7.94 (1H, s, C.sub.6—H), 8.62 (1H, t, J=5.6 Hz, NH).

(25) .sup.13C NMR δ ppm: 14.1, 20.0, 31.4, 39.2, 129.1, 132.1, 132.5, 134.4, 136.5, 140.4, 164.8.

(26) HRMS calcd. for C.sub.11H.sub.14Cl.sub.2N.sub.2O.sub.3S[(M+H).sup.+]: 325.0175, found: 325.0174.

(27) The compound 6. Recrystallization was accomplished from toluene:MeOH (5:1). Yield: 2.13 g, 65%, mp 137-139° C.

(28) .sup.1H NMR δ ppm: 3.29 (3H, s, CH.sub.3), 3.38-3.43 (2H, m, NHCH.sub.2), 3.45-3.48 (2H, m, OCH.sub.2), 7.80 (2H, s, SO.sub.2NH.sub.2), 7.91 (1H, s. C.sub.3—H), 7.93 (1H, s, C.sub.6—H), 8.74 (1H, t, J=5.6 Hz, NH).

(29) .sup.13C NMR δ ppm: 39.4, 58.4, 70.7, 129.2, 132.2, 132.5, 134.5, 136.3, 140.3, 165.1.

(30) HRMS calcd. for C.sub.10H.sub.12Cl.sub.2N.sub.2O.sub.4S[(M+H).sup.+]: 326.9968, found: 326.9967.

(31) The compound 7. The product was purified by chromatography on a column of silica gel with EtOAc, R.sub.t=0.80, Yield: 2.03 g, 55%, mp 138-140° C.

(32) .sup.1H NMR δ ppm: 1.77 (2H, quint, J=7.2 Hz, CH.sub.2), 2.41 (2H, t, J=7.6 Hz, COCH.sub.2), 3.27 (2H, q, J=6.8 Hz, NHCH.sub.2), 3.61 (3H, m, CH.sub.3), 7.82 (2H, s, SO.sub.2NH.sub.2), 7.92 (1H, s, C.sub.3—H), 7.95 (1H, s, C.sub.6—H), 8.69 (1H, t, J=5.6 Hz, NH).

(33) .sup.13C NMR δ ppm: 24.7, 31.1, 38.9, 51.8, 129.2, 132.2, 132.5, 134.4, 136.3, 140.4, 165.0, 173.5.

(34) HRMS calcd. for C.sub.12H.sub.14Cl.sub.2N.sub.2O.sub.5S[(M+H).sup.+]: 369.0073, found: 369.0074.

(35) The compound 8. Recrystallization was accomplished from EtOAc. Yield: 2.34 g, 69%, mp 235-236° C.

(36) .sup.1H NMR δ ppm: 3.17-3.20 (2H, m, CH.sub.2), 3.54-3.57 (2H, m, CH.sub.2), 3.58-3.74 (4H, m, 2CH.sub.2), 7.82 (2H, s, SO.sub.2NH.sub.2), 7.93 (1H, s, C.sub.3—H), 7.98 (1H, s, C.sub.6—H).

(37) .sup.13C NMR δ ppm: 42.2, 47.1, 66.3, 66.6, 128.6, 132.2, 132.5, 133.8, 134.9, 141.0, 164.3.

(38) HRMS calcd. for C.sub.11H.sub.12Cl.sub.2N.sub.2O.sub.4S[(M+H).sup.+]: 338.9968, found: 338.9966.

(39) The compound 9. Recrystallization was accomplished from H.sub.2O:MeOH (1:1) and then from toluene:MeOH (5:1). Yield: 2.21 g, 63%, mp 214-215° C.

(40) .sup.1H NMR δ ppm: 1.17-1.34 (5H, m, Cy-H), 1.57-1.59 (1H, m, Cy-H), 1.71 (2H, br s, Cy-H), 1.84-1.86 (2H, m, Cy-H), 3.73 (1H, br s, Cy-H), 7.82 (2H, s, SO.sub.2NH.sub.2), 7.88 (1H, s, C.sub.3—H), 7.93 (1H, s, C.sub.6—H), 8.56 (1H, d, J=7.2 Hz, NH).

(41) .sup.13C NMR δ ppm: 24.9, 25.6, 32.5, 48.8, 129.0, 132.0, 132.4, 134.5, 136.7, 140.3, 164.0.

(42) HRMS calcd. for C.sub.13H.sub.16Cl.sub.2N.sub.2O.sub.3S[(M+H).sup.+]: 351.0331, found: 351.0335.

(43) The compound 10. Recrystallization was accomplished from H.sub.2O:MeOH (1:1) and then from toluene:MeOH (5:1). Yield: 3.05 g, 85%, mp 179-181° C.

(44) .sup.1H NMR δ ppm: 4.49 (2H, d, J=6.0 Hz, CH.sub.2), 7.26-7.33 (1H, m, Ph-H), 7.35-7.40 (4H, m, Ph-H),

(45) 7.84 (2H, s, SO.sub.2NH.sub.2), 7.96 (1H, s, C.sub.3—H), 7.97 (1H, s, C.sub.6—H), 9.21 (1H, t, J=6.0 Hz, NH).

(46) .sup.13C NMR δ ppm: 43.1, 127.5, 127.8, 128.9, 129.3, 132.3, 132.6, 134.5, 136.1, 139.2, 140.4, 165.0.

(47) HRMS calcd. for C.sub.14H.sub.12Cl.sub.2N.sub.2O.sub.3S[(M+H).sup.+]: 359.0018, found: 359.0017.

(48) The compound 11. Recrystallization was accomplished from MeOH. Yield: 1.41 g, 35%, mp 196-198° C.

(49) .sup.1H NMR δ ppm: 3.30 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.51 (2H, br s, CH.sub.2OH), 4.77 (1H, s, OH), 7.74 (2H, s, SO.sub.2NH.sub.2), 7.91 (1H, s, C.sub.6—H), 8.19 (1H, s, C.sub.3—H), 8.64 (1H, t, J=6.0 Hz, NH).

(50) .sup.13C NMR δ ppm: 42.5, 59.9, 120.4, 123.6, 129.0, 138.5, 139.1, 142.5, 166.2.

(51) HRMS calcd. for C.sub.9H.sub.10Br.sub.2N.sub.2O.sub.4S[(M+H).sup.+]: 402.8780 (100%), found: 402.8782 (100%).

(52) The compound 12. Recrystallization was accomplished from MeOH:H.sub.2O (1:1). Yield: 1.33 g, 31%, mp 218-220° C.

(53) .sup.1H NMR δ ppm: 0.91 (3H, t, J=7.2 Hz, CH.sub.3), 1.36 (2H, sext, J=7.2 Hz, CH.sub.2), 1.50 (2H, quint, J=7.2 Hz, CH.sub.2), 3.23 (2H, q, J=6.8 Hz, NHCH.sub.3), 7.79 (2H, s, SO.sub.2NH.sub.2), 7.86 (1H, s, C.sub.6—H), 8.20 (1H, s, C.sub.3—H), 8.61 (1H, t, J=5.6 Hz, NH).

(54) .sup.13C NMR δ ppm: 14.1, 20.0, 31.4, 39.2, 120.3, 123.5, 128.8, 138.5, 139.3, 142.6, 165.9.

(55) HRMS calcd. for C.sub.12H.sub.16Br.sub.2N.sub.2O.sub.3S[(M+H).sup.+]: 428.9301 (100%), found: 428.9297 (100%).

Example 2

Preparation of 3-[(2,4-dichloro-5-sulfamoyl-benzoyl)amino]propyl acetate (Compound 13)

(56) 2,4-dichloro-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide (compound 4) (327 mg, 1.00 mmol) was refluxed in EtOAc (7 mL) with 3 drops of concentrated H.sub.2SO.sub.4 for 2 hours. The reaction mixture was concentrated under reduced pressure and the resultant precipitate was washed with H.sub.2O. Yield: 288 mg, 78%, mp 149-151° C.

(57) .sup.1H NMR δ ppm: 1.83 (2H, quint, J=6.4 Hz, CH.sub.2), 2.02 (3H, s, CH.sub.3), 3.30 (2H, q, J=6.8 Hz, NHCH.sub.2), 4.08 (2H, t, J=6:4 Hz, CH.sub.2O), 7.81 (2H, s, SO.sub.2NH.sub.2), 7.93 (1H, s, C.sub.3—H), 7.95 (1H, s, C.sub.6—H), 8.71 (1H, t, J=5.6 Hz, NH).

(58) .sup.13C NMR δ ppm: 21.2, 28.5, 36.5, 62.1, 129.1, 132.2, 132.5, 134.4, 136.1, 140.2, 164.9, 170.9.

(59) HRMS calcd. for C.sub.12H.sub.14Cl.sub.2N.sub.2O.sub.5S[(M+H).sup.+]: 369.0073, found: 369.0071.

Example 3

Preparation of methyl 2,4-dichloro-5-sulfamoyl-benzoate (Compound 14), 2-methoxyethyl 2,4-dichloro-5-sulfamoyl-benzoate (Compound 15), and methyl 2,4-dibromo-5-sulfamoyl-benzoate (Compound 16)

(60) The mixture of appropriate 2,4-dichloro-5-sulfamoylbenzoic acid (compound 1) or 2,4-dibromo-5-sulfamoylbenzoic acid (compound 2) (10:0 mmol) was refluxed in methanol (100 mL) with concentrated H.sub.2SO.sub.4 (1 mL) for 16 hours (for compounds 14 and 16), or was heated at 120° C. in 2-methoxyethanol (30 mL) with concentrated H.sub.2SO.sub.4 (1 mL) for 20 hours (for compound 15). The reaction mixture was concentrated under reduced pressure.

(61) The compound 14. Recrystallization was accomplished from MeOH. Yield: 2.70 g, 95%, mp 202° C.

(62) .sup.1H NMR δ ppm: 3.91 (3H, s, CH.sub.3), 7.87 (2H, s, SO.sub.2NH.sub.2), 8.04 (1H, s, C.sub.3—H), 8.40 (1H, s, C.sub.6—H).

(63) .sup.13C NMR δ ppm: 53.5, 128.8, 131.7, 134.0, 135.0, 136.8, 140.5, 164.1.

(64) HRMS calcd. for C.sub.8H.sub.7Cl.sub.2NO.sub.4S [(M+H).sup.+]: 283.9546, found: 283.9546.

(65) The compound 15. Recrystallization was accomplished from toluene:EtOAc (6:1). Yield: 0.985 g, 30%, mp 112-113° C.

(66) .sup.1H NMR δ ppm: 3.31 (3H, s, CH.sub.3), 3.66 (2H, t, J=4.8 Hz, CH.sub.2OCH.sub.3), 4.45 (2H, t, J=4.8 Hz, CO.sub.2CH.sub.2), 7.89 (2H, s, SO.sub.2NH.sub.2), 8.04 (1H, s, C.sub.3—H), 8.39 (1H, s, C.sub.6—H).

(67) .sup.13C NMR δ ppm: 58.6, 65.4, 70.0, 128.9, 131.6, 134.0, 135.0, 136.8, 140.6, 163.6.

(68) HRMS calcd. for C.sub.10H.sub.11Cl.sub.2NO.sub.5S [(M+H).sup.+]: 327.9808, found: 327.9811.

(69) The compound 16. Recrystallization was accomplished from MeOH. Yield: 2.35 g, 63%, mp 201-203° C. .sup.1H NMR δ ppm: 3.90 (3H, s, CH.sub.3), 7.84 (2H, s, SO.sub.2NH.sub.2), 8.33 (1H, s, C.sub.6—H), 8.35 (1H, s, C.sub.3—H). .sup.13C NMR δ ppm: 53.6, 123.6, 125.2, 131.3, 131.6, 140.2, 142.8, 164.9.

(70) HRMS calcd. for C.sub.8H.sub.7Br.sub.2NO.sub.4S[(M+H).sup.+]: 373.8515 (100%), found: 373.8514 (100%).

Example 4

Preparation of 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (Compound 19), 2-chloro-5-[2-(5,6-dimethylbenzimidazol-1-yl)acetyl]benzenesulfonamide (Compound 20), 2-chloro-5-[2-(5-methoxybenzimidazol-1-yl)acetyl]benzenesulfonamide 2-chloro-5-[2-(6-methoxybenzimidazol-1-yl)acetyl]benzenesulfonamide (Compounds Mixture 21), 2-chloro-5-(2-imidazol-1-ylacetyl)benzenesulfonamide (Compound 22), 2-chloro-5-[2-(2-ethylimidazol-1-yl)acetyl]benzenesulfonamide (Compound 23), ethyl 1-[2-(4-chloro-3-sulfamoyl-phenyl)-2-oxo-ethyl]imidazole-4-carboxylate and ethyl 3-[2-(4-chloro-3-sulfamoyl-phenyl)-2-oxo-ethyl]imidazole-4-carboxylate (Compounds Mixture 24), 2-chloro-5-[2-(2-phenylimidazol-1-yl)acetyl]benzenesulfonamide (Compound 25), 2-chloro-5-[2-(4,5-diphenylimidazol-1-yl)acetyl]benzenesulfonamide (Compound 26), 5-[2-(benzimidazol-1-yl)acetyl]-2,4-dichloro-benzenesulfonamide (Compound 29), 2,4-dichloro-5-[2-(5,6-dimethylbenzimidazol-1-yl)acetyl]benzenesulfonamide (Compound 30), 2,4-dichloro-5-[2-(5-methoxybenzimidazol-1-yl)acetyl]benzenesulfonamide and 2,4-dichloro-5-[2-(6-methoxybenzimidazol-1-yl)acetyl]benzenesulfonamide (Compounds Mixture 31), 2,4-dichloro-5-(2-imidazol-1-ylacetyl)benzenesulfonamide (Compound 32)

(71) A mixture of the appropriate benzimidazole or imidazole (0.750 mmol), appropriate compound 17 or 18 (0.500 mmol) and NaOAc (49.2 mg, 0.600 mmol) in THF (3 ml) was stirred at room temperature for 24 h. The reaction mixture was poured into H.sub.2O. The precipitate was filtered off, washed with H.sub.2O and then with Et.sub.2O.

(72) The compound 19 was synthesized as described previously (Čapkauskaité, E. et al. (2010), Bioorg. Med. Chem. 18, 7357).

(73) The compound 20. The product was purified by flash chromatography over silica gel with EtOAc then EtOAc:MeOH (2:1), R.sub.f=0.80. Yield: 77.5 mg, 41%, mp 247-249° C.

(74) .sup.1H NMR δ ppm: 2.29 (3H, s, CH.sub.3), 2.31 (3H, s, CH.sub.3), 6.01 (2H, s, CH.sub.2CO), 7.33 (1H, s, C.sub.7′—H), 7.45 (1H, s, C.sub.4′—H), 7.89 (2H, s, SO.sub.2NH.sub.2), 7.95 (2H, d, J=8.4 Hz, C.sub.3—H), 8.03 (1H, s, C.sub.2′—H), 8.35 (1H, dd, J=8.4 Hz, J=2.0 Hz, C.sub.4—H), 8.55 (1H, d, J=2.0 Hz, C.sub.6—H).

(75) .sup.13C NMR δ ppm: 20.3, 20.5, 51.3, 111.1, 119.8, 128.6, 130.3, 131.4, 132.8, 133.2, 133.6, 133.8, 136.2, 142.1, 142.2, 144.4, 192.7.

(76) HRMS calcd. for C.sub.17H.sub.16ClN.sub.3O.sub.3S[(M+H).sup.+]: 378.0674, found: 378.0679.

(77) The compounds mixture 21. The product was purified by flash chromatography over silica gel with EtOAc then EtOAc:MeOH (2:1), R.sub.f=0.79. Yield: 45.6 mg, 24%.

(78) .sup.1H NMR δ ppm: (1:0.9) 3.75 (3H, s, CH.sub.3, compound A), 3.80 (2.7H, s, CH.sub.3, compound B), 6.03 (2H, s, CH.sub.2CO, A), 6.04 (1.8H, s, CH.sub.2CO, B), 6.83 (1H, dd, J=8.8 Hz, J=2.4 Hz, C.sub.5′(6′)—H, A), 6.87 (0.9H, dd, J=8.8 Hz, J=2.4 Hz, C.sub.5′(6′)—H, B), 7.20 (1H, d, J=2.4 Hz, C.sub.7′(4′)—H, A), 7.22 (0.9H, d, J=2.0 Hz, C.sub.7′(4′)—H, B), 7.45 (0.9H, d, J=8.8 Hz, C.sub.4′(7′)—H, B), 7.55 (1H, d, J=8.8 Hz, C.sub.4′(7′)—H, A), 7.87 (1.8H, s, SO.sub.2NH.sub.2, B), 7.88 (2H, s, SO.sub.2NH.sub.2, A), 7.95 (0.9H, d, J=8.4 Hz, C.sub.3—H, B), 7.96 (1H, d, J=8.0 Hz, C.sub.3—H, A), 8.03 (1H, s, C.sub.2′—H, A), 8.10 (0.9H, s, C.sub.2′—H, B), 8.32-8.36 (1.9H, m, C.sub.4—H, A, B), 8.55 (1H, d, J=2.0 Hz, C.sub.6—H, A), 8.56 (0.9H, d, J=2.4 Hz, C.sub.6—H, B).

(79) HRMS calcd. for C.sub.16H.sub.14ClN.sub.3O.sub.4S[(M+H).sup.+]: 380.0466, found: 380.0462.

(80) The compound 22. The product was purified by chromatography on a column of silica gel with EtOAc:MeOH (2:1), R.sub.f=0.52. Yield: 80.9 mg, 54%, mp 228-230° C.

(81) .sup.1H NMR δ ppm: 5.78 (2H, s, CH.sub.2CO), 6.94 (1H, s, C.sub.4′—H), 7.13 (1H, s, C.sub.5′—H), 7.60 (1H, s, C.sub.2′—H), 7.87 (2H, s, SO.sub.2NH.sub.2), 7.91 (1H, d, J=8.0 Hz, C.sub.3—H), 8.26 (1H, dd, J=8.4 Hz, J=2.0 Hz, C.sub.4—H), 8.50 (1H, d, J=2.0 Hz, C.sub.6—H).

(82) .sup.13C NMR δ ppm: 53.2, 121.3, 128.4 (2C), 132.8, 133.0, 133.8, 136.1, 138.8, 142.2, 192.8.

(83) HRMS calcd. for C.sub.11H.sub.10ClN.sub.3O.sub.3S[(M+H).sup.+]: 300.0204, found: 300.0200.

(84) The compound 23. The product was purified by flash chromatography over silica gel with EtOAc then EtOAc:MeOH (2:1), R.sub.f=0.70. Yield: 52.5 mg, 32%, mp 223-225° C.

(85) .sup.1H NMR δ ppm: 1.14 (3H, d, J=7.2 Hz, CH.sub.3), 2.48-2.53 (2H, m, CH.sub.2, superposed with DMSO), 5.74 (2H, s, CH.sub.2CO), 6.81 (1H, d, J=1.2 Hz, C.sub.4′—H), 7.00 (1H, d, J=1.2 Hz, C.sub.5′—H), 7.86 (2H, s, SO.sub.2NH.sub.2), 7.92 (2H, d, J=8.0 Hz, C.sub.3—H), 8.29 (1H, dd, J=8.4 Hz, J=2.0 Hz, C.sub.4—H), 8.52 (1H, d, J=2.0 Hz, C.sub.6—H).

(86) .sup.13C NMR δ ppm: 12.5, 19.5, 52.4, 121.4, 126.4, 128.5, 132.7, 133.2, 133.7, 136.2, 142.2, 149.8, 192.9.

(87) HRMS calcd. for C.sub.13H.sub.14ClN.sub.3O.sub.3S[(M+H).sup.+]: 328.0517, found: 328.0518.

(88) The compounds mixture 24. The product was purified by flash chromatography over silica gel with EtOAc then EtOAc:MeOH (2:1), R.sub.f=0.80. Yield: 55.8 mg, 30%.

(89) .sup.1H NMR δ ppm: (1:0.8) 1.17 (2.4H, t, J=7.2 Hz, CH.sub.3, compound A), 1.28 (3H, t, J=7.2 Hz, CH.sub.3), compound B), 4.14 (1.6H, q, J=7.2 Hz, CH.sub.2CH.sub.3, A), 4.24 (3H, q, J=7.2 Hz, CH.sub.2CH.sub.3, B), 5.85 (2H, s, CH.sub.2CO, B), 5.99 (1.6H, s, CH.sub.2CO, A), 7.74 (1H, s, C.sub.5′(4′)—H, B), 7.75 (0.8H, s, C.sub.2—H, A), 7.88 (4.4H, s, SO.sub.2NH.sub.2, A and B, C.sub.5′(4′)—H, A), 7.93 (2H, d, J=8.4 Hz, C.sub.4—H, B), 7.93 (1.6H, d, J=8.0 Hz, C.sub.4—H, A), 7.99 (1H, s, C.sub.2′—H, B), 8.25 (1H, dd, J=8.4 Hz, J=2.4 Hz, C.sub.3—H, B), 8.31 (0.8H, dd, J=8.4 Hz, J=2.4 Hz, C.sub.3—H, A), 8.51 (1H, d, J=2.4 Hz, C.sub.6—H, B), 8.52 (0.8H, d, J=2.0 Hz, C.sub.6—H, A).

(90) HRMS calcd. for C.sub.14H.sub.14ClN.sub.3O.sub.5S[(M+H).sup.+]: 372.0415, found: 372.0410.

(91) The compound 25. The product was purified by chromatography on a column of silica gel with EtOAc, R.sub.f=0.39. Yield: 54.5 mg, 29%, mp 131-132° C.

(92) .sup.1H NMR δ ppm: 5.87 (2H, s, CH.sub.2CO), 7.07 (1H, d, J=0.8 Hz, C.sub.4′—H), 7.28 (1H, d, J=1.2 Hz, C.sub.5′—H), 7.37-7.44 (3H, m, Ph-H), 7.45-7.51 (2H, m, Ph-H), 7.85 (2H, s, SO.sub.2NH.sub.2), 7.89 (2H, d, J=8.4 Hz, C.sub.3—H), 8.26 (1H, dd, J=8.4 Hz, J=2.0 Hz, C.sub.4—H), 8.48 (1H, d, J=2.0 Hz, C.sub.6—H).

(93) .sup.13C NMR δ ppm: 54.0, 123.9, 128.2, 128.4 (2C), 129.0, 129.1, 131.1, 132.8, 133.2, 133.4, 136.5, 142.2, 147.7, 192.8.

(94) HRMS calcd. for C.sub.17H.sub.14ClN.sub.3O.sub.3S[(M+H).sup.+]: 376.0517, found: 376.0522.

(95) The compound 26. The product was washed with 2M HCl(aq), dried and then recrystallization was accomplished from toluene:MeOH (1:1). Yield: 90.4 mg, 40%, mp 111-112° C.

(96) .sup.1H NMR δ ppm: 5.96 (2H, s, CH.sub.2CO), 7.37-7.53 (10H, m, Ph-H), 7.87 (2H, d, J=8.4 Hz, C.sub.3—H), 7.89 (2H, s, SO.sub.2NH.sub.2), 8.17 (1H, dd, J=8.4 Hz, J=2.0 Hz, C.sub.4—H), 8.43 (1H, d, J=2.0 Hz, C.sub.5—H), 8.36 (1H, s, C.sub.2′—H).

(97) .sup.13C NMR δ ppm: 53.6, 126.0, 127.6, 127.7, 128.6, 129.4, 129.6, 129.9, 130.2, 130.5, 131.0, 131.3, 132.6, 132.9, 133.2, 137.0, 137.4, 142.3, 190.9.

(98) HRMS calcd. for C.sub.23H.sub.18ClN.sub.3O.sub.3S[(M+H).sup.+]: 452.0830, found: 452.0836.

(99) The compound 29. Recrystallizahon was accomplished from MeOH:H.sub.2O (2:1), (twice). Yield: 127 mg, 66%, mp 245-250° C. (dec.).

(100) .sup.1H NMR δ ppm: 5.95 (2H, s, CH.sub.2), 7.20-7.32 (2H, m, C.sub.5′,6′—H), 7.56 (1H, dd, J=6.8 Hz, J=1.6 Hz, C.sub.7′—H), 7.70 (1H, dd, J=6.8 Hz, J=1.6 Hz, C.sub.4′—H), 7.92 (2H, s, SO.sub.2NH.sub.2), 8.11 (1H, s, C.sub.3—H), 8.23 (1H, s, C.sub.2′—H), 8.53 (1H, s, C.sub.6—H).

(101) .sup.13C NMR δ ppm: 53.7, 111.1, 119.8, 122.2, 123.0, 130.3, 133.7, 134.8 (2C), 134.9, 135.3, 140.7, 143.4, 145.2, 194.6.

(102) HRMS calcd. for C.sub.15H.sub.11Cl.sub.2N.sub.3O.sub.3S[(M+H).sup.+]: 383.9971, found: 383.9973.

(103) The compound 30. Recrystallization was accomplished from MeOH:H.sub.2O (2:1), (twice). Yield: 132 mg, 64%, mp 248-251° C.

(104) .sup.1H NMR δ ppm: 2.31 (3H, s, CH.sub.3), 2.32 (3H, s, CH.sub.3), 5.86 (2H, s, CH.sub.2CO), 7.31 (1H, s, C.sub.7′—H), 7.45 (1H, s, C.sub.4′—H), 7.91 (2H, s, SO.sub.2NH.sub.2), 8.05 (1H, s, C.sub.2′—H), 8.10 (1H, s, C.sub.3—H), 8.51 (1H, s, C.sub.6—H).

(105) .sup.13C NMR δ ppm: 20.3, 20.6, 53.6, 111.0, 119.9, 130.3, 130.4, 131.5, 133.4, 133.7, 134.7, 134.9, 135.3, 140.7, 142.1, 144.3, 194.7.

(106) HRMS calcd. for C.sub.17H.sub.15Cl.sub.2N.sub.3O.sub.3S[(M+H).sup.+]: 412.0284, found: 412.0279.

(107) The compounds mixture 31. Recrystallization was accomplished from MeOH:H.sub.2O (1:1), (twice). Yield: 58.0 mg, 28%.

(108) .sup.1H NMR δ ppm: (1:0.8) 3.77 (3H, s, CH.sub.3, compound A), 3.80 (2.4H, s, CH.sub.3, compound B), 5.91 (3.6H, s, CH.sub.2CO, A and B), 6.86 (1H, dd, J=8.8 Hz, J=2.4 Hz, C.sub.5′(6′)—H, A), 6.91 (0.8H, dd J=8.8 Hz, J=2.4 Hz, C.sub.5′(6′)—H, B), 7.16 (1H, d, J=2.4 Hz, C.sub.7′(4′)—H, A), 7.22 (0.8H, d, J=2.0 Hz, C.sub.7′(4′)—H, B), 7.46 (0.8H, d, J=8.8 Hz, C.sub.4′(7′)—H, B), 7.57 (1H, d, J=8.8 Hz, C.sub.4′(7′)—H, A), 7.92 (1.6H, s, SO.sub.2NH.sub.2, B), 7.93 (2H, s, SO.sub.2NH.sub.2, A), 8.11 (1.8H, s, C.sub.3—H, A and B), 8.12 (1H, s, C.sub.2′—H, A), 8.19 (0.8H, s, C.sub.2′—H, B), 8.51 (0.8H, s, C.sub.6—H, B), 8.53 (1H, s, C.sub.6—H, A).

(109) HRMS calcd. for C.sub.16H.sub.13Cl.sub.2N.sub.3O.sub.4S[(M+H).sup.+]: 414.0077, found: 414.0076.

(110) The compound 32. Recrystallization was accomplished from MeOH:EtOAc (1:1), Yield: 26.7 mg, 16%, mp 208-210° C.

(111) .sup.1H NMR δ ppm: 5.62 (2H, s, CH.sub.2CO), 6.93 (1H, s, C.sub.4′—H), 7.15 (1H, s, C.sub.5′—H), 7.63 (1H, s, C.sub.2′—H), 7.88 (2H, s, SO.sub.2NH.sub.2), 8.07 (1H, s, C.sub.3—H), 8.43 (1H, s, C.sub.6—H).

(112) .sup.13C NMR δ ppm: 55.4, 121.1, 128.5, 130.2, 133.6, 134.7, 135.0, 135.1, 138.7, 140.6, 194.9.

(113) HRMS calcd. for C.sub.11H.sub.9Cl.sub.2N.sub.3O.sub.3S[(M+H).sup.+]: 333.9814, found: 333.9818.

Example 5

Preparation of 2-chloro-5-(2-indol-1-ylacetyl)benzenesulfonamide (27) and 2-chloro-5-[2-(3,4-dihydro-2H-quinolin-1-yl)acetyl]benzenesulfonamide (28)

(114) A mixture of the appropriate amine (1.30 mmol) and 5-(2-bromoacetyl)-2-chlorobenzene-1-sulfonamide 1 (200 mg, 0.640 mmol) in THF (4 ml) was stirred at om temperature for 48 h. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure.

(115) The compound 27. Recrystallization was accomplished from 2-PrOH:H.sub.2O (5:1). Yield: 114 mg, 1%, mp 195-198° C.

(116) .sup.1H NMR δ ppm: 2.96 (2H, t, J=8.4 Hz, CH.sub.2), 3.47 (2H, t, J=8.4 Hz, CH.sub.2), 4.76 (2H, s, CH.sub.2CO), 6.48 (1H, d, J=8.0 Hz, C.sub.7′—H), 6.58 (1H, t, J=7.6 Hz, C.sub.5′—H), 6.95 (1H, t, J=7.6 Hz, C.sub.6′—H), 7.05 (1H, d, J=7.2 Hz, C.sub.4′—H), 7.80 (2H, s, SO.sub.2NH.sub.2), 7.85 (1H, d, J=8.4 Hz, C.sub.3—H), 8.24 (1H, dd, J=8.0 Hz, J=2.0 Hz, C.sub.4—H), 8.50 (1H, d, J=2.0 Hz, C.sub.6—H).

(117) .sup.13C NMR δ ppm: 28.6, 53.4, 55.2, 107.0, 117.7, 124.7, 127.5, 128.4, 129.6, 132.6, 133.1, 134.6, 135.7, 142.0, 152.3, 195.6.

(118) HRMS calcd. for C.sub.16H.sub.15ClN.sub.2O.sub.3S[(M+H).sup.+]: 351.0565, found: 351.0569.

(119) The compound 28. Recrystallization was accomplished from 2-PrOH:H.sub.2O (5:1). Yield 195 mg, 84%, mp 210-213° C.

(120) .sup.1H NMR δ ppm: 1.91 (2H, quint, J=6.4 Hz, CH.sub.2), 2.74 (2H, t, J=6.4 Hz, CH.sub.2), 3.34 (2H, t, J=5.6 Hz, CH.sub.2), 4.93 (2H, s, CH.sub.2CO), 6.34 (1H, d, J=7.6 Hz, C.sub.8′—H), 6.48 (1H, td, J=7.2 Hz, J=1.2 Hz, C.sub.6′—H), 6.85 (1H, td, J=7.6 Hz, J=1.6 Hz, C.sub.7′—H), 6.90 (1H, dd, J=7.2 Hz, J=1.2 Hz, C.sub.5′—H), 7.80 (2H, s, SO.sub.2NH.sub.2), 7.87 (2H, d, J=8.4 Hz, C.sub.3—H), 8.26 (1H, dd, J=8.4 Hz, J=2.0 Hz, C.sub.4—H), 8.48 (1H, d, J=2.0 Hz, C.sub.6—H).

(121) .sup.13C NMR δ ppm: 22.3, 28.0, 50.1, 57.7, 110.8, 116.2, 122.3, 127.2, 129.3, 132.6, 132.9, 134.5, 135.8, 142.0, 145.6, 196.3.

(122) HRMS calcd. for C.sub.17H.sub.17ClN.sub.2O.sub.3S [(M+H).sup.+]: 365.0721, found: 365.0718.

Example 6

Preparation of 4-chloro-N-(2-hydroxyethyl)-2-phenylsulfanyl-5-sulfamoyl-benzamide (Compound 3a), 4-chloro-N-(3-hydroxypropyl)-2-phenylsulfanyl-5-sulfamoyl-benzamide (Compound 4a), N-butyl-4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzamide (Compound 5a), 4-chloro-N-(2-methoxyethyl)-2-phenylsulfanyl-5-sulfamoyl-benzamide (Compound 6a), 4-chloro-N-cyclohexyl-2-phenylsulfanyl-5-sulfamoyl-benzamide (Compound 9a), N-benzyl-4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzamide (Compound 10a), 4-bromo-N-(2-hydroxyethyl)-2-phenylsulfanyl-5-sulfamoyl-benzamide (Compound 11a), 4-bromo-N-butyl-2-phenylsulfanyl-5-sulfamoyl-benzamide (Compound 12a), 3-[(4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzoyl)amino]propyl acetate (Compound 13a), methyl 4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzoate (Compound 14a), 2-methoxyethyl 4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzoate (Compound 15a), methyl 4-bromo-2-phenylsulfanyl-5-sulfamoyl-benzoate (Compound 16a), 2-chloro-5-[2-(5,6-dimethylbenzimidazol-1-yl)acetyl]-4-phenylsulfanyl-benzenesulfonamide (Compound 30a)

(123) The mixture of appropriate 2,4-dihalogeno-N-substituted-5-sulfamoylbenzamides (compounds 3-6, 9-13) or appropriate substituted 2,4-dihalogeno-5-sulfamoylbenzoate (compounds 14-16) (1.00 mmol), or 2,4-dichloro-5-[2-(5,6-dimethylbenzimidazol-1-yl)acetyl]benzenesulfonamide (compound 30), MeOH (5 mL), thiophenol (121 mg, 1.10 mmol) and Et.sub.3N (121 mg, 1.20 mmol) was refluxed for 2-6 h. MeOH was evaporated under reduced pressure and the resultant precipitate was washed with H.sub.2O.

(124) The compound 3a. The product was purified by chromatography on a column of silica gel with EtOAc, R.sub.f=0.34, Yield: 255 mg, 66%, mp 192-193° C.

(125) .sup.1H NMR δ ppm: 3.32-3.36 (2H, m, NHCH.sub.2), 3.55 (2H, q, J=6.0 Hz, CH.sub.2OH), 4.79 (1H, t, J=5.6 Hz, OH), 6.80 (1H, s, C.sub.3—H), 7.53-7.57 (5H, m, Ph-H), 7.63 (2H, s, SO.sub.2NH.sub.2), 8.05 (1H, s, C.sub.6—H), 8.74 (1H, t, J=5.2 Hz, NH).

(126) .sup.13C NMR δ ppm: 42.6, 60.0, 128.8, 129.4, 130.4, 130.8, 131.5, 132.3, 133.4, 135.2, 137.8, 144.9, 166.1.

(127) HRMS calcd. for C.sub.15H.sub.15ClN.sub.2O.sub.4S.sub.2 [(M+H).sup.+]: 387.0235, found: 387.0233.

(128) The compound 4a. Recrystallization was accomplished from toluene:2-PrOH (8:1). Yield: 257 mg, 64%, mp 146-148° C.

(129) .sup.1H NMR δ ppm: 1.71 (2H, quint, J=6.4 Hz, CH.sub.2), 3.30-3.35 (2H, m, NHCH.sub.2), 3.51 (2H, q, J=6.0 Hz, CH.sub.2OH), 4.50 (1H, t, J=5.2 Hz, OH), 6.81 (1H, s, C.sub.3—H), 7.54-7.57 (5H, m, Ph-H), 7.64 (2H, s, SO.sub.2NH.sub.2), 8.00 (1H, s, C.sub.6—H), 8.73 (1H, t, J=5.2 Hz, NH).

(130) .sup.13C NMR δ ppm: 32.7, 37.0, 59.0, 128.6, 129.5, 130.4, 130.8, 131.4, 132.2, 133.8, 135.2, 137.9, 144.6, 166.0.

(131) HRMS calcd. for C.sub.16H.sub.17ClN.sub.2O.sub.4S.sub.2 [(M+H).sup.+]: 401.0391, found: 401.0386.

(132) The compound 5a. Recrystallization was accomplished from toluene. Yield: 168 mg, 42%, mp 184-186° C.

(133) .sup.1H NMR δ ppm: 0.92 (3H, t, J=7.0 Hz, CH.sub.3), 1.38 (2H, sext, J=7.6 Hz, CH.sub.2), 1.53 (2H, quint, J=6.8 Hz, CH.sub.2), 3.26 (2H, q, J=6.4 Hz, NHCH.sub.2), 6.82 (1H, s, C.sub.3—H), 7.55 (5H, s, Ph-H), 7.64 (2H, s, SO.sub.2NH.sub.2), 7.99 (1H, s, C.sub.6—H), 8.72 (1H, br s, NH).

(134) .sup.13C NMR δ ppm: 14.2, 20.1, 31.5, 39.3, 128.6, 129.6, 130.3, 130.8, 131.5, 132.2, 133.9, 135.1, 137.9, 144.4, 165.9.

(135) HRMS calcd. for C.sub.17H.sub.19ClN.sub.2O.sub.3S.sub.2 [(M+H).sup.+]: 399.0598, found: 399.0596.

(136) The compound 6a. Recrystallization was accomplished from toluene:2-PrOH (8:1). Yield: 249 mg, 62%, mp 170-172° C.

(137) .sup.1H NMR δ ppm: 3.30 (3H, s, CH.sub.3), 3.43 (2H, q, J=5.2 Hz, NHCH.sub.2), 3.49 (2H, t, J=5.2 Hz, OCH.sub.2), 6.81 (1H, s, C.sub.3—H), 7.54-7.57 (5H, m, Ph-H), 7.63 (2H, s, SO.sub.2NH.sub.2), 8.01 (1H, s, C.sub.6—H), 8.84 (1H, t, J=5.2 Hz, NH).

(138) .sup.13C NMR δ ppm: 39.5, 58.4, 70.7, 128.8, 129.5, 130.4, 130.8, 131.5, 132.4, 133.4, 135.2, 137.8, 144.8, 166.1.

(139) HRMS calcd. for C.sub.16H.sub.17ClN.sub.2O.sub.4S.sub.2 [(M+H).sup.+]: 401.0391, found: 401.0390.

(140) The compound 9a. Recrystallization was accomplished from toluene:2-PrOH (8:1). Yield: 344 mg, 81%, mp 236-238° C.

(141) .sup.1H NMR δ ppm: 1.14-1.19 (1H, m, Cy-H), 1.26-1.37 (4H, m, Cy-H), 1.58-1.61 (1H, m, Cy-H), 1.73-1.75 (2H, m, Cy-H), 1.85-1.87 (2H, m, Cy-H), 3.75 (1H, br s, Cy-H), 6.82 (1H, s, C.sub.3—H), 7.53-7.58 (5H, m, Ph-H), 7.65 (2H, s, SO.sub.2NH.sub.2), 7.95 (1H, s, C.sub.6—H), 8.62 (1H, d, J=8.0 Hz, NH).

(142) .sup.13C NMR δ ppm: 25.1, 25.7, 32.7, 48.9, 128.6, 129.6, 130.3, 130.8, 131.5, 132.1, 134.4, 135.0, 138.0, 144.1, 165.1.

(143) HRMS calcd. for C.sub.19H.sub.21ClN.sub.2O.sub.3S.sub.2 [(M+H).sup.+]: 425.0755, found: 425.0752.

(144) The compound 10a. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (3:1), R.sub.f=0.35. Yield: 377 mg, 87%, mp 208-211° C.

(145) .sup.1H NMR δ ppm: 4.49 (2H, d, J=6.0 Hz, CH.sub.2), 6.82 (1H, s, C.sub.3—H), 7.25-7.30 (1H, m, Ph-H), 7.37-7.40 (4H, m, Ph-H), 7.54-7.60 (5H, m, Ph-H), 7.66 (2H, s, SO.sub.2NH.sub.2), 8.07 (1H, s, C.sub.6—H), 9.34 (1H, t, J=6.0 Hz, NH.sub.2).

(146) .sup.13C NMR δ ppm: 43.2, 127.4, 127.8, 128.7, 128.8, 129.6, 130.4, 130.9, 131.5, 132.5, 133.2, 135.2, 137.9, 139.4, 144.9, 166.0.

(147) HRMS calcd. for C.sub.20H.sub.17ClN.sub.2O.sub.3S.sub.2 [(M+H).sup.+]: 433.0442, found: 433.0443.

(148) The compound 11a. The product was purified by chromatography on a column of silica gel with EtOAc, R.sub.f=0.34. Yield: 362 mg, 84%, mp 191-193° C.

(149) .sup.1H NMR δ ppm: 3.32 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.54 (2H, q, J=5.6 Hz, CH.sub.2OH), 4.80 (1H, t, J=5.2 Hz, OH), 6.79 (1H, s, C.sub.3—H), 7.55 (5H, br s, Ph-H), 7.61 (2H, s, SO.sub.2NH.sub.2), 8.05 (1H, s, C.sub.6—H), 8.74 (1H, br s, NH).

(150) .sup.13C NMR δ ppm: 42.6, 60.0, 121.0, 128.8, 130.4, 130.8, 131.5, 132.9, 134.0, 135.2, 139.5, 144.5, 166.2.

(151) HRMS calcd. for C.sub.15H.sub.15BrN.sub.2O.sub.4S.sub.2[(M+H).sup.+]: 432.9709 (100%), found: 432.9713 (100%).

(152) The compound 12a. Recrystallization was accomplished from toluene. Yield: 244 mg, 55%, mp 184-186° C.

(153) .sup.1H NMR δ ppm: 0.91 (3H, t, J=7.2, Hz, CH.sub.3), 1.37 (2H, sext, J=7.6 Hz, CH.sub.2), 1.52 (2H, quint, J=7.2 Hz, CH.sub.2), 3.25 (2H, q, J=6.8 Hz, NHCH.sub.2) 6.99 (1H, s, C.sub.3—H), 7.53-7.58 (5H, m, Ph-H), 7.62 (2H, s, SO.sub.2NH.sub.2), 7.99 (1H, s, C.sub.6—H), 8.72 (1H, t, J=5.6 Hz, NH).

(154) .sup.13C NMR δ ppm: 14.2, 20.1, 31.5, 39.3, 120.8, 128.6, 130.3, 130.8, 131.5, 133.1, 134.6, 135.1, 139.7, 144.1, 166.0.

(155) HRMS calcd. for C.sub.17H.sub.19BrN.sub.2O.sub.3S.sub.2[(M+H).sup.+]: 445.0073 (100%), found: 445.0071 (100%).

(156) The compound 13a. Recrystallization was accomplished from toluene:2-PrOH (8:1). Yield: 173 mg, 39%, mp 168-171° C.

(157) .sup.1H NMR δ ppm: 1.86 (2H, quint, J=6.4 Hz, CH.sub.2), 2.03 (3H, s, CH.sub.3), 3.32-3.36 (2H, m, NHCH.sub.2), 4.10 (2H, t, J=6.4 Hz, CH.sub.2O), 6.82 (1H, s, C.sub.3—H), 7.55-7.56 (5H, m, Ph-H), 7.64 (2H, s, SO.sub.2NH.sub.2), 8.01 (1H, s, C.sub.6—H), 8.81 (1H, t, J=5.2 Hz, NH).

(158) .sup.13C NMR δ ppm: 21.2, 28.6, 36.7, 62.3, 128.6, 129.6, 130.4, 130.8, 131.4, 132.3, 133.6, 135.2, 138.0, 144.6, 166.0, 170.9.

(159) HRMS calcd. for C.sub.18H.sub.19ClN.sub.2O.sub.5S.sub.2[(M+H).sup.+]: 443.0497, found: 443.0495.

(160) The compound 14a. The product was purified by chromatography on a column of silica gel with CHCl.sub.3EtOAc (10:1), R.sub.f=0.32. Yield: 161 mg, 45%, mp 223-226° C.

(161) .sup.1H NMR δ ppm: 3.94 (3H, s, CH.sub.3), 6.68 (1H, s, C.sub.3—H), 7.62-7.67 (5H, m, Ph-H), 7.71 (2H, s, SO.sub.2NH.sub.2), 8.50 (1H, s, C.sub.6—H).

(162) .sup.13C NMR δ ppm: 53.3, 124.3, 128.7, 130.1, 131.2 (2C), 131.8, 135.2, 136.2, 137.5, 149.6, 164.8.

(163) HRMS calcd. for C.sub.14H.sub.12ClNO.sub.4S.sub.2 [(M+H).sup.+]: 357.9969, found: 357.9970.

(164) The compound 15a. Recrystallization was accomplished from toluene (twice). Yield: 149 mg, 37%, mp 161-163° C.

(165) .sup.1H NMR δ ppm: 3.33 (3H, s, CH.sub.3), 3.70 (2H, t, J=4.8 Hz, CH.sub.2OCH.sub.3), 4.48 (2H, t, J=4.8 Hz, CO.sub.2CH.sub.2), 6.69 (1H, s, C.sub.3—H), 7.60-7.67 (5H, m, Ph-H), 7.75 (2H, s, SO.sub.2NH.sub.2), 8.52 (1H, s, C.sub.6—H).

(166) .sup.13C NMR δ ppm: 58.6, 65.1, 70.1, 124.3, 128.7, 130.1, 131.1 (2C), 131.8, 135.3, 136.2, 137.5, 149.7, 164.3.

(167) HRMS calcd. for C.sub.16H.sub.16ClNO.sub.5S.sub.2 [(M+H).sup.+]: 402.0231, found: 402.0234.

(168) The compound 16a. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (15:1), R.sub.f=0.20, then recrystallization was accomplished from toluene. Yield: 145 mg, 36%, mp 202-204° C.

(169) .sup.1H NMR δ ppm: 3.93 (3H, s, CH.sub.3), 6.89 (1H, s, C.sub.3—H), 7.58-7.63 (5H, m, Ph-H), 7.71 (2H, s, SO.sub.2NH.sub.2), 8.52 (1H, s, C.sub.6—H).

(170) .sup.13C NMR δ ppm: 25.6, 25.7, 32.4, 44.5, 53.2, 125.1, 127.5, 131.0, 133.6, 140.1, 142.5, 165.0.

(171) HRMS calcd. for C.sub.14H.sub.12BrNO.sub.4S.sub.2 [(M+H).sup.4]: 403.9113 (100%), found: 403.9437 (100%).

(172) The compound 30a. Recrystallization was accomplished from acetone:MeOH (1:1). Yield: 146 mg, 30%, mp 229-231° C.

(173) .sup.1H NMR δ ppm: 2.30 (3H, s, CH.sub.3), 2.32 (3H, s, CH.sub.3), 6.01 (2H, s, CH.sub.2CO), 6.78 (1H, s, C.sub.3—H), 7.36 (1H, s, C.sub.7′—H), 7.46 (1H, s, C.sub.4′—H), 7.60 (5H, br s, Ph-H), 7.81 (2H, s, SO.sub.2NH.sub.2), 8.04 (1H, s, C.sub.2′—H), 8.72 (1H, s, C.sub.6—H).

(174) .sup.13C NMR δ ppm: 20.3, 20.6, 51.8, 111.2, 119.8, 129.1, 129.2, 130.3, 130.6, 131.0, 131.1, 131.3, 131.4, 133.7, 135.3, 135.8, 137.5, 142.3, 144.5, 149.0, 193.2.

(175) HRMS calcd. for C.sub.23H.sub.20ClN.sub.3O.sub.3S.sub.2 [(M+H).sup.+]: 486.0707. found: 486.0701.

Example 7

(176) Preparation of 2-chloro-5-(morpholine-4-carbonyl)-4-phenylsulfanyl-benzenesulfonamide (compound 8a). The mixture of 2,4-dichloro-5-(morpholine-4-carbonyl)benzenesulfonamide (compound 8) (339 mg, 1.00 mmol), DMSO (2 mL), cyclohexanethiol (128 mg, 1.10 mmol) and Cs.sub.2CO.sub.3 (652 mg, 2.00 mmol) was heated at 120° C. temperature for 8 h. The mixture was cooled to room temperature and brine was added. The product was extracted with EtOAc (3×7 mL). The organic layer was washed with H.sub.2O, dried over anhydrous MgSO.sub.4, filtered and concentrated.

(177) Recrystallization was accomplished from toluene:2-PrOH (8:1). Yield: 103 mg, 25%, mp 152-154° C.

(178) .sup.1H NMR δ ppm: 3.17 (2H, br s, CH.sub.2), 3.54 (2H, br s, CH.sub.2), 3.62-3.69 (4H, m, 2CH.sub.2), 6.83 (1H, s, C.sub.3—H), 7.56-7.58 (3H, m, Ph-H), 7.62-7.64 (2H, m, Ph-H), 7.75 (2H, s, SO.sub.2NH.sub.2), 7.86 (1H, s, C.sub.6—H).

(179) .sup.13C NMR δ ppm: 42.2, 47.2, 66.3, 66.6, 128.1, 129.0, 130.6, 130.9, 131.0, 132.7, 133.3, 135.5, 140.1, 140.6, 164.6.

(180) HRMS calcd. for C.sub.17H.sub.17ClN.sub.2O.sub.4S.sub.2 [(M+H).sup.+]: 413.0391, found: 413.0393.

Example 8

Preparation of methyl 4-chloro-2-cyclohexylsulfanyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 3b), 4-chloro-2-cyclohexylsulfanyl-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide (Compound 4b), N-butyl-4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzamide (Compound 5b), 4-chloro-2-cyclohexylsulfanyl-N-(2-methoxyethyl)-5-sulfamoyl-benzamide (Compound 6b), methyl 4-[(4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzoyl)amino]butanoate (Compound 7b), 4-chloro-N-cyclohexyl-2-cyclohexylsulfanyl-5-sulfamoyl-benzamide (Compound 9b), N-benzyl-4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzamide (Compound 10b), 4-bromo-2-cyclohexylsulfanyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (compound 11b), 4-bromo-N-butyl-2-cyclohexylsulfanyl-5-sulfamoyl-benzamide (Compound 12b), methyl 4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzoate (Compound 14b), methyl 4-bromo-2-cyclohexylsulfanyl-5-sulfamoyl-benzoate (Compound 16b)

(181) The mixture of appropriate 2,4-dihalogeno-N-substituted-5-sulfamoylbenzamides (compounds 3-7, 9-12) or methyl 2,4-dihalogeno-5-sulfamoylbenzoate (compounds 14, 16) (1.00 mmol), DMSO (2 mL), cyclohexanethiol (128 mg, 1.10 mmol) and K.sub.2CO.sub.3 (553 mg, 4.00 mmol) was heated at 60° C. temperature for 2-4 h. The mixture was cooled to room temperature and brine was added. The product was extracted with EtOAc (3×7 mL). The organic layer was washed with H.sub.2O, dried over anhydrous MgSO.sub.4, filtered and concentrated.

(182) The compound 3b. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (1:2), R.sub.f=0.23. Yield: 307 mg, 78%, mp 136-140° C.

(183) .sup.1H NMR δ ppm: 1.23-1.45 (5H, m, Cy-H), 1.58-1.61 (1H, m, Cy-H), 1.69-1.72 (2H, m, Cy-H), 1.90-1.93 (2H, m, Cy-H), 3.29 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.49-3.58 (3H, m, CH.sub.2OH, Cy-H), 4.73 (1H, t, 5.6 Hz, OH), 7.62 (1H, s, C.sub.3—H), 7.63 (2H, s, SO.sub.2NH.sub.2), 7.86 (1H, s, C.sub.6—H), 8.50 (1H, t, J=5.6 Hz, NH).

(184) .sup.13H NMR δ ppm: 25.6, 25.7, 32.8, 42.5, 44.2, 60.1, 128.4, 130.4, 131.8, 136.4, 137.6, 141.6, 166.5.

(185) HRMS calcd. for C.sub.15H.sub.21ClN.sub.2O.sub.4S.sub.2[(M+H).sup.+]: 393.0704, found: 393.0707.

(186) The compound 4b. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (1:2), R.sub.f=0.23, Yield: 366 mg, 90%, mp 157-159° C.

(187) .sup.1H NMR δ ppm: 1.24-1.47 (5H, m, Cy-H), 1.58-1.61 (1H, m, Cy-H), 1.63-1.72 (4H, m, Cy-H, CH.sub.2), 1.90-1.93 (2H, m, Cy-H), 3.27 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.49 (2H, q, J=6.0 Hz, CH.sub.2OH), 3.52-3.58 (1H, m, Cy-H), 4.47 (1H, t, J=5.2 Hz, OH), 7.63 (1H, s, C.sub.3—H), 7.64 (2H, s, SO.sub.2NH.sub.2), 7.81 (1H, s, C.sub.6—H), 8.49 (1H, t, J=5.2 Hz, NH).

(188) .sup.13C NMR δ ppm: 25.6, 25.7, 32.7, 32.8, 36.9, 44.3, 59.0, 128.2, 130.6, 131.7, 136.7, 137.7, 141.4, 166.4.

(189) HRMS calcd. for C.sub.16H.sub.23ClN.sub.2O.sub.4S.sub.2[(M+H).sup.+]: 407.0861, found 407.0856.

(190) The compound 5b. The product was purified by chromatography on a column of silica gel with: CHCl.sub.3:EtOAc (3:1), R.sub.f=0.35. Yield: 340 mg, 84%, mp 153-154° C.

(191) .sup.1H NMR δ ppm: 0.91 (3H, t, J=7.2 Hz, CH.sub.3), 1.24-1.41 (7H, m, Cy-H, CH.sub.2), 1.49 (2H, quint, J=6.8 Hz, CH.sub.2), 1.57 (1H, br s, Cy-H), 1.69 (2H, br s, Cy-H), 1.90-1.93 (2H, m, Cy-H), 3.22 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.55 (1H, br s, Cy-H), 7.64 (3H, s, C.sub.3—H, SO.sub.2NH.sub.2), 7.80 (1H, s, C.sub.6—H), 8.48 (1H, br s, NH).

(192) .sup.13C NMR δ ppm: 14.1, 20.0, 25.5, 25.7, 31.5, 32.7, 39.1, 44.2, 128.2, 130.6, 131.7, 136.9, 137.8, 141.3, 166.3.

(193) HRMS calcd. for C.sub.17H.sub.25ClN.sub.2O.sub.3S.sub.2[(M+H).sup.+]: 405.1068, found: 405.1064.

(194) The compound 6b. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (1:1), R.sub.f=0.30. Yield: 285 mg, 70%, mp 130-133° C.

(195) .sup.1H NMR δ ppm: 1.24-1.42 (5H, m, Cy-H), 1.58-1.61 (1H, m, Cy-H), 1.69-1.71 (2H, m, Cy-H), 1.91-1.93 (2H, m, Cy-H), 3.29 (3H, m, CH.sub.3), 3.36-3.39 (2H, m, NHCH.sub.2), 3.44-3.46 (2H, m, OCH.sub.2), 3.55 (1H, br s, Cy-H), 7.64 (3H, s, C.sub.3—H, SO.sub.2NH.sub.2), 7.83 (1H, s, C.sub.6—H), 8.61 (1H, br s, NH).

(196) .sup.13C NMR δ ppm: 25.6, 25.7, 32.8, 39.4, 44.2, 58.4, 70.8, 128.4, 130.6, 131.8, 136.4, 137.7, 141.5, 166.5.

(197) HRMS calcd. for C.sub.16H.sub.23ClN.sub.2O.sub.4S.sub.2[(M+H).sup.+]: 407.0861, found: 407.0862.

(198) The compound 7b). Yield: 418 mg, 93%, mp 165-167° C.

(199) .sup.1H NMR δ ppm: 1.15-1.44 (5H, m, Cy-H), 1.57-1.60 (1H, m, Cy-H), 1.68-1.73 (2H, m, Cy-H), 1.77 (2H, quint, J=7.2 Hz, CH.sub.2), 1.89-1.92 (2H, m, Cy-H), 2.43 (2H, t, J=7.2 Hz, COCH.sub.2), 3.24 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.53-3.58 (1H, m, Cy-H), 3.61 (3H, s, CH.sub.3), 7.65 (3H, s, C.sub.3—H, SO.sub.2NH.sub.2), 7.81 (1H, s, C.sub.6—H), 8.55 (1H, t, J=5.6 Hz, NH).

(200) .sup.13C NMR δ ppm: 24.8, 25.5, 25.7, 31.1, 32.7, 38.7, 40.6, 51.8, 128.1, 130.8, 131.7, 136.9, 137.9, 141.2, 166.5, 173.6.

(201) HRMS calcd. for C.sub.18H.sub.25ClN.sub.2O.sub.5S.sub.2[(M+H).sup.+]: 449.0966, found: 449.0962.

(202) The compound 9b. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (5:1), R.sub.f=0.20. Yield: 410 mg, 95%, mp 92-94° C.

(203) .sup.1H NMR δ ppm: 1.10-1.38 (10H, m, Cy-H), 1.57-1.60 (2H, m, Cy-H), 1.69-1.73 (4H, m, Cy-H), 1.82-1.84 (2H, m, Cy-H), 1.90-1.92 (2H, m, Cy-H), 3.51-3.57 (1H, m, Cy-H), 3.67-3.75 (1H, m, Cy-H), 7.63 (1H, s, C.sub.3—H), 7.64 (2H, s, SO.sub.2NH.sub.2), 7.77 (1H, s, 8.40 (1H, d, J=7.6 Hz, NH).

(204) .sup.13C NMR δ ppm: 25.0, 25.6 (2C), 25.7, 32.6, 32.8, 40.4, 48.7, 128.2, 130.8, 131.5, 137.2, 137.8, 141.1, 165.5.

(205) HRMS calcd. for C.sub.19H.sub.22ClN.sub.2O.sub.3S.sub.2[(M+H).sup.+]: 431.1224, found: 431.1227.

(206) The compound 10b. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (3:1), R.sub.f=0.24. Yield: 378 mg, 86%, mp 160-162° C.

(207) .sup.1H NMR δ ppm: 1.21-1.43 (5H, m, Cy-H), 1.56-1.59 (1H, m, Cy-H), 1.68-1.71 (2H, m, Cy-H), 1.89-1.92 (2H, m, Cy-H), 3.54-3.60 (1H, m, Cy-H), 4.45 (2H, d, J=6.0 Hz, CH.sub.2), 7.25-7.29 (1H, m, Ph-H), 7.33-7.40 (4H, m, Ph-H), 7.67 (3H, s, C.sub.3—H, SO.sub.2NH.sub.2), 7.87 (1H, s, C.sub.6—H), 9.09 (1H, t, J=6.0 Hz, NH.sub.2).

(208) .sup.13C NMR δ ppm: 25.4, 25.7, 32.7, 43.0, 44.3, 127.4, 127.8, 128.3, 128.7, 130.8, 131.9, 136.5, 137.8, 139.5, 141.5, 166.5.

(209) HRMS calcd. for C.sub.20H.sub.23ClN.sub.2O.sub.3S.sub.2[(M+H).sup.+]: 439.0911, found: 439.0914.

(210) The compound and 11b. The product was purified by chromatography on a column of silica gel with EtOAc, R.sub.f=0.46. Yield: 367 mg, 84%, mp 118-120° C.

(211) .sup.1H NMR δ ppm: 1.23-1.44 (5H, m, Cy-H), 1.57-1.60 (1H, m, Cy-H), 1.69-1.72 (2H, m, Cy-H), 1.89-1.92 (2H, m, Cy-H), 3.29 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.48-3.56 (3H, m, HOCH.sub.2, Cy-H), 4.72 (1H, t, J=5.6 Hz, OH), 7.60 (2H, s, SO.sub.2NH.sub.2), 7.77 (1H, s, C.sub.3—H), 7.88 (1H, s, C.sub.6—H), 8.48 (1H, t, J=5.6 Hz, NH).

(212) .sup.13C NMR δ ppm: 25.6, 25.7, 32.8, 42.4, 44.4, 60.1, 120.3, 128.4, 134.1, 137.2, 139.5, 141.2, 166.6.

(213) HRMS calcd. for C.sub.15H.sub.21BrN.sub.2O.sub.4S.sub.2[(M+H).sup.+]: 439.0178 (100%), found: 439.0177 (100%).

(214) The compound 12b. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (4:1), R.sub.f=0.31. Yield: 166 mg, 37%, mp 127-129° C.

(215) .sup.1H NMR δ ppm: 0.90 (3H, t, J=7.2, Hz, CH.sub.3), 1.21-1.40 (7H, m, CH.sub.3CH.sub.2, Cy-H), 1.43-1.52 (2H, m, CH.sub.3CH.sub.2CH.sub.2), 1.57-1.60 (1H, m, Cy-H), 1.68-1.72 (2H, m, Cy-H), 1.89-1.92 (2H, m, Cy-H), 3.20 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.52-3.57 (1H, m, Cy-H), 7.62 (2H, s, SO.sub.2NH.sub.2), 7.78 (1H, s, C.sub.3—H), 7.82 (1H, s, C.sub.6—H), 8.48 (1H, t, J=5.6 Hz, NH).

(216) .sup.13C NMR δ ppm: 14.1, 20.0, 25.5, 25.7, 31.5, 32.7, 39.1, 44.4, 120.1, 128.2, 134.2, 137.7, 139.7, 140.9, 166.4.

(217) HRMS calcd. for C.sub.17H.sub.25BrN.sub.2O.sub.3S.sub.2[(M+H).sup.+]: 451.0542 (100%), found: 451.0546 (100%).

(218) The compound 14b. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (10:1). R.sub.f=0.40. Yield: 131 mg, 36%, mp 112-114° C.

(219) .sup.1H NMR δ ppm: 1.21-1.30 (2H, m, Cy-H), 1.38-1.50 (4H, m, Cy-H), 1.60-1.63 (1H, m, Cy-H), 1.70-1.76 (3H, m, Cy-H), 3.71-3.79 (1H, m, Cy-H), 3.88 (3H, s, CH.sub.3), 7.65 (2H, s, SO.sub.2NH.sub.2), 7.71 (1H, s, C.sub.3—H), 8.33 (1H, s, C.sub.6—H).

(220) .sup.13C NMR δ ppm: 25.6, 25.7, 32.4, 40.6, 53.2, 125.1, 130.2, 131.5, 136.4, 140.2, 142.9, 164.4.

(221) HRMS calcd. for C.sub.14H.sub.18ClNO.sub.4S.sub.2[(M+H).sup.+]: 364.0439, found: 364.0440.

(222) The compound 16b. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (15:1), R.sub.f=0.29. Yield: 180 mg, 44%, mp 123-125° C.

(223) .sup.1H NMR δ ppm: 1.24-1.31 (1H, m, Cy-H), 1.38-1.50 (4H, m, Cy-H), 1.60-1.63 (1H, m, Cy-H), 1.70-1.75 (2H, m, Cy-H), 1.95-1.97 (2H, m, Cy-H), 3.69-3.74 (1H, m, Cy-H), 3.88 (3H, s, CH.sub.3), 7.54 (2H, s, SO.sub.2NH.sub.2), 7.85 (1H, s, C.sub.6—H), 8.27 (1H, s, C.sub.3—H).

(224) .sup.13C NMR δ ppm: 25.6, 25.7, 32.4, 44.5, 53.2, 125.1, 127.5, 131.0, 133.6, 140.1, 142.5, 165.0.

(225) HRMS calcd. for C.sub.14H.sub.18BrNO.sub.4S.sub.2[(M+H).sup.+]: 409.9913 (100%), found: 409.9915 (100%).

Example 9

Preparation of methyl 4-[(2-benzylsulfanyl-4-chloro-5-sulfamoyl-benzoyl)amino]butanoate (Compound 7c), methyl 2-benzylsulfanyl-4-chloro-5-sulfamoyl-benzoate (Compound 14c), methyl 4-chloro-2-phenethylsulfanyl-5-sulfamoyl-benzoate (Compound 14d)

(226) The mixture of appropriate methyl 4-[(2,4-dichloro-5-sulfamoyl-benzoyl)amino]butanoate (compound 7) or methyl 2,4-dichloro-5-sulfamoyl-benzoate (compound 14) (1.00 mmol), DMSO (2 mL), appropriate phenylmethanethiol or 2-phenylethanethiol (1.10 mmol) and Et.sub.3N (121 mg, 1.20 mmol) was heated at 50° C. temperature for 6-12 h. The progress of reaction was monitored by TLC. The mixture was cooled to room temperature and brine was added. The product was extracted with EtOAc (3×7 mL). The organic layer was washed with H.sub.2O, dried over anhydrous MgSO.sub.4, filtered and concentrated.

(227) The compound 7c. The product was purified by chromatography on a column of silica gel with EtOAc:CHCl.sub.3 (1:1), R.sub.f=0.42, and then recrystallization was accomplished from H.sub.2O:MeOH (5:1). Yield: 306 mg, 67%, mp 115-118° C.

(228) .sup.1H NMR δ ppm: 1.75 (2H, quint, J=7.2 Hz, CH.sub.2), 2.38 (2H, t, J=7.6 Hz, COCH.sub.2), 3.22 (2H, q, J=6.8 Hz, NHCH.sub.2), 3.59 (3H, s, CH.sub.3), 4.37 (2H, s, CH.sub.2Ph), 7.25-7.36 (3H, m, Ph-H), 7.40-7.43 (2H, m, Ph-H), 7.62 (2H, s, SO.sub.2NH.sub.2), 7.64 (1H, s, C.sub.3—H), 7.86 (1H, s, C.sub.5—H), 8.64 (1H, t, J=6.0 Hz, NH).

(229) .sup.13C NMR δ ppm: 24.7, 31.1, 36.2, 38.8, 51.8, 127.9, 128.1, 129.0, 129.5, 132.2, 134.2, 136.6, 137.2, 143.4, 166.2, 173.5.

(230) HRMS calcd. for C.sub.19H.sub.21ClN.sub.2O.sub.5S.sub.2 [(M+H).sup.+]: 457.0653, found: 457.0652.

(231) The compound 14c. The product was purified by chromatography on a columu of silica gel with CHCl.sub.3:EtOAc (4:1), R.sub.f=0.48. Yield: 119 mg, 32%, mp 125-126° C.

(232) .sup.1H NMR δ ppm: 3.84 (3H, s, CH.sub.3), 4.50 (2H, s, CH.sub.2), 7.27-7.38 (3H, m, Ph-H), 7.50-7.52 (2H, m, Ph-H), 7.64 (2H, s, SO.sub.2NH.sub.2), 7.69 (1H, s, C.sub.3—H), 8.31 (1H, s, C.sub.6—H).

(233) .sup.13C NMR δ ppm: 36.3, 53.2, 124.9, 128.0, 129.1, 129.2, 129.8, 131.3, 135.8, 136.4, 139.1, 143.7, 164.3.

(234) HRMS calcd. for C.sub.15H.sub.14ClNO.sub.4S.sub.2 [(M+H).sup.+]: 372.0126, found: 372.0125.

(235) The compound 14d. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (5:1). R.sub.f=0.67. Yield: 96.5 mg, 25%, mp 111-112° C.

(236) .sup.1H NMR δ ppm: 2.97 (2H, t, J=7.6 Hz, CH.sub.2Ph), 3.46 (2H, t, J=7.6 Hz, CH.sub.2S), 3.88 (3H, s, CH.sub.3),

(237) 7.23 (1H, br s, Ph-H), 7.29-7.33 (4H, m, Ph-H), 7.59 (2H, s, SO.sub.2NH.sub.2), 7.65 (1H, s, C.sub.3—H), 8.31 (1H, s, C.sub.6—H).

(238) .sup.13C NMR δ ppm: 33.3, 34.1, 53.2, 124.8, 126.9, 128.9, 129.1, 129.2, 131.2, 136.5, 139.4, 140.0, 143.9, 164.4.

(239) HRMS calcd. for C.sub.16H.sub.16ClNO.sub.4S.sub.2 [(M+H).sup.+]: 386.0282, found: 386.0282.

Example 10

Preparation of 2-benzylsulfanyl-4-chloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 3c), 2-benzylsulfanyl-N-butyl-4-chloro-5-sulfamoyl-benzamide (Compound 5c), N-butyl-4-chloro-2-phenethylsulfanyl-5-sulfamoyl-benzamide (Compound 5d), 2-benzylsulfanyl-4-chloro-N-cyclohexyl-5-sulfamoyl-benzamide (Compound 9c), 4-chloro-N-cyclohexyl-2-(2-hydroxyethylsulfanyl)-5-sulfamoyl-benzamide (Compound 9e), 2-benzylsulfanyl-4-bromo-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 11e), 4-bromo-N-(2-hydroxyethyl)-2-phenethylsulfanyl-5-sulfamoyl-benzamide (Compound 11d), 2-benzylsulfanyl-4-bromo-N-butyl-5-sulfamoyl-benzamide (Compound 12c), 4-bromo-N-butyl-2-phenethylsulfanyl-5-sulfamoyl-benzamide (Compound 12d), 4-bromo-N-butyl-2-(2-hydroxyethylsulfanyl)-5-sulfamoyl-benzamide (Compound 12e)

(240) The mixture of appropriate 2,4-dihalogeno-N-substituted-5-sulfamoylbenzamides (compounds 3, 5, 9, 11, and 12) (1.00 mmol), DMSO (2 mL), appropriate phenylmethanethiol, 2-phenylethanethiol, or 2-mercaptoethanol (1.10 mmol) and Et.sub.3N (121 mg, 1.20 mmol) was heated at 50-70° C. temperature for 6-12 h. The progress of reaction was monitored by TLC. The mixture was cooled to room temperature and brine was added. The product was extracted with EtOAc (3×7 mL). The organic layer was washed with H.sub.2O, dried over anhydrous MgSO.sub.4, filtered and concentrated.

(241) The compound 3c. Recrystallization was accomplished from H.sub.2O:MeOH (5:1) and then from toluene:MeOH (5:1). Yield: 241 mg, 60%, mp 193-195° C.

(242) .sup.1H NMR δ ppm: 3.28 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.50 (2H, q, J=6.0 Hz, CH.sub.2OH), 4.35 (2H, s, CH.sub.2Ph), 4.73 (1H, t, J=5.6 Hz, OH), 7.26-7.44 (5H, m, Ph-H), 7.59 (2H, s, SO.sub.2NH.sub.2), 7.62 (1H, s, C.sub.3—H), 7.92 (1H, s, C.sub.6—H), 8.56 (1H, t, J=5.6 Hz, NH).

(243) .sup.13C NMR δ ppm: 36.2, 42.5, 60.0, 127.9, 128.3, 128.7, 129.0, 129.5, 132.2, 133.9, 136.6, 137.0, 134.8, 166.3.

(244) HRMS calcd. for C.sub.16H.sub.17ClN.sub.2O.sub.4S.sub.2 [(M+H).sup.+]: 401.0391, found: 401.0393.

(245) The compound 5c. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (3:1), R.sub.f=0.40, Yield: 153 mg, 37%, mp 148-150° C.

(246) .sup.1H NMR δ ppm: 0.89 (3H, t, J=7.2 Hz, CH.sub.3), 1.33 (2H, sext, J=7.2 Hz, CH.sub.2), 1.48 (2H, quint, J=7.2 Hz, CH.sub.2), 3.20 (2H, q, J=6.8 Hz, NHCH.sub.2), 4.36 (2H, s, CH.sub.2Ph), 7.25-7.36 (3H, m, Ph-H), 7.41-7.43 (2H, m, Ph-H), 7.61 (2H, s, SO.sub.2NH.sub.2), 7.63 (1H, s, C.sub.3—H), 7.85 (1H, s, C.sub.6—H), 8.56 (1H, t, J=5.6 Hz, NH).

(247) .sup.13C NMR δ ppm: 14.1, 20.0, 31.4, 36.2, 39.2, 127.8, 128.1, 128.8, 129.0, 129.5, 132.1, 134.4, 136.6, 137.2, 143.4, 166.1.

(248) HRMS calcd. for C.sub.18H.sub.21N.sub.2O.sub.3S.sub.2 [(M+H).sup.+]: 413.0755, found: 413.0757.

(249) The compound 5d. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (3:1), R.sub.f=0.45. Yield: 265 mg, 62%, mp 87-88° C.

(250) .sup.1H NMR δ ppm: 0.90 (3H, t, J=7.2 Hz, CH.sub.3), 1.34 (2H, sext, J=7.2 Hz, CH.sub.2), 1.48 (2H, quint, J=7.2 Hz, CH.sub.2), 2.89 (2H, t, J=7.6 Hz, CH.sub.2Ph), 3.20 (2H, q, J=6.8 Hz, NHCH.sub.2), 3.32-3.35 (2H, m, CH.sub.2S), 7.21-7.25 (1H, m, Ph-H), 7.28-7.33 (4H, m, Ph-H), 7.60 (1H, s, C.sub.3—H), 7.62 (2H, s, SO.sub.2NH.sub.2), 7.83 (1H, s, C.sub.6—H), 8.53 (1H, t, J=5.6 Hz, NH).

(251) .sup.13C NMR δ ppm: 14.1, 20.1, 31.5, 33.2, 34.3, 39.2, 126.9, 128.1, 128.7, 128.8, 129.1, 132.1, 135.1, 137.2, 140.1, 143.2, 166.2.

(252) HRMS calcd. for C.sub.19H.sub.23ClN.sub.2O.sub.3S.sub.2 [(M+H).sup.+]: 427.0911, found: 427.0907.

(253) The compound 9c. Recrystallization was accomplished from H.sub.2O:MeOH (5:1) and then from toluene:MeOH (5:1). Yield: 329 mg, 75%, mp 194-196° C.

(254) .sup.1H NMR δ ppm: 1.07-1.13 (1H, m, Cy-H), 1.22-1.33 (4H, m, Cy-H), 1.56-1.59 (1H, m, Cy-H), 1.66-1.72 (2H, m, Cy-H), 1.79-1.85 (2H, m, Cy-H), 3.63-3.72 (1H, m, Cy-H), 4.36 (2H, s, CH.sub.2Ph), 7.25-7.31 (1H, m, Ph-H), 7.33-7.36 (2H, m, Ph-H), 7.41-7.43 (2H, m, Ph-H), 7.61 (2H, s, SO.sub.2NH.sub.2), 7.62 (1H, s, C.sub.3—H), 7.81 (1H, s, C.sub.6—H), 8.47 (1H, d, J=7.6 Hz, NH).

(255) .sup.13C NMR δ ppm: 25.1, 25.6, 32.6, 36.2, 48.8, 127.9, 128.1, 128.8, 128.9, 129.0, 129.5, 129.9, 131.9, 136.7, 143.2, 165.3.

(256) HRMS calcd. for C.sub.20H.sub.23ClN.sub.2O.sub.3S.sub.2[(M+H).sup.+]: 439.0911, found: 439.0911.

(257) The compound 9e. The product was purified by chromatography on a column of silica gel with EtOAc:CHCl.sub.3 (1:1), R.sub.f=0.18, and then recrystallization was accomplished from H.sub.2O:MeOH (5:1). Yield: 185 mg, 47%, mp 180-181° C.

(258) .sup.1H NMR δ ppm: 1.09-1.18 (1H, m, Cy-H), 1.20-1.35 (4H, m, Cy-H), 1.57-1.60 (1H, m, Cy-H), 1.70-1.74 (2H, Cy-H), 1.82-1.84 (2H, m, Cy-H), 3.13 (2H, t, J=6.4 Hz, SCH.sub.2), 3.61 (2H, q, J=6.0 Hz, CH.sub.2OH), 3.66-3.74 (1H, m, Cy-H), 5.05 (1H, t, J=5.6 Hz, OH), 7.61 (1H, s, C.sub.3—H), 7.62 (2H, s, SO.sub.2NH.sub.2), 7.78 (1H, s, C.sub.6—H), 8.44 (1H, d, J=7.6 Hz, NH).

(259) .sup.13C NMR δ ppm: 25.1, 25.7, 32.6, 35.1, 48.7, 59.9, 128.1, 128.7, 131.9, 135.5, 137.2, 143.2, 165.5.

(260) HRMS calcd. for C.sub.15H.sub.21ClN.sub.2O.sub.4S.sub.2 [(M+H).sup.+]: 393.0704, found: 393.0706.

(261) The compound 11c. The product was purified by chromatography on a column of silica gel with EtOAc, R.sub.f=0.50. Yield: 352 mg, 79%, mp 147-149° C.

(262) .sup.1H NMR δ ppm: 3.28 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.50 (2H, q, J=6.4 Hz, HOCH.sub.2), 4.35 (2H, s, SCH.sub.2), 4.74 (1H, t, J=5.2 Hz, OH), 7.26-7.45 (5H, m, Ph-H), 7.56 (2H, s, SO.sub.2NH.sub.2), 7.77 (1H, s, C.sub.3—H), 7.94 (1H, s, C.sub.6—H), 8.55 (1H, t, J=5.6 Hz, NH).

(263) .sup.13C NMR δ ppm: 36.2, 42.5, 60.0, 120.9, 127.9, 128.3, 129.0, 129.5, 132.2, 134.6, 136.6, 138.9, 143.4, 166.4.

(264) HRMS calcd. for C.sub.16H.sub.17BrN.sub.2O.sub.4S.sub.2[(M+H).sup.+]: 446.9865 (100%), found: 446.9870 (100%).

(265) The compound 11d. The product was purified by chromatography on a column of silica gel with EtOAc, R.sub.f=0.42. Yield: 193 mg, 42%, mp 154-156° C.

(266) .sup.1H NMR δ ppm: 2.89 (2H, t, J=7.6 Hz, SCH.sub.2CH.sub.2), 3.26-3.32 (4H, m, NHCH.sub.2, SCH.sub.2), 3.50 (2H, q, J=6.0 Hz, HOCH.sub.2), 4.74 (1H, t, J=5.2 Hz, OH), 7.21-7.34 (5H, m, Ph-H), 7.58 (2H, s, SO.sub.2NH.sub.2), 7.74 (1H, s, C.sub.3—H), 7.92 (1H, s, C.sub.6—H), 8.53 (1H, t, J=5.6 Hz, NH).

(267) .sup.13C NMR δ ppm: 33.3, 34.3, 42.5, 60.1, 120.9, 126.9, 128.3, 128.9, 129.0, 132.1, 135.3, 138.9, 140.2, 143.1, 166.5.

(268) HRMS calcd. for C.sub.17H.sub.19BrN.sub.2O.sub.4S.sub.2[(M+H).sup.+]: 461.0022 (100%), found: 461.0016 (100%).

(269) The compound 12e. The product was purified by chromatography on a column of silica gel with EtOAc:CHCl.sub.3 (4:1), R.sub.f=0.24. Yield: 165 mg, 36%, mp 155-157° C.

(270) .sup.1H NMR δ ppm: 0.89 (3H, t, J=7.2, Hz, CH.sub.3), 1.34 (2H, sext, J=7.2 Hz, CH.sub.3CH.sub.2), 1.48 (2H, quint, J=6.8 Hz, CH.sub.3CH.sub.2CH.sub.2), 3.20 (2H, q, J=6.8 Hz, NHCH.sub.2), 4.36 (2H, s, SCH.sub.2), 7.25-7.43 (5H, m, Ph-H), 7.57 (2H, s, SO.sub.2NH.sub.2), 7.78 (1H, s, C.sub.6—H), 7.87 (1H, s, C.sub.6—H), 8.54 (1H, t, J=5.6 Hz, NH).

(271) .sup.13C NMR δ ppm: 14.1, 20.0, 31.4, 36.2, 39.2, 120.7, 127.8, 128.1, 129.0, 129.5, 132.3, 135.1 136.7, 139.0, 143.0, 166.2.

(272) HRMS calcd. for C.sub.18H.sub.21BrN.sub.2O.sub.3S.sub.2[(M+H).sup.+]: 459.0230 (100%), found: 459.0231 (100%).

(273) The compound 12d. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc(4:1), R.sub.f=0.28. Yield: 259 mg, 55%, mp 157-159° C.

(274) .sup.1H NMR δ ppm 0.91 (3H, t, J=7.2, Hz, CH.sub.3), 1.35 (2H, sext, J=7.2 Hz, CH.sub.3CH.sub.2), 1.49 (2H, quint, J=6.8 Hz, CH.sub.3CH.sub.2CH.sub.2), 2.90 (2H, t, J=7.2 Hz, SCH.sub.2CH.sub.2), 3.21 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.33 (2H, t, J=7.6 Hz, SCH.sub.2), 7.21-7.33 (5H, m, Ph-H), 7.53 (2H, s, SO.sub.2NH.sub.2), 7.74 (1H, s, C.sub.3—H), 7.87 (1H, s, C.sub.6—H), 8.44 (1H, t, J=5.2 Hz, NH).

(275) .sup.13C NMR δ ppm: 14.1, 20.0, 31.5, 33.3, 34.4, 39.2, 120.7, 126.9, 128.2, 128.8, 129.0, 132.1 135.9, 139.0, 140.1, 142.8, 166.3.

(276) HRMS calcd. for C.sub.19H.sub.23BrN.sub.2O.sub.3S.sub.2[(M+H).sup.+]: 473.0386 (100%), found: 473.0385 (100%).

(277) The compound 12e. The product was purified by chromatography on a column of silica gel with EtOAc:CHCl.sub.3 (3:1), R.sub.f=0.32. Yield: 144 mg, 35%, mp 153-155° C.

(278) .sup.1H NMR δ ppm: 0.91 (3H, t, J=7.2, Hz, CH.sub.3), 1.35 (2H, sext, J=7.2 Hz, CH.sub.3CH.sub.2), 1.49 (2H, quint, J=7.2 Hz, CH.sub.3CH.sub.2CH.sub.2), 3.13 (2H, t, J=6.4 Hz, SCH.sub.2), 3.21 (2H, q, J=6.8 Hz, NHCH.sub.2),

(279) 3.61 (2H, q, J=6.0 Hz, SCH.sub.2CH.sub.2), 5.05 (1H, t, J=5.6 Hz, OH), 7.58 (2H, s, SO.sub.2NH.sub.2), 7.77 (1H, s, C.sub.3—H), 7.84 (1H, s, C.sub.6—H), 8.51 (1H, t, J=5.6 Hz, NH).

(280) .sup.13C NMR δ ppm: 18.9, 24.8, 36.2, 39.8, 43.9, 64.7, 125.4, 132.9, 136.8, 140.6, 143.7, 147.8, 171.1.

(281) HRMS calcd. for C.sub.13H.sub.19BrN.sub.2O.sub.4S.sub.2[(M+H).sup.+]: 413.0022 (100%), found: 413.0018 (100%).

Example 11

Preparation of 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-4-phenethylsulfanyl-benzenesulfonamide (Compound 29d)

(282) The mixture of 5-[2-(benzimidazol-1-yl)acetyl]-2,4-dichloro-benzenesulfonamide (compound 29) (65.0 mg, 0.168 mmol), DMSO (1 mL), 2-phenylethanethiol (24.0 mg, 0.168 mmol) and Et.sub.3N (17.6 mg, 0.175 mmol) was stirred at room temperature for 24 h. The brine was added to the mixture and product was extracted with EtOAc (3×5 mL). The organic layer was washed with H.sub.2O, dried over anhydrous MgSO.sub.4, filtered and concentrated.

(283) Recrystallization was accomplished from EtOAc:MeOH (5:1). Yield: 25.0 mg, 31%, mp 205-207° C.

(284) .sup.1H NMR δ ppm: 2.92 (2H, t, J=7.2 Hz, CH.sub.2Ph), 3.33-3.40 (2H, m, CH.sub.2S), 6.00 (2H, s, CH.sub.2CO), 7.19-7.32 (7H, m, Ph-H, C.sub.5′,6′—H), 7.50 (1H, dd, J=6.0 Hz, J=2.8 Hz, C.sub.7′—H), 7.69 (1H, dd, J=5.6 Hz, J=2.8 Hz, C.sub.4′—H), 7.72 (1H, s, C.sub.3—H), 7.83 (2H, s, SO.sub.2NH.sub.2), 8.15 (1H, s, C.sub.2′—H), 8.66 (1H, s, C.sub.6—H).

(285) .sup.13C NMR δ ppm: 33.0, 33.7, 52.0, 111.1, 119.8, 122.0, 122.8, 126.9, 128.8, 128.9, 129.0, 129.1, 130.1, 135.1, 135.4, 136.8, 140.0, 143.6, 145.3, 147.7, 193.3.

(286) HRMS calcd. for C.sub.23H.sub.20ClN.sub.3O.sub.3S.sub.2 [(M+H).sup.+]: 486.0707, found: 486.0709.

Example 12

Preparation of 4-chloro-2-(cyclohexylamino)-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 3f), 2-(benzylamino)-4-chloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 3g), 4-chloro-2-(cyclohexylamino)-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide (Compound 4f), 2-(benzylamino)-4-chloro-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide (Compound 4g), N-butyl-4-chloro-2-(cyclohexylamino)-5-sulfamoyl-benzamide (Compound 5f), 2-(benzylamino)-N-butyl-4-chloro-5-sulfamoyl-benzamide (Compound 5g), N-butyl-4-chloro-2-(cyclooctylamino)-5-sulfamoyl-benzamide (Compound 5h), 4-chloro-2-(cyclohexylamino)-N-(2-methoxyethyl)-5-sulfamoyl-benzamide (Compound 6f), 2-(benzylamino)-4-chloro-N-(2-methoxyethyl)-5-sulfamoyl-benzamide (Compound 6g), N-benzyl-2-(benzylamino)-4-chloro-5-sulfamoyl-benzamide (Compound 10g), methyl 4-chloro-2-(cyclohexylamino)-5-sulfamoyl-benzoate (Compound 14f), methyl 2-(benzylamino)-4-chloro-5-sulfamoyl-benzoate (Compound 14g)

(287) The mixture of appropriate 2,4-dichloro-N-substituted-5-sulfamoylbenzamides (compounds 3-6, 10) or methyl 2,4-dichloro-5-sulfamoyl-benzoate (compound 14) (1.00 mmol), and appropriate amine (6 mmol) was heated at 120° C. for 3-4 h (for amides 3-6, 10) or at 60° C. for 3 h (for ester 14). The mixture was cooled to room temperature and 2N HCl(aq) (2 mL) was added. The resultant precipitate was washed with H.sub.2O.

(288) The compound 3f. The product was purified by chromatography on a column of silica gel with EtOAc, R.sub.f=0.65 and then recrystallization was accomplished from toluene:2-PrOH (5:1). Yield: 90.2 mg, 24%, mp 210-212° C.

(289) .sup.1H NMR δ ppm: 1.20-1.30 (3H, m, Cy-H), 1.38-1.46 (2H, m, Cy-H), 1.55-1.58 (1H, m, Cy-H), 1.64-1.68 (2H, m, Cy-H), 1.86-1.89 (2H, m, Cy-H), 3.29 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.48-3.54 (3H, m, CH.sub.2OH, Cy-H), 4.72 (1H, t, J=5.6 Hz, OH), 6.86 (1H, s, C.sub.3—H), 7.17 (2H, s, SO.sub.2NH.sub.2), 8.11 (1H, s, C.sub.6—H), 8.51 (1H, d, J=8.0 Hz, CyNH), 8.56 (1H, t, J=5.6 Hz, CONH).

(290) .sup.13C NMR δ ppm: 24.3, 25.7, 32.4, 40.6, 49.9, 60.0, 112.4, 113.1, 125.8, 130.7, 135.0, 151.3, 168.4.

(291) HRMS calcd. for C.sub.15H.sub.22ClN.sub.3O.sub.4S [(M+H).sup.+]: 376.1092, found: 376.1092.

(292) The compound 3g. Recrystallization was accomplished three times from toluene:2-PrOH (8:1). Yield: 61.4 mg, 16%, mp 225-228° C.

(293) .sup.1H NMR δ ppm: 3.31 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.51 (2H, t, J=6.0 Hz, CH.sub.2OH), 4.49 (2H, d, J=5.6 Hz, NHCH.sub.2Ph), 4.73 (1H, br s, OH), 6.76 (1H, s, C.sub.3—H), 7.19 (2H, s, SO.sub.2NH.sub.2), 7.25-7.39 (5H, m, Ph-H), 8.12 (1H, s, C.sub.6—H), 8.62 (1H, t, J=5.6 Hz, NHBn), 8.75 (1H, t, J=5.6 Hz, CONH).

(294) .sup.13C NMR δ ppm: 42.4, 46.2, 60.0, 113.4, 113.5, 126.6, 127.5, 127.6, 129.1, 130.4, 134.7, 138.9, 151.9, 168.2.

(295) HRMS calcd. for C.sub.16H.sub.18ClN.sub.3O.sub.4S [(M+H).sup.+]: 384.0779, found: 384.0781.

(296) The compound 4f. Recrystallization was accomplished from: toluene:2-PrOH (1:1). Yield: 179 mg, 46%, mp 192-194° C.

(297) .sup.1H NMR δ ppm: 1.20-1.30 (3H, m, Cy-H), 1.37-1.49 (2H, m, Cy-H), 1.56-1.58 (1H, m, Cy-H), 1.63-1.68 (4H, m, Cy-H, CH.sub.2), 1.87-1.89 (2H, m, Cy-H), 3.27 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.46 (2H, t, J=6.4 Hz, CH.sub.2OH), 3.51 (1H, br s, Cy-H), 4.41 (1H, br s, OH), 6.85 (1H, s, C.sub.3—H), 7.17 (2H, s, SO.sub.2NH.sub.2), 8.09 (1H, s, C.sub.6—H), 8.49 (1H, d, J=7.6 Hz, CyNH), 8.61 (1H, t, J=5.2 Hz, CONH).

(298) .sup.13C NMR δ ppm: 24.3, 25.7, 32.4, 32.7, 39.4, 49.9, 59.1, 112.5, 113.1, 125.8, 130.6, 135.0, 151.3, 168.3.

(299) HRMS calcd. for C.sub.16H.sub.24ClN.sub.3O.sub.4S [(M+H).sup.+]: 390.1249, found: 390.1252.

(300) The compound 4g. The product was purified by chromatography on a column of silica gel with EtOAc:CHCl.sub.3 (2:1), R.sub.f=0.25. Yield: 171 mg, 43%, mp 179-182° C.

(301) .sup.1H NMR δ ppm: 1.68 (2H, quint, J=6.8 Hz, CH.sub.2), 3.29 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.45-3.49 (2H, m, CH.sub.2OH), 4.48 (3H, d, J=6.0 Hz, NHCH.sub.2Ph, OH), 6.76 (1H, s, C.sub.3—H), 7.20 (2H, s, SO.sub.2NH.sub.2), 7.26-7.39 (5H, m, Ph-H), 8.10 (1H, s, C.sub.6—H), 8.68 (1H, t, J=5.6 Hz, NHBn), 8.74 (1H, t, J=5.6 Hz, CONH).

(302) .sup.13C NMR δ ppm: 32.7, 39.6, 46.2, 59.1, 113.4, 113.7, 126.6, 127.5, 127.6, 129.1, 130.3, 134.7, 138.9, 151.9, 168.0.

(303) HRMS calcd. for C.sub.17H.sub.20ClN.sub.3O.sub.4S [(M+H).sup.+]: 398.0936, found: 398.0936.

(304) The compound 5f. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (5:1), R.sub.f=0.33. Yield: 167 mg, 43%, mp 182-184° C.

(305) .sup.1H NMR δ ppm: 0.90 (3H, t, J=7.2 Hz, CH.sub.3), 1.20-1.58 (10H, m, Cy-H, CH.sub.2CH.sub.2), 1.64-1.67 (2H, m, Cy-H), 1.87-1.89 (2H, m, Cy-H), 3.21 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.50 (1H, br s, Cy-H), 6.85 (1H, s, C.sub.3—H), 7.17 (2H, s, SO.sub.2NH.sub.2), 8.09 (1H, s, C.sub.6—H), 8.47 (1H, d, J=7.6 Hz, CyNH), 8.62 (1H, t, J=5.2 Hz, CONH).

(306) .sup.13C NMR δ ppm: 14.2, 20.1, 24.2, 25.7, 31.5, 32.4, 39.4, 49.9, 112.7, 113.0, 125.8, 130.6, 134.9, 151.3, 168.2.

(307) HRMS calcd. for C.sub.17H.sub.26ClN.sub.3O.sub.3S [(M+H).sup.+]: 388.1456, found: 388.1456.

(308) The compound 5g. Recrystallization was accomplished from toluene:2-PrOH (8:1). Yield: 91.1 mg, 23%, mp 204-206° C.

(309) .sup.1H NMR δ ppm: 0.91 (3H, t, J=7.2 Hz, CH.sub.3), 1.33 (2H, sext, J=7.2 Hz, CH.sub.2), 1.50 (2H, quint, J=7.2 Hz, CH.sub.2), 3.23 (2H, q, J=6.8 Hz, CONHCH.sub.2), 4.48 (2H, d, J=5.6 Hz, NHCH.sub.2Ph), 6.76 (1H, s, C.sub.3—H), 7.19 (2H, s, SO.sub.2NH.sub.2), 7.25-7.39 (5H, m, Ph-H), 8.10 (1H, s, C.sub.6—H), 8.68 (1H, t, J=5.6 Hz, NHBn), 8.72 (1H, t, J=6.0 Hz, CONH).

(310) .sup.13C NMR δ ppm: 14.2, 20.1, 31.5, 39.1, 46.2, 13.4, 113.8, 126.6, 127.5, 127.6, 129.1, 130.3, 134.6, 138.9, 151.9, 167.9.

(311) HRMS calcd. for C.sub.18H.sub.22ClN.sub.3O.sub.3S [(M+H).sup.+]: 396.1143, found: 396.1145.

(312) The compound 5h. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (5:1), R.sub.f=0.35, Yield: 112 mg, 27%, mp 172-174° C.

(313) .sup.1H NMR δ ppm: 0.90 (3H, t, J=7.2 Hz, CH.sub.3), 1.32 (2H, sext, J=7.2 Hz, CH.sub.2), 1.45-1.65 (14H, m, Cy-H, CH.sub.2), 1.78-1.83 (2H, m, Cy-H), 3.19-3.23 (2H, m, NHCH.sub.2), 3.66 (1H, br s, Cy-H), 6.75 (1H, s, C.sub.3—H), 7.17 (2H, s, SO.sub.2NH.sub.2), 8.10 (1H, s, C.sub.6—H), 8.52 (1H, d, J=7.6 Hz, CyNH), 8.62 (1H, br s, CONH).

(314) .sup.13C NMR δ ppm: 14.2, 20.1, 23.4, 25.4, 27.3, 31.4, 31.5, 39.1, 51.4, 112.8, 113.3, 125.8, 130.6, 134.9, 151.1, 168.2.

(315) HRMS calcd. for C.sub.19H.sub.30ClN.sub.3O.sub.3S [(M+H).sup.+]: 416.1769, found: 416.1770.

(316) The compound 6f. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (3:1), R.sub.f=0.21. Yield: 129 mg, 33%, mp 214-216° C.

(317) .sup.1H NMR δ ppm: 1.16-1.30 (3H, m, Cy-H), 1.37-1.47 (2H, m, Cy-H), 1.55-1.58 (1H, m, Cy-H), 1.64-1.68 (2H, m, Cy-H), 1.86-1.92 (2H, m, Cy-H), 3.27 (3H, m, CH.sub.3), 3.35-3.40 (2H, m, NHCH.sub.2), 3.43-3.46 (2H, m, OCH.sub.2), 3.47-3.60 (1H, m, Cy-H), 6.87 (1H, s, C.sub.3—H), 7.19 (2H, s, SO.sub.2NH.sub.2), 8.11 (1H, s, C.sub.6—H), 8.50 (1H, d, J=8.0 Hz, CyNH), 8.68 (1H, t, J=5.6 Hz, CONH).

(318) .sup.13C NMR δ ppm: 24.3, 25.7, 32.4, 39.2, 49.9, 58.4, 70.7, 112.2, 113.1, 125.8, 130.7, 135.1, 151.3, 168.4.

(319) HRMS calcd. for C.sub.16H.sub.24ClN.sub.3O.sub.4S [(M+H).sup.+]: 390.1249, found: 390.1247.

(320) The compound 6g. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (1:1), R.sub.f=0.25. Yield: 163 mg, 41%, mp 194-197° C.

(321) .sup.1H NMR δ ppm: 3.28 (3H, s, CH.sub.3), 3.38-3.42 (2H, m, CONHCH.sub.2), 3.45-3.47 (2H, m, OCH.sub.2), 4.49 (2H, d, J=5.6 Hz, NHCH.sub.2Ph), 6.77 (1H, s, C.sub.3—H), 7.21 (2H, s, SO.sub.2NH.sub.2), 7.25-7.39 (5H, m, Ph-H), 8.12 (1H, s, C.sub.6—H), 8.75 (2H, br s, BnNH, CONH).

(322) .sup.13C NMR δ ppm: 39.2, 46.2, 58.4, 70.7, 113.3, 113.4, 126.6, 127.5, 127.6, 129.1, 130.4, 134.8, 138.8, 151.9, 168.2.

(323) HRMS calcd. for C.sub.17H.sub.20ClN.sub.3O.sub.4S [(M+H).sup.+]: 398.0936, found: 398.0932.

(324) The compound 10g. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (10:1), R.sub.f=0.13. Yield: 116 mg, 27%, mp 213-216° C.

(325) .sup.1H NMR δ ppm: 4.45 (2H, d, J=6.0 Hz, CONHCH.sub.2), 4.50 (2H, d, J=6.0 Hz, NHCH.sub.2), 6.80 (1H, s, C.sub.3—H).

(326) 7.22 (2H, s, SO.sub.2NH.sub.2), 7.26-7.39 (1H, m, Ph-H), 8.22 (1H, s, C.sub.6—H), 8.82 (1H, t, J=6.0 Hz, BnNH), 9.30 (1H, t, J=6.0 Hz, CONH.sub.2).

(327) .sup.13C NMR δ ppm: 42.9, 46.2, 113.1, 113.6, 126.6, 127.3, 127.5, 127.6, 127.7, 128.8, 129.1, 130.4, 134.9, 138.8, 139.9, 152.1, 168.1.

(328) HRMS calcd. for C.sub.21H.sub.20ClN.sub.3O.sub.3S [(M+H).sup.+]: 430.0987, found: 430.0987.

(329) The compound 14f. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (10:1), R.sub.f=0.30. Yield: 38.2 mg, 11%, mp 184-186° C.

(330) .sup.1H NMR δ ppm: 1.25-1.33 (3H, m, Cy-H), 1.40-1.48 (2H, m, Cy-H), 1.56-1.59 (1H, m, Cy-H), 1.65-1.69 (2H, m, Cy-H), 1.90-1.92 (2H, m, Cy-H), 3.60-3.66 (1H, m, Cy-H), 3.84 (3H, s, CH.sub.3), 7.02 (1H, s, C.sub.3—H), 7.34 (2H, s, SO.sub.2NH.sub.2), 8.18 (1H, d, J=8.0 Hz, NH), 8.40 (1H, s, C.sub.6—H).

(331) .sup.13C NMR δ ppm: 24.2, 25.6, 32.4, 50.0, 52.6, 106.7, 114.0, 126.6, 133.6, 137.3, 152.0, 167.7.

(332) HRMS calcd. for C.sub.14H.sub.19ClN.sub.2O.sub.4S [(M+H).sup.+]: 347.0827, found: 347.0828.

(333) The compound 14g. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (10:1), R.sub.f=0.29. Yield: 42.6 mg, 12%, mp 178-180° C.

(334) .sup.1H NMR δ ppm: 3.86 (3H, s, CH.sub.3), 4.59 (2H, d, J=6.0 Hz, CH.sub.2), 6.88 (1H, s, C.sub.3—H), 7.26-7.39 (7H, m, Ph-H, SO.sub.2NH.sub.2), 8.41 (1H, s, C.sub.6—H), 8.59 (1H, t, J=6.0 Hz, NH).

(335) .sup.13C NMR δ ppm: 46.2, 52.6, 107.7, 114.4, 127.2, 127.5, 127.7, 129.2, 133.4, 137.0, 138.5, 152.7, 167.3.

(336) HRMS calcd. for C.sub.15H.sub.15ClN.sub.2O.sub.4S [(M+H).sup.+]: 355.0514, found: 355.0513.

Example 13

Preparation of 4-bromo-N-butyl-2-(cyclohexylamino)-5-sulfamoyl-benzamide (Compound 12f), 2-(benzylamino)-4-bromo-N-butyl-5-sulfamoyl-benzamide (Compound 12g)

(337) The mixture of 2,4-dibromo-N-butyl-5-sulfamoyl-benzamide (compounds 16) (1.00 mmol), appropriate amine (2.50 mmol), and 1,4-dioxane was refluxed for 7 days. The solvent was removed under reduced pressure and 2N HCl(aq) (2 mL) was added. The resultant precipitate was washed with H.sub.2O.

(338) The compound 12f. The product was purified by chromatography on a column of silica gel with EtOAc:CHCl.sub.3 (5:1), R.sub.f=0.30. Yield: 151 mg, 35%, mp 203-205° C.

(339) .sup.1H NMR δ ppm: 0.90 (3H, t, J=7.2, Hz, CH.sub.3), 1.16-1.57 (10H, m, CH.sub.3CH.sub.2, CH.sub.3CH.sub.2CH.sub.2, Cy-H), 1.64-1.67 (2H, m, Cy-H), 1.86-1.88 (2H, m, Cy-H), 3.20 (2H, q, J=6.8 Hz, NHCH.sub.2), 3.49-3.51 (1H, m, Cy-H), 7.02 (1H, s, C.sub.3—H), 7.13 (2H, s, SO.sub.2NH.sub.2), 8.11 (1H, s, C.sub.6—H), 8.41 (1H, d, J=7.6 Hz, NHCy), 8.61 (1H, t, J=5.6 Hz, NHCH.sub.2).

(340) .sup.13C NMR δ ppm: 14.2, 20.1, 24.2, 25.7, 31.5, 32.4, 39.1, 49.8, 113.1, 116.6, 123.8, 127.4, 130.6, 151.0, 168.3.

(341) HRMS calcd. for C.sub.17H.sub.26BrN.sub.3O.sub.3S[(M+H).sup.+]: 434.0932 (100%), found: 434.0933 (100%).

(342) The compound 12g. The product was purified by chromatography on a column of silica gel with EtOAc:CHCl.sub.3 (5:1), R.sub.f=0.34. Yield: 176 mg, 40%, mp 207-209° C.

(343) .sup.1H NMR δ ppm: 0.90 (3H, t, J=7.2, Hz, CH.sub.3), 1.32 (2H, sext, J=7.2 Hz, CH.sub.3CH.sub.2), 1.50 (2H, quint, J=7.2 Hz, CH.sub.3CH.sub.2CH.sub.2), 3.21 (2H, q, J=6.8 Hz, NHCH.sub.2CH.sub.2), 4.48 (2H, d, J=5.6 Hz, NHCH.sub.2Ph), 6.95 (1H, s, C.sub.3—H), 7.15 (2H, s, SO.sub.2NH.sub.2), 7.26-7.39 (5H, m, Ph-H), 8.11 (1H, s, C.sub.6—H), 8.64-8.66 (2H, m, NHCH.sub.2Ph, NHCH.sub.2).

(344) .sup.13C NMR δ ppm: 14.2, 20.1, 31.5, 39.1, 46.2, 114.2, 117.0, 123.5, 127.5, 127.6, 128.2, 129.1, 130.3, 138.9, 151.6, 168.0.

(345) HRMS calcd. for C.sub.18H.sub.22BrN.sub.3O.sub.3S[(M+H).sup.+]: 442.0619 (100%), found: 442.0623 (100%).

Example 14

Preparation of 2-(benzenesulfonyl)-4-chloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 33a), 4-chloro-2-cyclohexylsulfonyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 33b), 2-benzylsulfonyl-4-chloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 33c), 2-(benzenesulfonyl)-4-chloro-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide (Compound 34a), 4-chloro-2-cyclohexylsulfonyl-N-(3-hydroxypropyl)-5-sulfamoyl-benzamide (Compound 34b), 4-bromo-2-cyclohexylsulfonyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 40b), 2-benzylsulfonyl-4-bromo-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 40c)

(346) The 30% H.sub.2O.sub.2(aq) (1.50 mmol, 148 mL) was added to a solution of appropriate 2-halogeno-4-substitutedsulfanyl-5-substitutedbenzenesulfonamide (compounds 3(a-c), 4(a, b), 11(b, c)) (0.500 mmol) in AcOH (1.77 mL) at 70° C. and allowed stirring for 2-3 h. The solvent was removed under reduced pressure, then methanol (2 mL), H.sub.2O (1 mL) and concentrated HCl (aq) (1 mL) was added and solution was refluxed for 3 hours. The solvents were removed at a reduced pressure and the resultant precipitate was washed with H.sub.2O.

(347) The compound 33a. Yield: 182 mg, 87%, mp 168-170° C.

(348) .sup.1H NMR δ ppm: 3.31-3.36 (2H, m, NHCH.sub.2), 3.57 (2H, t, J=6.0 Hz, CH.sub.2OH), 4.62 (1H, br s, OH), 7.64 (2H, t, J=7.2 Hz, C.sub.3′5′—H), 7.74 (1H, t, J=7.6 Hz, C.sub.4′—H), 7.94 (1H, s, C.sub.3—H), 7.96 (2H, s, SO.sub.2NH.sub.2), 8.11 (2H, d, J=7.6 Hz, C.sub.2′,6′—H), 8.35 (1H, s, C.sub.6—H), 8.73 (1H, br s, NH).

(349) .sup.13C NMR δ ppm: 42.7, 59.9, 129.0, 129.8 (2C), 132.1, 132.7, 134.8, 136.9, 140.4, 142.1, 145.4, 165.9.

(350) HRMS calcd. for C.sub.15H.sub.15ClN.sub.2O.sub.6S.sub.2 [(M+H).sup.+]: 419.0133, found: 419.0135.

(351) The compound 33b. Yield: 170 mg, 80%, mp 246-248° C.

(352) .sup.1H NMR δ ppm: 1.17-1.24 (3H, m, Cy-H), 1.38-1.46 (2H, m, Cy-H), 1.64 (1H, br s, Cy-H), 1.80-1.83 (4H, m, Cy-H), 3.31 (2H, q, J=5.6 Hz, NHCH.sub.2), 3.52 (2H, t, J=6.0 Hz, CH.sub.2OH), 3.80 (1H, t, J=12.0 Hz, Cy-H), 4.69 (1H, br s, OH), 7.99 (2H, s, SO.sub.2NH.sub.2), 8.00 (1H, s, C.sub.3—H), 8.06 (1H, s, C.sub.6—H), 8.83 (1H, t, J=5.6 Hz, NH).

(353) .sup.13C NMR δ ppm: 24.9 (2C), 25.2, 42.6, 59.8, 63.0, 130.1, 131.8, 133.5, 137.6, 139.4, 145.4, 166.2.

(354) HRMS calcd. for C.sub.15H.sub.21ClN.sub.2O.sub.6S.sub.2 [(M+H).sup.+]: 425.0602, found: 425.0600.

(355) The compound 33c. Yield: 165 mg, 76%, mp 118-120° C.

(356) .sup.1H NMR δ ppm: 3.37 (2H, s, NHCH.sub.2, superposed with H.sub.2O), 3.56 (2H, br s, CH.sub.2OH), 4.78 (1H, br s, OH), 4.98 (2H, br s, CH.sub.2Ph), 7.24 (2H, br s, Ph-H), 7.34 (3H, br s, Ph-H), 7.59 (1H, s, C.sub.3—H) 8.00 (2H, s, SO.sub.2NH.sub.2), 8.07 (1H, s, C.sub.6—H), 8.95 (1H, br s, NH).

(357) .sup.13C NMR δ ppm: 42.7, 59.9, 62.2, 128.2, 129.0, 129.3, 129.7, 131.5 (2C), 133.3, 137.2, 140.1, 145.5, 166.5.

(358) HRMS calcd. for C.sub.16H.sub.17ClN.sub.2O.sub.6S.sub.2 [(M+H).sup.+]: 433.0289, found: 433.0293.

(359) The compound 34a. Yield: 188 mg, 87%, mp 142-144° C.

(360) .sup.1H NMR δ ppm: 1.72 (2H, quint, J=6.8 Hz, CH.sub.2), 3.31 (2H, q, J=6.8 Hz, NHCH.sub.2), 3.52 (2H, t, J=6.0 Hz, CH.sub.2OH), 4.50 (1H, br s, OH), 7.64 (2H, t, J=7.6 Hz, C.sub.3′,5′—H), 7.74 (1H, t, J=7.2 Hz, C.sub.4′—H), 7.89 (1H, s, C.sub.3—H), 7.97 (2H, s, SO.sub.2NH.sub.2), 8.11 (2H, d, J=7.6 Hz, C.sub.2′,6′—H), 8.35 (1H, s, C.sub.6—H), 8.69 (1H, t, J=5.6 Hz, NH).

(361) .sup.13C NMR δ ppm: 32.4, 37.1, 58.9, 129.0, 129.7, 129.8, 132.1, 132.7, 134.8, 136.9, 140.4, 142.1, 145.4, 165.7.

(362) HRMS calcd. for C.sub.16H.sub.17ClN.sub.2O.sub.6S.sub.2 [(M+H).sup.+]: 433.0289, found: 433.0288.

(363) The compound 34b, Yield: 189 mg, 86%, mp 153-155° C.

(364) .sup.1H NMR δ ppm: 1.14-1.24 (3H, m, Cy-H), 1.38-1.46 (2H, m, Cy-H), 1.64-1.71 (3H, m, Cy-H, CH.sub.2), 1.81-1.83 (4H, m, Cy-H), 3.29 (2H, q, J=6.8 Hz, NHCH.sub.2), 3.49 (2H, t, J=6.4 Hz, CH.sub.2OH), 3.79 (1H, t, J=11.6 Hz, Cy-H), 4.47 (1H, br s, OH), 8.00 (2H, s, C.sub.3,6—H), 8.01 (2H, s, SO.sub.2NH.sub.2), 8.90 (1H, t, J=5.2 Hz, NH).

(365) .sup.13C NMR δ ppm: 24.9 (2C), 25.2, 32.4, 7.1, 58.9, 63.1, 130.0, 111.8, 133.6, 137.7, 139.4, 145.5, 166.0.

(366) HRMS calcd. for C.sub.16H.sub.23ClN.sub.2O.sub.6S.sub.2 [(M+H).sup.+]: 439.0759, found: 439.0760.

(367) The compound 40b. Yield: 178 mg, 76%, mp 235-237° C.

(368) .sup.1H NMR δ ppm: 1.16-1.24 (3H, m, Cy-H), 1.37-1.45 (2H, m, Cy-H), 1.60-1.65 (1H, m, Cy-H), 1.80-1.82 (4H, m, Cy-H), 3.30 (2H, q, J=6.0 Hz, NHCH.sub.2), 3.52 (2H, q, J=5.6 Hz, HOCH.sub.2), 3.75-3.81 (1H, m, Cy-H), 4.70 (1H, t, J=5.2 Hz, OH), 7.94 (2H, s, SO.sub.2NH.sub.2), 8.07 (1H, s, C.sub.6—H), 8.13 (1H, s, C.sub.3—H), 8.81 (1H, t, J=5.6 Hz, NH).

(369) .sup.13C NMR δ ppm: 24.8, 24.9, 25.2, 42.6, 59.8, 63.0, 120.1, 130.0, 136.8, 138.1, 139.0, 147.3, 166.3.

(370) HRMS calcd, for C.sub.15H.sub.21BrN.sub.2O.sub.6S.sub.2[(M+H).sup.+]: 471.0077 (100%), found: 471.0081 (100%).

(371) The compound 40e. Yield: 168 mg, 78%, mp 139-141° C.

(372) .sup.1H NMR δ ppm: 3.36-3.42 (2H, m, NHCH.sub.2), 3.56-3.59 (2H, m, HOCH.sub.2), 4.77 (1H, br, s, OH), 4.98 (2H, s, SCH.sub.2), 7.23-7.36 (5H, m, Ph-H), 7.75 (1H, s, C.sub.6—H), 7.96 (2H, s, SO.sub.2NH.sub.2), 8.09 (1H, s, C.sub.3—H), 8.94 (1H, t, J=5.6 Hz, NH).

(373) .sup.13C NMR δ ppm: 42.7, 59.9, 62.2, 119.9, 128.2, 129.0, 129.2, 129.7, 131.5, 136.7, 137.7, 139.7, 147.3, 166.6.

(374) HRMS calcd. for C.sub.16H.sub.17BrN.sub.2O.sub.6S.sub.2[(M+H).sup.+]: 478.9764 (100%), found: 478.9769 (100%).

Example 15

Preparation of 2-(benzenesulfonyl)-N-butyl-4-chloro-5-sulfamoyl-benzamide (Compound 35a), N-butyl-4-chloro-2-cyclohexylsulfonyl-5-sulfamoyl-benzamide (Compound 35b), 2-(benzenesulfonyl)-4-chloro-N-(2-methoxyethyl)-5-sulfamoyl-benzamide (Compound 36a), 4-chloro-2-cyclohexylsulfonyl-N-(2-methoxyethyl)-5-sulfamoyl-benzamide (Compound 36b), methyl 4-[(4-chloro-2-cyclohexylsulfonyl-5-sulfamoyl-benzoyl)amino]butanoate (Compound 37b), methyl 4-[(2-benzylsulfonyl-4-chloro-5-sulfamoyl-benzoyl)amino]butanoate (Compound 37c), 2-(benzenesulfonyl)-4-chloro-N-cyclohexyl-5-sulfamoyl-benzamide (Compound 38a), 4-chloro-N-cyclohexyl-2-cyclohexylsulfonyl-5-sulfamoyl-benzamide (Compound 38b), 2-benzylsulfonyl-4-chloro-N-cyclohexyl-5-sulfamoyl-benzamide (Compound 38c), 4-chloro-N-cyclohexyl-2-(2-hydroxyethylsulfonyl)-5-sulfamoyl-benzamide (Compound 38e), 2-(benzenesulfonyl)-N-benzyl-4-chloro-5-sulfamoyl-benzamide (Compound 39a), N-benzyl-4-chloro-2-cyclohexylsulfonyl-5-sulfamoyl-benzamide (Compound 39b), 2-(benzenesulfonyl)-4-bromo-N-butyl-5-sulfamoyl-benzamide (Compound 41a), 4-bromo-N-butyl-2-cyclohexylsulfonyl-5-sulfamoyl-benzamide (Compound 41b), methyl 2-(benzenesulfonyl)-4-chloro-5-sulfamoyl-benzoate (Compound 42a), methyl 4-chloro-2-cyclohexylsulfonyl-5-sulfamoyl-benzoate (Compound 42b), methyl 2-benzylsulfonyl-4-chloro-5-sulfamoyl-benzoate (Compound 42c), methyl 2-(benzenesulfonyl)-4-bromo-5-sulfamoyl-benzoate (Compound 43a), methyl 4-bromo-2-cyclohexylsulfonyl-5-sulfamoyl-benzoate (Compound 43b)

(375) The 30% H.sub.2O.sub.2(aq) (1.50 mmol, 0.148 mL) was added to a solution of appropriate benzenesulfonamide (compounds 5(a, b), 6(a, b), 7(b, c), 9(a-c, e), 10(a, b), 12(a, b), 14(a-c), 16(a, b)) (0.500 mmol) in AcOH (1.77 mL) at 70° C. and allowed stirring for 2-3 h. The solvent was removed under reduced pressure and the resultant precipitate was washed with H.sub.2O.

(376) The compound 35a. Yield: 198 mg, 92%, mp 182-184° C.

(377) .sup.1H NMR δ ppm: 0.93 (3H, t, J=7.2 Hz, CH.sub.3), 1.39 (2H, sext, J=7.2 Hz, CH.sub.2), 1.54 (2H, quint, J=7.2 Hz, CH.sub.2), 3.26 (2H, q, J=6.8 Hz, NHCH.sub.2), 7.65 (2H, t, J=7.2 Hz, C.sub.3′,5′—H), 7.74 (1H, t, j=7.2 Hz, C.sub.4′—H), 7.89 (1H, s, C.sub.3—H), 7.98 (2H, s, SO.sub.2NH.sub.2), 8.11 (2H, d, J=7.6 Hz, C.sub.2′,6′—H), 8.35 (1H, s, C.sub.6—H), 8.69 (1H, t, J=5.6 Hz, NH).

(378) .sup.13C NMR δ ppm: 14.2, 20.1, 31.2, 39.5, 129.0, 129.7, 129.8, 132.1, 132.7, 134.7, 137.0, 140.4, 142.1, 145.4, 165.6.

(379) HRMS calcd. for C.sub.17H.sub.19ClN.sub.2O.sub.5S.sub.2 [(M+H).sup.+]: 431.0497, found: 431.0494.

(380) The compound 35b. Yield: 175 mg, 80%, mp 213-214° C.

(381) .sup.1H NMR δ ppm: 0.91 (3H, t, j=7.6 Hz, CH.sub.3), 1.14-1.24 (3H, m, Cy-H), 1.32-1.54 (6H, m, Cy-H, (CH.sub.2).sub.2), 1.64 (1H, br s, Cy-H), 1.80-1.83 (4H, m, Cy-H), 3.24 (2H, q, J=6.8 Hz, NHCH.sub.2), 3.80 (1H, t, J=12.0 Hz, Cy-H), 8.00 (4H, s, SO.sub.2NH.sub.2, C.sub.3,6—H), 8.81 (1H, t, J=5.6 Hz, NH).

(382) .sup.13C NMR δ ppm: 14.1, 20.0, 24.9 (2C), 25.2, 31.2, 39.4, 63.0, 130.0, 131.7, 133.6, 137.7, 139.4, 145.5, 165.9.

(383) .sup.13C HRMS calcd. for C.sub.17H.sub.25ClN.sub.2O.sub.5S.sub.2 [(M+H).sup.+]: 437.0966 found: 437.0966.

(384) The compound 36a. Yield: 186 mg, 86%, mp 208-211° C.

(385) .sup.1H NMR δ ppm: 3.31 (3H, s, CH.sub.3), 3.42 (2H, q, J=5.2 Hz, NHCH.sub.2), 3.51 (2H, t, J=5.6 Hz, OCH.sub.2), 7.65 (2H, t, J=7.6 Hz, C.sub.3′,5′—H), 7.74 (1H, t, J=7.2 Hz, C.sub.4′—H), 7.89 (1H, s, C.sub.3—H), 7.96 (2H, s, SO.sub.2NH.sub.2), 8.12 (2H, d, J=7.6 Hz, C.sub.2′,6′—H), 8.34 (1H, s, C.sub.6—H), 8.82 (1H, t, J=5.6 Hz, NH).

(386) .sup.13C NMR δ ppm: 39.7, 58.5, 70.6, 129.0, 129.8, 1299, 132.1, 132.7, 134.7, 136.7, 140.4, 142.1, 145.4, 165.9.

(387) HRMS calcd. for C.sub.16H.sub.17ClN.sub.2O.sub.6S.sub.2[(M+H).sup.+]: 433.0289, found: 433.0293.

(388) The compound 36b. Yield: 178 mg, 81%, mp 207-209° C.

(389) .sup.1H NMR δ ppm: 1.13-1.24 (3H, m, Cy-H), 1.38-1.46 (2H, m, Cy-H), 1.64 (1H, br s, Cy-H), 1.81-1.83 (4H, m, Cy-H), 3.29 (3H, s, CH.sub.3), 3.40 (2H, q, J=5.2 Hz, NHCH.sub.2), 3.47 (2H, t, J=5.2 Hz, OCH.sub.2), 3.78 (1H, t, J=12.0 Hz, Cy-H), 8.00 (2H, s, C.sub.3,6—H), 8.01 (2H, s, SO.sub.2NH.sub.2), 8.93 (1H, t, J=5.2 Hz, NH).

(390) .sup.13C NMR δ ppm: 24.9 (2C), 25.2, 39.6, 58.4, 63.1, 70.6, 130.1, 131.8, 133.6, 137.5, 139.4, 145.4, 166.2.

(391) HRMS calcd. for C.sub.16H.sub.23ClN.sub.2O.sub.6S.sub.2 [(M+H).sup.+]: 439.0759, found: 439.0757.

(392) The compound 37b. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (1:1), R.sub.f=0.41. Yield: 123 mg, 51%, mp 150-152° C.

(393) .sup.1H NMR δ ppm: 1.10-1.24 (3H, m, Cy-H), 1.38-1.46 (2H, m, Cy-H), 1.63 (1H, br s, Cy-H), 1.73-1.82 (6H, m, Cy-H, CH.sub.2), 2.41 (2H, t, J=7.2 Hz, COCH.sub.2), 3.27 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.61 (3H, s, CH.sub.3), 3.78 (1H, m, Cy-H), 8.00 (3H, s, C.sub.3—H, SO.sub.2NH.sub.2), 8.02 (1H, s, C.sub.6—H), 8.86 (1H, t, J=5.6 Hz, NH).

(394) .sup.13C NMR δ ppm: 24.5, 24.9 (2C), 25.2, 31.0, 39.0, 51.7, 63.1, 129.9, 131.8, 133.6, 137.6, 139.4, 145.5, 166.1, 173.6.

(395) HRMS calcd. for C.sub.18H.sub.25ClN.sub.2O.sub.7S.sub.2 [(M+H).sup.+]: 481.0864, found: 481.0867.

(396) The compound 37c. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (1:1), R.sub.f=0.48. Yield: 215 mg, 88%, mp 108-110° C.

(397) .sup.1H NMR δ ppm: 1.82 (2H, quint, J=7.2 Hz, CH.sub.2), 2.47 (2H, t, J=7.6 Hz, COCH.sub.2), 3.31-3.35 (2H, m, NHCH.sub.2, superposed with H.sub.2O), 3.62 (3H, s, CH.sub.3), 4.99 (2H, s, CH.sub.2Ph), 7.24-7.26 (2H, m, Ph-H), 7.32-7.39 (3H, m, Ph-H), 7.61 (1H, s, C.sub.3—H), 8.02 (2H, s, SO.sub.2NH.sub.2), 8.04 (1H, s, C.sub.6—H), 8.98 (1H, t, J=5.6 Hz, NH).

(398) .sup.13C NMR δ ppm: 24.5, 31.1, 39.1, 51.8, 62.1, 128.2, 129.0, 129.3, 129.6, 131.5, 131.6, 133.3, 137.2, 140.1, 145.6, 166.4, 173.6.

(399) HRMS calcd. for C.sub.19H.sub.21ClN.sub.2O.sub.7S.sub.2 [(M+H).sup.+]: 489.0551, found: 489.0553.

(400) The compound 38a. Recrystallization was accomplished from MeOH. Yield: 128 mg 56%, mp 259-261° C.

(401) .sup.1H NMR δ ppm: 1.13-1.22 (1H, m, Cy-H), 1.23-1.39 (4H, m, Cy-H), 1.58-1.61 (1H, m, Cy-H), 1.73-1.76 (2H, m, Cy-H), 1.91-1.94 (2H, m, Cy-H), 3.71-3.78 (1H, m, Cy-H), 7.64 (2H, t, J=8.0 Hz, C.sub.3′,5′—H), 7.73 (1H, t, J=7.6 Hz, C.sub.4—H), 7.86 (1H, s, C.sub.3—H), 7.96 (2H, s, SO.sub.2NH.sub.2), 8.11 (2H, d, J=7.2 Hz, C.sub.2′,6′—H), 8.33 (1H, s, C.sub.6—H), 8.61 (1H, d, J=7.6 Hz, NH).

(402) .sup.13C NMR δ ppm: 24.9, 25.7, 32.3, 48.9, 129.0, 129.7, 129.8, 131.9, 132.7, 134.7, 137.1, 140.5, 142.0, 145.4, 164.9.

(403) HRMS calcd. for C.sub.19H.sub.21ClN.sub.2O.sub.5S.sub.2[(M+H).sup.+]: 457.0653, found: 457.0656.

(404) The compound 38b. Yield: 201 mg, 87%, mp 264-266° C.

(405) .sup.1H NMR δ ppm: 1.11-1.46 (10H, m, Cy-H), 1.56-1.64 (2H, m, Cy-H), 1.71-1.74 (2H, m, Cy-H), 1.80-1.92 (6H, m, Cy-H), 3.68-3.80 (2H, m, Cy-H), 7.97 (1H, s, C.sub.3—H), 7.99 (1H, s, C.sub.6—H), 8.00 (2H, s, SO.sub.2NH.sub.2),

(406) 8.71 (1H, d, J=7.6 Hz, NH).

(407) .sup.13C NMR δ ppm: 24.9 (3C), 25.2, 25.7, 32.3, 48.8, 63.0, 130.0, 131.6, 133.5, 137.8, 139.3, 145.4, 165.1.

(408) HRMS calcd. for C.sub.19H.sub.27ClN.sub.2O.sub.5S.sub.2 [(M+H).sup.+]: 463.1123, found: 463.1123.

(409) The compound 38c. Yield: 186 mg, 79%, mp 248-251° C.

(410) .sup.1H NMR δ ppm: 1.12-1.40 (5H, m, Cy-H), 1.58-1.61 (1H, m, Cy-H), 1.73-1.76 (2H, m, Cy-H), 1.91-1.93 (2H, m, Cy-H), 3.74-3.83 (1H, m, Cy-H), 4.98 (2H, s, CH.sub.2Ph), 7.23-7.25 (2H, m, Ph-H), 7.31-7.37 (3H, m, Ph-H), 7.57 (1H, s, C.sub.3—H), 7.99 (1H, s, C.sub.6—H), 8.02 (2H, s, SO.sub.2NH.sub.2), 8.83 (1H, d, J=8.0 Hz, NH).

(411) .sup.13C NMR δ ppm: 24.9, 25.7, 32.3, 49.0, 62.2, 128.3, 129.0, 129.2, 129.6, 131.4, 131.5, 133.2, 137.4, 140.0, 145.5, 165.4.

(412) HRMS calcd. for C.sub.20H.sub.23ClN.sub.2O.sub.5S.sub.2 [(M+H).sup.+]: 471.0810, found: 471.0810.

(413) The compound 38e. Yield: 95.6 mg, 45%, mp 257-260° C.

(414) .sup.1H NMR δ ppm: 1.13-1.35 (5H, m, Cy-H), 1.56-1.59 (1H, m, Cy-H), 1.70-1.73 (2H, m, Cy-H), 1.85-1.88 (2H, m, Cy-H), 3.66-3.80 (5H, m, SCH.sub.2, CH.sub.2OH, Cy-H), 5.03 (1H, t, J=4.8 Hz, OH), 7.94 (1H, s, C.sub.3—H), 8.00 (2H, s, SO.sub.2NH.sub.2), 8.05 (1H, s, C.sub.6—H), 8.71 (1H, d, J=7.6 Hz, NH).

(415) .sup.13C NMR δ ppm: 24.9, 25.6, 32.3, 48.9, 55.4, 59.4, 129.5, 131.5, 133.2, 137.1, 142.0, 145.2, 165.4.

(416) HRMS calcd. for C.sub.15H.sub.21ClN.sub.2O.sub.6S.sub.2 [(M+H).sup.+]: 425.0602, found: 425.0603.

(417) The compound 39a. Yield: 212 mg, 91%, mp 250-253° C.

(418) .sup.1H NMR δ ppm: 4.51 (2H, d, J=5.6 Hz, CH.sub.2), 7.29 (1H, t, J=7.2 Hz, C.sub.4—H), 7.38 (2H, t, J=7.2 Hz, C.sub.3″,5″—H), 7.43 (2H, d, J=7.2 Hz, C.sub.2″,6″—H), 7.63 (2H, t, J=7.6 Hz, C.sub.3′,5′—H), 7.73 (1H, t, J=7.6 Hz, C.sub.4′—H), 7.94 (1H, s, C.sub.3—H), 7.98 (2H, s, SO.sub.2NH.sub.2), 8.11 (2H, d, J=7.6 Hz, C.sub.2′,6′—H), 8.38 (1H, s, C.sub.6—H), 9.22 (1H, t, J=5.6 Hz, NH).

(419) .sup.13C NMR δ ppm: 43.4, 127.5, 128.1, 128.8, 129.0, 129.8 (2C), 132.3, 132.8, 134.8, 136.6, 139.0, 140.4, 142.2, 145.5, 165.8.

(420) HRMS calcd. for C.sub.20H.sub.17ClN.sub.2O.sub.5S.sub.2 [(M+H).sup.+]: 465.0340, found: 465.0338.

(421) The compound 39b. Recrystallization was accomplished from 1-BuOH:toluene (8:1). Yield: 113 mg, 48%, mp 270-272° C.

(422) .sup.1H NMR δ ppm: 1.17 (3H, br s, Cy-H), 1.42-1.45 (2H, m, Cy-H), 1.62 (1H, br s, Cy-H), 1.81 (4H, br s, Cy-H), 3.80 (1H, t, J=11.2 Hz, Cy-H), 4.49 (2H, d, J=4.8 Hz, CH.sub.2), 7.28-7.39 (5H, m, Ph-H), 8.01 (2H, s, SO.sub.2NH.sub.2), 8.03 (1H, s, C.sub.3—H), 8.07 (1H, s, C.sub.6—H), 9.35 (1H, br s, NH).

(423) .sup.13C NMR δ ppm: 24.8 (2C), 25.2, 43.3, 63.1, 127.5, 127.9, 128.8, 130.1, 132.0, 133.7, 137.3, 139.0, 139.5, 145.5, 166.0

(424) HRMS calcd. for C.sub.20H.sub.23ClN.sub.2O.sub.5S.sub.2 [(M+H).sup.+]: 471.0810, found: 471.0811.

(425) The compound 41a. Yield: 155 mg, 65%, mp 212-214° C.

(426) .sup.1H NMR δ ppm: 0.93 (3H, t, J=7.2 Hz, CH.sub.3), 1.39 (2H, sext, J=7.2 Hz, CH.sub.3CH.sub.2), 1.53 (2H, quint, J=7.2 Hz, CH.sub.3CH.sub.2CH.sub.2), 3.25 (2H, q, J=6.8 Hz, NHCH.sub.2), 7.62-7.75 (3H, m, Ph-H), 7.90 (1H, s, C.sub.6—H), 7.93 (2H, s, SO.sub.2NH.sub.2), 8.08-8.10 (2H, m, Ph-H), 8.45 (1H, s, C.sub.3—H), 8.66 (1H, t, J=5.6 Hz, NH).

(427) .sup.13C NMR δ ppm: 14.2, 20.0, 31.1, 39.5, 120.3, 128.9, 129.7, 129.8, 134.7, 135.9, 137.5, 140.4, 141.7, 147.3, 165.7.

(428) HRMS calcd. for C.sub.17H.sub.19BrN.sub.2O.sub.5S.sub.2[(M+H).sup.+]: 476.9971 (100%), found: 476.9972 (100%).

(429) The compound 41b. Yield: 205 mg, 85%, mp 222-224° C.

(430) .sup.1H NMR δ ppm: 0.91 (3H, t, J=7.2, Hz, CH.sub.3), 1.16-1.24 (3H, m, Cy-H), 1.32-1.53 (2H, m, CH.sub.3CH.sub.2, 2H, m, CH.sub.3CH.sub.2CH.sub.2 ir 2H, m, Cy-H), 1.63 (1H, m, Cy-H), 1.80-1.82 (4H, m, Cy-H), 3.23 (2H, q, J=6.8 Hz, NHCH.sub.2), 3.75-3.81 (1H, m, Cy-H), 7.96 (2H, s, SO.sub.2NH.sub.2), 8.02 (1H, s, C.sub.3—H), 8.14 (1H, s, C.sub.6—H), 8.78 (1H, t, J=5.6 Hz, NH).

(431) .sup.13C NMR δ ppm: 14.1, 20.0, 24.8, 24.9, 25.2, 31.2, 39.4, 63.0, 120.0, 130.0, 136.8, 138.2, 139.0, 147.3, 166.0.

(432) HRMS calcd. for C.sub.17H.sub.25BrN.sub.2O.sub.5S.sub.2[(M+H).sup.+]: 483.0441 (100%), found: 483.0435 (100%).

(433) The compound 42a. The product was purified by chromatography on a column of silica gel with CHCl.sub.3:EtOAc (4:1), R.sub.f=0.33. Yield: 158 mg, 81%, mp 166-168° C.

(434) .sup.1H NMR δ ppm: 3.86 (3H, s, CH.sub.3), 7.68 (2H, t, J=7.6 Hz, C.sub.3′,5′—H), 7.68 (1H, t, J=7.6 Hz, C.sub.4′—H), 8.03 (2H, s, SO.sub.2NH.sub.2), 8.07 (2H, d, J=7.6 Hz, C.sub.2′,6′—H), 8.23 (1H, s, C.sub.3—H), 8.51 (1H, s, C.sub.6—H).

(435) .sup.13C NMR δ ppm: 53.8, 128.5, 130.1, 130.3, 131.7, 133.5, 134.2, 134.9, 140.0, 142.3, 146.0, 165.7.

(436) HRMS calcd. for C.sub.14H.sub.12ClNO.sub.6S.sub.2 [(M+H).sup.+]: 389.9867, found: 389.9869.

(437) The compound 42b. Yield: 164 mg, 83%, mp 184-187° C.

(438) .sup.1H NMR δ ppm: 1.16-1.20 (3H, m, Cy-H), 1.42-1.50 (2H, m, Cy-H), 1.63 (1H, br s, Cy-H), 1.81-1.87 (4H, m, Cy-H), 3.89-3.92 (1H, m, Cy-H), 3.96 (3H, s, CH.sub.3), 7.48 (2H, s, SO.sub.2NH.sub.2), 8.11 (1H, s, C.sub.3—H), 8.57 (1H, s, C.sub.6—H).

(439) .sup.13C NMR δ ppm: 24.9 (2C), 25.1, 53.9, 62.2, 133.3, 135.1, 135.5, 136.7, 138.6, 142.1, 163.9.

(440) HRMS calcd. for C.sub.14H.sub.18ClNO.sub.6S.sub.2 [(M+H).sup.+]: 396.0337, found: 396.0336.

(441) The compound 42c. Recrystallization was accomplished from MeOH. Yield: 123 mg, 61%, mp 154-156° C.

(442) .sup.1H NMR δ ppm: 3.95 (3H, s, CH.sub.3), 5.04 (2H, s, CH.sub.2), 7.24-7.26 (2H, m, Ph-H), 7.33-7.40 (3H, m, Ph-H), 7.58 (2H, s, SO.sub.2NH.sub.2), 7.77 (1H, s, C.sub.3—H), 8.57 (1H, s, C.sub.6—H).

(443) .sup.13C NMR δ ppm: 53.9, 60.9, 127.5, 129.1, 129.5, 131.7, 132.9, 135.0, 135.4, 136.3, 139.2, 142.0, 163.8.

(444) HRMS calcd. for C.sub.15H.sub.14ClNO.sub.6S.sub.2 [(M+H).sup.+]: 404.0024, found: 404.0023.

(445) The compound 43a. Yield: 189 mg, 87%, mp 191-193° C.

(446) .sup.1H NMR δ ppm: 3.86 (3H, s, CH.sub.3), 7.67-7.79 (3H, m, Ph-H), 7.98 (2H, s, SO.sub.2NH.sub.2), 8.04-8.07 (2H, m, Ph-H), 8.22 (1H, s, C.sub.6—H), 8.62 (1H, s, C.sub.3—H).

(447) .sup.13C NMR δ ppm: 53.8, 122.7, 128.5, 130.1, 130.2, 132.2, 134.9, 136.7, 140.0, 141.9, 147.8, 165.8.

(448) HRMS calcd. for C.sub.14H.sub.12BrNO.sub.6S.sub.2[(M+H).sup.+]: 435.9342 (100%), found: 435.9345 (100%).

(449) The compound 43b. Yield: 172 mg, 78%, mp 217-219° C.

(450) .sup.1H NMR δ ppm: 1.16-1.24 (3H, m, Cy-H), 1.42-1.50 (2H, m, Cy-H), 1.57-1.63 (1H, m, Cy-H), 1.79-1.86 (4H, m, Cy-H), 3.89-3.92 (1H, m, Cy-H), 3.95 (3H, s, CH.sub.3), 7.47 (2H, s, SO.sub.2NH.sub.2), 8.25 (1H, s, C.sub.3—H), 8.50 (1H, s, C.sub.6—H).

(451) .sup.13C NMR δ ppm: 21.5, 24.9, 25.1, 53.9, 62.2, 125.3, 132.8, 137.7, 138.1, 138.4, 142.6, 164.6.

(452) HRMS calcd. for C.sub.14H.sub.18BrNO.sub.6S.sub.2[(M+H).sup.+]: 441.9811 (100%), found: 441.9806 (100%).

Example 16

Preparation of 2-benzylsulfinyl-4-chloro-N-cyclohexyl-5-sulfamoyl-benzamide (Compound 44) and 2-(benzenesulfinyl)-4-bromo-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide (Compound 45)

(453) The ˜38% AcOOH (0.748 mmol) solution in AcOH (0.130 mL) was added dropwise to a solution of 2-benzylsulfanyl-4-chloro-N-cyclohexyl-5-sulfamoyl-benzamide (compound 9c) or 4-bromo-N-(2-hydroxyethyl)-2-phenylsulfanyl-5-sulfamoyl-benzamide (compound 11a) (219 mg, 0.500 mmol) in AcOH (2 mL) at 50-60° C. and allows stirring for 2-3 h. The progress of reaction was monitored by TLC. The solvent was removed under reduced pressure and the resultant precipitate was filtered, washed with H.sub.2O.

(454) The compound 44. The product was purified by chromatography on a column of silica gel with EtOAc:CHCl.sub.3 (1:1), R.sub.f=0.35. Yield: 150 mg, 66%, mp 240-243° C.

(455) .sup.1H NMR δ ppm: 1.11-1.39 (5H, m, Cy-H), 1.61-1.64 (1H, m, Cy-H), 1.76 (2H, br s, Cy-H), 1.83-1.92 (2H, m, Cy-H), 3.76-3.85 (1H, m, Cy-H), 4.05 (1H.sub.A, d, J=12.4 Hz, CH.sub.2Ph), 4.51 (1H.sub.B, d, J=12.4 Hz, CH.sub.2Ph), 7.06-7.09 (2H, m, Ph-H), 7.28-7.32 (3H, m, Ph-H), 7.57 (1H, s, C.sub.3—H), 7.81 (2H, s, SO.sub.2NH.sub.2), 8.40 (1H, s, C.sub.5—H), 9.05 (1H, d, J=8.0 Hz, NH).

(456) .sup.13C NMR δ ppm: 25.3, 25.6, 32.7, 49.3, 62.2, 128.2, 128.4, 128.5, 128.6, 130.9, 131.2, 131.5, 133.9, 142.7, 151.2, 163.8.

(457) HRMS calcd. for C.sub.20H.sub.23ClN.sub.2O.sub.4S.sub.2 [(M+H).sup.+]: 455.0861, found: 455.0856.

(458) The compound 45. Yield: 127 mg, 57%, mp 138-142° C. (dec).

(459) .sup.1H NMR δ ppm: 3.28 (2H, q, J=5.6 Hz, NHCH.sub.2), 3.45 (2H, br s, CH.sub.2OH), 4.78 (1H, s, OH), 7.48-7.49 (3H, m, C.sub.3′,4′,5′—H), 7.71-7.73 (2H, m, C.sub.2′,6′—H), 7.77 (2H, s, SO.sub.2NH.sub.2), 8.34 (1H, s, C.sub.3—H), 8.38 (1H, s, C.sub.6—H), 9.03 (1H, t, J=5.2 Hz, NH).

(460) .sup.13C NMR δ ppm: 42.8, 59.8, 123.0, 126.2, 129.1, 129.7, 130.5, 131.6, 132.5, 144.6, 146.4, 152.0, 164.5.

(461) HRMS calcd. for C.sub.15H.sub.15BrN.sub.2O.sub.5S.sub.2[(M+H).sup.+]: 448.9658 (100%), found: 448.9663 (100%).

Example 17

Preparation of 4-[(2,4-dichloro-5-sulfamoyl-benzoyl)amino]butanoic acid (Compound 46), 4-[(4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzoyl)amino]butanoic acid (Compound 47), and 4-[(2-benzylsulfonyl-4-chloro-5-sulfamoyl-benzoyl)amino]butanoic acid (Compound 48)

(462) Appropriate methyl 4-[(2,4-dichloro-5-sulfamoyl-benzoyl)amino]butanoate (compound 7), methyl 4-[(4-chloro-2-cyclohexylsulfanyl-5-sulfamoyl-benzoyl)amino]butanoate (compound 7b), or methyl 4-[(2-benzylsulfonyl-4-chloro-5-sulfamoyl-benzoyl)amino]butanoate (compound 37c) (0.501 mmol) was refluxed in methanol (2 mL), H.sub.2O (1 mL), and concentrated HCl (aq) (1 mL) solution for 12-24 hours. The progress of reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure.

(463) The compound 46. Recrystallization was accomplished from NaOAc (20.6 mg, 0.251 mmol) solution in H.sub.2O. Yield: 107 mg, 60%, mp 136-139° C.

(464) .sup.1H NMR δ ppm: 1.74 (2H, quint, J=7.2 Hz, CH.sub.2), 2.31 (2H, t, J=7.2 Hz, COCH.sub.2), 3.27 (2H, q, J=6.8 Hz, NHCH.sub.2), 7.82 (2H, s, SO.sub.2NH.sub.2), 7.92 (1H, s, C.sub.3—H), 7.95 (1H, s, C.sub.6—H), 8.69 (1H, t, J=5.6 Hz, NH), 12.11 (1H, br s, CO.sub.2H).

(465) .sup.13C NMR δ ppm: 24.8, 31.4, 39.0, 129.1, 132.2, 132.5, 134.4, 136.4, 140.4, 164.9, 174.6.

(466) HRMS calcd. for C.sub.11H.sub.12Cl.sub.2N.sub.2O.sub.5S [(M+H).sup.+]: 354.9917, found: 354.9918.

(467) The compound 47. Recrystallization was accomplished from NaOAc (20.6 mg, 0.251 mmol) solution in H.sub.2O. Yield: 142 mg, 65%, mp 163-165° C.

(468) .sup.1H NMR δ ppm: 1.18-1.45 (5H, m, Cy-H), 1.57-1.60 (1H, m, 1.69-1.71 (2H, m, Cy-H), 1.73 (2H, quint, J=7.2 Hz, CH.sub.2), 1.90-1.92 (2H, m, Cy-H), 2.32 (2H, t, J=7.2 Hz, COCH.sub.2), 3.23 (2H, q, J=6.4 Hz, NHCH.sub.2), 3.53-3.58 (1H, m, Cy-H), 7.64 (1H, s, C.sub.3—H), 7.66 (2H, br s, SO.sub.2NH.sub.2), 7.82 (1H, s, C.sub.6—H), 8.56 (1H, t, J=5.6 Hz, NH), 12.17 (1H, br s, CO.sub.2H).

(469) .sup.13C NMR δ ppm: 24.9, 25.5, 25.7, 31.6, 32.7, 38.9, 44.3, 128.2, 130.7, 131.7, 136.9, 137.8, 141.2, 166.4, 174.7.

(470) HRMS calcd. for C.sub.17H.sub.23ClN.sub.2O.sub.5S.sub.2[(M+H).sup.+]: 435.0810, found: 435.0809.

(471) The compound 48. Recrystallization was accomplished, from NaOAc (20.6 mg, 0.251 mmol) solution in H.sub.2O. Yield: 164 mg, 69%, mp 252-254° C.

(472) .sup.1H NMR δ ppm: 1.79 (2H, quint, J=7.2 Hz, CH.sub.2), 2.37 (2H, t, J=7.2 Hz, COCH.sub.2), 3.30-3.35 (2H, m, NHCH.sub.2, superposed with H.sub.2O), 4.99 (2H, s, CH.sub.2Ph), 7.24-7.26 (2H, m, Ph-H), 7.32-7.39 (3H, m, Ph-H), 7.61 (1H, s, C.sub.3—H), 8.03 (2H, s, SO.sub.2NH.sub.2), 8.04 (1H, s, C.sub.6—H), 8.98 (1H, t, J=6.0 Hz, NH), 12.10 (1H, s, OH),

(473) .sup.13C NMR δ ppm: 24.6, 31.4, 39.2, 62.1, 128.2, 129.0, 129.2, 129.6, 131.5 (2C), 133.3, 137.2, 140.1, 145.6, 166.3, 174.7.

(474) HRMS calcd. for C.sub.18H.sub.19ClN.sub.2O.sub.7S.sub.2 [(M+H).sup.+]: 475.0395, found: 475.0394.

(475) The Measurements of Compound Binding to Proteins and Inhibition of Enzymes

(476) Carbonic anhydrases (CA) catalyse reversible carbon dioxide conversion to bicarbonate ion and maintain pH of the cell surroundings (Krebs, J. F. and Fierke, C. A. (1993). J. Biol. Chem. 268, 948). Dysfunctional expression of this enzyme in the cells causes diseases such as glaucoma, edema, epilepsy, cancer, etc. Thus, CA inhibitors are clinically used for treatment and new compounds are being synthesized. The most successful design of inhibitors is tail modification of already known sulfonamide drugs.

Example 18

Determination of the Observed Binding Constants by the Fluorescent Thermal Assay (FTSA) and Isothermal Titration Calorimetry (ITC)

(477) To determine the binding affinity of newly synthesized compounds to CA, the fluorescent thermal shift assay (FTSA) and isothermal titration calorimetry (ITC) were used. These methods complement each other. It is known that bound ligands stabilize the protein. FTSA is based on the protein melting temperature (T.sub.m) shift between protein with and without bound ligand. FTSA shows dissociation constant (K.sub.d) with no limitation—tight and weak binding can be determined. However, ITC is not appropriate to observe millimolar (weak) or subnanomolar (very tight) binding, but the heat evolved upon binding can be measured.

(478) The X-ray crystallographic structures of several compounds demonstrated that the sulfonamide-bearing compounds bound to the active center of CAs with a stoichiometry of 1:1 (Čapkauskaité, E. et al. (2010), Bioorg. Med. Chem. 18, 7357).

(479) Table 1 shows the dissociation constants of several selected CA VA-selective compounds for all twelve catalytically active human CAs. Data was obtained by VISA and FIG. 1 shows representative binding curves. FTSA experiments were performed as previously described by Čapkauskaité et al. (Čapkauskaité, E. et al. (2012), Eur. Med. Chem. 51, 259) and fit and analysed as described by Kazlauskas et al. (Kazlauskas, E. et al. (2012), PLoS ONE, 7, e36899).

(480) The data in the Table 1 show that compound with general structural formula II bind CA XIV isozyme with nanomolar affinity (K.sub.ds of selected compounds presented in the table are in the range of 20-300 nM), but exhibiting especially strong binding to CA VA (subnanomolar affinity from 0.3 to 6.0 nM).

(481) Selected selective inhibitors of CA XIV are shown in table 2. FTSA results show that these compounds bind to CA XIV with subnanomolar affinity (K.sub.ds of selected compounds are in the range of 0.03-6.7 nM). Affinities are more than 10 times higher between CA XIV and other CA isoforms. Compounds in the table show nanomolar affinity to CA II, CA VII, IX and XII. Binding to CA I, IV, VA, VB, VI and XIII is weaker. The last row of the table shows ITC data of compound 3 binding to several CA isoforms. ITC measurements were performed as previously described by Čapkauskaité et al. (Čapkauskaité, E. et al. (2012), Eur. J. Med. Chem. 51, 259). Due to laborious nature of ITC measurements, only few compounds were tested by ITC and demonstrated that there is relatively good agreement between TSA and ITC data.

(482) Compounds listed in Table 3 are strong inhibitors for cancer-related CAs (CA IX and CA XII). Table shows the dissociation constants observed for CA I, II, IX and XII. CA I and II are the most abundant isoforms in human body, thus it is very important to avoid inhibition of these CAs. All compounds that are selective to cancer CAs have low affinity to CA I (from 83 to 33000 nM). Compounds, that have longer tail or ring at the end of the tail in meta position, show higher affinity to CA II compared to compounds that have shorter tail moiety and do not have ring in this position.

(483) ITC raw and integrated data of 13a binding to CA IX are shown in FIG. 2. FIG. 3 shows integrated ITC curves of 13a binding to CA I, II, IX and XII. The binding of 13a to CA I shows the case of a very weak binding and the curve can not be fit precisely.

(484) TABLE-US-00001 TABLE 1 Dissociation constants (nM) of selected CA VA-selective compounds binding to 12 human recombinant CA isoforms as determined by FTSA at 37° C. and pH 7.0. CA CA CA CA CA CA CA CA CA CA CA CA I II III IV VA VB VI VII IX XII XIII XIV 19 11000 1600 >200000 600 0.3 3300 700 1000 800 3100 800 50 20 7100 600 80000 3300 0.8 500 2000 1700 600 3100 800 50 29 5000 300 17000 1100 2.0 1000 1400 100 400 3300 700 20 30 7700 500 22000 2900 5.0 2500 4000 700 1100 4000 1100 300 31 7700 500 40000 1400 6.0 700 1800 300 400 2800 600 40

(485) TABLE-US-00002 TABLE 2 Dissociation constants (nM) of selected CA XIV-selective compounds binding to twelve human recombinant CA isoforms as determined by FTSA and ITC (the last row) at 37° C., pH 7.0. CA CA CA CA CA CA CA CA CA CA CA CA I II III IV VA VB VI VII IX XII XIII XIV  3 100000 83 8300 400 5000 400 630 10 170 325 560 6.7  3c 2100 13 50000 33 500 150 1600 3.3 15 10 91 0.7  6a 5000 8.3 10000 1.4 4500 40 670 2.5 1.7 2.5 140 0.1  7c 3200 7.7 >200000 11 670 43 1700 4.3 45 7.1 180 0.3 33b 1400 3.3 25000 33 330 10 1300 4.0 3.1 20 2.5 0.2 42a 140 0.9 3300 25 770 13 56 0.5 3.3 22 5.6 0.03 3 (by ITC) n/d 39.4 n/d n/d n/d n/d n/d n/d n/d 79.9 218 n/d

(486) TABLE-US-00003 TABLE 3 Dissociation constants (nM) of selected compounds binding to four human recombinant CA isoforms as determined by FTSA at 37° C., pH 7.0. CA I CA II CA IX CA XII  3a 10000 31 4.0 6.3  3b 1000 10 1.3 2.0  3f 14000 420 20 4.0  3g 1100 8.3 1.4 2.0  4a 6700 5.0 0.3 0.8  4b 1300 3.7 0.7 1.0  4f 33000 170 8.3 660  5a 1100 4.5 1.3 1.0  5b 400 2.5 0.8 0.5  7b 2000 10 2.0 1.3  9b 560 50 3.3 33 10b 83 1.4 1.1 1.0 11a 3100 50 13 2.0 12a 830 10 2.5 0.8 13a 10000 25 5.0 10 14a 10000 36 2.5 6.7 14b 17000 250 0.3 33 14c 6900 110 2.9 22 14d 13000 170 13 53 38b 2000 22 2.0 33 47 3300 13 2.2 0.4

(487) Newly synthesized compounds of general formulas (I) and (II)

(488) ##STR00012##

(489) exhibit significant affinity and selectivity, often better than the existing compounds, promising to help in solving the issue of non-specific binding of clinically used inhibitors.