Substituted N,2-diarylquinoline-4-carboxamides and the use thereof as anti-inflammatory agents

Abstract

The present application relates to novel substituted N,2-diarylquinoline-4-carboxamide derivatives, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of fibrotic and/or inflammatory disorders.

Claims

1. A method for treatment of idiopathic pulmonary fibrosis in a human or an animal, comprising administering to the human or animal in need thereof a compound of the formula (I) ##STR00218## in which R.sup.A is hydrogen, halogen, pentafluorosulfanyl, cyano, nitro, (C.sub.1-C.sub.4)-alkyl, hydroxyl, (C.sub.1-C.sub.4)-alkoxy, amino or a group of the formula NHC(O)R.sup.6, NHC(O)NHR.sup.6 or S(O)R.sup.7, where (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkoxy may be up to trisubstituted by fluorine, and in which R.sup.6 is hydrogen or (C.sub.1-C.sub.4)-alkoxy which may be up to trisubstituted by fluorine, R.sup.7 is (C.sub.1-C.sub.4)-alkyl which may be substituted by hydroxyl, methoxy or ethoxy or up to trisubstituted by fluorine, and n is the number 0, 1 or 2, D is CR.sup.b or N, E is CR.sup.E or N, G is CR.sup.G or N, where not more than two of the ring members D, E and G at the same time are N, and in which R.sup.D and R.sup.E are each independently hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy, and R.sup.G is hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl, Z is OH or a group of the formula NHR.sup.8, NHSO.sub.2R.sup.9 or NHSO.sub.2NR.sup.10AR.sup.10B, in which R.sup.8 is hydrogen or (C.sub.1-C.sub.4)-alkoxy which may be up to trisubstituted by fluorine, R.sup.9 is (C.sub.1-C.sub.4)-alkoxy which may be up to trisubstituted by fluorine, or phenyl, and R.sup.10A and R.sup.10B are each independently hydrogen or (C.sub.1-C.sub.4)-alkyl which may be up to trisubstituted by fluorine, R.sup.1 is halogen, trifluoromethoxy, (trifluoromethyl)sulfanyl, pentafluorosulfanyl, (C.sub.1-C.sub.4)-alkyl, trimethylsilyl, cyclopropyl or cyclobutyl, where (C.sub.1-C.sub.4)-alkyl may be up to trisubstituted by fluorine and cyclopropyl and cyclobutyl may be up to disubstituted by fluorine, R.sup.2, R.sup.3 and R.sup.4 are each independently hydrogen, fluorine, chlorine, methyl or trifluoromethyl, R.sup.5 is (C.sub.1-C.sub.4)-alkyl which may be up to trisubstituted by fluorine, or is fluorine, chlorine, methoxy or cyclopropyl, and Ar is phenyl which may be mono- or disubstituted identically or differently by fluorine and chlorine, or is pyridyl or thienyl, and an N-oxide, salt, solvate, salt of the N-oxide and solvate of the N-oxide and salt thereof.

2. The method of claim 1, wherein the compound of the formula (I) is in a medicament, wherein the medicament comprises the compound of the formula (I) in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

3. The method of claim 2 wherein the medicament further comprises at least one compound selected from the group consisting of PDE 5 inhibitor, sGC activator, sGC stimulator, prostacyclin analog, IP receptor agonist, endothelin antagonist, compound that inhibit the signal transduction cascade, and pirfenidone.

4. The method of claim 1, wherein the compound is a compound of formula (I) in which R.sup.A is hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula S(O).sub.nR.sup.7 in which R.sup.7 is methyl or trifluoromethyl, and n is the number 0 or 2, D is CR.sup.D or N, in which R.sup.D is hydrogen or fluorine, E is C-H, G is CR.sup.G or N, in which R.sup.G is hydrogen, fluorine or chlorine, Z is OH, R.sup.1 is chlorine, bromine, iodine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, (trifluoromethyl)sulfanyl, pentafluorosulfanyl or trimethylsilyl, R.sup.2 and R.sup.3 are each hydrogen, R.sup.4 is hydrogen, fluorine or chlorine, R.sup.5 is methyl, chlorine or cyclopropyl, and Ar is phenyl which may be monosubstituted by fluorine, or pyridyl, and a salt, solvate and solvate of the salt thereof.

5. The method of claim 1, wherein the compound is a compound of formula (I) in which R.sup.A is fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula S(O).sub.nR.sup.7 in which R.sup.7 is methyl or trifluoromethyl, and n is the number 0 or 2, D is C-H, E is C-H, G is CR.sup.G or N, in which R.sup.G is hydrogen, fluorine or chlorine, Z is OH, R.sup.1 is chlorine, bromine, methyl, trifluoromethyl or trimethylsilyl, R.sup.2 and R.sup.3 are each hydrogen, R.sup.4 is hydrogen or chlorine, R.sup.5 is methyl, and Ar is phenyl which may be monosubstituted by fluorine, or 4-pyridyl, and a salt, solvate and solvate of the salt thereof.

6. The method of claim 1, wherein the compound is 6-{[6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-fluoronicotinic acid ##STR00219##

7. The method of claim 1, wherein the compound is 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3 fluorobenzoic acid ##STR00220##

8. The method of claim 1, wherein the compound is 3-Fluoro-4-{[6-iodo-3-methyl-2-phenylquinolin-4-yl)carbonyl]-amino}-benzoic acid ##STR00221##

9. The method of claim 1, wherein the compound is 4-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid ##STR00222##

10. The method of claim 1, wherein the compound is 4-{[(6-Bromo-3-cyclopropyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid ##STR00223##

Description

WORKING EXAMPLES

Example 1

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic acid

(1) ##STR00140##

(2) To 177 mg (0.36 mmol) of the compound from example 34A were added first 4.5 ml of THF and then a solution of 13 mg (0.54 mmol) of lithium hydroxide in 1.5 ml of water. The reaction mixture was stirred at RT for eight days and then adjusted to pH 1-2 with 2 M hydrochloric acid. The precipitated solids were filtered off, washed with water, and dried under reduced pressure at 60 C. overnight. 109 mg (65% of theory, 100% purity) of the title compound were obtained.

(3) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=11.25 (s, 1H), 8.06 (d, 1H), 8.01-7.99 (m, 2H), 7.95 (dd, 1H), 7.92-7.87 (m, 3H), 7.65-7.63 (m, 2H), 7.58-7.51 (m, 3H), 2.41 (s, 3H).

(4) LC/MS (Method 1, ESIpos): R.sub.t=1.08 min, m/z=461/463 [M+H].sup.+.

Example 2

6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}nicotinic acid imidazole salt

(5) ##STR00141##

(6) To 100 mg (0.26 mmol) of the compound from example 2A were successively added 2 ml of THF, 47 mg (0.31 mmol) of methyl 6-aminonicotinate and 22 mg (0.56 mmol) of sodium hydride (60% in mineral oil). The reaction mixture was stirred at RT overnight, and then it was purified, without further workup, by means of preparative HPLC (method 8). 15 mg (11% of theory, 100% purity) of the title compound were obtained.

(7) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=12.54 (br. s, 1H), 11.65 (s, 1H), 8.85 (d, 1H), 8.43 (d, 1H), 8.36 (dd, 1H), 8.03 (d, 1H), 7.93-7.90 (m, 2H), 7.64-7.61 (m, 4H), 7.58-7.49 (m, 4H), 7.01 (s, 1H), 2.40 (s, 3H).

(8) LC/MS (Method 1, ESIpos): R.sub.t=1.07 min, m/z=462/464 [M+H].sup.+.

Example 3

5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}pyrazine-2-carboxylic Acid

(9) ##STR00142##

(10) 100 mg (0.26 mmol) of the compound from example 2A and 43 mg (0.26 mmol) of ethyl 5-aminopyrazine-2-carboxylate were dissolved in 2 ml of DMF. 72 mg (0.64 mmol) of potassium tert-butoxide were added in portions to the solution. The reaction mixture was stirred at RT overnight, and then 1.3 ml (1.3 mmol) of 1 M sodium hydroxide solution were added. After stirring at 80 C. for 1 h and cooling to RT, the mixture was adjusted to pH 1-2 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phase was removed and washed with saturated sodium chloride solution. After the organic phase had been dried over sodium sulfate and the solvent had been removed on a rotary evaporator, the residue was taken up in a little DMF and purified by means of preparative HPLC (method 6). After the solvent-water mixture had been removed, the residue was taken up in a little acetonitrile, water was added and then the mixture was lyophilized. Since solvent residues were still present, the lyophilizate was redissolved in dichloromethane and ethyl acetate, water was added again and the mixture was lyophilized again. The resulting lyophilizate was redissolved once again in dichloromethane and tert-butanol, water was added and the mixture was lyophilized again. The lyophilizate thus obtained was dried at 100 C. under high vacuum for a total 9 h. In this way, 39 mg (29% of theory, 90% purity) of the title compound were obtained.

(11) .sup.1H-NMR (600 MHz, DMSO-d.sub.6): [ppm]=13.54 (br. s, 1H), 12.03 (s, 1H), 9.71 (s, 1H), 9.01 (s, 1H), 8.10 (d, 1H), 8.04 (d, 1H), 7.93 (dd, 1H), 7.66-7.60 (m, 2H), 7.58-7.50 (m, 3H), 2.41 (s, 3H).

(12) LC/MS (Method 1, ESIpos): R.sub.t=0.96 min, m/z=463/465 [M+H].sup.+.

Example 4

5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}pyrimidine-2-carboxylic Acid

(13) ##STR00143##

(14) A solution of 23 mg (0.05 mmol) of the compound from example 36A in 0.7 ml of a THF/methanol mixture (5:1) was admixed with 0.24 ml (0.24 mmol) of 1 M sodium hydroxide solution and stirred under reflux for 1 h. After cooling to RT, the mixture, without further workup, was purified by means of preparative HPLC (method 15). The acetonitrile-water mixture was removed on a rotary evaporator and the residue was dried under reduced pressure overnight. 10 mg (22% of theory, 98% purity) of the title compound were obtained.

(15) .sup.1H-NMR (400 MHz, CD.sub.3OD): [ppm]=9.41 (br. s, 2H), 8.12 (s, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.71-7.51 (m, 5H), 2.50 (s, 3H).

(16) LC/MS (Method 1, ESIpos): R.sub.t=0.90 min, m/z=463/465 [M+H].sup.+.

Example 5

5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-6-methylpyridine-2-carboxylic Acid

(17) ##STR00144##

(18) To 250 mg (0.64 mmol) of the compound from example 2A were added 10 ml of THF, 127 mg (0.77 mmol) of methyl 5-amino-6-methylpyridine-2-carboxylate and 56 mg (1.40 mmol) of sodium hydride (60% in mineral oil). The reaction mixture was stirred at RT for two days, then water was added, and the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was separated off and the solvent was removed on a rotary evaporator. The residue was purified by means of preparative HPLC (method 11). 41 mg (13% of theory, 100% purity) of the title compound were obtained.

(19) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.76 (s, 1H), 8.43 (d, 1H), 8.07-8.02 (m, 3H), 7.97-7.94 (m, 1H), 7.66-7.64 (m, 2H), 7.59-7.49 (m, 3H), 2.58 (s, 3H), 2.48 (s, 3H).

(20) LC/MS (Method 1, ESIpos): R.sub.t=0.96 min, m/z=476/478 [M+H].sup.+.

Example 6

6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-fluoronicotinic Acid

(21) ##STR00145##

(22) To a solution of 156 mg (0.31 mmol) of the compound from example 37A in 3.9 ml of THF and 0.8 ml of methanol were added, at RT, 1.54 ml (1.54 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the organic solvent was removed. The remaining residue was diluted with water, and the mixture was acidified with 1 M hydrochloric acid while stirring. The solids formed were filtered off and washed twice with water. Drying under reduced pressure gave 131 mg (89% of theory, purity 100%) of the title compound.

(23) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.67 (br. s, 1H), 11.60 (s, 1H), 8.86 (br. s, 1H), 8.30 (d, 1H), 8.10-7.89 (m, 3H), 7.67-7.60 (m, 2H), 7.58-7.49 (m, 3H), 2.47 (s, 3H).

(24) LC/MS (Method 1, ESIpos): R.sub.t=0.99 min, m/z=480/482 [M+H].sup.+.

Example 7

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(25) ##STR00146##

(26) 100 mg (0.20 mmol) of the compound from example 38A were dissolved in 2.5 ml of THF and 0.5 ml of methanol. 0.61 ml (0.61 mmol) of 1 M sodium hydroxide solution was added to the solution. The reaction mixture was stirred under reflux for 1 h. The volume of the solution was then reduced on a rotary evaporator, and the concentrated solution was adjusted to pH 3 with 0.6 ml of 1 M hydrochloric acid. The mixture was diluted with 5 ml of water, and the precipitated solids were filtered off. The solids were washed with water and dried under reduced pressure. 94 mg (97% of theory, 100% purity) of the title compound were obtained.

(27) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.27 (br. s, 1H), 11.04 (s, 1H), 8.17 (t, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.94 (dd, 1H), 7.88 (dd, 1H), 7.80 (dd, 1H), 7.65-7.61 (m, 2H), 7.58-7.50 (m, 3H), 2.44 (s, 3H).

(28) LC/MS (Method 1, ESIpos): R.sub.t=1.08 min, m/z=479/481 [M+H].sup.+.

Example 8

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-fluorobenzoic acid

(29) ##STR00147##

(30) To 95 mg (0.19 mmol) of the compound from example 41A were added 2 ml of THF and 1.9 ml of 4 M sodium hydroxide solution. The reaction mixture was stirred at 80 C. overnight. Thereafter, the organic phase was removed and, without further workup, purified by means of preparative HPLC (method 9). 16 mg (17% of theory, 100% purity) of the title compound were obtained.

(31) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=11.38 (s, 1H), 8.07-8.04 (m, 1H), 7.96-7.92 (m, 3H), 7.85 (dd, 1H), 7.65-7.62 (m, 2H), 7.58-7.50 (m, 4H), 2.40 (s, 3H).

(32) LC/MS (Method 1, ESIpos): R.sub.t=1.11 min, m/z=479/481 [M+H].sup.+.

Example 9

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-chlorobenzoic acid

(33) ##STR00148##

(34) To a solution of 1.53 g (3.00 mmol) of the compound from example 42A in 38 ml of THF and 8 ml of methanol were added, at RT, 15 ml (15 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the organic solvent was removed. The remaining residue was diluted with water, and the mixture was acidified with 1 M hydrochloric acid while stirring. The solids present were filtered off and washed twice with water and once with tert-butyl methyl ether. Drying under reduced pressure gave 1.40 g (94% of theory, 100% purity) of the title compound.

(35) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.34 (br. s, 1H), 10.93 (s, 1H), 8.13-7.99 (m, 5H), 7.94 (dd, 1H), 7.68-7.60 (m, 2H), 7.59-7.49 (m, 3H), 2.48 (s, 3H, partially hidden).

(36) LC/MS (Method 1, ESIpos): R.sub.t=1.11 min, m/z=495/497 [M+H].sup.+.

Example 10

3-Bromo-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic acid

(37) ##STR00149##

(38) To a solution of 120 mg (0.22 mmol) of the compound from example 43A in 2.5 ml of THF and 0.5 ml of methanol was added, at RT, 1.0 ml (1.0 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the mixture was introduced into 30 ml of water and then acidified with 1 M hydrochloric acid while stirring. The solids present were filtered off and washed twice with water and once with tert-butyl methyl ether. Drying under reduced pressure gave 113 mg (95% of theory, purity 98%) of the title compound.

(39) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.35 (s, 1H), 10.88 (s, 1H), 8.23 (d, 1H), 8.14 (d, 1H), 8.09-8.02 (m, 2H), 8.01-7.97 (m, 1H), 7.94 (dd, 1H), 7.66-7.61 (m, 2H), 7.59-7.49 (m, 3H), 2.50 (s, 3H, hidden).

(40) LC/MS (Method 1, ESIpos): R.sub.t=1.13 min, m/z=539/541/543 [M+H].sup.+.

Example 11

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-iodobenzoic Acid

(41) ##STR00150##

(42) 100 mg (0.26 mmol) of the compound from example 2A and 71 mg (0.26 mmol) of methyl 4-amino-3-iodobenzoate were dissolved in 2 ml of DMF. Subsequently, 72 mg (0.64 mmol) of potassium tert-butoxide were added in portions, and the reaction mixture was stirred at RT overnight. Thereafter, the mixture was admixed with 1.3 ml (1.3 mmol) of 1 M sodium hydroxide solution and stirred at 80 C. for 1 h. After cooling to RT, the mixture, without further workup, was purified by means of preparative HPLC (method 6). After the solvent-water mixture had been removed, the mixture was dried under reduced pressure overnight. 81 mg (53% of theory, 99% purity) of the title compound were obtained.

(43) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): [ppm]=13.30 (br. s, 1H), 10.77 (s, 1H), 8.45 (d, 1H), 8.17 (d, 1H), 8.10-8.01 (m, 2H), 7.94 (dd, 1H), 7.86 (d, 1H), 7.68-7.60 (m, 2H), 7.60-7.49 (m, 3H), 2.53 (s, 3H).

(44) LC/MS (Method 1, ESIpos): R.sub.t=1.11 min, m/z=586/588 [M+H].sup.+.

Example 12

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3,5-difluorobenzoic Acid

(45) ##STR00151##

(46) 500 mg (1.28 mmol) of the compound from example 2A and 286 mg (1.53 mmol) of methyl 4-amino-3,5-difluorobenzoate were dissolved in 10 ml of THF, and 112 mg (2.80 mmol) of sodium hydride (60% in mineral oil) were added at RT. After stirring overnight, the solvent was removed on a rotary evaporator. The residue, without further workup, was purified by means of preparative HPLC (method 13). The product thus obtained was stirred with acetonitrile, and the resulting solids were filtered off and washed with acetonitrile. Drying under reduced pressure gave 124 mg (18% of theory, purity 94%) of the title compound.

(47) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.69 (s, 1H), 8.08 (d, 1H), 8.06-8.03 (d, 1H), 7.96-7.94 (dd, 1H), 7.65-7.63 (m, 2H), 7.58-7.50 (m, 5H), 2.48 (s, 3H).

(48) LC/MS (Method 1, ESIpos): R.sub.t=1.08 min, m/z=497/499 [M+H].sup.+.

Example 13

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3,5-dichlorobenzoic Acid

(49) ##STR00152##

(50) To a solution of 62 mg (0.11 mmol) of the compound from example 44A in 1.4 ml of THF and 0.3 ml of methanol was added, at RT, 0.56 ml (0.56 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the organic solvent was removed. The remaining residue was diluted with water, and the mixture was acidified with 1 M hydrochloric acid while stirring. The solids formed were filtered off and washed twice with water. After drying under air, the solids were taken up in DMSO and purified by means of preparative HPLC (method 5). The combined product-containing fractions were concentrated, the residue was taken up in dichloromethane/methanol, and the mixture was concentrated again. After the residue had been dried under reduced pressure, 20 mg (34% of theory, 100% purity) of the title compound were obtained.

(51) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.68 (br. s, 1H), 11.22 (s, 1H), 8.42 (d, 1H), 8.16-8.01 (m, 3H), 7.95 (dd, 1H), 7.67-7.61 (m, 2H), 7.59-7.48 (m, 3H), 2.58 (s, 3H).

(52) LC/MS (Method 1, ESIpos): R.sub.t=1.10 min, m/z=529/531/533 [M+H].sup.+.

Example 14

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-methylbenzoic Acid

(53) ##STR00153##

(54) To 128 mg (0.26 mmol) of the compound from example 45A were added 3.3 ml of THF and then a solution of 9 mg (0.39 mmol) of lithium hydroxide in 1.1 ml of water. The reaction mixture was first stirred at RT for two days, then 2.6 ml of 4 M sodium hydroxide solution were added, and the mixture was stirred at RT for a further 24 h. Thereafter, the reaction mixture was heated to 100 C. for 3 h. After cooling to RT, the reaction mixture was adjusted to pH 1-2 with hydrochloric acid. The precipitated solids were filtered off with suction, washed with water and dried under reduced pressure. 70 mg (56% of theory, 99% purity) of the title compound were obtained.

(55) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.57 (s, 1H), 8.06 (d, 1H), 8.02 (d, 1H), 7.95 (dd, 1H), 7.92-7.87 (m, 3H), 7.66-7.64 (m, 2H), 7.59-7.51 (m, 3H), 2.54 (s, 3H), 2.38 (s, 3H).

(56) LC/MS (Method 1, ESIpos): R.sub.t=1.09 min, m/z=475/477 [M+H].sup.+.

Example 15

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(trifluoromethyl)benzoic Acid

(57) ##STR00154##

(58) To a solution of 300 mg (0.87 mmol) of the compound from example 1A in 3 ml of DMF were added, at RT, 267 mg (0.96 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride and 211 mg (0.96 mmol) of methyl 4-amino-3-(trifluoromethyl)benzoate. The mixture was stirred at RT for 20 h. Subsequently, about 100 mg (about 2.63 mmol) of sodium hydride (60% dispersion in mineral oil) were gradually added in portions, and the mixture was first stirred at RT for 1 h and then left to stand at RT for 2 days. Thereafter, the mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (method 5). The combined product-containing fractions were concentrated down to a residual volume of aqueous phase and extracted twice with ethyl acetate. The combined organic phases were again dried over magnesium sulfate, filtered and concentrated. The residue was taken up in a methanol/dichloromethane mixture, concentrated again and finally dried under reduced pressure. 153 mg (33% of theory, 100% purity) of the title compound were obtained.

(59) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.54 (br. s, 1H), 10.95 (s, 1H), 8.35 (dd, 1H), 8.31-8.29 (m, 1H), 8.08-8.00 (m, 3H), 7.95 (dd, 1H), 7.67-7.61 (m, 2H), 7.60-7.50 (m, 3H), 2.50 (s, 3H, hidden).

(60) LC/MS (Method 1, ESIpos): R.sub.t=1.17 min, m/z=529/531 [M+H].sup.+.

Example 16

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-cyanobenzoic acid

(61) ##STR00155##

(62) To 250 mg (0.64 mmol) of the compound from example 2A and 133 mg (0.70 mmol) of ethyl 4-amino-3-cyanobenzoate were added 2 ml of THF and 56 mg (1.40 mmol) of sodium hydride (60% in mineral oil). The reaction mixture was stirred at RT overnight. Then the mixture was admixed with water, acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The organic phase was removed and washed with saturated sodium chloride solution. After the organic phase had been dried over sodium sulfate and the solvent had been removed, the residue was stirred with acetonitrile. The solids were filtered off, washed with acetonitrile and then purified by means of preparative HPLC (method 8). 102 mg (31% of theory, 96% purity) of the title compound were obtained.

(63) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.54 (br. s, 1H), 11.54 (s, 1H), 8.39 (d, 1H), 8.32 (dd, 1H), 8.17 (d, 1H), 8.06 (d, 1H), 7.96 (dd, 1H), 7.91 (d, 1H), 7.65-7.63 (m, 2H), 7.59-7.51 (m, 3H), 2.49 (s, 3H).

(64) LC/MS (Method 1, ESIpos): R.sub.t=1.07 min, m/z=486/488 [M+H].sup.+.

Example 17

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-nitrobenzoic Acid

(65) ##STR00156##

(66) To 100 mg (0.26 mmol) of the compound from example 2A and 60 mg (0.31 mmol) of methyl 4-amino-3-nitrobenzoate were added 2 ml of THF. Then, at RT, 22 mg (0.56 mmol) of sodium hydride (60% in mineral oil) were added. After stirring at RT overnight, the reaction mixture was admixed with a few drops of water and, without further workup, purified by means of preparative HPLC (method 8). 110 mg (85% of theory, 100% purity) of the title compound were obtained.

(67) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.62 (br. s, 1H), 11.65 (s, 1H), 8.45 (d, 1H), 8.32-8.29 (dd, 1H), 8.12 (d, 1H), 8.06 (d, 1H), 7.96 (dd, 1H), 7.81 (d, 1H), 7.65-7.61 (m, 2H), 7.59-7.51 (m, 3H), 2.43 (s, 3H).

(68) LC/MS (Method 1, ESIpos): R.sub.t=1.15 min, m/z=507 [M+H].sup.+.

Example 18

3-Amino-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic Acid

(69) ##STR00157##

(70) To 282 mg (0.56 mmol) of the compound from example 17 were added 1.6 ml of acetic acid, 2.5 ml of ethanol, 2.5 ml of water and 628 mg (2.79 mmol) of tin(II) chloride. The reaction mixture was stirred at 80 C. for 3 h and then, without further workup, purified by means of preparative HPLC (method 13). 211 mg (80% of theory, 100% purity) of the title compound were obtained.

(71) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=12.69 (br. s, 1H), 10.30 (s, 1H), 8.05 (d, 1H), 8.01 (d, 1H), 7.94 (dd, 1H), 7.74 (d, 1H), 7.65-7.63 (m, 2H), 7.58-7.50 (m, 3H), 7.47 (d, 1H), 7.28 (dd, 1H), 5.25 (br. s, 2H), 2.46 (s, 3H).

(72) LC/MS (Method 1, ESIpos): R.sub.t=0.97 min, m/z=476/478 [M+H].sup.+.

Example 19

3-Acetamido-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic Acid

(73) ##STR00158##

(74) To 100 mg (0.21 mmol) of the compound from example 18 were added 1 ml of DMF and 0.12 ml (0.84 mmol) of triethylamine. At 0 C., 0.02 ml (0.25 mmol) of acetyl chloride were added dropwise. After 5 min, the ice bath was removed, and the reaction mixture was stirred at RT overnight. The mixture was then, without further workup, purified by means of preparative HPLC (method 8). The acetonitrile-water mixture was removed on a rotary evaporator, and the resulting residue was purified further by another preparative HPLC (method 13). 14 mg (13% of theory, 100% purity) of the title compound were obtained.

(75) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.07 (br. s, 1H), 10.60 (s, 1H), 9.64 (s, 1H), 8.04-7.99 (m, 4H), 7.93 (dd, 1H), 7.82 (d, 1H), 7.63-7.61 (m, 2H), 7.57-7.50 (m, 3H), 2.45 (s, 3H), 2.04 (s, 3H).

(76) LC/MS (Method 1, ESIpos): R.sub.t=0.99 min, m/z=518/520 [M+H].sup.+.

Example 20

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(ethylcarbamoyl)amino]benzoic Acid

(77) ##STR00159##

(78) To 100 mg (0.21 mmol) of the compound from example 18 were added 1 ml of DMF and 0.12 ml (0.84 mmol) of triethylamine. At 0 C., 0.02 ml (0.25 mmol) of ethyl isocyanate were added dropwise. After 5 min, the ice bath was removed, and the reaction mixture was stirred at RT for 3 h. The precipitated solids were then filtered off, washed with acetonitrile, dried under reduced pressure and then purified by means of preparative HPLC (method 14). 38 mg (33% of theory, 100% purity) of the title compound were obtained.

(79) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.72 (s, 1H), 8.12 (s, 1H), 8.06-8.01 (m, 3H), 7.93 (dd, 1H), 7.83 (d, 1H), 7.70 (d, 1H), 7.63-7.61 (m, 2H), 7.58-7.45 (m, 3H), 6.76 (m, 1H), 3.06 (m, 2H), 2.46 (s, 3H), 0.98 (t, 3H).

(80) LC/MS (Method 1, ESIpos): R.sub.t=1.03 min, m/z=547/549 [M+H].sup.+.

Example 21

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-methoxybenzoic Acid

(81) ##STR00160##

(82) To a solution of 660 mg (1.31 mmol) of the compound from example 46A in 16.5 ml of THF and 3.5 ml of methanol were added, at RT, 6.6 ml (6.6 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the organic solvent was removed. The remaining residue was diluted with water, and the mixture was acidified with 1 M hydrochloric acid while stirring. The solids present were filtered off and washed twice with water and once with tert-butyl methyl ether. Drying under reduced pressure gave 599 mg (93% of theory, purity 100%) of the title compound.

(83) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.02 (br. s, 1H), 10.50 (br. s, 1H), 8.17-7.84 (m, 4H), 7.75-7.43 (m, 7H), 3.93 (s, 3H), 2.43 (s, 3H, partially hidden).

(84) LC/MS (Method 1, ESIpos): R.sub.t=1.09 min, m/z=491/493 [M+H]+.

Example 22

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-hydroxybenzoic Acid

(85) ##STR00161##

(86) To a suspension of 90 mg (0.18 mmol) of the compound from example 21 in 2 ml of dichloromethane was added, at 0 C., 0.55 ml (0.55 mmol) of a 1 M solution of boron tribromide in dichloromethane.

(87) The mixture was stirred at RT for 2 h. The reaction mixture thus obtained was then combined with an analogously obtained reaction mixture from a proceeding experiment [amount of compound from example 21 used: 10 mg (0.02 mmol)]. After the solvent had been removed, the residue was taken up in DMSO and purified by means of preparative HPLC (method 5). The combined product-containing fractions were concentrated, the residue was taken up in dichloromethane, and the mixture was concentrated again. After drying under reduced pressure, 86 mg (100% purity, 89% of theory, based on a total of 100 mg (0.20 mmol) of the compound from example 21) of the title compound were obtained.

(88) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=12.79 (br. s, 1H), 10.37 (s, 1H), 10.35 (s, 1H), 8.09-7.99 (m, 3H), 7.91 (dd, 1H), 7.66-7.59 (m, 2H), 7.59-7.46 (m, 5H), 2.43 (s, 3H).

(89) LC/MS (Method 1, ESIpos): R.sub.t=0.99 min, m/z=477/479 [M+H].sup.+.

Example 23

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(trifluoromethoxy)benzoic acid

(90) ##STR00162##

(91) A solution of 75 mg (0.13 mmol) of the compound from example 47A in 2 ml of a THF/methanol mixture (5:1) was admixed with 0.65 ml (0.65 mmol) of 1 M sodium hydroxide solution and stirred under reflux for 1 h. After cooling to RT, the mixture, without further workup, was purified by means of preparative HPLC (method 6). The acetonitrile-water mixture was removed on a rotary evaporator and the residue was dried under reduced pressure overnight. 49 mg (69% of theory, 100% purity) of the title compound were obtained.

(92) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.42 (br. s, 1H), 11.14 (s, 1H), 8.29 (d, 1H), 8.12-8.01 (m, 2H), 7.98-7.91 (m, 3H), 7.68-7.60 (m, 2H), 7.60-7.49 (m, 3H), 2.43 (s, 3H).

(93) LC/MS (Method 1, ESIpos): R.sub.t=1.15 min, m/z=545/547 [M+H].sup.+.

Example 24

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(methylsulfanyl)benzoic Acid

(94) ##STR00163##

(95) To a solution of 100 mg (0.19 mmol) of the compound from example 48A in 2.5 ml of THF and 0.5 ml of methanol were added, at RT, 0.50 ml (0.50 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the organic solvent was removed. The remaining residue was diluted with water, and the mixture was acidified with 1 M hydrochloric acid while stirring. After stirring for a few minutes, the solids present were filtered off and washed twice with water. Drying under reduced pressure gave 88 mg (86% of theory, purity 95%) of the title compound.

(96) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.17 (br. s, 1H), 10.70 (s, 1H), 8.27 (d, 1H), 8.04 (d, 1H), 7.96-7.90 (m, 2H), 7.86 (dd, 1H), 7.69 (d, 1H), 7.66-7.60 (m, 2H), 7.59-7.49 (m, 3H), 2.56 (s, 3H, partially hidden), 2.50 (s, 3H, partially hidden).

(97) LC/MS (Method 1, ESIpos): R.sub.t=1.09 min, m/z=507/509 [M+H].sup.+.

Example 25

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(methylsulfinyl)benzoic Acid

(98) ##STR00164##

(99) To a solution of 140 mg (0.26 mmol) of the compound from example 49A in 3.5 ml of THF and 0.7 ml of methanol were added, at RT, 1.31 ml (1.31 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, 0.10 ml (1.31 mmol) of trifluoroacetic acid was added. Subsequently, the mixture was purified by means of preparative HPLC (method 5). The combined product-containing fractions were concentrated, the residue was taken up in dichloromethane, and the mixture was concentrated again. After the residue had been dried under reduced pressure, 126 mg (93% of theory, 100% purity) of the title compound were obtained.

(100) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.39 (br. s, 1H), 11.22 (s, 1H), 8.53 (d, 1H), 8.20 (dd, 1H), 8.11-8.03 (m, 2H), 7.97 (dd, 1H), 7.81 (d, 1H), 7.67-7.61 (m, 2H), 7.61-7.50 (m, 3H), 2.92 (s, 3H), 2.50 (s, 3H, hidden).

(101) LC/MS (Method 1, ESIpos): R.sub.t=0.97 min, m/z=523/525 [M+H].sup.+.

Example 26

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(methylsulfonyl)benzoic Acid

(102) ##STR00165##

(103) To a solution of 100 mg (0.18 mmol) of the compound from example 50A in 2.5 ml of THF and 0.5 ml of methanol were added, at RT, 0.91 ml (0.91 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, 0.07 ml (0.91 mmol) of trifluoroacetic acid was added. Subsequently, the mixture was purified by means of preparative HPLC (method 5). The combined product-containing fractions were concentrated, the residue was taken up in dichloromethane, and the mixture was concentrated again. After the residue had been dried under reduced pressure, 83 mg (85% of theory, 100% purity) of the title compound were obtained.

(104) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.55 (br. s, 1H), 10.75 (s, 1H), 8.54 (d, 1H), 8.37 (dd, 1H), 8.32-8.24 (m, 2H), 8.04 (d, 1H), 7.94 (dd, 1H), 7.67-7.61 (m, 2H), 7.60-7.49 (m, 3H), 3.41 (s, 3H), 2.50 (s, 3H, hidden).

(105) LC/MS (Method 1, ESIpos): R.sub.t=1.08 min, m/z=539/541 [M+H].sup.+.

Example 27

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(ethylsulfonyl)-2-methoxybenzoic Acid

(106) ##STR00166##

(107) To a solution of 221 mg (0.37 mmol) of the compound from example 51A in 4.7 ml of THF and 1.0 ml of methanol were added, at RT, 1.86 ml (1.86 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the organic solvent was removed. The remaining residue was diluted with water, and the mixture was acidified with 1 M hydrochloric acid while stirring. The solids formed were filtered off and washed twice with water. Drying under reduced pressure gave 180 mg (84% of theory, purity 100%) of the title compound.

(108) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.03 (br. s, 1H), 10.61 (s, 1H), 8.27-8.22 (m, 2H), 8.12 (s, 1H), 8.08-8.01 (m, 1H), 7.95 (dd, 1H), 7.68-7.61 (m, 2H), 7.60-7.49 (m, 3H), 4.02 (s, 3H), 3.47-3.36 (m, 2H, partially hidden), 2.49 (s, 3H, hidden), 1.14 (t, 3H).

(109) LC/MS (Method 1, ESIpos): R.sub.t=1.12 min, m/z=583/585 [M+H].sup.+.

Example 28

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(trifluoromethyl)sulfanyl]benzoic Acid

(110) ##STR00167##

(111) A mixture of 50 mg (0.09 mmol) of the compound from example 53A in 1.6 ml of THF and 0.3 ml of methanol was admixed with 0.32 ml (0.32 mmol) of 1 M sodium hydroxide solution and then stirred under reflux for 1 h. After cooling to RT, the mixture was adjusted to pH 4 with about 0.03 ml of trifluoroacetic acid and, without further workup, was purified by means of preparative HPLC (method 5). After the solvent-water mixture had been removed, the residue was taken up in dichloromethane, the mixture was concentrated again and the residue was dried under reduced pressure. 35 mg (72% of theory, 100% purity) of the title compound were obtained.

(112) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.46 (br. s, 1H), 11.34 (br. s, 1H), 8.50-7.80 (m, 6H), 7.73-7.33 (m, 5H), 2.47 (s, 3H, partially hidden).

(113) LC/MS (Method 1, ESIpos): R.sub.t=1.19 min, m/z=561/563 [M+H].sup.+.

Example 29

3-Fluoro-4-{[(6-fluoro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic Acid

(114) ##STR00168##

(115) To a solution of 184 mg (0.43 mmol) of the compound from example 54A in 5.5 ml of THF and 1.1 ml of methanol were added, at RT, 2.14 ml (2.14 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the organic solvent was removed. The aqueous solution that remained was introduced into 20 ml of 1 M hydrochloric acid while stirring. After stirring for a few minutes, the solids formed were filtered off and washed twice with water and once with pentane. Drying under reduced pressure gave 148 mg (83% of theory, purity 100%) of the title compound.

(116) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.24 (br. s, 1H), 11.03 (s, 1H), 8.22 (t, 1H), 8.17 (dd, 1H), 7.88 (dd, 1H), 7.80 (dd, 1H), 7.73 (td, 1H), 7.64-7.59 (m, 2H), 7.59-7.49 (m, 4H), 2.43 (s, 3H).

(117) LC/MS (Method 1, ESIpos): R.sub.t=0.99 min, m/z=419 [M+H].sup.+.

Example 30

3-Fluoro-4-{[(6-iodo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic Acid

(118) ##STR00169##

(119) 100 mg (0.23 mmol) of the compound from example 6A and 39 mg (0.23 mmol) of methyl 4-amino-3-fluorobenzoate were dissolved in 1.7 ml of DMF. 64 mg (0.57 mmol) of potassium tert-butoxide were added in portions to the solution. The reaction mixture was stirred at RT for 1 h, and then 1.3 ml (1.3 mmol) of 1 M sodium hydroxide solution were added. The mixture was then stirred at 80 C. for 1 h. After cooling to RT, the mixture, without further workup, was purified by means of preparative HPLC (method 6). After the solvent-water mixture had been removed and the residue had been dried under reduced pressure, 76 mg (62% of theory, 98% purity) of the title compound were obtained.

(120) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.25 (br. s, 1H), 11.04 (s, 1H), 8.19 (t, 1H), 8.18 (d, 1H), 8.06 (dd, 1H), 7.93-7.84 (m, 2H), 7.82 (dd, 1H), 7.66-7.59 (m, 2H), 7.59-7.47 (m, 3H), 2.42 (s, 3H).

(121) LC/MS (Method 1, ESIpos): R.sub.t=1.07 min, m/z=527 [M+H].sup.+.

Example 31

4-{[(3,6-Dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid

(122) ##STR00170##

(123) To a solution of 124 mg (0.27 mmol, 93% purity) of the compound from example 55A in 3.5 ml of THF and 0.7 ml of methanol were added, at RT, 1.35 ml (1.35 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, 0.10 ml (1.35 mmol) of trifluoroacetic acid was added. Subsequently, the mixture was purified by means of preparative HPLC (method 5). The combined product-containing fractions were concentrated, the residue was taken up in dichloromethane, and the mixture was concentrated again. Drying under reduced pressure gave 83 mg (75% of theory, purity 100%) of the title compound.

(124) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.17 (br. s, 1H), 10.99 (s, 1H), 8.24 (t, 1H), 7.98 (d, 1H), 7.88 (dd, 1H), 7.80 (dd, 1H), 7.68-7.58 (m, 4H), 7.58-7.47 (m, 3H), 2.53 (s, 3H, partially hidden), 2.40 (s, 3H).

(125) LC/MS (Method 1, ESIpos): R.sub.t=1.01 min, m/z=415 [M+H].sup.+.

Example 32

4-{[(6-Ethyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(126) ##STR00171##

(127) To a solution of 186 mg (0.38 mmol, 91% purity) of the compound from example 56A in 5.0 ml of THF and 1.0 ml of methanol were added, at RT, 1.92 ml (1.92 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, 0.15 ml (2.00 mmol) of trifluoroacetic acid was added. After being left to stand overnight, the mixture was purified by means of preparative HPLC (Method 5). The combined product-containing fractions were concentrated, the residue was taken up in dichloromethane, and the mixture was concentrated again. Drying under reduced pressure gave 139 mg (85% of theory, purity 100%) of the title compound.

(128) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.30 (br. s, 1H), 11.25-10.78 (m, 1H), 8.20 (t, 1H), 8.03 (d, 1H), 7.89 (dd, 1H), 7.81 (dd, 1H), 7.72 (dd, 1H), 7.66-7.60 (m, 3H), 7.59-7.49 (m, 3H), 2.84 (q, 2H), 2.41 (s, 3H), 1.27 (t, 3H).

(129) LC/MS (Method 1, ESIpos): R.sub.t=1.06 min, m/z=429 [M+H]+.

Example 33

3-Fluoro-4-{[(6-isopropyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic Acid

(130) ##STR00172##

(131) To 108 mg (0.24 mmol) of the compound from example 57A were added 2.4 ml of THF and 2.4 ml of 4 M sodium hydroxide solution. The reaction mixture was stirred at 60 C. for 10 h. Thereafter, the organic phase was removed and, without further workup, purified by means of preparative HPLC (method 9). The acetonitrile-water mixture was removed on a rotary evaporator and the residue was stirred with acetonitrile. The solids were filtered off and dried under reduced pressure. 45 mg (43% of theory, 100% purity) of the title compound were obtained.

(132) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.26 (br. s, 1H), 11.01 (s, 1H), 8.14 (t, 1H), 8.02 (d, 1H), 7.92-7.71 (m, 3H), 7.67-7.44 (m, 6H), 3.20-3.04 (m, 1H), 2.41 (s, 3H), 1.29 (d, 6H).

(133) LC/MS (Method 1, ESIpos): R.sub.t=1.10 min, m/z=443 [M+H].sup.+.

Example 34

3-Fluoro-4-({[3-methyl-2-phenyl-6-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)benzoic acid

(134) ##STR00173##

(135) To 105 mg (0.22 mol) of the compound from example 58A were added 2.2 ml of THF and 2.2 ml of 4 M sodium hydroxide solution. The reaction mixture was stirred at 60 C. overnight. Thereafter, the organic phase was removed and, without further workup, purified by means of preparative HPLC (method 9). After the solvent-water mixture had been removed, the mixture was dried at 60 C. under reduced pressure overnight. 97 mg (95% of theory, 100% purity) of the title compound were obtained.

(136) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.30 (br. s, 1H), 11.13 (s, 1H), 8.32 (d, 1H), 8.18-8.14 (m, 2H), 8.08 (dd, 1H), 7.90 (dd, 1H), 7.83 (dd, 1H), 7.68-7.66 (m, 2H), 7.61-7.53 (m, 3H), 2.48 (s, 3H).

(137) LC/MS (Method 1, ESIpos): R.sub.t=1.13 min, m/z=469 [M+H].sup.+.

Example 35

3-Fluoro-4-({[3-methyl-2-phenyl-6-(trifluoromethoxy)quinolin-4-yl]carbonyl}amino)benzoic Acid

(138) ##STR00174##

(139) To a solution of 150 mg (0.27 mmol, 91% purity) of the compound from example 59A in 3.5 ml of THF and 0.7 ml of methanol were added, at RT, 1.38 ml (1.38 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, 0.11 ml (1.38 mmol) of trifluoroacetic acid was added. Subsequently, the mixture was purified by means of preparative HPLC (method 5). The combined product-containing fractions were concentrated, the residue was taken up in dichloromethane, and the mixture was concentrated again. Drying under reduced pressure gave 115 mg (87% of theory, purity 100%) of the title compound.

(140) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.25 (br. s, 1H), 11.07 (s, 1H), 8.24 (d, 1H), 8.16 (t, 1H), 7.89 (dd, 1H), 7.82 (dd, 2H), 7.74 (s, 1H), 7.68-7.61 (m, 2H), 7.60-7.48 (m, 3H), 2.45 (s, 3H).

(141) LC/MS (Method 1, ESIpos): R.sub.t=1.08 min, m/z=485 [M+H].sup.+.

Example 36

3-Fluoro-4-({[3-methyl-2-phenyl-6-(trimethylsilyl)quinolin-4-yl]carbonyl}amino)benzoic Acid

(142) ##STR00175##

(143) To a mixture of 34 mg (0.06 mmol) of the compound from Example 60A in 1 ml of dichloromethane was added 0.5 ml (6.49 mmol) of trifluoroacetic acid, and the mixture was stirred at RT for 1 h. Then the mixture was concentrated. The residue was taken up in DMSO and purified by means of preparative HPLC (method 5). The combined product-containing fractions were concentrated, the residue was taken up in dichloromethane, and the mixture was concentrated again. Drying under reduced pressure gave 25 mg (81% of theory, purity 100%) of the title compound.

(144) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.19 (br. s, 1H), 11.03 (s, 1H), 8.11-7.99 (m, 3H), 7.97-7.87 (m, 2H), 7.83 (d, 1H), 7.67-7.61 (m, 2H), 7.60-7.47 (m, 3H), 2.44 (s, 3H), 0.32 (s, 9H).

(145) LC/MS (Method 1, ESIpos): R.sub.t=1.19 min, m/z=473 [M+H].sup.+.

Example 37

4-({[6-Bromo-3-(fluoromethyl)-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoic Acid

(146) ##STR00176##

(147) To a solution of 60 mg (0.12 mmol) of the compound from example 63A in 1.5 ml of THF and 0.3 ml of methanol was added, at RT, 0.59 ml (0.59 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 30 min. After cooling to RT, 0.05 ml (0.60 mmol) of trifluoroacetic acid was added. Subsequently, the mixture was purified by means of preparative HPLC (method 12). 39 mg (66% of theory, 100% purity) of the title compound were obtained.

(148) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): [ppm]=13.23 (br. s, 1H), 11.16 (s, 1H), 8.23 (t, 1H), 8.15-8.10 (m, 2H), 8.07 (dd, 1H), 7.90 (dd, 1H), 7.82 (dd, 1H), 7.70-7.64 (m, 2H), 7.63-7.54 (m, 3H), 5.57 (dd, 2H).

(149) LC/MS (Method 1, ESIpos): R.sub.t=1.05 min, m/z=497/499 [M+H].sup.+.

Example 38

4-({[6-Bromo-3-(difluoromethyl)-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoic acid

(150) ##STR00177##

(151) To a solution of 20 mg (0.04 mmol) of the compound from example 64A in 0.6 ml of THF and 0.13 ml of methanol was added, at RT, 0.19 ml (0.19 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 30 min. After cooling to RT, 0.015 ml (0.19 mmol) of trifluoroacetic acid was added. Subsequently, the mixture was purified by means of preparative HPLC (method 5). The combined product-containing fractions were concentrated, the residue was taken up in dichloromethane, and the mixture was concentrated again. Drying under reduced pressure gave 11 mg (54% of theory, purity 100%) of the title compound.

(152) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.24 (br. s, 1H), 11.13 (s, 1H), 8.26 (t, 1H), 8.18-8.09 (m, 3H), 7.90 (dd, 1H), 7.81 (dd, 1H), 7.65-7.54 (m, 5H), 7.09 (t, 1H).

(153) LC/MS (Method 1, ESIpos): R.sub.t=1.05 min, m/z=515/517 [M+H].sup.+.

Example 39

4-{[(6-Bromo-3-ethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid

(154) ##STR00178##

(155) To a solution of 187 mg (0.37 mmol) of the compound from example 65A in 5.8 ml of THF and 1.2 ml of methanol were added, at RT, 1.86 ml (1.86 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 30 min. After cooling to RT, the organic solvent was removed by distillation, and 0.14 ml (1.86 mmol) of trifluoroacetic acid was added to the aqueous phase that remained. The solids formed were filtered off, washed twice with 1 ml of water and dried under reduced pressure. 178 mg (98% of theory, 100% purity) of the title compound were obtained.

(156) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.99 (s, 1H), 8.05-7.97 (m, 3H), 7.94 (dd, 1H), 7.84 (dd, 1H), 7.76 (dd, 1H), 7.60-7.48 (m, 5H), 2.83 (d, 2H), 0.99 (t, 3H).

(157) LC/MS (Method 1, ESIpos): R.sub.t=1.07 min, m/z=493/495 [M+H].sup.+.

Example 40

4-{[(6-Bromo-2-phenyl-3-propylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(158) ##STR00179##

(159) To a solution of 139 mg (0.27 mmol) of the compound from example 66A in 4.2 ml of THF and 0.9 ml of methanol were added, at RT, 1.34 ml (1.34 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 3 h. After cooling to RT, the organic solvent was removed by distillation, and 0.10 ml (1.34 mmol) of trifluoroacetic acid was added to the aqueous phase that remained. The solids formed were filtered off, washed twice with 1 ml of water and dried under reduced pressure. 86 mg (64% of theory, 100% purity) of the title compound were obtained.

(160) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.74 (s, 1H), 8.04-7.99 (m, 2H), 7.94 (dd, 1H), 7.74 (dd, 1H), 7.70-7.62 (m, 2H), 7.59-7.48 (m, 5H), 2.88-2.74 (m, 2H), 1.40 (br. s, 2H), 0.69 (t, 3H).

(161) LC/MS (Method 1, ESIpos): R.sub.t=1.14 min, m/z=507/509 [M+H].sup.+.

Example 41

4-{[(6-Bromo-7-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(162) ##STR00180##

(163) To a solution of 52 mg (0.10 mmol) of the compound from example 67A in 1.3 ml of THF and 0.25 ml of methanol was added, at RT, 0.49 ml (0.49 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 30 min. After cooling to RT, 0.04 ml (0.50 mmol) of trifluoroacetic acid was added. The solids formed were filtered off and washed twice with 1 ml of THF. After drying under reduced pressure, 13 mg (26% of theory, 100% purity) of a first batch of the title compound were obtained. The filtrate was concentrated, and the residue was taken up in a mixture of DMSO, THF and water, and purified by means of preparative HPLC (method 12). In this way, 30 mg (60% of theory, 100% purity) of a second batch of the title compound were obtained.

(164) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): [ppm]=13.25 (br. s, 1H), 11.08 (s, 1H), 8.39 (s, 1H), 8.23 (t, 1H), 8.20 (s, 1H), 7.89 (dd, 1H), 7.82 (dd, 1H), 7.66-7.61 (m, 2H), 7.60-7.50 (m, 3H), 2.43 (s, 3H).

(165) LC/MS (Method 1, ESIpos): R.sub.t=1.16 min, m/z=513/515 [M+H].sup.+.

Example 42

4-{[(6,7-Dichloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(166) ##STR00181##

(167) 100 mg (0.26 mmol) of the compound from example 22A and 44.4 mg (0.26 mmol) of methyl 4-amino-3-fluorobenzoate were dissolved in 2 ml of DMF. 73 mg (0.65 mmol) of potassium tert-butoxide were added in portions to the solution. The reaction mixture was stirred at RT for 1 h, and then 1.3 ml (1.3 mmol) of 1 M sodium hydroxide solution were added. The mixture was then stirred at 80 C. for 1 h. After cooling to RT, the mixture, without further workup, was purified by means of preparative HPLC (method 6). After the solvent-water mixture had been removed and the residue had been dried under reduced pressure, 78 mg (59% of theory, 93% purity) of the title compound were obtained.

(168) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.25 (br. s, 1H), 11.07 (s, 1H), 8.41 (s, 1H), 8.24 (t, 1H), 8.06 (s, 1H), 7.89 (dd, 1H), 7.81 (dd, 1H), 7.69-7.60 (m, 2H), 7.60-7.48 (m, 3H), 2.43 (s, 3H).

(169) LC/MS (Method 1, ESIpos): R.sub.t=1.15 min, m/z=469/471 [M+H].sup.+.

Example 43

4-({[6-Bromo-2-(4-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoic Acid

(170) ##STR00182##

(171) To a solution of 173 mg (0.34 mmol) of the compound from example 68A in 5.4 ml of THF and 1.1 ml of methanol were added, at RT, 1.71 ml (1.71 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 30 min. After cooling to RT, the organic solvent was removed by distillation, and 0.13 ml (1.71 mmol) of trifluoroacetic acid was added to the aqueous phase that remained. The solids formed were filtered off, washed twice with 1 ml of water and dried under reduced pressure. 166 mg (99% of theory, 100% purity) of the title compound were obtained.

(172) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.20 (br. s, 1H), 11.04 (s, 1H), 8.19 (t, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.94 (dd, 1H), 7.88 (dd, 1H), 7.81 (dd, 1H), 7.73-7.65 (m, 2H), 7.42-7.33 (m, 2H), 2.44 (s, 3H).

(173) LC/MS (Method 1, ESIpos): R.sub.t=1.06 min, m/z=497/499 [M+H].sup.+.

Example 44

4-({[6-Bromo-2-(3-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoic Acid

(174) ##STR00183##

(175) To a solution of 96 mg (0.19 mmol) of the compound from example 69A in 3.0 ml of THF and 0.6 ml of methanol was added, at RT, 0.95 ml (0.95 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 3 h. After cooling to RT, the organic solvent was removed by distillation, and 0.07 ml (0.95 mmol) of trifluoroacetic acid was added to the aqueous phase that remained. The solids formed were filtered off, washed twice with 1 ml of water and dried under reduced pressure. Subsequently, the solids were taken up in DMSO and purified by means of preparative HPLC (method 12). 68 mg (72% of theory, 100% purity) of the title compound were obtained.

(176) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.25 (s, 1H), 11.05 (s, 1H), 8.21 (t, 1H), 8.06 (d, 1H), 8.00 (d, 1H), 7.95 (dd, 1H), 7.89 (dd, 1H), 7.82 (dd, 1H), 7.64-7.57 (m, 1H), 7.51-7.44 (m, 2H), 7.42-7.33 (m, 1H), 2.44 (s, 3H).

(177) LC/MS (Method 1, ESIpos): R.sub.t=1.09 min, m/z=497/499 [M+H].sup.+.

Example 45

4-({[6-Bromo-2-(2-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoic Acid

(178) ##STR00184##

(179) To a solution of 95 mg (0.19 mmol) of the compound from example 70A in 3 ml of THF and 0.6 ml of methanol was added, at RT, 0.94 ml (0.94 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 3 h. After cooling to RT, the organic solvent was removed by distillation, and 0.07 ml (0.94 mmol) of trifluoroacetic acid was added to the aqueous phase that remained. The solids formed were filtered off, washed twice with 1 ml of water and dried under reduced pressure. 83 mg (86% of theory, 96% purity) of the title compound were obtained.

(180) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.25 (br. s, 1H), 11.14 (s, 1H), 8.19 (t, 1H), 8.06 (d, 1H), 8.02 (d, 1H), 7.96 (dd, 1H), 7.89 (dd, 1H), 7.82 (dd, 1H), 7.65-7.50 (m, 2H), 7.45-7.37 (m, 2H), 2.32 (s, 3H).

(181) LC/MS (Method 3, ESIpos): R.sub.t=1.34 min, m/z=497/499 [M+H].sup.+.

Example 46

4-({[6-Bromo-3-methyl-2-(pyridin-4-yl)quinolin-4-yl]carbonyl}amino)-3-fluorobenzoic Acid

(182) ##STR00185##

(183) A mixture of 90 mg (0.18 mmol) of the compound from example 71A in 1 ml (1 mmol) of 1 M sodium hydroxide solution, 1 ml of methanol and 1 ml of THF was stirred at RT overnight. Subsequently, the mixture was adjusted to pH 7 by adding a few drops of 1 M hydrochloric acid and the solvent was removed under reduced pressure. The residue was purified by means of preparative RP-HPLC (eluent: acetonitrile/10 mM aq. ammonium carbonate gradient). 55 mg (63% of theory) of the title compound were obtained.

(184) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): [ppm]=8.79 (d, 2H), 8.14 (m, 2H), 8.05 (d, 1H), 7.92 (m, 2H), 7.82 (m, 1H), 7.72 (m, 2H), 2.55 (s, 3H).

(185) LC/MS (Method 4, ESIpos): R.sub.t=1.36 min, m/z=479/481 [M+H]+.

Example 47

6-Bromo-N-(4-carbamoylphenyl)-3-methyl-2-phenylquinoline-4-carboxamide

(186) ##STR00186##

(187) To 208 mg (0.43 mmol) of the compound from example 35A were gradually added 3.5 ml (30 mmol) of ammonia solution (33% in water), and the mixture was stirred at RT for 1 h. Subsequently, the mixture was diluted with water, and the solids formed were filtered off, washed twice with water and dried under air. The crude product was purified by preparative HPLC (Method 5). The combined product-containing fractions were concentrated, the residue was taken up in a mixture of dichloromethane and methanol, and the mixture was concentrated again. After the residue had been dried under reduced pressure, 113 mg (57% of theory, 100% purity) of the title compound were obtained.

(188) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=11.10 (s, 1H), 8.05 (d, 1H), 7.97-7.89 (m, 5H), 7.84 (d, 2H), 7.66-7.60 (m, 2H), 7.59-7.47 (m, 3H), 7.31 (br. s, 1H), 2.41 (s, 3H).

(189) LC/MS (Method 1, ESIpos): R.sub.t=0.92 min, m/z=460/462 [M+H].sup.+.

Example 48

6-Bromo-N-(4-carbamoyl-2-fluorophenyl)-3-methyl-2-phenylquinoline-4-carboxamide

(190) ##STR00187##

(191) To 260 mg (0.52 mmol) of the compound from example 40A were gradually added 4.0 ml (33.9 mmol) of ammonia solution (33% in water), and the mixture was stirred at RT for 30 min. Subsequently, the solids formed were filtered off, washed twice with water and dried under air. The crude product was purified by preparative HPLC (Method 5). The combined product-containing fractions were concentrated, the residue was taken up in a mixture of dichloromethane and methanol, and the mixture was concentrated again. After the residue had been dried under reduced pressure, 181 mg (73% of theory, 100% purity) of the title compound were obtained.

(192) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.96 (s, 1H), 8.12-8.02 (m, 3H), 8.00 (d, 1H), 7.94 (dd, 1H), 7.87-7.80 (m, 2H), 7.66-7.61 (m, 2H), 7.60-7.48 (m, 4H), 2.44 (s, 3H).

(193) LC/MS (Method 1, ESIpos): R.sub.t=0.98 min, m/z=478/480 [M+H].sup.+.

Example 49

4-{[(6-Bromo-3-methyl-1-oxido-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(194) ##STR00188##

(195) To a suspension of 100 mg (0.21 mmol) of the compound from example 7 in 3 ml of dichloromethane were added, at RT, 113 mg (0.46 mmol, content of 70%, remainder water) of 3-chloroperbenzoic acid, suspended in 1 ml of dichloromethane. The mixture was stirred at RT for 2 h. Subsequently, 0.5 ml of THF was added, and the mixture was left to stand at RT for 3 days. Thereafter, another 113 mg (0.46 mmol, content of 70%) of 3-chloroperbenzoic acid, suspended in 1 ml of dichloromethane, were added, and the mixture was stirred at RT for a further day. Subsequently, a further 57 mg (0.23 mmol, content of 70%) of 3-chloroperbenzoic acid, suspended in 0.5 ml of dichloromethane, were added, and the mixture was stirred at RT for another day. The mixture was then admixed with 20 ml each of saturated aqueous sodium hydrogencarbonate solution and dichloromethane, the phases were separated and then the aqueous phase was extracted once with 20 ml of dichloromethane. The aqueous phase was adjusted to pH 1 by addition of concentrated hydrochloric acid and extracted twice more with 30 ml each time of dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in DMSO and purified by means of preparative HPLC (method 12). In this way, 67 mg (65% of theory, 100% purity) of the title compound were obtained.

(196) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.24 (br. s, 1H), 10.98 (s, 1H), 8.51 (d, 1H), 8.23 (t, 1H), 8.07 (d, 1H), 7.99 (dd, 1H), 7.88 (dd, 1H), 7.80 (dd, 1H), 7.63-7.48 (m, 3H), 7.43 (d, 2H), 2.16 (s, 3H).

(197) LC/MS (Method 1, ESIpos): R.sub.t=0.87 min, m/z=495/497 [M+H].sup.+.

Example 50

Sodium 4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

(198) ##STR00189##

(199) Method A:

(200) 50 mg (0.10 mmol) of the compound from Example 7 were dissolved in 1.5 ml of THF, and 1 M sodium hydroxide solution was added dropwise until pH 8 was attained. The mixture was then concentrated to dryness on a rotary evaporator. The residue was dissolved in a little acetonitrile and methanol, and lyophilized overnight. 50 mg (95% of theory, 99% purity) of the title compound were obtained.

(201) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.73 (s, 1H), 8.03-8.01 (m, 2H), 7.93-7.91 (d, 1H), 7.71 (s, 2H), 7.66-7.62 (m, 3H), 7.57-7.50 (m, 3H), 2.44 (s, 3H).

(202) LC/MS (Method 1, ESIpos): R.sub.t=1.07 min, m/z=479/481 [M+H].sup.+.

(203) Method B:

(204) To 2.0 g (4.18 mmol) of the compound from example 7 were added 100 ml of 1,4-dioxane, and the mixture was heated briefly to boiling. To the hot solution was added a solution of 167 mg (4.18 mmol) of sodium hydroxide in 20 ml of water. After cooling to RT, the mixture was left to stand at RT under air until the solvent had evaporated. After decanting, 2.3 g of the title compound were obtained (quant., 100% purity, still contains water).

Example 51

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid L-Arginine Salt

(205) ##STR00190##

(206) To 1.1 g (2.30 mmol) of the compound from example 7 were added 200 ml of methanol and 5 ml of DMF, and the mixture was heated briefly to boiling. To the hot solution was added a solution of 401 mg (2.30 mmol) of L-(+)-arginine in 30 ml of water. After cooling to RT, the mixture was left to stand at RT under air until the solvent had evaporated. The remaining residue was suspended in 40 ml of water and stirred at RT for one day. Thereafter, the suspension was filtered and the solids were dried at RT under air. 1.0 g (73% of theory, 100% purity) of the title compound was obtained.

(207) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.76 (br. s, 1H), 8.04 (d, 1H), 8.00 (d, 1H), 8.0-7.7 (br. m, 2H), 7.93 (dd, 1H), 7.89-7.82 (m, 1H), 7.77 (dd, 1H), 7.69 (dd, 1H), 7.65-7.60 (m, 2H), 7.55 (d, 3H), 3.30-3.03 (m, 2H, partially hidden), 2.44 (s, 3H), 1.81-1.53 (m, 4H).

(208) LC/MS (Method 1, ESIpos): R.sub.t=1.08 min, m/z=479/481 [M+H].sup.+.

Example 52

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(methoxymethyl)sulfanyl]benzoic Acid

(209) ##STR00191##

(210) To a solution of 50 mg (0.09 mmol) of the compound from example 72A in 1.5 ml of THF and 0.4 ml of methanol was added, at RT, 0.46 ml (0.46 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the mixture was admixed with 0.035 ml (0.46 mmol) of trifluoroacetic acid and purified by means of preparative HPLC (method 18). After the solvent had been removed, the residue was taken up in a dichloromethane/methanol mixture and the solution was concentrated again. After the residue had been dried under reduced pressure, 42 mg (87% of theory, 100% purity) of the title compound were obtained.

(211) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.14 (br. s, 1H), 10.75 (s, 1H), 8.25 (dd, 2H), 8.04 (d, 1H), 7.97-7.89 (m, 2H), 7.78 (d, 1H), 7.66-7.61 (m, 2H), 7.60-7.49 (m, 3H), 5.09 (s, 2H), 3.34 (s, 3H, hidden), 2.50 (s, 3H, hidden).

(212) LC/MS (Method 1, ESIpos): R.sub.t=1.12 min, m/z=537/539 [M+H].sup.+.

Example 53

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(trifluoromethyl)sulfonyl]benzoic Acid

(213) ##STR00192##

(214) To a solution of 45 mg (0.07 mmol) of the compound from example 75A in 1.2 ml of THF and 0.3 ml of methanol was added, at RT, 0.37 ml (0.37 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 2 h. After cooling to RT, the mixture was admixed with 0.029 ml (0.37 mmol) of trifluoroacetic acid and purified by means of preparative HPLC (method 18). After the solvent had been removed, the residue was taken up in a dichloromethane/methanol mixture and the solution was concentrated again. After the residue had been dried under reduced pressure, 41 mg (94% of theory, 100% purity) of the title compound were obtained.

(215) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.91 (br. s, 1H), 11.01 (s, 1H), 8.60 (dd, 1H), 8.58-8.55 (m, 1H), 8.37 (d, 1H), 8.07-8.04 (m, 2H), 7.95 (dd, 1H), 7.66-7.61 (m, 2H), 7.60-7.50 (m, 3H), 2.48 (s, 3H).

(216) LC/MS (Method 1, ESIpos): R.sub.t=1.25 min, m/z=593/595 [M+H]+.

Example 54

4-{[(6-Bromo-3-methyl-1-oxido-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(trifluoromethyl)sulfanyl]benzoic Acid

(217) ##STR00193##

(218) To a solution of 43 mg (0.07 mmol) of the compound from example 76A in 1.5 ml of THF and 0.3 ml of methanol was added, at RT, 0.37 ml (0.37 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the mixture was admixed with 0.028 ml (0.37 mmol) of trifluoroacetic acid and purified by means of preparative HPLC (method 5). After the solvent had been removed, the residue was taken up in dichloromethane and the solution was concentrated again. After the residue had been dried under reduced pressure, 33 mg (78% of theory, 100% purity) of the title compound were obtained.

(219) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): [ppm]=13.45 (br. s, 1H), 11.27 (s, 1H), 8.53 (d, 1H), 8.33 (s, 1H), 8.25-8.21 (m, 2H), 8.01 (dd, 1H), 7.93 (d, 1H), 7.62-7.57 (m, 2H), 7.56-7.50 (m, 1H), 7.45 (d, 2H), 2.19 (s, 3H).

(220) LC/MS (Method 1, ESIpos): R.sub.t=1.00 min, m/z=577/579 [M+H].sup.+.

Example 55

4-{[(6-Bromo-5-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(221) ##STR00194##

(222) To a solution of 285 mg (0.02 mmol, 4% purity) of the compound from example 79A in 7 ml of THF and 1.5 ml of methanol were added, at RT, 0.09 ml (0.09 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 2 h. After cooling to RT, the mixture was admixed with 0.008 ml (0.11 mmol) of trifluoroacetic acid and left to stand at RT for about 80 h. Thereafter, the precipitate formed was filtered off and washed twice with 0.5 ml of THF. The precipitate newly formed in the filtrate was likewise filtered off. The filtrate was concentrated, and the residue obtained was prepurified by means of preparative HPLC (method 19). The product thus obtained was purified once more by means of preparative HPLC [column: Sunfire C18, 5 m, 100 mm30 mm; flow rate: 75 ml/min; detection: 210 nm; injection volume: 2.0 ml; temperature: 40 C.; eluent: water/acetonitrile/(acetonitrile/2% formic acid in water 80:20); gradient: 70:10:20-5:90:5, 10 min]. In this way, 6.1 mg (55% of theory, 100% purity) of the title compound were obtained.

(223) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.16 (br. s, 1H), 10.99 (s, 1H), 8.33 (t, 1H), 8.13 (d, 1H), 8.02 (d, 1H), 7.88 (dd, 1H), 7.77 (dd, 1H), 7.66-7.61 (m, 2H), 7.60-7.53 (m, 3H), 2.44 (s, 3H).

(224) LC/MS (Method 1, ESIpos): R.sub.t=1.10 min, m/z=513/515 [M+H].sup.+.

Example 56

6-Bromo-N-[2-fluoro-4-(methylcarbamoyl)phenyl]-3-methyl-2-phenylquinoline-4-carboxamide

(225) ##STR00195##

(226) To 298 mg (0.60 mmol) of the compound from example 40A in 3 ml of THF were gradually added, at 0 C., 1.90 ml (3.80 mmol) of a 2 M solution of methylamine in THF, and the mixture was stirred at RT for 2 h. Subsequently, a further 3 ml of THF and 1 ml (1.90 mmol) of the methylamine solution were added, and the mixture was heated to 70 C. in a microwave apparatus for 30 min. After cooling to RT, another 1 ml (1.90 mmol) of the methylamine solution was added, and the mixture was heated in the microwave at 100 C. for a further 15 min. After cooling to RT, the mixture was admixed with saturated sodium chloride solution, water and 1 M hydrochloric acid, and extracted twice with ethyl acetate. The combined organic phases were washed once with 1 M sodium hydroxide solution, dried over magnesium sulfate and concentrated. The residue was purified by means of preparative HPLC (method 12). 43 mg (15% of theory, 100% purity) of the title compound were obtained.

(227) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.96 (s, 1H), 8.55 (q, 1H), 8.09 (t, 1H), 8.04 (d, 1H), 8.00 (d, 1H), 7.94 (dd, 1H), 7.82-7.76 (m, 2H), 7.65-7.61 (m, 2H), 7.59-7.50 (m, 3H), 2.81 (d, 3H), 2.44 (s, 3H).

(228) LC/MS (Method 1, ESIpos): R.sub.t=1.00 min, m/z=492/494 [M+H].sup.+.

Example 57

4-({[6-Bromo-2-phenyl-3-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3-fluorobenzoic Acid

(229) ##STR00196##

(230) To a solution of 4.5 mg (0.008 mmol) of the compound from example 81A in 1 ml of THF and 0.5 ml of methanol was added, at RT, 0.03 ml (0.03 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 14 h. After cooling to RT, the mixture was admixed with 0.003 ml (0.035 mmol) of trifluoroacetic acid and concentrated. The residue was purified by means of preparative HPLC (column: Phenomenex Luna C18, 5 m, 100 mm21.2 mm; flow rate: 25 ml/min; eluent: water with 1% formic acid/acetonitrile; gradient: 95:5.fwdarw.5:95, 16 min). In this way, 4.5 mg (92% of theory, 90% purity) of the title compound were obtained. Also isolated as a secondary component was 0.5 mg (9% of theory, 92% purity) of the compound listed as example 62 (see therein for analysis).

(231) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): [ppm]=11.27 (s, 1H), 8.28-8.10 (m, 4H), 7.91 (dd, 1H), 7.83 (dd, 1H), 7.56-7.54 (m, 5H).

(232) LC/MS (Method 23, ESIpos): R.sub.t=3.54 min, m/z=533/535 [M+H].sup.+.

Example 58

4-{[(6-Bromo-3,8-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic Acid

(233) ##STR00197##

(234) To a solution of 42 mg (0.08 mmol, 96% purity) of methyl 4-{[(6-bromo-3,8-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoate (commercially available) in 1.5 ml of THF and 0.3 ml of methanol was added, at RT, 0.4 ml (0.4 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the mixture was admixed with 0.03 ml (0.4 mmol) of trifluoroacetic acid and purified by means of preparative HPLC (method 5). In this way, 30 mg (78% of theory, 100% purity) of the title compound were obtained.

(235) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=12.83 (br. s, 1H), 11.16 (s, 1H), 8.00 (d, 2H), 7.89 (d, 2H), 7.86-7.84 (m, 1H), 7.73 (d, 1H), 7.70-7.64 (m, 2H), 7.60-7.49 (m, 3H), 2.73 (s, 3H), 2.42 (s, 3H).

(236) LC/MS (Method 1, ESIpos): R.sub.t=1.23 min, m/z=475/477 [M+H].sup.+.

Example 59

4-{[(6-Chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(237) ##STR00198##

(238) To a solution of 60 mg (0.13 mmol) of the compound from example 82A in 2.7 ml of THF and 0.5 ml of methanol was added, at RT, 0.39 ml (0.39 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the mixture was admixed with 0.045 ml (0.59 mmol) of trifluoroacetic acid, diluted with 2 ml of DMSO and then purified by means of preparative HPLC (method 18). 51 mg (88% of theory, 100% purity) of the title compound were obtained.

(239) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.22 (br. s, 1H), 11.06 (s, 1H), 8.22 (t, 1H), 8.15-8.09 (m, 1H), 7.89 (dd, 1H), 7.86-7.78 (m, 3H), 7.66-7.60 (m, 2H), 7.59-7.49 (m, 3H), 2.43 (s, 3H).

(240) LC/MS (Method 1, ESIpos): R.sub.t=1.06 min, m/z=435 [M+H].sup.+.

Example 60

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(methoxymethyl)sulfonyl]benzoic Acid

(241) ##STR00199##

(242) To a solution of 70 mg (0.12 mmol) of the compound from example 83A in 2.6 ml of THF and 0.5 ml of methanol was added, at RT, 0.60 ml (0.60 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the mixture was admixed with 0.047 ml (0.61 mmol) of trifluoroacetic acid and purified by means of preparative HPLC (method 18). 64 mg (91% of theory, 98% purity) of the title compound were obtained.

(243) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.50 (br. s, 1H), 10.62 (s, 1H), 8.49 (d, 1H), 8.46-8.37 (m, 2H), 8.21 (d, 1H), 8.05 (d, 1H), 7.95 (dd, 1H), 7.67-7.61 (m, 2H), 7.59-7.50 (m, 3H), 5.02 (s, 2H), 3.42 (s, 3H), 2.49 (s, 3H).

(244) LC/MS (Method 1, ESIpos): R.sub.t=1.15 min, m/z=569/571 [M+H].sup.+.

Example 61

4-{[(6-tert-Butyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(245) ##STR00200##

(246) To a solution of 80 mg (0.17 mmol) of the compound from example 85A in 3.5 ml of THF and 0.7 ml of methanol was added, at RT, 0.86 ml (0.86 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1 h. After cooling to RT, the mixture was admixed with 0.066 ml (0.86 mmol) of trifluoroacetic acid and purified by means of preparative HPLC (method 5). 61 mg (77% of theory, 98% purity) of the title compound were obtained.

(247) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.24 (br. s, 1H), 11.01 (s, 1H), 8.07-8.00 (m, 2H), 7.94 (dd, 1H), 7.89 (d, 1H), 7.83 (dd, 1H), 7.77 (d, 1H), 7.64-7.59 (m, 2H), 7.59-7.48 (m, 3H), 2.42 (s, 3H), 1.38 (s, 9H).

(248) LC/MS (Method 1, ESIpos): R.sub.t=1.09 min, m/z=457 [M+H].sup.+.

Example 62

3-Bromo-4-({[6-bromo-2-phenyl-3-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-5-fluorobenzoic Acid

(249) ##STR00201##

(250) The title compound was obtained as a secondary component in the preparation and purification of the compound from example 57 (for description see therein).

(251) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): [ppm]=11.28 (s, 1H), 8.49 (d, 1H), 8.23 (dd, 1H), 8.18 (d, 1H), 8.13-8.10 (m, 1H), 7.94 (dd, 1H), 7.57-7.52 (m, 5H).

(252) LC/MS (Method 1, ESIpos): R.sub.t=1.14 min, m/z=611/613/615 [M+H].sup.+.

Example 63

3-Fluoro-4-({[3-methyl-6-(pentafluoro-6-sulfanyl)-2-phenylquinolin-4-yl]carbonyl}amino)benzoic Acid

(253) ##STR00202##

(254) 110 mg (0.20 mmol) of the compound from example 90A were dissolved in 4 ml of a THF/methanol mixture (5:1), and 1.02 ml (1.02 mmol) of a 1 M solution of lithium hydroxide in water were added. The reaction mixture was stirred at 50 C. for 3 h. Subsequently, the mixture was cooled to RT, adjusted to pH 1-2 with 4 M hydrochloric acid and, without further workup, purified by means of preparative HPLC (method 6). The product fractions were concentrated and the residue was dried under reduced pressure. 85 mg (79% of theory, 100% purity) of the title compound were obtained.

(255) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.28 (br. s, 1H), 11.14 (s, 1H), 8.35-8.22 (m, 3H), 8.09 (t, 1H), 7.90 (dd, 1H), 7.84 (dd, 1H), 7.73-7.63 (m, 2H), 7.63-7.50 (m, 3H), 2.49 (s, 3H).

(256) LC/MS (Method 1, ESIpos): R.sub.t=1.14 min, m/z=527 [M+H].sup.+.

Example 64

4-({[6-(Difluoromethyl)-3-methyl-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoic Acid

(257) ##STR00203##

(258) 55 mg (0.18 mmol) of the compound from example 94A were dissolved in 2 ml of DMF under argon, and 57 mg (0.35 mmol) of N,N-carbonyldiimidazole were added at RT. The reaction mixture was stirred at 60 C. overnight, and then water and ethyl acetate added. The phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was dissolved in 1.55 ml of dichloromethane, and 29.8 mg (0.26 mmol) of methyl 4-amino-3-fluorobenzoate were added. Subsequently, 0.44 ml (0.44 mmol) of a 1 M solution of potassium tert-butoxide in THF was added. The reaction mixture was stirred at RT overnight, and then 0.88 ml (0.88 mmol) of a 1 M solution of lithium hydroxide in water was added. The reaction mixture was then stirred at 50 C. for 3 h. The mixture was then cooled to RT, adjusted to pH 1-2 with 4 M hydrochloric acid and, without further workup, purified by means of preparative HPLC (method 6). The product fractions were concentrated and the residue was dried under reduced pressure. In this way, 20 mg (23% of theory, 90% purity) of the title compound were obtained.

(259) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.24 (br. s, 1H), 11.08 (s, 1H), 8.35-8.17 (m, 2H), 8.09 (s, 1H), 7.98-7.87 (m, 2H), 7.82 (dd, 1H), 7.67-7.62 (m, 2H), 7.60-7.51 (m, 3H), 7.31 (t, 1H), 2.45 (s, 3H).

(260) LC/MS (Method 1, ESIpos): R.sub.t=1.03 min, m/z=451 [M+H].sup.+.

Example 65

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,3-difluorobenzoic Acid

(261) ##STR00204##

(262) 105 mg (0.21 mmol) of the compound from example 95A were dissolved in 5 ml of a THF/methanol mixture (5:1), and 1.03 ml (1.03 mmol) of a 1 M solution of lithium hydroxide in water were added. The reaction mixture was stirred at 50 C. for 3 h, then cooled to RT and adjusted to pH 1-2 with 4 M hydrochloric acid. Subsequently, the mixture, without further workup, was purified by means of preparative HPLC (method 6). The product fractions were concentrated, and the residue was lyophilized and then recrystallized from water. Drying under reduced pressure gave 69 mg (68% of theory, purity 100%) of the title compound.

(263) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.51 (br. s, 1H), 11.24 (s, 1H), 8.08-8.03 (m, 1H), 8.03-7.96 (m, 2H), 7.93 (dd, 1H), 7.85-7.74 (m, 1H), 7.66-7.60 (m, 2H), 7.60-7.48 (m, 3H), 2.43 (s, 3H).

(264) LC/MS (Method 1, ESIpos): R.sub.t=1.03 min, m/z=497/499 [M+H].sup.+.

Example 66

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,5-difluorobenzoic Acid

(265) ##STR00205##

(266) 99 mg (0.17 mmol, 85% purity) of the compound from example 96A were dissolved in 5 ml of a THF/methanol mixture (5:1), and 0.82 ml (0.82 mmol) of a 1 M solution of lithium hydroxide in water were added. The reaction mixture was stirred at 50 C. for 3 h, then cooled to RT and adjusted to pH 1-2 with 4 M hydrochloric acid. Subsequently, the mixture, without further workup, was purified by means of preparative HPLC (method 6). The product fractions were concentrated and the residue was dried under reduced pressure. 81 mg (99% of theory, >99% purity) of the title compound were obtained.

(267) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.47 (br. s, 1H), 11.23 (s, 1H), 8.25 (dd, 1H), 8.04 (d, 1H), 8.01 (d, 1H), 7.93 (dd, 1H), 7.77 (dd, 1H), 7.66-7.60 (m, 2H), 7.60-7.48 (m, 3H), 2.41 (s, 3H).

(268) LC/MS (Method 1, ESIpos): R.sub.t=1.07 min, m/z=497/499 [M+H].sup.+.

Example 67

6-Bromo-N-(2-fluoro-4-{[(trifluoromethyl)sulfonyl]carbamoyl}phenyl)-3-methyl-2-phenylquinoline-4-carboxamide

(269) ##STR00206##

(270) To a suspension of 20 mg (0.50 mmol) of sodium hydride (60% in mineral oil) in 2.5 ml of THF were added 75 mg (0.50 mmol) of trifluoromethanesulfonamide, and the mixture was stirred at RT for 30 min. Subsequently, 124 mg (0.25 mmol) of the compound from example 40A were added, and the mixture was stirred at RT for a further 30 min. Then the mixture was concentrated. The residue was taken up in DMSO and purified by means of preparative HPLC (method 18). The product-containing fractions were concentrated, and the residue was taken up in a mixture of dichloromethane and methanol, concentrated again and then dried under reduced pressure. 77 mg (50% of theory, 100% purity) of the title compound were obtained.

(271) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.90 (s, 1H), 8.07-7.98 (m, 3H), 7.95 (dd, 1H), 7.85 (dd, 1H), 7.75 (dd, 1H), 7.66-7.61 (m, 2H), 7.60-7.50 (m, 3H), 2.44 (s, 3H).

(272) LC/MS (Method 1, ESIpos): R.sub.t=1.10 min, m/z=610/612 [M+H].sup.+.

Example 68

6-Bromo-N-{4-[(dimethylsulfamoyl)carbamoyl]-2-fluorophenyl}-3-methyl-2-phenylquinoline-4-carboxamide

(273) ##STR00207##

(274) To a suspension of 20 mg (0.50 mmol) of sodium hydride (60% in mineral oil) in 2.5 ml of THF were added 62 mg (0.50 mmol) of N,N-dimethylsulfonamide, and the mixture was stirred at RT for 30 min. Subsequently, 1 ml of DMF was added and the mixture was stirred at 50 C. for 2 h. After cooling to RT, 124 mg (0.25 mmol) of the compound from example 40A were added, and the mixture was stirred at RT for a further 30 min. Then the mixture was concentrated. The residue was taken up in DMSO and purified by means of preparative HPLC (method 18). The product-containing fractions were concentrated, and the residue was taken up in a mixture of dichloromethane and methanol, concentrated again and then dried under reduced pressure. 40 mg (27% of theory, 100% purity) of the title compound were obtained.

(275) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=11.92 (s, 1H), 11.08 (s, 1H), 8.22 (t, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.95 (d, 1H), 7.94-7.87 (m, 2H), 7.66-7.61 (m, 2H), 7.59-7.48 (m, 3H), 2.91 (s, 6H), 2.43 (s, 3H).

(276) LC/MS (Method 1, ESIpos): R.sub.t=1.11 min, m/z=585/587 [M+H].sup.+.

Example 69

Potassium 4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

(277) ##STR00208##

(278) To 1.10 g (2.30 mmol) of the compound from example 7 were added 200 ml of methanol and 5 ml of DMF, and the mixture was heated briefly to boiling. To the hot solution was added a solution of 129 mg (2.30 mmol) of potassium hydroxide in 30 ml of water. After cooling to RT, the mixture was left to stand at RT under air until the solvent had evaporated. A portion of the residue was subjected to heat treatment at 200 C. for 1-1.5 h. After cooling to RT and decanting, 0.50 g (42% of theory, 100% purity) of the title compound was obtained.

(279) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.72 (br. s, 1H), 8.05-8.00 (m, 2H), 7.95-7.90 (m, 1H), 7.76-7.68 (m, 2H), 7.67-7.60 (m, 3H), 7.59-7.49 (m, 3H), 2.45 (s, 3H).

(280) LC/MS (Method 1, ESIpos): R.sub.t=1.05 min, m/z=479/481 [M+H].sup.+.

Example 70

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid L-Lysine Salt

(281) ##STR00209##

(282) To 2.0 g (4.18 mmol) of the compound from example 7 were added 100 ml of 1,4-dioxane, and the mixture was heated briefly to boiling. To the hot solution was added a solution of 610 mg (4.18 mmol) of L-lysine in 20 ml of water. After cooling to RT, the mixture was left to stand at RT under air until the solvent had evaporated. The residue was suspended in 20 ml of an ethanol/water mixture (1:1) and stirred at RT for one week. Subsequently, the solids were filtered off and dried under air at RT. 2.2 g of the title compound were obtained (84% of theory, 100% purity, still contains solvent).

(283) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.70 (br. s, 1H), 8.03 (d, 1H), 8.00 (d, 1H), 7.93 (dd, 1H), 7.82 (t, 1H), 7.75 (dd, 1H), 7.68 (dd, 1H), 7.65-7.60 (m, 2H), 7.59-7.49 (m, 3H), 3.16 (t, 1H), 2.75 (t, 2H), 2.44 (s, 3H), 1.79-1.29 (m, 6H).

(284) LC/MS (Method 1, ESIpos): R.sub.t=1.05 min, m/z=479/481 [M+H].sup.+.

Example 71

2-Hydroxy-N,N,N-trimethylethanaminium 4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

(285) ##STR00210##

(286) To 2.0 g (4.18 mmol) of the compound from example 7 were added 100 ml of 1,4-dioxane, and the mixture was heated briefly to boiling. To the hot solution was added a mixture of 1.23 g (5.09 mmol) of a 50% by weight aqueous solution of 2-hydroxy-N,N,N-trimethylethanaminium hydroxide (choline hydroxide) and 20 ml of water. After cooling to RT, the mixture was left to stand at RT under air until the solvent had evaporated. 2.5 g of the title compound were obtained (quant., 100% purity, still contains water).

(287) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.62 (br. s, 1H), 8.07-7.98 (m, 2H), 7.96-7.87 (m, 1H), 7.74-7.65 (m, 2H), 7.65-7.59 (m, 3H), 7.59-7.47 (m, 3H), 3.87-3.82 (m, 2H), 3.43-3.38 (m, 2H), 3.11 (s, 9H), 2.44 (s, 3H).

(288) LC/MS (Method 1, ESIpos): R.sub.t=1.06 min, m/z=479/481 [M+H].sup.+.

Example 72

4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid 2-amino-2-(hydroxymethyl)propane-1,3-diol Salt

(289) ##STR00211##

(290) To 2.0 g (4.18 mmol) of the compound from example 7 were added 100 ml of 1,4-dioxane, and the mixture was heated briefly to boiling. To the hot solution was added a solution of 507 mg (4.18 mmol) of 2-amino-2-(hydroxymethyl)propane-1,3-diol (TRIS) in 20 ml of water. After cooling to RT, the mixture was left to stand at RT under air until the solvent had evaporated. After decanting, 2.5 g of the title compound were obtained (quant., 100% purity, still contains water).

(291) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=10.89 (br. s, 1H), 8.04 (d, 1H), 8.01 (d, 1H), 7.97-7.90 (m, 2H), 7.80 (dd, 1H), 7.72 (dd, 1H), 7.66-7.60 (m, 2H), 7.60-7.49 (m, 3H), 3.44 (s, 6H), 2.45 (s, 3H).

(292) LC/MS (Method 1, ESIpos): R.sub.t=1.07 min, m/z=479/481 [M+H].sup.+.

Example 73

4-{[(6-Bromo-3-fluoro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(293) ##STR00212##

(294) To a solution of 45 mg (0.06 mmol, 69% purity) of the compound from example 98A in 1.0 ml of THF and 0.2 ml of methanol was added, at RT, 0.31 ml (0.31 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1.5 h. After cooling to RT, 0.03 ml (0.37 mmol) of trifluoroacetic acid was added. Subsequently, the mixture was purified directly by means of preparative HPLC (method 18). 5 mg (16% of theory, 94% purity) of the title compound were obtained.

(295) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.22 (br. s, 1H), 11.21 (s, 1H), 8.33 (t, 1H), 8.17-8.12 (m, 2H), 8.09-8.04 (m, 2H), 8.00 (dd, 1H), 7.89 (dd, 1H), 7.81 (dd, 1H), 7.65-7.57 (m, 3H).

(296) LC/MS (Method 1, ESIpos): R.sub.t=1.14 min, m/z=483/485 [M+H].sup.+.

Example 74

4-{[(6-Bromo-3-methoxy-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(297) ##STR00213##

(298) The title compound was obtained as a further product of the reaction described in example 73. In the purification of the reaction mixture by preparative HPLC by method 18 (see example 73), a further product fraction had been obtained, which was purified further by another preparative HPLC [column: Kinetix C18, 5 m, 10021.2 mm; flow rate: 60 ml/min; detection: 210 nm; injection volume: 1.0 ml; temperature: 40 C.; eluent: gradient 95% water/0% acetonitrile/5% (acetonitrile/water 80:20+2% formic acid).fwdarw.30% water/65% acetonitrile/5% (acetonitrile/water 80:20+2% formic acid); run time: 10.8 min]. In this way, 9 mg (29% of theory, 100% purity) of the title compound were obtained.

(299) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=11.03 (s, 1H), 8.23 (t, 1H), 8.07 (d, 1H), 8.02-7.98 (m, 3H), 7.91 (dd, 1H), 7.88 (d, 1H), 7.80 (d, 1H), 7.61-7.53 (m, 3H), 3.65 (s, 3H).

(300) LC/MS (Method 1, ESIpos): R.sub.t=1.08 min, m/z=495/497 [M+H].sup.+.

Example 75

4-{[(3-Chloro-6-iodo-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(301) ##STR00214##

(302) To a solution of 46 mg (0.07 mmol, 90% purity) of the compound from example 101A in 2.3 ml of THF and 0.5 ml of methanol was added, at RT, 0.44 ml (0.44 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred at RT for 20 h. Subsequently, the mixture was acidified to pH 3 with trifluoroacetic acid and purified by means of preparative HPLC (method 18). 32 mg (77% of theory, 98% purity) of the title compound were obtained.

(303) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.24 (br. s, 1H), 11.20 (s, 1H), 8.31 (t, 1H), 8.21 (d, 1H), 8.17 (dd, 1H), 7.94 (d, 1H), 7.90 (dd, 1H), 7.82 (dd, 1H), 7.78-7.73 (m, 2H), 7.61-7.52 (m, 3H).

(304) LC/MS (Method 1, ESIpos): R.sub.t=1.11 min, m/z=547 [M+H].sup.+.

Example 76

4-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(305) ##STR00215##

(306) To a solution of 45 mg (0.07 mmol, 85% purity) of the compound from example 104A in 2.3 ml of THF and 0.5 ml of methanol was added, at RT, 0.44 ml (0.44 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred at RT for 20 h. Subsequently, the mixture was acidified to pH 3 with trifluoroacetic acid and prepurified by means of preparative HPLC (method 18). The product thus obtained was dissolved in 10 ml of an acetonitrile/methanol/DMSO/formic acid mixture while heating and purified further by another preparative HPLC [column: Kinetix C18, 5 m, 10021.2 mm; flow rate: 25 ml/min; detection: 210 nm; injection volume: 2.75 ml; temperature: 35 C.; eluent: gradient 50% water/45% acetonitrile/5% formic acid (1% in water).fwdarw.20% water/75% acetonitrile/5% formic acid (1% in water); run time: 6.0 min]. In this way, 22 mg (56% of theory, 95% purity) of the title compound were obtained.

(307) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.24 (br. s, 1H), 11.21 (s, 1H), 8.32 (t, 1H), 8.14-8.09 (m, 1H), 8.07-8.02 (m, 2H), 7.92-7.87 (m, 1H), 7.81 (dd, 1H), 7.78-7.73 (m, 2H), 7.61-7.54 (m, 3H).

(308) LC/MS (Method 1, ESIpos): R.sub.t=1.09 min, m/z=499/501 [M+H].sup.+.

Example 77

4-{[(6-Bromo-3-cyclopropyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(309) ##STR00216##

(310) To a solution of 33 mg (0.05 mmol, 77% purity) of the compound from example 106A in 1.5 ml of THF and 0.3 ml of methanol was added, at RT, 0.073 ml (0.073 mmol) of 1 M sodium hydroxide solution, and the mixture was left to stand at RT for 2 h. Subsequently, the mixture was stirred at 60 C. for 5 h and then left to stand again at RT for 2 days. After adding a further 0.15 ml (0.15 mmol) of 1 M sodium hydroxide solution, the mixture was stirred once again at 60 C. for one day. Thereafter, the mixture was acidified to pH 3 with trifluoroacetic acid and purified by means of preparative HPLC (method 18). 19 mg (75% of theory, 100% purity) of the title compound were obtained.

(311) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.24 (br. s, 1H), 11.00 (s, 1H), 8.25 (t, 1H), 8.07-8.02 (m, 2H), 7.94 (dd, 1H), 7.90 (dd, 1H), 7.82 (dd, 1H), 7.76 (dd, 2H), 7.57-7.46 (m, 3H), 2.46-2.30 (m, 1H), 0.68 (d, 2H), 0.33 (d, 2H).

(312) LC/MS (Method 1, ESIpos): R.sub.t=1.15 min, m/z=505/507 [M+H].sup.+.

Example 78

4-{[(6-Bromo-3,8-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic Acid

(313) ##STR00217##

(314) To a solution of 649 mg (1.02 mmol, 80% purity) of the compound from example 108A in 13 ml of THF and 2.6 ml of methanol was added, at RT, 4.3 ml (4.3 mmol) of 1 M sodium hydroxide solution, and the mixture was stirred under reflux for 1.5 h. After cooling to RT, the mixture was acidified to pH 3 with trifluoroacetic acid and then purified by means of preparative HPLC [column: Kinetix C18, 5 m, 10021.2 mm; flow rate: 60 ml/min; detection: 210 nm; injection volume: 1.0 ml; temperature: 40 C.; eluent: gradient 50% water/30% acetonitrile/20% (acetonitrile/water 80:20+2% formic acid).fwdarw.30% water/65% acetonitrile/5% (acetonitrile/water 80:20+2% formic acid); run time: 5.7 min]. 419 mg (83% of theory, 100% purity) of the title compound were obtained.

(315) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=13.25 (br. s, 1H), 11.02 (s, 1H), 8.19 (t, 1H), 7.89 (dd, 1H), 7.86-7.83 (m, 1H), 7.81 (td, 2H), 7.70-7.64 (m, 2H), 7.60-7.49 (m, 3H), 2.73 (s, 3H), 2.45 (s, 3H).

(316) LC/MS (Method 1, ESIpos): R.sub.t=1.19 min, m/z=493/495 [M+H].sup.+.

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

(317) The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vivo studies as known to the person skilled in the art. The application examples which follow describe the biological action of the compounds of the invention, without restricting the invention to these examples.

Abbreviations and Acronyms

(318) BSA bovine serum albumin CRTH2 chemoattractant receptor-homologous molecule expressed on T helper type 2 cells DMEM Dulbecco's modified Eagle's medium DMSO dimethyl sulfoxide DP PGD2 receptor EC.sub.50 half-maximum effective concentration em. emission EP PGE2 receptor ex. excitation FCS fetal calf serum FP PGF2 receptor HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid IC.sub.50 half-maximum inhibitory concentration IP PGI2 receptor MES 2-(N-morpholino)ethanesulfonic acid Pen/Strep penicillin/streptomycin PGD2 prostaglandin D2 PGE2 prostaglandin E2 PGF2 prostaglandin F2 PGI2 prostaglandin 12 TC tissue culture TP thromboxane A2 receptor Tris tris(hydroxymethyl)aminomethane v/v volume to volume ratio (of a solution) w/w weight to weight ratio (of a solution)
B-1. In Vitro Test of Inhibition of Human FP Receptor Activity
Variant B-1A:

(319) For the characterization of test substances in respect of FP antagonism, PGF2-induced calcium flux in FP-expressing CHEM1 cells (Millipore, HTS093C) was used.

(320) 3000 cells in 25 l of full medium [DMEM F12, 10% FCS, 1.35 mM sodium pyruvate, 20 mM HEPES, 4 mM GlutaMAX, 2% sodium bicarbonate, 1% Pen/Strep, 1% 100 non-essential amino acids] are sown per well of a 384 multititer plate (from Greiner, TC plate, black with clear base) and incubated at 37 C./5% CO.sub.2 for 24 hours. Prior to the measurement, the medium is replaced by 30 l of Fluo-8 AM loading buffer [calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4), 2 mM CaCl.sub.2, 1 SmartBlock (from CANDOR Bioscience GmbH), 4.5 mM Probenecid, 5 M Fluo-8 AM, 0.016% Pluronic, 0.04% Brilliant black] and incubated at 37 C./5% CO.sub.2 for 30 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with calcium-free Tyrode/2 mM CaCl.sub.2. 10 l of the prediluted substance solution are added to the Fluo-8-laden cells and incubated at 37 C./5% CO.sub.2 for 10 minutes. The FP receptor is activated by adding 20 l of 3 nM (final concentration) PGF2 in calcium-free Tyrode/2 mM CaCl.sub.2/0.04% Brilliant black, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm in a fluorescence measuring instrument (FLIPR Tetra, Molecular Devices) for 120 seconds.

(321) Table 1A below lists the IC.sub.50 values from this assay for individual working examples of the invention (some as mean values from multiple independent individual determinations):

(322) TABLE-US-00001 TABLE 1A FP receptor activity Example no. IC.sub.50 [mol/l] 1 0.166 2 0.148 3 0.170 4 0.880 5 0.905 6 0.079 7 0.020 8 0.795 9 0.065 10 0.041 11 0.053 12 0.022 13 0.150 14 0.617 15 0.045 16 0.278 17 0.060 18 0.335 19 0.650 20 0.530 21 0.204 22 0.290 23 0.057 24 0.124 25 0.720 26 0.086 27 0.097 28 0.017 29 0.890 30 0.006 31 0.165 32 0.245 33 0.272 34 0.093 35 0.290 36 0.078 37 0.039 38 0.265 39 0.190 40 0.560 41 0.025 42 0.033 43 0.052 44 0.033 45 0.205 46 0.140 47 0.197 48 0.102 49 0.120 50 0.037 51 0.091 52 0.017 53 0.031 54 0.102 55 0.049 56 0.285 57 0.437 58 0.557 59 0.203 60 0.027 61 0.131 62 0.301 63 0.246 64 0.362 65 0.105 66 0.282 67 0.239 68 0.318 69 0.104 70 0.089 71 0.090 72 0.079 74 0.220 75 0.009 76 0.017 77 0.027 78 0.154
Variant B-1B:

(323) For the characterization of test substances in respect of FP antagonism, the PGF2-induced calcium flux in recombinant FP-expressing CHO cells which additionally express the Ca.sup.2+ sensor protein GCaMP6 was used.

(324) 3000 cells in 25 l of full medium [DMEM F12, 10% FCS, 1.35 mM sodium pyruvate, 20 mM HEPES, 4 mM GlutaMAX, 2% sodium bicarbonate, 1% Pen/Strep, 1% 100 non-essential amino acids] are sown per well of a 384 multititer plate (from Greiner, TC plate, black with clear base) and incubated at 37 C., 5% CO.sub.2 for 24 hours. Prior to the measurement, the medium is replaced by 30 l of buffer [calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4), 2 mM CaCl.sub.2, 0.01% BSA] and incubated at 37 C., 5% CO.sub.2 for 30 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with calcium-free Tyrode/2 mM CaCl.sub.2/0.01% BSA. 10 l of the prediluted substance solution are added to the cells and incubated at 37 C., 5% CO.sub.2 for 10 minutes. The FP receptor is activated by adding 20 l of 3 nM (final concentration) PGF2 in calcium-free Tyrode/2 mM CaCl.sub.2, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm in a fluorescence measuring instrument (FLIPR Tetra, MolecularDevices) for 120 seconds.

(325) Table 1B below lists the IC.sub.50 values from this assay for individual working examples of the invention (some as mean values from multiple independent individual determinations):

(326) TABLE-US-00002 TABLE 1B FP receptor activity Example no. IC.sub.50 [mol/l] 7 0.034 50 0.044 51 0.038 52 0.006 61 0.079 65 0.060 67 0.134 68 0.182 69 0.059 70 0.053 71 0.047 72 0.043 73 0.098
B-2. In Vitro FP Receptor Binding Inhibition Test

(327) For the FP receptor binding test, human recombinant prostanoid FP receptors, expressed in HEK293 cells, in modified MES buffer, pH 6.0, are used. This test is conducted commercially (at Eurofins Panlabs, catalog #268510). 80 g of membrane are incubated with 1 nM [.sup.3H]-PGF2 at 25 C. for 60 minutes. The amount of membrane protein can vary from batch to batch and is adjusted if required. Unspecific binding is determined in the presence of 1 M cloprostenol. The membranes are filtered, washed and then analyzed in order to determine the specific binding of [.sup.3H]-PGF2. Substances are tested for inhibitory activity at a concentration of 10 M or in the form of a dose-response curve [lit.: Abramovitz et al., J. Biol. Chem. 1994, 269 (4): 2632].

(328) B-3. In Vitro CRTH2 Receptor Binding Inhibition Test

(329) For this test, human recombinant prostanoid CRTH2 receptors, expressed in CHO-K1 cells, in modified Tris-HCl buffer, pH 7.4, are used. This test is conducted commercially (at Eurofins Panlabs, catalog #268030). 4 g of membrane are incubated with 1 nM [.sup.3H]-PGD2 at 25 C. for 120 minutes. The amount of membrane protein can vary from batch to batch and is adjusted if required. Unspecific binding is determined in the presence of 1 M PGD2. The membranes are filtered, washed and then analyzed in order to determine the specific binding of [.sup.3H]-PGD2. Substances are tested for inhibitory activity at a concentration of 10 M or in the form of a dose-response curve [lit.: Sugimoto et al., J. Pharmacol. Exp. Ther. 2003, 305 (1): 347].

(330) B-4. In Vitro DP Receptor Binding Inhibition Test

(331) For this test, human recombinant prostanoid DP receptors, expressed in Chem-1 cells, in modified HEPES buffer, pH 7.4, are used. This test is conducted commercially (at Eurofins Panlabs, catalog #268060). 10 g of membrane are incubated with 2 nM [.sup.3H]-PGD2 at 25 C. for 120 minutes. The amount of membrane protein can vary from batch to batch and is adjusted if required. Unspecific binding is determined in the presence of 1 M PGD2. The membranes are filtered, washed and then analyzed in order to determine the specific binding of [.sup.3H]-PGD2. Substances are tested for inhibitory activity at a concentration of 10 M or in the form of a dose-response curve [lit.: Wright et al., Br. J. Pharmacol. 1998, 123 (7): 1317; Sharif et al., Br. J. Pharmacol. 2000, 131 (6): 1025].

(332) B-5. In Vitro EP1 Receptor Binding Inhibition Test

(333) For this test, human recombinant prostanoid EP1 receptors, expressed in HEK293 cells, in modified MES buffer, pH 6.0, are used. This test is conducted commercially (at Eurofins Panlabs, catalog #268110). 14 g of membrane are incubated with 1 nM [.sup.3H]-PGE2 at 25 C. for 60 minutes. The amount of membrane protein can vary from batch to batch and is adjusted if required. Unspecific binding is determined in the presence of 10 M PGE2. The membranes are filtered, washed and then analyzed in order to determine the specific binding of [.sup.3H]-PGE2. Substances are tested for inhibitory activity at a concentration of 10 M or in the form of a dose-response curve [lit.: Abramovitz et al., Biochim. Biophys. Acta 2000, 1483 (2): 285; Funk et al., J. Biol. Chem. 1993, 268 (35): 26767].

(334) B-6. In Vitro EP2 Receptor Binding Inhibition Test

(335) For this test, human recombinant prostanoid EP2 receptors, expressed in HEK293 cells, in modified MES/KOH buffer, pH 6.0, are used. This test is conducted commercially (at Eurofins Panlabs, catalog #268200). 25 mg/ml of membrane are incubated with 4 nM [.sup.3H]-PGE2 at 25 C. for 120 minutes. The amount of membrane protein can vary from batch to batch and is adjusted if required. Unspecific binding is determined in the presence of 10 M PGE2. The membranes are filtered, washed and then analyzed in order to determine the specific binding of [.sup.3H]-PGE2. Substances are tested for inhibitory activity at a concentration of 10 M or in the form of a dose-response curve [lit.: Bastien et al., J. Biol. Chem. 1994, 269 (16): 11873; Boie et al., Eur. J. Pharmacol. 1997, 340 (2-3): 227].

(336) B-7. In Vitro EP3 Receptor Binding Inhibition Test

(337) For this test, human recombinant prostanoid EP3 receptors, expressed in HEK293 cells, in modified MES buffer, pH 6.0, are used. This test is conducted commercially (at Eurofins Panlabs, catalog #268310). 3 g of membrane are incubated with 0.5 nM [.sup.3H]-PGE2 at 25 C. for 120 minutes. The amount of membrane protein can vary from batch to batch and is adjusted if required. Unspecific binding is determined in the presence of 10 M PGE2. The membranes are filtered, washed and then analyzed in order to determine the specific binding of [.sup.3H]-PGE2. Substances are tested for inhibitory activity at a concentration of 10 M or in the form of a dose-response curve [lit.: Schmidt et al., Eur. J. Biochem. 1995, 228 (1): 23].

(338) B-8. In Vitro EP4 Receptor Binding Inhibition Test

(339) For this test, human recombinant prostanoid EP4 receptors, expressed in Chem-1 cells, in modified MES buffer, pH 6.0, are used. This test is conducted commercially (at Eurofins Panlabs, catalog #268420). 3 g of membrane are incubated with 1 nM [.sup.3H]-PGE2 at 25 C. for 120 minutes. The amount of membrane protein can vary from batch to batch and is adjusted if required. Unspecific binding is determined in the presence of 10 M PGE2. The membranes are filtered, washed and then analyzed in order to determine the specific binding of [.sup.3H]-PGE2. Substances are tested for inhibitory activity at a concentration of 10 M or in the form of a dose-response curve [lit.: Davis et al., Br. J. Pharmacol. 2000, 130 (8): 1919].

(340) B-9. In Vitro IP Receptor Binding Inhibition Test

(341) For this test, human recombinant prostanoid IP receptors, expressed in HEK293 cells, in modified HEPES buffer, pH 6.0, are used. This test is conducted commercially (at Eurofins Panlabs, catalog #268600). 15 g of membrane are incubated with 5 nM [.sup.3H]-iloprost at 25 C. for 60 minutes. The amount of membrane protein can vary from batch to batch and is adjusted if required. Unspecific binding is determined in the presence of 10 M iloprost. The membranes are filtered, washed and then analyzed in order to determine the specific binding of [.sup.3H]-iloprost. Substances are tested for inhibitory activity at a concentration of 10 M or in the form of a dose-response curve [lit.: Armstrong et al., Br. J. Pharmacol. 1989, 97 (3): 657; Boie et al., J. Biol. Chem. 1994, 269 (16): 12173].

(342) B-10. In Vitro TP Receptor Binding Inhibition Test

(343) For this test, human recombinant prostanoid TP receptors, expressed in HEK-293 EBNA cells, in modified Tris/HCl buffer, pH 7.4, are used. This test is conducted commercially (at Eurofins Panlabs, catalog #285510). 18.4 g of membrane are incubated with 5 nM [.sup.3H]-SQ-29 548 at 25 C. for 30 minutes. The amount of membrane protein can vary from batch to batch and is adjusted if required. Unspecific binding is determined in the presence of 1 M SQ-29 548. The membranes are filtered, washed and then analyzed in order to determine the specific binding of [.sup.3H]-SQ-29 548. Substances are tested for inhibitory activity at a concentration of 10 M or in the form of a dose-response curve [lit.: Saussy Jr. et al., J. Biol. Chem. 1986, 261: 3025; Hedberg et al., J. Pharmacol. Exp. Ther. 1988, 245: 786].

(344) B-11. In Vitro Test for DP Agonism and Antagonism

(345) For the characterization of test substances in respect of DP agonism and antagonism, PGD2-induced calcium flux in DP-expressing CHEM1 cells (Millipore, HTS091C) was used: 3000 cells in 25 l of full medium [DMEM, 4.5 g/l glucose, 10% heat-inactivated FCS, 1% 100 non-essential amino acids, 10 mM HEPES, 0.25 mg/ml Geneticin (G418), 100 U/ml penicillin and streptomycin] are sown per well of a 384 multititer plate (from Greiner, TC plate, black with clear base) and incubated at 37 C./5% CO.sub.2 for 24 hours. Prior to the measurement, the medium is replaced by 30 l of calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 C./5% CO.sub.2 for 60 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4)/2 mM CaCl.sub.2. For the measurement of DP agonism, in a fluorescence measuring instrument (FLIPR Tetra, Molecular Devices), 10 l of the prediluted substance solution are added to the calcium dye-laden cells, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 C./5% CO.sub.2 for 10 minutes. For the measurement of DP antagonism, the DP receptor is activated in the FLIPR Tetra by adding 20 l of 76 nM (2EC.sub.50, final concentration) PGD2 in, for example, calcium-free Tyrode/2 mM CaCl.sub.2, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds [lit.: T. Matsuoka et al. (2000) Science 287: 2013-2017; S. Narumiya and G. A. Fitzgerald (2001) J. Clin. Invest. 108: 25-30].

(346) B-12. In Vitro Test for EP1 Agonism and Antagonism

(347) For the characterization of test substances in respect of EP 1 agonism and antagonism, PGE2-induced calcium flux in EP1-expressing CHEM1 cells (Millipore, HTS099C) was used: 3000 cells in 25 l of full medium [DMEM, 4.5 g/l glucose, 10% heat-inactivated FCS, 1% 100 non-essential amino acids, 10 mM HEPES, 0.25 mg/ml Geneticin (G418), 100 U/ml penicillin and streptomycin] are sown per well of a 384 multititer plate (from Greiner, TC plate, black with clear base) and incubated at 37 C./5% CO.sub.2 for 24 hours. Prior to the measurement, the medium is replaced by 30 l of calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 C./5% CO.sub.2 for 60 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4)/2 mM CaCl.sub.2. For the measurement of EP1 agonism, in a fluorescence measuring instrument (FLIPR Tetra, Molecular Devices), 10 l of the prediluted substance solution are added to the calcium dye-laden cells, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 C./5% CO.sub.2 for 10 minutes. For the measurement of EP 1 antagonism, the EP 1 receptor is activated in the FLIPR Tetra by adding 20 l of 6 nM (2EC.sub.50, final concentration) PGE2 in, for example, calcium-free Tyrode/2 mM CaCl.sub.2, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds [lit.: Y. Matsuoka et al. (2005) Proc. Natl. Acad. Sci. USA 102: 16066-16071; S. Narumiya and G. A. Fitzgerald (2001) J. Clin. Invest. 108: 25-30; K. Watanabe et al. (1999) Cancer Res. 59: 5093-5096].

(348) B-13. In Vitro Test for EP2 Agonism and Antagonism

(349) For the characterization of test substances in respect of EP2 agonism and antagonism, PGE2-induced calcium flux in EP2-expressing CHEM9 cells (Millipore, HTS185C) was used: 3000 cells in 25 l of plating medium [DMEM, 4.5 g/l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100 non-essential amino acids, 10 mM HEPES, 100 U/ml penicillin and streptomycin] are sown per well of a 384 multititer plate (from Greiner, TC plate, black with clear base) and incubated at 37 C./5% CO.sub.2 for 24 hours. Prior to the measurement, the medium is replaced by 30 l of calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 C./5% CO.sub.2 for 60 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4)/2 mM CaCl.sub.2. For the measurement of EP2 agonism, in a fluorescence measuring instrument (FLIPR Tetra, Molecular Devices), 10 l of the prediluted substance solution are added to the calcium dye-laden cells, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 C./5% CO.sub.2 for 10 minutes. For the measurement of EP2 antagonism, the EP2 receptor is activated in the FLIPR Tetra by adding 20 l of 22 nM (2EC.sub.50, final concentration) PGE2 in, for example, calcium-free Tyrode/2 mM CaCl.sub.2, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds [lit.: C. R. Kennedy et al. (1999) Nat. Med. 5: 217-220; S. Narumiya and G. A. Fitzgerald (2001) J. Clin. Invest. 108: 25-30; N. Yang et al. (2003) J. Clin. Invest. 111: 727-735].

(350) B-14. In Vitro Test for EP3 Agonism and Antagonism

(351) For the characterization of test substances in respect of EP3 agonism and antagonism, PGE2-induced calcium flux in EP3 (splice variant 6)-expressing CHEM1 cells (Millipore, HTS092C) was used: 3000 cells in 25 l of plating medium [DMEM, 4.5 g/l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100 non-essential amino acids, 10 mM HEPES, 100 U/ml penicillin and streptomycin] are sown per well of a 384 multititer plate (from Greiner, TC plate, black with clear base) and incubated at 37 C./5% CO.sub.2 for 24 hours. Prior to the measurement, the medium is replaced by 30 l of calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 C./5% CO.sub.2 for 60 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4)/2 mM CaCl.sub.2. For the measurement of EP3 agonism, in a fluorescence measuring instrument (FLIPR Tetra, Molecular Devices), 10 l of the prediluted substance solution are added to the calcium dye-laden cells, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 C./5% CO.sub.2 for 10 minutes. For the measurement of EP3 antagonism, the EP3 receptor is activated in the FLIPR Tetra by adding 20 l of 2 nM (2EC.sub.50, final concentration) PGE2 in, for example, calcium-free Tyrode/2 mM CaCl.sub.2, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds [lit.: M. Kotani et al. (1995) Mol. Pharmacol. 48: 869-879; M. Kotani et al. (1997) Genomics 40: 425-434; T. Kunikata et al. (2005) Nat. Immunol. 6: 524-531; S. Narumiya and G. A. Fitzgerald (2001) J. Clin. Invest. 108: 25-30; F. Ushikubi et al. (1998) Nature 395: 281-284].

(352) B-15. In Vitro Test for EP4 Agonism and Antagonism

(353) For the characterization of test substances in respect of EP4 agonism and antagonism, PGE2-induced calcium flux in EP4-expressing CHEM1 cells (Millipore, HTS142C) was used: 3000 cells in 25 l of plating medium [DMEM, 4.5 g/l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100 non-essential amino acids, 10 mM HEPES, 100 U/ml penicillin and streptomycin] are sown per well of a 384 multititer plate (from Greiner, TC plate, black with clear base) and incubated at 37 C./5% CO.sub.2 for 24 hours. Prior to the measurement, the medium is replaced by 30 l of calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 C./5% CO.sub.2 for 60 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4)/2 mM CaCl.sub.2. For the measurement of EP4 agonism, in a fluorescence measuring instrument (FLIPR Tetra, Molecular Devices), 10 l of the prediluted substance solution are added to the calcium dye-laden cells, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 C./5% CO.sub.2 for 10 minutes. For the measurement of EP4 antagonism, the EP4 receptor is activated in the FLIPR Tetra by adding 20 l of 26 nM (2EC.sub.50, final concentration) PGE2 in, for example, calcium-free Tyrode/2 mM CaCl.sub.2, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds [lit.: S. Narumiya and G. A. Fitzgerald (2001) J. Clin. Invest. 108: 25-30; M. Nguyen et al. (1997) Nature 390: 78-81; K. Yoshida et al. (2002) Proc. Natl. Acad. Sci. USA 99: 4580-4585].

(354) B-16. In Vitro Test for IP Agonism and Antagonism

(355) For the characterization of test substances in respect of IP agonism and antagonism, iloprost-induced calcium flux in IP-expressing CHEM1 cells (Millipore, HTS131C) was used: 3000 cells in 25 l of plating medium [DMEM, 4.5 g/l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100 non-essential amino acids, 10 mM HEPES, 100 U/ml penicillin and streptomycin] are sown per well of a 384 multititer plate (from Greiner, TC plate, black with clear base) and incubated at 37 C./5% CO.sub.2 for 24 hours. Prior to the measurement, the medium is replaced by 30 l of calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 C./5% CO.sub.2 for 60 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4)/2 mM CaCl.sub.2. For the measurement of IP agonism, in a fluorescence measuring instrument (FLIPR Tetra, Molecular Devices), 10 l of the prediluted substance solution are added to the calcium dye-laden cells, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 C./5% CO.sub.2 for 10 minutes. For the measurement of IP antagonism, the IP receptor is activated in the FLIPR Tetra by adding 20 l of 106 nM (2EC.sub.50, final concentration) iloprost in, for example, calcium-free Tyrode/2 mM CaCl.sub.2, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds [lit.: S. Narumiya et al. (1999) Physiol. Rev. 79: 1193-1226; T. Murata et al. (1997) Nature 388: 678-682; Y. Cheng et al. (2002) Science 296: 539-541; C. H. Xiao et al. (2001) Circulation 104: 2210-2215; G. A. Fitzgerald (2004) N. Engl. J. Med. 351: 1709-1711].

(356) B-17. In Vitro Test for TP Agonism and Antagonism

(357) For the characterization of test substances in respect of TP agonism and antagonism, U46619-induced calcium flux in TP-expressing CHEM1 cells (Millipore, HTS081C) was used: 3000 cells in 25 l of plating medium [DMEM, 10% heat-inactivated FCS, 10% heat-inactivated FCS, 1% 100 non-essential amino acids, 10 mM HEPES, 0.25 mg/ml Geneticin (G418), 100 U/ml penicillin and streptomycin] are sown per well of a 384 multititer plate (from Greiner, TC plate, black with clear base) and incubated at 37 C./5% CO.sub.2 for 24 hours. Prior to the measurement, the medium is replaced by 30 l of calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 C./5% CO.sub.2 for 60 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4)/2 mM CaCl.sub.2. For the measurement of TP agonism, in a fluorescence measuring instrument (FLIPR Tetra, Molecular Devices), 10 l of the prediluted substance solution are added to the calcium dye-laden cells, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 C./5% CO.sub.2 for 10 minutes. For the measurement of TP antagonism, the TP receptor is activated in the FLIPR Tetra by adding 20 l of 88 nM (2EC.sub.50, final concentration) U46619 in, for example, calcium-free Tyrode/2 mM CaCl.sub.2, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for 120 seconds [lit.: S. Ali et al. (1993) J. Biol. Chem. 268: 17397-17403; K. Hanasaki et al. (1989) Biochem. Pharmacol. 38: 2967-2976; M. Hirata et al. (1991) Nature 349: 617-620].

(358) B-18. Animal Model of Bleomycin-Induced Pulmonary Fibrosis

(359) Bleomycin-induced pulmonary fibrosis in the mouse or rat is a widely used animal model of pulmonary fibrosis. Bleomycin is a glycopeptide antibiotic employed in oncology for the therapy of testicular tumors and Hodgkin- and Non-Hodgkin tumors. It is eliminated renally, has a half-life of about 3 hours and, as cytostatic, influences various phases of the division cycle [Lazo et al., Cancer Chemother. 15, 44-50 (1994)]. Its anti-neoplastic effect is based on an oxidatively damaging effect on DNA [Hay et al., Arch. 65, 81-94 (1991)]. Lung tissue is at a particular risk when exposed to bleomycin since it contains only a small number of cysteine hydrolases which, in other tissues, lead to inactivation of bleomycin. Following administration of bleomycin, the animals suffer an acute respiratory distress syndrome (ARDS) with subsequent development of pulmonary fibrosis.

(360) Administration of bleomycin may be by single or repeat intratracheal, inhalative, intravenous or intraperitoneal administration. Treatment of the animals with the test substance (by gavage, by addition to the feed or drinking water, using an osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) starts at the day of the first bleomycin administration or therapeutically 3-14 days later and extends over a period of 2-6 weeks. At the end of the study, a bronchio-alveolar lavage to determine the cell content and the pro-inflammatory and pro-fibrotic markers and a histological assessment of pulmonary fibrosis are carried out.

(361) B-19. Animal Model of DQ12 Quartz-Induced Pulmonary Fibrosis

(362) DQ12 quartz-induced pulmonary fibrosis in the mouse or rat is a widely used animal model of pulmonary fibrosis [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. DQ12 quartz is quartz which is highly active owing to breaking or grinding. In mice and rats, intratracheal or inhalative administration of DQ12 quartz leads to alveolar proteinosis followed by interstitial pulmonary fibrosis. The animals receive a single or repeat intratracheal or inhalative instillation of DQ12 quartz. Treatment of the animals with the test substance (by gavage, by addition to the feed or drinking water, using an osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) starts at the day of the first silicate instillation or therapeutically 3-14 days later and extends over a period of 3-12 weeks. At the end of the study, a bronchio-alveolar lavage to determine the cell content and the pro-inflammatory and pro-fibrotic markers and a histological assessment of pulmonary fibrosis are carried out.

(363) B-20. Animal Model of DQ12 Quartz or FITC-Induced Pulmonary Inflammation

(364) In the mouse and the rat, intratracheal administration of DQ12 quartz or fluorescein isothiocyanate (FITC) leads to an inflammation in the lung [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. At the day of the instillation of DQ12 quartz or FITC or a day later the animals are treated with the test substance for a duration of 24 h up to 7 days (by gavage, by addition to the feed or drinking water, using an osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation). At the end of the experiment, a bronchio-alveolar lavage to determine the cell content and the pro-inflammatory and pro-fibrotic markers is carried out.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

(365) The compounds of the invention can be converted to pharmaceutical preparations as follows:

(366) Tablet:

(367) Composition:

(368) 100 mg of the compound of the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

(369) Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

(370) Production:

(371) The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (w/w) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed using a conventional tableting press (see above for format of the tablet). The guide value used for the pressing is a pressing force of 15 kN.

(372) Suspension for Oral Administration:

(373) Composition:

(374) 1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

(375) 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

(376) Production:

(377) The Rhodigel is suspended in ethanol; the compound of the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

(378) Solution for Oral Administration:

(379) Composition:

(380) 500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound of the invention.

(381) Production:

(382) The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring operation is continued until dissolution of the compound of the invention is complete.

(383) i.v. solution:

(384) The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. isotonic saline solution, glucose solution 5% and/or PEG 400 solution 30%). The solution is subjected to sterile filtration and dispensed into sterile and pyrogen-free injection vessels.