Cyclooxygenase-2 selective inhibitors, compositions and methods of use

Abstract

The invention provides novel cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions and kits comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and / or at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and / or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and / or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and / or preventing renal and / or respiratory toxicity; for treating and / or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

Description

RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application Ser. No. 10 / 628,375, now allowed, which claims priority to U.S. Application No. 60 / 398,829 filed Jul. 29, 2002, the disclosures of which are incorporated by reference herein in their entireties.FIELD OF THE INVENTION

[0002] The invention describes novel nitrosated and / or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one nitrosated and / or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and / or at least one therapeutic agent. The invention also provides novel compositions comprising at least one COX-2 selective inhibitor, that is optionally nitrosated and / or nitrosylated, and at least one compoun...

Examples

example 1

1-(1-Cyclohexylmethyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

1a. N-((1Z)-1-Aza-2-cyclohexylvinyl)(tert-butoxy)carboxamide

[1162] Cyclohexane carboxaldehyde (5.0 g, 44.5 mmol) and t-butyl carbazate (5.89 g, 44.5 mmol) in methanol (140 mL) was stirred at room temperature for 1 hour. The solvent was evaporated and the resulting solid dried under vacuo to give a white solid in quantitative yield; mp 123-125° C. 1H NMR (300 MHz, CDCl3) δ 7.61 (bs, 1H), 7.02 (d, J=5.9 Hz, 1H), 2.22-2.39 (m, 1H), 1.60-1.89 (m, 5H), 1.49 (s, 9H), 1.19-1.47 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 152.5, 151.5, 81.0, 40.7, 30.4, 28.5, 26.0, 25.6; mass spectrum (API-TIS) m / z 227 (MH+), 249 (MNa+). Anal. calcd for C12H22N2O2: C, 63.69; H, 9.80; N, 12.38. Found: C, 63.97; H, 9.76; N, 12.26.

1b. (tert-Butoxy)-N-((cyclohexylmethyl)amino)carboxamide

[1163] Sodium cyanoborohydride (2.8 g, 44.6 mmol) was added portionwise to a suspension of the product of Example 1a (10.1 g, 44.6 mmol) in 50% acetic a...

example 2

1-(1-Cyclohexylmethyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

2a. Methyl (2Z)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-4-oxobut-2-enoate

[1170] Sodium methoxide was prepared by dissolving Na (6.9 g, 30 mmol) in MeOH (400 mL). The solution was cooled to 0° C. Dimethyl oxalate (33 g, 280 mmol) was added followed by 1-(4-(methylsulfonyl)phenyl)ethan-1-one (28 g, 140 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The MeOH was evaporated and the residue triturated with 1N HCl (600 mL). The solid was collected on filter paper, washed with H2O (2×250), and dried in vacuo. This gave the title compound (39 g, 100%) as a tan solid. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=6.9 Hz, 2H), 8.09 (d, J=6.9 Hz, 2H), 7.10 (s, 1H), 3.97 (s, 3H), 3.10 (s, 3H).

2b. Methyl 1-(cyclohexylmethyl)-5-(4-(methylsulfonyl)phenyl)pyrazole-3-carboxylate

[1171] The product of Example 1c (8 mL, 23 mmol) and the product of Example 2a (4.5 g, 16 mmol) were ad...

example 3

4-(Methylsulfonyl)-1-(3-((nitrooxy)methyl)-1-benzylpyrazol-5-yl)benzene

3a. Methyl 5-(4-(methylthiophenyl)-1-benzylpyrazole-3-carboxylate

[1176] A mixture of the product Example 1d (2 g, 7.9 mmol) and benzylhydrazine hydrochloride (1.64 g, 10.3 mmol) in methanol (40 mL) and trifluoroacetic acid (0.5 mL) was heated at 70° C. for 2 hours and cooled to room temperature. The mixture was made basic with 5% Na2CO3 and extracted with EtOAc which was then washed with saturated NaHCO3 and water. The organic extracts were dried over Na2SO4 and the solvent was evaporated. The residue was recrystallized from CH2Cl2 / EtOAc / Hex to give the title compound as a white solid (1.88 g, 70%); mp 94-96° C. 1H NMR (300 MHz, CDCl3) δ 7.12-7.30 (m, 7H), 7.00-7.08 (m, 2H), 6.87 (s, 1H), 5.41 (s, 2H), 3.95 (s, 3H), 2.50 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 163.0, 145.2, 143.1, 140.6, 136.7, 129.4, 128.8, 127.9, 126.9, 126.3, 126.0, 109.4, 54.2, 52.2, 15.4; mass spectrum (API-TIS) m / z 339 (MH+), 307 (M-OCH3); Ana...

RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application Ser. No. 10 / 628,375, now allowed, which claims priority to U.S. Application No. 60 / 398,829 filed Jul. 29, 2002, the disclosures of which are incorporated by reference herein in their entireties.FIELD OF THE INVENTION

[0002] The invention describes novel nitrosated and / or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one nitrosated and / or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and / or at least one therapeutic agent. The invention also provides novel compositions comprising at least one COX-2 selective inhibitor, that is optionally nitrosated and / or nitrosylated, and at least one compoun...

Examples

example 1

1-(1-Cyclohexylmethyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

1a. N-((1Z)-1-Aza-2-cyclohexylvinyl)(tert-butoxy)carboxamide

[1162] Cyclohexane carboxaldehyde (5.0 g, 44.5 mmol) and t-butyl carbazate (5.89 g, 44.5 mmol) in methanol (140 mL) was stirred at room temperature for 1 hour. The solvent was evaporated and the resulting solid dried under vacuo to give a white solid in quantitative yield; mp 123-125° C. 1H NMR (300 MHz, CDCl3) δ 7.61 (bs, 1H), 7.02 (d, J=5.9 Hz, 1H), 2.22-2.39 (m, 1H), 1.60-1.89 (m, 5H), 1.49 (s, 9H), 1.19-1.47 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 152.5, 151.5, 81.0, 40.7, 30.4, 28.5, 26.0, 25.6; mass spectrum (API-TIS) m / z 227 (MH+), 249 (MNa+). Anal. calcd for C12H22N2O2: C, 63.69; H, 9.80; N, 12.38. Found: C, 63.97; H, 9.76; N, 12.26.

1b. (tert-Butoxy)-N-((cyclohexylmethyl)amino)carboxamide

[1163] Sodium cyanoborohydride (2.8 g, 44.6 mmol) was added portionwise to a suspension of the product of Example 1a (10.1 g, 44.6 mmol) in 50% acetic a...

example 2

1-(1-Cyclohexylmethyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

2a. Methyl (2Z)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-4-oxobut-2-enoate

[1170] Sodium methoxide was prepared by dissolving Na (6.9 g, 30 mmol) in MeOH (400 mL). The solution was cooled to 0° C. Dimethyl oxalate (33 g, 280 mmol) was added followed by 1-(4-(methylsulfonyl)phenyl)ethan-1-one (28 g, 140 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The MeOH was evaporated and the residue triturated with 1N HCl (600 mL). The solid was collected on filter paper, washed with H2O (2×250), and dried in vacuo. This gave the title compound (39 g, 100%) as a tan solid. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=6.9 Hz, 2H), 8.09 (d, J=6.9 Hz, 2H), 7.10 (s, 1H), 3.97 (s, 3H), 3.10 (s, 3H).

2b. Methyl 1-(cyclohexylmethyl)-5-(4-(methylsulfonyl)phenyl)pyrazole-3-carboxylate

[1171] The product of Example 1c (8 mL, 23 mmol) and the product of Example 2a (4.5 g, 16 mmol) were ad...

example 3

4-(Methylsulfonyl)-1-(3-((nitrooxy)methyl)-1-benzylpyrazol-5-yl)benzene

3a. Methyl 5-(4-(methylthiophenyl)-1-benzylpyrazole-3-carboxylate

[1176] A mixture of the product Example 1d (2 g, 7.9 mmol) and benzylhydrazine hydrochloride (1.64 g, 10.3 mmol) in methanol (40 mL) and trifluoroacetic acid (0.5 mL) was heated at 70° C. for 2 hours and cooled to room temperature. The mixture was made basic with 5% Na2CO3 and extracted with EtOAc which was then washed with saturated NaHCO3 and water. The organic extracts were dried over Na2SO4 and the solvent was evaporated. The residue was recrystallized from CH2Cl2 / EtOAc / Hex to give the title compound as a white solid (1.88 g, 70%); mp 94-96° C. 1H NMR (300 MHz, CDCl3) δ 7.12-7.30 (m, 7H), 7.00-7.08 (m, 2H), 6.87 (s, 1H), 5.41 (s, 2H), 3.95 (s, 3H), 2.50 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 163.0, 145.2, 143.1, 140.6, 136.7, 129.4, 128.8, 127.9, 126.9, 126.3, 126.0, 109.4, 54.2, 52.2, 15.4; mass spectrum (API-TIS) m / z 339 (MH+), 307 (M-OCH3); Ana...

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