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AssigneeWarner-Lambert Company
InventorsNicole Chantel Barvian, Patrick Michael O'Brien, William Chester Patt, Drago Robert Sliskovic
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Inhibitors of MMP enzymes are cyclic sulfonamides of Formula I or a pharmaceutically acceptable salt thereof, and cyclic sulfonamides of Formula III or a pharmaceutically acceptable salt thereof, wherein R1 and R2 include hydrogen, alkyl, and substituted alkyl; R3 and R4 include hydrogen, halo, and alkyl; X is OH or NHOH: Z is (CH2)n: and Y is S, SO or SO2. The compounds of Formulas I and III are useful for the treatment of diseases mediated by an MMP enzyme, including cancer, osteoarthritis, rheumatoid arthritis, heart failure, and inflammation.
A compound of Formula I
A compound of Formula II
A compound selected from:
A compound of Formula III
A compound of Formula IV
A compound selected from:
Dependencies are inferred from the claim text.
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From the US filing history. Foreign family members aren’t listed.
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
Drugs for disorders of the cardiovascular system
Drugs for disorders of the cardiovascular system: inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Drugs for skeletal disorders
Term ended 9 Mar 2022 (estimated)
This invention relates to a group of biphenyl sulfonamide compounds and derivatives which inhibit matrix metalloproteinase enzymes and thus are useful for treating diseases resulting from connective tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
Matrix metalloproteinases (sometimes referred to as MMPs) are naturally-occurring enzymes found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and inhibitors of MMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP) family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and other newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65). These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis. A method for preventing and treating these and other diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
(a) To a stirred solution of 3(S)-2,2-dimethyl-3-thiomorpholine carboxylic acid, 1,1-dimethylethyl ester hydrochloride (11.5 g, 0.049 mol) in pyridine (100 mL), cooled to 0° C., was added in portions over 15 minutes 4′-bromo-4-biphenylsulfonyl chloride (15 g, 0.045 mol). The solution was stirred at 0° C. for 4 hours, then concentrated in vacuo. The crude product was partitioned between aq. HCl (1 M) and ethyl acetate, the layers separated, and the organic phase was washed with aq. HCl (1 M), dried (MgSO4), and concentrated. The resulting orange liquid was diluted with chloroform and passed through a pad of silica gel. Fractions containing the product were combined and concentrated to give a colorless liquid. Trituration with petroleum ether/diethyl ether (9:1) yielded a white solid (13.5 g, 57%). 1HNMR (CDCl3) δ 7.8 (d, 2H), 7.6 (m, 4H), 7.4 (d, 2H), 4.3 (s, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.2 (m, 1H), 2.4 (m, 1H), 1.6 (s, 3H0, 1.3 (s, 3H), 1.2 (s, 9H) ppm.
(b) The ester obtained in (a) (13.5 g, 0.026 mol) was added in portions to a solution of anisole (2.8 g, 0.026 mol) in trifluoroacetic acid (100 mL). The solution was stirred at room temperature for 3 hours, and then poured over ice. The resulting precipitate was collected by filtration and oven-dried (40° C.). The crude product was triturated with petroleum ether/diethyl ether (4: 1) to give the carboxylic acid as a white solid. Yield: 11 g (90%); mp 178-180° C.; 1HNMR (DMSO-d6) δ 12.8 (bs, 1H), 7.9 (d, 2H), 7.8 (d, 2H), 7.7 (s, 4H), 4.3 (s, 1H), 3.9 (m, 1H), 3.7 (m, 1H), 2.9 (m, 1H), 2.5 (m, 1H), 1.4 (s, 3H), 1.2 (s, 3H) ppm.
The carboxylic acid obtained in Example 1 (12.2 g, 0.026 mol) was diluted with dichloromethane (150 mL) and oxalyl chloride (16.5 g, 0.13 mol). N,N-Dimethylformamide was added as a catalyst. The solution was stirred at room temperature for 14 hours, at which time the solvent was concentrated in vacuo. The crude acid chloride was triturated with hexane and collected by filtration. The solid was diluted with tetrahydrofuran (75 mL) and added dropwise to a mixture of hydroxylamine hydrochloride (9 g, 0.13 mol) and sodium bicarbonate (16.4 g, 0.19 mol) in tetrahydrofuran (150 mL)/water (75 mL) cooled to 0° C. The reaction mixture gradually warmed to room temperature and was stirred for 14 hours. Ethyl acetate and aq. HCl (1M) were added, the layers were separated, and the organic portion was washed with brine, dried (MgSO4), and concentrated. The resulting viscous liquid yielded a white solid (11.4 g, 90%) upon treatment with cold diethyl ether/petroleum ether (4:1), mp 190-192° C.; 1HNMR (DMSO-d6) δ 10.7 (s, 1H), 8.9 (s, 1H), 4.1 (s, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 2.9 (m, 1H), 2.5 (m, 1H), 1.4, (s, 3H), 1.1 (s, 3H) ppm.