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N-hydroxy-2-(alkyl, aryl or heteroaryl sulfanyl, sulfinyl or sulfonyl-3-substituted-alkyl, aryl or heteroarylamides) as matrix metallo protein inhibitors

A technology of heteroaryl and alkyl, applied in the direction of active ingredients of amides, anti-inflammatory agents, metabolic diseases, etc., can solve problems such as bioavailability and pharmacokinetics, limit clinical effects, etc.

Inactive Publication Date: 2001-04-11
WYETH HOLDINGS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although various MMP and TACE inhibitors have been identified and disclosed in the literature, many of these molecules are peptides and peptide analogs that have bioavailability and pharmacokinetic issues that limit their clinical effectiveness

Method used

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  • N-hydroxy-2-(alkyl, aryl or heteroaryl sulfanyl, sulfinyl or sulfonyl-3-substituted-alkyl, aryl or heteroarylamides) as matrix metallo protein inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide

[0112] To a stirred solution of 4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in anhydrous acetone (100 mL) in a round bottom flask was added 2-bromo-propionic acid Ethyl ester (3.6 g, 20 mmol), and the reaction mixture was heated at reflux for 8 hours with good stirring. Finally, the reaction was cooled and the potassium salt was filtered off, and the above reaction mixture was concentrated. The residue was extracted with chloroform and washed with water and 0.5N sodium hydroxide solution. The organic layer was further washed extensively with water, dried over magnesium sulfate, filtered and concentrated to give ethyl 2-(4-methoxy-phenylsulfanyl)-propionate as a light yellow oil. Yield 4.5 g (94%); MS; 241 (M+H) + .

[0113] To a stirred solution of ethyl 2-(4-methoxy-phenylsulfanyl)-propionate (2.44 g, 10 mmol) in THF (100 ml) at -4°C, slowly add b...

Embodiment 2

[0117] N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide

[0118] Ethyl 2-(4-methoxyphenylsulfanyl)-phenylacetate was prepared according to the general procedure described in Example 1. Starting from ethyl α-bromophenylacetate (7.18 g, 31.4 mmol) and 4-methoxythiophenol (4.4 g, 31.4 mmol), 8 was isolated as a pale yellow oil. 5 g of product. Yield 90%; MS: 303.1 (M+H) + .

[0119] First, 2-(4-methoxy-phenylsulfanyl)-phenyl-acetic acid ethyl ester (3.0 g, 10 mmol) was dissolved in methanol (50 ml) and 10N sodium hydroxide (20 ml) to prepare 2- (4-Methoxy-phenylsulfanyl)-2-phenylacetic acid. The resulting reaction mixture was worked up as in Example 1. Yield 1.9 g, 70%. Low melting solid. MS: 273(M+H) + .

[0120] Using 2-(4-methoxy-phenylsulfanyl)-2-phenylacetic acid (1.05 g, 3.83 mmol) as raw material, according to the method described in the examples, 154 mg of N was isolated as a colorless solid. -Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetam...

Embodiment 3

[0122] 2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide

[0123] According to the method in the second paragraph of Example 1, 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester was prepared. Using ethyl (4-methoxy-phenylsulfanyl)-propionate (3.5 g, 14.3 mmol) and isoprene bromide (2.25 g, 15 mmol) as starting materials, 2.2 g of The product of an oily substance. Yield 50%; MS: 310(M+H) + .

[0124] First, ethyl 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoate (2.0 g, 6.4 mmol) was dissolved in methanol (50 ml) and 2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid was prepared in 10N sodium hydroxide (20ml). The resulting reaction mixture was worked up as described in Example 1. Yield of low melting solid was 1.9 g, 99%. MS: 280(M+H) + .

[0125] Using 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid (1.67g, 5.8mmol) as raw material, according to the method described in the examples, 1.5 g of 2-(4...

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Abstract

Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. TNF-alpha converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the formation of TNF-alpha from membrane bound TNF-alpha precursor protein. It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. The present invention provides low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-alpha converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection having the formula wherein R2 and R3 form a heterocyclic ring and A is S, S(O), or S(O)2, and R1 and R4 are defined herein.

Description

Background of the invention [0001] Matrix metalloproteinases (MMPs) are a group of enzymes involved in the pathological destruction of connective tissue and basement membrane. These zinc-containing endopeptidases consist of several subtypes of enzymes, including collagenases, stromelysins, and gelatinases. Among these enzymes, gelatinase has been shown to be the MMP enzyme most closely related to the growth and spread of tumors. Gelatinase is known to be expressed at elevated levels in malignant tumors, and gelatinase can degrade basement membranes, leading to tumor metastasis. Angiogenesis required for the growth of solid tumors has also recently been demonstrated to have a gelatinase component in their pathology. Additionally, there is evidence that gelatinase is involved in plaque rupture associated with atherosclerosis. Other diseases mediated by MMPs include restenosis, MMP-mediated osteopenia, central nervous system inflammatory diseases, skin aging, tumor growth, ost...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/08A61K31/16A61K31/351A61K31/381A61K31/403A61K31/4035A61K31/423A61K31/426A61K31/428A61K31/4406A61K31/4418A61K31/4427A61K31/4433A61K31/4436A61K31/445A61K31/4453A61K31/4458A61K31/4535A61K31/454A61K31/4545A61K31/47A61K31/5375A61K31/5377A61K31/55A61P1/02A61P1/04A61P1/16A61P7/02A61P9/00A61P9/10A61P13/12A61P15/06A61P17/00A61P17/02A61P19/02A61P19/08A61P27/02A61P29/00A61P35/00A61P35/04A61P43/00C07C259/06C07C317/44C07C323/60C07D207/12C07D209/48C07D211/12C07D211/20C07D211/54C07D211/62C07D211/66C07D213/56C07D215/12C07D223/02C07D241/04C07D263/58C07D277/20C07D277/36C07D277/70C07D295/092C07D307/54C07D309/12C07D333/28C07D333/34C07D401/10C07D409/04C07D409/10
CPCC07D211/20C07D211/54C07D211/62C07D295/088A61P1/02A61P1/04A61P1/16A61P13/12A61P15/06A61P17/00A61P17/02A61P19/00A61P19/02A61P19/08A61P27/02A61P29/00A61P31/18A61P35/00A61P35/04A61P43/00A61P5/10A61P7/02A61P9/00A61P9/10A61P3/10C07C239/14
Inventor A·M·文卡特桑G·T·格罗苏J·M·达维斯J·L·巴克尔J·I·莱文
Owner WYETH HOLDINGS CORP
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