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Alpha-hydroxy, amino and -fluoro derivatives of beta-sulphenyl hydroxamic acids matrix metalloproteinases inhibitors

A hydroxyl and alkyl technology, applied in the field of α-hydroxyl, amino and halogenated derivatives, can solve problems such as no tissue damage

Inactive Publication Date: 2000-12-27
PHARMACIA & UPJOHN CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the high incidence of these diseases in developed countries, there is still no treatment to prevent the tissue damage they produce

Method used

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  • Alpha-hydroxy, amino and -fluoro derivatives of beta-sulphenyl hydroxamic acids matrix metalloproteinases inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] It will be beneficial to further understand the compound of the present invention and its preparation in combination with the following examples, and these examples are only illustrative and do not limit the scope of the present invention. Example 1 Preparation Step 1 of N-hydroxyl-2-hydroxyl-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-phenylbenzenesulfonyl)propanamide 2-[(4- Preparation of ethyl methoxyphenylthio)methyl]acrylate

[0179] To a mixture of ethyl bromomethacrylate (1.6 g, 8.3 mmol) and 1.0 ml (8.1 mmol) of 4-methoxythiophenol in ethanol cooled in an ice bath, gradually 8 ml of 1M aqueous sodium bicarbonate solution was added dropwise. The reaction mixture was warmed to room temperature and stirred for 6 hours. The mixture was then concentrated, extracted with ethyl acetate, and washed twice with 10% aqueous hydrochloric acid and once with brine; then, it was dried over sodium sulfate and evaporated in vacuo to give a pale yellow oil. Chromatography on sil...

Embodiment 2

[0191] Chiral chromatography was accomplished with a preparative Chiralpak AD column 5.0 x 50 cm eluting with methanol at 70 ml / min. The two samples resulting from the above chromatography were separately dissolved in methanol, stirred with charcoal, filtered through celite, and evaporated to dryness to give purified enantiomer A and enantiomer B. The preparation of embodiment 2N-hydroxyl-2-hydroxyl-2-[(4-methoxybenzenesulfonyl) methyl]-3-(4-fluorobenzenesulfonyl) propanamide

[0192] Following the general procedure outlined in Example 1 (Steps 1 to 7) with non-critical changes, except that p-fluorophenylthiol was used instead of biphenylthiol in Step 3 and stirred together, the title compound was obtained. m.p.85-90°C (softening), 110-115°C (decomposition under bubbling conditions);

[0193] 1 H NMR (DMSO-d 6 )δ10.6, 8.86, 7.92-7.87, 7.75-7.72, 7.46-7.40, 7.11-7.08,

[0194] 5.64, 3.85-3.69. Preparation of Example 3 N-hydroxyl-2-hydroxyl-2-[(4-methoxybenzenesulfonyl)methy...

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Abstract

The present invention provides a compound of formula (I), or pharmaceutical acceptable salts thereof wherein R1 is C4-12 alkyl, C4-12 alkenyl, C4-12 alkynyl, -(CH2)h-C3-8 cycloalkyl, substituted and unsubstituted -(CH2)h-aryl, substituted and unsubstituted-(CH2)h-het, R2 is substituted and unsubstituted C1-12 alkyl, substituted and unsubstituted C2-12 alkenyl, substituted and unsubstituted C2-12 alkynyl, substituted and unsubstituted-(CH2)h-C3-8 cycloakyl, substituted and unsubstituted -(CH2)h-C3-8 cycloalkenyl, substituted and unsubstituted -(CH2)h-aryl, substituted and unsubstituted -(CH2)h-heterocyclic ring, substituted and unsubstituted -(CH2)i-X-R4 (X is -O-, -S(=O)j-, -NR7-, -S(=O)2NR8-, or -C(=O)-), and -(CH2)iCHR5R6. The compounds are inhibitors of matrix metalloproteinases involved in tissue degradation.

Description

[0001] The present invention relates to novel α-hydroxyl, amino and halogenated derivatives of β-sulfonyl hydroxamic acid, as well as pharmaceutical compositions containing said derivatives and methods of use of said derivatives; the compounds of the present invention are related to tissue degradation Inhibitors of matrix metalloproteinases. Background technique [0002] Loss of connective tissue integrity occurs in many disease processes, including osteoarthritis, rheumatoid arthritis, septic arthritis, aneutrophic bone diseases exemplified by osteoporosis, neoplastic metastasis (invasion and growth ), periodontitis, gingivitis, corneal ulcers, skin ulcers, gastric ulcers, inflammation, asthma and other diseases related to the degradation of connective tissue. Despite the high incidence of these diseases in developed countries, there are no treatments to prevent the tissue damage they cause. Significant scientific evidence demonstrates that the uncontrolled activity of conne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D253/06A61K31/16A61K31/165A61K31/41A61K31/4164A61K31/4166A61K31/42A61K31/426A61K31/433A61K31/4402A61K31/4409A61K31/4418A61K31/4427A61K31/4439A61K31/496A61K31/5025A61K31/53A61P1/02A61P1/04A61P11/06A61P13/00A61P13/10A61P17/02A61P29/00A61P35/04A61P43/00C07C317/46C07C317/50C07D213/52C07D213/68C07D213/70C07D233/64C07D233/74C07D233/84C07D257/04C07D261/08C07D277/20C07D277/40C07D285/12C07D401/12C07D487/04
CPCC07C2101/08C07C317/50C07C317/46C07C2601/08A61P1/02A61P1/04A61P11/06A61P13/00A61P13/10A61P17/02A61P19/00A61P19/04A61P29/00A61P35/04A61P43/00C07C317/44
Inventor 马萨·A·沃普霍斯金马克·艾伦·米切尔唐纳德·E·哈珀琳达·路易斯·马乔拉
Owner PHARMACIA & UPJOHN CO
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