Bis-sulfonomides hydroxamic acids as MMP inhibitors

A compound, butanamide technology, applied in the direction of amide active ingredients, medical preparations containing active ingredients, drug combinations, etc., can solve the problem of no treatment method for preventing tissue damage and the like

Inactive Publication Date: 2000-02-02
PHARMACIA & UPJOHN CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Despite the high incidence of these diseases in develo...

Method used

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  • Bis-sulfonomides hydroxamic acids as MMP inhibitors

Examples

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preparation example Construction

[0028] The compound of the present invention can be prepared according to any one of the following two preparation methods. When the two sulfonamide groups are the same, the steps outlined in Scheme A are used. When the sulfonamide groups are different, the steps outlined in Scheme B are used.

[0029] As shown in Scheme A, bissulfonamide 2 can be prepared from amino acid 1 by the method described in the Proceedings of the American Chemical Society, Volume 59, Page 1116 (1937). Simply put, in the presence of 1N sodium hydroxide, the amino acid 1 is exposed to a predetermined at least 2 equivalents of sulfonyl chloride to obtain bissulfonamide 2. The starting reactant, amino acid 1, can be either a commercially available product or can be conveniently prepared according to the method disclosed in the Journal of the Chemical Society (English), No. 1564 (1939). Disulfonamide 2 reacts with a peptide coupling agent in the presence of o-benzyl hydroxylamine hydrochloride, 4-methylmorpho...

Embodiment 1

[0039] The following related examples can better understand the compounds and their preparations of the present invention. The purpose of the examples is to illustrate the present invention but does not limit the scope of protection of the present invention. Example 1 of N-hydroxy-2,4-bis-[[4-methylphenylsulfonyl]amino]butyramide

[0040] preparation Step 1. Preparation of 2,4-bis-[[4-methylphenylsulfonyl]amino]butyric acid

[0041] At room temperature, to a solution of 5.00g (26.2mmol) 2,4-diaminobutyric acid dihydrochloride and 130ml (130mmol) 1N sodium hydroxide was added 11.0g (57.6mmol) in 130ml ether at a time. Toluenesulfonyl chloride solution. The two-layer solution was stirred at room temperature for 16 hours. Separate the ether layer and acidify the aqueous layer to pH 2. The solid was collected, washed with water, air dried, and dried at 50°C under high vacuum. The product was crystallized from isopropanol / pentane to obtain 4.33 g of the title comp...

Embodiment 2

[0046] The o-benzyl hydroxamic acid intermediate (0.50 g, 0.94 mmol) and 0.10 g Pearlman's catalyst were hydrogenated in 75 ml methanol under 5 psi conditions for 2.5 hours. The mixture was filtered through Celite, the filtrate was evaporated, and the product was dried under vacuum to obtain 0.395 g of the title compound. 1 H NMR(CDCl 3 ) 1.88, 2.32, 2.35, 4.01, 7.21, 7.7; MS m / z[MH + ]442. Example 2. (R)-N-hydroxy-2,4-bis-[[4-methylphenylsulfonyl]amino]butyryl

[0047] Preparation of amine

[0048] According to the conventional method of Example 1 without important changes, but with (R)-2,4-diaminobutyric acid as the starting reactant, the title compound (melting point: 152-153°C) was prepared. [α] D =-8°(DMSO); 1 H NMR(DMSO) 1.54, 2.35, 2.37, 3.3, 7.28-7.36, 7.57; MS[MH + ]m / z 442.

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Abstract

The present invention provides a compound of formula (I) or pharmaceutically acceptable salts thereof wherein R<1> and R<2> are the same or different and are C1-10alkyl, phenyl, hetero-aryl, or phenyl substituted with C1-4alkyl, OR<3>, NHR<3>, CONHR<3>, NHCOR<3>, or halo; wherein R<3> is H, or C1-4alkyl; and n is 1, 2, 3, 4, 5 or 6. The compounds are inhibitors of matrix metalloproteinases involved in tissue degradation.

Description

Invention field [0001] The present invention relates to novel bissulfonamide hydroxamic acid compounds, pharmaceutical compositions containing them, and application methods of these compounds. Specifically, the compounds of the present invention are inhibitors of matrix metalloproteinases involved in tissue degradation. Background of the invention [0002] Connective tissue loses its integrity during many diseases, including: osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenia (such as osteoporosis), tumor metastasis (invasion and growth) ), periodontitis, gingivitis, corneal ulcer, skin ulcer, gastric ulcer and other diseases related to the degradation of connective tissue. Although the above-mentioned diseases have a high incidence in developed countries, there is no treatment to prevent tissue damage. A series of important scientific evidence shows that the above-mentioned damage is attributed to the uncontrolled activity of connective matrix...

Claims

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Application Information

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IPC IPC(8): A61P1/02A61K31/18A61K31/255A61P1/04A61P17/02A61P19/02A61P19/10A61P27/02A61P35/04C07C311/19C07C311/29
CPCC07C311/19C07C311/29A61P1/02A61P1/04A61P17/02A61P19/02A61P19/10A61P27/02A61P35/04
Inventor E·J·加科森L·L·斯卡勒策凯
Owner PHARMACIA & UPJOHN CO
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