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Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases

A compound, phenyl technology, applied in the field of drug therapy, can solve the problem of affecting the phenotype of adjacent glomerular mesangial cells

Inactive Publication Date: 2001-08-29
WARNER-LAMBERT CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although MMP-2 specifically degrades the outer ECM, it can also affect the phenotype of adjacent mesangial cells

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0304] (R)3-Methyl-2-(6,7,8,9-tetrahydro-oxyfluorene-3-sulfonylamino)-butyric acid

[0305] Step (a): Preparation of 6,7,8,9-tetrahydro-oxyfluorene-3-sulfonic acid

[0306] To a solution of tetrahydrofluorene (4 g, 0.023 mol) in dichloroethane (50 mL) was added sulfur dioxide-DMF complex (6 g, 0.039 mol) in one portion. The reaction mixture was refluxed for 14 hours, cooled and concentrated in vacuo. The resulting crude liquid was dissolved in warm diethyl ether / ethanol and precipitated upon cooling. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound as a pink solid (2.3 g, 40%). 1 HNMR (CDCl 3 )δ7.9(s,1H),7.7(d,1H),7.4(d,1H),2.8(m,2H),2.6(m,2H),2.0-1.8(m,4H)ppm.

[0307] Step (b): Preparation of 6,7,8,9-tetrahydro-oxyfluorene-3-sulfonyl chloride

[0308] 6,7,8,9-Tetrahydrooxyfluorene-3-sulfonic acid (2.1 g, 8.3 mmol) was suspended in thionyl chloride (25 mL) and stirred at room temperature for 6 hours. The so...

Embodiment 2

[0315] (S) 3-Methyl-2-(6,7,8,9-tetrahydro-oxyfluorene-3-sulfonylamino)-butanoic acid; mp 162-165°C. 1 HNMR (CDCl 3 )δ7.9(s,1H),7.7(d,1H),7.5(d,1H),5.1(d,1H),3.8(dd,1H),2.8(m,2H),2.6(m,2H ),2.1(m,1H),2.0-1.8(m,4H),0.9(d,3H),0.8(d,3H)ppm.

Embodiment 3

[0317] (S) 2-(6,7,8,9-Tetrahydro-oxyfluorene-3-sulfonylamino)-succinic acid; mp 176-179°C. 1 HNMR (CDCl 3 / DMSO -d 6 )δ7.8(s,1H),7.6(d,1H),7.4(d,1H),5.9(d,1H),3.9(m,1H),2.9-2.5(m,7H),1.9-1.7 (m, 4H)ppm. Using a method similar to that described in Example 1, but replacing D-valine and tert-butyl ester with L-homophenylalanine and methyl ester, and utilizing alkali hydrolysis to prepare the following Compound:

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PUM

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Abstract

Tricyclic sulfonamide compounds and derivatives are described as well as methods for the preparation and pharmaceutical compositions of same, which are useful as inhibitors of matrix metalloproteinases, particularly gelatinase A, collagenase-3, and stromelysin-1 and for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurysm, heart failure, left ventricular dilation, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound healing, cancer, inflammation, pain, arthritis, osteoporosis, renal disease, or other autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson's disease, Huntington's disease, prion diseases, myasthenia gravis, and Duchenne's muscular dystrophy.

Description

Background of the invention [0001] The present invention relates to novel tricyclic sulfonamide compounds and their derivatives used as medicines, their preparation methods, pharmaceutical compositions comprising these compounds and pharmaceutically acceptable carriers, and medical treatment methods. The novel compounds of the present invention are inhibitors of matrix metalloproteinases such as gelatinase A (MMP-2), collagenase-3 (MMP-13) and stromelysin-1 (MMP-2). More specifically, the novel compounds of the present invention are useful in the treatment of atherosclerotic plaque rupture, aortic aneurysm, heart failure, left ventricular dilatation, restenosis, periodontal disease, corneal ulcer, burn management, decubitus ulcer, wound repair , cancer, inflammation, pain, arthritis, osteoporosis, multiple sclerosis, kidney disease, and other autoimmune or inflammatory diseases that depend on tissue invasion by leukocytes or other activated mobile cells. In addition, the comp...

Claims

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Application Information

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IPC IPC(8): A61K31/18A61K31/198A61K31/34A61K31/343A61K31/38A61K31/381A61K31/403A61K31/4035A61K31/404A61K31/4178A61P1/02A61P9/04A61P9/10A61P13/12A61P17/02A61P19/02A61P19/10A61P21/04A61P25/04A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/18A61P35/00A61P37/00A61P43/00C07C311/19C07C311/21C07D209/88C07D307/91C07D307/93C07D333/76C07D405/04C07D405/12H04M15/00H04M15/28H04M15/30
CPCH04M15/28H04M15/30H04M15/49H04M2215/42H04M2215/82H04M2215/0168H04M15/8044C07D307/93C07C311/21C07D405/04H04M2215/96H04M2215/92C07D307/91C07D333/76H04M2215/46H04M15/00H04M15/31H04M2215/745H04M15/83C07D209/88A61P1/02A61P13/12A61P17/02A61P19/02A61P19/10A61P21/04A61P25/04A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/18A61P35/00A61P37/00A61P43/00A61P9/04A61P9/10
Inventor P·M·欧布瑞恩J·A·皮卡德D·R·斯利思科维克
Owner WARNER-LAMBERT CO
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