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Last Updated: March 28, 2024

Claims for Patent: 5,455,258


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Summary for Patent: 5,455,258
Title: Arylsulfonamido-substituted hydroxamic acids
Abstract:Particularly the invention relates to the compounds of formula I ##STR1## (a) wherein Ar is carbocyclic or heterocyclic aryl; R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, amino, mono- or di-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-aryl-lower alkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl; R.sub.1 is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, (carbocyclic or heterocyclic aryl)-lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, (N-lower alkyl-piperazino or N-aryl-lower alkylpiperazino)-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl, acylamino-lower alkyl, piperidyl or N-lower alkylpiperidyl; R.sub.2 is hydrogen or lower alkyl; pharmaceutically acceptable prodrug derivatives; and pharmaceutically acceptable salts thereof.
Inventor(s): MacPherson; Lawrence J. (Hampton, NJ), Parker; David T. (Livingston, NJ)
Assignee: Ciba-Geigy Corporation (Ardsley, NY)
Application Number:08/001,136
Patent Claims:1. A compound of the formula I ##STR13## wherein Ar is carbocyclic or heterocyclic aryl;

R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, amino, mono- or di-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-aryl-lower alkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl;

R.sub.1 is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, (carbocyclic or heterocyclic aryl)-lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, (N-lower alkyl-piperazino or N-aryl-lower alkylpiperazino)-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl, acylamino-lower alkyl, piperidyl or N-lower alkylpiperidyl;

R.sub.2 is hydrogen or lower alkyl;

and wherein in the above definitions aryl represents monocyclic or bicyclic aryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclic aryl and heterocyclic aryl represents monocyclic or bicyclic heterocyclic aryl; a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein Ar is phenyl or phenyl mono-, di- or tri-substituted by C.sub.1 -C.sub.10 -alkoxy, hydroxy, aryl-lower alkoxy, C.sub.3 -C.sub.7 -cycloalkyl-lower alkoxy, (lower alkyl, aryl-lower alkyl or C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl)-thio, lower alkyloxy-lower alkoxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl-(sulfinyl or sulfonyl), amino or mono- or di-lower alkylamino; or Ar is phenyl substituted on adjacent carbon atoms by C.sub.1 -C.sub.2 -alkylene-dioxy or oxy-C.sub.2 -C.sub.3 -alkylene; or Ar is thienyl or thienyl substituted by lower alkyl.

3. A compound according to claim 1 of the formula ##STR14## wherein R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, amino, mono- or di-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-aryl-lower alkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino or N-lower alkylpiperidyl)-lower alkyl;

R.sub.1 is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C.sub.5 -C.sub.7 -cycloalkyl, C.sub.5 -C.sub.7 -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, (N-lower alkyl-piperazino or N-aryl-lower alkylpiperazino)-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl, piperidyl, N-lower alkylpiperidyl, or acylamino-lower alkyl represented by R.sub.3 -CONH-lower alkyl;

R.sub.2 is hydrogen;

R.sub.3 in R.sub.3 -CONH-lower alkyl is lower alkyl, carbocyclic or heterocyclic aryl, di-lower alkylamino, N-lower alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, N-alkylpiperidyl, or (di-lower alkylamino, N-lower alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, pyridyl or N-lower alkylpiperidyl)-lower alkyl;

R.sub.4 is hydrogen, lower alkoxy, hydroxy, aryl-lower alkoxy, lower alkythio or aryl-lower alkylthio, lower alkyloxy-lower alkoxy, halogen, trifluoromethyl, lower alkyl, nitro or cyano;

R.sub.5 is hydrogen, lower alkyl or halogen;

or R.sub.4 and R.sub.5 together on adjacent carbon atoms represent methylenedioxy, ethylenedioxy, oxyethylene, or oxypropylene; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 of formula III ##STR15## wherein R represents lower alkyl, trifluoromethyl, C.sub.5 -C.sub.7 -cycloalkyl, biaryl, carbocyclic monocyclic aryl or heterocyclic monocyclic aryl; R.sub.1 represents hydrogen, lower alkyl, C.sub.5 -C.sub.7 -cycloalkyl, monocyclic carbocyclic aryl, carbocyclic aryl-lower alkyl, heterocyclic aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, di-lower alkylamino-lower alkyl, (N-lower alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino)-lower alkyl or R.sub.3 -CONH-lower alkyl; R.sub.3 represents lower alkyl, carbocyclic aryl, heterocyclic aryl, di-lower alkylamino, N-lower alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, N-alkylpiperidyl, or (di-lower alkylamino, N-lower alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino or N-alkylpiperidyl)-lower alkyl; R.sub.4 represents lower alkoxy or aryl-lower alkoxy; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4 wherein R represents monocyclic carbocyclic aryl or monocyclic heterocyclic aryl.

6. A compound according to claim 4 wherein R represents heterocyclic monocyclic aryl selected from tetrazolyl, triazolyl, thiazolyl, imidazolyl and pyridyl, each optionally substituted by lower alkyl; or R represents phenyl or phenyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl; R.sub.1 represents lower alkyl, cyclohexyl, or R.sub.3 -CONH-lower alkyl wherein R.sub.3 represents (di-lower alkylamino, N-lower alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino or N-alkylpiperidyl)-lower alkyl; and R.sub.4 represents lower alkoxy or aryl-lower alkoxy.

7. A compound according to claim 4 wherein R represents 2- or 3-pyridyl or phenyl; R.sub.1 represents C.sub.1 -C.sub.4 -alkyl, cyclohexyl, or R.sub.3 -CONH-C.sub.1 -C.sub.4 -alkyl wherein R.sub.3 represents di-C.sub.1 -C.sub.4 -alkylamino-C.sub.1 -C.sub.4 -lower alkyl; and R.sub.4 represents lower alkoxy.

8. A compound according to claim 4 wherein the asymmetric carbon to which is attached R.sub.1 is assigned the (R)-configuration.

9. A compound according to claim 4 which is N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutan amide, a pharmaceutically acceptable prodrug derivative thereof or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 4 which is N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-2-cyclohexylac etamide, a pharmaceutically acceptable prodrug derivative thereof or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 4 which is N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanami de, a pharmaceutically acceptable prodrug derivative thereof or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 4 which is N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylg lycyl)amino] hexanamide hydrochloride, a pharmaceutically acceptable prodrug derivative thereof or a pharmaceutically acceptable salt thereof.

13. A matrix-degrading metalloproteinase inhibiting pharmaceutical composition comprising an effective matrix-degrading metalloproteinase inhibiting amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable carriers.

14. A method of treating matrix-degrading metalloproteinase dependent conditions in mammals which comprises administering to a mammal in need thereof an effective matrix-degrading metalloproteinase inhibiting amount of a compound of claim 1.

15. A method of treating stromelysin and collagenase dependent conditions in mammals which comprises administering to a mammal in need thereof an effective stromelysin and collagenase inhibiting amount of a compound of claim 4.

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