Ciba-geigy Corporation

Novartis Corporation

Lawrence J MacPherson

David Thomas Parker

James L Stanton

Arco Yingcheu Jeng

Philippe G Nantermet

The present invention relates to the alpha-(N-substituted pyrrolidinyl and piperidinyl) alpha-(arysulfonamido)-aceto-hydroxamic acids of formula I ##STR1## wherein R represents acyl derived from a carboxylic acid, from a carbonic acid or from a carbamic acid; or R represents (lower alkyl, aryl-lower alkyl or aryl)-sulfonyl, di-(aryl-lower alkyl or alkyl)-aminosulfonyl, or aryl-lower alkyl; Ar represents carbocyclic aryl, heterocyclic aryl or biaryl; R.sub.1 and R.sub.2 represent independently hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, acyloxy, lower alkoxy-lower alkoxy, trifluoromethyl or cyano; or R.sub.1 and R.sub.2 together on adjacent carbon atoms represent lower alkylenedioxy; m represents zero or one; n represents an integer from 1 to 5; pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; further to a process for the preparation of these compounds, to pharmaceutical compositions comprising these compounds, to the use of these compounds for the therapeutic treatment of the human or animal body or for the manufacture of a pharmaceutical composition.

Certain alpha-azacycloalkyl substituted arylsulfonamido acetohydroxamic

Disclosed are the compounds of formula I ##STR1## wherein R and R.sub.1 together with the chain to which they are attached or R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a ring; pharmaceutically acceptable prodrug derivatives and pharmaceutically salts thereof; methods of preparation thereof; pharmaceutical compositions comprising said compounds; and a method of inhibiting matrix-degrading metalloproteinase and of treating matrix-degrading metalloproteinase dependent conditions in mammals using such compounds.

Arylsulfonamido-substituted hydrodxamic acids

Disclosed are compounds of formula I ##STR1## wherein R, R.sub.1, R.sub.2 and Ar have meanings as defined; pharmaceutically acceptable prodrug derivatives and pharmaceutically acceptable salts thereof; methods for preparation thereof; pharmaceutical compositions comprising said compounds; and methods of inhibiting matrix-degrading metalloproteinase and of treating matrix-degrading metalloproteinase dependent conditions in mammals using such compounds.

Arylsulfonamido-substituted hydroxamix acids

The invention relates to the compounds of formula I ##STR1## pharmaceutically acceptable prodrug derivatives and pharmaceutically acceptable salts thereof; methods for preparation thereof; pharmaceutical compositions comprising said compounds; and a method of inhibiting matrix-degrading metalloproteinase and of treating matrix-degrading metalloproteinase dependent conditions in mammals using such compounds.

Arylsulfonamido-substituted hydroxamic acids

The invention relates to a method of inhibiting metalloellastase activity, of inhibiting the degradation of elastin, or of treating macrophage metalloelastase dependent conditions in mammals which comprises administering to a mammal in need thereof an effective macrophage metalloelastase inhibiting amount of a compound of formula I ##STR1## wherein Ar, R, R.sub.1 and R.sub.2 have meanings as defined, or of a pharmaceutically acceptable prodrug derivative thereof, or of a pharmaceutically acceptable salt thereof, or of pharmaceutical compositions comprising a said compound.

Arylsufonamido-substituted hydroxamic acids

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.

The invention relates to macrocyclic lactam derivatives of formula I ##STR1## wherin R is hydrogen or acyl; m is an integer from 4 to 9 inclusive; n is 1 or 2; p is zero, 1 or 2; X is --CONH-- or --NHCO--; Y is S, O or CH.sub.2 ; R.sub.1 is --COOH; or R.sub.1 is ##STR2## in which R.sub.2 is hydrogen, lower alkyl, aryl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, mercapto-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, or carboxy-lower alkyl, R.sub.3 is hydrogen or lower alkyl, and q is zero or an integer from 1 to 5 inclusive; or R.sub.1 is ##STR3## in which R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy or acyloxy, and r is 1 or 2; or R.sub.1 is ##STR4## in which s is 1 or 2; or R.sub.1 is ##STR5## in which R.sub.5 and R.sub.6 independently represent hydrogen, lower alkyl, C.sub.5 - or C.sub.6 -cycloalkyl, (hydroxy-, acyloxy or lower alkoxy-) lower alkyl, carbocyclic or heterocyclic monocyclic aryl, or (hydroxy-, acyloxy- or alkoxy-) lower alkyloxy-lower alkyl; or R.sub.5 and R.sub.6 together with the nitrogen to which they are attached represent pyrrolidino, piperidino, morpholino, piperazino or N-alkylpiperazino; and macrocyclic sulfur and oxygen containing lactam ring isomers in which a CH.sub.2 group of (CH.sub.2).sub.m in formula I is is replaced by O or S, and Y represents CH.sub.2 ; and pharmaceutically acceptable prodrug esters of any above said compound with a free carboxyl group; and pharmaceutically acceptable salts of any said compounds with a free acid or basic salt forming group; pharmaceutical compositions comprising said compounds; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.

Certain macrocyclic lactam derivatives

The invention relates to macrocyclic lactam derivatives of formula I ##STR1## wherein R is hydrogen or acyl; m is an integer from 4 to 9 inclusive; n is 1 or 2; p is zero, 1 or 2; X is --CONH-- or --NHCO--; Y is S, O or CH.sub.2 ; R.sub.1 is --COOH; or R.sub.1 is ##STR2## in which R.sub.2 is hydrogen, lower alkyl, aryl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, mercapto-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, or carboxy-lower alkyl, R.sub.3 is hydrogen or lower alkyl, and q is zero or an integer from 1 to 5 inclusive; or R.sub.1 is ##STR3## in which R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy or acyloxy, and r is 1 or 2; or R.sub.1 is ##STR4## in which s is 1 or 2; or R.sub.1 is ##STR5## in which R.sub.5 and R.sub.6 independently represent hydrogen, lower alkyl, C.sub.5 - or C.sub.6 -cycloalkyl, (hydroxy-, acyloxy or lower alkoxy-) lower alkyl, carbocyclic or heterocyclic monocyclic aryl, or (hydroxy-, acyloxy- or alkoxy-) lower alkyloxy-lower alkyl; or R.sub.5 and R.sub.6 together with the nitrogen to which they are attached represent pyrrolidino, piperidino, morpholino, piperazino or N-alkylpiperazino; and macrocyclic sulfur and oxygen containing lactam ring isomers in which a CH.sub.2 group of (CH.sub.2).sub.m in formula I is replaced by O or S, and Y represents CH.sub.2 ; and pharmaceutically acceptable prodrug esters of any above said compound with a free carboxyl group; and pharmaceutically acceptable salts of any said compounds with a free acid or basic salt forming group; pharmaceutical compositions comprising said compounds; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.

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Hampton, NJ, United States of America

Lawrence J MacPherson