Inhibition of TNF production with matrix metaloproteinase inhibitors

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I) or formula (Ib):

• ##STR6## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 hydrogen, NH.sub.2, OH, SH, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylamino, C.sub.1 -C.sub.6 alkylthio or aryl(C.sub.1 -C.sub.6 alkyl) group or amino-C.sub.1 -C.sub.6 alkyl, hydroxy-C.sub.1 -C.sub.6 alkyl, mercapto-C.sub.1 -C.sub.6 alkyl or carboxy-C.sub.1 -C.sub.6 alkyl;
• R.sub.2 C.sub.2 -C.sub.5 alkyl;
• R.sub.3 the characteristic side chain a natural .alpha. amino acid, with the proviso that R.sub.3 is not H or methyl;
• R.sub.4 a group --CHBD wherein B is H or methyl and D is H or C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, di(C.sub.1 -C.sub.6 alkoxy)methyl, carboxy, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, arylmethoxycarbonyl, C.sub.1 -C.sub.5 alkylaminocarbonyl or arylaminocarbonyl, or B and D together form a trimethylene group;
• or R.sub.3 and B together form a group (CH.sub.2)n where n is an integer from 4-11 ;
• R.sub.5 H or methyl.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR7## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 hydrogen;
• R.sub.2 isobutyl;
• R.sub.3 isopropyl, 4-aminobutyl, n-butyl, 2-methylmercaptoethyl;
• R.sub.4 hydrogen, phenyl(C.sub.1 -C.sub.2 alkyl), or trifluoromethylphenyl(C.sub.1 -C.sub.2 alkyl);
• R.sub.5 hydrogen.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR8## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, phenyl, phenyl(C.sub.1 -C.sub.6 alkyl), or a group BSO.sub.n CH.sub.2 -wherein n is 0, 1 or 2 and B is hydrogen or a (C.sub.1 -C.sub.6) alkyl, phenyl, substituted phenyl, phenyl(C.sub.1 -C.sub.6)alkyl, or heterocyclyl group;
• R.sub.2 hydrogen atom or an (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, phenyl(C.sub.1 -C.sub.6)alkyl, cycloalkyl (C.sub.1 -C.sub.6)alkyl or cycloalkenyl (C.sub.1 -C.sub.6)alkyl group;
• R.sub.3 an amino acid residue or a (C.sub.1 -C.sub.6)alkyl, benzyl, (C.sub.1 -C.sub.6) alkoxy benzyl or benzyloxy (C.sub.1 -C.sub.6) alkyl group;
• R.sub.4 a group --(CH.sub.2).sub.n A wherein n is an integer from 1 to 6 and A represents the group --NH.sub.2, a substituted acyclic amine or a heterocyclic base;
• R.sub.5 a hydrogen atom or a methyl group.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR9## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 a group BSO.sub.n A-wherein n is 0, 1 or 2 and B is hydrogen or an alkyl, phenyl, phenylalkyl, heterocyclyl, alkylcarbonyl or phenacyl, and A represents a hydrocarbon chain optionally substituted with one or more alkyl or phenyl groups;
• R.sub.2 a hydrogen atom or an alkyl, alkenyl, phenylalkyl, cycloalkylalkyl or cycloalkenylalkyl group;
• R.sub.3 an amino acid residue or a (C.sub.1 -C.sub.6)alkyl, benzyl, (C.sub.1 -C.sub.6 alkoxy) benzyl or benzyloxy (C.sub.1 -C.sub.6 alkyl) group;
• R.sub.4 a hydrogen atom or an alkyl group;
• R.sub.5 a hydrogen atom or a methyl group.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR10## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 hydrogen or a (C.sub.1 -C.sub.6) alkyl, (C.sub.2 -C.sub.6) alkenyl, phenyl, phenyl (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthiomethyl, phenylthiomethyl, phenyl(C.sub.1 -C.sub.6)alkylthiomethyl or heterocyclylthiomethyl group;
• R.sub.2 a hydrogen atom or an (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, phenyl(C.sub.1 -C.sub.6)alkyl, cycloalkyl (C.sub.1 -C.sub.6)alkyl or cycloalkenyl (C.sub.1 -C.sub.6)alkyl group;
• R.sub.3 an amino acid residue or a (C.sub.1 -C.sub.6)alkyl, benzyl, (C.sub.1 -C.sub.6)alkoxy benzyl, benzyloxy (C.sub.1 -C.sub.6)alkyl or benzyloxybenzyl group;
• R.sub.4 a group (CH.sub.2).sub.n A wherein n is an integer from 1 to 6 and A represents a hydroxy, (C.sub.1 -C.sub.6)alkoxy, (C.sub.2 -C.sub.7)acyloxy, (C.sub.1 -C.sub.6)alkylthio, phenylthio, (C.sub.2 -C.sub.7)acylamino or N-pyrrolidone group;
• R.sub.5 a hydrogen atom or a methyl group.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR11## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 an alkyl, alkenyl, aryl, aralkyl, heteroalkyl, or heteroarylthioalkyl;
• R.sub.2 an alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aralkoxy, or aralkylthio group, or an amino, substituted amino, carboxyl, or esterified carboxyl group;
• R.sub.3 a group -›Alk!.sub.n R.sup.6 where Alk is an alkenyl group optionally interrupted by one or more --O--, or --S-- atoms or --N(R.sup.7)-groups, where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, n is zero or an integer 1, and R.sup.6 is a cycloalkyl or cycloalkenyl group;
• R.sub.4 a hydrogen atom, a straight or branched alkyl group, optionally interrupted by one or more --O-- or --S-- atoms or --N(R.sup.7)-groups (where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group), or aminocarbonyloxy groups;
• or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are attached may form a C.sub.3 -C.sub.6 cyclic amino group optionally possessing one or more other heteroatoms selected from --O-- or --S-- or --N(R.sup.7)-groups (where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group);
• R.sub.5 a hydrogen atom, a straight or branched alkyl group, optionally interrupted by one or more --O-- or --S-- atoms or --N(R.sup.7)-groups (where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group), or aminocarbonyloxy groups.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR12## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 an alkyl, alkenyl, aryl, aralkyl, heteroalkyl, or heteroarylthioalkyl;
• R.sub.2 a phenylethyl, phenylpropyl or phenylbutyl group;
• R.sub.3 an alkyl or alkenyl group optionally interrupted by one or more --O--, or --S-- atoms or --N(R.sup.7)-groups (where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group;
• R.sub.4 a hydrogen atom, a substituted straight or branched alkyl group, optionally interrupted by one or more --O-- or --S-- atoms or --N(R.sup.7)-groups (where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group), or aminocarbonyloxy groups;
• or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are attached may form a substituted C.sub.3 -C.sub.6 cyclic amino group optionally possessing one or more other heteroatoms selected from --O-- or --S-- or --N(R.sup.7)-groups (where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group);
• R.sub.5 a hydrogen atom, a substituted straight or branched alkyl group, optionally interrupted by one or more --O-- or --S-- atoms or --N(R.sup.7)-groups (where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group), or aminocarbonyloxy groups.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR13## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 hydrogen, amino, acylamino, or lower alkyl optionally substituted by aryl, hydroxy, protected hydroxy, amino, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3-dioxo-1H-benz›d,e!isoquinol-2-yl, carboxy, carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, carboxy-lower alkanoylamino, pyrrolidino or morpholino;
• R.sub.2 isobutyl;
• R.sub.3 tert-butyl;
• R.sub.4 hydrogen or lower alkyl optionally substituted by aryl, amino, di(lower alkyl)amino, guanidino, carboxyl, carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or morpholino;
• R.sub.5 hydrogen.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR14## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 hydrogen (C.sub.1 -C.sub.6) alkyl, phenyl, phenyl(C.sub.1 -C.sub.6)alkyl, or heterocyclyl;
• or R.sup.1 represents ASO.sub.n R.sup.7 wherein A represents a (C.sub.1 -C.sub.6) hydrocarbon chain, optionally substituted with one or more (C.sub.1 -C.sub.6)alkyl, phenyl and n=0, 1 or 2;
• R.sup.7 is (C.sub.1 -C.sub.6)alkyl, phenyl, phenyl (C.sub.1 -C.sub.6) alkyl, heterocyclyl, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6)acyl, thienyl or phenacyl;
• R.sub.2 hydrogen or an (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, phenyl(C.sub.1 -C.sub.6)alkyl, or cycloalkyl(C.sub.1 -C.sub.6)alkyl group;
• R.sub.3 a benzyl group with one or two substituents in the phenyl ring selected from hydrogen, halogen, cyano, amino, amino (C.sub.1 -C.sub.6)alkyl, amino di (C.sub.1 -C.sub.6)alkyl, amino (C.sub.1 -C.sub.6)alkylacyl, aminophenacyl, amino(substituted) phenacyl, amino acid or derivative thereof, hydroxy, oxy (C.sub.1 -C.sub.6)alkyl, oxyacyl, formyl, carboxylic acid, carboxamide, carboxy (C.sub.1 -C.sub.6)alkylamide, carboxyphenylamide, carboxy (C.sub.1 -C.sub.6)alkyl, hydroxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyloxy (C.sub.1 -C.sub.6)alkyl or acyloxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6 alkylcarboxylic acid, or (C.sub.1 -C.sub.6)alkylcarboxy (C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkylacyl carboxylic acid or amino(C.sub.1 -C.sub.6)alkylcarboxylate;
• or a benzyl group with one substituent in the phenyl ring selected from groups of formula --OCH.sub.2 CN, --OCH.sub.2 COR.sup.8 and --OCH.sub.2 CH.sub.2 OR.sup.9, where R.sup.8 is hydroxyl, (C.sub.1 -C.sub.6)oxyalkyl, (C.sub.1 -C.sub.6)oxyalkylphenyl, amino, (C.sub.1 -C.sub.6)aminoalkyl, (C.sub.1 -C.sub.6)aminodialkyl, (C.sub.1 -C.sub.6)aminoalkylphenyl, an amino acid;
• and R.sup.9 is (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylphenyl, phenyl, phenyl (C.sub.1 -C.sub.6)alkylacyl or phenacyl;
• R.sub.4 hydrogen or a (C.sub.1 -C.sub.6)alkyl, or phenyl(C.sub.1 -C.sub.6)alkyl group;
• R.sub.5 hydrogen or methyl.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR15## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 hydrogen, lower alkyl, aryl, or aryl lower alkyl;
• R.sub.2 hydrogen, lower alkyl, aryl, or aryl lower alkyl;
• R.sub.3 aryl lower alkyl, or heterocyclic lower alkyl, either being unsubstituted or mono- or di-substituted with fluoro, bromo, chloro, halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl lower alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, di-lower alkyl amino, mercapto, lower alkylthio, or mercapto lower alkyl;
• R.sub.4 a group --XD wherein X is a bond, lower alkylene, or a group --(CAB).sub.m --C(O)--N(Z)--, or --(CAB).sub.m --CH.sub.2 O--, or --(CAB).sub.m --C(O)O-- wherein A is hydrogen, methyl or ethyl, and B and Z are independently hydrogen or lower alkyl, and m is 1, 2 or 3 with the proviso that when X is a chemical bond then the group R.sub.3 is not unsubstituted benzyl or benzyl monosubstituted with hydroxy or lower alkoxy, and the further proviso that when X is a group --(CAB).sub.m --C(O)--N(Z)-- wherein m is 1 and A, B and Z are as defined above, then the group R.sub.3 is not indole or imidazole or unsubstituted benzyl or benzyl substituted with hydroxy or lower alkoxy, and wherein D is hydrogen or lower alkyl;
• R.sub.5 hydrogen or lower alkyl.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR16## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 lower alkyl which may be substituted by a substituent selected from mercapto, loweralkylthio, arylthio and lower acylthio;
• R.sub.2 a group --Y--X--Z, wherein Y is a single bond or lower alkylene, X is O or S, and Z is lower alkyl;
• R.sub.3 4-(lower alkyl)phenylmethyl;
• R.sub.4 lower alkyl;
• R.sub.5 hydrogen.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR17## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 hydrogen;
• R.sub.2 hydrogen, alkyl, or aralkyl;
• R.sub.3 a group --CH.sub.2 --CH.sub.2 --CH.sub.2 --NH-- where the right hand bond is formed with the N atom adjacent to the C atom carrying R.sub.3, thereby replacing the H atom shown on that C atom in formula (I);
• R.sub.4 hydrogen, alkyl, alkoxy, or (when R.sup.5 is hydrogen) --CH(R.sup.6)COR.sup.7 where R.sup.6 is hydrogen or alkyl and R.sup.7 is alkyl, or --CH(R.sup.6)COOR.sup.8 where R.sup.6 is hydrogen or alkyl and R.sup.8 is alkyl, or --CH(R.sup.6)CONR.sup.9 R.sup.10 where R.sup.9 and R.sup.10 are each alkyl, or R.sup.4 taken together with R.sup.5 and the nitrogen atom to which they are attached form a heterocyclic group;
• R.sub.5 hydrogen or alkyl.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative as defined by a compound of formula (I):

• ##STR18## wherein the five substituents R.sub.1 -R.sub.5 may vary as follows:
• R.sub.1 hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, phenyl, phenyl(C.sub.1 -C.sub.6 alkyl), heterocyclyl, or a group BSO.sub.n A- wherein n is 0, 1 or 2 and B is hydrogen or a (C.sub.1 -C.sub.6) alkyl, phenyl, heterocyclyl, C.sub.1 -C.sub.6 acyl, phenacyl, and A represents C.sub.1 -C.sub.6 alkyl;
• amino;
• acylamino;
• OH;
• SH;
• C.sub.1 -C.sub.6 alkoxy;
• C.sub.1 -C.sub.6 alkylamino;
• C.sub.1 -C.sub.6 alkylthio;
• aryl(C.sub.1 -C.sub.6 alkyl);
• amino(C.sub.1 -C.sub.6 alkyl);
• hydroxy(C.sub.1 -C.sub.6 alkyl), mercapto(C.sub.1 -C.sub.6 alkyl) or carboxy(C.sub.1 -C.sub.6 alkyl);
• lower alkyl substituted by maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3-dioxo-1H-benz›d,e!isoquinol-2-yl, carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, carboxy-lower alkanoylamino, pyrrolidino or morpholino;
• R.sub.2 (C.sub.1 -C.sub.6)alkyl;
• (C.sub.2 -C.sub.6)alkenyl;
• phenyl(C.sub.1 -C.sub.6)alkyl;
• cycloalkyl (C.sub.1 -C.sub.6)alkyl;
• cycloalkenyl (C.sub.1 -C.sub.6)alkyl;
• amino;
• carboxyl;
• esterified carboxyl;
• or a group --Y--X--Z wherein Y is a single bond or (C.sub.1 -C.sub.6)alkylene, X is O or S, and Z is (C.sub.1 -C.sub.6)alkyl;
• R.sub.3 C.sub.1 -C.sub.6 alkyl;
• benzyl;
• benzyloxybenzyl;
• (C.sub.1 -C.sub.6 alkoxy)benzyl;
• benzyloxy (C.sub.1 -C.sub.6 alkyl);
• the characteristic side chain of a natural .alpha. amino acid;
• a group - ›Alk!.sub.n R.sup.6 where Alk is an C.sub.1 -C.sub.6 alkyl or C.sub.2 -C.sub.6 alkenyl group optionally interrupted by one or more --O--, or --S-- atoms or --N(R.sup.7)-groups (where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group), n is 0 or 1, and R.sup.6 is a cycloalkyl or cycloalkenyl group;
• a benzyl group with one or two substituents in the phenyl ring selected from hydrogen, halogen, cyano amino, amino (C.sub.1 -C.sub.6)alkyl, amino di (C.sub.1 -C.sub.6)alkyl, amino (C.sub.1 -C.sub.6)alkylacyl, aminophenacyl, amino(substituted)phenacyl, amino acid, hydroxy, oxy (C.sub.1 -C.sub.6)alkyl, oxyacyl, formyl, carboxylic acid, carboxamide, carboxy (C.sub.1 -C.sub.6)alkylamide, carboxyphenylamide, carboxy (C.sub.1 -C.sub.6)alkyl, hydroxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyloxy (C.sub.1 -C.sub.6)alkyl or acyloxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylcarboxylic acid, or (C.sub.1 -C.sub.6)alkylcarboxy (C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkylacyl carboxylic acid or amino(C.sub.1 -C.sub.6)alkylcarboxylate;
• or a benzyl group with one substituent in the phenyl ring selected from groups of formula --OCH.sub.2 CN, --OCH.sub.2 COR.sup.8 and --OCH.sub.2 CH.sub.2 OR.sup.9, where R.sup.8 is hydroxyl, (C.sub.1 -C.sub.6)oxyalkyl, (C.sub.1 -C.sub.6)oxyalkylphenyl, amino, (C.sub.1 -C.sub.6)aminoalkyl, (C.sub.1 -C.sub.6)aminodialkyl, (C.sub.1 -C.sub.6)aminoalkylphenyl, an amino acid;
• and R.sup.9 is (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylphenyl, phenyl, phenyl (C.sub.1 -C.sub.6)alkylacyl or phenacyl;
• heterocyclic lower alkyl, either being unsubstituted or mono- or di-substituted with halo, nitro, carboxy, C.sub.1 -C.sub.6 alkoxy, cyano, C.sub.1 -C.sub.6 alkanoyl, trifluoromethyl C.sub.1 -C.sub.6 alkyl, hydroxy, formyl, amino, C.sub.1 -C.sub.6 alkyl amino, di-C.sub.1 -C.sub.6 alkyl amino, mercapto, C.sub.1 -C.sub.6 alkylthio, or mercapto C.sub.1 -C.sub.6 alkyl;
• C.sub.1 -C.sub.6 alkyl)phenylmethyl;
• R.sub.4 hydrogen, C.sub.1 -C.sub.6 alkyl;
• a group --CHBD wherein B is H and D is H or C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy-C.sub.1 -C.sub.6 alkyl, di(C.sub.1 -C.sub.6 alkoxy)methyl, carboxy, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, arylmethoxycarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl or arylaminocarbonyl;
• or R.sub.3 and B together form a group (CH.sub.2)n where n is an integer from 4-11;
• phenyl(C.sub.1 -C.sub.2 alkyl), or trifluoromethylphenyl(C.sub.1 -C.sub.2 alkyl);
• a group --(CH.sub.2).sub.n A wherein n is an integer from 1 to 6 and A represents the group --NH.sub.2, a substituted acyclic amine, a heterocyclic base, hydroxy, (C.sub.1 -C.sub.6)alkoxy , (C.sub.2 -C.sub.7)acyloxy, (C.sub.1 -C.sub.6)alkylthio, phenylthio, (C.sub.2 -C.sub.7)acylamino or an N-pyrrolidone group;
• a straight or branched alkyl group, optionally interrupted by one or more --O-- or --S-- atoms or --N(R.sup.7)- groups (where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group), or aminocarbonyloxy groups;
• C.sub.1 -C.sub.6 alkyl optionally substituted by aryl, amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl, protected carboxyl, carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or morpholino;
• R.sub.5 hydrogen.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative selected from the group consisting of:

• 2S-(4-methoxyphenylsulfanylmethyl)-3R-(2-phenyl-1S-methylcarbamoyl-ethylcar bamoyl)-5-methyl-hexanohydroxamic acid,
• 2S-(3-chlorophenylsulfanylmethyl)-3R-(2-phenyl-1S-methylcarbamoyl-ethylcarb amoyl)-5-methyl-hexanohydroxamic acid,
• 2S-(phenylsulfanylmethyl)-3R-(2-phenyl-1S-(pyrid-3-ylmethylcarbamoyl)-ethyl carbamoyl)-5-methyl-hexanohydroxamic acid,
• 2S-(3-methylphenylsulfanylmethyl)-3R-(2-phenyl-1S-methylcarbamoyl-ethylcarb amoyl)-5-methyl-hexanohydroxamic acid,
• 2S-(thien-2-ylsulphanylmethyl)-3R-(2-(4-carboxymethoxyphenyl)-1S-methylcarb amoyl-ethylcarbamoyl-5-methyl-hexanohydroxamic acid,
• 2S-thien-2-ylsulphanylmethyl)-3R-(2-phenyl-1S-(pyrid-3-ylmethylcarbamoyl)-e thylcarbamoyl)-5-methyl-hexanohydroxamic acid,
• 2S-(4-hydroxyphenylsulphanylmethyl)-3R-(2-phenyl-1S-(pyrid-3-ylmethylcarbam oyl)-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid,
• 2S-(thien-2-ylsulfanylmethyl)-3R-(2-naph-2-yl-1S-methylcarbamoyl-ethylcarba moyl)-5-methyl-hexanohydroxamic acid,
• 2S-(4-hydroxyphenylsulfanylmethyl)-3R-(2R-hydroxy-1S-methylcarbamoyl-propyl carbamoyl)-5-methyl-hexanohydroxamic acid,
• 2S-(4-hydroxyphenylsulfanylmethyl)-3R-(5-acetamido-1S-methylcarbamoyl-penty lcarbamoyl)-5-methyl-hexanohydroxamic acid, and
• 2S-(4-hydroxyphenylsulfanylmethyl)-3R-(3-›1,1-dimethylethoxycarbonyl!-1S-me thylcarbamoyl-propylcarbamoyl 5-methyl-hexanohydroxamic acid.

A method for the inhibition of the release of and the effects of tumor necrosis factor (TNF) in a condition mediated by TNF in a mammal comprising administering to the mammal an effective amount of a matrix metalloproteinase (MMP) inhibitor derivative selected from the group consisting of:

• 2S-(thien-2-ylsufonylmethyl)-3R-(2-phenyl-1S-methylcarbamoyl-ethylcarbamoyl )-5-methyl-hexanohydroxamic acid,
• 3S-(2-›4-acetamido-phenyl!-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexa nohydroxamic acid,
• 2S-(4-phthalimido-butyl)-3R-(3-methyl-1S-ethoxycarbonylmethylcarbamoyl-buty lcarbamoyl)-5-methyl-hexanohydroxamic acid,
• 3R-(2-›4-methoxy-phenyl!-1S-methylcarbamoyl-ethylcarbamoyl)-2S,5-dimethyl-h exanohydroxamic acid,
• 3R-(2-phenyl-1S-›2-oxo-pyrolid-1-yl!propylcarbamoyl-ethylcarbamoyl)-5-methy l-hexanohydroxamic acid,
• 3R-(2-›4-methoxy-phenyl!-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexano hydroxamic acid,
• 3R-(2-phenyl-1S-›pyrid-3-ylmethylcarbamoyl!-ethylcarbamoyl)-5-methyl-hexano hydroxamic acid,
• 3R-(2,2-dimethyl-1S-methylcarbamoyl-propylcarbamoyl)5-methyl-hexanohydroxam ic acid, and
• 2S-(thien-2-ylsulphanylmethyl)-3R-(2-(4-carboxymethoxyphenyl)-1S-methylcarb amoyl-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid.