Synthetic inhibitors of mammalian collagenase

A pharmaceutical composition comprising a pharmaceutically effective amount of a compound having the formula:

• R.sub.1 S CH (R.sub.2) CH (R.sub.3) CO-AA.sub.1 -(AA.sub.2).sub.m --X
• wherein
• m is 0 or 1;
• AA.sub.1 is phenylalanine, naphthylalanine, tryptophan, tyrosine or .epsilon.-amino blocked lysine;
• AA.sub.2 is leucine;
• R.sub.1 is hydrogen, alkyl having 1-10 carbon atoms, alkanoyl having from 2-10 carbon atoms or aroyl having from 7-11 carbon atoms;
• R.sub.2 is hydrogen or alkyl having from 1-6 carbon atoms;
• R.sub.3 is alkyl having 2-10 carbon atoms, cycloalkyl having from 3-6 carbon atoms, aryl or arylalkyl, wherein the aryl moieties have from 6-10 carbon atoms;
• and
• X is NH.sub.2, ›OH,! OCH.sub.3 or OCH.sub.2 CH.sub.3 and a pharmaceutical carrier therefor.

A method of reducing the adverse effects of mammalian collagenase in a mammal which comprises administering to said mammal a pharmaceutically effective amount of a compound of the formula:

• R.sub.1 S CH (R.sub.2) CH (R.sub.3) CO-AA.sub.1 - (AA.sub.2)m--X
• or pharmaceutically acceptable salts thereof
• wherein
• m is an integer 0 or 1;
• AA.sub.1 is phenylalanine, naphthylalanine, tryptophan, tyrosine or .epsilon.-amino blocked lysine;
• AA.sub.2 is alanine, glycine, phenylalanine or isoleucine;
• R.sub.1 is hydrogen, alkyl having 1-10 carbon atoms, alkanoyl having 2-10 carbon atoms, or aroyl having from 7-11 carbon atoms;
• R.sub.2 is hydrogen or alkyl having from 1-6 carbon atoms;
• R.sub.3 is alkyl having from 2-10 carbon atoms, cycloalkyl having from 3-6 carbon atoms, aryl or arylalkyl wherein the aryl moieties have from 6-10 ring carbon atoms;
• X is NH.sub.2, OH, OCH.sub.3 or OCH.sub.2 CH.sub.3.

A method of reducing the adverse effects of mammalian collagenase in a mammal which comprises administering to said mammal a pharmaceutically effective amount of a compound of the formula:

• R.sub.1 S CH (R.sub.2) CH (R.sub.3) CO-AA.sub.1 -(AA.sub.2).sub.m --X
• wherein
• m is an integer 0 or 1;
• AA.sub.1 is phenylalanine, naphthylalanine, tryptophan, tyrosine or .epsilon.-amino blocked lysine;
• AA.sub.2 is leucine;
• R.sub.1 is hydrogen, alkyl having 1-10 carbon atoms, alkanoyl having from 2-10 carbon atoms or aroyl having from 7-11 carbon atoms;
• R.sub.2 is hydrogen or alkyl having from 1-6 carbon atoms;
• R.sub.3 is alkyl having 2-10 carbon atoms, cycloalkyl having from 3-6 carbon atoms, aryl or arylalkyl, wherein aryl moieties have from 6-10 carbon atoms;
• X is NH.sub.2, OH, OCH.sub.3 or OCH.sub.2 CH.sub.3.

A method for treating corneal ulceration in mammals comprising administering to a mammal in need of such treatment a corneal ulceration inhibiting effective amount of a compound having the formula:

• R.sub.1 S CH (R.sub.2) CH (R.sub.3) CO-AA.sub.1 -(AA.sub.2).sub.m --X
• or pharmaceutically acceptable salts thereof
• wherein
• m is an integer 0 or 1;
• AA.sub.1 is phenylalanine, naphthylalanine, tryptophan, tyrosine or .epsilon.-amino blocked lysine;
• AA.sub.2 is alanine, glycine, phenylalanine or isoleucine;
• R.sub.1 is hydrogen, alkyl having 1-10 carbon atoms, alkanoyl having 2-10 carbon atoms, or aroyl having from 7-11 carbon atoms;
• R.sub.2 is hydrogen or alkyl having from 1-6 carbon atoms;
• R.sub.3 is alkyl having from 2-10 carbon atoms, cycloalkyl having from 3-6 carbon atoms;
• aryl or arylalkyl wherein the aryl moieties having from 6-10 ring carbon atoms;
• X is NH.sub.2, OH, OCH.sub.3 or OCH.sub.2 CH.sub.3.

A method for treating corneal ulceration in mammals comprising administering to a mammal having corneal ulceration a corneal ulceration inhibiting effective amount of a compound having the formula:

• R.sub.1 S CH (R.sub.2) CH (R.sub.3) CO-AA.sub.1 -(AA.sub.2).sub.m --X
• wherein
• m is an integer 0 or 1;
• AA.sub.1 is phenylalanine, naphthylalanine, tryptophan, tyrosine, or .epsilon.-amino blocked lysine;
• AA.sub.2 is leucine;
• R.sub.1 is hydrogen, alkyl having 1-10 carbon atoms, alkanoyl having from 2-10 carbon atoms or aroyl having from 7-11 carbon atoms;
• R.sub.2 is hydrogen or alkyl having from 1-6 carbon atoms;
• R.sub.3 is alkyl having 2-10 carbon atoms, cycloalkyl having from 3-6 carbon atoms, aryl or arylalkyl, wherein aryl moieties have from 6-10 carbon atoms;
• X is NH.sub.2, OH, OCH.sub.3 or OCH.sub.2 CH.sub.3.

A compound of the formula:

• R.sub.1 S CH (R.sub.2) CH (R.sub.3) CO-AA.sub.1 -(AA.sub.2).sub.m --X
• or pharmaceutically acceptable salts thereof
• wherein
• m is an integer 0 or 1;
• AA.sub.1 is phenylalanine, naphthylalanine, tryptophan, tyrosine or .epsilon.-amino blocked lysine
• AA.sub.2 is alanine, glycine, Phenylalanine or isoleucine,
• R.sub.1 is hydrogen, alkyl having 1-10 carbon atoms, alkanoyl having 2-10 carbon atoms, or aroyl having from 7-11 carbon atoms,
• R.sub.2 is hydrogen or alkyl having 1-6 carbon atoms,
• R.sub.3 is alkyl having from 2-10 carbon atoms, cycloalkyl having from 3-6 carbon atoms, aryl or arylalkyl wherein the aryl moieties have from 6-10 ring carbon atoms;
• and
• X is NH.sub.2, ›OH,! OCH.sub.3 or OCH.sub.2 CH.sub.3.

A compound having the formula:

• ##STR7## wherein m is an integer 0 or 1;
• AA.sub.1 is phenylalanine, naphthylalanine, tryptophan tyrosine or .epsilon.-amino blocked lysine;
• AA.sub.2 is leucine;
• R.sub.1 is hydrogen, alkyl having 1-10 carbon atoms, alkanoyl having from 2-10 carbon atoms or aroyl having from 7-11 carbon atoms;
• R.sub.2 is hydrogen or alkyl having from 1-6 carbon atoms;
• R.sub.3 is alkyl having 2-10 carbon atoms, cycloalkyl having from 3-6 carbon atoms, aryl or arylalkyl, wherein aryl moieties have from 6-10 carbon atoms;
• X is NH.sub.2, OCH.sub.3 or OCH.sub.2 CH.sub.3 .

A compound of the formula:

• R.sub.1 SCH (R.sub.2)CH(R.sub.3) CO-AA.sub.1 (AA.sub.2).sub.m (AA.sub.3).sub.n --X
• wherein
• AA.sub.1 is phenylalanine, naphthylalanine, tryptophan tyrosine or .epsilon.-amino blocked lysine;
• AA.sub.2 is alanine, glycine, phenylalanine, leucine or isoleucine,
• AA.sub.3 is glutamine or arginine,
• m is an integer 0 or 1,
• n is an integer 1 or 2,
• R.sub.1 is hydrogen, alkyl having 1-10 carbon atoms, alkanoyl having 2-10 carbon atoms, or aroyl having from 7-11 carbon atoms,
• R.sub.2 is hydrogen or alkyl having 1-6 carbon atoms,
• R.sub.3 is alkyl having from 2-10 carbon atoms, cycloalkyl having from 3-6 carbon atoms, aryl or arylalkyl wherein the aryl moieties have from 6-10 ring carbon atoms, and
• X is NH.sub.2, OH, OCH.sub.3 or OCH.sub.2 CH.sub.3.