Inhibitors of TNF-.alpha. secretion
AssigneeImmunex Corporation
InventorsRoy A. Black, Jeffrey N. Fitzner, Paul R. Sleath
Life of this patent
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Abstract
Compounds and methods are disclosed that are useful in inhibiting the TNF-.alpha. converting enzyme (TACE) responsible for cleavage of TNF-.alpha. precursor to provide biologically active TNF-.alpha.. The compounds employed in the invention are peptidyl derivatives having active groups capable of inhibiting TACE such as, hydroxamates, thiols, phosphoryls and carboxyls.
Claims19
A method for treating a mammal having a disease characterized by an overproduction or an unregulated production of TNF-.alpha., comprising administering to the mammal a composition comprising an effective amount of a biologically active compound of the formula:
- wherein:
- X is hydroxamic acid, phosphoryl or carboxyl;
- m is 0, 1 or 2;
- R.sup.1, R.sup.2 and R.sup.3 each independent of the other is hydrogen, alkylene(cycloalkyl), OR.sup.4, SR.sup.4, N(R.sup.4)(R.sup.5), halogen, substituted or unsubstituted C.sub.1 to C.sub.8 alkyl, C.sub.1 to C.sub.8 alkylenearyl, aryl, a protected or unprotected side chain of a naturally occurring .alpha.-amino acid;
- or the group --R.sup.6 R.sup.7, wherein R.sup.6 is C.sub.1 to C.sub.8 alkyl and R.sup.7 is OR.sup.4, SR.sup.4, N(R.sup.4)(R.sup.5) or halogen, wherein R.sup.4 and R.sup.5 are each, independent of the other, hydrogen or substituted or unsubstituted C.sub.1 to C.sub.8 alkyl;
- n is 1 or 2;
- Y is hydrogen, unsubstituted or substituted C.sub.1 to C.sub.8 alkyl, alkylene(cycloalkyl), the group --R.sup.8 --COOR.sup.9 or the group --R.sup.10 N(R.sup.11)(R.sup.12);
- wherein R.sup.8 is C.sub.1 to C.sub.8 alkylene;
- R.sup.9 is hydrogen or C.sub.1 to C.sub.8 alkyl;
- R.sup.10 is C.sub.1 to C.sub.8 alkylene;
- and R.sup.11 and R.sup.12 are each, independent of the other, hydrogen or unsubstituted or substituted C.sub.1 to C.sub.8 alkyl;
- provided that when n is 1, A is a protected or an unprotected .alpha.-amino acid radical;
- and when n is 2, A is the same or different protected or unprotected .alpha.-amino acid radical;
- and when n is 2, A is the same or different protected or unprotected .alpha.-amino acid radical;
- and the pharmaceutically acceptable salts thereof;
- wherein the compound is capable of reducing serum TNF-.alpha. levels by at least 80% when administered at 25 mg/kg in a murine model of LPS-induced sepsis syndrome;
- and a pharmaceutically acceptable carrier.
A pharmaceutical composition for treating TNF-.alpha. related disorders, conditions or diseases, comprising an effective amount of a biologically active compound of the formula:
- ##STR16## wherein:
- X is hydroxamic acid, phosphoryl or carboxyl;
- m is 0, 1 or 2;
- R.sup.1, R.sup.2 and R.sup.3 each independent of the other is hydrogen, alkylene(cycloalkyl), OR.sup.4, SR.sup.4, N(R.sup.4)(R.sup.5), halogen, substituted or unsubstituted C.sub.1 to C.sub.8 alkyl, C.sub.1 to C.sub.8 alkylenearyl, aryl, a protected or unprotected side chain of a naturally occurring .alpha.-amino acid;
- or the group --R.sup.6 R.sup.7, wherein R.sup.6 is substituted or unsubstituted C.sub.1 to C.sub.8 alkyl and R.sup.7 is OR.sup.4, SR.sup.4, N(R.sup.4)(R.sup.5) or halogen, wherein R.sup.4 and R.sup.5 are each, independent of the other, hydrogen or substituted or unsubstituted C.sub.1 to C.sub.8 alkyl;
- n is 1 or 2;
- provided that when n is 1, A is a protected or an unprotected .alpha.-amino acid radical;
- when n is 2, A is the same or different protected or unprotected .alpha.-amino acid radical;
- B is unsubstituted or substituted C2 to C8 alkylene;
- and
- the pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.