US 2003/0232986 A1 · Inhibitors of caspases

Abstract

The present invention relates to novel classes of compounds which are caspase inhibitors, in particular interleukin-1β converting enzyme (“ICE”) inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting caspase activity and consequently, may be advantageously used as agents against interleukin-1-(“IL-1”) , apoptosis-, interferon-γ inducing factor-(IGIF), or interferon-γ-(“IFN-γ”) mediated diseases, including inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, and degenerative diseases. This invention also relates to methods for inhibiting caspase activity and decreasing IGIF production and IFN-γ production and methods for treating interleukin-1, apoptosis-, and interferon-γ-mediated diseases using the compounds and compositions of this invention. This invention also relates to methods of preparing the compounds of this invention.

A compound represented by formula I:

284
provided that when R7 is —OH then Y can also be:
285
X is —C(R3)2— or —N(R3)—;
m is 0 or 1;
R1 is H, —R8, —C(O)R8, —C(O)C(O)R8, —S(O)2R8, —S(O)R8, —C(O)OR8, —C(O)N(H)R8, —S(O)2N(H)—R8, —S(O)N(H)—R8, —C(O)C(O)N(H)R8, —C(O)CH═CHR8, —C(O)CH2OR8, —C(O)CH2N(H)R8, —C(O)N(R8)2, —S(O)2N(R8)2, —S(O)N(R8)2, —C(O)C(O)N(R8)2, —C(O)CH2N(R8)2, —CH2R8, —CH2-alkenyl-R8, or —CH2-alkynyl-R8;
R2 is —H and each R3 is independently —H, an amino acid side chain, —R8, alkenyl-R9, or alkynyl-R9, or each R3 together with the atom to which they are bound, form a 3 to 7 membered cyclic or heterocyclic cyclic ring system, or R2 and one R3 together with the atoms to which they are bound, form a 3 to 7 membered cyclic or heterocyclic ring system, wherein a hydrogen atom bound to any -alkyl or -cycloalkyl carbon atom is optionally replaced by —R10, a hydrogen atom bound to any -aryl or -heteroaryl carbon atom is optionally replaced by —R11, a hydrogen atom bound to any nitrogen atom of the ring system is optionally replaced by —R1;
R4 is —H and each R5 is independently —H, an amino acid side chain, —R8, -alkenyl-R9, or -alkynyl-R9, or R4 and one R5 together with the atoms to which they are bound form a 3 to 7 membered cyclic or heterocyclic ring system, wherein a hydrogen atom bound to any -alkyl or -cycloalkyl carbon atom is optionally replaced by R10, a hydrogen atom bound to any -aryl or -heteroaryl carbon atom is optionally replaced by R11, and a hydrogen atom bound to any nitrogen atom of the ring system is optionally replaced with R1;
R6 is —H;
R7 is —OH, —OR8, or —N(H)OH;
each R8 is independently -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, -alkylcycloalkyl -alkylaryl, -alkylheteroaryl, or -alkylheterocyclyl, wherein a hydrogen atom bound to any -alkyl or -cycloalkyl carbon atom is optionally replaced by R10, a hydrogen atom bound to any -aryl or -heteroaryl carbon atom is optionally replaced by R11 and a hydrogen atom bound to any nitrogen atom is optionally replaced by R1;
each R9 is independently -aryl, -heteroaryl, cycloalkyl, or -heterocyclyl, wherein a hydrogen atom bound to any -alkyl or -cycloalkyl carbon atom is optionally replaced by R10, a hydrogen atom bound to any -aryl or -heteroaryl carbon atom is optionally replaced by R11 and a hydrogen atom bound to any nitrogen atom is optionally replaced by R1;
each R10 is independently —OH, —SH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, -perfluoroalkyl, —O-alkyl, —O-aryl, —O-alkylaryl, —N(H)alkyl, —N(H)aryl, —N(H)-alkylaryl, —N(alkyl)2, —C(O)N(H)alkyl, —C(O)N(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)Oalkyl, —N(H)C(O)Oaryl, —N(H)C(O)Oalkylaryl, —N(H)C(O)Oheteroaryl, —N(H)C(O)Oalkylheteroaryl, —N(H)C(O)Ocycloalkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —N(H)C(O)N(H)aryl, —N(H)C(O)N(H)alkylaryl, —N(H)C(O)N(H)heteroaryl, —N(H)C(O)N(H)alkylheteroaryl, —N(H)C(O)N(H)cycloalkyl, —S-alkyl, —S-aryl, —S-alkylaryl, —S(O)2alkyl, —S(O)alkyl, —C(O)alkyl, —CH2NH2, —CH2N(H)alkyl, or —CH2N(alkyl)2, -alkyl, —N(alkyl)2, —C(O)N(H)alkyl, —C(O)N(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)Oalkyl, —N(H)C(O)Oaryl, —N(H)C(O)Oalkylaryl, —N(H)C(O)Oheteroaryl, —N(H)C(O)Oalkylheteroaryl, —N(H)C(O)Ocycloalkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —N(H)C(O)N(H)aryl, —N(H)C(O)N(H)alkylaryl, —N(H)C(O)N(H)heteroaryl, —N(H)C(O)N(H)alkylheteroaryl, —N(H)C(O)N(H)cycloalkyl, —S-alkyl, —S-aryl, —S-alkylaryl, —S(O)2alkyl, —S(O)alkyl, —C(O)alkyl, —CH2NH2, —CH2N(H)alkyl, or —CH2N(alkyl)2, -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, -alkylcycloalkyl, -alkylaryl, alkylheteroaryl, or -alkylheterocyclyl, wherein a hydrogen atom bound to any -aryl or -heteroaryl carbon atom is optionally replaced by R11 and a hydrogen atom bound to any nitrogen atom is optionally replaced by R1;
and
each R11 is independently —OH, —SH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —O-aryl, —O-alkylaryl, —N(H)alkyl, —N(H)aryl, —N(H)-alkylaryl, —N(alkyl)2, —C(O)N(H)alkyl, —C(O)N(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S-alkyl, —S-aryl, —S-alkylaryl, —S(O)2alkyl, —S(O)alkyl, —C(O)alkyl, —CH2NH2, —CH2N(H)alkyl, or —CH2N(alkyl)2;
and
R12 is —C(O)alkyl, —C(O)cycloalkyl, —C(O)alkyenyl, —C(O)alkyaryl, —C(O)alkylheteroaryl, —C(O)heterocyclyl, or —C(O)alkylheterocyclyl. -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, -alkylcycloalkyl -alkylaryl, -alkylheteroaryl, or -alkylheterocyclyl, wherein a hydrogen atom bound to any -aryl or -heteroaryl carbon atom is optionally replaced by R11 and a hydrogen atom bound to any nitrogen atom is optionally replaced by R1;
and
each R11 is independently —OH, —SH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —O-aryl, —O-alkylaryl, —N(H)alkyl, —N(H)aryl, —N(H)-alkylaryl, —N(alkyl)2, —C(O)N(H)alkyl, —C(O)N(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S-alkyl, —S-aryl, —S-alkylaryl, —S(O)2alkyl, —S(O)alkyl, —C(O)alkyl, —CH2NH2, —CH2N(H)alkyl, or —CH2N(alkyl)2.

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Inhibitors of caspases

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Inhibitors of caspases

Life of this patent

Abstract

Claims26