US 6,333,324 B1 · Piperazine compounds as inhibitors of MMP or TNF

Abstract

A compound of formula (I) wherein A is a sulfonyl or a carbonyl; R1 is an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl; R2 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; R3 is an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted aryloxy, an optionally substitued lower alkenyl, an optionally substituted aryl, an optionally substituted heterocyclic group or an optionally substitued amino; R4 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; R5 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; and R10 is a hydroxy or a protected hydroxy, and a pharmaceutically acceptable salt thereof. The compound of the present invention is useful as a medicament for prophylactic and therapeutic treatment of MMP- or TNFα-mediated diseases.

A compound of the formula (I):

wherein
A is a sulfonyl;
R1 is
a lower alkyl optionally substituted by halogen,
a lower alkenyl optionally substituted by aryl, or
a heterocyclic group optionally substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy, lower alkyl, aryl, heterocyclic group, haloaryl, hydroxyaryl, lower alkoxyaryl, lower alkylaryl, nitroaryl, biphenylyl, aryloxyaryl, trihaloalkylaryl, cyano(lower)alkoxyaryl, cyanoaryl, cyano(lower) alkylaryl, lower alkanoyloxyaryl, lower alkanoyloxy(lower)alkylaryl, di(lower)alkylaminosulfonylaryl, hydroxy(lower)alkylaryl, lower alkoxycarbonylaryl, lower alkoxycarbonyl(lower)alkoxyaryl, lower alkylsulfonyloxyaryl, aryl substituted by halogen and hydroxy, aryl substituted by halogen and alkanoyloxy, aryl substituted by halogen and lower alkoxy, lower alkyl-heterocyclic group, and aryl-heterocyclic group;
R2 is a hydrogen or lower alkyl;
R3 is
a lower alkyl optionally substituted by a substituent selected from the group consisting of halogen, heterocyclic group, carbamoyl, lower alkylcarbamoyl, carboxy, protected carboxy, heterocyclic-carbonyl, di(lower)alkylamino, protected amino, arylcarbonylamino, heterocyclic-carbonylamino, lower alkanoylamino, lower alkylsulfonylamino, di(lower)alkylaminosulfonylamino, heterocyclic-sulfonylamino, heterocyclic-thio, lower alkylheterocyclic-thio, and heterocyclic-thio,
a lower alkoxy,
an aryloxy,
an aryl(lower)alkoxy,
a heterocyclic(lower)alkenyl, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, a heterocyclic group, said heterocyclic group being selected from the group consisting of unsaturated 5- or 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms, saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms and unsaturated 5- or 6-membered heteromonocyclic group containing a sulfur atom, which is optionally substituted by heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, or a group of the formula:
wherein R8 and R9 are the same or different and each is hydrogen, lower alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, carbamoyl(lower)alkyl, hydroxy(lower)alkyl, aryl, cyclo(lower)alkyl, heterocyclic-(lower)alkyl;
R4 is a hydrogen or lower alkyl;
R5 is a hydrogen;
and
R10 is a hydroxy or a protected hydroxy,
and the above-mentioned heterocyclic group is each selected from the group consisting of
unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
saturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 to 5 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,
saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing a sulfur atom,
unsaturated 3- to 8-membered heteromonocyclic group containing an oxygen atom,
saturated 3- to 8-membered heteromonocyclic group containing an oxygen atom,
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, and
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 to 2 oxygen atoms,
or a pharmaceutically acceptable salt thereof.

30 more elements

Piperazine compounds as inhibitors of MMP or TNF

Life of this patent

Piperazine compounds as inhibitors of MMP or TNF

Life of this patent

Abstract

Claims9