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US 2003/0191309 A1Published application
N-substituted arylsulfonylamino hydroxamic acids useful as inhibitors of C-proteinase and for treating or preventing disorders related to unregulated collagen production
OwnerWen-Bin Hoinventor
Life of this patent
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Abstract
The present invention relates to a novel class of organic molecules capable of inhibiting C-proteinase, and to their use to regulate, modulate and/or inhibit abnormal collagen formation as a therapeutic approach towards the treatment of fibrotic disorders.
Claims70
A compound having an inhibitory effect on C-proteinase and having the structural formula:
- 135
- or pharmaceutically acceptable salts thereof, wherein:
- a is an integer from 1 to 4;
- b is an integer from 0 to 4;
- c is an integer from 0 to 4;
- Ar1 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y1, 5-20 membered heteroaryl, and 5-20 membered heteroaryl independently substituted with one or more Y1;
- Ar2 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y2, 5-20 membered heteroaryl, and 5-20 membered heteroaryl independently substituted with one or more Y2;
- each Y1 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group;
- and
- each Y2 is independently selected from the group consisting of a functional group having an acidic hydrogen, a functional group capable of participating in a hydrogen bond, a polar functional group, an electron-withdrawing functional group, an electron-donating functional group, and a lipophilic functional group,
- with the provisos that
- (i) when a and b are each one, c is zero and Ar2 is 4′-methoxyphenyl, then Ar1 is other than phenyl, 4′-fluorophenyl, 4′-chlorophenyl, 4′-trifluoromethylphenyl or 4′-methoxyphenyl;
- (ii) when a and b are each one, c is zero and Ar2 is phenyl, then Ar1 is other than 4′-chlorophenyl;
- (iii) when a is two, b and c are each zero and Ar1 is phenyl, then Ar2 is other than 4′-chlorophenyl or 4′-bromophenyl;
- and
- (iv) when a and b are each one, c is zero and Ar2 is phenyl, then Ar1 is other than carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, or (N-aryl-lower alkylpiperazino)-lower alkyl,
- wherein, in proviso (iv), aryl represents monocyclic or bicyclic aryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclic aryl and heterocyclic aryl represents monocyclic or bicyclic heterocyclic aryl.
14 more elements
A compound having an inhibitory effect on C-proteinase, said compound having the formula:
- 144
- or pharmaceutically acceptable salts thereof, wherein:
- g is an integer from 1 to 4;
- h is an integer from 0 to 4;
- i is an integer from 0 to 4;
- Z is selected from the group consisting of (C3-C10) cycloalkyl, (C3-C10) cycloalkyl independently substituted with one or more Y5, 3-10 membered heterocycloalkyl, and 3-10 membered heterocycloalkyl independently substituted with one or more Y5;
- Ar6 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y6, 5-20 membered heteroaryl, and 5-20 membered heteroaryl independently substituted with one or more Y6;
- each Y5 is independently selected from the group consisting of a lipophilic functional group, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl;
- each Y6 is independently selected from the group consisting of —R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO2, —CN, -halogen, -trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′, —C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO2R′, —SO2R″, —NR′—SO2—R′, —NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′, —S(O)—R″, and —NR′—C(S)—NR′R′;
- each R′ is independently selected from the group consisting of —H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8,) alkynyl;
- and
- each R″ is independently selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more —OR′, —SR′, —NR′R′, —NO2, —CN, halogen or trihalomethyl groups,
- with the proviso that when g and h are 1, i is 0, and Ar6 is phenyl, then Z is other than C3-C7-cycloalkyl, C3-C7-cycloalkyl-lower alkyl, N-lower alkyl-piperazino-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl.
10 more elements
A compound having an inhibitory effect on C-proteinase, said compound having the structural formula:
- 146
- or pharmaceutically acceptable salts thereof, wherein
- r is an integer from 1 to 4;
- s is an integer from 0 to 4;
- Ar11 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y11 5-20 membered heteroaryl, and 5-20 membered heteroaryl independently substituted with one or more Y11;
- G is selected from the group consisting of:
- 147
- R90 and R91 are independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C10) cycloalkyl, (C5-C20) aryl, (C5-C20) substituted aryl, (C6-C26) alkaryl, (C6-C26) substituted alkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 membered substituted alk-heteroaryl;
- R92 is independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl;
- and
- each Y11, R93, R94, R95, R96, R97, R98, R99, R100, R101, and R102 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
8 more elements
Dependencies are inferred from the claim text.