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US 6,316,503 B1Granted
LXR modulators
AssigneeTularik Inc.
InventorsLeping Li, Julio C. Medina, Kevin Lustig, Bei Shan, Hirohiko Hasegawa, Serena T. Cutler, Jiwen Liu, Liusheng Zhu
Life of this patent
Estimating the term…
Abstract
The invention provides compounds, compositions and methods for modulating the effects of LXR in a cell. The compounds and compositions are useful both as diagnostic indicators of LXR function and as pharmacologically active agents. The compounds and compositions find particular use in the treatment of disease states associated with cholesterol metabolism, particularly atherosclerosis and hypercholesterolemia.
Claims47
A composition for modulation of LXR function in a cell, said composition comprising a pharmaceutically acceptable excipient and a compound having the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- Ar is an aryl group;
- R1 is a member selected from the group consisting of —OH, —CO2H, —O—(C1-C7)alkyl, —OC(O)—(C1-C7)alkyl, —O—(C1-C7)heteroalkyl, —OC(O)—(C1-C7)heteroalkyl, —NH2, —NH(C1-C7)alkyl, —N((C1-C7)alkyl)2 and —NH—S(O)2—(C1-C5)alkyl;
- R2 is a member selected from the group consisting of (C1-C7)alkyl, (C1-C7)heteroalkyl, aryl and aryl(C1-C7)alkyl;
- X1, X2, X3, X4, X5 and X6 are each independently a member selected from the group consisting of H, (C1-C5)alkyl, (C1-C5)heteroalkyl, F and Cl, with the proviso that no more than three of X1 through X6 are H, (C1-C5)alkyl or (C1-C7)heteroalkyl;
- and
- Y is a divalent linking group selected from the group consisting of —N(R12)S(O)m—, —N(R12)S(O)mN(R13)—, —N(R12)C(O)—, —N(R12)C(O)N(R13)—, —N(R12)C(S)— and —N(R12)C(O)O—;
- wherein R12 and R13 are each independently selected from the group consisting of H, (C1-C7)alkyl, (C1-C7)heteroalkyl, aryl and aryl(C1-C7)alkyl, and optionally when Y is —N(R12)S(O)m— or —N(R12)S(O)mN(R13)—, R12 forms a five- or six-membered ring fused to Ar or to R2 through covalent attachment to Ar or to R2, respectively;
- and the subscript m is an integer of from 1 to 2;
- with the proviso that when R1 is OH, and —Y—R2 is —N(R12)S(O)m—R2 or —N(R12)C(O)N(R13)—R2 and is attached to a position para to the quaternary carbon attached to Ar, and when R2 is phenyl, benzyl or benzoyl, then i) at least one of R12 or R13 is other than hydrogen and contains an electron-withdrawing substituent, or ii) R2 is substituted with a moiety other than amino, acetamido, di(C1-C7)alkylamino, (C1-C7)alkylamino, halogen, hydroxy, nitro, or (C1-C7)alkyl, or iii) the benzene ring portion of R2 is substituted with at least three independently selected groups in addition to the Y group or point of attachment to Y.
7 more elements
A compound having the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- Ar is an aryl group;
- R1 is a member selected from the group consisting of —OH, —CO2H, —O—(C1-C7)alkyl, —OC(O)—(C1-C7)alkyl, —O—(C1-C7)heteroalkyl, —OC(O)—(C1-C7)heteroalkyl, —NH2, —NH(C1-C7)alkyl, —N((C1-C7)alkyl)2 and —NH—S(O)2—(C1-C5)alkyl;
- R2 is a member selected from the group consisting of (C1-C7)alkyl, (C1-C7)heteroalkyl, aryl and aryl(C1-C7)alkyl;
- X1, X2, X3, X4, X5 and X6 are each independently a member selected from the group consisting of H, (C1-C5)alkyl, (C1-C5)heteroalkyl, F and Cl, with the proviso that no more than three of X1 through X6 are H, (C1-C5)alkyl or (C1-C5)heteroalkyl;
- and
- Y is a divalent linking group selected from the group consisting of —N(R12)S(O)m—, N(R12)S(O)mN(R13)—, —N(R12)C(O)—, —N(R12)C(O)N(R13)—, —N(R12)C(S)— and —N(R12)C(O)O—;
- wherein R12 and R13 are each independently selected from the group consisting of H, (C1-C7)alkyl, (C1-C7)heteroalkyl, aryl and aryl(C1-C7)alkyl, and optionally when Y is —N(R12)S(O)m— or N(R12)S(O)mN(R13)—, R12 forms a five- or six-membered ring fused to Ar or to R2 through covalent attachment to Ar or to R2, respectively;
- and the subscript m is an integer of from 1 to 2;
- with the proviso that when R1 is OH, and —Y—R2 is —N(R12)S(O)mR2 or —N(R12)C(O)N(R13)—R2 and is attached to a position para to the quaternary carbon attached to Ar, and when R2 is phenyl, benzyl or benzoyl, then i) at least one of R12 or R13 is other than hydrogen and contains an electron-withdrawing substituent, or ii) R2 is substituted with a moiety other than amino, acetamido, di(C1-C7)alkylamino, (C1-C7)alkylamino, halogen, hydroxy, nitro, or (C1-C7)alkyl, or iii) the benzene ring portion of R2 is trisubstituted in addition to the attached Y group.
7 more elements
A method of modulating LXR function in a cell, tissue or animal, said method comprising contacting said cell, tissue or animal with a pharmaceutical composition comprising an LXR-modulating amount of a compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- Ar is an aryl group;
- R1 is a member selected from the group consisting of —OH, —CO2H, —O—(C1-C7)alkyl, —OC(O)—(C1-C7)alkyl, —O—(C1-C7)heteroalkyl, —OC(O)—(C1-C7)heteroalkyl, —NH2, —NH(C1-C7)alkyl, —N((C1-C7)alkyl)2 and —NH—S(O)2—(C1-C5)alkyl;
- R2 is a member selected from the group consisting of (C1-C7)alkyl, (C1-C7)heteroalkyl, aryl and aryl(C1-C7)alkyl;
- X1, X2, X3, X4, X5 and X6 are each independently a member selected from the group consisting of H, (C1-C5)alkyl, (C1-C5)heteroalkyl, F and Cl, with the proviso that no more than three of X1 through X6 are H, (C1-C5)alkyl or (C1-C5)heteroalkyl;
- and
- Y is a member selected from the group consisting of —N(R12)S(O)m—, —N(R12)S(O)mN(R13)—, —N(R12)C(O)—, —N(R12)C(O)N(R13)—, —N(R12)C(S)— and —N(R12)C(O)O—;
- wherein R12 and R13 are each independently selected from the group consisting of H, (C1-C7)alkyl, (C1-C7)heteroalkyl, aryl and aryl(C1-C7)alkyl, and optionally when Y is —N(R12)S(O)m— or —N(R12)S(O)mN(R13)—, R12 forms a five- or six-membered ring fused to Ar or to R2 through covalent attachment to Ar or to R2, respectively;
- and the subscript m is an integer of from 1 to 2.
6 more elements
Dependencies are inferred from the claim text.