US 2002/0120137 A1 · FXR modulators

Abstract

The present invention provides compounds, pharmaceutical compositions and methods that are useful in modulating the farnesoid X receptor (FXR). As FXR is involved in negatively controlling the expression level of cholesterol 7α-hydroxylase (cyp7a), the rate-limiting enzyme involved in the oxidative metabolism of cholesterol into bile acids, the compounds described herein find utility in treating diseases associated with abnormally high or low cholesterol levels. In certain aspects, the FXR modulators (e.g., antagonists) described herein block the negative feed-back downregulation of cyp7a expression produced by certain cholic acids, the endogenous ligands for FXR. Moreover, as FXR forms heterodimers with the retinoid X receptor (RXR) in some cell types, modulation of the level of FXR activity in cells has a wide range of effects on a variety of biological processes which are mediated by RXR or other RXR-interacting proteins such as PPARγ and PPARα. Thus, compounds described herein are useful in treating other biological activities such as obesity, diabetes, lipid associated disorders, cancer, inflammatory disorders, disorders involving a disrupted or dysfunctional epidermal barrier, and various other metabolic disorders.

Claims35

Dependent claims

A compound of the formula

B1—L1—A1—L2—B2 I
wherein:
A1 is a member selected from the group consisting of alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heteroarylene, heterocycloalkylene, and heterocycloalkenylene, or, alternatively, A1 represents a single or double bond linking L1 and L2;
L1 and L2 are each independently a member selected from the group consisting of O—, —S—, —N(R1)—, —C(O)—, —C(O)N(R1)—, —O-alkylene-, —S-alkylene-, —N(R1)-alkylene, —C(O)-alkylene, —C(O)N(R1)-alkylene, —C(O)—O-alkylene, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heteroarylene, heterocycloalkylene, and heterocycloalkenylene;
B1 and B2 are each independently a member selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl;
alternatively, L1 can be additionally linked to B1 via a group X1 to form a 5-9 member ring;
and L2 can be additionally linked to B2 via a group X2 to form a 5-9 member ring;
X1 and X2 are each independently a member selected from the group consisting of —O—, —S—, —N(R2)—, —C(O)—, —C(O)N(R2)—, —O-alkylene, —S-alkylene, —N(R2)-alkylene, —C(O)-alkylene, —C(O)N(R2)-alkylene, and —C(O)—O-alkylene;
and
R1 and R2 are each independently a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl.

7 more elements

A compound of the formula:

23
wherein:
A4 is a member selected from the group consisting of hydrogen, —(O)R5, —C(O)N(R5R6), —S(O)nN(R5R6), -alkylene-N(R5R6), -alkylene-OR5 and —C(O)OR5;
L3and L4 are each independently a member selected from the group consisting of a single bond, —C(O)—, —S(O)p—, and alkylene, wherein the subscript p is an integer from 0-2;
B4, B5 and B6 are each independently a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, fused-benzoheterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl;
alternatively, B4 and B5 join to form a divalent arylene, heteroarylene, alkylene, or cycloalkylene linkage between L3 and L4, and B6 is a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, heterocycloalkyl, arylalkyl, or (heteroaryl)alkyl.
X3 and Y are each independently a trivalent nitrogen atom or a trivalent or tetravalent carbon atom;
and
R5 and R6 are each independently a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl.

6 more elements

A compound of the formula:

26
wherein:
A5 is a member selected from the group consisting of —C(O)—, -alkylene-, —S(O)n—, —C(O)N(R12)—, —S(O)2N(R12)—, -alkylene-N(R12)—, -alkylene-O—, and —C(O)O—;
L5 and L6 are each independently a member selected from the group consisting of —C(O)—, —S(O)n—;
and alkylene, wherein the subscript n is an integer from 0-2;
B7, B8, and B9 are each independently a member selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, benzoheterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl;
alternatively, B7 and B8 join to form a divalent arylene, heteroarylene, alkylene, or cycloalkylene linkage between L5 and L6;
Z is a member selected from the group consisting of alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene;
X7 and Y1 are each independently a trivalent nitrogen atom or a trivalent or tetravalent carbon atom;
and
R12 is a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl.

8 more elements

Dependencies are inferred from the claim text.

FXR modulators

Life of this patent

FXR modulators

Life of this patent

Abstract

Claims35