FXR NR1H4 nuclear receptor binding compounds
View Patent ↗The invention provides compounds according to the general formula ( 1 ) which bind to the NR 1 H 4 receptor and act as agonists, antagonists or mixed agonists/antagonists of the NR 1 H 4 receptor. The invention further provides methods of treating diseases and/or conditions through binding of the nuclear receptor by the compounds and the production of medicaments using the compounds.
1. A compound having the following formula (I)
wherein:
R 1 in formula (I) is hydrogen, C 1 to C 7 acyl or C 1 to C 7 substituted acyl;
R 2 is phenyl, substituted phenyl, C 5 to C 6 heteroaryl, or C 5 to C 6 substituted heteroaryl, naphthyl, or substituted naphthyl,
R 3 is hydrogen, C 1 to C 4 alkyl, C 1 to C 12 substituted alkyl, C 7 to C 12 alkylphenyl, C 1 to C 3 substituted alkylphenyl, and
R 4 is a structure selected from one of the following formulas (II) or (III),
or R 3 and R 4 together with the nitrogen form a heterocycle or substituted heterocycle ring;
R 5 is hydrogen, C 1 to C 8 alkyl, halogen, C 1 to C 8 alkoxy, carboxy, ester, amide, substituted amide or C 1 to C 8 aminoacyl;
R 6 is hydrogen, C 1 to C 8 alkyl, or C 1 to C 8 substituted alkyl;
R 8 is hydrogen, methyl or ethyl; or
a resolved (diastereoisomer, enantiomer, tautomer, or a pharmaceutical acceptable salt thereof.
2. The compound of claim 1 wherein R 1 is hydrogen.
3. The compound of claim 1 wherein R 2 is selected from substituted phenyl, C 5 to C 6 heteroaryl, or C 5 to C 6 substituted heteroaryl.
4. The compound of claim 1 wherein the compound has the following formula:
5. The compound of claim 1 wherein the compound has the following formula:
6. The compound of claim 1 wherein the compound has the following formula:
7. The compound of claim 1 wherein the compound has the following formula:
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen; R 5 is hydrogen or a halogen; R 6 is hydrogen; and R 4 is formula (II), wherein the COOR 8 and the methylene substituents are in double axial (a,a) positions.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, R 2 is substituted phenyl, C 5 to C 6 heteroaryl, or C 5 to C 6 substituted heteroaryl; R 3 is hydrogen; R 5 is hydrogen or a halogen; R 6 is hydrogen; and R 4 is formula (III), wherein the COOR 8 and the methylene substituents can adopt all possible diastereomeric configurations.
10. A method for the treatment of a disease or condition which is mediated or can be addressed by the NR1H4 receptor in a mammal comprising administration of a therapeutically effective amount of a compound according to any one of claims 1 – 3 , 4 – 7 , 8 and 9 , wherein said disease or condition is selected from the group consisting of cholestasis and hyperlipidemias.
11. A method for regulating bile flow or the bile acid transport system in a mammal which comprises activating or repressing the NR1H4 receptor with a therapeutically effective amount of a compound according to any one of claims 1 – 3 , 4 – 7 , 8 , and 9 .
12. A method for treating in a mammal a malignant proliferative disease, which can be treated by inducing apoptosis in the affected cells or tissues comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 – 3 , 4 – 7 , 8 and 9 , wherein said malignant proliferative disease is selected from the group consisting of colon cancer, ovarian cancer, metastatic heart tumors, bronchial adenocarcinoma, and lymphoma.
13. A method according to claim 10 where the mammal is a human.