US 2006/0235015 A1Published application

Pyrrole-2,5-dione derivatives as liver x receptor modulators

AssigneeAstraZeneca AB

InventorsJonas Boström, Kay Brickmann, Pemilla Sandberg, Marianne Swanson, Christer Westerlund

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Abstract

The present invention relates to certain novel compounds of the Formula I to processes for preparing such compounds, to their the utility in modulation of nuclear hormone receptors Liver X Receptor (LXR) α (NR1H3) and/or β (NR1H2) and in treating and/or preventing clinical conditions including cardiovascular diseases such as atherosclerosis; inflammatory diseases, Alzheimer's disease, lipid disorders (dyslipidemias) whether or not associated with insulin resistance, type 2 diabetes and other manifestations of the metabolic syndrome, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Claims30

Dependent claims

A compound of Formula I:

wherein
R1 is or a group of formula NRaRb in which Ra and Rb independently represent H or (1-4C) selected from phenyl(1-4C)alkyl wherein the phenyl is substituted by (1-4C)alkoxycarbonyl alkyl;
heteroaryl(1-4C)alkyl wherein the heteroaryl is optionally substituted by (1-4C)alkyl or a group of formula NRaRb in which Ra and Rb independently represent H or (1-4C)alkyl;
or a (1-4C)alkyl group which is substituted by one or more of the following:
fluoro, (1-4C)alkoxycarbonyl, (1-3C)alkylthio or (1-3C)alkoxy optionally substituted by one or more fluoro;
R2 is phenyl;
R3 is selected from phenyl, indolyl or benzofuranyl each optionally substituted by one or more of the following:
(1-3C)alkanoyl, (1-3C)alkoxy optionally substituted by one or more fluoro;
(1-3C)alkylthio;
or a group of formula NRaRb in which Ra and Rb independently represent H, (1-3C)alkyl or (1-3C)alkanoyl or Ra and Rb together with the nitrogen atom to which they are attached represent morpholino,
or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.

8 more elements

A compound selected from the following:

1-(2-Methoxyethyl)-3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;
3-{[4-(Difluoromethoxy)phenyl]amino}-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione;
N-(4-{[2,5-Dihydro-1-(2-methoxyethyl)-2,5-dioxo-4-phenyl-1H-pyrrol-3-yl]amino}phenyl)-acetamide;
1-(2-Methoxyethyl)-3-{[4(methylthio)phenyl]amino}-4-phenyl-1H-pyrrole-2,5-dione;
3-[(2-Acetyl-5-benzofuranyl)amino]-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(2-Methoxyethyl)-3-[(4-morpholin-4-ylphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;
3-[(4-Morpholin-4-ylphenyl)amino]-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione;
3-[(2-Acetyl-5-benzofuranyl)amino]-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione;
3-Phenyl-1-(pyridin-3-ylmethyl)-4-{[4-(trifluoromethoxy)phenyl]amino}-1H-pyrrole-2,5-dione;
3-[(4-Methoxyphenyl)amino]-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione;
3-Anilino-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione;
3-[[4-(Difluoromethoxy)phenyl]amino]-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione;
1-[4-(Dimethylamino)benzyl]-3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;
3-[(4-Methoxyphenyl)amino]-4-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrrole-2,5-dione;
3-[(4-Methoxyphenyl)amino]-4-phenyl-1-(pyridin-2-ylmethyl)-1H-pyrrole-2,5-dione;
3-[(4-Methoxyphenyl)amino]-1-(3-methoxypropyl)-4-phenyl-1H-pyrrole-2,5-dione;
Methyl 4-({3-[(4-methoxyphenyl)amino]-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl}methyl)benzoate;
3-[(4-Methoxyphenyl)amino]-1-[2-(methylthio)ethyl]-4-phenyl-1H-pyrrole-2,5-dione;
3-[(4-Methoxyphenyl)amino]-4-phenyl-1-(3,3,3-trifluoropropyl)-1H-pyrrole-2,5-dione;
1-(3-Furylmethyl)-3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;
3-[(4-Methoxyphenyl)amino]-4-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2,5-dione;
3-[(4-Methoxyphenyl)amino]-1-[(5-methylisoxazol-3-yl)methyl]-4-phenyl-1H-pyrrole-2,5-dione;
Ethyl {3-[(4-methoxyphenyl)amino]-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl}acetate;
3-Phenyl-1-(2,2,2-trifluoroethyl)-4-{[4-(trifluoromethoxy)phenyl]amino}-1H-pyrrole-2,5-dione;
1-[(6-Aminopyridin-3-yl)methyl]-3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;
1-[(6-Aminopyridin-3-yl)methyl]-3-{[4-(difluoromethoxy)phenyl]amino}-4-phenyl-1H-pyrrole-2,5-dione;
or
1-[(6-Aminopyridine-3-yl)methyl]-3-[(4-morpholin-4-ylphenyl)amino]-4-phenyl-1-H-pyrrole-2,5-dione
or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.

26 more elements

Dependencies are inferred from the claim text.