US 7,442,696 B2Granted

Mineralocorticoid receptor modulator compounds, processes for their preparation, and their uses

AssigneeLigand Pharmaceuticals Incorporated

InventorsRobert I. Higuchi, Lin Zhi, Mark E. Adams, Yan Liu, Donald S. Karanewsky

Life of this patent

Estimating the term…

Abstract

This invention relates to compounds that bind to mineralocorticoid receptors and/or modulate activity of mineralocorticoid receptors, and to methods for making and using such compounds. Some embodiments relate to compounds of Formula I: or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein R1 —R10 are as defined herein.

Claims60

Dependent claims

A compound selected from the group consisting of:

5-Chloro-6-(3-cyanophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 101);
5-Chloro-1,4-dihydro-4,4-dimethyl-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-one (Compound 102);
6-(3-Acetylphenyl)-5-chloro-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 103);
5-Chloro-1,4-dihydro-4,4-dimethyl-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-thione (Compound 104);
5-Chloro-6-(3-chlorophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 105);
5-Chloro-6-(3-cyanophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-thione (Compound 106);
6-(3-Carboxymethylphenyl)-5-chloro-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 107);
5-Chloro-6-(3-cyanophenyl)-1,4-dihydro-1,4,4-trimethyl-2H-3,1-benzoxazin-2-one (Compound 108);
5-Chloro-6-(3-cyano-2-methoxyphenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 109);
(±)-5-Chloro-1,4-dihydro-4-methyl-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-one (Compound 110);
(±)-5-Chloro-1,4-dihydro-4-methyl-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-thione (Compound 111);
(±)-5-Chloro-6-(3-cyanophenyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (Compound 112);
(±)-5-Chloro-6-(3-cyanophenyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-thione (Compound 113);
(±)-5-Chloro-6-(3-cyanophenyl)-4-(4-fluorophenyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (Compound 114);
(±)-5-Chloro-4-ethyl-1,4-dihydro-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-one (Compound 115);
(±)-5-Chloro-6-(3-cyanophenyl)-4-(4-fluorophenyl)-1,4-dihydro-2H-3,1-benzoxazin-2-thione (Compound 116);
(±)-5-Chloro-4-ethyl-1,4-dihydro-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-thione (Compound 117);
(±)-5-Chloro-4-(4-fluorophenyl)-1,4-dihydro-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-one (Compound 118);
(±)-5-Chloro-6-(3-cyanophenyl)-4-cyclopentyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (Compound 119);
(±)-5-Chloro-6-(3-cyanophenyl)-4-cyclopentyl-1,4-dihydro-2H-3,1-benzoxazin-2-thione (Compound 120);
(±)-5-Chloro-6-(3-cyanophenyl)-4-(3,4-difluorobenzyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (Compound 121);
(±)-5-Chloro-6-(3-cyanophenyl)-4-(3,4-difluorobenzyl)-1,4-dihydro-2H-3,1-benzoxazin-2-thione (Compound 122);
5-Chloro-1,4-dihydro-6-(2,6-dimethoxyphenyl)-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 123);
7-Chloro-6-(3-cyanophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 124);
7-Chloro-6-(3-cyanophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-thione (Compound 125);
7-Chloro-6-(3-cyano-2-methoxyphenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 126);
7-Chloro-6-(3-cyano-2-methoxyphenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-thione (Compound 127);
6-(3,5-Dimethylisoxazol-4-yl)-1,4-dihydro-4,4,8-trimethyl-2H-3,1-benzoxazin-2-one (Compound 128);
1,4-Dihydro-6-(indol-7-yl)-4,4,8-trimethyl-2H-3,1-benzoxazin-2-one (Compound 129);
and
a pharmaceutically acceptable salt, ester, or amide of any of those compounds.

28 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/622,983Filed 12 Jan 2007 · continuation
Priority: 14 Jul 2004
Published: US 2007/0197520 A123 Aug 2007
Granted: 28 Oct 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 265/18
Condensed with one six-membered ring: with hetero atoms directly attached in position 2
A61P 9/00
Drugs for disorders of the cardiovascular system
C07D 413/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D
Heterocyclic compounds

Family

Application60/587,947Us provisional application · filed 14 Jul 2004
PCT/US2005/024748Parent of this continuation · filed 12 Jul 2005
US 2007/0197520 A1Pre-grant publication · published 23 Aug 2007
US 7,442,696 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound selected from the group consisting of:

5-Chloro-6-(3-cyanophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 101);
5-Chloro-1,4-dihydro-4,4-dimethyl-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-one (Compound 102);
6-(3-Acetylphenyl)-5-chloro-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 103);
5-Chloro-1,4-dihydro-4,4-dimethyl-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-thione (Compound 104);
5-Chloro-6-(3-chlorophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 105);
5-Chloro-6-(3-cyanophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-thione (Compound 106);
6-(3-Carboxymethylphenyl)-5-chloro-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 107);
5-Chloro-6-(3-cyanophenyl)-1,4-dihydro-1,4,4-trimethyl-2H-3,1-benzoxazin-2-one (Compound 108);
5-Chloro-6-(3-cyano-2-methoxyphenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 109);
(±)-5-Chloro-1,4-dihydro-4-methyl-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-one (Compound 110);
(±)-5-Chloro-1,4-dihydro-4-methyl-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-thione (Compound 111);
(±)-5-Chloro-6-(3-cyanophenyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (Compound 112);
(±)-5-Chloro-6-(3-cyanophenyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-thione (Compound 113);
(±)-5-Chloro-6-(3-cyanophenyl)-4-(4-fluorophenyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (Compound 114);
(±)-5-Chloro-4-ethyl-1,4-dihydro-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-one (Compound 115);
(±)-5-Chloro-6-(3-cyanophenyl)-4-(4-fluorophenyl)-1,4-dihydro-2H-3,1-benzoxazin-2-thione (Compound 116);
(±)-5-Chloro-4-ethyl-1,4-dihydro-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-thione (Compound 117);
(±)-5-Chloro-4-(4-fluorophenyl)-1,4-dihydro-6-[3-(trifluoromethyl)phenyl]-2H-3,1-benzoxazin-2-one (Compound 118);
(±)-5-Chloro-6-(3-cyanophenyl)-4-cyclopentyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (Compound 119);
(±)-5-Chloro-6-(3-cyanophenyl)-4-cyclopentyl-1,4-dihydro-2H-3,1-benzoxazin-2-thione (Compound 120);
(±)-5-Chloro-6-(3-cyanophenyl)-4-(3,4-difluorobenzyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (Compound 121);
(±)-5-Chloro-6-(3-cyanophenyl)-4-(3,4-difluorobenzyl)-1,4-dihydro-2H-3,1-benzoxazin-2-thione (Compound 122);
5-Chloro-1,4-dihydro-6-(2,6-dimethoxyphenyl)-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 123);
7-Chloro-6-(3-cyanophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 124);
7-Chloro-6-(3-cyanophenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-thione (Compound 125);
7-Chloro-6-(3-cyano-2-methoxyphenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-one (Compound 126);
7-Chloro-6-(3-cyano-2-methoxyphenyl)-1,4-dihydro-4,4-dimethyl-2H-3,1-benzoxazin-2-thione (Compound 127);
6-(3,5-Dimethylisoxazol-4-yl)-1,4-dihydro-4,4,8-trimethyl-2H-3,1-benzoxazin-2-one (Compound 128);
1,4-Dihydro-6-(indol-7-yl)-4,4,8-trimethyl-2H-3,1-benzoxazin-2-one (Compound 129);
and
a pharmaceutically acceptable salt, ester, or amide of any of those compounds.

28 more elements

Facts

Application

11/622,983Filed 12 Jan 2007 · continuation

Priority

14 Jul 2004

Published

US 2007/0197520 A123 Aug 2007

Granted

28 Oct 2008

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 265/18
Condensed with one six-membered ring: with hetero atoms directly attached in position 2
A61P 9/00
Drugs for disorders of the cardiovascular system
C07D 413/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D
Heterocyclic compounds