US 7,605,156 B2 · Methods for the use of inhibitors of cytosolic phospholipase A2

Abstract

This invention provides methods for the use of substituted indole compounds of the general formula: and pharmaceutically acceptable salt forms thereof. The invention provides methods for the use of the compounds as inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2 enzymes, and for the medical treatment, prevention and inhibition diseases and disorders including asthma, stroke, atherosclerosis, multiple sclerosis, Parkinson's disease, arthritic disorders, rheumatic disorders, central nervous system damage resulting from stroke, central nervous system damage resulting from ischemia, central nervous system damage resulting from trauma, inflammation caused or potentiated by prostaglandins, inflammation caused or potentiated by leukotrienes, inflammation caused or potentiated by platelet activation factor, pain caused or potentiated by prostaglandins, pain caused or potentiated by leukotrienes, and pain caused or potentiated by platelet activation factor.

A method for treating a disease or disorder in a mammal, wherein the disease or disorder is selected from the group consisting of stroke, atherosclerosis, multiple sclerosis, Parkinson's disease, central nervous system damage resulting from stroke, central nervous system damage resulting from ischemia, and central nervous system damage resulting from trauma, the method comprising administering to a mammal in need thereof an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R is —(CH2)n—A, wherein A is:
wherein
B and C are each phenyl, each independently optionally substituted by from 1 to 3 substituents selected independently from halogen, —CN, —CHO, —CF3, —OCF3, —OH, C1-C6 alkyl, C1-C6 alkoxy, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6 alkyl), —NH—C(O)—(C1-C6 alkyl), and —NO2;
and
n is an integer from 0 to 3;
n1 is an integer from 1 to 3;
n2 is an integer from 0 to 4;
n3 is an integer from 0 to 3;
n4 is an integer from 0 to 2;
X1 is selected from a chemical bond, —S—, —O—, —S(O)—, —S(O)2—, —NH—, —NHC(O)—, —C═C—,
R1 is selected from C1-C6 alkyl, C1-C6 fluorinated alkyl, C3-C6 cycloalkyl, tetrahydropyranyl, camphoryl, adamantyl, CN, —N(C1-C6 alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperazinyl, thiazolidinyl, thiomorpholinyl, tetrazolyl, indolyl, benzoxazolyl, benzofuranyl, imidazolidine-2-thionyl, 7,7-dimethyl-bicyclo[2.2.1]heptan-2-onyl, benzo[1,2,5]oxadiazolyl, 2-oxa-5-aza-bicyclo[2.2.1 ]heptanyl, piperazin-2-onyl and pyrrolyl groups, each optionally substituted by from 1 to 3 substituents independently selected from halogen, —CN, —CHO, —CF3, —OCF3, —OH, C1-C6 alkyl, C1-C6 alkoxy, —NH2, —N(C1-C6 alkyl)2, —NH(C1-C6 alkyl), —NH—C(O)—(C1-C6 alkyl), —NO2, —SO2(C1-C3 alkyl), —SO2NH2, —SO2NH(C1-C3 alkyl), —SO2N(C1-C3 alkyl)2, —COOH, —CH2—COOH, —CH2—NH(C1-C6 alkyl), —CH2N(C1-C6 alkyl)2, —CH2—NH2, pyridinyl, 2-methyl-thiazolyl, morpholino, 1-chloro-2-methyl-propyl, C1-C6 thioalkyl, phenyl (further optionally substituted with one or more halogens), benzyloxy, —(C1-C3 alkyl)C(O)CH3, —(C1-C3 alkyl)OCH3, —C(O)NH2,
X2 is selected from —O—, —CH2—, —S—, —SO—, —SO2—, —NH—, —C(O)—,
R2 is phenyl substituted by a group of the formula —(CH2)n4—CO2H or a pharmaceutically acceptable acid mimic or mimetic;
and also optionally substituted by 1 or 2 additional substituents independently selected from halogen, —CN, —CHO, —CF3, —OCF3, —OH, —C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, —NH2, —N(C1-C6 alkyl)2, —NH(C1-C6 alkyl), —NH—C(O)—(C1-C6 alkyl), and —NO2;
R3 is H, halogen, —CN, —CHO, —CF3, —OCF3, —OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, —NH2, —N(C1-C6 alkyl)2, —NH(C1-C6 alkyl), —NH—C(O)—(C1-C6 alkyl), or —NO2;
and
R4 is H, halogen, —CN, —CHO, —CF3, —OCF3, —OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, —NH2, —N(C1-C6 alkyl)2, —NH(C1-C6 alkyl), —NH—C(O)1-C6 alkyl), —NO2, morpholino pyrrolidino, piperidinyl, or piperizinyl.

15 more elements

Facts

Application

11/140,390Filed 27 May 2005 · continuation in part

Priority

3 Dec 2001

Published

US 2006/0014759 A119 Jan 2006

Granted

20 Oct 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification19 codes

A61K 31/505
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrimidines; Hydrogenated…
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
C07D 209/14
With substituted hydrocarbon radicals attached to carbon atoms of the hetero ring: radicals substituted by nitrogen atoms, not forming part of a…

Family

Application60/334,588Us provisional application · filed 3 Dec 2001

Application10/302,636Parent of this continuation-in-part · filed 22 Nov 2002

Application10/722,782Parent of this continuation-in-part · filed 26 Nov 2003

US 2006/0014759 A1Pre-grant publication · published 19 Jan 2006

US 6,984,735 B2Parent of this continuation-in-part

US 6,797,708 B2Parent of this continuation-in-part

US 2003/0144282 A1Published application

US 2004/0082785 A1Published application

US 7,605,156 B2This patent

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

Methods for the use of inhibitors of cytosolic phospholipase A2

Life of this patent

Methods for the use of inhibitors of cytosolic phospholipase A2

Life of this patent

Abstract

Claims34