IP Library Granted Patent US 6,964,980
Granted Patent B2
US 6,964,980 · App. 10/397,140 · Granted Nov 15, 2005

Method of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis using substitute indolealkanoic acids

Assignee: The Institute for Pharmaceutical Discovery, Inc.
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Quick Facts
Patent No.
US 6,964,980
App. No.
10/397,140
Granted
Nov 15, 2005
Kind
B2
Abstract

Disclosed are methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis, the methods comprising administration of substituted indolealkanoic acids to patients in need of such treatment. Also disclosed are such compounds useful in the treatment of angiogenesis, hyperglycemia, hyperlipidemia and chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds.

Claims (27)

1. A method for promoting wound healing in mammals, which method comprises administering to a mammal in need of such treatment an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof wherein

A is a C 1 -C 4 alkylene group optionally substituted with C 1 -C 2 alkyl or mono- or disubstituted with halogen;

Z is a bond, O, S, C(O)NH, or C 1 -C 3 alkylene optionally substituted with C 1 -C 2 alkyl;

R 1 is hydrogen, alkyl having 1-6 carbon atoms, halogen, 2-, 3-, or 4-pyridyl, or phenyl, where the phenyl or pyridyl is optionally substituted with up to three groups selected from halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, nitro, amino, or mono- or di(C 1 -C 6 )alkylamino;

R 2 , R 3 , R 4 and R 5 are each independently

hydrogen, halogen, nitro, an alkyl group of 1-6 carbon atoms, or an alkyl group of 1-6 carbon atoms substituted with one or more halogens;

OR 7 , SR 7 , S(O)R 7 , S(O) 2 N(R 7 ) 2 , C(O)N(R 7 ) 2 , or N(R 7 ) 2 , wherein each R 7 is independently hydrogen, an alkyl group of 1-6 carbon atoms or an alkyl group of 1-6 carbon atoms substituted with one or more halogens or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino;

phenyl or heteroaryl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino;

phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino; or

a group of the formula

 where

J is a bond, CH 2 , oxygen, or nitrogen; and

each r is independently 2 or 3;

R 6 is hydroxy or a prodrug group;

R a is hydrogen, C 1 -C 6 alkyl, fluoro, or trifluoromethyl;

and Ar represents

a phenyl group optionally substituted with up to 5 groups independently selected from halogen, an alkyl group of 1-6 carbon atoms, an alkyl group of 1-6 carbon atoms substituted with one or more halogens, nitro, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7 or N(R 7 ) 2 wherein R 7 is hydrogen, an alkyl group of 1-6 carbon atoms, an alkyl group of 1-6 carbon atoms substituted with one or more halogens or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino, or the phenyl group is optionally condensed with benzo where the benzo is optionally substituted with one or two of halogen, cyano, nitro, trifluoromethyl, perfluoroethyl, trifluoroacetyl, or (C 1 -C 6 )alkanoyl, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, trifluoromethoxy, trifluoromethylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl;

a heterocyclic 5-membered ring having one nitrogen, oxygen or sulfur, two nitrogens one of which is optionally replaced by oxygen or sulfur, or three nitrogens one of which is optionally replaced by oxygen or sulfur, said heterocyclic 5-membered ring substituted by one or two fluoro, chloro, (C 1 -C 6 )alkyl or phenyl, or condensed with benzo, or substituted by one of pyridyl, furyl or thienyl, said phenyl or benzo optionally substituted by one of iodo, cyano, nitro, perfluoroethyl, trifluoroacetyl, or (C 1 -C 6 )alkanoyl, one or two of fluoro, chloro, bromo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, trifluoromethoxy, trifluoromethylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl or trifluoromethyl, or two fluoro or two trifluoromethyl with one hydroxy or one (C 1 -C 6 )alkoxy, or one or, two fluoro and one trifluoromethyl, or three fluoro, said pyridyl, furyl or thienyl optionally substituted in the 3-position by fluoro, chloro, bromo, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

a heterocyclic 6-membered ring having one to three nitrogen atoms, or one or two nitrogen atoms and one oxygen or sulfur, said heterocyclic 6-membered ring substituted by one or two (C 1 -C 6 )alkyl or phenyl, or condensed with benzo, or substituted by one of pyridyl, furyl or thienyl, said phenyl or benzo optionally substituted by one of iodo or trifluoromethylthio, or one or two of fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, or trifluoromethyl, and said pyridyl, furyl or thienyl optionally substituted in the 3-position by fluoro, chloro, (C 1 -C 6 )alkyl or (C 1 -C 6 ) alkoxy;

said benzo-condensed heterocyclic 5-membered or 6-membered rings optionally substituted in the heterocyclic 5-membered or 6-membered ring by one of fluoro, chloro, bromo, methoxy, or trifluoromethyl;

oxazole or thiazole condensed with a 6-membered aromatic group containing one or two nitrogen atoms, with thiophene or with furane, each optionally substituted by one of fluoro, chloro, bromo, trifluoromethyl, methylthio or methylsulfinyl;

imidazolopyridine or triazolopyridine optionally substituted by one of trifluoromethyl, trifluoromethylthio, bromo, or (C 1 -C 6 )alkoxy, or two of fluoro or chloro;

thienothiophene or thienofuran optionally substituted by one of fluoro, chloro or trifluoromethyl;

thienotriazole optionally substituted by one of chloro or trifluoromethyl;

naphthothiazole; naphthoxazole; or thienoisothiazole.

2. A method according to claim 1 , wherein the mammal is human.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 27, 2011
From: THE INSTITUTES FOR PHARMACEUTICAL DISCOVERY, LLC
To: ALINEA PHARMACEUTICALS, INC.
Reel/Frame 026357/0203 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 24, 2011
From: SREDY, JANET; JACOT, JORGE
To: THE INSTITUTE FOR PHARMACEUTICAL DISCOVERY, INC.
Reel/Frame 026333/0662 →
SECURITY RELEASE LETTER Recorded Sep 12, 2005
From: MPM BIOVENTURES III, L.P.; MPM BIOVENTURES III-QP, L.P.; MPM BIOVENTURES III GMBH & CO., BETEILIGUNGS KG; MPM BIOVENTURES III PARALLEL FUND, L.P.; MPM ASSET MANAGEMENT INVESTORS 2005, BVIII LLC.
To: INSTITUTES FOR PHARMACEUTICAL DISCOVERY, L.L.C.; INSTITUTE FOR DIABETES DISCOVERY, L.L.C.
Reel/Frame 016513/0792 →
SECURITY AGREEMENT Recorded Mar 3, 2005
From: INSTITUTES FOR PHARMACEUTICAL DISCOVERY, LLC, THE; INSTITUTE FOR DIABETES DISCOVERY, LLC
To: MPM BIOVENTURES III, L.P.; MPM BIOVENTURES III-QP, L.P.; MPM BIOVENTURES III GMBH & CO. BETEILIGUNGS KG; MPM BIOVENTURES III PARALLEL FUND, L.P.; MPM ASSET MANAGEMENT INVESTORS 2005 BVIII LLC
Reel/Frame 016323/0360 →
Continuity (3)
Division 0945225200 · Dec 1, 1999
Provisional Application 6011039500 · Dec 1, 1998
Related Publication 20030216452A1 · Nov 20, 2003