US 8,263,641 B2Granted

Compounds that modulate intracellular calcium

AssigneeCalcimedica, Inc.

InventorsGonul Velicelebi, Kenneth A. Stauderman, David P. M. Pleynet, Soan Cheng, Jeffrey P. Whitten

Life of this patent

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Abstract

Described herein are compounds of Formula I and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also describe herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of SOC channel activity.

Claims8

Dependent claims

A compound of Formula (I), or pharmaceutically acceptable salt thereof:

wherein:
R1 is hydrogen;
R2 is aryl, benzothienyl, benzofuranyl, or —CH2CH2-phenyl;
wherein R2 is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OCF3, C1-C6alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, tetrazolyl, C2-C6heterocycloalkyl, phenyl, —NHS(═O)2R8, —S(═O)2N(R9)2, —C(═O)CF3, —C(═O)NHS(═O)2R8, —S(═O)2NHC(═O)R8, —N(R9)2, —N(R9)C(═O)R8, —CO2R9, —C(═O)R8, —OC(═O)R8, —CON(R9)2, —SR8, —S(═O)R8, and —S(═O)2R8;
R4 is an aryl, substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OCF3, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, tetrazolyl, C2-C6heterocycloalkyl, phenyl, —NHS(═O)2R8, S(═O)2N(R9)2, —C(═O)CF3, —C(═O)NHS(═O)2R8, —S(═O)2NHC(═O)R9, N(R9)2, —N(R9)C(═O) R8, —CO2R9, —C(═O)R8, —OC(═O)R8, —C(═O)N(R9)2, —SR8, —S(═O)R8, and —S(═O)2R8;
each R8 is independently selected from C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl;
and
each R9 is independently selected from H, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl.

5 more elements

A compound selected from among:

2-(4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(4-fluorobenzamido)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-fluorobenzamido)-4-(4-trifluoromethylphenyl)thiophene-3-carboxylic acid;
2-(4-fluorobenzamido)-4-(2-bromophenyl)thiophene-3-carboxylic acid;
2-(4-fluorobenzamido)-4-(3,4-dimethylphenyl)thiophene-3-carboxylic acid;
2-(4-fluorobenzamido)-4-(2-chlorophenyl)thiophene-3-carboxylic acid;
2-(4-fluorobenzamido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-fluorobenzamido)-4-(4-methylphenyl)thiophene-3-carboxylic acid;
2-(3-fluorobenzamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(4-iodobenzamido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(benzothien-2-ylamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzamido)-4-(4-methylphenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzamido)-4-(3,5-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzamido)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzamido)-4-(3,4-dimethylphenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzamido)-4-(4-trifluoromethylphenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzamido)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzamido)-4-(2-bromophenyl)thiophene-3-carboxylic acid;
2-(3-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(3-fluorobenzamido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(3-fluorobenzamido)-4-(3,4-dimethylphenyl)thiophene-3-carboxylic acid;
2-(3-fluorobenzamido)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;
2-(3-fluorobenzamido)-4-(4-methylphenyl)thiophene-3-carboxylic acid;
2-(3-fluorobenzamido)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(3-fluorobenzamido)-4-(2-bromophenyOthiophene-3-carboxylic acid;
2-(3-fluorobenzamido)-4-(4-trifluoromethylphenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(4-chlorophenypthiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(4-methylphenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(4-fluorophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(3,4-dimethylphenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(4-trifluromethylphenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(2-bromophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;
2-(benzothien-2-ylamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(benzothien-2-ylamido)-4-(4-methylphenyl)thiophene-3-carboxylic acid;
2-(benzothien-2-ylamido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(benzothien-2-ylamido)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;
2-(benzothien-2-ylamido)-4-(4-trifluoromethylphenyl)thiophene-3-carboxylic acid;
2-(benzothien-2-ylamido)-4-(2-bromophenyl)thiophene-3-carboxylic acid;
2-(benzothien-2-ylamido)-4-(3,4-dimethylphenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamido)-4-(4-methylphenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamido)-4-(phenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamido)-4-(2-bromophenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamido)-4-(4-fluorophenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamido)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;
2-(3 -methylbenzamido)-4-(4-trifluoromethylphenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamido)-4-(3,4-dimethylphenyl)thiophene-3-carboxylic acid;
methyl 2-(4-chlorobenzamido)-4-(4-fluorophenyl)thiophene-3-carboxylate;
ethyl 2-(4-chlorobenzamido)-4-(4-fluorophenyl)thiophene-3-carboxylate;
2-(4-iodobenzamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
4-(2,4-dichlorophenyl)-2-(3-phenylpropanamido)thiophene-3-carboxylic acid;
4-(3,4-dichlorophenyl)-2-(3-phenylpropanamido)thiophene-3-carboxylic acid;
4-(3,5-dichlorophenyl)-2-(3-phenylpropanamido)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-phenylpropanamido)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(3-fluorophenyl)propanamido)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(3-chlorophenyl)propanamido)thiophene-3-carboxylic acid;
4-(3-chlorophenyl)-2-(3-phenylpropanamido)thiophene-3-carboxylic acid;
4-(2-chlorophenyl)-2-(3-phenylpropanamido)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(2-chloro-4-fluorobenzamido)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3,4-difluorobenzamido)thiophene-3-carboxylic acid;
2-(2-chloro-4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(2-fluorobenzamido)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3-fluoro-4-methoxybenzamido)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(4-methylbenzamido)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(4-cyanobenzamido)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(4-ethylbenzamido)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(4-(trifluoromethypbenzamido)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(3-fluorophenyl)propanamido)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3-(3-fluorophenyl)propanamido)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(2,4-difluorophenyl)propanamido)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3-(4-fluorophenyl)propanamido)thiophene-3 -carboxylic acid;
4-(4-chlorophenyl)-2-(3-(3,4-difluorophenyl)propanamido)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3-(2,4-difluorophenyl)propanamido)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3-(3,4-difluorophenyl)propanamido)thiophene-3 -carboxylic acid;
4-(4-chlorophenyl)-2-(3-(4-fluorophenyl)propanamido)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(3-chlorophenyl)propanamido)thiophene-3-carboxylic acid;
and
4-(4-chlorophenyl)-2-(3-(4-chlorophenyl)propanamido)thiophene-3-carboxylic acid;
or pharmaceutically acceptable salt thereof.

84 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/192,812Filed 15 Aug 2008 · us provisional application
Priority: 10 Sep 2007
Published: US 2009/0137659 A128 May 2009
Granted: 11 Sep 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 333/68
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61K 31/00
Medicinal preparations containing organic active ingredients
A61K 31/405
Indoles, e.g. pindolol: indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system

Family

Application60/971,161Us provisional application · filed 10 Sep 2007
US 2009/0137659 A1Pre-grant publication · published 28 May 2009
US 8,263,641 B2This patent

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

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Abstract

Facts

Application

12/192,812Filed 15 Aug 2008 · us provisional application

Priority

10 Sep 2007

Published

US 2009/0137659 A128 May 2009

Granted

11 Sep 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 333/68
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61K 31/00
Medicinal preparations containing organic active ingredients
A61K 31/405
Indoles, e.g. pindolol: indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system