US 2005/0038104 A1Published application

Substitute benzothiophene compounds

AssigneeBoehringer Ingelheim Pharmaceuticals, Inc.

InventorsZhidong Chen, John Ginn, Eugene Hickey, Weimin Liu, Can Mao, Tina Morwick, Peter Nemoto, Denice Spero, Sanxing Sun

Life of this patent

Estimating the term…

Abstract

Disclosed are compounds of the formula I shown below, wherein R1, R2, R3 and R4 are described herein, which are active as anti-inflammatory agents. Also disclosed are methods of using and making such compounds.

Claims14

Dependent claims

A compound of formula (I):

wherein R1 is:
a) hydrogen,
b) halogen,
c) C1-8 alkyl, optionally partially or fully halogenated,
d) C3-7 heterocycle or C3-7 cycloalkyl, optionally substituted with one or two R8,
e) C1-8 alkoxy, optionally partially or fully halogenated and optionally substituted with C3-7 cycloalkyl, phenyl, pyridyl, morpholine, —OH, —N(R5)(R6), —C(O)NR5R6 or C1-6 alkoxy,
f) C3-8 cycloalkoxy, optionally partially or fully halogenated and optionally substituted with C3-7 cycloalkyl, phenyl, pyridyl, morpholine, —OH, —N(R5)(R6), —C(O)NR5R6 or C1-6 alkoxy,
g) —N(R5)(R6)
h) C1-6alkylthio, optionally partially or fully halogenated,
i) aryl, optionally substituted with one or two R8, or
j) heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl, triazolyl and benzofuranyl, optionally substituted with one or two R8;
R2 is
a) hydrogen,
b) halogen,
c) phenyl,
d) methoxy, or
e) methyl;
R3 is
a) hydrogen,
b) halogen,
c) C1-6alkyl, optionally partially or fully halogenated and optionally substituted with —N(R5)(R6);
d) C1-6alkoxy, optionally partially or fully halogenated and optionally substituted with —N(R5)(R6);
e) —N(R5)(R6);
f) C1-6alkylthio, optionally partially or fully halogenated and optionally substituted with —N(R5)(R6);
g) heterocyclyl selected from from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, 1,4-diazacycloheptan-1-yl, 1-azepanyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, oxazepan-4-yl and 4-thiomorpholino, optionally independently substituted with one to three R7,
h) aryl, optionally substituted with one or two R8, or
i) heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl, and benzofuranyl, optionally substituted with one or two R8;
R4 is
a) hydrogen,
b) halogen,
c) heteroaryl selected from furyl, imidazolyl, pyridyl or thienyl,
d) phenyl, optionally substituted with cyano, C1-6alkoxy, hydroxyC1-6alkyl, aminoC1-6alkyl, halogen or phenyl,
e) C1-6 alkyl, optionally partially or fully halogenated and optionally substituted with —NH2, —OH, or —C(O)NH2,
f) —C(O)NR5R6,
g) C1-6 alkoxy, optionally partially or fully halogenated and optionally substituted with —OH, —N(R5)(R6), or C1-8 alkoxy,
h) cyano, or
i) —N(R5)(R6);
R5 and R6 are independently selected from
H, C1-6alkyl, —C(O)C1-6alkyl, —SO2C1-6alkyl, —S(O)2phenyl, pyridyl, benzyl, piperidinyl, phenylethyl, —C(O)morpholin-4-yl, —C(O)NH2, —C(NH)NH2 or —C(O)OMe;
R7 is
—OH, —CN, oxo, —C(O)NH2, —NH2, —NHC1-3alkyl, —CH2NH2, —CH3, —NHC(O)NH2, —NHC(NH)NH2, —NHC(O)morpholin-4-yl, —NHSO2C1-3alkyl, —NHC(O)NH2, —NHC(O)OC1-3alkyl, C1-6alkoxy, H2NCH(R10)C(O)—, HOCH(R9)CH2NH—, R9CH2CH(OH)CH2NH— or R9OCH2CH(OH)CH2NH—, or R7 is 2-hydroxyethylamino, methylcarbamimidoyl, methanesulfonylamino, methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino, carbamoylmethylamino or N′-phenylhydrazinocarbonyl, —NHCH2CO2H;
R8 is
C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, halogen, —CN, —CO2H, —CO2C1-6alkyl, —S(O)2C1-6alkyl, SC1-6alkyl, —NO2, —OH, —CF3, —N(R5)(R6), —NHC(O)NHC1-6alkyl, —C(O)N(R5)(R6) or phenyl or pyridyl, optionally substituted with halogen, C1-6alkyl, —CN or C1-6alkoxy;
R9 is
C1-6alkyl, an aryl or a heteroaryl group selected from phenyl, naphthly, imidazolyl, thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzothiophenyl, benzothiazolyl, indolyl, benzimidazoyl, quinolinyl, isoquinolinyl, benzo[1,3]dioxoly, 2,3-dihydro-benzo[1,4]dioxinyl, 1-oxo-1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl and 2-oxo-2,3-dihydro-benzooxazoly, and wherein R9 is optionally substituted with one to three R11
R10 is
C1-6alkyl, —(CH2)14NH2, phenyl or benzyl;
R11 is
halogen, hydroxyl, C1-6alkyl, benzyl, C1-6alkoxy, phenoxy, phenylamino, hydroxyC1-6alkyl, —CN, —CO2H, —CO2C1-6alkyl, —N(R5)(R6), C1-6alkylN(R5)(R6), —C(O)N(R5)(R6), —NO2, —S(O)nC1-6alkyl and —S(O)nN(R5)(R6), morpholinyl, or an aryl or a heteroaryl group selected from phenyl, imidazolyl, pyrazolyl, thienyl, oxazoly, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, and benzo[1,3]dioxoly, and wherein R11 is optionally substituted with one to three R12;
and
R12 is
halogen, hydroxyl, C1-6alkyl, C1-6alkoxy, —CN, —CO2H, —CO2C1-6alkyl, —N(R5)(R6) and C(O)N(R5)(R6);
or the pharmaceutically acceptable salts, acids, esters or isomers thereof.

50 more elements

A compound chosen from:

3-Amino-6-(4-amino-piperidin-1-yl)-4-(2-dimethylamino-ethoxy)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-(2,2,2-trifluoro-ethoxy)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-4-cyclopentyloxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-(2-morpholin-4-yl-ethoxy)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-(pyridin-4-ylmethoxy)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-(2-benzylamino-ethoxy)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-ethoxy-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-4-cyclopentylmethoxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-cyclobutoxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-cyclopropylmethoxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-ethoxy-6-(4-hydroxy-piperidin-1-yl)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-(pyridin-3-ylmethoxy)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-4-ethoxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-cyclobutylmethoxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-cyclohexylmethoxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-propoxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-6-(2-amino-ethyl)-4-cyclopentylmethoxy-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-4-methoxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-(2-hydroxy-ethoxy)-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-isopropoxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-ethoxy-5,7-diiodo-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-4-ethoxy-7-furan-3-yl-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-7-(4-cyano-phenyl)-4-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-4-benzyloxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-4-ethoxy-7-iodo-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-7-furan-3-yl-4-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-4-cyclopentylmethoxy-6-[2-(diaminomethyl-amino)-ethyl]-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-7-iodo-4-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-(2-benzenesulfonylamino-ethoxy)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-benzyloxy-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-7-furan-3-yl-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-7-((Z)-2-carbamoyl-vinyl)-4-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-4-phenethyloxy-benzo[b]thiophene-2,7-dicarboxylic acid diamide;
3-Amino-7-pyridin-4-yl-4-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-fluoro-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(2-amino-ethyl)-4-ethoxy-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(2-amino-ethyl)-4-(2,2,2-trifluoro-ethoxy)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(2-amino-ethyl)-4-cyclopentyloxy-benzo[b]thiophene-2-carboxylic acid amide;
{2-[3-Amino-2-carbamoyl-4-(2,2,2-trifluoro-ethoxy)-benzo[b]thiophen-6-yl]-ethyl}-carbamic acid methyl ester;
3-Amino-4-(2-amino-ethoxy)-6-(4-amino-piperidin-1-yl)-benzo[b]thiophene-2-carboxylic acid amide;
4-(2-Acetylamino-ethoxy)-3-amino-6-(4-amino-piperidin-1-yl)-benzo[b]thiophene-2-carboxylic acid amide;
3-Amino-6-(4-amino-piperidin-1-yl)-4-methylsulfanyl-benzo[b]thiophene-2-carboxylic acid amide;
or the pharmaceutically acceptable salts, acids, esters or isomers thereof.

40 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/902,562Filed 29 Jul 2004
Priority: 31 Jul 2003
Published: 17 Feb 2005
Term ends: Not estimatedThe source records don’t support an estimate.

Classification28 codes

C07D 409/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/38
Heterocyclic compounds: having sulfur as a ring hetero atom
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application60/491,575Us provisional application · filed 31 Jul 2003
US 7,329,764 B2Related patent
US 2005/0038104 A1This patent

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

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Abstract

A compound of formula (I):

wherein R1 is:
a) hydrogen,
b) halogen,
c) C1-8 alkyl, optionally partially or fully halogenated,
d) C3-7 heterocycle or C3-7 cycloalkyl, optionally substituted with one or two R8,
e) C1-8 alkoxy, optionally partially or fully halogenated and optionally substituted with C3-7 cycloalkyl, phenyl, pyridyl, morpholine, —OH, —N(R5)(R6), —C(O)NR5R6 or C1-6 alkoxy,
f) C3-8 cycloalkoxy, optionally partially or fully halogenated and optionally substituted with C3-7 cycloalkyl, phenyl, pyridyl, morpholine, —OH, —N(R5)(R6), —C(O)NR5R6 or C1-6 alkoxy,
g) —N(R5)(R6)
h) C1-6alkylthio, optionally partially or fully halogenated,
i) aryl, optionally substituted with one or two R8, or
j) heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl, triazolyl and benzofuranyl, optionally substituted with one or two R8;
R2 is
a) hydrogen,
b) halogen,
c) phenyl,
d) methoxy, or
e) methyl;
R3 is
a) hydrogen,
b) halogen,
c) C1-6alkyl, optionally partially or fully halogenated and optionally substituted with —N(R5)(R6);
d) C1-6alkoxy, optionally partially or fully halogenated and optionally substituted with —N(R5)(R6);
e) —N(R5)(R6);
f) C1-6alkylthio, optionally partially or fully halogenated and optionally substituted with —N(R5)(R6);
g) heterocyclyl selected from from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, 1,4-diazacycloheptan-1-yl, 1-azepanyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, oxazepan-4-yl and 4-thiomorpholino, optionally independently substituted with one to three R7,
h) aryl, optionally substituted with one or two R8, or
i) heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl, and benzofuranyl, optionally substituted with one or two R8;
R4 is
a) hydrogen,
b) halogen,
c) heteroaryl selected from furyl, imidazolyl, pyridyl or thienyl,
d) phenyl, optionally substituted with cyano, C1-6alkoxy, hydroxyC1-6alkyl, aminoC1-6alkyl, halogen or phenyl,
e) C1-6 alkyl, optionally partially or fully halogenated and optionally substituted with —NH2, —OH, or —C(O)NH2,
f) —C(O)NR5R6,
g) C1-6 alkoxy, optionally partially or fully halogenated and optionally substituted with —OH, —N(R5)(R6), or C1-8 alkoxy,
h) cyano, or
i) —N(R5)(R6);
R5 and R6 are independently selected from
H, C1-6alkyl, —C(O)C1-6alkyl, —SO2C1-6alkyl, —S(O)2phenyl, pyridyl, benzyl, piperidinyl, phenylethyl, —C(O)morpholin-4-yl, —C(O)NH2, —C(NH)NH2 or —C(O)OMe;
R7 is
—OH, —CN, oxo, —C(O)NH2, —NH2, —NHC1-3alkyl, —CH2NH2, —CH3, —NHC(O)NH2, —NHC(NH)NH2, —NHC(O)morpholin-4-yl, —NHSO2C1-3alkyl, —NHC(O)NH2, —NHC(O)OC1-3alkyl, C1-6alkoxy, H2NCH(R10)C(O)—, HOCH(R9)CH2NH—, R9CH2CH(OH)CH2NH— or R9OCH2CH(OH)CH2NH—, or R7 is 2-hydroxyethylamino, methylcarbamimidoyl, methanesulfonylamino, methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino, carbamoylmethylamino or N′-phenylhydrazinocarbonyl, —NHCH2CO2H;
R8 is
C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, halogen, —CN, —CO2H, —CO2C1-6alkyl, —S(O)2C1-6alkyl, SC1-6alkyl, —NO2, —OH, —CF3, —N(R5)(R6), —NHC(O)NHC1-6alkyl, —C(O)N(R5)(R6) or phenyl or pyridyl, optionally substituted with halogen, C1-6alkyl, —CN or C1-6alkoxy;
R9 is
C1-6alkyl, an aryl or a heteroaryl group selected from phenyl, naphthly, imidazolyl, thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzothiophenyl, benzothiazolyl, indolyl, benzimidazoyl, quinolinyl, isoquinolinyl, benzo[1,3]dioxoly, 2,3-dihydro-benzo[1,4]dioxinyl, 1-oxo-1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl and 2-oxo-2,3-dihydro-benzooxazoly, and wherein R9 is optionally substituted with one to three R11
R10 is
C1-6alkyl, —(CH2)14NH2, phenyl or benzyl;
R11 is
halogen, hydroxyl, C1-6alkyl, benzyl, C1-6alkoxy, phenoxy, phenylamino, hydroxyC1-6alkyl, —CN, —CO2H, —CO2C1-6alkyl, —N(R5)(R6), C1-6alkylN(R5)(R6), —C(O)N(R5)(R6), —NO2, —S(O)nC1-6alkyl and —S(O)nN(R5)(R6), morpholinyl, or an aryl or a heteroaryl group selected from phenyl, imidazolyl, pyrazolyl, thienyl, oxazoly, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, and benzo[1,3]dioxoly, and wherein R11 is optionally substituted with one to three R12;
and
R12 is
halogen, hydroxyl, C1-6alkyl, C1-6alkoxy, —CN, —CO2H, —CO2C1-6alkyl, —N(R5)(R6) and C(O)N(R5)(R6);
or the pharmaceutically acceptable salts, acids, esters or isomers thereof.

50 more elements

Facts

Application

10/902,562Filed 29 Jul 2004

Priority

31 Jul 2003

Published

17 Feb 2005

Term ends

Not estimatedThe source records don’t support an estimate.

Classification28 codes

C07D 409/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/38
Heterocyclic compounds: having sulfur as a ring hetero atom
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics