US 8,946,438 B2Granted

Benzamides, production thereof, and use thereof as medicaments

AssigneeBoehringer Ingelheim International GmbH

InventorsHolger Wagner, Elke Langkopf, Frank Himmelsbach, Rolf Goeggel, Birgit Jung

Life of this patent

Estimating the term…

Abstract

Heteroaryloxy-substituted benzoic acid amides of general formula I wherein the groups R1 to R7 as well as X and Y are defined according to claim 1, including the tautomers, the stereoisomers, the mixtures and the salts thereof. The compounds according to the invention are suitable for the treatment of respiratory complaints, particularly COPD and asthma.

Claims13

Dependent claims

A compound of formula I

wherein
R1 is selected from hydrogen fluorine, chlorine, bromine, methyl, ethyl and trifluoromethyl
R2 is selected from hydrogen, C1-4-alkyl, C3-6-cycloalkyl-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl, C3-6-cycloalkylamino-C1-3-alkyl, pyrrolidinyl-C1-3-alkyl, piperidin-C1-3-alkyl, azepanyl-C1-3-alkyl, piperazinyl-C1-3-alkyl, morpholinyl-C1-3-alkyl, homopiperazinyl-C1-3-alkyl, pyrrolidin-3-ylamino-C1-3-alkyl, piperidin-3-ylamino-C1-3-alkyl, piperidin-4-ylamino-C1-3-alkyl, C3-6-cycloalkyl trifluoromethyl, cyano, aminocarbonyl, C1-4-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, carboxy, C1-4-alkyloxycarbonyl,
amino, C1-4-alkylamino, C3-6-cycloalkylamino, C3-6-cycloalkyl -C1-3-alkylamino, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, C1-3-alkylamino-C2-3-alkylamino, pyrrolidin-3-ylamino, piperidin-3-ylamino, piperidin-4-ylamino,
pyrrolidinyl-C1-3-alkyl-amino, piperidin-C1-3-alkyl-amino, piperazinyl-C1-3-alkyl-amino, morpholinyl-C1-3-alkyl-amino, homopiperazinyl-C1-3-alkyl-amino, acetylamino, methylsulphonylamino,
hydroxy, C1-4-alkyloxy, trifluoromethoxy, difluoromethoxy, C3-6-cycloalkyloxy C3-6-cycloalkyl-C1-3-alkyloxy, C1-3-alkylamino-C2-3-alkyloxy, di-(C1-3-alkyl)-amino-C2-3-alkyloxy, pyrrolidinyl-C2-3-alkyloxy, piperidin-C2-3-alkyloxy, piperazinyl-C2-3-alkyloxy, morpholinyl -C2-3-alkyloxy, homopiperazinyl-C2-3-alkyloxy,
wherein the above mentioned alkyl, cycloalkyl and N-heterocycloalkyl groups may be mono- or disubstituted by identical or different substituents selected from C1-3-alkyl, cyano, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, acetylamino, methylsulphonylamino, hydroxy and C1-3-alkyloxy, and
wherein in the above mentioned cycloalkyl groups one or two methylene groups may be substituted independently of one another by O and/or CO and in the above-mentioned N-heterocycloalkyl groups a methylene group may be substituted by CO or SO2 , and wherein optional all the NH groups contained in the above mentioned groups are replaced by N-Me, N-Et, N-iPr, N-acetyl and N-SO2Me, and
R3 is selected from hydrogen, methyl, fluorine and chlorine, and
wherein R3 is not hydrogen if R1 denotes hydrogen,
R4 is hydrogen,
R5 is selected from methyl, ethyl and isopropyl,
R6 is L5-R12,
wherein L5 is selected from a bond, NH, C1-3-alkene-NH, NHCO, CONH,
wherein R12 is C1-6-alkyl, NH—(C1-3-alkyl)2, C3-8-cycloalkyl, C3-8-heterocycloalkyl, OH, C1-4-alkylsulphinyl, C1-4-alkylsulphonyl, C1-4-alkylsulphonyl, C3-8-cycloalkylsulphonylamino,
R7 is selected from tert-butyl, trifluoromethyl and pentafluoroethyl
X,Y denote C-R13, and R13 is selected from hydrogen, RN L.

14 more elements

A compound chosen from

N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-(pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-(2-piperazin-1-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-methyl-5-(pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-(2-morpholin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-[2-(4-methyl-piperazin-1-ylmethyl)-pyridin-4-yloxy]-benzamide;
(S)-N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-{2-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-4-yloxy}-benzamide;
(R)-N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-[2-(3-hydroxy-pyrrolidin-1-ylmethyl)-pyridin-4-yloxy]-4-methyl-benzamide;
(S)-N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-[2-(3-hydroxy-pyrrolidin-1-ylmethyl)-pyridin-4-yloxy]-4-methyl-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-(2-methylaminomethyl-pyridin-4-yloxy)-benzamide;
(S)-N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-{2-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-4-yloxy}-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-[2-(4-methyl-homopiperazin-1-ylmethyl)-pyridin-4-yloxy]-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-(2-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-pyridin-4-yloxy)-4-methyl-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-{2-[(2-dimethylamino-ethylamino)-methyl]-pyridin-4-yloxy}-4-methyl-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-[2-(1-methyl-piperidin-4-ylmethyl)-pyridin-4-yloxy]-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-[2-(1-methyl-piperidin-4-ylamino)-pyridin-4-yloxy]-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-[2-(piperidin-4-ylamino)-pyridin-4-yloxy]-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-(2-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-{2-[(2-dimethylamino-ethylamino)-methyl]-pyridin-4-yloxy}-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-(2-piperazin-1-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-[2-(4-methyl-piperazin-1-ylmethyl)-pyridin-4-yloxy]-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-[2-(4-methyl-[1,4]diazepan-1-ylmethyl)-pyridin-4-yloxy]-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-(2-[1,4]diazepan-1-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-chloro-3-[2-(1-methyl-piperidin-4-ylmethyl)-pyridin-4-yloxy]-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-(2-[1,4]diazepan-1-ylmethyl-pyridin-4-yloxy)-4-methyl-benzamide;
N-(5-tert-butyl-2-methoxy-3-methylsulphanylmethyl-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylmethyl-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphinylmethyl-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-[5-tert-butyl-3-(cyclopropanecarbonyl-amino)-2-methoxy-phenyl]-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-2-isopropoxy-3-methanesulphonylamino-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-2-ethoxy-3-methanesulphonylamino-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-[5-tert-butyl-2-methoxy-3-(2-methyl-propane-1-sulphinylamino)-phenyl]-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy) -benzamide;
N-[3-(butan-1-sulphonylamino)-5-tert-butyl-2-methoxy-phenyl]-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-2-methoxy-3-pentanoylamino-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonyl-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-[5-tert-butyl-2-methoxy-3-(3-methyl-butyrylamino)-phenyl]-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-isobutyrylamino-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphinyl-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphinylmethyl-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphinylmethyl-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-cyclopropanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
3-(2-azepan-4-ylmethyl-pyridin-4-yloxy)-N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-[2-(1-methyl-azepan-4-ylmethyl)-pyridin-4-yloxy]-benzamide;
N-(3-methanesulphonylamino-2-methoxy-5-pentafluoroethyl-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-dimethylaminomethyl-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-{2-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-ylmethyl]-pyridin-4-yloxy}-benzamide;
N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-[2-(4-cyanomethyl-piperazin-1-ylmethyl)-pyridin-4-yloxy]-4-methyl-benzamide;
N-(5-tert-butyl-2-methoxy-3-pyrrolidin-1-ylmethyl-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-hydroxymethyl-2-methoxy-phenyl)-4-methyl-3-(2-piperazin-1-ylmethyl-pyridin-4-yloxy)-benzamide;
N-(5-tert-butyl-3-hydroxymethyl-2-methoxy-phenyl)-4-methyl-3-[2-(4-methyl-piperazin-1-ylmethyl)-pyridin-4-yloxy]-benzamide;
N-(5-tert-butyl-3-hydroxymethyl-2-methoxy-phenyl)-3-(2-[1,4]diazepan-1-ylmethyl-pyridin-4-yloxy)-4-methyl-benzamide;
N-(5-tert-butyl-3-hydroxymethyl-2-methoxy-phenyl)-4-methyl-3-[2-(4-methyl-[1,4]diazepan-1-ylmethyl)-pyridin-4-yloxy]-benzamide;
and
N-(5-tert-butyl-3-cyclopropylaminomethyl-2-methoxy-phenyl)-4-methyl-3-(2-piperidin-4-ylmethyl-pyridin-4-yloxy)-benzamide
or a tautomer, stereoisomer or mixture thereof or a physiologically acceptable salt thereof.

53 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/196,436Filed 4 Mar 2014 · division
Priority: EP 081635252 Sep 2008
Published: US 2014/0187539 A13 Jul 2014
Granted: 3 Feb 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 403/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 11/00
Drugs for disorders of the respiratory system
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00

Family

PCT/EP2009/061024Parent of this division · filed 26 Aug 2009
US 2014/0187539 A1Pre-grant publication · published 3 Jul 2014
Application13/060,761Parent of this division
US 8,735,579 B2Parent of this division
US 2012/0108572 A1Published application
US 8,946,438 B2This 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 selected from hydrogen fluorine, chlorine, bromine, methyl, ethyl and trifluoromethyl
R2 is selected from hydrogen, C1-4-alkyl, C3-6-cycloalkyl-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl, C3-6-cycloalkylamino-C1-3-alkyl, pyrrolidinyl-C1-3-alkyl, piperidin-C1-3-alkyl, azepanyl-C1-3-alkyl, piperazinyl-C1-3-alkyl, morpholinyl-C1-3-alkyl, homopiperazinyl-C1-3-alkyl, pyrrolidin-3-ylamino-C1-3-alkyl, piperidin-3-ylamino-C1-3-alkyl, piperidin-4-ylamino-C1-3-alkyl, C3-6-cycloalkyl trifluoromethyl, cyano, aminocarbonyl, C1-4-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, carboxy, C1-4-alkyloxycarbonyl,
amino, C1-4-alkylamino, C3-6-cycloalkylamino, C3-6-cycloalkyl -C1-3-alkylamino, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, C1-3-alkylamino-C2-3-alkylamino, pyrrolidin-3-ylamino, piperidin-3-ylamino, piperidin-4-ylamino,
pyrrolidinyl-C1-3-alkyl-amino, piperidin-C1-3-alkyl-amino, piperazinyl-C1-3-alkyl-amino, morpholinyl-C1-3-alkyl-amino, homopiperazinyl-C1-3-alkyl-amino, acetylamino, methylsulphonylamino,
hydroxy, C1-4-alkyloxy, trifluoromethoxy, difluoromethoxy, C3-6-cycloalkyloxy C3-6-cycloalkyl-C1-3-alkyloxy, C1-3-alkylamino-C2-3-alkyloxy, di-(C1-3-alkyl)-amino-C2-3-alkyloxy, pyrrolidinyl-C2-3-alkyloxy, piperidin-C2-3-alkyloxy, piperazinyl-C2-3-alkyloxy, morpholinyl -C2-3-alkyloxy, homopiperazinyl-C2-3-alkyloxy,
wherein the above mentioned alkyl, cycloalkyl and N-heterocycloalkyl groups may be mono- or disubstituted by identical or different substituents selected from C1-3-alkyl, cyano, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, acetylamino, methylsulphonylamino, hydroxy and C1-3-alkyloxy, and
wherein in the above mentioned cycloalkyl groups one or two methylene groups may be substituted independently of one another by O and/or CO and in the above-mentioned N-heterocycloalkyl groups a methylene group may be substituted by CO or SO2 , and wherein optional all the NH groups contained in the above mentioned groups are replaced by N-Me, N-Et, N-iPr, N-acetyl and N-SO2Me, and
R3 is selected from hydrogen, methyl, fluorine and chlorine, and
wherein R3 is not hydrogen if R1 denotes hydrogen,
R4 is hydrogen,
R5 is selected from methyl, ethyl and isopropyl,
R6 is L5-R12,
wherein L5 is selected from a bond, NH, C1-3-alkene-NH, NHCO, CONH,
wherein R12 is C1-6-alkyl, NH—(C1-3-alkyl)2, C3-8-cycloalkyl, C3-8-heterocycloalkyl, OH, C1-4-alkylsulphinyl, C1-4-alkylsulphonyl, C1-4-alkylsulphonyl, C3-8-cycloalkylsulphonylamino,
R7 is selected from tert-butyl, trifluoromethyl and pentafluoroethyl
X,Y denote C-R13, and R13 is selected from hydrogen, RN L.

14 more elements

Facts

Application

14/196,436Filed 4 Mar 2014 · division

Priority

EP 081635252 Sep 2008

Published

US 2014/0187539 A13 Jul 2014

Granted

3 Feb 2015

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 403/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 11/00
Drugs for disorders of the respiratory system
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00

Family

PCT/EP2009/061024Parent of this division · filed 26 Aug 2009

US 2014/0187539 A1Pre-grant publication · published 3 Jul 2014

Application13/060,761Parent of this division

US 8,735,579 B2Parent of this division

US 2012/0108572 A1Published application

US 8,946,438 B2This patent

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