Estra-1,3,5(10),16-tetraene-3-carboxamides for inhibition of 17.beta.-hydroxysteroid dehydrogenase (AKR1C3)

Patent metadata

Field	Value
Publication number	US-9714266-B2
Application number	US-201414770444-A
Country	US
Kind code	B2
Filing date	Feb 18, 2014
Priority date	Feb 21, 2013
Publication date	Jul 25, 2017
Grant date	Jul 25, 2017

Abstract

The invention relates to AKR1C3 inhibitors of formula (I) and to processes for preparation thereof, to the use thereof for treatment and/or prophylaxis of diseases and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of bleeding disorders and endometriosis.

First claim

The invention claimed is:

1. A compound of the general formula (I)

where
X is independently carbon or nitrogen, where the carbon is optionally substituted by R 1 ,
Y is carbon or nitrogen, where the carbon is optionally substituted by R 2 ,
R 1 and R 2
are each independently hydrogen, halogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, nitrile, nitro, —SO 2 CH 3 , —SO 2 CH 2 CH 3 , —(C═O)CH 3 , carboxyl, hydroxyl, —NH 2 , —CH 2 NH 2 , —CH 2 OH, —CH(OH)CH 3 , —C(CH 3 ) 2 OH, —(C═O)NH 2 , —(C═O)NHCH 3 , —(C═O)NHCH 2 CH 3 , —(C═O)N(CH 3 ) 2 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 N(CH 3 ) 2 ,

R 3 is hydrogen or halogen,
R 4 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl or C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkyl, which are optionally substituted by up to 6 halogen atoms and are optionally mono- or disubstituted by hydroxyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy,
R 5 is hydrogen, C 1 -C 6 -alkyl or C 3 -C 6 -cycloalkyl, where C 1 -C 6 -alkyl and C 3 -C 6 -cycloalkyl are optionally substituted by up to 6 halogen atoms and are optionally mono- or disubstituted by hydroxyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxy-C 2 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 3 -C 6 -cycloalkyl, aryl, heteroaryl, 3-10-membered heterocycloalkyl, aryl-C 1 -C 6 -alkyl, heteroaryl-C 1 -C 6 -alkyl, —C(═O)R′, —C(═O)NH 2 , —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH 2 ,
—NHR′—N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO 2 , —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O) 2 R′, —N(R′)S(═O) 2 R′, —N═S(═O)(R′)R″, —S(═O)R′, —S(═O) 2 R′, —S(═O) 2 NH 2 , —S(═O) 2 NHR′, —S(═O) 2 N(R′)R″, —S(═O)(═NR′)R″, where aryl, heteroaryl, aryl-C 1 -C 6 -alkyl and heteroaryl-C 1 -C 6 -alkyl are optionally each independently mono- or polysubstituted by R 6 , and 3-10-membered heterocycloalkyl is optionally independently mono- or polysubstituted by R′, or

R 4 and R 5 together with the directly joining nitrogen atom are a 4-7-membered ring which is optionally substituted by one or two substituents from the group consisting of:
halogen, nitrile, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 10 -cycloalkyl, aryl, heteroaryl,
—C(═O)NH 2 , —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′, —NH 2 , —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O) 2 R′, —N(R′)S(═O) 2 R′, —N═S(═O)(R′)R″, —OH,
C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, —OC(═O)R′, —OC(═O)NH 2 , —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C 1 -C 6 -alkyl-S—, —S(═O)R′, —S(═O) 2 R′, —S(═O) 2 NH 2 , —S(═O) 2 NHR′, —S(═O) 2 N(R′)R″, where aryl and heteroaryl are optionally each independently mono- or polysubstituted by R 6 ,
and in which 5-, 6- or 7-membered ring one or more methylene groups are optionally replaced by NH, NR′, O or S,

R 6 is halogen, nitrile, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 10 -cycloalkyl, 3-10-membered heterocycloalkyl, aryl, heteroaryl, —C(═O)R′, —C(═O)NH 2 , —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH 2 , —NHR′,
—N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH 2 , —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH 2 , —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO 2 , —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O) 2 R′, —N(R′)S(═O) 2 R′, —N═S(═O)(R′)R″, —OH, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, —OC(═O)R′, —OC(═O)NH 2 , —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C 1 -C 6 -alkyl-S—, —S(═O)R′, —S(═O) 2 R′, —S(═O) 2 NH 2 , —S(═O) 2 NHR′, —S(═O) 2 N(R′)R″, —S(═O)(═NR′)R″,

R′ and R″ are each independently C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl or C 1 -C 6 -haloalkyl, or the stereoisomers, tautomers, N-oxides, or salts thereof.

2. The compound of claim 1 ,
wherein
X is carbon substituted by hydrogen,
Y is carbon or nitrogen, where the carbon is optionally substituted by R 2 ,
R 2 is hydrogen, fluorine, chlorine, nitrile, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, —(C═O)CH 3 ,
R 3 is hydrogen or fluorine,
R 4 is hydrogen, methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl or 2,2,2-trifluoroethyl,
R 5 is hydrogen, methyl, ethyl, propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-fluoroethyl, 2-sulphamoylethyl, 3-sulphamoylpropyl, (1S,2R)-2-hydroxycyclopentyl, 3-hydroxy-2,2-dimethylpropyl, (1S,2S)-2-hydroxycyclopentyl, (3R)-4-hydroxy-3-methylbutyl, 1-(hydroxymethyl)cyclopentyl, (2S)-1-hydroxybutan-2-yl, (2R)-1-hydroxy-3-methylbutan-2-yl, 3-hydroxybutan-2-yl, 2-hydroxyethyl, 3,3,3-trifluoro-2-hydroxypropyl, 2-(1H-tetrazol-5-yl)ethyl, 1H-tetrazol-5-ylmethyl, 2-(methylsulphamoyl)ethyl, 3-amino-3-oxopropyl, 3-(methylamino)-3-oxopropyl, 2-methyl-2-[(methylsulphonyl)amino]propyl, (2S)-2,3-dihydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, (2RS)-2,3-dihydroxypropyl, (2R)-2,3-dihydroxypropyl, 2,3-dihydroxybutyl, 2-(methylsulphinyl)ethyl, 3-(methylsulphinyl)propyl, 2-(methyl sulphonyl)ethyl, 3-(methylsulphonyl)propyl, 2-(S-methylsulphonimidoyl)ethyl, (2R)-2-hydroxypropyl, (2S)-1-hydroxypropan-2-yl, 2-methoxyethyl, 3-methoxypropyl, 2-(isopropylsulphonyl)ethyl, (3-methyloxetan-3-yl)methyl, (2S)-2-hydroxypropyl, 2-(2-hydroxyethoxy)ethyl,
or

R 4 and R 5 together with the directly joining nitrogen atom are piperidinyl, pyrrolidinyl, morpholinyl, N-methylpiperazinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholin-4-yl, 4-hydroxypiperidinyl, 4-(trifluoromethyl)piperidin-4-yl, (3R)-3-hydroxypiperidinyl, (2S)-2-(1H-tetrazol-5-yl)pyrrolidinyl, N-methyl-L-prolinamidyl and L-prolinamidyl,
or the stereoisomers, tautomers, N-oxides, or salts thereof.

3. The compound of claim 1 ,
wherein
X is carbon substituted by hydrogen,
Y is carbon or nitrogen, where the carbon is optionally substituted by R 2 ,
R 2 is hydrogen, fluorine, chlorine, methyl, nitrile, methoxy, trifluoromethyl,
R 3 is hydrogen or fluorine,
R 4 is hydrogen, methyl, ethyl, isopropyl, propyl or cyclopropyl,
R 5 is hydrogen, methyl, ethyl, 2-sulphamoylethyl, 3-sulphamoylpropyl, (1S,2R)-2-hydroxycyclopentyl, 3-hydroxy-2,2-dimethylpropyl, (1S,2S)-2-hydroxycyclopentyl, (3R)-4-hydroxy-3-methylbutyl, 1-(hydroxymethyl)cyclopentyl, (2S)-1-hydroxybutan-2-yl, (2R)-1-hydroxy-3-methylbutan-2-yl, 3-hydroxybutan-2-yl, 2-hydroxyethyl, 3,3,3-trifluoro-2-hydroxypropyl, 2-(1H-tetrazol-5-yl)ethyl, 1H-tetrazol-5-ylmethyl, 2-(methylsulphamoyl)ethyl, 3-amino-3-oxopropyl, 3-(methylamino)-3-oxopropyl, 2-methyl-2-[(methylsulphonyl)amino]propyl, (2S)-2,3-dihydroxypropyl, 3-hydroxypropyl, (2RS)-2,3-dihydroxypropyl, (2R)-2,3-dihydroxypropyl, 2-(methylsulphinyl)ethyl, (2R)-2-hydroxypropyl, (2S)-1-hydroxypropan-2-yl, 2-methoxyethyl, 2-(isopropylsulphonyl)ethyl, (3-methyloxetan-3-yl)methyl, (2S)-2-hydroxypropyl or 2-(2-hydroxyethoxy)ethyl or
R 4 and R 5 together with the directly joining nitrogen atom are piperidinyl, pyrrolidinyl, morpholinyl, 4-hydroxypiperidinyl, (3R)-3-hydroxypiperidinyl, (2S)-2-(1H-tetrazol-5-yl)pyrrolidinyl, N-methyl-L-prolinamidyl or L-prolinamidyl
or the stereoisomers, tautomers, N-oxides, or salts thereof.

4. The compound of claim 1 ,
wherein
X is carbon substituted by hydrogen,
Y is carbon or nitrogen, where the carbon is optionally substituted by R 2 ,
R 2 is hydrogen, fluorine, nitrile, methoxy or trifluoromethyl,
R 3 is hydrogen or fluorine,
R 4 is hydrogen, methyl, ethyl or isopropyl,
R 5 is hydrogen, ethyl, 2-sulphamoylethyl, (1S,2R)-2-hydroxycyclopentyl, 3-hydroxy-2,2-dimethylpropyl, (1S,2S)-2-hydroxycyclopentyl, (3R)-4-hydroxy-3-methylbutyl, 1-(hydroxymethyl)cyclopentyl, (2S)-1-hydroxybutan-2-yl, (2R)-1-hydroxy-3-methylbutan-2-yl, 3-hydroxy

Assignees

• Bayer Pharma AG

Inventors

• Bothe Ulrich
• Busemann Matthias
• Barak Naomi
• Rotgeri Andrea
• Fischer Oliver Martin
• Marquardt Tobias

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P37/02

  Immunomodulators · CPC title