N3-cyclically substituted thienouracils and use thereof

Patent metadata

Field	Value
Publication number	US-2020016159-A1
Application number	US-201716335282-A
Country	US
Kind code	A1
Filing date	Sep 18, 2017
Priority date	Sep 23, 2016
Publication date	Jan 16, 2020
Grant date	—

Abstract

The present application relates to novel thieno[2,3-d]pyrimidine-2,4-dione (“thienouracil”) derivatives having cyclic substituents in the 3 position, to processes for the preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of pulmonary and cardiovascular disorders and of cancer.

First claim

1 . A compound of formula (I)

wherein
the ring A is an azaheterocycle of formula

wherein * marks the bond to the adjoining C(R 1A )(R 1B ) group,
R 5A and R 5B are the same or different and are independently hydrogen or (C 1 -C 4 )-alkyl,
R 6 is hydrogen or (C 1 -C 4 )-alkyl,
and
X is O, S or N(R 7 ) wherein
R 7 represents cyano, methoxycarbonyl or ethoxycarbonyl,

R 1A and R 1B are independently hydrogen or deuterium,
R 2 is methyl or ethyl,
R 3 is cyclopropyl, cyclobutyl, cyclopentyl, spiro[3.3]hept-2-yl, 3-oxetanyl or 3-tetrahydrofuranyl,
where cyclopropyl, cyclobutyl, cyclopentyl and spiro[3.3]hept-2-yl may be up to disubstituted identically or differently by a radical selected from fluorine, methyl, ethyl, trifluoromethyl and methoxy,
and
where 3-oxetanyl and 3-tetrahydrofuranyl may be up to disubstituted identically or differently by a radical selected from fluorine and methyl,

and
R 4 is methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, 3-cyanopropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl, 4-fluorobutyl, 4,4,4-trifluorobutyl, 3,3,4,4-tetrafluorobutyl, n-pentyl, iso-pentyl or n-hexyl,
or
R 4 is a group of formula —CH 2 —R 8 wherein
R 8 is cyano, cyclopropyl, cyclobutyl, cyclopentyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl or 3-tetrahydrofuranyl,
where cyclopropyl, cyclobutyl and cyclopentyl may be up to disubstituted by fluorine,

or
R 4 is a group of formula —CH 2 —CH 2 —OR 9 or —CH 2 —CH 2 —SR 10 wherein
R 9 is methyl, trifluoromethyl, ethyl or iso-propyl
and
R 10 is methyl or trifluoromethyl,

and solvates thereof.

2 . The compound of formula (I) according to claim 1 wherein
the ring A is an azaheterocycle of formula

wherein * marks the bond to the adjoining C(R 1A )(R 1B ) group,
R 5A and R 5B are the same or different and are independently hydrogen or (C 1 -C 4 )-alkyl,
R 6 is hydrogen or (C 1 -C 4 )-alkyl,
and
X is O, S or N(R 7 ) wherein
R 7 represents cyano, methoxycarbonyl or ethoxycarbonyl,

R 1A and R 1B are independently hydrogen or deuterium,
R 2 is methyl or ethyl,
R 3 is cyclopropyl, cyclobutyl, cyclopentyl, spiro[3.3]hept-2-yl, 3-oxetanyl or 3-tetrahydrofuranyl,
where cyclopropyl, cyclobutyl, cyclopentyl and spiro[3.3]hept-2-yl may be up to disubstituted identically or differently by a radical selected from fluorine, methyl, ethyl, trifluoromethyl and methoxy,
and
where 3-oxetanyl and 3-tetrahydrofuranyl may be up to disubstituted identically or differently by a radical selected from fluorine and methyl,

and
R 4 is methyl, ethyl, n-propyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl, n-pentyl, iso-pentyl or n-hexyl,
or
R 4 is a group of formula —CH 2 —R 8 wherein
R 8 is cyano, cyclopropyl, cyclobutyl, cyclopentyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl or 3-tetrahydrofuranyl,
where cyclopropyl, cyclobutyl and cyclopentyl may be up to disubstituted by fluorine,

or
R 4 is a group of formula —CH 2 —CH 2 —OR 9 wherein
R 9 is methyl, trifluoromethyl, ethyl or iso-propyl,

And/or a solvate thereof.

3 . The compound of formula (I) according to claim 1 wherein
the ring A is an azaheterocycle of formula

wherein * marks the bond to the adjoining C(R 1A )(R 1B ) group,
R 5A and R 5B are the same or different and are independently hydrogen or methyl,
R 6 is hydrogen or methyl,
and
X is O or N(R 7 ) wherein
R 7 represents cyano or methoxycarbonyl,

R 1A and R 1B are both hydrogen or both deuterium,
R 2 is methyl,
R 3 is cyclopropyl, cyclobutyl, cyclopentyl or spiro[3.3]hept-2-yl,
where cyclopropyl, cyclobutyl, cyclopentyl and spiro[3.3]hept-2-yl may be up to disubstituted identically or differently by a radical selected from fluorine, methyl and methoxy,

and
R 4 is methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl, 4,4,4-trifluorobutyl, n-pentyl or n-hexyl,
or
R 4 is a group of formula —CH 2 —R wherein
R 8 is cyclopropyl, cyclobutyl or 2-tetrahydrofuranyl,
where cyclopropyl and cyclobutyl may be up to disubstituted by fluorine,

or
R 4 is a group of formula —CH 2 —CH 2 —OR 9 wherein
R 9 is methyl or trifluoromethyl,

And/or a solvate thereof.

4 . The compound of formula (I) according to claim 1 wherein
the ring A is an azaheterocycle of formula

wherein * marks the bond to the adjoining C(R 1A )(R 1B ) group,
R 5A and R 5B are the same or different and are independently hydrogen or methyl,
R 6 is hydrogen or methyl,
and
X is O or N(R 7 ) wherein
R 7 represents cyano or methoxycarbonyl,

R 1A and R 1B are both hydrogen or both deuterium,
R 2 is methyl,
R 3 is cyclopropyl, cyclobutyl, cyclopentyl or spiro[3.3]hept-2-yl,
where cyclopropyl, cyclobutyl, cyclopentyl and spiro[3.3]hept-2-yl may be up to disubstituted identically or differently by a radical selected from fluorine, methyl and methoxy,

and
R 4 is n-propyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl, n-pentyl or n-hexyl,
or
R 4 is a group of formula —CH 2 —R 8 wherein
R 8 is cyclopropyl, cyclobutyl or 2-tetrahydrofuranyl,

or
R 4 is a group of formula —CH 2 —CH 2 —OR 9 wherein
R 9 is methyl or trifluoromethyl,

And/or a solvate thereof.

5 . The compound of formula (I) according to claim 1 , wherein
the ring A is an azaheterocycle of formula

wherein * marks the bond to the adjoining C(R 1A )(R 1B ) group,
R 5A and R 5B are each hydrogen,
R 6 is hydrogen,
and
X is O or N(R 7 ) wherein
R 7 represents cyano or methoxycarbonyl,

R 1A and R 1B are both hydrogen or both deuterium,
R 2 is methyl,
R 3 is cyclopropyl, cyclobutyl or cyclopentyl,
where cyclopropyl, cyclobutyl and cyclopentyl may be up to disubstituted, identically or differently, by a radical selected from fluorine and methyl,

and
R 4 is methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, 3-fluoropropyl, 3,3,3-trifluoropropyl or n-butyl,
or
R 4 is a group of formula —CH 2 —R 8 wherein
R 8 is cyclopropyl or cyclobutyl,
where cyclopropyl and cyclobutyl may be up to disubstituted by fluorine,

or
R 4 is a group of formula —CH 2 —CH 2 —OR 9 wherein
R 9 is methyl or trifluoromethyl,

And/or a solvate thereof.

6 . The compound of formula (I) according to claim 1 wherein

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Haerter Michael
• Kosemund Dirk
• Cancho Grande Yolanda
• Delbeck Martina
• Kalthof Bernd
• Lustig Klemens
• Suessmeier Frank

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · 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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/06

  Antianaemics · CPC title