Heterocyclylmethyl-thienouracile as antagonists of the adenosine-A2B-receptor

Patent metadata

Field	Value
Publication number	US-10428083-B2
Application number	US-201615560265-A
Country	US
Kind code	B2
Filing date	Mar 21, 2016
Priority date	Mar 26, 2015
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

Abstract

The present application relates to novel thieno[2,3-d]pyrimidine-2,4-dione (“thienouracil”) derivatives bearing a particular type of (azaheterocyclyl)methyl substituent, 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

The invention claimed is:

1. Compound of the formula (I)

in which
the ring A is an azaheterocycle of the formula

in which * marks the bond to the adjoining CH(R 1 ) group,
R 5 is hydrogen, (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, amino, (C 1 -C 5 )-alkanoylamino or (C 1 -C 4 )-alkoxycarbonylamino,
R 6 is hydrogen, methyl or ethyl,
R 7A and R 7B are the same or different and are independently hydrogen or (C 1 -C 4 )-alkyl,
R 8 is hydrogen, (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkenyl, (C 1 -C 5 )-alkanoyl or (C 1 -C 4 )-alkoxycarbonyl,
where (C 1 -C 4 )-alkyl may be up to disubstituted by hydroxyl,

R 9A and R 9B are the same or different and are independently hydrogen or (C 1 -C 4 )-alkyl
and
X is O, N(R 10 ) or S, in which
R 10 is hydrogen, cyano or (C 1 -C 4 )-alkoxycarbonyl,

R 1 is hydrogen or methyl,
R 2 is hydrogen, methyl or ethyl, where methyl and ethyl may be up to trisubstituted by fluorine,
R 3 is (C 2 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl,
where (C 2 -C 6 )-alkyl may be substituted by a radical selected from the group of hydroxyl, methoxy, ethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, oxetanyl and phenyl, and up to trisubstituted by fluorine,
and
(C 2 -C 6 )-alkenyl may be up to trisubstituted by fluorine,
where the cyclopropyl and cyclobutyl groups mentioned may in turn be up to disubstituted, identically or differently, by a radical selected from fluorine and methyl,

or
R 3 is a group of the formula —CH 2 —R 14 in which
R 14 is cyclopropyl, cyclobutyl, oxetanyl or tetrahydrofuranyl, where cyclopropyl, cyclobutyl and oxetanyl may be up to disubstituted, identically or differently, by a radical selected from fluorine and methyl,

and
R 4 is (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl,
where (C 1 -C 6 )-alkyl may be up to pentasubstituted and (C 2 -C 6 )-alkenyl up to trisubstituted by fluorine
and
where one CH 2 group in (C 1 -C 6 )-alkyl may be exchanged for —O—, —S— or —S(O) 2 —, with the proviso that there are at least two carbon atoms between such a heteroatom and the uracil N 1 atom,

or
R 4 is a group of the formula —(CH 2 ) m —CN, —(CH 2 ) n —R 11 or —(CH 2 ) p —R 12 , in which
m is the number 1, 2, 3 or 4,
n is the number 2 or 3,
p is the number 1 or 2,
R 11 is dimethylamino, diethylamino or azetidino
and
R 12 is (C 3 -C 6 )-cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 5-membered azaheteroaryl,
where (C 3 -C 6 )-cycloalkyl may be up to disubstituted, identically or differently, by a radical selected from fluorine and methyl
and
azaheteroaryl may be up to disubstituted, identically or differently, by a radical selected from methyl and trifluoromethyl,

or
R 4 is a group of the formula —(CH 2 ) 2 —O—R 13 in which
R 13 is (C 3 -C 6 )-cycloalkyl,

and a salt, a solvate, and a solvate of the salt thereof.

2. Compound of the formula (I) according to claim 1 , in which
the ring A is an azaheterocycle of the formula

in which * marks the bond to the adjoining CH(R 1 ) group,
R 5 is hydrogen, (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, amino, (C 1 -C 5 )-alkanoylamino or (C 1 -C 4 )-alkoxycarbonylamino,
R 6 is hydrogen, methyl or ethyl,
R 7A and R 7B are the same or different and are independently hydrogen or (C 1 -C 4 )-alkyl,
R 8 is hydrogen, (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkenyl, (C 1 -C 5 )-alkanoyl or (C 1 -C 4 )-alkoxycarbonyl,
where (C 1 -C 4 )-alkyl may be up to disubstituted by hydroxyl,

R 9A and R 9B are the same or different and are independently hydrogen or (C 1 -C 4 )-alkyl
and
X is O, N(R 10 ) or S, in which
R 10 is hydrogen, cyano or (C 1 -C 4 )-alkoxycarbonyl,

R 1 is hydrogen,
R 2 is methyl or ethyl which may be up to trisubstituted by fluorine,
R 3 is (C 2 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl,
where (C 2 -C 6 )-alkyl may be substituted by a radical selected from the group of hydroxyl, methoxy, ethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, oxetanyl and phenyl, and up to trisubstituted by fluorine,
and
(C 2 -C 6 )-alkenyl may be up to trisubstituted by fluorine,
where the cyclopropyl and cyclobutyl groups mentioned may in turn be up to disubstituted, identically or differently, by a radical selected from fluorine and methyl,

or
R 3 is a group of the formula —CH 2 —R 14 in which
R 14 is cyclopropyl, cyclobutyl, oxetanyl or tetrahydrofuranyl,
where cyclopropyl and cyclobutyl may be up to disubstituted, identically or differently, by a radical selected from fluorine and methyl,

and
R 4 is (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl,
where (C 1 -C 6 )-alkyl and (C 2 -C 6 )-alkenyl may be up to trisubstituted by fluorine and
where one CH 2 group in (C 1 -C 6 )-alkyl may be exchanged for —O—, —S— or —S(O ) 2 —, with the proviso that there are at least two carbon atoms between such a heteroatom and the uracil N 1 atom,

or
R 4 is a group of the formula —(CH 2 ) m —CN, —(CH 2 ) n —R 11 or —(CH 2 ) p —R 12 , in which
m is the number 1, 2, 3 or 4,
n is the number 2 or 3,
P is the number 1 or 2,
R 11 is dimethylamino, diethylamino or azetidino
and
R 12 is (C 3 -C 6 )-cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 5-membered azaheteroaryl,
where (C 3 -C 6 )-cycloalkyl may be up to disubstituted, identically or differently, by a radical selected from fluorine and methyl and
azaheteroaryl may be up to disubstituted, identically or differently, by a radical selected from methyl and trifluoromethyl,

or
R 4 is a group of the formula —(CH 2 ) 2 —O—R 13 in which
R 13 is cyclopropyl or cyclobutyl,

and a salt, a solvate, and a solvate of the salt thereof.

3. Compound of the formula (I) according to claim 1 , in which the ring A is an azaheterocycle of the formula

in which * marks the bond to the adjoining CH(R 1 ) group,
R 5 is hydroxy, methoxy or ethoxy,
R 7A and R 7B are each independently hydrogen or methyl,
R 8 is hydrogen, methyl, ethyl, n-propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, allyl, formyl or acetyl,
R 9A and R 9B are each independently hydrogen or methyl
and
X is O, N(R 10 ) or S, in which
R 10 is cyano or (C 1 -C 4 )-alkoxycarbonyl,

R 1 is hydrogen,
R 2 is methyl or ethyl which may be up to trisubstituted by fluorine,
R 3 is (C 2 -C 5 )-alkyl or (C 2 -C 4 )-alkenyl,
where (C 2 -C 5 )-alkyl may be substituted by a radical selected from the group of hydroxyl, methoxy, cyclopropyl, cyclobutyl, oxetanyl and phenyl, and up to trisubstituted by fluorine,
and
(C 2 -C 4 )-alkenyl may be up to trisubstituted by fluorine,
where the cyclopropyl and cyclobutyl groups mentioned may in turn be up to disubstituted by fluorine,

or
R 3 is a group of the formula —CH 2 —R 14 in which
R 14 is cyclopropyl, cyclobutyl or oxetanyl,
where cyclopropyl and cyclobutyl may be up to disubstituted, identica

Assignees

• Bayer Pharma AG

Inventors

• Härter Michael
• Kosemund Dirk
• Delbeck Martina
• Kalthof Bernd
• Wasnaire Pierre
• Süβmeier Frank
• Lustig Klemens

Classifications

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/12

  Antihypertensives · CPC title