Heterocyclylmethyl-thienouracile as antagonists of the adenosine-A2B-receptor
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.
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, 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— or —S—, 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 the —CH 2 —R 12 group in which
R 12 is (C 3 -C 6 )-cycloalkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl,
where (C 3 -C 6 )-cycloalkyl may be up to disubstituted, identically or differently, by a radical selected from fluorine and methyl,
and a salt, a solvate, and a solvate of the salt thereof.
4. 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 7A and R 7B are each independently hydrogen or methyl,
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, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl,
R 1 is hydrogen,
R 2 is methyl, difluoromethyl or trifluoromethyl,
R 3 is (C 2 -C 5 )-alkyl which may be substituted by hydroxyl, methoxy or cyclopropyl or up to trisubstituted by fluorine,
where cyclopropyl may in turn be up to disubstituted by fluorine,
and
R 4 is (C 1 -C 4 )-alkyl which may be up to trisubstituted by fluorine, is 2-methoxyethyl or 2-ethoxyethyl or is the —CH 2 —R 12 group in which
R 12 is cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl,
where cyclopropyl and cyclobutyl may be up to disubstituted by fluorine,
and a salt, a solvate, and a solvate of the salt thereof.
5. Compound as defined in claim 1 , which is 3-Ethyl-1-(2-methoxyethyl)-5-methyl-6-[(2-oxoimidazolidin-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione of the formula
or a salt, solvate or solvate of the salt thereof.
6. Compound as defined in claim 1 , which is 3-Isopropyl-5-methyl-6-[(2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl]-1-(tetrahydrofuran-2-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (enantiomer 1) of the formula
or a salt, solvate or solvate of the salt thereof.
7. Compound as defined in claim 1 , which is [1-{[3-Ethyl-5-methyl-2,4-dioxo-1-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]methyl}imidazolidin-2-ylidene]cyanamide (enantiomer 1) of the formula
or a salt, solvate or solvate of the salt thereof.
8. Compound as defined in claim 1 , which is 3-(4,4-Difluorobut-3-en-1-yl)-1-(2-methoxyethyl)-5-methyl-6-[(2-oxoimidazolidin-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione of the formula
or a salt, solvate or solvate of the salt thereof.
9. Compound as defined in claim 1 for use in a method for treatment of idiopathic pulmonary fibrosis, pulmonary hypertension, Bronchiolitis obliterans syndrome, chronic-obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, sickle cell anaemia or cancer.
10. Medicament comprising a compound as defined in claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.
11. Medicament comprising a compound as defined in claim 1 in combination with one or more further active ingredients selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogues, IP receptor agonists, endothelin antagonists, antifibrotic agents, antiinflammatory, immunomodulating, immunosuppressive and/or cytotoxic agents and/or compounds that inhibit the signal transduction cascade.
12. Medicament according to claim 10 for the treatment of idiopathic pulmonary fibrosis, pulmonary hypertension, Bronchiolitis obliterans syndrome, chronic-obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, sickle cell anaemia or cancer.
13. Method for treatment of a disease by administration of an effective amount of at least one compound of claim 1 .
14. Method for treatment of idiopathic pulmonary fibrosis, pulmonary hypertension, Bronchiolitis obliterans syndrome, chronic-obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, sickle cell anaemia or cancer by administration of an effective amount of at least one compound of claim 1 .
15. Method for treatment of idiopathic pulmonary fibrosis, pulmonary hypertension, Bronchiolitis obliterans syndrome, chronic-obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, sickle cell anaemia or cancer in a human or an animal by administration of an effective amount of at least one medicament as defined in claim 10 .
16. Method for providing antagonistic activity at an adenosine A2b receptor by administration of an effective amount of at least one compound of claim 1 .
17. Compound of the formula (I-A)
in which the ring A and the R 2 , R 3 and R 4 radicals are as defined in claim 1 ,
and a salt, a solvate and a solvate of the salt thereof.