Substituted-4-(pyrrolo pyrimidin-6-yl)benzenesulphonamide derivatives
This invention is directed to selective antagonists of A 2A and/or A 2B adenosine receptors having the general formula (I); to processes for their preparation; to pharmaceutical compositions comprising them; and to their use in therapy.
1. A compound of formula (I)
wherein
R 1 and R 2 each independently represents:
a) a hydrogen atom;
b) a hydrocarbon chain chosen from an alkyl, alkenyl and alkynyl groups, wherein said hydrocarbon chain is optionally substituted by one or more substituents chosen from halogen, hydroxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, cyano, oxo, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy and dialkoxyphosphoryloxy groups; or
c) a group of formula
—(CH 2 ) n —R 6
n is an integer from 0 to 4 and
R 6 represents a 3- to 7-membered aromatic or non-aromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S, wherein said 3- to 7-membered aromatic or non-aromatic cyclic group is optionally bridged and/or fused to another 3- to 7-membered aromatic or non-aromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S; and
wherein each of the cyclic groups in the moiety R 6 being is independently optionally substituted by one or more R 7 substituents;
R 7 represents a group chosen from halogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, hydroxy, alkylenedioxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, nitro, cyano, oxo, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy and dialkoxyphosphoryloxy groups;
wherein each of the hydrocarbon chains and each of the cyclic moieties in R 7 is independently optionally substituted by one or more further R 8 substituents,
R 8 represents a group chosen from halogen, hydroxy, oxo, cyano, alkyl, difluoromethyl, trifluoromethyl, alkoxy, alkylenedioxy, alkylthio acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy, dialkoxyphosphoryloxy, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and hydroxycarbonyl groups;
R 3 represents a hydrogen or halogen atom, or a nitro, alkoxycarbonyl or alkyl group; wherein the alkyl group is optionally substituted by one or more substituents chosen from hydroxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl sand alkylcarbamoyl groups;
R 4 and R 5 are the same or different, each independently representing:
a) hydrogen;
b) a group of formula —(CH 2 ) n —R 6 ;
c) or a hydrocarbon chain chosen from alkyl, alkenyl and alkynyl, wherein said hydrocarbon chain is optionally substituted by one or more substituents chosen from —(CH 2 ) n —R 6 , —O—(CH 2 ) n —R 6 , —S—(CH 2 ) n —R 6 , —NH—(CH 2 ) n —R 6 , hydroxy, oxo, halogen, alkoxy, alkylthio, amino, monoalkylamino, and dialkylamino groups; wherein each of the alkyl chains in the alkoxy, alkylthio, monoalkylamino or dialkylamino substituents is independently optionally substituted by one or more further substituents chosen from —(CH 2 ) n —R 6 , hydroxy, oxo, halogen, alkoxy, alkylthio, amino, monoalkylamino and dialkylamino groups; wherein each n is independently an integer from 0 to 4 and each R 6 is independently chosen from each other; or
d) alternatively, R 4 and R 5 , together with the nitrogen atom to which they are attached, form a 3- to 7-membered aromatic or non-aromatic cyclic group containing from 1 to 4 heteroatoms chosen from N, O and S, wherein said 3- to 7-membered aromatic or non-aromatic cyclic group is optionally bridged and/or fused to another 3- to 7-membered aromatic or non-aromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S;
wherein each of the cyclic groups is independently optionally substituted by one or more substituents chosen from —(CH 2 ) n R 6 and R 7 ; wherein each of the hydrocarbon chains and each of the cyclic moieties of the R 7 substituents is independently optionally substituted by one or more further substituents chosen from—(CH 2 ) n —R 6 and R 8 ; wherein each of the alkyl chains in the R 8 substituents is independently optionally substituted by one or more further substitutents chosen from —(CH 2 ) n —R 6 , hydroxy, halogen, alkoxy, alkylthio, amino, monoalkylamino and dialkylamino groups; wherein each of the R 6 substituents is independently chosen from each other;
or an N-oxide or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein each of R 1 and R 2 independently represents:
a) an alkyl group optionally substituted by one or more substituents chosen from hydroxy, halogen, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, hydroxycarbonyl, and alkoxycarbonyl groups; or
b) a group of formula —(CH 2 ) n —R 6 , wherein n is an integer from 0 to 2 and R 6 represents a 3- to 7-membered aromatic or non-aromatic cyclic group having from 0 to 2 heteroatoms chosen from nitrogen and oxygen.
3. A compound according to claim 2 wherein R 1 and R 2 are both unsubstituted C 1 -C 6 alkyl groups.
4. A compound according to claim 1 , wherein R 3 represents hydrogen or a halogen atom.
5. A compound according to claim 1 , wherein
R 5 is hydrogen, a group of formula —(CH 2 ) n R 6 or a hydrocarbon chain chosen from alkyl, alkenyl and alkynyl,
wherein said hydrocarbon chain is optionally substituted by one or more groups chosen from —(CH 2 ) n —R 6 and —O—(CH 2 ) n —R 6 ;
wherein each R 6 is independently a phenyl or a pyridyl group, and
wherein each R 6 is independently optionally substituted by one or more substituents chosen from halogen, hydroxy, alkyl, alkoxy and alkylthio groups.
6. A compound according to claim 5 , wherein R 5 is hydrogen or an alkyl group.
7. A compound of formula (I)
wherein
R 1 and R 2 each independently represents:
a) hydrogen atom;
b) hydrocarbon chain chosen from an alkyl, alkenyl and alkynyl groups, wherein said hydrocarbon chain is optionally substituted by one or more substituents chosen from halogen, hydroxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, cyano, oxo, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy and dialkoxyphosphoryloxy groups; or
c) a group of formula
—(CH 2 ) n —R 6
n is an integer from 0 to 4 and
R 6 represents a 3- to 7-membered aromatic or non-aromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S, wherein said 3- to 7-membered aromatic or non-aromatic cyclic group is optionally bridged and/or fused to another 3- to 7-membered aromatic or non-aromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S; and
wherein each of the cyclic groups in the moiety R 6 is independently optionally substituted by one or more R 7 substituents;
R 7 represents a group chosen from halogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, hydroxy, alkylenedioxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, nitro, cyano, oxo, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy and dialkoxyphosphoryloxy groups;
wherein each of the hydrocarbon chains and each of the cyclic moieties in R 7 is independently optionally substituted by one or more further R 8 substituents;
R 8 represents a group chosen from halogen, hydroxy, oxo, cyano, alkyl, difluoromethyl, trifluoromethyl, alkoxy, alkylenedioxy, alkylthio, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy, dialkoxyphosphoryloxy, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, and hydroxycarbonyl groups;
R 3 represents a hydrogen or halogen atom, or a nitro, alkoxycarbonyl or alkyl group; wherein the alkyl group is optionally substituted by one or more substituents chosen from hydroxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl and alkylcarbamoyl groups;
R 4 represents:
a) hydrogen;
b) a group of formula —(CH 2 ) n —R 6 wherein n is 0, 1 or 2 and R 6 is a 5- to 6-membered heteroaryl or heterocyclyl group containing up to 2 heteroatoms chosen from N, O and S, wherein R 6 is optionally substituted by a R 7 substituent chosen from alkyl, alkoxy, arylalkyl or heteroarylalkyl groups, wherein each of the aryl and heteroaryl moieties of these arylalkyl and heteroarylalkyl R 7 substituents is independently optionally substituted by 1 or 2 further R 8 substituents chosen from halogen, cyano, alkyl, trifluoromethyl, alkoxy and alkylenedioxy; or
c) an alkyl group, which is optionally substituted by 1 or 2 substituents chosen from amino, monoalkylamino, dialkylamino, —OR 6 and —SR 6 substituents, wherein R 6 is a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms, and is optionally substituted by one or more R 7 substituents chosen from hydroxy, halogen, amino, monoalkylamino, dialkylamino, cyano, hydroxycarbonyl, alkoxycarbonyl, alkoxy, alkylenedioxy and alkylthio; and wherein the alkyl chains of each of the said monoalkylamino and dialkylamino substituents are independently optionally substituted by 1 or 2 further substituents chosen from a hydroxy group and a group of formula —(CH 2 ) n —R 6 , wherein n is an integer from 0 to 4 and R 6 is an aryl group;
R 5 is hydrogen, a group of formula —(CH 2 ) n R 6 or a hydrocarbon chain chosen from alkyl, alkenyl and alkynyl,
wherein said hydrocarbon chain is optionally substituted by one or more groups chosen from —(CH 2 ) n —R 6 and —O—(CH 2 ) n —R 6 ;
wherein each R 6 is independently a phenyl or a pyridyl group, and
wherein each R 6 is independently optionally substituted by one or more substituents chosen from halogen, hydroxy, alkyl, alkoxy and alkylthio groups; or
an N-oxide or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 , wherein R 4 and R 5 form, together with the nitrogen atom to which they are attached, an optionally bridged 5- to 7-membered aromatic or non-aromatic cyclic group, which contains up to two nitrogen atoms, and which is optionally substituted by a group of formula —(CH 2 ) n —R 6 or by a R 7 substituent chosen from alkyl, alkenyl and alkynyl chains; wherein each of said alkyl, alkenyl and alkynyl chains is independently optionally substituted by one or more groups of formula —(CH 2 ) n —R 6 or R 8 substituents chosen from hydroxy, halogen, alkoxy, alkylthio, amino, monoalkylamino, and dialkylamino groups; wherein each of the alkyl chains in these R 8 substituents is independently optionally substituted by one or more further substituents chosen from a group of formula —(CH 2 ) n —R 6 , and hydroxy, halogen, alkoxy, alkylthio, amino, monoalkylamino and dialkylamino groups;
wherein each of the R 6 groups is independently chosen from each other.
9. A compound according to claim 1 , wherein R 4 and R 5 form, together with the N atom to which they are attached, a 5-, 6- or 7-membered saturated heterocyclic group, which contains 1 or 2 nitrogen atoms and which optionally carries a bridging alkylene group,
wherein said saturated heterocyclic cyclic group is optionally substituted by a group of formula —(CH 2 ) n —R 6 wherein n is 0, 1 or 2 and R 6 is a 5- or 6-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms chosen from N, O and S, or by a R 7 substituent chosen from alkyl and alkenyl groups,
wherein the group R 6 is optionally substituted by 1, 2 or 3 further substituents chosen from haloalkyl, alkyl, alkoxy, alkylenedioxy, cyano and halogen groups, and the said R 7 substituent optionally substituted by 1 or 2 phenyl substituents.
10. A compound according to claim 1 chosen from:
4-(1,3-Dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)-N-[2-(pyridin-2-yloxy)ethyl]benzenesulfonamide;
4-(1,3-Dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)-N-[2-(6 methoxypyridin-2-yloxy)ethyl]benzenesulfonamide;
6-[4-(4-Benzylpiperazine-1-sulphonyl)phenyl]-1,3-dimethyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione;
6-{4-[4-(4-Fluorobenzyl)piperazine-1-sulphonyl]phenyl}-1-methyl-3-propyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione;
6-[4-(4-Benzo[1,3]dioxol-5-ylmethylpiperazine-1-sulphonyl)phenyl]-1-methyl-3-propyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione;
6-{4-[4-(3-Fluorobenzyl)piperazine-1-sulphonyl]phenyl}-1,3-dimethyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione;
1-Methyl-3-propyl-6-[4-(4-pyridin-2-ylpiperazine-1-sulphonyl)phenyl]-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione,
4-(1,3-Dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)-N-(2-pyridin-2-ylethyl)benzenesulphonamide;
4-(1-Methyl-2,4-dioxo-3-propyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)-N-(2-pyridin-2-ylethyl)benzenesulphonamide;
4-(1,3-Dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)-N-pyridin-2-ylbenzenesulphonamide;
4-(1,3-Dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)-N-(6-methoxypyridin-3-yl)benzenesulphonamide;
6-{4-[4-(5-Chlorothiophen-2-ylmethyl)piperazine-1-sulphonyl]phenyl}-1,3-dimethyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione;
6-{4-[4-(5-Chlorothiophen-2-ylmethyl)piperazine-1-sulphonyl]phenyl}-1,3-diethyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione;
N-(1-Benzylpiperidin-4-yl)-4-(2,4-dioxo-1,3-dipropyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)benzenesulphonamide;
4-(1,3-Diethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)-N-[1-(4-fluorobenzyl)piperidin-4-yl]benzenesulphonamide;
or a pharmaceutically acceptable salt or an N-oxide thereof.
11. A process for producing a compound of formula I as claimed in claim 1 , comprising reacting a sulphonyl chloride of formula II
with the corresponding amine III
and
optionally converting the product of the reaction into the corresponding N-oxide or pharmaceutically acceptable salt thereof.
12. A process according to claim 11 , wherein the sulphonyl chloride of formula II is obtained from the corresponding compound of formula IV:
by reaction with an excess of chlorosulphonic acid.
13. A compound of formula II
wherein
R 1 and R 2 each independently represents:
a) a hydrogen atom;
b) a hydrocarbon chain chosen from an alkyl, alkenyl and alkynyl group, wherein said hydrocarbon chain is optionally substituted by one or more substituents chosen from halogen, hydroxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, cyano, oxo, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy and dialkoxyphosphoryloxy groups; or
c) a group of formula
—(CH 2 ) n —R 6
n is an integer from 0 to 4 and
R 6 represents a 3- to 7-membered aromatic or non-aromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S, wherein said 3- to 7-membered aromatic or non-aromatic cyclic group is optionally bridged and/or fused to another 3- to 7-membered aromatic or non-aromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S;
wherein each of the cyclic groups in the moiety R 6 is independently optionally substituted by one or more R 7 substituents;
R 7 represents a group chosen from halogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, hydroxy, alkylenedioxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, nitro, cyano, oxo, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy and dialkoxyphosphoryloxy groups;
wherein each of the hydrocarbon chains and each of the cyclic moieties in R 7 is independently optionally substituted by one or more further R 8 substituents;
R 8 represents a group chosen from halogen, hydroxy, oxo, cyano, alkyl, difluoromethyl, trifluoromethyl, alkoxy, alkylenedioxy, alkylthio, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy, dialkoxyphosphoryloxy, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and hydroxycarbonyl groups;
R 3 represents a hydrogen or halogen atom, or a nitro, alkoxycarbonyl or alkyl group; wherein the alkyl group is optionally substituted by one or more substituents chosen from hydroxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl and alkylcarbamoyl groups;
or an N-oxide or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable diluent or carrier.