Condensed Pyridine Derivatives Useful as A2B Adenosine Receptor Antagonists
New antagonists of the A 2B adenosine receptor represented by formula (I) are disclosed; as well as processes for their preparation, pharmaceutical compositions comprising them and their use in therapy as antagonists of the A 2B adenosine receptor.
1 . A method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by antagonism of the A 2B adenosine receptor comprising administering to said subject an effective amount of a compound of formula (I)
wherein:
A represents an optionally substituted monocyclic or polycyclic aryl or heteroaryl group,
B represents an optionally substituted monocyclic nitrogen-containing heterocyclic group,
and either
a) R 1 represents a hydrogen atom and R 2 represents a group chosen from —NH 2 and optionally substituted alkynyl groups
or
b) R 2 , R 1 and the —NH— group to which R 1 is attached form a moiety chosen from the moieties of formulae (IIa), (IIb), (IIc), (IId) and (IIe):
wherein:
R a is a group chosen from a hydrogen atom, halogen atoms and groups chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 3 , —SR 3 , —COOR 3 , —CONR 3 R 4 , —NR 3 R 4 , —NR 3 COR 4 and —CN groups wherein R 3 and R 4 are independently chosen from a hydrogen atom and lower alkyl groups or cycloalkyl groups, and
R b is a group chosen from a hydrogen atom and groups chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl groups.
2 . A method according to claim 1 , wherein B represents an optionally substituted monocyclic, six-membered heterocyclic ring having one or two nitrogen atoms.
3 . A method according to claim 2 , wherein B represents a group chosen from optionally substituted pyridines, optionally substituted pyrimidines, optionally substituted pyridazines and optionally substituted pyridinones.
4 . A method according to claim 1 , wherein the group B is unsubstituted or substituted with one group chosen from —OR 3 , —SR 3 , —R 3 and —NHR 3 .
5 . A method according to claim 1 , wherein A represents an optionally substituted phenyl, furyl or thienyl group.
6 . A method according to claim 1 , wherein the group A is unsubstituted or substituted with one group chosen from halogen atoms and lower alkyl groups.
7 . A method according to claim 1 , wherein B represents a pyrimidinyl group and A represents a furyl group.
8 . A method according to claim 1 , wherein either R 1 represents a hydrogen atom, or R 2 , R 1 and the —NH— group to which R 1 is attached, form a moiety chosen from the moieties of formulae (IIc) and (IIe).
9 . A method according to claim 1 , wherein R 2 represents an —NH 2 group or an optionally substituted alkynyl group.
10 . A method according to claim 1 , wherein R a is chosen from lower alkyl groups and cycloalkyl groups.
11 . A method according to claim 1 , wherein R b is chosen from lower alkyl groups and hydrogen atoms.
12 . A method according to claim 1 , wherein the compound is chosen from:
2-(3-Fluorophenyl)-3,4′-bipyridine-5,6-diamine,
5-(3-Fluorophenyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine
5-(3-Fluorophenyl)-2-methyl-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
2-Cyclopropyl-5-(3-fluorophenyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
2-Ethyl-5-(3-fluorophenyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(3-Fluorophenyl)-6-pyridin-4-yl-3H-[1,2,3]triazolo[4,5-b]pyridine
5-(3-Fluorophenyl)-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,
5-Ethynyl-2-(3-fluorophenyl)-3,4′-bipyridin-6-amine,
6-(3-Fluorophenyl)-5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridine,
6-(2-Furyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-amine,
N-[6-(2-Furyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide,
5-(2-Furyl)-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
2-(2-Thienyl)-3,4′-bipyridine-5,6-diamine,
2-(2-Furyl)-3,4′-bipyridine-5,6-diamine,
6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyridine-2,3-diamine,
6-(2-Furyl)-5-pyrimidin-4-ylpyridine-2,3-diamine,
6-Pyridin-4-yl-5-(2-thienyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,
2-Ethoxy-5-(2-furyl)-6-pyrimidin-4-yl-3H-imidazo[4,5-b]pyridine
5-(2-Furyl)-6-pyrimidin-4-yl-3H-imidazo[4,5-b]pyridine
5-(2-Furyl)-2-methyl-6-pyrimidin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-2-methyl-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine
2-Cyclopropyl-5-(2-furyl)-6-pyrimidin-4-yl-3H-imidazo[4,5-b]pyridine,
2-Cyclopropyl-5-(2-furyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-6-[2-(methylthio)pyrimidin-4-yl]-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-1-methyl-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,
6-(2-Furyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridine
3-Chloro-6-(2-furyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridine,
3-Ethoxy-6-(2-furyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridine,
6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazolo[3,4-b]pyridin-3-amine,
6-(2-Furyl)-5-pyrimidin-4-yl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazolo[3,4-b]pyridine,
6-(2-Furyl)-5-(2-methoxypyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine
N-Cyclopropyl-4-[6-(2-furyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2-amine,
4-[6-(2-Furyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N-isopropylpyrimidin-2-amine
5-(2-Ethoxypyrimidin-4-yl)-6-(2-furyl)-1H-pyrazolo[3,4-b]pyridine,
6-(2-Furyl)-5-(2-isopropoxypyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine,
5-[2-(Cyclohexyloxy)pyrimidin-4-yl]-6-(2-furyl)-1H-pyrazolo[3,4-b]pyridine
6-(2-Furyl)-N-isobutyl-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-amine,
N-{6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}acetamide,
6-(3-Fluorophenyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-amine
6-(3-Fluorophenyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridine
6-(2-Furyl)-5-pyrimidin-4-yl-1H-pyrrolo[2,3-b]pyridine
2-(3-Fluorophenyl)-6-(2-furyl)-5-pyrimidin-4-yl-1H-pyrrolo[2,3-b]pyridine
6-(2-Furyl)-2-phenyl-5-pyrimidin-4-yl-1H-pyrrolo[2,3-b]pyridine,
6-(5-Bromo-2-furyl)-3-chloro-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridine,
5-(5-Bromo-2-furyl)-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,
6-(2-Furyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-amine, and
N-[6-(2-Furyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide.
13 . A compound of formula (I)
wherein:
A represents an optionally substituted monocyclic or polycyclic aryl or heteroaryl group,
B represents an optionally substituted monocyclic nitrogen-containing heterocyclic group,
and either
a) R 1 represents a hydrogen atom and R 2 represents a group chosen from —NH 2 and optionally substituted alkynyl groups,
or
b) R 2 , R 1 and the —NH— group to which R 1 is attached, form a moiety chosen from the moieties of formulae (IIa), (IIb), (IIc) and (IId):
wherein:
R a is a group chosen from a hydrogen atom, halogen atoms and groups chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 3 , —SR 3 , —COOR 3 , —CONR 3 R 4 , —NR 3 R 4 , —NR 3 COR 4 and —CN groups, wherein R 3 and R 4 are independently chosen from a hydrogen atoms and lower alkyl groups or cycloalkyl groups, and
R b is a group chosen from a hydrogen atom and groups chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl groups.
14 . A compound according to claim 13 , wherein B represents an optionally substituted monocyclic, six-membered heterocyclic ring having one or two nitrogen atoms.
15 . A compound according to claim 13 , wherein B represents a group chosen from optionally substituted pyridines, optionally substituted pyrimidines, optionally substituted pyridazines and optionally substituted pyridinones.
16 . A compound according to claim 13 , wherein the group B is unsubstituted or substituted with one group chosen from —OR 3 , —SR 3 , —R 3 and —NHR 3 .
17 . A compound according to claim 13 , wherein A represents an optionally substituted phenyl, furyl or thienyl group.
18 . A compound according to claim 13 , wherein the group A is unsubstituted or substituted with one group chosen from halogen atoms and lower alkyl groups.
19 . A compound according to claim 13 , wherein B represents a pyrimidinyl group and A represents a furyl group.
20 . A compound according to claim 13 , wherein either R 1 represents a hydrogen atom, or R 2 , R 1 and the —NH— group to which R 1 is attached, form a moiety of formulae (IIc).
21 . A compound according to claim 13 , wherein R 2 represents an —NH 2 group or an optionally substituted alkynyl group.
22 . A compound according to claim 13 , wherein R a is chosen from lower alkyl groups and cycloalkyl groups.
23 . A compound according to claim 13 , wherein R b is chosen from lower alkyl groups and hydrogen atoms.
24 . A compound according to claim 13 chosen from:
2-(3-Fluorophenyl)-3,4′-bipyridine-5,6-diamine
5-(3-Fluorophenyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(3-Fluorophenyl)-2-methyl-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine
2-Cyclopropyl-5-(3-fluorophenyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
2-Ethyl-5-(3-fluorophenyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine.
5-(3-Fluorophenyl)-6-pyridin-4-yl-3H-[1,2,3]triazolo[4,5-b]pyridine
5-(3-Fluorophenyl)-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,
5-Ethynyl-2-(3-fluorophenyl)-3,4′-bipyridin-6-amine,
6-(3-Fluorophenyl)-5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridine,
5-(2-Furyl)-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
2-(2-Thienyl)-3,4′-bipyridine-5,6-diamine,
2-(2-Furyl)-3,4′-bipyridine-5,6-diamine,
6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyridine-2,3-diamine,
6-(2-Furyl)-5-pyrimidin-4-ylpyridin-2,3-diamine,
6-Pyridin-4-yl-5-(2-thienyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,
2-Ethoxy-5-(2-furyl)-6-pyrimidin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-6-pyrimidin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-2-methyl-6-pyrimidin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-2-methyl-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
2-Cyclopropyl-5-(2-furyl)-6-pyrimidin-4-yl-3H-imidazo[4,5-b]pyridine,
2-Cyclopropyl-5-(2-furyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-6-pyridin-4-yl-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-6-[2-(methylthio)pyrimidin-4-yl]-3H-imidazo[4,5-b]pyridine,
5-(2-Furyl)-1-methyl-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,
6-(2-Furyl)-5-pyrimidin-4-yl-1H-pyrrolo[2,3-b]pyridine,
2-(3-Fluorophenyl)-6-(2-furyl)-5-pyrimidin-4-yl-1H-pyrrolo[2,3-b]pyridine,
6-(2-furyl)-2-phenyl-5-pyrimidin-4-yl-1H-pyrrolo[2,3-b]pyridine, and
5-(5-Bromo-2-furyl)-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one.
25 . A pharmaceutical composition comprising a compound according to claim 13 and pharmaceutically acceptable diluent or carrier.
26 . A method according to claim 1 , wherein the pathological condition or disease is asthma, bronchoconstriction, allergic diseases, hypertension, atherosclerosis, reperfusion injury, myocardial ischemia, retinopathy, inflammation, gastrointestinal tract disorders, cell proliferation disorders, diabetes mellitus, and/or autoimmune diseases.
27 . A method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by antagonism of the A 2B adenosine receptor, which comprises administering to said subject an effective amount of a compound according to claim 13 .
28 . A method according to claim 27 , wherein the pathological condition or disease is asthma, bronchoconstriction, allergic diseases, hypertension, atherosclerosis, reperfusion injury, myocardial ischemia, retinopathy, inflammation, gastrointestinal tract disorders, cell proliferation disorders, diabetes mellitus, and/or autoimmune diseases.