Imidazoquinoline derivatives and their use as adenosine A3 ligands
View Patent ↗The present invention relates to adenosine A 3 receptor ligands of the general formula (I), within those preferably antagonists, as well as their salts, solvates and isomers, and the pharmaceutical compositions containings them, to the use of the compounds of the general formula (I), as well as their salts, solvates and isomers, to the preparation of the compounds of the general formula (I) and their salts, solvates and isomers, furthermore to the new intermediates of the general formulae (II) and (III) and to the preparation thereof.
1. A compound of formula (I)
wherein
R 1 is hydrogen atom or a straight or branched C 1-4 alkyl group;
R 2 is hydrogen atom or a straight or branched C 1-4 alkyl group;
R 3 is hydrogen atom, a straight or branched C 1-4 alkyl group, C 3-6 cycloalkyl group,
a phenyl group, thienyl group, or furyl group, each of which is optionally substituted by one or more straight or branched C 1-4 alkyl group, straight or branched C 1-4 alkoxy group, or halogen atom, or
a 5 or 6 membered heteroaromatic ring, containing one, two or three nitrogen atoms, or a 5 membered heteroaromatic ring, containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom, each of which is optionally substituted by one or more straight or branched C 1-4 alkyl group, straight or branched C 1-4 alkoxy group, or halogen atom;
R 4 , R 5 , R 6 and R 7 are independently from each other hydrogen atom, a straight or branched C 1-4 alkyl group, straight or branched C 1-4 alkoxy group, hydroxy group or halogen atom, or
R 4 and R 7 are hydrogen atom, and R 5 and R 6 form together a methylenedioxy group;
R 8 is hydrogen atom, a cyano group, aminocarbonyl group, C 1-4 alkoxycarbonyl group, or carboxy group;
R 9 and R 10 are independently from each other hydrogen atom, a straight or branched C 1-4 alkyl group, a C 3-6 cycloalkyl group,
a phenyl group, phenyl-straight or branched (C 1-4 )alkyl group, thienyl-straight or branched (C 1-4 )alkyl group or furyl-straight or branched (C 1-4 )alkyl group, wherein phenyl, thienyl or furyl moiety of the phenyl group, phenyl-straight or branched (C 1-4 )alkyl group, thienyl-straight or branched (C 1-4 )alkyl group or furyl-straight or branched (C 1-4 )alkyl group is optionally substituted by a methylenedioxy group, or one or more straight or branched C 1-4 alkyl group, straight or branched C 1-4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom,
a 5 or 6 membered heteroaromatic ring, containing one, two or three nitrogen atoms, or a 5 membered heteroaromatic ring, containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom, each of which is optionally substituted by one or more straight or branched C 1-4 alkyl group, straight or branched C 1-4 alkoxy group, or halogen atom, or
a —(CH 2 ) m —OH or —(CH 2 ) o —NR 12 R 13 group, or
R 9 and R 10 taken together with the nitrogen atom to which they are attached form a 3–7 membered heterocyclic group containing only one heteroatom, optionally substituted by a straight or branched C 1-4 alkyl group;
R 12 and R 13 are independently from each other hydrogen atom, a straight or branched C 1-4 alkyl group, a C 3-6 cycloalkyl group,
a phenyl group, phenyl-straight or branched (C 1-4 )alkyl group, thienyl-straight or branched (C 1-4 )alkyl group or furyl-straight or branched (C 1-4 )alkyl group, wherein phenyl, thienyl or furyl moiety of the phenyl group, phenyl-straight or branched (C 1-4 )alkyl group, thienyl-straight or branched (C 1-4 )alkyl group or furyl-straight or branched (C 1-4 )alkyl group is optionally substituted by a methylenedioxy group, or one or more straight or branched C 1-4 alkyl group, straight or branched C 1-4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom,
a 5 or 6 membered heteroaromatic ring, containing one, two or three nitrogen atoms, or a 5 membered heteroaromatic ring, containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom, each of which is optionally substituted by one or more straight or branched C 1-4 alkyl group, straight or branched C 1-4 alkoxy group, or halogen atom, or
a —(CH 2 ) m —OH or —(CH 2 ) o —NR 12 R 13 group, or
R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 3–7 membered heterocyclic group, optionally substituted by a straight or branched C 1-4 alkyl group,
X is a —CH 2 — group, —NH— group, —NR 11 — group, a sulphur atom, an oxygen atom, a sulpho group or a sulphoxy group, wherein R 11 is a straight or branched C 1-4 alkyl group or C 3-6 cycloalkyl group;
n 0, 1 or 2;
m is 1, 2, 3 or 4; and
o 0, 1, 2, 3 or 4;
or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer.
2. The compound of formula (I) according to claim 1 , wherein
R 9 and R 10 are independently from each other hydrogen atom, a straight or branched C 1-4 alkyl group or C 3-6 cycloalkyl group;
a phenyl group, phenyl-straight or branched (C 1-4 )alkyl group, thienyl-straight or branched (C 1-4 )alkyl group or furyl-straight or branched (C 1-4 )alkyl group, wherein phenyl, thienyl or furyl moiety of the phenyl group, phenyl-straight or branched (C 1-4 )alkyl group, thienyl-straight or branched (C 1-4 )alkyl group or furyl-straight or branched (C 1-4 )alkyl group is optionally substituted by a methylenedioxy group, or one or more straight or branched C 1-4 alkyl group, straight or branched C 1-4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom, or
a —(CH 2 ) m —OH or —(CH 2 ) o —NR 12 R 13 group, or
R 9 and R 10 taken together with the nitrogen atom to which they are attached form a 3–7 membered heterocyclic group, optionally substituted by a straight or branched C 1-4 alkyl group; and
R 12 and R 13 are independently from each other hydrogen atom, a straight or branched C 1-4 alkyl group, a C 3-6 cycloalkyl group,
a phenyl group, phenyl-(C 1-4 )alkyl group, thienyl-(C 1-4 )alkyl group or furyl-(C 1-4 )alkyl group, wherein phenyl, thienyl or furyl moiety of the phenyl group, phenyl-(C 1-4 )alkyl group, thienyl-(C 1-4 )alkyl group or furyl-(C 1-4 )alkyl group is optionally substituted by a methylenedioxy group, or one or more straight or branched C 1-4 alkyl group, straight or branched C 1-4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom, or
a —(CH 2 ) m —OH or —(CH 2 ) o —NR 12 R 13 group, or
R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 3–7 membered heterocyclic group, optionally substituted by a straight or branched C 1-4 alkyl group,
or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer.
3. The compound of formula (I) according to claim 1 wherein
R 1 is hydrogen atom, or methyl group;
R 2 is hydrogen atom, or methyl group;
R 3 is phenyl, thienyl or furyl group;
R 8 is hydrogen atom, or cyano group;
R 9 and R 10 are independently methyl group, ethyl group or cyclopropyl group, or
R 9 and R 10 taken together with the nitrogen atom to which they are attached form a 3–7 membered heterocyclic group, optionally substituted by a straight or branched C 1-4 alkyl group;
X is —NH— group or oxygen atom; and
n is 1;
or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer.
4. The compound according to claim 1 , which is:
1-(9-benzylamino-10-cyano-imidazo[1,2-a]quinolin-2-carbonyl)pyrrolidine;
N,N-dimethyl-9-benzylamino-10-cyano-imidazo[1,2-a]quinolin-2-carboxamide-hemihydrate;
N-ethyl-9-benzylamino-10-cyano-imidazo[1,2-a]quinolin-2-carboxamide-hemihydrate;
1-(9-furfurylamino-10-cyano-imidazo[2-a]quinolin-2-carbonyl)-pyrrolidine-hemihydrate; or
1-(9-thienylamino-10-cyano-imidazo[1,2-a]quinolin-2-carbonyl)-pyrrolidine-hemihydrate;
or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer.
5. A process for the preparation of a compound Or formula (I),
a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X, and n, have the same meaning as defined in claim 1 , comprising acylating a compound of formula (VIII),
wherein R 9 and R 10 have the same meaning as defined in claim 1 , with an acid of formula (II),
wherein R 1 , R 2 , R 3 ,R 4 , R 5 , R 6 , R 7 , R 8 , X and n have the same meaning as defined in claim 1 , or a reactive derivative of the acid of formula (II), to form the compound of formula (I) corresponding thereto, wherein the reactive derivative is an acid halid or anhydride of the acid of formula (II).
6. The process according to claim 5 wherein the acylation is carried out in an organic solvent, and in the presence of a base.
7. The process according to claim 5 wherein the acylation is carried out in a halogenated hydrocarbon organic solvent.
8. The process according to claim 5 wherein the acylation is carried out in the presence of an organic base.
9. A pharmaceutical composition comprising one or more compounds according to claim 1 or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer, in admixture with one or more excipients.
10. A pharmaceutical composition comprising one or more compounds of claim 3 or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer, in admixture with one or more excipients.
11. A pharmaceutical composition comprising one or more compounds of claim 4 or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer, in admixture with one or more excipients.
12. A method for treating asthma, an inflammatory disease, ischemia, arrhythmia or a renal disease, wherein receptor A 3 plays a role, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound according to claim 1 .
13. A compound of formula (II)
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and n have the same meaning as defined in claim 1 , provided that if —X—(CR 1 R 2 ) n —R 3 together form an alkoxy, alkylthio, alkylsulfo or alkylsulfoxy group, R 8 is not hydrogen.
14. A compound of formula (III)
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and n have the same meaning as defined in claim 1 , and R 14 is C 1-4 alkyl group, provided that if —X—(CR 1 R 2 ) n —R 3 together form an alkoxy or alkylthio group, R 8 is not hydrogen.
15. The compound of formula (I) according to claim 2 wherein
R 1 is hydrogen atom, or methyl group;
R 2 is hydrogen atom, or methyl group;
R 3 is phenyl, thienyl or furyl group;
R 8 stands for hydrogen atom, or cyano group;
R 9 and R 10 are independently methyl group, ethyl group or cyclopropyl group, or
R 9 and R 10 taken together with the nitrogen atom to which they are attached form a 3–7 membered heterocyclic group, optionally substituted by a straight or branched C 1-4 alkyl group;
X is —NH— group or oxygen atom; and
n is 1;
or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer.
16. The process according to claim 6 wherein the organic solvent is a halogenated hydrocarbon organic solvent.
17. The process according to claim 7 wherein the halogenated hydrocarbon organic solvent is chloroform.
18. The process according to claim 16 , wherein the halogenated hydrocarbon organic solvent is chloroform.
19. The process according to claim 6 wherein the base is an organic base.
20. The process according to claim 7 wherein the acylation is carried out in the presence of an organic base.
21. The process according to claim 8 wherein the organic base is triethylamine.
22. The process according to claim 19 wherein the organic base is triethylamine.
23. The process according to claim 20 wherein the organic base is triethylamine.
24. A pharmaceutical composition comprising one or more compounds of claim 2 or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer, in admixture with one or more excipients.
25. A pharmaceutical composition comprising one or more compounds of claim 15 or a salt, solvate, or optically active isomer thereof, or a salt or solvate of the optically active isomer, in admixture with one or more excipients.