Tetrahydrocarboline derivative
An object of the present invention is to provide a drug having the inhibitory activity on ENPP2 which is a different target from that of the existing drug, as a medicament useful in a urinary excretion disorder patient for whom the existing drug has the insufficient effect. The present invention provides a compound represented by the general formula (I): (wherein definition of each group is as defined in the description) having the ENPP2 inhibitory activity, a salt thereof or a solvate thereof or a prodrug thereof, and an agent for preventing or treating urinary excretion disorder and/or improving symptoms thereof, containing them as an active ingredient.
1. A compound represented by the general formula (I):
wherein R 1 represents a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkyl group, a C1-4 haloalkoxy group, a carboxyl group, a cyano group, a C1-3 alkylsulfonyl group, a carbamoyl group or
wherein the ring A S represents a 5- to 7-membered monocycle, E represents a bond, a methylene group or an oxygen atom, R 1-1 represents a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkyl group or a C1-4 haloalkoxy group, and m represents an integer of 0 to 3, provided that groups represented by a plurality of R 1-1 s may be the same or different, respectively,
R 2 represents a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group or a C1-4 haloalkyl group, R 3 represents a C1-4 alkyl group, R 4 represents a hydrogen atom or a C1-4 alkyl group,
the ring A represents (i) a C3-7 monocyclic carbon ring, (ii) a C8-10 bicyclic carbon ring, (iii) a 4- to 7-membered monocyclic heterocyclic ring containing one to four heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom or (iv) a 8- to 10-membered bicyclic heterocyclic ring containing one to four heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, X represents a nitrogen atom or a carbon atom, T represents a bond, or a straight C1-4 alkylene group, a C2-4 alkenylene group or a C2-4 alkynylene group, optionally substituted with one or two R 5 s wherein R 5 represents a C1-4 alkyl group, a hydroxy group or an amino group, U represents (i) a methylene group, (ii) an oxygen atom, (iii) —NR 6 — wherein R 6 represents a hydrogen atom or a methyl group or (iv) a 3- to 7-membered monocycle, a C5-10 bridged carbon ring or a 5- to 10-membered bridged heterocyclic ring, optionally substituted with one to five R 7 s wherein R 7 represents a halogen atom, a C1-4 alkyl group, a hydroxy group, an oxo group, a C1-4 alkoxy group, a C1-4 haloalkoxy group, a cyano group or a benzyloxy group, Y represents (i) a bond or (ii) a straight C1-3 alkylene group or a C2-3 alkenylene group, optionally substituted with one or two R 8 s wherein R 8 represents a methyl group, W represents a bond or a straight C1-3 alkylene group, Z represents a methylene group, an oxygen atom or an optionally oxidized sulfur atom, q represents an integer of 1 to 4, r represents an integer of 0 to 5, and t represents an integer of 0 to 2, provided that groups represented by a plurality of R 1 s, R 2 s , R 3 s, R 5 s, R 7 s and R 8 s may be the same or different, respectively, and two R 3 s and R 5 s bound to the same carbon atom may be taken together with the bound carbon atom to form C3-5 cycloalkyl, respectively;
a salt thereof or a solvate thereof.
2. The compound according to claim 1 , which is represented by the general formula (II):
wherein R 3a and R 3b each represent independently a hydrogen atom or a methyl group, and other symbols are as defined in claim 1 , provided that R 3a and R 3b are taken together with a carbon atom to which they are bound, to form a cyclopropyl.
3. The compound according to claim 2 , wherein Y is a straight C1-3 alkylene group optionally substituted with one or two R 8 s wherein R 8 is as defined in claim 1 .
4. The compound according to claim 3 , wherein X is a nitrogen atom.
5. The compound according to claim 3 , wherein X is a carbon atom.
6. The compound according to claim 4 , wherein R 4 is a hydrogen atom.
7. The compound according to claim 6 , which is represented by the general formula (IV-2):
wherein U 1 represents a 5- to 7-membered monocycle or a C5-10 bridged carbon ring, optionally substituted with one to five R 7 s wherein , R 7 is as defined in claim 1 , Y 1 represents a methylene group or an ethylene group, optionally substituted with one or two R 8 s, T 1 represents a bond, or a methylene group or an ethylene group, optionally substituted with one or two R 5 s, R 3a and R 3b each represent independently a hydrogen atom or a methyl group, or R 3a and R 3b are taken together with a carbon atom to which they are bound, to form a cyclopropyl and other symbols are as defined in claim 1 .
8. The compound according to claim 7 , wherein Y 1 is an unsubstituted methylene group, and T 1 is a bond or an unsubstituted methylene group.
9. The compound according to claim 7 , wherein the C5-10 bridged carbon ring in the C5-10 bridged carbon ring optionally substituted with one to five R 7 s is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane.
10. The compound according to claim 7 , wherein the 5- to 7-membered monocycle in the 5- to 7-membered monocycle optionally substituted with one to five R 7 s is (i) a C5-7 monocyclic carbon ring or (ii) a 5- to 7-membered monocyclic heterocyclic ring containing one to four heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
11. The compound according to claim 10 , wherein the C5-7 monocyclic carbon ring is benzene, cyclopentane or cyclohexane.
12. The compound according to claim 6 , which is represented by the general formula (IV-3):
wherein all symbols are as defined in claim 7 .
13. The compound according to claim 6 , which is represented by the general formula (V):
wherein U 2 represents a methylene group, an oxygen atom or —NR 6 —, R 5a and R 5b each represent independently a hydrogen atom or a methyl group, other symbols are as defined in claim 1 , provided that R 5a and R 5b are taken together with a carbon atom to which they are bound, to form cyclopropyl.
14. The compound according to claim 7 , wherein the ring A is a C5-6 monocyclic carbon ring or a C9-10 bicyclic carbon ring.
15. The compound according to claim 7 , wherein the ring A is (i) a 5- to 6-membered monocyclic heterocyclic ring containing one to four heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom or (ii) a 9- to 10-membered bicyclic heterocyclic ring containing one to four heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
16. The compound according to claim 14 , wherein the C5-6 monocyclic carbon ring is cyclopentane, cyclohexane, cyclohexene or benzene, and the C9-10 bicyclic carbon ring is naphthalene.
17. The compound according to claim 15 , wherein the 5- to 6-membered monocyclic heterocyclic ring containing one to four heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom is thiophene, furan, pyrazole, isooxazole, thiazole or pyridine, and the 9- to 10-membered bicyclic heterocyclic ring containing one to four heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom is benzothiophene, indole or imidazopyridine.
18. The compound according to claim 16 , wherein the compound represented by the general formula (IV-2) is:
(1) cis-4-{2-[9-(3-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}cyclohexanecarboxylic acid,
(2) trans-4-{2-[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}cyclohexanecarboxylic acid,
(3) trans-4-{2-[9-(4-chlorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}cyclohexanecarboxylic acid,
(4) 4-{2-[9-(3-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}bicyclo[2.2.2]octane-1-carboxylic acid,
(5) 4-{2-[9-(3,5-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}bicyclo[2.2.2]octane-1-carboxylic acid,
(6) 4-{2-oxo-2-[9-(2,4,5-trifluorobenzyl)-5,6,8,9-tetrahydro-7H -pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]ethyl}bicyclo[2.2.2]octane-1-carboxylic acid,
(7) 4-{2-[9-(4-chlorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}bicyclo[2.2.2]octane-1-carboxylic acid,
(8) 4-{2-[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}bicyclo[2.2.2]octane-1-carboxylic acid,
(9) (1R,3R)-3-{2-[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}-1,2,2-trimethylcyclopentanecarboxylic acid,
(10) (1R,3R)-3-{2-[9-(4-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}-1,2,2-trimethylcyclopentanecarboxylic acid,
(11) (1R,3R)-3-{2-[9-(3-chloro-4-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}-1,2,2-trimethylcyclopentanecarboxylic acid,
(12) 4-{2-[9-(3-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}bicyclo[2.2.1]heptane-1-carboxylic acid,
(13) 4-{2-[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}bicyclo[2.2.1]heptane-1-carboxylic acid,
(14) trans-4-{2-[9-(4-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}-1-methylcyclohexanecarboxylic acid,
(15) trans-4-{2-[9-(4-chlorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}-1-methylcyclohexanecarboxylic acid,
(16) 2-methoxy-4-{2-oxo-2-[9-(2,4,5-trifluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]ethyl}benzoic acid,
(17) 4-{2-[9-(3,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}bicyclo[2.2.2]octane-1-carboxylic acid,
(18) 4-{2-[9-(4-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}bicyclo[2.2.1]heptane-1-carboxylic acid,
(19) 4-{2-[9-(4-chlorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}bicyclo[2.2.1]heptane-1-carboxylic acid, or
(20) 4-{2-[9-(3,5-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2-oxoethyl}-2-methoxybenzoic acid.
19. The compound according to claim 16 , wherein the compound represented by the general formula (V) is 6-[9-(3-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl]-2,2-dimethyl-6-oxohexanoic acid.
20. The compound according to claim 17 , wherein the compound represented by the general formula (IV-2) is 4-(2-{9-[(5-chloro-3-thienyl)methyl]-5,6,8,9-tetrahydro-7H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-7-yl}-2-oxoethyl)-2-methylbenzoic acid.
21. The compound according to claim 12 , wherein the compound represented by the general formula (IV-3) is:
(1) cis-4-(2-{9-[(2,5-dimethyl-1,3-thiazol-4-yl)methyl]-1,3,4,9-tetrahydro-2H-β-carbolin-2-yl}-2-oxoethyl)cyclohexanecarboxylic acid or
(2) rel-[(2R,6S)-4-(2-{9-[(5-chloro-2-thienyl)methyl]-1,3,4,9-tetrahydro-2H-β-carbolin-2-yl}-2-oxoethyl)-2,6-dimethyl-1-piperazinyl]acetic acid.
22. A pharmaceutical composition containing the compound represented by the general formula (I) as defined in claim 1 , or a salt thereof or a solvate thereof as an active ingredient.