Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
View Patent ↗The compounds of the present invention are represented by the chemical structure found in Formula (I): wherein: the carbon atom designated * is in the R or S configuration; and X is a fused bicyclic carbocycle or heterocycle selected from the group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, benzoisoxazolyl, indazolyl, indolyl, isoindolyl, indolizinyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, benzotriazolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3 -a]pyridinyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, indenyl, indanyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, indolinyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, 9aH-quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 2H-chromenyl, 4H-chromenyl, and a fused bicyclic carbocycle or fused bicyclic heterocycle optionally substituted with substituents (1 to 4 in number) as defined below in R 14 ; with R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 14 defined herein.
1. A compound of Formula (I):
wherein:
the carbon atom designated * is in the R or S configuration;
X is selected from the group consisting of naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, 9aH-quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 2H-chromenyl, 4H-chromenyl, dihydrobenzocycloheptenyl, and a fused bicyclic carbocycle or heterocycle optionally substituted from 1 to 4 times with R 14 ;
R 1 is methyl;
R 2 is H, CH 3 , or gem-dimethyl;
R 3 is H, CH 3 , OH, OCH 3 , —CN, or F;
R 4 is pyridazinyl;
R 5 is H or F;
R 6 is H, F, or methoxy;
R 7 is H;
R 8 is H, OH, OCH 3 , —CN, F, Cl, or CH 3 ;
R 9 and R 10 are each independently selected from the group consisting of: H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 13 , phenyl, and benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of: halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy; or
R 9 and R 10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, thiomorpholine, [1,2]oxazinane, isoxazolidine, or 2-oxo-2H-pyridine, which is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
R 11 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 13 , phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 12 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; or
R 11 and R 12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R 9 and R 10 or R 11 and R 12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R 13 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
n is 0, 1, or 2; and
R 14 is independently selected at each occurrence from a substituent selected from the group consisting of: halogen, —NO 2 , —OR 11 , —NR 11 R 12 , —NR 11 C(O)R 12 , —NR 11 C(O) 2 R 12 , —NR 11 C(O)NR 12 R 13 , —S(O) n R 12 , —CN, —C(O)R 12 , —C(O)NR 11 R 12 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, where C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of: C 1 -C 3 alkyl, halogen, aryl, —CN, —OR 9 , and —NR 9 R 10 ;
or an oxide thereof or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein R 2 is H.
3. The compound according to claim 1 , wherein R 3 is H.
4. The compound according to claim 1 , wherein:
R 4 is selected from the group consisting of pyridazin-3-yl, 5-methylpyridazin-3-yl, 6-methylpyridazin-3-yl, 6-dimethylamino-pyridazine-3-yl, 6-methylamino-pyridazine-3-yl, 6-amino-pyridazine-3-yl, 6-morpholin-4-yl-pyridazine-3-yl, 6-trifluoromethyl-pyridazin-3-yl, 6-cyano-pyridazine-3, and pyridazin-4-yl; and
X is naphthalen-1-yl, 4-methyl-naphthalen-1-yl, naphthalen-2-yl, 1-fluoro-naphthalen-2-yl, 1-chloro-naphthalen-2-yl, 1-methoxy-naphthalen-2-yl, 1-methyl-naphthalen-2-yl, 3-fluoro-naphthalen-2-yl, 3-chloro-naphthalen-2-yl, 3-methoxy-naphthalen-2-yl, 3-cyano-naphthalen-2-yl, 4-fluoro-naphthalen-2-yl, 4-chloro-naphthalen-2-yl, 4-methyl-naphthalen-1-yl, 5-fluoro-naphthalen-2-yl, 5-chloro-naphthalen-2-yl, 5-cyano-naphthalen-2-yl, 5-methyl-naphthalen-2-yl, 6-methoxy-naphthalen-2-yl, 6-chloro-naphthalen-2-yl, 6-fluoro-naphthalen-2-yl, 6-cyano-naphthalen-2-yl, 6-methanesulfonyl-naphthalen-2-yl, 7-methoxy-naphthalen-2-yl, 7-chloro-naphthalen-2-yl, 7-fluoro-naphthalen-2-yl, 7-cyano-naphthalen-2-yl, 8-methoxy-naphthalen-2-yl, 8-chloro-naphthalen-2-yl, 8-fluoro-naphthalen-2-yl, 8-cyano-naphthalen-2-yl, 5,6,7,8-tetrahydro-naphthalen-2-yl, 2-quinolinyl, 3-quinolinyl, 6-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 2-quinoxalinyl, 6-quinoxalinyl, 2-quinazolinyl, 2-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 3-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 6-phthalazinyl, 2H-chromen-3-yl, or 8,9-dihydro-7H-benzocyclohepten-6-yl.
5. The compound according to claim 4 , wherein R 4 is selected from the group consisting of pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-dimethylamino-pyridazine-3-yl, 6-methylamino-pyridazine-3-yl, 6-amino-pyridazine-3-yl, 6-morpholin-4-yl-pyridazine-3-yl, 6-trifluoromethyl-pyridazin-3-yl, 6-cyano-pyridazin-3-yl, and pyridazin-4-yl.
6. The compound according to claim 5 , wherein R 4 is 6-amino-pyridazin-3-yl.
7. The compound according to claim 1 , wherein X is selected from the group consisting of indenyl, indanyl, naphthyl, dihydronaphthyl, tetrahydronapthyl, benzocycloheptenyl, dihydrobenzocycloheptenyl, and tetrahydrobenzocyloheptenyl.
8. The compound according to claim 7 , wherein X is naphthalen-2-yl.
9. The compound according to claim 1 , wherein the carbon atom designated * is in the S configuration.
10. The compound according to claim 1 , wherein the compound is a (+) stereoisomer.
11. A compound of Formula (I):
wherein:
the carbon atom designated * is in the R or S configuration;
X is selected from the group consisting of indenyl, indanyl, naphthyl, dihydronaphthyl, tetrahydronapthyl, benzocycloheptenyl, dihydrobenzocycloheptenyl, and tetrahydrobenzocyloheptenyl;
R 1 is methyl;
R 2 is H;
R 3 is H;
R 4 is selected from the group consisting of pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-dimethylamino-pyridazine-3-yl, 6-methylamino-pyridazine-3-yl, 6-amino-pyridazine-3-yl, 6-morpholin-4-yl-pyridazine-3-yl, 6-trifluoromethyl-pyridazin-3-yl, 6-cyano-pyridazin-3-yl, and pyridazin-4-yl;
R 5 is H or F;
R 6 is H, F, or methoxy;
R 7 is H; and
R 8 is H, OH, OCH 3 , —CN, F, Cl, or CH 3 ;
or an oxide thereof or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 11 , wherein R 4 is 6-amino-pyridazin-3-yl.
13. The compound according to claim 11 , wherein X is naphthalen-2-yl.
14. The compound according to claim 11 , wherein the carbon atom designated * is in the S configuration.
15. The compound according to claim 11 , wherein the compound is a (+) stereoisomer.
16. A compound of Formula (I):
wherein:
the carbon atom designated * is in the R or S configuration;
X is naphthalen-2-yl;
R 1 is methyl;
R 2 is H;
R 3 is H;
R 4 is 6-amino-pyridazin-3-yl;
R 5 is H;
R 6 is H;
R 7 is H;
R 8 is H;
or an oxide thereof or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 16 , wherein the carbon atom designated * is in the S configuration.
18. The compound according to claim 16 , wherein the compound is a (+) stereoisomer.
19. A compound of Formula (I):
wherein:
the carbon atom designated * is in the R or S configuration;
X is naphthalen-2-yl;
R 1 is H;
R 2 is H;
R 3 is H;
R 4 is 6-amino-pyridazin-3-yl;
R 5 is H;
R 6 is H;
R 7 is H; and
R 8 is H.