Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

Patent metadata

Field	Value
Publication number	US-9403776-B2
Application number	US-201414304833-A
Country	US
Kind code	B2
Filing date	Jun 13, 2014
Priority date	Jul 15, 2005
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The compounds of the present invention are represented by the following aryl- and heteroaryl-substituted tetrahydrobenzazepine and dihydrobenzazapine derivatives having formulae I(A-E) and formula (II):

where the carbon atom designated * is in the R or S configuration, and the substituents X and R 1 -R 9 are as defined herein.

First claim

What is claimed:

1. A compound of formulae I(A-E) having the following structure:

wherein:
the carbon atom designated * is in the R or S configuration;
X is phenyl, optionally substituted from 1 to 4 times with substituents as defined in R 14 ;
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H, methyl, or gem-dimethyl;
R 3 is H, methyl, hydroxy, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 4 is pyrimidinyl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ;
R 5 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or methoxy;
R 6 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or methoxy;
R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, wherein each of the C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 15 ;
R 8 is H;
R 9 is H;
R 10 and R 11 are each independently selected from the group consisting of H, —C(O)R 13 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, where each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; or
R 10 and R 11 are each independently selected from the group consisting of phenyl, benzyl, and other 5- or 6-membered monocyclic heterocycles, where each of the phenyl, benzyl, and 5- or 6-membered monocyclic heterocycle is optionally substituted from 1 to 3 times with substituents as defined below in R 14 ; or
R 10 and R 11 are taken together with the nitrogen to which they are attached to form a saturated or partially saturated monocyclic or fused bicyclic heterocycle selected from the group consisting of piperidine, pyrrolidine, morpholine, thiomorpholine, [1,2]oxazinane, isoxazolidine, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 3-oxomorpholino, 3-oxothiomorpholino, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine, and other monocyclic or fused bicyclic heterocycles containing 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the heterocycle is attached to the benzazepine core via the nitrogen atom, and is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OR 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , and C 1 -C 4 alkyl, where each of C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; or
R 10 and R 11 are taken together with the nitrogen to which they are attached to form a heterocycle selected from the group consisting of piperazine, 2-oxopiperazinyl, 2-oxo-1,4-diazepanyl, 5-oxo-1,4-diazepanyl, 1,4-diazepane, and other heterocycles containing one additional nitrogen atom in the ring, where the heterocycle is optionally substituted on a ring carbon with from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OR 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , and C 1 -C 4 alkyl, or on the additional nitrogen atom from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of S(O) n R 13 , —C(O)R 13 , and C 1 -C 4 alkyl, wherein each of C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; or
R 10 and R 11 are taken together with the nitrogen to which they are attached to form a heterocycle selected from the group consisting of piperazine, 2-oxopiperazinyl, 2-oxo-1,4-diazepanyl, 5-oxo-1,4-diazepanyl, 1,4-diazepane, and other heterocycles containing one additional nitrogen atom in the ring, where the heterocycle is optionally substituted on the additional nitrogen atom with a substituent selected independently at each occurrence thereof from the group consisting of phenyl, benzyl, and 5- or 6-membered aromatic heterocycles containing 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where each of the phenyl, benzyl, and 5- and 6-membered heterocycle is optionally substituted from 1 to 3 times with substituents as defined below in R 14 ;
R 12 is selected from the group consisting of H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and —C(O)R 13 , where each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;
R 13 is C 1 -C 4 alkyl;
R 14 is independently selected at each occurrence from a substituent in the group consisting of halogen, —NO 2 , —OR 12 , —NR 10 R 11 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(o) n R 13 , —CN, —C(O)R 13 , 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, wherein each of 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 is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; and
R 15 is independently selected at each occurrence from a substituent in the group consisting of —CN, halogen, C(O)R 13 , C 1 -C 3 alkyl, —OR 12 , —NR 10 R 11 , —S(O) n R 13 , aryl, and heteroaryl, wherein each of the aryl or heteroaryl groups is optionally substituted from 1 to 4 times with substituents as defined above in R 14 ; and
n is 0, 1, or 2.

2. The compound according to claim 1 , wherein X is phenyl substituted from 1 to 4 times with halogen.

3. The compound according to claim 2 , wherein the halogen is F.

4. The compound according to claim 1 , wherein R 1 is H.

5. The compound according to claim 1 , wherein R 2 is H.

6. The compound according to claim 1 , wherein R 3 is H.

7. The compound according to claim 1 , wherein R 4 is pyrimidin-2-yl.

8. The compound according to claim 1 , R 4 is substituted with —S(O) n R 13 .

9. The compound according to claim 1 , wherein R 5 is H.

10. The compound according to claim 1 , wherein R 6 is H.

11. The compound according to claim 1 , wherein R 7 is gem-dimethyl.

12. The compound according to claim 1 , wherein
R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are H;
R 4 is pyrimidin-2-yl;
R 7 is gem-dimethyl; and
X is phenyl substituted from 1 to 4 times with halogen.

13. The compound according to claim 8 , wherein n is 2 and R 13 is methyl.

14. The compound according to claim 1 , wherein
R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are H;
R 4 is pyrimidin-2-yl substituted with —S(O) n R 13 ;
R 7 is gem-dimethyl; and
X is phenyl substituted from 1 to 4 times with F.

Assignees

• Albany Molecular Res Inc
• Bristol Myers Squibb Co

Inventors

• Molino Bruce F
• Liu Shuang
• Sambandam Aruna
• Guzzo Peter R
• Hu Min
• Zha Congxiang
• Nacro Kassoum
• Manning David D
• Isherwood Matthew L
• Ryan Kristen N
• Cui Wenge
• Olson Richard E

Classifications

• A61P5/24

  of the sex hormones · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/34

  Tobacco-abuse · CPC title