# US 7,612,090 B2 · Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof

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- Number: US 7,612,090 B2
- Document ID: US7612090B2
- Status: Granted
- Kind: B2
- Application number: 10/426,097
- Filed: 2003-04-29
- Published: 2003-10-30
- Granted: 2009-11-03
- Earliest claimed: 1999-11-03
- Assignees: Albany Molecular Research, Inc.
- Inventors: James P. Beck; Matt A. Curry; Mark A. Smith
- Web page: https://patentgrep.com/patent/US7612090B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/30: for treating abuse or dependence
- A61P 25/34: Tobacco-abuse
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 217/04: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are compounds of the formula (I): wherein R1-R8 are as described herein, R4 being aryl or heteroaryl Such compounds are particularly useful in the treatment of a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine or dopamine.

## Claims

### Claim 1

A method of treating a disorder which is created by decreased availability of serotonin, norepinephrine or dopamine or is dependent upon decreased availability of serotonin, norepinephrine or dopamine, wherein in the disorder is depression, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula (I):
wherein:
the carbon atom designated * is in the R or S configuration;
R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or C4-C7 cycloalkylalkyl, each of which is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of: C1-C3 alkyl, halogen, Ar,—CN, —OR9 and —NR9R10;
R2 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl or C1-C6 haloalkyl;
R3 is H, halogen, —OR11, —S(O)nR12, —CN, —C(O)R12, —C(O)NR11R12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or C4-C7 cycloalkylalkyl and wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of: C1-C3 alkyl, halogen, —CN, —OR9, —NR9R10 and phenyl which is optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy, —CN, —OR9, and —NR9R10;
R4 is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, triazinyl, triazolyl, furanyl, pyranyl, indazolyl, benzimidazolyl, quinolinyl, quinazolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, benzthiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl or thiadiazolyl, wherein the R4 group is optionally substituted with from 1 to 4 R14 substituents;
R5 and R6 and R7 are each independently selected from the group consisting of: H, halogen, —OR11, —NR11R12, —NR11C(O)R12, —NR11C(O)2R12—NR11C(O)NR12R13, —S(O)nR12, —CN, —C(O)R12,—C(O)NR11R12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or C4-C7 cycloalkylalkyl, and wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of: C1-C3 alkyl, halogen, —CN, —OR9, —NR9R10 and phenyl which is optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy, —CN, —OR9, or NR9R10;
or R5 and R6 taken together may be —O—C(R12)2—O—,
R8 is H, halogen or OR11;
R9 and R10 are each independently selected from the group H, C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R13, 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, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy;
or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
R11 is H, C1-C4alkyl, C1-C4 haloalkyl, C1-C4alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R13, phenyl or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;
R12 is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;
or R11 and R12 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 R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
R13 is C1-C4 alkyl, C1-C4 haloalkyl or phenyl,
n is 0, 1, or 2; and,
R14 is independently selected at each occurrence from a substituent selected from the group consisting of: halogen, —NO2, —OR11, —NR11R12, —NR11C(O)R12, —NR11C(O)2R12, —NR11C(O)NR12R13, —S(O)nR12, —CN, —C(O)R12, C(O)NR11R12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where C1-C6 alkyl, C2-C6 alkenyl C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of C1-C3 alkyl, halogen, Ar, —CN, —OR9, and —NR9R10, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof.

### Claim 2 (depends on 1)

A method according to claim 1 which further comprises administering a therapeutically effective amount of a serotonin 1A receptor antagonist, or pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

A method according to claim 2 wherein the serotonin 1A receptor antagonist is chosen from the group consisting of WAY 100135 and spiperone.

### Claim 4 (depends on 1)

A method according to claim 1, which further comprises administering a therapeutically effective amount of a selective neurokinin-1 receptor antagonist, or pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A method according to claim 1, which further comprises administering a therapeutically effective amount of a norepinephrine precursor, or pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

A method according to claim 5, wherein the norepinephrine precursor is selected from the group consisting of L-tyrosine and L-phenylalanine.

### Claim 7 (depends on 1)

The method of claim 1 wherein the (+)-stereoisomer of the compound is employed.

### Claim 8 (depends on 1)

The method of claim 1 wherein the (−)-stereoisomer of the compound is employed.