# US 7,608,626 B2 · Substituted indolizines and derivatives as CNS agents

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- Number: US 7,608,626 B2
- Document ID: US7608626B2
- Status: Granted
- Kind: B2
- Application number: 11/260,716
- Filed: 2005-10-27
- Published: 2006-05-04
- Granted: 2009-10-27
- Earliest claimed: 2004-11-01
- Assignees: Wyeth
- Inventors: Annmarie Louise Sabb; Robert Lewis Vogel
- Web page: https://patentgrep.com/patent/US7608626B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/10: for impotence
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula 1 or pharmaceutically acceptable salts thereof are provided: which are agonists or partial agonists of the 2C subtype of brain serotonin receptors. The compounds, and compositions containing the compounds, can be used to treat a variety of central nervous system disorders such as schizophrenia.

## Claims

### Claim 1

A compound of formula (1):
or a pharmaceutically acceptable salt thereof;
wherein
R is H, C1-C6 alkyl, C6-C10 aryl, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur, or —C(O)R′, wherein R′ is C1-C6 alkyl, C6-C10 aryl, or 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur;
R1 is H, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 fluoroalkyl;
R2 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 fluoroalkyl, C6-C10 aryl, or 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur;
R3 is C3-C6 alkyl, C1-C6 alkyl-C3-C8 cycloalkyl, or C1-C6 fluoroalkyl;
or alternatively R2 and R3 can be taken together with the carbon atoms to which they are attached to form a ring of 5-8 carbon atoms;
R4, R5, R6, and R7 are each independently H, halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, C6-C10 aryl, C6-C10 aryloxy, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur, C2-C8 alkenyl, C2-C6 alkanoyl, C2-C6 alkanoyloxy, C2-C6 alkoxycarbonyl, carboxamido, C2-C6 alkanamido, C1-C6 alkanesulfonamido, amino, C1-C6 monoalkylamino, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, C3-C8 cycloalkyl, or a 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur;
R8 is H, C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C10 aryl;
wherein any cycloalkyl or heterocycloalkyl group is saturated or partially saturated, and any aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, and C1-C6 fluoroalkoxy.

### Claim 2 (depends on 1)

A compound of claim 1 wherein R is selected from H and C1-C6 alkyl.

### Claim 3 (depends on 1)

A compound of claim 1 wherein R1 is selected from H and C1-C6 alkyl.

### Claim 4 (depends on 2)

A compound of claim 2 wherein R1 is selected from H and C1-C6 alkyl.

### Claim 5 (depends on 1)

A compound of claim 1 wherein R2 is selected from optionally substituted phenyl and C1-C6 alkyl.

### Claim 6 (depends on 1)

A compound of claim 1 wherein R3 is C3-C6 alkyl.

### Claim 7 (depends on 4)

A compound of claim 4 wherein R3 is C3-C6 alkyl.

### Claim 8 (depends on 5)

A compound of claim 5 wherein R3 is C3-C6 alkyl.

### Claim 9 (depends on 1)

A compound of claim 1 wherein R and R1 are each independently selected from H and C1-C6 alkyl, R2 is selected from optionally substituted phenyl and C1-C6 alkyl, and R3 is C3-C6 alkyl.

### Claim 10 (depends on 1)

A compound of claim 1 wherein R2 and R3 are taken together to form a ring of 5-8 carbon atoms.

### Claim 11 (depends on 4)

A compound of claim 4 wherein R2 and R3 are taken together to form a ring of 5-8 carbon atoms.

### Claim 12 (depends on 1)

A compound of claim 1 wherein R4, R5, R6, and R7 are each independently selected from H, halogen, C1-C6 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, and C2-C8 alkenyl.

### Claim 13 (depends on 12)

A compound of claim 12 wherein R4, R5, R6, and R7 are each independently selected from H, halogen, and C1-C6 alkyl.

### Claim 14 (depends on 13)

A compound of claim 13, wherein R4, R5, R6, and R7 are each H.

### Claim 15 (depends on 4, 5, 6, 7, 8, 9, 10)

A compound of any one of claims 4 to 10 wherein R4, R5, R6, and R7 are each H.

### Claim 16 (depends on 1)

A compound of claim 1 wherein R8 is selected from H and C1-C6 alkyl.

### Claim 17 (depends on 1)

A compound of claim 1 wherein R8 is H.

### Claim 18 (depends on 15)

A compound of claim 15 wherein R8 is H.

### Claim 19 (depends on 1)

A compound of claim 1 which is:
2-(3-ethyl-2-phenylindolizin-1-yl)ethylamine;
2-(2-phenyl-3-propylindolizin-1-yl)ethylamine;
2-(2,3-diethylindolizin-1-yl)ethylamine;
N-[2-(2,3-diethylindolizin-1-yl)ethyl]-N-ethylamine;
2-(2-ethyl-3-propylindolizin-1-yl)ethylamine;
N-[2-(2-ethyl-3-propylindolizin-1-yl)ethyl]-N-propylamine;
2-(2-ethyl-3-propylindolizin-1-yl)-1-methylethylamine;
1-(2-methyl-3-propylindolizin-1-yl)propan-2-amine;
1-(2-methyl-3-propylindolizin-1-yl)butan-2-amine; or
2-(1,2,3,4-tetrahydropyrido[1,2-a]indol-10-yl)ethylamine; or
a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

### Claim 21

A compound which is 2-(2-phenylindolizin-1-yl)ethylamine or 2-(2-ethylindolizin-1yl)ethylamine.