Cyclopropylmethanamines as selective 5-HT(2C) receptor agonists

Patent metadata

Field	Value
Publication number	US-10407381-B2
Application number	US-201615544548-A
Country	US
Kind code	B2
Filing date	Jan 27, 2016
Priority date	Jan 29, 2015
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

Abstract

Disclosed are 2-phenyl-cyclopropylmethanamines which are selective 5-HT(2C) receptor agonists and are used in the treatments of diseases and conditions wherein modulation of 5-HT(2C) receptors provides a benefit, such as obesity and psychiatric disorders.

First claim

What is claimed:

1. A compound having a structural formula:

wherein R 1 is halo;
R 2 is C 1-5 alkyl, fluorinated C 1-3 alkyl, phenyl, benzyl,

—CH 2 —C≡CH, or —(CH 2 ) 1-3 XCH 3 ;
X is O or S;
R a is hydrogen, fluoro, or C 1-3 alkyl; and
n is an integer 1, 2, or 3,
wherein when R 2 is methyl and n is 1, then R 1 is chloro; and when R 2 is methyl and n is 2, then at least one R 1 is chloro,
or a pharmaceutically acceptable salt or hydrate thereof.

2. The compound of claim 1 wherein R 1 is fluoro or chloro.

3. The compound of claim 1 wherein when n is 1, R 1 is fluoro or chloro, and when n is 2, R 1 is fluoro and fluoro, chloro and chloro, or fluoro and chloro.

4. The compound of claim 1 wherein R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, n-pentyl, iso-pentyl, phenyl, benzyl, —CH 2 CH 2 F, —CH 2 CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH═CH 2 ,

or —CH 2 C≡CH.

5. The compound of claim 1 wherein R 2 is —CH 2 CH 2 —O—CH 3 or —CH 2 CH 2 —S—CH 3 .

6. The compound of claim 1 wherein R 1 is F, n is 1, and R 2 is —CH 2 CH 2 CH 3 , —CH 2 CH═CH 2 ,

or —CH 2 CH 2 F.

7. A compound selected from the group consisting of

8. A compound selected from the group consisting of
(+) (2-(2-(allyloxy)-5-fluorophenyl)cyclopropyl)methanamine;
(+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine;
(+) (2-(5-chloro-2-(3-fluoropropoxy)phenyl)cyclopropyl)methanamine; and
(+) (2-(5-chloro-2-((2-fluoroallyl)oxy)phenyl)cyclopropyl)methanamine;
or a salt thereof.

9. A composition comprising (a) compound of claim 1 , (b) a second therapeutic agent, and (c) an optional excipient and/or pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.

11. A method of treating a disease or condition via modulation of 5-HT(2C) receptors comprising administering a therapeutically effective amount of a compound of claim 1 to an individual in need thereof.

12. The method of claim 11 wherein the disease or condition is a central nervous system disorder, damage to the central nervous system, a metabolic or eating disorder a neurological disorder.

13. The method of claim 12 wherein the central nervous system disorder is anxiety, a panic disorder, a schizoaffective disorder, schizophrenia, psychosis, an adjustment disorder, dystonia, clinical depression, bipolar disorder, an addictive behavior, a compound addiction, obsessive compulsive disorder, a movement disorder, e a cognition disorder, dyslipidemia, Type 2 diabetes, diabetes insipidus, metabolic syndrome, obesity or Rett Syndrome.

14. The method of claim 11 wherein the disease or condition is a gastrointestinal disorder, sleep apnea, hypertension, hyperlipidemia, a cardiovascular disease, dementia, memory deficit, mild cognitive impairment, Parkinson's Disease, Alzheimer's Disease, an intellectual deficit associated with Alzheimer's disease, Huntington's Disease, dyskinesia, chronic pain, migraine, epilepsy, abuse or addiction to alcohol and drugs, or sexual dysfunction in males or females.

Assignees

• Univ Illinois

Inventors

• Kozikowski Alan
• Cheng Jianjun

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/28

  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 · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/22

  Anxiolytics · CPC title