3-phenoxymethylpyrrolidine compounds

Patent metadata

Field	Value
Publication number	US-9227933-B2
Application number	US-201514594382-A
Country	US
Kind code	B2
Filing date	Jan 12, 2015
Priority date	Jul 13, 2009
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

In one aspect, the invention relates to compounds of formula I:

where R 1-6 are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula I are serotonin and norepinephrine reuptake inhibitors. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

First claim

What is claimed is:

1. A compound of formula I:

where:
R 1 is isopropyl;
R 2 through R 6 are independently selected from hydrogen, halo, —C 1-6 alkyl, —CF 3 , —O —C 1-6 alkyl, —CN, —C(O)—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-8 cycloalkyl, and —NO 2 ; or R 4 and R 5 are taken together to form —CH═CH—CH═CH—; or R 5 and R 6 are taken together to form —CH═CH—CH═CH—;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , where R 2 is hydrogen, halo, —C 1-6 alkyl, —CF 3 , —O—C 1-6 alkyl, —C(O)—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-8 cycloalkyl, or —NO 2 .

3. The compound of claim 2 , where R 2 is hydrogen, fluoro, chloro, —CH 3 , —CH 2 CH 3 , —CF 3 , —O—CH 3 , —O—CH 2 CH 3 , —C(O)—CH 3 , —S—CH 3 , cyclohexyl, or —NO.

4. The compound of claim 1 , where R 3 is hydrogen, halo, —C 1-6 alkyl, —CF 3 , —O—C 1-6 alkyl, or —S—C 1-6 alkyl.

5. The compound of claim 4 , where R 3 is hydrogen, fluoro, chloro, —CH 3 , —CF 3 , —O—CH 3 , or —S—CH 3 .

6. The compound of claim 1 , where R 4 is hydrogen, halo, —C 1-6 alkyl, —CF 3 , or —O—C 1-6 alkyl.

7. The compound of claim 6 , where R 4 is hydrogen, fluoro, chloro, —CH 3 , —CF 3 , or —O—CH 3 .

8. The compound of claim 1 , where R 5 is hydrogen, halo, —C 1-6 alkyl, or —O—C 1-6 alkyl.

9. The compound of claim 8 , where R 5 is hydrogen, fluoro, chloro, —CH 3 , or —O—CH 3 .

10. The compound of claim 1 , where R 6 is hydrogen, halo, or —C 1-6 alkyl.

11. The compound of claim 10 , where R 6 is hydrogen, fluoro, chloro, or —CH 3 .

12. The compound of claim 1 , where R 5 and R 6 are taken together to form —CH═CH—CH═CH—.

13. The compound of claim 1 , where R 2 and R 3 are non-hydrogen moieties, and R 4 , R 5 , and R 6 are hydrogen.

14. The compound of claim 1 , where R 2 and R 4 are non-hydrogen moieties, and R 3 , R 5 , and R 6 are hydrogen.

15. The compound of claim 1 , where R 3 and R 4 are non-hydrogen moieties, and R 2 , R 5 , and R 6 are hydrogen.

16. The compound of claim 1 , where R 2 , R 3 , and R 4 are non-hydrogen moieties, and R 5 and R 6 are hydrogen.

17. The compound of claim 1 , where R 2 , R 4 , and R 6 are non-hydrogen moieties, and R 3 and R 5 are hydrogen.

18. The compound of claim 1 , which is 3-[1-(4-chloro-phenoxy)-2-methylpropyl]pyrrolidine.

19. The compound of claim 1 , which has a configuration selected from:

or enriched in a stereoisomeric form having such configuration.

20. The compound of claim 19 , which is selected from (R)-3-[(R)-1-(4-chloro-phenoxy)-2-methylpropyl]pyrrolidine, (S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine, (S)-3-[(R)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine, and(R)-3- [(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine.

21. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition of claim 21 , further comprising a second therapeutic agent selected from anti-Alzheimer's agents, anticonvulsants, antidepressants, anti-Parkinson's agents, dual serotonin-norepinephrine reuptake inhibitors, non-steroidal anti-inflammatory agents, norepinephrine reuptake inhibitors, opioid agonists, selective serotonin reuptake inhibitors, sodium channel blockers, sympatholytics, and combinations thereof.

23. A method of causing regression of, suppressing, or alleviating the symptoms of a disorder or disease is selected from pain disorders, depressive disorders, affective disorders, attention deficit hyperactivity disorders, stress urinary incontinence, chronic fatigue syndrome, obesity, and vasomotor symptoms associated with menopause, comprising administering a therapeutically effective amount of the compound of claim 1 to a patient that is suffering from said disease or disorder.

24. The method of claim 23 , wherein the pain disorder is neuropathic pain, fibromyalgia, or chronic pain.

Assignees

• Stangeland Eric
• Saito Daisuke Roland
• Van Dyke Priscilla
• Patterson Lori Jean
• Theravance Biopharma R&D Ip Llc

Inventors

• Stangeland Eric
• Saito Daisuke Roland
• Van Dyke Priscilla
• Patterson Lori Jean

Classifications

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P43/00

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

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title