Serotonin receptor modulators

Patent metadata

Field	Value
Publication number	US-9981909-B2
Application number	US-201514925835-A
Country	US
Kind code	B2
Filing date	Oct 28, 2015
Priority date	Oct 30, 2008
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

Certain biphenyic compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases.

First claim

What is claimed is:

1. A compound selected from the group consisting of (a) compounds of Formula (I):

wherein
R 1 is —H, or —C 1-4 alkyl;
m is 1;
n is 2;
R 2 and R 3 are each independently —H or —C 1-4 alkyl;
R 4 is —H;
L is —O—;
Z is —O—, or —OCH(R b )—;
where R b is —H;

R 5 is:
a phenyl group, unsubstituted or substituted with one, two, or three R g substituents;
where each R g substituent is selected from the group consisting of: —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —OS(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SCF 3 , halo, —CF 3 , —OCF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —CH 2 OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl;
or two R g substituents taken together form —OCH 2 O—, —OCF 2 O—, or —OCH 2 CH 2 O—;

X is C; and
R 6 and R 7 are each independently —H, and halo;
and (b) pharmaceutically acceptable salts of the compounds of Formula (I).

2. A compound as defined in claim 1 , wherein R 1 is —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 .

3. A compound as defined in claim 2 , wherein R 1 is —H.

4. A compound as defined in claim 1 , wherein R 2 is —H or —CH 3 .

5. A compound as defined in claim 1 , wherein R 3 is —H or —CH 3 .

6. A compound as defined in claim 1 , wherein R 2 and R 3 are each —H.

7. A compound as defined in claim 1 , wherein Z is —O—.

8. A compound as defined in claim 1 , wherein Z is —OCH 2 .

9. A compound as defined in claim 1 , wherein R 5 is phenyl, optionally substituted with halo, —OCH 3 , —OSO 2 CH 3 , and CF 3 .

10. A compound as defined in claim 1 , wherein R 5 is selected from the group consisting of:
phenyl, 3- or 4-bromo-phenyl, 2-, 3- or 4-chloro-phenyl, 3,4-dichloro-phenyl, 3- or 4-cyano-phenyl, 2-, 3- or 4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl, 4-chloro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-methyl-phenyl, 3- or 4-methylsulfanyl-phenyl, 3- or 4-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 3-methanesulfonyloxy-phenyl, 3- or 4-methoxy-phenyl, 3-trifluoromethoxy-phenyl, 2-, 3- or 4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-trifluoromethyl sulfanyl-phenyl, and 3-trifluoromethoxy-phenyl.

11. A compound as defined in claim 1 , wherein R 6 and R 7 are H.

12. A compound as defined in claim 1 , wherein R 6 is —H or Cl.

13. A compound as defined in claim 1 , wherein R 6 is —H or Cl and R 7 is —H, Br, or Cl.

14. A compound as defined in claim 1 , selected from the group consisting of:
(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine;
(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine;
(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine;
(±)-Methanesulfonic acid 3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;
(±)-Methanesulfonic acid 3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;
(S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;
(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;
(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine;
(S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine;
(S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine;
(S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine;
(S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine;
(S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine;
(S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine;
(S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine;
(S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine; and
(±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine;
and pharmaceutically acceptable salts thereof.

15. A pharmaceutical composition, comprising an effective amount of at least one compound selected from compounds of Formula (I):

wherein
R 1 is —H, or —C 1-4 alkyl;
m is 1;
n is 2;
R 2 and R 3 are each independently —H or —C 1-4 alkyl;
R 4 is —H;
L is —O—;
Z is —O—, or —OCH(R b )—
where R b is —H;

R 5 is:
a phenyl group, unsubstituted or substituted with one, two, or three R g substituents;
where each R g substituent is selected from the group consisting of: —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —OS(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SCF 3 , halo, —CF 3 , —OCF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —CH 2 OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl;
or two R g substituents taken together form —OCH 2 O—, —OCF 2 O—, or —OCH 2 CH 2 O—;

X is C; and
R 6 and R 7 are each independently —H, and halo;
and (b) pharmaceutically acceptable salts of the compounds of Formula (I).

16. A pharmaceutical composition according to claim 15 ,
wherein said at least one compound is selected from the group consisting of:
(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine;
(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine;
(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine;
(±)-Methanesulfonic acid 3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;
(±)-Methanesulfonic acid 3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;
(S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;
(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;
(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine;
(S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine;
(S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine;
(S)-3-(4-Ch

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Carruthers Nicholas I
• Chai Wenying
• Jablonowski Jill A
• Shah Chandravadan R
• Shireman Brock T
• Swanson Devin M
• Tran Vi
• Wong Victoria

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P25/18

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

• A61P25/22

  Anxiolytics · CPC title