Cannabinoid type 1 receptor modulators

Patent metadata

Field	Value
Publication number	US-2018118681-A1
Application number	US-201515507079-A
Country	US
Kind code	A1
Filing date	Aug 26, 2015
Priority date	Aug 27, 2014
Publication date	May 3, 2018
Grant date	—

Abstract

The present disclosure relates to indole derivatives of the formula (I) which are cannabinoid type 1 receptor modulators and which are useful in the treatment of diseases in which modulation of the receptor is beneficial; to processes for their preparation; to pharmaceutical compositions comprising them; and to methods of using them.

First claim

1 . A compound of the Formula (I)

wherein,
W is (C 1 -C 10 )-alkyl, (C 3 -C 10 )-cycloalkyl, (C 3 -C 10 )-heterocycloalkyl, (C 6 -C 10 )-aryl, or (C 5 -C 10 )-heteroaryl, each of which is optionally substituted with one or more of halo, —CF 3 , —CN, —NO 2 , —R, —OR, —SR, —NR 2 , —C(═O)R, —C(═O)OR, —NRC(═O)R, —C(═O)NR 2 , —C(═O)NR′ 2 , —S(═O) 2 NR 2 , —S(═O) 2 NR′ 2 , —NRS(═O) 2 R, —S(═O) 2 R or —S(═O)CF 3 ,
wherein R is independently or simultaneously H, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, phenyl or benzyl, and
R′ is independently or simultaneously H, azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano;
X and X′ are independently or simultaneously (C 0 -C 4 )-alkylene, optionally substituted with one or more of halo, —CF 3 , OH, OCF 3 , or —O—(C 1 -C 4 )alkyl;
Z is —CH 2 CN, —CH(CN) 2 , —CH 2 CF 3 , or —C(═O)CF 3 ;
Ring V is (C 3 -C 10 )-cycloalkyl, (C 3 -C 10 )-heterocycloalkyl, (C 6 -C 10 )-aryl, or (C 5 -C 10 )-heteroaryl, each of which is optionally substituted with one or more of the optional substituents defined in the variable W;
R 1 is halo, —CF 3 , —CN, —NO 2 , —R 2 , —OR 2 , —SR, —N(R 2 ) 2 , —(NR 2′ ) 2 , —C(═O)R 2 , —C(═O)OR 2 , —NR 2 C(═O)R 2 , —C(═O)N(R 2 ) 2 , —C(═O)N(R 2′ ) 2 , —S(═O) 2 N(R 2 ) 2 ,
—S(═O) 2 N(R 2′ ) 2 , —NRS(═O) 2 R, —S(═O) 2 R 2 or —S(═O)CF 3 ,
wherein R 2 is independently or simultaneously H, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, phenyl or benzyl, and
R 2′ is independently or simultaneously H, azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano;
R 3 is H or (C 1 -C 6 )alkyl;
R″ is halo, —CF 3 , —OCF 3 , —CN, —NO 2 , —R 4 , —OR 4 , —SR, —N(R 4 ) 2 , —(NR 4′ ) 2 , —C(═O)R 4 , —C(═O)OR 4 , —NR 4 C(═O)R 4 , —C(═O)N(R 4 ) 2 , —C(═O)N(R 4′ ) 2 , —S(═O) 2 N(R 4 ) 2 , —S(═O) 2 N(R 4′ ) 2 , —NR 4 S(═O) 2 R 4 , —S(═O) 2 R 4 or —S(═O)CF 3 ,
wherein R 4 is independently or simultaneously H, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, phenyl or benzyl, and
R 4′ is independently or simultaneously H, azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano;
p is the integer 0, 1, 2 or 3, and
pharmaceutically acceptable salts, stereoisomers, and/or solvates thereof.

2 . The compound of the Formula (I) as claimed in claim 1 , wherein W is (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 3 -C 6 )-heterocycloalkyl, (C 6 )-aryl, or (C 5 -C 6 )-heteroaryl, each of which is optionally substituted.

3 . (canceled)

4 . The compound of the Formula (I) as claimed in claim 1 , wherein W is isopropyl, cyclopropyl, piperidine, tetrahydropyran, phenyl, thiophenyl, furanyl, pyridinyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted.

5 . The compound of the Formula (I) as claimed in claim 1 , wherein W is phenyl, furanyl, cyclopropyl or thiophenyl, each of which is optionally substituted.

6 . The compound of the Formula (I) as claimed claim 1 , wherein the optional substituents on W are one or more of halo, —CF 3 , —OCF 3 , —CN, —R, or —OR.

7 . The compound of the Formula (I) as claimed in claim 1 , wherein X and X′ are independently or simultaneously (C 0 -C 2 )-alkylene.

8 . (canceled)

9 . The compound of the Formula (I) as claimed in claim 1 , wherein Ring V is (C 3 -C 6 )-cycloalkyl, (C 3 -C 6 )-heterocycloalkyl, (C 6 )-aryl, or (C 5 -C 6 )-heteroaryl, each of which is optionally substituted.

10 . (canceled)

11 . The compound of the Formula (I) as claimed in claim 1 , wherein Ring V is cyclopropyl, cyclopentyl, piperidinyl, tetrahydropyranyl, phenyl, thiophenyl, furanyl, pyridinyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted.

12 . The compound of the Formula (I) as claimed in claim 11 , wherein Ring V is phenyl or cyclopentyl, each of which is optionally substituted.

13 . The compound of the Formula (I) as claimed in claim 1 , wherein the optional substituents on Ring V are one or more of halo, —CF 3 , —OCF 3 , —CN, —R, or —OR.

14 . The compound of the Formula (I) as claimed in claim 1 , wherein R 1 is halo, —CF 3 , —OCF 3 , —CN, —R 2 , —OR 2 , —SR, or —N(R 2 ) 2 , wherein R 2 is independently or simultaneously H, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, phenyl or benzyl.

15 . (canceled)

16 . The compound of the Formula (I) as claimed in claim 1 , wherein R 1 is halo, —CF 3 , —OCF 3 , —CN, or —R 2 wherein R 2 is independently or simultaneously H, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, phenyl or benzyl.

17 . (canceled)

18 . The compound of the Formula (I) as claimed in claim 1 , wherein R 1 is halo, —CF 3 , or —R 2 , wherein R 2 is independently or simultaneously H, (C 1 -C 3 )-alkyl, (C 2 -C 3 )-alkenyl, (C 2 -C 3 )-alkynyl, or (C 3 -C 6 )-cycloalkyl.

19 . (canceled)

20 . The compound of the Formula (I) as claimed in claim 18 , wherein R 1 is Cl, —CF 3 , methyl.

21 . (canceled)

22 . The compound of the Formula (I) as claimed in claim 1 , wherein the compound of the Formula (I) is

23 . A method for the treatment of a disease or condition in which modulation of the cannabinoid type 1 receptor is beneficial, comprising administering to a patient in need thereof an effective amount of a compound of claim 1 .

24 . The method of claim 23 , wherein the disease or condition is:
a) pain, wherein the pain is neuropathic pain, inflammatory pain, pain associated with multiple sclerosis, pain of undefined origin, pain associated with cancer or cancer chemotherapy, pain associated with diabetic neuropathy, or pain associated with surgery; b) multiple sclerosis or spasticity associated with multiple sclerosis; c) depression; d) an eating disorder, wherein the eating disorder is cachexia or anorexia associated with cancer chemotherapy or cachexia or anorexia associated with HIV/AIDS; e) a cardiovascular disease, wherein the cardiovascular disease is hypertension, congestive heart failure, cardiac hypertrophy, peripheral artery disease, atherosclerosis, stroke, kidney disease, myocardial infarction, steatohepatitis, myocardial reperfusion injury, or cardiotoxicity associated with chemotherapy; f) non-alcoholic fatty liver disease associated with metabolic syndrome; g) addiction or a symptom of addiction, wherein the addiction or symptom of addiction is smoking addiction and/or smoking withdrawal, alcohol addiction and/or alcohol withdrawal, or drug addiction and/or drug withdrawal; h) a bone disorder, wherein the bone disease is osteoporosis, Paget's disease, joint destruction, bone loss, neoplasia of bones, aseptic loosening of prosthetic implants, or bone related cancer; i) cancer, wherein the cancer is breast cancer; j) an inflam

Assignees

• Governing Council Univ Toronto
• The Univ Court Of The Univ Of Aberdeen

Inventors

• Ross Ruth
• Greig Iain
• ZANDA Matteo
• Tseng Chih-Chung

Classifications

• A61P25/22

  Anxiolytics · CPC title

• A61P1/08

  for nausea, cinetosis or vertigo; Antiemetics · CPC title

• A61P25/34

  Tobacco-abuse · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title