IP Library › Granted Patent US 7,071,213
Granted Patent B2
US 7,071,213 · App. 10/292,778 · Granted Jul 4, 2006

Cannabinoid receptor ligands

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Quick Facts
Patent No.
US 7,071,213
App. No.
10/292,778
Granted
Jul 4, 2006
Kind
B2
Abstract

There are disclosed compounds of the formula I: or a pharmaceutically acceptable salt of the compound, which exhibit anti-inflammatory and immunomodulatory activity. Also disclosed are pharmaceutical compositions containing said compounds.

Claims (1425)

1. A compound of the formula I:

or a pharmaceutically acceptable salt or solvate of said compound, wherein:

L 1 is —S(O 2 )—;

L 3 is —C(O)— or —S(O 2 )—;

R 1 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, —NHR 7 , —N(R 7 ) 2 , —Si(alkyl) n (aryl) 3-n , substituted aryl and substituted or unsubstituted heteroaryl,

wherein each substituted aryl or heteroaryl can be independently substituted with one to five moieties which can be the same or different and are independently selected from the group consisting of halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy, —N(R 7 ) 2 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —NC(O)R 7 , —NC(O)OR 7 , —NC(O)N(R 7 ) 2 , —NO 2 , —CN, —S(O 2 )R 7 , —S(O 2 )N(R 7 ) 2 , —NC(═N—CN)NHR 7 , and OH;

R 2 is H, —OH, halogen, —N(R 7 ) 2 —, —CF 3 , alkoxy, alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl;

R 3 and R 4 are the same or different, and are independently H or alkyl;

R 5 is H or alkyl;

R 6 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, NHR 7 , N(R 7 ) 2 , aryl and heteroaryl, wherein each said aryl and heteroaryl can be unsubstituted or optionally independently substituted with one to five moieties which moieties can be the same or different and are independently selected from the group consisting of halogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy and OH;

R 7 is selected from H, alkyl, haloalkyl, cycloalkyl, heterocyclylalkyl, aryl and heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or optionally independently substituted with one to five moieties which moieties can be the same or different and are independently selected from the group consisting of halogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy and/or OH;

A is indolyl;

X is independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, alkoxycarbonyl, haloalkoxy, —N(R 7 ) 2 , —N(R 7 )(C(O)R 7 ), —N(R 7 )(C(O)OR 7 ), —NO 2 , oxide, and —CN; and

n is 1,

with the proviso that (i) the two R 7 moieties in —N(R 7 ) 2 can be the same or different and are independently selected, and (ii) the moiety —N(R 5 )-L 3 —R 6 can optionally form a ring system.

2. A compound according to claim 1 wherein

L 1 is —S(O 2 )—;

L 2 is —S(O 2 )—;

L 3 is —C(O)— or —S(O 2 )—;

R 1 is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said aryl and heteroaryl can be unsubstituted or optionally independently substituted with one to five moieties which can be the same or different and are independently selected from the group consisting of halogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy, —N(R 7 ) 2 , —CN, (C 1 -C 6 )alkoxy and OH;

R 2 is H, OH, halogen, CF 3 , alkoxy, —N(R 7 ) 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CH 2 —(C 3 -C 5 )cycloalkyl, or (C 3 -C 5 )cycloalkyl;

R 3 and R 4 are the same or different, and are independently selected from H or (C 1 -C 6 )alkyl;

R 5 is H or (C 1 -C 6 )alkyl;

R 6 is H, (C 1 -C 6 )alkyl, or haloalkyl;

X is selected from the group consisting of H, halogen, alkyl, haloalkyl, (C 3 -C 5 )cycloalkyl, hydroxy, alkoxy, and haloalkoxy; and

n is 1.

3. A compound according to claim 1 wherein

L 1 is —S(O 2 )—;

L 2 is —S(O 2 )—;

L 3 is —C(O)— or S(O 2 )—;

R 1 is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said aryl and heteroaryl can be unsubstituted or optionally independently substituted with one to five moieties which can be the same or different and are independently selected from the group consisting of halogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy, (C 1 -C 6 )alkoxy and OH;

R 2 is H, OH, halogen, CF 3 , alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CH 2 —(C 3 -C 5 )cycloalkyl or (C 3 -C 5 )cycloalkyl;

R 3 and R 4 are H;

R 5 is H or C 1 -C 6 alkyl;

R 5 is C 1 -C 6 alkyl, or haloalkyl;

X is selected from the group consisting of H, halogen, alkyl, haloalkyl, (C 3 -C 5 )cycloalkyl, hydroxy, alkoxy, and haloalkoxy and

n is 1.

4. The compound according to claim 1 having the formula 4:

wherein:

L 3 is —C(O)— or —S(O 2 )—;

R 1 is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said aryl and heteroaryl can be unsubstituted or optionally independently substituted with one to five moieties which can be the same or different and are independently selected from the group consisting of halogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy, (C 1 -C 6 )alkoxy and OH;

R 2 is H, OH, F, (C 1 -C 6 )alkyl, (C 1 -C 5 )haloalkyl, alkoxy, (C 3 -C 5 )cycloalkyl, or CH 2 —(C 3 -C 5 )cycloalkyl;

R 6 is C 1 -C 6 alkyl, or haloalkyl;

X is selected from the group consisting of H, halogen, alkyl, haloalkyl, (C 3 -C 5 )cycloalkyl, alkoxy, hydroxy and haloalkoxy; and

n is 1.

5. The compound according to claim 1 having the formula 5:

wherein:

L 3 is —C(O)— or —S(O 2 )—;

R 1 is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said aryl and heteroaryl can be unsubstituted or optionally independently substituted with one to five moieties which can be the same or different and are independently selected from the group consisting of halogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy, (C 1 -C 6 )alkoxy and OH;

R 2 is H, OH, F, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, alkoxy or (C 3 -C 5 )cycloalkyl, or CH 2 —(C 3 -C 5 )cycloalkyl;

R 6 is C 1 -C 6 alkyl, or haloalkyl;

X is selected from the group consisting of H, halogen, alkyl, haloalkyl, (C 3 -C 5 )cycloalkyl, alkoxy, hydroxy and haloalkoxy;

X is H or alkyl; and

n is 1.

6. The compound according to claim 1 wherein:

L 1 is —S(O 2 )—;

L 2 is —S(O 2 )—;

L 3 is —C(O)— or —S(O 2 )—;

R 1 is selected from the group consisting of t-butyl, i-propyl, neopentyl, 2-trifluoromethyl-2-propyl, 1,1-bis(trifluoromethyl)-1-ethyl, 2-fluorophenyl, 2,6-difluorophenyl, 2-pyridyl, and 2-pyrimidyl;

R 2 is H, F, (C 1 -C 6 )alkyl, OH, or alkoxy;

R 3 ═R 4 ═H;

R 5 is H;

R 6 is CH 3 or CF 3 ;

X is selected from the group consisting of H, F, Cl, Br, CF 3 , —OCH 3 , —OCF 3 and —OCHF 2 ; and

n is 1.

7. The compound according to claim 1 of the formula:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 6 , A, L 1 , L 2 , L 3 and X are as set forth in the following table:

Cmp

R 1

R 2

R 3

R 4

R 6

A =

L 1

L 2

L 3

X

A

H

H

H

CF 3

CO 2

SO 2

SO 2

Cl

B

H

H

H

CH 3

CO 2

SO 2

SO 2

OCF 3

C

H

H

H

CF 3

CO 2

SO 2

SO 2

Cl

D

H

H

H

CF 3

CO 2

SO 2

SO 2

H

E

H

H

H

CF 3

CO 2

SO 2

SO 2

Cl

F

H

H

H

CH 3

CO 2

SO 2

SO 2

Cl

G

H

H

H

CF 3

CO 2

SO 2

SO 2

Cl

H

i-propyl

H

H

H

CF 3

CO 2

SO 2

SO 2

Cl

I

H

H

H

CH 3

CO 2

SO 2

SO 2

H

J

H

H

H

CH 3

SO 2

SO 2

SO 2

OCH 3

K

H

H

H

CH 3

SO 2

SO 2

SO 2

OCH 3

L

H

H

H

CH 3

SO 2

SO 2

SO 2

OCF 2 H

M

H

H

H

CH 3

SO 2

SO 2

SO 2

OCF 3

N

H

H

H

C 2 H 5

SO 2

SO 2

SO 2

OCF 2 H

O

H

H

H

CH 3

SO 2

SO 2

SO 2

Cl

P

H

H

H

C 2 H 5

SO 2

SO 2

SO 2

OCF 3

Q

H

H

H

CF 3

SO 2

SO 2

SO 2

CF 3

R

H

H

H

CF 3

SO 2

SO 2

SO 2

Cl

S

H

H

H

CF 3

SO 2

SO 2

C═O

OCH 3

T

H

H

H

CH 3

SO 2

SO 2

SO 2

H

U

H

H

H

CF 3

SO 2

SO 2

C═O

OCH 3

V

Br

H

H

H

CH 3

CB

SO 2

SO 2

H

W

H

H

H

CH 3

CB

SO 2

SO 2

H

X

C 3 H 7

H

H

H

CH 3

SO 2

SO 2

SO 2

OCH 3

Y

H

H

H

CF 3

SO

SO 2

C═O

Cl

Z

H

H

H

CF 3

SO 2

CH 2

C═O

Cl

AA

H

H

H

CF 3

S

CH 2

C═O

Cl

AB

H

H

H

CH 3

CH 2

SO 2

SO 2

Cl

AC

H

H

H

CH 3

CH 2

SO 2

SO 2

Cl

AD

H

H

H

CH 3

C═O

SO 2

SO 2

Cl

AE

H

H

H

H

CF 3

CB

SO 2

SO 2

H

AF

H

H

H

H

CH 3

CB

SO 2

SO 2

H

AG

H

H

H

CH 3

SO 2

SO 2

SO 2

H

AH

Si(CH 3 ) 3

H

H

H

CH 3

CB

SO 2

SO 2

Cl

AI

Br

H

H

H

CH 3

CB

SO 2

SO 2

H

AJ

H

H

H

CH 3

NH

SO 2

SO 2

H

AK

OCH 3

H

H

CH 3

CO 2

SO 2

SO 2

Cl

AL

CH 3

H

H

CF 3

SO 2

SO 2

SO 2

Cl

AM

CH 3

H

H

CH 3

SO 2

SO 2

SO 2

Cl

AN

CH 3

H

H

CF 3

CO 2

SO 2

SO 2

Cl

AO

H

H

H

CF 3

SO 2

SO 2

SO 2

H

AP

H

H

H

CF 3

CO 2

SO 2

SO 2

OCH 3

AQ

F

H

H

CF 3

SO 2

SO 2

SO 2

Cl

AR

F

H

H

CF 3

CO 2

SO 2

SO 2

Cl

AS

F

H

H

CF 3

SO 2

SO 2

SO 2

Cl

AT

F

H

H

CF 3

SO 2

SO 2

SO 2

H

AU

F

H

H

CF 3

SO 2

SO 2

SO 2

Cl

AV

OCH 3

H

H

CF 3

SO 2

SO 2

SO 2

Cl

AW

OCH 3

H

H

CF 3

SO

SO 2

SO 2

Cl

AX

OCH 3

H

H

CF 3

CO 2

SO 2

SO 2

Cl

AY

H

H

H

CH 3

SO 2

SO 2

SO 2

OCF 3

AZ

H

H

H

CF 3

SO 2

SO 2

SO 2

OCF 3

BA

H

H

H

CF 3

SO 2

SO 2

SO 2

Cl

BB

H

H

H

CF 3

SO 2

SO 2

SO 2

H

BC

H

H

H

CH 3

SO 2

SO 2

SO 2

H

BD

H

H

H

CF 3

CO 2

SO 2

SO 2

OCF 3

BE

H

H

H

CF 3

CO 2

SO 2

SO 2

Cl

BF

H

CH 3

CH 3

CF 3

SO 2

SO 2

SO 2

Cl

BG

H

CH 3

CH 3

CF 3

SO 2

SO 2

C═O

CF 3

BH

H

CH 3

CH 3

CF 3

SO 2

SO 2

C═O

Cl

BI

H

CH 3

CH 3

CF 3

SO 2

SO 2

SO 2

CF 3

BJ

H

CH 3

CH 3

H

SO 2

SO 2

CB

CF 3

BK

H

CH 3

CH 3

CF 3

CO 2

SO 2

SO 2

Cl

BL

F

H

H

CF 3

SO 2

SO 2

SO 2

CF 3

BM

OCH 3

H

H

CF 3

S

SO 2

SO 2

Cl

BN

F

H

H

CF 3

CO 2

SO 2

SO 2

CF 3

BO

F

H

H

CF 3

SO 2

SO 2

SO 2

Cl

BP

OH

H

H

CF 3

CO 2

SO 2

SO 2

Cl

BQ

H

H

CH 3

CO 2

SO 2

SO 2

Cl

BR

F

H

H

CF 3

SO 2

SO 2

SO 2

Cl

BS

H

H

CH 3

CO 2

SO 2

SO 2

Cl

BT

CH 3

H

H

CF 3

SO 2

SO 2

C═O

Cl

BU

H

H

CF 3

CO 2

SO 2

SO 2

Cl

BV

OH

H

H

CH 3

CO 2

SO 2

SO 2

Cl

BW

F

H

H

CF 3

SO 2

SO 2

C═O

Cl

BX

C 3 H 7

H

H

CF 3

CO 2

SO 2

SO 2

Cl

BY

F

H

H

CF 3

SO 2

SO 2

SO 2

Cl

BZ

H

H

CF 3

CO 2

SO 2

SO 2

Cl

CA

H

H

H

CF 3

SO 2

SO 2

C═O

Cl

CB

H

H

H

CF 3

SO 2

SO 2

SO 2

H

CC

H

H

H

CF 3

SO 2

SO 2

SO 2

Cl

CD

H

H

H

CF 3

SO 2

SO 2

C═O

Cl

CE

H

H

H

CF 3

SO 2

SO 2

C═O

OCF 2 H

CF

H

H

H

CH 3

SO 2

SO 2

SO 2

H

CG

H

H

H

CF 3

SO 2

SO 2

C═O

H

CH

H

H

H

CF 3

SO 2

SO 2

C═O

OCH 3

CI

H

H

H

C 2 H 5

SO 2

SO 2

SO 2

OCF 3

CJ

H

H

H

CH 3

SO 2

SO 2

SO 2

OCF 3

CK

H

H

H

CF 3

SO 2

SO 2

SO 2

OCF 3

CL

H

H

H

CF 3

SO 2

SO 2

C═O

OCF 3

CM

H

H

H

CF 3

SO 2

SO 2

C═O

CF 3

CN

H

H

H

CF 3

SO 2

SO 2

C═O

OCF 3

CO

H

H

H

CH 3

SO 2

SO 2

SO 2

Cl

CP

C 4 H 9

H

H

H

CH 3

SO 2

SO 2

SO 2

Cl

CQ

H

H

H

C 2 H 5

CO 2

SO 2

SO 2

Cl

CR

CH 3

H

H

H

CF 3

CO 2

SO 2

C═O

H

CS

H

H

H

CF 3

CO 2

SO 2

SO 2

CF 3

CT

H

H

H

CF 3

CB

SO 2

C═O

H

CU

H

H

H

CH 3

CB

SO 2

SO 2

H

CV

Cl

H

H

H

CH 3

CB

SO 2

SO 2

Br

CW

H

H

H

CH 3

CB

SO 2

SO 2

H

CX

F

H

H

CF 3

CO 2

SO 2

C═O

Cl

CY

H

H

H

H

CH 3

CB

SO 2

SO 2

H

DA

F

H

H

CF 3

SO

SO 2

SO 2

Cl

DB

F

H

H

CF 3

SO

SO 2

SO 2

Cl

DC

H

H

H

CF 3

SO 2

CH 2

C═O

OCF 3

DD

CH 3

H

O*

O*

H

CO 2

SO 2

CB

H

DE

H

H

H

CH 3

CB

SO 2

SO 2

H

DF

H

H

H

CH 3

CB

SO 2

SO 2

H

DG

H

H

H

N(CH 3 ) 2

CO 2

SO 2

SO 2

Cl

DH

Br

H

H

H

CH 3

CB

SO 2

SO 2

H

DI

CH 3

H

H

H

CH 3

CB

SO 2

SO 2

t-butyl

DK

OCH 3

H

H

CF 3

SO 2

SO 2

SO 2

Cl

DL

OC 2 H 5

H

H

H

S

SO 2

CB

Cl

DM

OCH 3

H

H

CH 3

SO 2

SO 2

SO 2

Cl

DN

F

H

H

CF 3

SO

SO 2

SO 2

Cl

DO

OC 2 H 5

H

H

CF 3

SO 2

SO 2

SO 2

Cl

DP

OCH 3

H

H

CH 3

SO 2

SO 2

SO 2

Cl

DQ

F

H

H

CF 3

SO 2

SO 2

SO 2

Cl

DR

F

H

H

CF 3

SO 2

SO 2

SO 2

Cl

DS

F

H

H

CF 3

SO 2

SO 2

SO 2

Cl

DT

CH 3

H

H

H

CH 3

SO 2

SO 2

SO 2

Cl

CB = covalent bond

*R 3 and R 4 taken together form a carbonyl group (C═O).

8. The compound according to claim 1 having the formula:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , A, L 1 , and X are as set forth in the following table:

Cmp.

R 1

R 2

R 6

A

L 1

X

A

H

CF 3

CO 2

Cl

C

H

CF 3

CO 2

Cl

D

H

CF 3

CO 2

H

E

H

CF 3

CO 2

Cl

F

H

CH 3

CO 2

Cl

G

H

CF 3

CO 2

Cl

H

i-propyl

H

CF 3

CO 2

Cl

J

H

CH 3

SO 2

OCH 3

L

H

CH 3

SO 2

OCF 2 H

M

H

CH 3

SO 2

OCF 3

N

H

C 2 H 5

SO 2

OCF 2 H

Q

H

CF 3

SO 2

CF 3

AK

OCH 3

CH 3

CO 2

Cl

AL

CH 3

CF 3

SO 2

Cl

AM

CH 3

CH 3

SO 2

Cl

AN

CH 3

CF 3

CO 2

Cl

AO

H

CF 3

SO 2

H

AP

H

CF 3

CO 2

OCH 3

AQ

F

CF 3

SO 2

Cl

AR

F

CF 3

CO 2

Cl

AS

F

CF 3

SO 2

Cl

AT

F

CF 3

SO 2

H

AU

F

CF 3

SO 2

Cl

AV

OCH 3

CF 3

SO 2

Cl

AW

OCH 3

CF 3

SO

Cl

AX

OCH 3

CF 3

CO 2

Cl

AZ

H

CF 3

SO 2

OCF 3

BB

H

CF 3

SO 2

H

BD

H

CF 3

CO 2

OCF 3

BE

H

CF 3

CO 2

Cl

DK

OCH 3

CF 3

SO 2

Cl

DM

OCH 3

CH 3

SO 2

Cl

DO

OC 2 H 5

CF 3

SO 2

Cl

DP

OCH 3

CH 3

SO 2

Cl

EF

H

CH 3

SO 2

OCH3

EG

H

CH 3

SO 2

OH

EH

F

CF 3

SO 2

OCH3

EI

CH 3

CF 3

SO 2

H

FG

H

CF 3

SO 2

H

FH

CH 3

CF 3

SO 2

H

CB = covalent bond

* R 3 and R 4 taken together form a carbonyl group (C═O).

9. The compound according to claim 1 having the formula:

10. The compound according to claim 1 having the formula:

11. The compound according to claim 1 having the formula:

wherein X and R 2 are the same as in claim 1 ; and

R 1 is aryl or heteroaryl, wherein each of said aryl or heteroaryl can be unsubstituted or optionally independently substituted with one to five moieties which moieties can be the same or different and are independently selected from the group consisting of halogen, alkyl-cycloalkyl, haloalkyl, haloalkoxy, (C 1 -C 6 )alkoxy and OH.

12. The compound according to claim 1 having the formula:

wherein X is F, Cl, OH or CN;

R 1 is aryl or heteroaryl, wherein each of said aryl or heteroaryl can be unsubstituted or optionally independently substituted with one to five X moieties; and

R 2 is H, OH, F, CH 3 , CF 3 or cyclopropyl.

13. The compound according to claim 1 having the formula:

wherein

X and R 2 are the same as in claim 1 .

14. The compound according to claim 1 having the formula:

wherein

R 1 is aryl or heteroaryl, wherein each of said aryl or heteroaryl can be unsubstituted or optionally independently substituted with one to five X moieties; and

R 2 is H, OH, F, CH 3 , CF 3 or cyclopropyl;

X is alkyl; and

n is 1.

15. The compound according to claim 14 having the formula:

16. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising an effective amount of a compound according to claim 7 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising an effective amount of a compound according to claim 8 and a pharmaceutically acceptable carrier.

19. A method of treating inflammatory diseases, comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1 .

20. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.

Assignments (2)
CHANGE OF NAME Recorded Aug 30, 2012
From: SCHERING CORPORATION
To: MERCK SHARP & DOHME CORP.
Reel/Frame 028884/0151 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 11, 2004
From: FRIARY, RICHARD J.; KOZLOWSKI, JOSEPH A.; SHANKAR, BANDARPALLE B.; WONG, MICHAEL K.C.; ZHOU, GUOWEI; LAVEY, BRIAN J.; SHIH, NENG-YANG; TONG, LING; CHEN, LEI; SHU, YOUHENG
To: SCHERING CORPORATION
Reel/Frame 015055/0562 →