IP Library › Granted Patent US 7,645,774
Granted Patent B2
US 7,645,774 · App. 11/197,979 · Granted Jan 12, 2010

Cannabinoid receptor ligands

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Quick Facts
Patent No.
US 7,645,774
App. No.
11/197,979
Granted
Jan 12, 2010
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 (1128)

1. A compound of the formula I:

or a pharmaceutically acceptable salt said compound, wherein:

L 1 is —C(O)—, —C(O)O—, —S(O 2 )—, —S(O)—, or —S—;

L 2 is —S(O 2 )—;

L 3 is —C(O)— or —S(O 2 )—;

R 1 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, —Si(alkyl) n (aryl) 3-n , aryl and heteroaryl, wherein each of said aryl or 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, 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, with the proviso that:

when R 1 is —NHR 7 or —N(R 7 ) 2 , L 1 —C(O)—, —S(O 2 )— or —SO—;

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, or R 3 and R 4 taken together form a carbonyl group, i.e. C(═O);

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 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 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 phenyl;

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 and —CN, and when A is selected from the group consisting of pyridyl, thienyl, thiazolyl, quinolyl, isoquinolyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrimidyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, and benzothienyl, X can be oxide; and

n is 0-3,

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 —C(O)—, —S(O)—, —C(O)O—, or —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, —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;

A is phenyl;

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

n is 0-2.

3. A compound according to claim 1 wherein

L 1 is —C(O)O— or —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 6 is H, C 1 -C 6 alkyl, or haloalkyl;

A is phenyl;

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

n is 0-2.

4. The compound according to claim 1 having the formula 2:

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;

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 alkoxy, hydroxy and haloalkoxy and

n is 0-2.

5. The compound according to claim 1 having the formula 3:

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;

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, alkoxy, hydroxy and haloalkoxy and

n is 0-2.

6. The compound according to claim 1 wherein:

L 1 is —C(O)O— or —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 ;

A is phenyl;

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

n is 0-2.

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

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

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

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

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

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 2

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

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

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

CX

F

H

H

CF 3

CO 2

SO 2

C═O

Cl

DA

F

H

H

CF 3

SO

SO 2

SO 2

Cl

DB

F

H

H

CF 3

SO

SO 2

SO 2

Cl

DG

H

H

H

N(CH 3 ) 2

CO 2

SO 2

SO 2

Cl

DK

OCH 3

H

H

CF 3

SO 2

SO 2

SO 2

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 , R 6 , 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

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

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

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

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:

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

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

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

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

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

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

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

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

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

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

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

23. A pharmaceutical composition comprising an effective amount of a compound according to claim 9 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising an effective amount of a compound according to claim 10 and a pharmaceutically acceptable carrier.

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

26. A method of treating allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, or bronchitis comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1 .

27. The method of claim 25 wherein the condition or disease treated is seasonal allergic rhinitis.

28. The method of claim 25 wherein the condition or disease treated is asthma.

29. The method of claim 25 wherein the condition or disease treated is bronchitis.

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

Assignments (1)
CHANGE OF NAME Recorded Aug 30, 2012
From: SCHERING CORPORATION
To: MERCK SHARP & DOHME CORP.
Reel/Frame 028884/0151 →