Novel cannabinoid receptor cb2 ligand 4-(aminomethyl)-n, n-dialkylanilines

Patent metadata

Field	Value
Publication number	US-2020270205-A1
Application number	US-202016872138-A
Country	US
Kind code	A1
Filing date	May 11, 2020
Priority date	Jun 18, 2015
Publication date	Aug 27, 2020
Grant date	—

Abstract

Disclosed herein are novel cannabionid receptor-2 (CB2) agonists and inverse agonists represented by Formula (I), and method of modulating the activity of CB2 by contacting the CB-2 receptor with a compound of Formula (I). Also, disclosed are methods for treating multiple myeloma or osteoporosis in a mammal in need thereof by modulating the activity of a cannabinoid receptor-2 (CB2).

First claim

1 .- 15 . (canceled)

16 . A method for treating multiple myeloma in a mammal in need thereof by modulating the activity of a cannabinoid receptor-2 (CB2), comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (I):

wherein:
R is A-B-Y,
A is —SO 2 — or —C(O)—;
B is a bond or —CHCH—,
X is selected from the group consisting of substituted phenyl, substituted or unsubstituted pyridine, and substituted or unsubstituted C 3-5 alkyl, wherein the substituted phenyl, pyridine and alkyl is substituted with two or three moieties selected from C 1-4 alkyl, C 1-4 alkoxy, —C(O)H, C 1-4 perfluroalkyl, and C 1-4 perfluroalkoxy, or the substituted phenyl or pyridine is substituted with —O—(CH 2 ) 1-2 —O— where the O molecules are covalently bound to adjacent carbon atoms on the substituted phenyl or pyridine;
Y is a ringed moiety selected from phenyl, naphthyl, and thiophenyl, wherein one or two of the ring carbons is optionally replaced with N, and wherein the ringed moiety is optionally substituted with one to three C 1-4 alkyl, C 1-4 alkoxy, —C(O)H, C 1-4 perfluroalkyl, C 1-4 perfluroalkoxy, or substituted or unsubstituted phenyl; and
R′ is, in each instance a C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.

17 . A method for treating osteoporosis in a mammal in need thereof by modulating the activity of a cannabinoid receptor-2 (CB2), comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (I):

wherein:
R is A-B-Y;
A is —SO 2 — or —C(O)—;
B is a bond or —CHCH—;
X is selected from the group consisting of substituted phenyl, substituted or unsubstituted pyridine, and substituted or unsubstituted C 3-5 alkyl, wherein the substituted phenyl, pyridine and alkyl is substituted with two or three moieties selected from C 1-4 alkyl, C 1-4 alkoxy, —C(O)H, C 1-4 perfluroalkyl, and C 1-4 perfluroalkoxy, or the substituted phenyl or pyridine is substituted with—O—(CH 2 ) 1-2 —O— where the O molecules are covalently bound to adjacent carbon atoms on the substituted phenyl or pyridine;
Y is a ringed moiety selected from phenyl, naphthyl, and thiophenyl, wherein one or two of the ring carbons is optionally replaced with N, and wherein the ringed moiety is optionally substituted with one to three C 1-4 alkyl, C 1-4 alkoxy, —C(O)H, C 1-4 perfluroalkyl, C 1-4 perfluroalkoxv, or substituted or unsubstituted phenyl; and
R′ is, in each instance a C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.

18 . A method for modulating the activity of a cannabinoid receptor-2 (CB2) in a mammal in need thereof, comprising contacting the CB-2 receptor with a compound represented by Formula (I):

wherein:
R is A-B-Y;
A is —SO 2 — or —C(O)—;
B is a bond or —CHCH—;
X is selected from the group consisting of substituted phenyl, substituted or unsubstituted pyridine, and substituted or unsubstituted C 3-5 alkyl, wherein the substituted phenyl, pyridine and alkyl is substituted with two or three moieties selected from C 1-4 alkyl, C 1-4 alkoxy, —C(O)H, C 1-4 perfluroalkvl, and C 1-4 perfluroalkoxy, or the substituted phenyl or pyridine is substituted with—O—(CH 2 ) 1-2 —O— where the O molecules are covalently bound to adjacent carbon atoms on the substituted phenyl or pyridine;
Y is a ringed moiety selected from phenyl, naphthyl, and thiophenyl, wherein one or two of the ring carbons is optionally replaced with N, and wherein the ringed moiety is optionally substituted with one to three C 1-4 alkyl, C 1-4 alkoxy, —C(O)H, C 1-4 perfluroalkyl, C 1-4 perfluroalkoxv, or substituted or unsubstituted phenyl; and
R′ is, in each instance a C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.

19 .- 20 . (canceled)

21 . The method of claim 16 , wherein:
(a) A is SO 2 ; and/or (b) B is a bond; and/or (c) B is —CHCH—; and/or (d) X is phenyl substituted with three C 1-4 alkoxy; and/or (e) X is phenyl substituted with three methoxy; and/or (f) X is phenyl substituted with —O—(CH 2 ) 1-2 —O—; and/or (g) X is unsubstituted pyridine; and/or (h) X is an unsubstituted C 3-5 alkyl; and/or (i) X is selected from

and n-pentyl; and/or
(j) Y is phenyl; and/or
(k) Y is phenyl, and is substituted only at the para position; and/or
(l) R is selected from the R groups in Tables 1-4; and/or
(m) Y is selected from the Y groups in Tables 1-4.

22 . The method of claim 16 , wherein the compound is co-administered with a drug useful in treating and/or preventing multiple myeloma.

23 . The method of claim 22 , wherein the drug comprises one or more of lenalidomide, dexamethasone, and bortezomib.

24 . The method of claim 22 , wherein the compound of Formula (I) is co-administered before administration of the drug useful in treating and/or preventing multiple myeloma.

25 . The method of claim 22 , wherein the compound of Formula (I) is co-administered during administration of the drug useful in treating and/or preventing multiple myeloma.

26 . The method of claim 22 , wherein the compound of Formula (I) is co-administered after administration of the drug useful in treating and/or preventing multiple myeloma.

27 . The method of claim 17 , wherein:
(a) A is SO 2 ; and/or (b) B is a bond; and/or (c) B is —CHCH—; and/or (d) X is phenyl substituted with three C 1-4 alkoxy; and/or (e) X is phenyl substituted with three methoxy; and/or (f) X is phenyl substituted with —O—(CH 2 ) 1-2 —O—; and/or (g) X is unsubstituted pyridine; and/or (h) X is an unsubstituted C 3-5 alkyl; and/or (i) X is selected from

and n-pentyl; and/or
(j) Y is phenyl; and/or
(k) Y is phenyl, and is substituted only at the para position; and/or
(l) R is selected from the R groups in Tables 1-4; and/or
(m) Y is selected from the Y groups in Tables 1-4.

28 . The method of claim 17 , wherein the compound is co-administered with a drug useful in treating and/or preventing osteoporosis.

29 . The method of claim 28 , wherein the drug comprises one or more of estrogen therapy, a selective estrogen receptor modulator, a bisphosphonate, and calcitonin.

30 . The method of claim 28 , wherein the compound of Formula (I) is co-administered before administration of the drug useful in treating and/or preventing osteoporosis.

31 . The method of claim 28 , wherein the compound of Formula (I) is co-administered during administration of the drug useful in treating and/or preventing osteoporosis.

32 . The method of claim 28 , wherein the compound of Formula (I) is co-administered after administration of the drug useful in treating and/or preventing osteoporosis.

33 . The method of claim 17 , wherein the mammal is a post-menopausal female who suffers from bone loss or post-menopausal osteoporosis.

34 . The metho

Assignees

• Univ Of Pittsburgh - Of The Commonwealth System Of Higher Education

Inventors

• Xie xiang-qun
• Almehizia Abdulrahman
• Yang Peng

Classifications

• C07C311/13

  the carbon skeleton containing six-membered aromatic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D241/44

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title