Cannabinoid receptor 2 (CB2) inverse agonists and therapeutic potential for multiple myeloma and osteoporosis bone diseases

Patent metadata

Field	Value
Publication number	US-9376380-B2
Application number	US-201414305941-A
Country	US
Kind code	B2
Filing date	Jun 16, 2014
Priority date	Dec 15, 2011
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

Cannabionid receptor-2 inverse antagonists include compounds represented by Formula IV, or a pharmaceutically acceptable salt thereof:

wherein: R 1 and R 2 are independently H, alkyl, or alkenyl; R 3 is alkyl, alkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; R 4 and R 5 are independently a bond, alkylenyl, or alkenylenyl; each R 6 and R 7 is independently selected from the group consisting of OH, F, Cl, Br, I, (C 1 -C 6 )alkyl, alkoxy, amino, COOH, CONH 2 , SO 3 H, PO 3 H 2 , CN, SH, NO 2 and CF 3 ; and p and q are independently 0, 1, 2, 3, 4, or 5. Such compounds may be used to treat osteoporosis or multiple myeloma.

First claim

We claim:

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

wherein:
A is selected from the group consisting of —NR 2 , OR, (C 1 -C 6 )alkyl, and (C 3 -C 8 ) heterocycloalkyl;
R is selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 2 -C 6 ) alkenyl;
R′ is selected from the group consisting of sub-formula X, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, unsubstituted (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, adamantyl and C 6 H 4 R′″;
R″ is

wherein (i) l, m, n, p and q are each an integer 1, (ii) four of G, H, J, L and M are —CH and (iii) the remaining one of G, H, J, L and M is CR a ′″, or wherein (i) l, m and q are an integer 1, (ii) n is zero, (iii) p is an integer 2, and (iv) G, H and M are —CH and L is CR b ′″; and
R a ′″ is selected from the group consisting of H, substituted or unsubstituted (C 1 -C 6 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , halogen, (C 1 -C 6 )haloalkoxy, and (C 1 -C 6 )alkoxy,
wherein when substituted (C 1 -C 6 )alkyl is present, the (C 1 -C 6 )alkyl is substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkoxy groups, carbonyl, ester, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, thiol, sulfide, sulfoxide, sulfone, sulfonyl, sulfonamide, amine, N-oxide, hydrazine, hydrazide, hydrazine, azide, amide, urea, amidine, guanidine, enamine, imide, isocyanate, isothiocyanate, cyanate, thiocyanate, imine, nitro group, and nitrile;
R b ′″ is an unsubstituted aryl;
wherein sub-formula X is represented by:

wherein Q′ is a bond or a (C 1 -C 6 )alkyl,
G, H, J, L, and M are each independently selected from the group consisting of a bond, CR′″—, —N—, —O—, and —S—, and no two adjacent members of G, H, J, L, or M can simultaneously be —O—, —S—, or N, and

 represents the option of having one or more double bonds, or a pharmaceutically acceptable salt thereof; or (b) a compound of Formula B

wherein:
R is a (C 1 -C 6 )alkyl;
R′ is selected from the group consisting of (C 1 -C 7 )alkyl, adamantyl and C 6 H 4 R′′;
R″ is C 6 H 4 R′″; R′″ is selected from the group consisting of H, (C 1 -C 6 )alkyl, halogen, and (C 1 -C 6 )alkoxy, or a pharmaceutically acceptable salt thereof.

2. 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, or a pharmaceutically acceptable salt thereof, wherein the compound is shown in the following table:

1

2

3

4

5

6

7

8

9

10

11

12

13

Assignees

• Univ Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Xie xiang-qun
• Yang Peng
• Feng Rentian

Classifications

• C07C311/29

  having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C233/40 Primary

  having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings · CPC title

• C07D213/56

  Amides · CPC title

• C07C233/36

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton · CPC title

• C07C311/05 Primary

  to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups · CPC title