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

摘要

Cannabionid receptor-2 inverse antagonists include compounds represented by Formula IV, or a pharmaceutically acceptable salt thereof:;wherein: R1 and R2 are independently H, alkyl, or alkenyl; R3 is alkyl, alkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; R4 and R5 are independently a bond, alkylenyl, or alkenylenyl; each R6 and R7 is independently selected from the group consisting of OH, F, Cl, Br, I, (C1-C6)alkyl, alkoxy, amino, COOH, CONH2, SO3H, PO3H2, CN, SH, NO2 and CF3; and p and q are independently 0, 1, 2, 3, 4, or 5. Such compounds may be used to treat osteoporosis or multiple myeloma.

主权项

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 —NR2, OR, (C1-C6)alkyl, and (C3-C8) heterocycloalkyl; R is selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, and (C2-C6) alkenyl; R′ is selected from the group consisting of sub-formula X, (C3-C14)aryl(C1-C6)alkylene-, unsubstituted (C3-C14)heteroaryl-(C1-C6)alkylene-, (C1-C6)alkyl, (C2-C6)alkenyl, adamantyl and C6H4R′″; 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 CRa′″, 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 CRb′″; and Ra′″ is selected from the group consisting of H, substituted or unsubstituted (C1-C6)alkyl, —NH2, —NH(C1-C6)alkyl, —N[(C1-C6)alkyl]2, halogen, (C1-C6)haloalkoxy, and (C1-C6)alkoxy, wherein when substituted (C1-C6)alkyl is present, the (C1-C6)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; Rb′″ is an unsubstituted aryl; wherein sub-formula X is represented by: wherein Q′ is a bond or a (C1-C6)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 (C1-C6)alkyl; R′ is selected from the group consisting of (C1-C7)alkyl, adamantyl and C6H4R′′; R″ is C6H4R′″; R′″ is selected from the group consisting of H, (C1-C6)alkyl, halogen, and (C1-C6)alkoxy, or a pharmaceutically acceptable salt thereof.