Novel Cannabinergic Nitrate Esters and Related Analogs

A compound of the Formula I:

• V—V1-V2-R—W′, wherein
• V is ONO2;
• or
• V is H or absent when one of V1, V2, R or W′ is ONO2;
• or
• V is H or is absent when W′ is -A-C′-B′-D and one of A, C′, B′ or D is ONO2;
• V1 if present is selected from alkyl, amide, alcohol, ester, heteroalkyl, aryl, heteroaryl, —S-alkyl-, —O-alkyl, —N-alkyl, and —NH-alkyl-;
• V2 if present is selected from alkyl, amide, alcohol, ester, heteroalkyl, —S— alkyl-, —O—, alkyl, —N-alkyl, —NH-alkyl, —C(O)O—, O, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, aryloxy and heteroaryloxy;
• R is selected from aryl, heteroaryl, alkyl and heteroalkyl;
• W′ is -A-C′-B′-D wherein
• A is selected from a direct bond, O, —C(=D1)- or —(CH2)lN(D2)-, wherein l is an integer between 0 and 3;
• C′ is a direct bond,
• B′ is selected from a direct bond, O, —N(D2)-, —N(D1)(D2)-, —C(D1)(D2)-, —(CH2)l−), alkyl, aryl, heteroalkyl, heteroarl, alkoxy, aryloxy, heteroarylalkoxy, heteroaryloxy —NH-alkyl-, —NHSO2—, wherein l is an integer between 0 and 3;
• D1 is selected from O, S, aryl, ND2, and NSO2D2
• D2 is selected from H, C(═NH), OD3, O, alcohol, alkyl, amine, heteroalkyl,
• aryl, heteroaryl, and SO2alkyl;
• D3 is H or NO2;
• and
• D is selected from a carbocyclic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;
• or
• D is
• wherein G is selected from CH, C(CH3), C(CN) and N;
• L, K′ and J are each independently selected from (CH2)n, (CH3)2, C═O, O, —CHOH, C(CH3)OM1, C(CH2)n(X)Y, C(K1)K2, NM1, SO2, SO and S;
• n is an integer from 0 to 7;
• K1 and K2 are each independently selected from CH3, halogen, OM1, CONM1M2, NM1M2, alkyl, alkylNM1M2, aryl, alcohol, heteroalkyl and heteroaryl,
• M1 is selected from H, alkyl, SO2(M2), C(O)M2, and CONHM2,
• M2 is selected from H, alkyl, NM3M4, OM5 and M3,
• M4 and M5 are each independently selected from H, OH, ONO2, alcohol and alkyl, and
• X and Y are each independently selected from H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, —C≡CX8;
• X1 and X2 are independently selected from H and alkyl, or
• X1 and X2 together are part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or
• X1 and X2 together are part of an imide ring having 5 to 6 members,
• X3 is selected from H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NX1X2,
• X4, X5, and X6 are independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7,
• X7 is selected from H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H and COX8,
• X8 is selected from H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and CX9═CHX10
• X9 and X10 are independently selected from H and alkyl;
• m is an integer from 0 to 7;
• j is an integer from 0 to 6;
• and
• k is an integer from 0 to 2;
• or
• D is
• wherein G, L and J is each independently selected from CH and N;
• or
• D is selected from
• wherein X and Y are independently selected from H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8 and —C≡CX8;
• X1 and X2 are independently selected from H and alkyl, or
• X1 and X2 together are members of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or
• X1 and X2 together are members of an imide ring having 5 to 6 members,
• X3 is selected from H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl and alkyl-NX1X2,
• X4, X5, and X6 are independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7 and O-alkyl-X7,
• X7 is selected from H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H and COX8,
• X8 is selected from H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring and —CX9═CHX10,
• X9 and X10 are independently selected from H and alkyl;
• m is an integer from 0 to 7;
• j is an integer from 0 to 6;
• k is an integer from 0 to 2;
• and
• W′ is H or alkyl;
• or
• D is selected from a carbocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heteroaromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms or a heteroaromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms;
• or
• D is selected from H, OH, ONO2, alkyl, amide, amine, alcohol and ester.