Novel Bicyclic Cannabinoids

A compound of formula Ia below, including physiologically acceptable salts, diastereomers, enantiomers, double bond isomers, or mixtures thereof;

• wherein:
• Y is >CH—(CH2)h—Y6,
• Y6 is CN and h is an integer from about 1 to about 3, or
• Y6 is selected from I, N3, SO2Cl, SO2F, SO3H, COOH, COalkyl, CF3, SO2alkyl, COfluoroalkyl, OH, alkoxy, acyloxy, NCS, NCO or NH2, and h is an integer from 0 to about 3;
• R1 and R2 are each independently selected from H, OH, NH2, NO2, CN, OCOCH3, OC(O)CH═CHCOOH, halogen, alkyl, —O-alkyl, acyl, aroyl, benzoyl, substituted benzoyl, phenacyl, substituted phenacyl, —O-alkyl-aryl, —O-alkyl-NR10R11, —O-alkyl-COOR (where R is selected from H or alkyl), —O-alkyl-CONR10R11, —N(alkyl)2, —CO(alkyl)X or —OCO(alkyl)X or OCO(alkenyl)X (where X is selected from H, COOH, dialkylamino, a cyclic amine, a carbocyclic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring), —O—P(O)(OR)2 or —O—P(O)(OH)(OR) (where R is selected from H or alkyl), —P(O)(OR)2 (where R is selected from H or alkyl), —P(O)(OH)(OR) (where R is selected from H or alkyl) or —OC(O)—CH(NH2)—R16 (where R16 is selected from H, CH(OH)CH3 or alkyl-X3 and X3 is selected from:
• H, —NH—C(═NH)NH2, C(O)NH2, COOH, SH, SCH3, OH, NH2, a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted heterocyclic ring,
• R10 and R11 are each independently selected from H, alkyl, hydroxyalkyl or R10 and R11 together comprise part of a 3 to 7 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S;
• and
• R3 is
• R5 is selected from H, halogen, CN, CF3, N3, COOH, NH2, N(CH3)2, ⊕N(CH3)3, Sn(alkyl)3, phenyl, OH, NCS, NCO, NO2, CHO, SO3H, SO2Cl, SO2F, PO3H2, C(O)CF3, SH, —CH═CH2, —C≡CH, NH(alkyl), N(alkyl)2, O-aryl, alkoxy, thioalkoxy, sulfonamide, COOR (where R is selected from H or alkyl), a substituted or unsubstituted carbocylic ring, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, a polycarbocyclic ring structure having 2 to about 5 rings, a polyheterocyclic ring structure having 2 to about 5 rings or CONR10R11 (where R10 and R11 are each independently selected from H, alkyl, hydroxyalkyl, or R10 and R11 together comprise part of a 5 or 6 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S),
• n is an integer from 0 to about 7, wherein when an integer is 0 the structural portion modified by that integer is absent and the adjacent subunits are directly connected.

A compound of formula Ia below, including physiologically acceptable salts, diastereomers, enantiomers, double bond isomers, or mixtures thereof;

• wherein:
• Y is selected from >C═O or >C═CY7Y8, including all isomers,
• Y7 and Y8 are each independently selected from H, alkyl, alkenyl, CN, OH, alkoxy or —(CH2)n—NR10R11,
• R10 and R11 are each independently selected from H, alkyl, hydroxyalkyl, or R10 and R11 together comprise part of a 3 to 7 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S,
• n is an integer from 0 to about 4, wherein when an integer is 0 the structural portion modified by that integer is absent and the adjacent subunits are directly connected;
• R1 and R2 are each independently selected from H, OH, NH2, NO2, CN, OCOCH3, OC(O)CH═CHCOOH, halogen, alkyl, —O-alkyl, acyl, aroyl, benzoyl, substituted benzoyl, phenacyl, substituted phenacyl, —O-alkyl-aryl, —O-alkyl-NR10R11, —O-alkyl-COOR (where R is selected from H or alkyl), —O-alkyl-CONR10R11, —N(alkyl)2, —CO(alkyl)X or —OCO(alkyl)X or OCO(alkenyl)X (where X is selected from H, COOH, dialkylamino, a cyclic amine, a carbocyclic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring), —O—P(O)(OR)2 or —O—P(O)(OH)(OR) (where R is selected from H or alkyl), —P(O)(OR)2 (where R is selected from H or alkyl), —P(O)(OH)(OR) (where R is selected from H or alkyl) or —OC(O)—CH(NH2)—R16 (where R16 is selected from H, CH(OH)CH3 or alkyl-X3 and X3 is selected from:
• H, —NH—C(═NH)NH2, C(O)NH2, COOH, SH, SCH3, OH, NH2, a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted heterocyclic ring,
• R10 and R11 are each independently selected from H, alkyl, hydroxyalkyl or R10 and R11 together comprise part of a 3 to 7 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S;
• and
• R3 is
• wherein R5 is selected from H, halogen, CN, CF3, N3, COOH, NH2, N(CH3)2, ⊕N(CH3)3, Sn(alkyl)3, phenyl, OH, NCS, NCO, NO2, CHO, SO3H, SO2Cl, SO2F, PO3H2, C(O)CF3, SH, —CH═CH2, —C≡CH, NH(alkyl), N(alkyl)2, O-aryl, alkoxy, thioalkoxy, sulfonamide, COOR (where R is selected from H or alkyl), a substituted or unsubstituted carbocylic ring, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, a polycarbocyclic ring structure having 2 to about 5 rings, a polyheterocyclic ring structure having 2 to about 5 rings or CONR10R11 (where R10and R11 are each independently selected from H, alkyl, hydroxyalkyl, or R10 and R11 together comprise part of a 5 or 6 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S),
• n is an integer from 0 to about 7, wherein when an integer is 0 the structural portion modified by that integer is absent and the adjacent subunits are directly connected;
• with the following provisos:
• if Y is C═O, and R1 and R2 are both OH, then R3 cannot be C(CH3)2(CH2)nCH3 (where n is an integer from 3-5).

A compound of formula Ib below, including physiologically acceptable salts, diastereomers, enantiomers, double bond isomers, or mixtures thereof;

• wherein:
• Y is selected from >C═O, >CH—(CH2)f—Y1—(CH2)g—Y2, >C═N—Y3, >CH—NY4Y5 or >CH—(CH2)h—Y6, including all isomers,
• Y1 is independently selected from O, C(O)O or CH2,
• Y2 is independently selected from H, I, CN, CF3, N3, NCS or NCO,
• Y3 is independently selected from OH, NH2, C1-C4 alkoxy, C1-C4 alkyl, —(CH2)n—NR10R11, —(CH2)n—CO2R (where R comprises H or alkyl), —O—(CH2)n—NR10R11, —O—(CH2)n—CO2R (where R comprises H or alkyl) or —O—(CH2)n—CONR10R11,
• Y4 is independently selected from H, OH, C1-C4 alkoxy or C1-C4 alkyl,
• Y5 is independently selected from H, OH, C1-C4 alkoxy or C1-C4 alkyl, wherein Y4 and Y5 cannot both be OH and wherein Y4 and Y5 cannot both be C1-C4 alkoxy,
• Y6 is independently selected from I, CN, SO2Cl, SO2F, COalkyl, CF3, COfluoroalkyl, N3, NCS or NCO,
• R10 and R11 are each independently selected from hydroxyalkyl, or R10 and R11 together comprise part of a 3 to 7 membered saturated heterocyclic ring containing one additional heteroatom selected from N, O and S,
• f comprises an integer from 0 to about 5,
• g comprises an integer from 0 to about 5,
• h comprises an integer from 0 to about 5,
• n comprises an integer from 0 to about 4, wherein when an integer is 0 the structural portion modified by that integer is absent and the adjacent subunits are directly connected,
• R1 and R2 are each independently selected from OH, OCH3, NO2, CN, OCOCH3, aroyl, benzoyl, substituted benzoyl, phenacyl, substituted phenacyl, —O-alkyl-aryl, —O-alkyl-NR10R11, —O-alkyl-CONR10R11, —CO(alkyl)X or —OCO(alkyl)X (where X is selected from a cyclic amine, a carbocyclic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring), —OC(O)—CH(NH2)—R (where R comprises H or CH(OH)CH3) or alkyl-X (where X is selected from H, —NH—C(═NH)NH2, C(O)NH2, COOH, SH, SCH3, OH, NH2, a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted heterocyclic ring),
• R10 and R11 are each independently selected from hydroxyalkyl, or R10 and R11 together comprise part of a 3 to 7 membered saturated heterocyclic ring containing one additional heteroatom selected from N, O and S;
• and
• R3 is selected from the following structures:
• wherein each Z is independently selected from CH2, S, O, NH, N(CH3), SO or SO2,
• D is selected from a heterocyclic ring, an adamantyl ring, an heteroadamantyl ring or any above ring optionally substituted by R4 in any possible position with the proviso that ring D can not be bonded to R4 from the 1′ position,
• L is selected from a cycloalkyl ring, a heterocyclic ring, a heteroaromatic ring, an adamantyl ring, a heteroadamantyl ring or any above ring optionally substituted by R4 in any possible position,
• R4 is —(CH2)j-A-(CH2)k—R5,
• A is selected from —CH2—CH2—, —CH═CH—, —C═C—, O, S, SO, SO2 or NH,
• R5 is selected from H, halogen, CN, CF3, N3, COOH, NH2, N(CH3)2, ⊕N(CH3)3, Sn(alkyl)3, phenyl, pyrrolidine ring, piperidine ring, morpholine ring, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, NCS, NCO, SO3H, SO2Cl, SO2F, PO3H2, C(O)CF3, —O-aryl, sulfonamide, a carbocylic ring, a heterocyclic ring, a heteroaromatic ring, a polycarbocyclic ring structure having 2 to about 5 rings, a polyheterocyclic ring structure having 2 to about 5 rings or CONR10R11 (where R10 and R11 are each independently selected from hydroxyalkyl, or R10 and R11 together comprise part of a 5 or 6 membered saturated heterocyclic ring containing one additional heteroatom selected from N, O and S),
• n is an integer from 0 to about 3,
• j is an integer from 0 to about 7,
• k is an integer from 0 to about 7, wherein when an integer is 0 the structural portion modified by that integer is absent and the adjacent subunits are directly connected,
• R6 and R7 are each independently selected from H or CH3,
• R8 is selected from —(CH2)j—C≡C—(CH2)k—R5 or —(CH2)j—CH═CH—(CH2)k—R5,
• R5 is selected from H, halogen, CN, CF3, N3, COOH, NH2, N(CH3)2, ⊕N(CH3)3, Sn(alkyl)3, phenyl, pyrrolidine ring, piperidine ring, morpholine ring, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, NCS, NCO, SO3H, SO2Cl, SO2F, PO3H2, C(O)CF3, —O-aryl, sulfonamide, a carbocylic ring, a heterocyclic ring, a heteroaromatic ring, a polycarbocyclic ring structure having 2 to about 5 rings, a polyheterocyclic ring structure having 2 to about 5 rings or CONR10R11 (where R10 and R11 are each independently selected from hydroxyalkyl, or R10 and R11 together comprise part of a 5 or 6 membered saturated heterocyclic ring containing one additional heteroatom selected from N, O and S),
• j is an integer from 0 to about 7,
• k is an integer from 0 to about 7, wherein when an integer is 0 the structural portion modified by that integer is absent and the adjacent subunits are directly connected,
• Q is selected from O, S, NH or N(R18) (where R18 is selected from SO2-aryl, alkyl-R5, aryl-R5 or heteroaryl-R5),
• R17 is selected from alkyl-R5, aryl-R5 or heteroaryl-R5 with the proviso that R5 cannot be hydrogen;
• with the following proviso:
• if Y is C═O, and R1 and R2 are both OH, then R3 cannot be structure Ib 4, where R6 and R7 are both H and R8 is (CH2)j—CH═CH—(CH2)k—R5 where R5 is H and the sum of j and k is equal to 4-9.

A compound of formula Ib below, including physiologically acceptable salts, diastereomers, enantiomers, double bond isomers, or mixtures thereof;

• wherein:
• Y is >CH—(CH2)h—Y6,
• Y6 is selected from CN and h is an integer from about 1 to about 3, or
• Y6 is selected from N3, SO2Cl, SO2F, COalkyl, CF3, COfluoroalkyl, NCS or NCO and h is an integer from 0 to about 3;
• R1 and R2 are each independently selected from OH or OCH3;
• and
• R3 is
• R5 is selected from H, halogen, CN, CF3, N3, COOH, NH2, N(CH3)2, ⊕N(CH3)3, Sn(alkyl)3, phenyl, pyrrolidine ring, piperidine ring, morpholine ring, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, NCS, NCO, SO3H, SO2Cl, SO2F, PO3H2, C(O)CF3, —O-aryl, sulfonamide, a carbocylic ring, a heterocyclic ring, a heteroaromatic ring, a polycarbocyclic ring structure having 2 to about 5 rings, a polyheterocyclic ring structure having 2 to about 5 rings or CONR10R11 (where R10 and R11 are each independently selected from hydroxyalkyl, or R10 and R11 together comprise part of a 5 or 6 membered saturated heterocyclic ring containing one additional heteroatom selected from N, O and S),
• n comprises an integer from 0 to about 7, wherein when an integer is 0 the structural portion modified by that integer is absent and the adjacent subunits are directly connected.

A compound of the formula below, and physiologically acceptable salts thereof:

• wherein X is selected from >C═O, >CH—(CH2)f—X1—(CH2)g—X2, >C═N—X3, >CH—NX4X5, >CH—(CH2)h—X6, —C(O)N(X7)—, —N(X7)C(O), >NX11, >N—(CH2)f—X1—(CH2)g—X2, a spirocycle, or CX9X10, including all isomers;
• X1 is independently selected from O, CO, C(O)O, OCO or CH2;
• X2 is independently selected from H, halogen, CN, CF3, N3, OH, COOH, alkoxy, acyloxy, NCS, NCO or NX7X8;
• X3 is independently selected from —OH, —NH2, alkoxy, alkyl, —(CH2)n—NR10R11, —(CH2)n—CO2R where R is selected from H or alkyl, —O—(CH2)n—NR10R11, —O—(CH2)n—CO2R or —O—(CH2)n—CONR10R11;
• X4 is independently selected from H, OH, alkoxy or alkyl;
• X5 is independently selected from H, OH, alkoxy or alkyl, wherein X4 and X5 cannot both be OH and wherein X4 and X5 cannot both be alkoxy;
• X6 is independently selected from H, halogen, CN, COOH, COalkyl, CF3, SO2alkyl, COfluoroalkyl, N3, OH, alkoxy, acyloxy, NCS, NCO or NX7X8;
• X7 is independently selected from H, alkyl, hydroxyalkyl, an aromatic ring, an aromatic ring substituted by at least one member selected from alkyl, alkoxy, halogen and CF3, a heterocyclic ring or a heteroaromatic ring;
• X8 is independently selected from H, alkyl, hydroxyalkyl, an aromatic ring, an aromatic ring substituted by at least one member selected from alkyl, alkoxy, halogen and CF3, a heterocyclic ring or a heteroaromatic ring;
• or alternatively, X7 and X8 taken together comprise part of a 3 to 7 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S;
• X9 is independently selected from H, alkyl or alkoxycarbonylmethyl;
• X10 is independently selected from H, alkyl or alkoxycarbonylmethyl;
• X11 is independently selected from H, alkyl, CO, CN, COalkyl, SO2alkyl or CF3;
• f is an integer from 0 to about 3;
• g is an integer from 0 to about 3;
• h is an integer from 0 to about 3;
• n is an integer from 0 to about 4;
• R1 is independently selected from H, OH, halogen, alkyl, —O-alkyl, NH2, NO2, CN, acyl, aroyl, benzoyl, substituted benzoyl, arylalkyl, substituted arylalkyl, phenacyl, substituted phenacyl, —O-alkyl-NR10R11, —O-alkyl-COOR where R is selected from H or alkyl, —O-alkyl-CONR10R11, OCOCH3, —N(alkyl)2, —CO(alkyl)X or —OCO(alkyl)X where X is selected from H, dialkylamino, a cyclic amine, a carbocyclic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic;
• and
• R10 and R11 are each independently selected from H, alkyl, hydroxyalkyl or R10 and R11 together comprise part of a 3 to 7 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S;
• and
• R3 is selected from:
• wherein each Z is independently selected from S, O, NH, N(CH3), SO, SO2 or CR12R13 where R12 and R13 are each independently selected from H or alkyl;
• R4 is selected from —(CH2)j—R5, —(CH2)j-A-(CH2)k—R5 or —(CH2)j-A-(CH2)k—B—R5,
• A and B are each independently selected from —CH2—CH2—, —CH═CH—, —C≡C—, O, S, SO, SO2 or NH;
• R5 is selected from H, halogen, CN, CF3, N3, COOH, NH2, N(CH3)2, ⊕N(CH3)3, Sn(alkyl)3, phenyl, COOR where R is selected from H or alkyl, a carbocylic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, a polycarbocyclic ring structure having 2 to about 5 rings, a polyheterocyclic ring structure having 2 to about 5 rings or CONR10R11 where R10 and R11 are each independently selected from H, alkyl, hydroxyalkyl or R10 and R11 together comprise part of a 5 or 6 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S;
• n is an integer from 1 to about 4;
• j is an integer from 0 to about 7;
• and
• k is an integer from 0 to about 7;
• or
• R3 is:
• wherein, R6 and R7 are each independently selected from H or alkyl;
• R8 is —(CH2)j—C≡C—(CH2)k—R9;
• R9 is selected from H, halogen, CN, CF3, N3, COOH, NH2, N(CH3)2, ⊕N(CH3)3, Sn(alkyl)3, phenyl, COOR where R is selected from H or alkyl, a carbocylic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, a polycarbocyclic ring structure having 2 to about 5 rings, a polyheterocyclic ring structure having 2 to about 5 rings or CONR10R11 where R10 and R11 are each independently selected from H, alkyl, hydroxyalkyl or R10 and R11 together comprise part of a 5 or 6 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S;
• j is an integer from 0 to about 7;
• and
• k is an integer from 0 to about 7;
• or
• R1 is independently selected from H, OH, alkyl or alkoxy;
• and
• R3 is:
• wherein R13 and R14 are each independently selected from H or alkyl;
• R15 is selected from halogen, CN, CF3, N3, COOH, NH2, N(CH3)2, ⊕N(CH3)3, Sn(alkyl)3, phenyl, COOR where R is selected from H or alkyl, a carbocylic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, a polycarbocyclic ring structure having 2 to about 5 rings, a polyheterocyclic ring structure having 2 to about 5 rings or CONR10R11 where R10 and R11 are each independently selected from H, alkyl, hydroxyalkyl or R10 and R11 together comprise part of a 5 or 6 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S;
• j is an integer from 0 to about 7;
• and
• k is an integer from 0 to about 7;
• or
• X is >CH—(CH2)h—X6;
• X6 is independently selected from I, CN, N3 or COOH and h is an integer from about 1 to about 3, or X6 is selected from I, N3 or COOH and h is an integer from 0 to about 3, including all isomers;
• R1 is independently selected from H, OH, alkyl or alkoxy;
• and
• R3 is:
• wherein R16 is selected from H, halogen, CN, CF3, N3, COOH, NH2, N(CH3)2, ⊕N(CH3)3, Sn(alkyl)3, phenyl, COOR where R is selected from H or alkyl, a carbocylic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, a polycarbocyclic ring structure having 2 to about 5 rings, a polyheterocyclic ring structure having 2 to about 5 rings or CONR10R11 where R10 and R11 are each independently selected from H, alkyl, hydroxyalkyl or R10 and R11 together comprise part of a 5 or 6 membered saturated heterocyclic ring containing up to one additional heteroatom selected from N, O and S;
• and
• n is an integer from 0 to about 7;
• with the provisos that,
• X can not be >CH—N3 when R1 is OH and R3 is
• wherein R16 is I and n is 6;
• and
• X6 can not be I or COOH when X is >CH—(CH2)h—X6 and R3 is,
• wherein R16 is H;
• and
• if X is >C═O and R1 is OH and R3 is
• wherein each Z is CH3, than R4 can not be H;
• and
• if R1 is OH, and X is >CH2, >CHOH, >CHOCH3, >CHOCH2CH3, >CHhalogen, >CHCN, >CHCH3, >CHCF3, >CHCH2OH, >CHCH2OCH3, >CHCH2OCH2CH3, >CHCH2(halogen), >CHCH2CN, >CHCH2CH3, >CHCH2CF3, >CHCH2NH2, >CHCH2NHCH3 or >CHCH2N(CH3)2, than R3 cannot be a carbocyclic ring, a heterocyclic ring, or any above group substituted with one or more members selected from the group consisting of —H, —OH, —OCH3, —OCH2CH3, halogen, —CN, —N3, —NCO, —NCS, —NO2, —CH3, —C(halogen)3, CH2OH, —CH2OCH3, —CH2OCH2CH3, —CH2(halogen), —CH2CN, —CH2NO2, —CH2CH3, —CH2C(halogen)3, —CH2NH2, —CH2NHCH3 and —CH2N(CH3)2.