US 2016/0108016 A1Published application

Novel Cannabinergic Compounds and Uses Thereof

AssigneeNortheastern University

InventorsAlexandros MAKRIYANNIS, Ganesh A. THAKUR, Rishi SHARMA

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Abstract

Disclosed are compounds and compositions that modulate cannabinoid receptors, methods of modulating cannabinoid receptors, and methods of treating various disorders related to the modulation of cannabinoid receptors. This disclosure is directed to methods of treating cannabinoid dependence, neuropathy, inflammation, glaucoma, a neurodegenerative disorder, a motor function disorder, a gastrointestinal disorder, hypothermia, emesis, loss of appetite, or anorexia associated with AIDS.

Claims41

Dependent claims

A compound of formulae (I), (II) or (III):

wherein can be a single bond or a double bond, provided that no more than one double bond is present in C ring of Formula (I);
when between C8-C9 or C9-C10 is a single bond,
X is —C(O)—, —CH(OH)—, —C(O)O—, —OC(O)—, —CHCH2OR12, —CHOCOR12, —CHCO2R12, or —CHR12;
when between C8-C9 or C9-C10 is a double bond,
X is —C(CH3)—, —CCH2O H—, —COCOH, or —CCO2R4;
R1 and R2 are independently H, —(C1-C2)-alkyl, —OH, or —CH2CO2H, wherein R1 and R2 are both not simultaneously OH, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-cycloalkyl or a —(C3-C6)-lactone;
R3 is R4, —CH2OH, —CO2H, —C(O)SR4, —C(O)N(R6)R4, —OC(O)R4, —(C1-C3 alkyl)-OC(O)R4, —C(O)OR4, or —(C1-C3 alkyl)-C(O)OR4, provided that when R3 is R4, then either X is —C(O)O— or —OC(O)—, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-lactone so that at least one ester group is present in Formula (I);
R4 is —(C1-C8)-alkyl-R5, —(C1-C8)-alkenyl-R5, or —(C1-C8)-alkynyl-R5;
R5 is H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, —NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R6 is H or —(C1-C2)-alkyl;
R7 and R8 are independently H, halogen, CN, —(C1-C2)-alkyl, OH, or —O—(C1-C2)-alkyl;
and
R9 and R10 are independently H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, —NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R11 is H, —(CH2)p-halogen, —(CH2)p—CN, —(CH2)pOH, or —(C1-C2)-alkyl, in which p is 0, 1, or 2;
R12 is H or —(C1-C6)-alkyl;
and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that
when X is —C(CH3)—, R3 is CO2H and R1 is H or methyl, then R2 is not hydrogen;
and
when X is —C(CH2OH)—, R1 and R2 are —(C1-C2)-alkyl, and R3 is —C(O)OR4, —(C1-C3 alkyl) C(O)OR4, —OC(O)R4, or —(C1-C3 alkyl) OC(O)R4, then R5 is not hydrogen.

21 more elements

A method of treating cannabinoid dependence, neuropathy, inflammation, glaucoma, a neurodegenerative disorder, a motor function disorder, anxiety disorder, a gastrointestinal disorder, hypothermia, emesis, loss of appetite, or anorexia associated with AIDS in a subject comprising administration of a compound of formulae (I), (II) or (III):

wherein can be a single bond or a double bond, provided that no more than one double bond is present in C ring of Formula (I);
when between C8-C9 or C9-C10 is a single bond,
X is —C(O)—, —CH(OH)—, —C(O)O—, —OC(O)—, —CHCH2OR12, —CHOCOR12, —CHCO2R12, or —CHR12;
when between C8-C9 or C9-C10 is a double bond,
X is —C(CH3)—, —CCH2OH, —COCOH, or —CCO2R4;
R1 and R2 are independently H, —(C1-C2)-alkyl, —OH, or —CH2CO2H, wherein R1 and R2 are both not simultaneously OH, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-cycloalkyl or a —(C3-C6)-lactone;
R3 is R4, —CH2OH, —CO2H, —C(O)SR4, —C(O)N(R6)R4, —OC(O)R4, —(C1-C3 alkyl)-OC(O)R4, —C(O)OR4, or —(C1-C3 alkyl)-C(O)OR4, provided that when R3 is R4, then either X is —C(O)O— or —OC(O)—, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-lactone so that at least one ester group is present in Formula (I);
R4 is —(C1-C8)-alkyl-R5, —(C1-C8)-alkenyl-R5, or —(C1-C8)-alkynyl-R5;
R5 is H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R6 is H or —(C1-C2)-alkyl;
R7 and R8 are independently H, halogen, CN, —(C1-C2)-alkyl, OH, or —O—(C1-C2)-alkyl;
R9 and R10 are independently H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, —NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R11 is H, —(CH2)p-halogen, —(CH2)p—CN, —(CH2)pOH, or —(C1-C2)-alkyl, in which p is 0, 1, or 2;
R12 is H or —(C1-C6)-alkyl;
and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that
when X is —C(CH3)—, R3 is CO2H and R1 is H or methyl, then R2 is not hydrogen;
and
when X is —C(CH2OH)—, R1 and R2 are —(C1-C2)-alkyl, and R3 is —OC(O)R4, —(C1-C3 alkyl)-OC(O)R4, —C(O)OR4, or —(C1-C3 alkyl)-C(O)OR4, then R5 is not hydrogen.

20 more elements

A method of treating anxiety disorder in a subject comprising administration of a compound of formulae (I), (II) or (III):

wherein can be a single bond or a double bond, provided that no more than one double bond is present in C ring of Formula (I);
when between C8-C9 or C9-C10 is a single bond,
X is —C(O)—, —CH(OH)—, —C(O)O—, —OC(O)—, —CHCH2OR12, —CHOCOR12, —CHCO2R12, or —CHR12;
when between C8-C9 or C9-C10 is a double bond,
X is —C(CH3)—, —CCH2OH, —COCOH, or —CCO2R4;
R1 and R2 are independently H, —(C1-C2)-alkyl, —OH, or —CH2CO2H, wherein R1 and R2 are both not simultaneously OH, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-cycloalkyl or a —(C3-C6)-lactone;
R3 is R4, —CH2OH, —CO2H, —C(O)SR4, —C(O)N(R6)R4, —OC(O)R4, —(C1-C3 alkyl)-OC(O)R4, —C(O)OR4, or —(C1-C3 alkyl)-C(O)OR4, provided that when R3 is R4, then either X is —C(O)O— or —OC(O)—, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-lactone so that at least one ester group is present in Formula (I);
R4 is —(C1-C8)-alkyl-R5, —(C1-C8)-alkenyl-R5, or —(C1-C8)-alkynyl-R5;
R5 is H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, —NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R6 is H or —(C1-C2)-alkyl;
R7 and R8 are independently H, halogen, CN, —(C1-C2)-alkyl, OH, or —O—(C1-C2)-alkyl;
R9 and R10 are independently H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, —NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R11 is H, —(CH2)p-halogen, —(CH2)p—CN, —(CH2)pOH, or —(C1-C2)-alkyl, in which p is 0, 1, or 2;
R12 is H or —(C1-C6)-alkyl;
and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that
when X is —C(CH3)—, R3 is CO2H and R1 is H or methyl, then R2 is not hydrogen;
and
when X is —C(CH2OH)—, R1 and R2 are —(C1-C2)-alkyl, and R3 is C(O)OR4, —(C1-C3 alkyl) C(O)OR4, —OC(O)R4, or —(C1-C3 alkyl) OC(O)R4, then R5 is not hydrogen.

20 more elements

A method of treating a motor function disorder in a subject comprising administration of a compound of formulae (I), (II) or (III):

wherein can be a single bond or a double bond, provided that no more than one double bond is present in C ring of Formula (I);
when between C8-C9 or C9-C10 is a single bond,
X is —C(O)—, —CH(OH)—, —C(O)O—, —OC(O)—, —CHCH2OR12, —CHOCOR12, —CHCO2R12, or —CHR12;
when between C8-C9 or C9-C10 is a double bond,
X is —C(CH3)—, —CCH2OH, —COCOH, or —CCO2R4;
R1 and R2 are independently H, —(C1-C2)-alkyl, —OH, or —CH2CO2H, wherein R1 and R2 are both not simultaneously OH, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-cycloalkyl or a —(C3-C6)-lactone;
R3 is R4, —CH2OH, —CO2H, —C(O)SR4, —C(O)N(R6)R4—OC(O)R4, —(C1-C3 alkyl)-OC(O)R4, —C(O)OR4, or —(C1-C3 alkyl)-C(O)OR4, provided that when R3 is R4, then either X is —C(O)O— or —OC(O)—, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-lactone so that at least one ester group is present in Formula (I);
R4 is —(C1-C8)-alkyl-R5, —(C1-C8)-alkenyl-R5, or —(C1-C8)-alkynyl-R5;
R5 is H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, —NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R6 is H or —(C1-C2)-alkyl;
R7 and R8 are independently H, halogen, CN, —(C1-C2)-alkyl, OH, or —O—(C1-C2)-alkyl;
R9 and R10 are independently H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, —NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R11 is H, —(CH2)p-halogen, —(CH2)p—CN, —(CH2)pOH, or —(C1-C2)-alkyl, in which p is 0, 1, or 2;
R12 is H or —(C1-C6)-alkyl;
and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that
when X is —C(CH3)—, R3 is CO2H and R1 is H or methyl, then R2 is not hydrogen;
and
when X is —C(CH2OH)—, R1 and R2 are —(C1-C2)-alkyl, and R3 is —C(O)OR4, —(C1-C3 alkyl) C(O)OR4, —OC(O)R4, or —(C1-C3 alkyl) OC(O)R4, then R5 is not hydrogen.

20 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formulae (I), (II) or (III):

wherein can be a single bond or a double bond, provided that no more than one double bond is present in C ring of Formula (I);
when between C8-C9 or C9-C10 is a single bond,
X is —C(O)—, —CH(OH)—, —C(O)O—, —OC(O)—, —CHCH2OR12, —CHOCOR12, —CHCO2R12, or —CHR12;
when between C8-C9 or C9-C10 is a double bond,
X is —C(CH3)—, —CCH2O H—, —COCOH, or —CCO2R4;
R1 and R2 are independently H, —(C1-C2)-alkyl, —OH, or —CH2CO2H, wherein R1 and R2 are both not simultaneously OH, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-cycloalkyl or a —(C3-C6)-lactone;
R3 is R4, —CH2OH, —CO2H, —C(O)SR4, —C(O)N(R6)R4, —OC(O)R4, —(C1-C3 alkyl)-OC(O)R4, —C(O)OR4, or —(C1-C3 alkyl)-C(O)OR4, provided that when R3 is R4, then either X is —C(O)O— or —OC(O)—, or R1 and R2 together with the carbon to which they are attached form a —(C3-C6)-lactone so that at least one ester group is present in Formula (I);
R4 is —(C1-C8)-alkyl-R5, —(C1-C8)-alkenyl-R5, or —(C1-C8)-alkynyl-R5;
R5 is H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, —NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R6 is H or —(C1-C2)-alkyl;
R7 and R8 are independently H, halogen, CN, —(C1-C2)-alkyl, OH, or —O—(C1-C2)-alkyl;
and
R9 and R10 are independently H, halogen, —OH, —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, —O—(C1-C6)-alkynyl, —CN, —N3, —NCS, —SO2NH2, —SO2CF3, imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C1-C6)-alkyl, —O—(C1-C6)-alkenyl, and —O—(C1-C6)-alkynyl are optionally substituted with —CN, —N3, or —NCS;
R11 is H, —(CH2)p-halogen, —(CH2)p—CN, —(CH2)pOH, or —(C1-C2)-alkyl, in which p is 0, 1, or 2;
R12 is H or —(C1-C6)-alkyl;
and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that
when X is —C(CH3)—, R3 is CO2H and R1 is H or methyl, then R2 is not hydrogen;
and
when X is —C(CH2OH)—, R1 and R2 are —(C1-C2)-alkyl, and R3 is —C(O)OR4, —(C1-C3 alkyl) C(O)OR4, —OC(O)R4, or —(C1-C3 alkyl) OC(O)R4, then R5 is not hydrogen.

21 more elements