US2016108016A1PendingUtilityA1
Novel Cannabinergic Compounds and Uses Thereof
Est. expirySep 6, 2032(~6.1 yrs left)· nominal 20-yr term from priority
C07C 255/57C07D 405/12C07C 57/58C07D 493/04C07D 311/80C07D 407/04
54
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Claims
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.
Claims
exact text as granted — not AI-modified1 . 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)—, —CHCH 2 OR 12 , —CHOCOR 12 , —CHCO 2 R 12 , or —CHR 12 ;
when between C8-C9 or C9-C10 is a double bond,
X is —C(CH 3 )—, —CCH 2 O H—, —COCOH, or —CCO 2 R 4 ;
R 1 and R 2 are independently H, —(C 1 -C 2 )-alkyl, —OH, or —CH 2 CO 2 H, wherein R 1 and R 2 are both not simultaneously OH, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-cycloalkyl or a —(C 3 -C 6 )-lactone;
R 3 is R 4 , —CH 2 OH, —CO 2 H, —C(O)SR 4 , —C(O)N(R 6 )R 4 , —OC(O)R 4 , —(C 1 -C 3 alkyl)-OC(O)R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl)-C(O)OR 4 , provided that when R 3 is R 4 , then either X is —C(O)O— or —OC(O)—, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-lactone so that at least one ester group is present in Formula (I);
R 4 is —(C 1 -C 8 )-alkyl-R 5 , —(C 1 -C 8 )-alkenyl-R 5 , or —(C 1 -C 8 )-alkynyl-R 5 ;
R 5 is H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS;
R 6 is H or —(C 1 -C 2 )-alkyl;
R 7 and R 8 are independently H, halogen, CN, —(C 1 -C 2 )-alkyl, OH, or —O—(C 1 -C 2 )-alkyl; and
R 9 and R 10 are independently H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS;
R 11 is H, —(CH 2 ) p -halogen, —(CH 2 ) p —CN, —(CH 2 ) p OH, or —(C 1 -C 2 )-alkyl, in which p is 0, 1, or 2;
R 12 is H or —(C 1 -C 6 )-alkyl; and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that
when X is —C(CH 3 )—, R 3 is CO 2 H and R 1 is H or methyl, then R 2 is not hydrogen; and
when X is —C(CH 2 OH)—, R 1 and R 2 are —(C 1 -C 2 )-alkyl, and R 3 is —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , then R 5 is not hydrogen.
2 . The compound of claim 1 , having the structure of formula (I), wherein
when between C8-C9 or C9-C10 is a double bond, R 3 is R 4 , —CH 2 OH, —C(O)SR 4 , —C(O)N(R 6 )R 4 , —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , provided that when R 3 is R 4 , then either X is —C(O)O— or —OC(O)—, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-lactone so that at least one ester group is present in Formula (I), and provided that when R 3 is —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , then R 5 is not hydrogen.
3 . The compound of claim 2 , having the structure of formula (I), wherein
when between C8-C9 or C9-C10 is a single bond,
R 3 is R 4 , —CO 2 H, —C(O)OR 4 , or —(C 1 -C 3 alkyl) C(O)OR 4 ;
R 5 is H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS; and
when between C8-C9 or C9-C10 is a double bond,
R 3 is R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl) C(O)OR 4 , —C(O)SR 4 , —C(O)N(R 6 )R 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 ; and
R 5 is halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS.
4 . The compound of claim 2 , having the structure of formula (I), wherein
when between C8-C9 or C9-C10 is a single bond,
R 1 and R 2 are independently H, —(C 1 -C 2 )-alkyl;
R 3 is R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl) C(O)OR 4 ;
R 5 is H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS; and
when between C8-C9 or C9-C10 is a double bond,
R 3 is R 4 , —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —C(O)SR 4 , —C(O)N(R 6 )R 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 ; and
R 5 is halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS.
5 . The compound of claim 4 , having the structure of formula (I), wherein
when between C8-C9 or C9-C10 is a single bond,
R 1 and R 2 are independently H or —(C 1 -C 2 )-alkyl;
R 3 is R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl) C(O)OR 4 ;
R 5 is halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS; and
when between C8-C9 or C9-C10 is a double bond,
R 1 and R 2 are independently H or —(C 1 -C 2 )-alkyl, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 5 )-cycloalkyl or a —(C 3 -C 5 )-lactone;
R 3 is R 4 , —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —C(O)SR 4 , —C(O)N(R 6 )R 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 ; and
R 5 is halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS.
6 . The compound claim 5 , having the structure of formula (I), wherein
when between C8-C9 or C9-C10 is a single bond,
R 1 and R 2 are independently H or methyl;
R 3 is R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl) C(O)OR 4 ;
R 5 is halogen, OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS; and
when between C8-C9 or C9-C10 is a double bond,
R 1 and R 2 are independently H or methyl, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 5 )-cycloalkyl or a —(C 3 -C 5 )-lactone;
R 3 is R 4 , —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —C(O)SR 4 , —C(O)N(R 6 )R 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 ; and
R 5 is halogen, OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS.
7 . The compound of claim 6 , having the structure of formula (I), wherein
when between C8-C9 or C9-C10 is a single bond,
R 1 and R 2 are independently H or methyl;
R 3 is R 4 , —C(O)OR 4 or —(CH 2 )C(O)OR 4 ;
R 5 is halogen, OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS; and
when between C8-C9 or C9-C10 is a double bond,
R 1 and R 2 are independently H or methyl, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 5 )-cycloalkyl or a —(C 3 -C 5 )-lactone;
R 3 is R 4 , —C(O)OR 4 , —(CH 2 )C(O)OR 4 , —C(O)SR 4 , —C(O)N(R 6 )R 4 , —OC(O)R 4 , or —(CH 2 )OC(O)R 4 ; and
R 5 is halogen, OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS.
8 . The compound of claim 7 , having the structure of formula (I), wherein
when between C8-C9 or C9-C10 is a single bond,
R 1 and R 2 are independently H or methyl;
R 3 is R 4 or —C(O)OR 4 ;
R 5 is halogen, OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS; and
when between C8-C9 or C9-C10 is a double bond,
R 1 and R 2 are independently H or methyl, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 5 )-cycloalkyl or a —(C 3 -C 5 )-lactone;
R 3 is R 4 , —C(O)OR 4 , —C(O)SR 4 , —C(O)N(R 6 )R 4 , or —OC(O)R 4 ; and
R 5 is halogen, OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS.
9 . The compound of claim 8 , having the structure of formula (I), wherein between C8-C9 is a double bond.
10 . The compound of claim 1 , having the structure of formula (I), wherein between C8-C9 is a single bond.
11 . The compound of claim 1 , having the structure of formula (I), wherein between C9-C10 is a double bond.
12 . The compound of claim 1 , having the structure of formula (I), wherein between C9-C10 is a single bond.
13 . The compound of claim 1 , having the structure of formula (I), wherein the compound is of formula (Ia):
14 . The compound of claim 1 , having the structure of formula (I), wherein the compound is of formula (Ib):
15 . The compound of claim 1 , having the structure of formula (I), wherein the compound is of formula (Ic):
16 . The compound of claim 1 , having the structure of formula (II).
17 . The compound of claim 16 , having the structure of formula (II), wherein the compound is of formula (IIa):
18 . The compound of claim 17 , having the structure of formula (IIa), wherein
R 1 and R 2 are independently H or methyl; R 3 is —C(O)O—(C 1 -C 4 )-alkyl; R 7 and R 8 are independently OH or OCH 3 ; R 9 and R 10 are independently H, halogen, —CN, NCS, N 3 , —SO 2 NH 2 , —SO 2 CF 3 , or —(C 1 -C 2 )-alkyl; and m is 1.
19 . The compound of claim 18 , having the structure of formula (IIa), wherein
R 1 and R 2 are each methyl; R 3 is —C(O)O-ethyl; R 7 and R 8 are independently OH or OCH 3 ; R 9 and R 10 are independently H, halogen, —CN, or —(C 1 -C 2 )-alkyl; and m is 1.
20 . The compound of claim 19 , having the structure of formula (IIa), wherein
R 1 and R 2 are each methyl; R 3 is —C(O)O-ethyl; R 7 and R 8 are independently OH or OCH 3 ; R 9 and R 10 are independently halogen, or methyl; and m is 1.
21 . The compound of claim 20 , having the structure of formula (IIa), wherein
R 1 and R 2 are each methyl; R 3 is —C(O)O-ethyl; R 7 and R 8 are independently OH or OCH 3 ; R 9 and R 10 are each methyl or R 9 and R 10 are each halogen; and m is 1.
22 . The compound of claim 1 , having the structure of formula (III).
23 . The compound of claim 22 , having the structure of formula (III), wherein
R 1 and R 2 are independently H, —(C 1 -C 2 )-alkyl, —OH, or —CH 2 CO 2 H, wherein R 1 and R 2 are both not simultaneously OH, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-cycloalkyl or a —(C 3 -C 6 )-lactone; R 3 is R 4 , —CH 2 OH, —CO 2 H, —C(O)SR 4 , —C(O)N(R 6 )R 4 , —OC(O)R 4 , —(C 1 -C 3 alkyl)-OC(O)R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl)-C(O), provided that when R 3 is R 4 , then R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-lactone so that at least one ester group is present in Formula (III); R 4 is —(C 1 -C 8 )-alkyl-R 5 , —(C 1 -C 8 )-alkenyl-R 5 , or —(C 1 -C 8 )-alkynyl-R 5 ; and R 5 is H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS.
24 . A method of modulating a cannabinoid receptor in a subject comprising administration of a compound of claim 1 .
25 . 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)—, —CHCH 2 OR 12 , —CHOCOR 12 , —CHCO 2 R 12 , or —CHR 12 ;
when between C8-C9 or C9-C10 is a double bond,
X is —C(CH 3 )—, —CCH 2 OH, —COCOH, or —CCO 2 R 4 ;
R 1 and R 2 are independently H, —(C 1 -C 2 )-alkyl, —OH, or —CH 2 CO 2 H, wherein R 1 and R 2 are both not simultaneously OH, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-cycloalkyl or a —(C 3 -C 6 )-lactone;
R 3 is R 4 , —CH 2 OH, —CO 2 H, —C(O)SR 4 , —C(O)N(R 6 )R 4 , —OC(O)R 4 , —(C 1 -C 3 alkyl)-OC(O)R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl)-C(O)OR 4 , provided that when R 3 is R 4 , then either X is —C(O)O— or —OC(O)—, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-lactone so that at least one ester group is present in Formula (I);
R 4 is —(C 1 -C 8 )-alkyl-R 5 , —(C 1 -C 8 )-alkenyl-R 5 , or —(C 1 -C 8 )-alkynyl-R 5 ;
R 5 is H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS;
R 6 is H or —(C 1 -C 2 )-alkyl;
R 7 and R 8 are independently H, halogen, CN, —(C 1 -C 2 )-alkyl, OH, or —O—(C 1 -C 2 )-alkyl;
R 9 and R 10 are independently H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS;
R 11 is H, —(CH 2 ) p -halogen, —(CH 2 ) p —CN, —(CH 2 ) p OH, or —(C 1 -C 2 )-alkyl, in which p is 0, 1, or 2;
R 12 is H or —(C 1 -C 6 )-alkyl; and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that
when X is —C(CH 3 )—, R 3 is CO 2 H and R 1 is H or methyl, then R 2 is not hydrogen; and
when X is —C(CH 2 OH)—, R 1 and R 2 are —(C 1 -C 2 )-alkyl, and R 3 is —OC(O)R 4 , —(C 1 -C 3 alkyl)-OC(O)R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl)-C(O)OR 4 , then R 5 is not hydrogen.
26 . The method of claim 25 , wherein the compound is a compound of formula (I), wherein when between C8-C9 or C9-C10 is a double bond,
R 3 is R 4 , —CH 2 OH, —C(O)SR 4 , —C(O)N(R 6 )R 4 , —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , provided that when R 3 is R 4 , then either X is —C(O)O— or —OC(O)—, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-lactone so that at least one ester group is present in Formula (I), and provided that when R 3 is —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , then R 5 is not hydrogen.
27 . The method of claim 25 , wherein neuropathy comprises inflammation, pain, neuropathic pain, neuropathic low back pain, complex regional pain syndrome, post trigeminal neuralgia, causalgia, toxic neuropathy, reflex sympathetic dystrophy, diabetic neuropathy, chronic neuropathy caused by chemotherapeutic agents, central pain, peripheral pain, pellagric neuropathy, alcoholic neuropathy, Beriberi neuropathy, or burning feet syndrome.
28 . The method of claim 25 , wherein neuropathy comprises a neurodegenerative disease.
29 . The method of claim 28 , wherein the neurodegenerative disease is multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, amyotrophic lateral sclerosis, memory disorder, mood disorder, sleep disorder, gastrointestinal motility disorder, irritable bowel syndrome, diarrhea, cardiovascular disease, hypertension, osteoporosis, osteoarthritis, emesis, epilepsy, a mental disorder, schizophrenia, depression, glaucoma, cachexia, insomnia, traumatic brain injury, spinal cord injury, seizures, excitotoxin exposure, ischemia, or AIDS wasting syndrome
30 . The method of claim 25 , wherein the method comprises treating hypothermia.
31 . The method of claim 25 , wherein the method comprises cannabinoid dependence.
32 . 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)—, —CHCH 2 OR 12 , —CHOCOR 12 , —CHCO 2 R 12 , or —CHR 12 ;
when between C8-C9 or C9-C10 is a double bond,
X is —C(CH 3 )—, —CCH 2 OH, —COCOH, or —CCO 2 R 4 ;
R 1 and R 2 are independently H, —(C 1 -C 2 )-alkyl, —OH, or —CH 2 CO 2 H, wherein R 1 and R 2 are both not simultaneously OH, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-cycloalkyl or a —(C 3 -C 6 )-lactone;
R 3 is R 4 , —CH 2 OH, —CO 2 H, —C(O)SR 4 , —C(O)N(R 6 )R 4 , —OC(O)R 4 , —(C 1 -C 3 alkyl)-OC(O)R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl)-C(O)OR 4 , provided that when R 3 is R 4 , then either X is —C(O)O— or —OC(O)—, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-lactone so that at least one ester group is present in Formula (I);
R 4 is —(C 1 -C 8 )-alkyl-R 5 , —(C 1 -C 8 )-alkenyl-R 5 , or —(C 1 -C 8 )-alkynyl-R 5 ;
R 5 is H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS;
R 6 is H or —(C 1 -C 2 )-alkyl;
R 7 and R 8 are independently H, halogen, CN, —(C 1 -C 2 )-alkyl, OH, or —O—(C 1 -C 2 )-alkyl;
R 9 and R 10 are independently H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS;
R 11 is H, —(CH 2 ) p -halogen, —(CH 2 ) p —CN, —(CH 2 ) p OH, or —(C 1 -C 2 )-alkyl, in which p is 0, 1, or 2;
R 12 is H or —(C 1 -C 6 )-alkyl; and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that
when X is —C(CH 3 )—, R 3 is CO 2 H and R 1 is H or methyl, then R 2 is not hydrogen; and
when X is —C(CH 2 OH)—, R 1 and R 2 are —(C 1 -C 2 )-alkyl, and R 3 is C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , then R 5 is not hydrogen.
33 . The method of claim 32 , wherein the compound is a compound of formula (I), wherein when between C8-C9 or C9-C10 is a double bond,
R 3 is R 4 , —CH 2 OH, —C(O)SR 4 , —C(O)N(R 6 )R 4 , —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , provided that when R 3 is R 4 , then either X is —C(O)O— or —OC(O)—, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-lactone so that at least one ester group is present in Formula (I), and provided that when R 3 is —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , then R 5 is not hydrogen.
34 . The method of claim 32 , wherein the anxiety disorder is panic disorder, acute stress disorder, post-traumatic stress disorder, substance-induced anxiety disorder, obsessive compulsive disorder, agoraphobia, specific phobia, or social phobia.
35 . 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)—, —CHCH 2 OR 12 , —CHOCOR 12 , —CHCO 2 R 12 , or —CHR 12 ;
when between C8-C9 or C9-C10 is a double bond,
X is —C(CH 3 )—, —CCH 2 OH, —COCOH, or —CCO 2 R 4 ;
R 1 and R 2 are independently H, —(C 1 -C 2 )-alkyl, —OH, or —CH 2 CO 2 H, wherein R 1 and R 2 are both not simultaneously OH, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-cycloalkyl or a —(C 3 -C 6 )-lactone;
R 3 is R 4 , —CH 2 OH, —CO 2 H, —C(O)SR 4 , —C(O)N(R 6 )R 4 —OC(O)R 4 , —(C 1 -C 3 alkyl)-OC(O)R 4 , —C(O)OR 4 , or —(C 1 -C 3 alkyl)-C(O)OR 4 , provided that when R 3 is R 4 , then either X is —C(O)O— or —OC(O)—, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-lactone so that at least one ester group is present in Formula (I);
R 4 is —(C 1 -C 8 )-alkyl-R 5 , —(C 1 -C 8 )-alkenyl-R 5 , or —(C 1 -C 8 )-alkynyl-R 5 ;
R 5 is H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS;
R 6 is H or —(C 1 -C 2 )-alkyl;
R 7 and R 8 are independently H, halogen, CN, —(C 1 -C 2 )-alkyl, OH, or —O—(C 1 -C 2 )-alkyl;
R 9 and R 10 are independently H, halogen, —OH, —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, —O—(C 1 -C 6 )-alkynyl, —CN, —N 3 , —NCS, —SO 2 NH 2 , —SO 2 CF 3 , imidazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, morpholine, thiomorpholine,
wherein —O—(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkenyl, and —O—(C 1 -C 6 )-alkynyl are optionally substituted with —CN, —N 3 , or —NCS;
R 11 is H, —(CH 2 ) p -halogen, —(CH 2 ) p —CN, —(CH 2 ) p OH, or —(C 1 -C 2 )-alkyl, in which p is 0, 1, or 2;
R 12 is H or —(C 1 -C 6 )-alkyl; and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that
when X is —C(CH 3 )—, R 3 is CO 2 H and R 1 is H or methyl, then R 2 is not hydrogen; and
when X is —C(CH 2 OH)—, R 1 and R 2 are —(C 1 -C 2 )-alkyl, and R 3 is —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , then R 5 is not hydrogen.
36 . The method of claim 35 , wherein the compound is a compound of formula (I), wherein when between C8-C9 or C9-C10 is a double bond,
R 3 is R 4 , —CH 2 OH, —C(O)SR 4 , —C(O)N(R 6 )R 4 , —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , provided that when R 3 is R 4 , then either X is —C(O)O— or —OC(O)—, or R 1 and R 2 together with the carbon to which they are attached form a —(C 3 -C 6 )-lactone so that at least one ester group is present in Formula (I), and provided that when R 3 is —C(O)OR 4 , —(C 1 -C 3 alkyl) C(O)OR 4 , —OC(O)R 4 , or —(C 1 -C 3 alkyl) OC(O)R 4 , then R 5 is not hydrogen.
37 . The method of claim 35 , wherein the motor function disorder is Tourette's syndrome.
38 . (canceled)
39 . (canceled)
40 . The method of claim 25 , wherein neuropathy comprises neuropathic pain.
41 .- 42 . (canceled)Join the waitlist — get patent alerts
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