Novel Cannabinergic Compounds and Uses Thereof

Patent metadata

Field	Value
Publication number	US-2016108016-A1
Application number	US-201214426257-A
Country	US
Kind code	A1
Filing date	Sep 6, 2012
Priority date	Sep 6, 2012
Publication date	Apr 21, 2016
Grant date	—

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.

First claim

1 . 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

Assignees

• Univ Northeastern

Inventors

• Makriyannis Alexandros
• Thakur Ganesh A
• Sharma Rishi

Classifications

• C07C255/57

  containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07C57/58

  containing six-membered aromatic rings · CPC title

• C07D493/04

  Ortho-condensed systems · CPC title

• C07D311/80 Primary

  Dibenzopyrans; Hydrogenated dibenzopyrans · CPC title