Cannabigerol derivatives and use thereof as cannabinoid receptor modulators

Patent metadata

Field	Value
Publication number	US-12084407-B2
Application number	US-202017780047-A
Country	US
Kind code	B2
Filing date	Nov 25, 2020
Priority date	Nov 26, 2019
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

The synthesis of a range of pentylbezene-1,3-diol compounds of formula I is disclosed. These compounds bind to cannabinoid 1 and 2 receptors (CB1 and CB2), and are thus presumed to be useful in modulating the activity of such receptors. Accordingly, the use of such synthetic cannabinoids in the treatment of various disorders mediated by CB1 and CB2 is contemplated.

First claim

We claim:

1. A compound having structural formula:

or an enantiomer, diastereomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate of the compound, enantiomer, diastereomer, racemate, or tautomer, wherein
R 1 is hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —CO 2 H, —(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-OC(O)O—(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-N(R 1b )—C(O)—O—(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-O—C(O)—NR 1b R 1c , —(C 0 -C 4 alkyl)-N(Rib)-C(O)—NR 1b R 1c , —OR 1a , —(C 1 -C 4 alkyl)OR 1a , —SR 1a , —(C 1 -C 4 alkyl)S(O) 0-2 R 1a , —NR 1b R 1c , —(C 1 -C 4 alkyl)NR 1b R 1c , —(C 1 -C 4 alkyl)C(O)NR 1b R 1c , —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, or —(C 0 -C 4 alkyl)-heterocycloalkyl, wherein
R 1a , R 1b , and R 1c are independently hydrogen, C 1 -C 4 alkyl, or —C(O)(C 1 -C 4 ) alkyl;

R 2 is hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —CO 2 H, —(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-OC(O)O—(C 1 -C 6 alkyl), —(C 1 -C 4 alkyl)OR 2a , —(C 1 -C 4 alkyl)SR 2a , —NR 2b R 2 c —(C 1 -C 4 alkyl)NR 2b R 2 c, —(C 1 -C 4 alkyl)C(O)NR 2b R 2 c, —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, or —(C 0 -C 4 alkyl)-heterocycloalkyl, wherein
R 2a , R 2b , and R 2c are independently hydrogen, C 1 -C 4 alkyl, or —C(O)(C 1 -C 4 ) alkyl;

R 3 is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —(OCH 2 CH 2 ) 0-6 O(C 1 -C 8 alkyl), —(C 0 -C 4 alkyl)-NR 3a R 3b , —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl or —(C 0 -C 4 alkyl)-heterocycloalkyl, wherein R 3 a and R 3b are each independently hydrogen or C 1 -C 6 alkyl;
R 4 is

wherein
R 4a is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —OR 4a , —(C 1 -C 4 alkyl)OR 4e , —(C 1 -C 4 alkyl)-C(O)(C 1 -C 4 alkyl), —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, —(C 0 -C 4 alkyl)-heterocycloalkyl, —NR 4d R 4e , or —(C 1 -C 4 alkyl)NR 4d R 4e , and
R 4b is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —CH 2 —(OCH 2 CH 2 ) 0-6 O(C 1 -C 8 alkyl), —(C 1 -C 4 alkyl)OR 4e , —(C 1 -C 4 alkyl)-C(O)(C 1 -C 4 alkyl), —(C 1 -C 4 alkyl)-C(O)O(R 4e ), —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, —(C 0 -C 4 alkyl)-heterocycloalkyl, or —(C 1 -C 4 alkyl)NR 4d R 4e , wherein
R 4d is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —(C 1 -C 4 alkyl)-C(O)(C 1 -C 4 alkyl), —(C 1 -C 4 alkyl)-C(O)O(R 4e ), —(C 1 -C 4 alkyl)-OC(O)(R 4e ), —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, or —(C 0 -C 4 alkyl)-heterocycloalkyl,
R 4e is hydrogen, C 1 -C 4 alkyl, or aryl, and

R 4c is hydrogen or C 1 -C 4 alkyl;
R 5 is hydrogen, C 1 -C 8 alkyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —C(O)O(C 1 -C 4 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)N(C 1 -C 4 alkyl) 2 , —(C 1 -C 4 alkyl)C(O)O(C 1 -C 4 alkyl), or —(C 1 -C 4 alkyl)OC(O)(C 1 -C 4 alkyl); and
R 6 is hydrogen or —OR 6a , wherein R 6a is hydrogen, C 1 -C 8 alkyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —C(O)O(C 1 -C 4 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)N(C 1 -C 4 alkyl) 2 , —(C 1 -C 4 alkyl)C(O)O(C 1 -C 4 alkyl), or —(C 1 -C 4 alkyl)OC(O)(C 1 -C 4 alkyl);

wherein
each alkyl, alkenyl and alkynyl is unsubstituted, halogenated, substituted with one or two hydroxyl or C 1 -C 6 alkoxy groups, or substituted with one or two oxo groups;
each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each fused cycloalkyl ring having 3-8 ring members, and is substituted with 0-6 R 7 ;
each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms where each heteroatom is independently nitrogen, oxygen or sulfur and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each fused cycloalkyl ring having 3-8 ring members, and is substituted with 0-6 R 7 ;
each aryl is a phenyl or a naphthyl, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members, and is substituted with 0-5 R 8 ;
each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms, where each heteroatom is independently nitrogen, oxygen or sulfur or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms where each heteroatom is independently nitrogen, oxygen or sulfur, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members, and is substituted with 0-5 R 8 ,
in which
each R 7 is independently oxo, C 1 -C 4 alkyl, —C 1 , —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —(C 0 -C 3 alkyl)-OR B , —NR B R A , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-2 OR A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , —NR B S(O) 1-2 R A , —OCO 2 R A , —OC(O)NR B R A , —NR B CO 2 R A , —NR B C(O)NR B R A , —SCO 2 R A , —OC(O)SR A , —SC(O)SR A , —SC(O)NR B R A , —NBC(O)SR A , —OC(S)OR A , —OC(S)NR B R A , —NR B C(S)OR A , —NR B C(S)NR B R A , —SC(S)OR A , —OC(S)SR A , —SC(S)SR A , —SC(S)NR B R A , —NR B C(S)SR A , —NR B C(NR B )NR B R A , —NR B S(O) 1-2 NR B R A , phenyl, C 3 -C 8 cycloalkyl, a five to six-membered heteroaryl, or a five to six-membered heterocycloalkyl; and
each R 7 , is independently optionally-substituted C 1 -C 4 alkyl, —C 1 , —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —(C 0 -C 3 alkyl)-OR B , —NR B R A , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —SO 3 H, —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-20 R A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , —NR BS(O) 1-2 R A , —OCO 2 R A , —OC(O)NR B R A , —NR B CO 2 R A , —NR B C(O)NR B R A , —SCO 2 R A , —OC(O)SR A , —SC(O)SR A , —SC(O)NR B R A , —NR B C(O)SR A , —OC(S)OR A , —OC(S)NR B R A , —NR B C(S)OR A , —NR B C(S)NR B R A , —SC(S)OR A , —OC(S)SR A , —SC(S)SR A , —SC(S)NR B R A , —NR B C(S)SR A , —NR B C(NR B )NR B R A , —NR B S(O) 1-2 NR B R A ; phenyl, C 3 -C 8 cycloalkyl, a five to six-membered heteroaryl, or a five to six-membered heterocycloalkyl;
wherein each R A is independently H or C 1 -C 3 alkyl, and each R B is independently H, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 hydroxyalkyl, —S(O) 1-2 (C 1 -C 3 alkyl), —C(O)(C 1 -C 3 alkyl) or —CO 2 (C 1 -C 3 alkyl), or R A and R B together with the nitrogen atom to which they are attached come together to form an unsubstituted heterocycloalkyl ring of 3-6 ring members.

2. The compound according to claim 1 , wherein R 1 is hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, —C 02 H, —(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-N(R 1b )—C(O)—O—(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-O—C(O)—NR 1b R 1c , —(C 0 -C 4 alkyl)-N(R 1b )—C(O)-NR 1 bR 1c , —OR 1a , —(C 1 -C 4 alkyl)OR 1a , —SR 1a , —(C 1 -C 4 alkyl)SR 1a , —NR 1b R 1c , —(C 1 -C 4 alkyl)NR 1b R 1c , —(C 1 -C 4 alkyl)C(O)NR 1b R 1c , —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, or —(C 0 -C 4 alkyl)-heterocycloalkyl.

3. The compound according to

Assignees

• Canopy Growth Corp

Inventors

• Ahmar Siawash
• Gnanasekaran Krishna Kumar
• Omeara Jeffrey Alan

Classifications

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D307/64

  Sulfur atoms · CPC title

• C07D305/08

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms · CPC title

• C07D295/26

  Sulfur atoms · CPC title

• C07D295/15

  to an acyclic saturated chain · CPC title