Cannabinoid derivatives

Patent metadata

Field	Value
Publication number	US-12012373-B2
Application number	US-202017626519-A
Country	US
Kind code	B2
Filing date	Jul 10, 2020
Priority date	Jul 12, 2019
Publication date	Jun 18, 2024
Grant date	Jun 18, 2024

Abstract

This disclosure relates to cannabinoid derivatives having the structure of formula (I), pharmaceutical compositions comprising them, and methods of using the cannabinoid derivatives in treating or preventing a diseases associated with a cannabinoid receptor in subject in need thereof, wherein the cannabinoid receptor is one or more of CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TRPV2, PPARγ or a μ-opioid receptor.

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
the

 moiety is

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), —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, —(C 0 -C 4 alkyl)-heterocycloalkyl, or oxo when attached to a ring of appropriate saturation, 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), —OR 2a , —(C 1 -C 4 alkyl)OR 2a , —SR 2a , —(C 1 -C 4 alkyl)SR 2a , —NR 2b R 2c , —(C 1 -C 4 alkyl)NR 2b R 2c , —(C 1 -C 4 alkyl)C(O)NR 2b R 2c , —(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 oxo when attached to a ring of appropriate saturation, 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 C 1 -C 12 alkyl;
R 4 is

wherein
R 4a is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —OR 4c , —(C 1 -C 4 alkyl)OR 4c , —(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 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 or C 1 -C 4 alkyl, 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 0 -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 0 -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 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 is independently nitrogen, oxygen or sulfur and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each 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 is independently nitrogen, oxygen or sulfur or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms where each 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, —Cl, —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 , —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; and

each R 8 is independently optionally-substituted C 1 -C 4 alkyl, —Cl, —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) 1-2 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 , —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).

2. The compound according to claim 1 , wherein the moiety

is

3. The compound according to claim 1 , wherein R 1 is hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, —CO 2 H, —(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), —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, —(C 0 -C 4 alkyl)-heterocycloalkyl, or oxo.

4. The compound according to cla

Assignees

• Canopy Growth Corp

Inventors

• Ahmar Siawash
• Gnanasekaran Krishna Kumar
• Omeara Jeffrey Alan
• Park Ji Sung

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

• C07D277/30

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