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US-12617765-B2 - Cannabinoid derivatives

US12617765B2US 12617765 B2US12617765 B2US 12617765B2US-12617765-B2

Abstract

The present application discloses a compound of formula (I), compositions comprising said compound, and a method of using said compound as a cannabinoid receptor ligand in the treatment or prevention of diseases associated with a cannabinoid receptor, such as, CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR119, TRPV1, TPRV2, PPARγ or a μ-opioid receptor.

Inventors

  • Patrick Thomas Gunning
  • JEFFREY ALAN OMEARA
  • QUANG HUY TO

Assignees

  • CANOPY GROWTH CORPORATION

Dates

Publication Date
20260505
Application Date
20201127

Claims (6)

  1. 1 . A compound having structural formula: or an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof, or a pharmaceutically acceptable salt, solvate or hydrate of the compound, enantiomer, diastereomer, racemate, tautomer, or metabolite, wherein R 1 is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl; R 2 is hydrogen, C 1 -C 8 alkyl, hydroxy, —CO 2 H, or —CO 2 (C 1 -C 8 alkyl); R 3 is hydrogen, C 2 -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)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl or —(C 0 -C 4 alkyl)-heterocycloalkyl, wherein R 3a and R 3b are each independently hydrogen or C 1 -C 6 alkyl; R 4 is hydrogen, —CO 2 H or —CO 2 (C 1 -C 6 alkyl); R 5a and R 5b are independently: hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, hydroxy, halo, —(C 0 -C 4 alkyl)O(C 1 -C 6 alkyl), —(CH 2 CH 2 O) 1-8 (C 1 -C 4 alkyl), —(C 0 -C 4 alkyl)C(O)(C 1 -C 8 alkyl), —CO 2 H, —CO 2 (C 1 -C 8 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, or —NR 5c R 5d , wherein R 5c and R 5d are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or —(C 0 -C 4 alkyl)C(O) 1-2 (C 1 -C 6 alkyl); or R 5a and R 5b together with a carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; Q 5 is O, S, or NR 5 , wherein R 5e is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(CH 2 CH 2 O) 1-8 (C 1 -C 4 alkyl), —C(O)R 5f , —CO 2 R 5f , —(C 1 -C 4 alkyl)-aryl, —(C 1 -C 4 alkyl)-heteroaryl, —(C 1 -C 4 alkyl)-cycloalkyl or —(C 1 -C 4 alkyl)-heterocycloalkyl, wherein each R 5f is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or —(CH 2 CH 2 O) 1-6 (C 1 -C 4 alkyl); and R 6 is hydrogen, hydroxy or wherein R 6a and R 6b are each independently: hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, hydroxy, halo, —O(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (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 or —NR 6c R 6d , wherein: R 6c and R 6d are independently hydrogen, C 1 -C 4 alkyl, or —C(O)(C 1 -C 4 alkyl), or R 6c and R 6d together with a carbon atom to which they are attached form a heterocycloalkyl ring; or R 6a and R 6b together with a carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; Q 6 is —Y 6 R 6e or —NR 6f R 6g , wherein Y 6 is O or S, R 6e , R 6f and R 6g are independently hydrogen, C 1 -C 8 alkyl, —(CH 2 CH 2 O) 1-8 (C 1 -C 4 alkyl), —C(O)R 6h , —CO 2 R 6h , C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(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, or R 6f and R 6g together with the nitrogen to which they are attached form a heterocyclic ring, wherein each R 6h is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or —(CH 2 CH 2 O) 1-6 (C 1 -C 4 alkyl); wherein each alkyl, alkenyl and alkynyl is unsubstituted, fluorinated, chlorinated, 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 , —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 or —NR B S(O) 1-2 NR B R A ; 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 , —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 or —NR B S(O) 1-2 NR B R A ; 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 comprised of 3-6 ring members; and which is: 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-5-pentyl-2-phenyl -4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-5-pentyl-2-(4(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-2-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxin-2-carboxylic acid; ethyl 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylate; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-2-(2-methylprop-1-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-5-pentyl-4H-spiro[benzo[d][1,3]dioxine-2,1′-cyclopentan]-4-one; 2-(3-chloropropyl)-8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(methoxymethyl)-2-methyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-2-(4-fluorophenyl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 2-butyl-8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-2-ethyl-7-hydroxy-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(4-methoxyphenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one; 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-5-propyl-4H-benzo[d][1,3]dioxin-4-one; or 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one, provided that the compound is not
  2. 2 . A pharmaceutical composition comprising a compound to claim 1 , or an enantiomer, diastereomer, racemate, tautomer, a pharmaceutically acceptable salt, solvate or hydrate together with a pharmaceutically acceptable excipient, diluent, or carrier.
  3. 3 . A method of treating a disease associated with a cannabinoid receptor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient, diluent, or carrier.
  4. 4 . The method according to claim 3 , wherein the cannabinoid receptor is one or more of CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ or a μ-opioid receptor.
  5. 5 . The method according to claim 4 , wherein the cannabinoid receptor is CB1 or CB2.
  6. 6 . A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient, diluent, or carrier, wherein the disease is acute pain, ADHD/ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer's, anorexia, anxiety disorders, arthritis, atherosclerosis, autism, bipolar disorder, burns, cancer, cancer pain, Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathies, chronic pain, chronic allograft nephropathy, cocaine use disorder, complex regional pain syndrome, congestive heart failure, depression, fibromyalgia, fragile X syndrome/FXTAS, frontotemporal dementias, gingivitis pyrexia, glaucoma, glioblastoma, glomerulonephropathy, Huntington's disease, hypertrophic scars, IBD/IBS, inflammation, Inflammatory myopathies, ischemia, kidney fibrosis, keloids, leukodystrophies, liver fibrosis, liver cirrhosis, lung fibrosis, migraine, multiple sclerosis, myocardial infarction, nausea, neuropathic pain, nightmare disorder, non-alcoholic fatty liver disease, obesity, obsessive-compulsive disorder, opioid sparing, opioid use disorder, osteoarthritis, osteoporosis, Parkinson's, post-concussion syndrome/traumatic brain injury, psychosis/schizophrenia, PTSD, regulation of bone mass, REM sleep behaviour disorder, reperfusion injury, Rett syndrome, rheumatoid arthritis, skin conditions, sleep disorders, spinocerebellar ataxias, systemic fibrosis, systemic sclerosis, thermal injury, tobacco use disorder/nicotine dependence, Tourette's, tumors, or trigeminal neuralgia.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is the U.S. National Stage Application of International Patent Application No. PCT/CA2020/051639, filed Nov. 27, 2020, which claims priority to and benefit of U.S. Provisional Patent Application Ser. No. 62/945,676 filed on Dec. 9, 2019; U.S. Provisional Patent Application Ser. No. 63/074,571 filed on Sep. 4, 2020; and U.S. Provisional Patent Application Ser. No. 63/113,044 filed on Nov. 12, 2020, each of which is hereby incorporated by reference in its entirety. BACKGROUND OF THE DISCLOSURE Field of the Disclosure This disclosure relates generally to cannabinoid derivatives, pharmaceutical compositions comprising them, and methods of using the cannabinoid derivatives. Technical Background Every individual has an endocannabinoid system comprised of chemical receptors in the brain, immune system, and central nervous system, for example including the cannabinoid 1 (CB1) receptor and cannabinoid 2 (CB2) receptor. The endocannabinoid system regulates many important physiological processes and several components of the endocannabinoid system, such as receptors, transporters, endocannabinoids and enzymes involved in the synthesis and degradation of endocannabinoids, are under active investigation as targets to treat a diverse array of indications. CB1 and CB2 receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor (GPCR) superfamily. The CB1 and CB2 receptors are distinguished from each other by their amino acid sequence, tissue distribution, signaling mechanisms, and ability to bind sub-type specific ligands. The CB1 receptor is mainly expressed in the central nervous system (CNS), lungs, liver, adipose tissue, and kidneys, and the CB2 receptor is mainly localized in immune cells (e.g. macrophages and T-cells), on cells that are involved in bone formation and bone loss, and in the gastrointestinal system. These receptors have been associated with many human diseases including obesity, diabetes, fibrosis, liver diseases, cardiovascular disease, cancer, pain, inflammation, MS spasticity, and glaucoma, among others. Cannabinoids are compounds active on cannabinoid receptors in humans and have been implicated in many of the pharmacological benefits on the diseases noted above. Cannabinoids of plant origin, also known as phytocannabinoids, are abundant in Cannabis. Medical use of cannabis and associated phytocannabinoids is becoming widely accepted in the many countries, including United States, as an alternative form of medicine. Many states have legalized its use for qualified medical conditions such as chronic pain, epilepsy, sleep disorders, anxiety, cancer, glaucoma, nausea, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Crohn's disease, Post-traumatic Stress Disorder (PTSD), arthritis, fibromyalgia, and others. In addition to the CB1 and CB2 receptors, other receptors have also been implicated in modulating the activity of cannabinoids in the human and/or animal body. For example, the serotonin receptors, such as 5HT1A and 5HT2A, are likewise GPCRs that have been identified as cannabinoid targets. The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine/norepinephrine and acetylcholine, as well as many hormones. Like the CB1 and CB2 receptors, the serotonin receptors influence various biological and neurological processes, such as anxiety, appetite, cognition, and mood, among others. Other receptors identified as being influenced by cannabinoid or cannabinoid-like compounds include GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARs (e.g. PPARγ), and the μ-opioid receptors. Indeed, binding of these receptors may be responsible for off-target effects of cannabinoids. One of the most common ways that cannabinoids are used for medicinal use in many countries is through smoking of cannabis. Although proven to be beneficial in certain indications, smoking medical cannabis has disadvantages. For example, the smoke from the plant matter comprises carcinogens and other toxins in addition to the desired cannabinoids. Heavy cannabis use through smoking has also been associated with accelerated pulmonary decline, lung damage, and emphysema. Another disadvantage of smoking medical cannabis is difficulty in maintaining control over the proper dosing of medicinal cannabis due to active ingredients fluctuations (e.g., the amounts of active ingredients may differ depending on the differences present in plant varietals as well as changing growing conditions which result in intravarietal variations). Finally, consumption through smoking has a relatively low bioavailability of target compounds compared to other delivery methods. A less common way to utilize cannabis for medical use is to extract beneficial cannabinoids from cannabis. Many extraction processes have been developed for isolating and purifying natural cannabinoids. But there has been difficulty in isolating ind