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US-12617749-B2 - Cannabinoid derivatives and precursors, and asymmetric synthesis for same

US12617749B2US 12617749 B2US12617749 B2US 12617749B2US-12617749-B2

Abstract

The present disclosure relates to new cannabinoid derivatives and precursors and catalytic asymmetric processes for their preparation. The disclosure also relates to pharmaceutical compositions and pharmaceutical and analytical uses of the new cannabinoid derivatives. The disclosure also relates to the deuterium, carbon-13 and carbon-14 containing derivatives of the compounds that can be prepared and purified prior to transformation to the desired individual deuterated cannabinoid products.

Inventors

  • Kamaluddin Abdur-Rashid
  • Wenli Jia
  • Kareem Abdur-Rashid

Assignees

  • KARE CHEMICAL TECHNOLOGIES INC.

Dates

Publication Date
20260505
Application Date
20200909

Claims (10)

  1. 1 . A compound of Formula (I): wherein, the R 1 groups are independently or simultaneously selected from the group consisting of hydrogen and deuterium; R 3 to R 4 are selected from the group consisting of hydrogen, deuterium, an optionally substituted C 1 -C 20 -alkyl group, an optionally substituted C 2 -C 20 -alkenyl group, an optionally substituted C 2 -C 20 -alkynyl group, an optionally substituted C 3 -C 20 -cycloalkyl group, an optionally substituted C 6 -C 14 -aryl group, an optionally substituted C 5 -C 14 -heteroaryl, and an optionally substituted acyl group, and one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of R 3 and R 4 is optionally replaced with a heteroatom selected from the group consisting of O, S, N, P and Si, which, where possible, is optionally substituted, wherein the optional substituents are one or more groups selected from the group consisting of OH, halo and C 1 -C 6 -alkyl; Y is selected from the group consisting of O and NR c , in which R c is selected from the group consisting of hydrogen atom, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 6 -C 10 -aryl and C 2 -C 6 -alkenyl group; R 2 is selected from the group consisting of a hydrogen atom, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 6 -C 10 -aryl, C 2 -C 6 -alkenyl group and OR c ; R 5 and R 6 are selected from the group consisting of hydrogen, deuterium, halide, an optionally substituted C 1 -C 20 -alkyl group, an optionally substituted C 2 -C 20 -alkenyl group, an optionally substituted C 2 -C 20 -alkynyl group, an optionally substituted C 3 -C 20 -cycloalkyl group, an optionally substituted C 6 -C 14 -aryl group, an optionally substituted C 5 -C 14 -heteroaryl, an optionally substituted acyl group, or an optionally substituted carboxylate group, and one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl or carboxylate groups of R 5 and/or R 6 is optionally replaced with a heteroatom selected from the group consisting of O, S, N, P and Si, which, where possible, is optionally substituted, wherein the optional substituents are one or more groups selected from the group consisting of OH, halo and C 1 -C 6 -alkyl; and X is selected from the group consisting of halide, sulfonate, carboxylate, carbonate and a group having the formula MW n , wherein M is selected from the group consisting of Li, Mg, Zn, Sn, B, and Si, W is selected from the group consisting of halide, OH, and OR, and R is selected from the group consisting of C 1 -C 10 -alkyl group and C 6 -C 10 -aryl group.
  2. 2 . The compound of Formula (I) according to claim 1 , wherein at least one of the carbon-12 atoms in the cyclohexene ring and its substituents, is replaced with a carbon-13 or carbon-14 atom.
  3. 3 . The compound of Formula (I) according to claim 1 , wherein X is bromide.
  4. 4 . The compound of Formula (I) according to claim 1 , wherein R 3 and R 4 are selected from the group consisting of hydrogen, deuterium, or an optionally substituted C 1 -C 3 -alkyl group.
  5. 5 . The compound of Formula (I) according to claim 1 , wherein R 5 and R 6 are selected from the group consisting of hydrogen, deuterium, or an optionally substituted C 1 -C 3 -alkyl group.
  6. 6 . The compound of Formula (I) according to claim 1 , wherein Y is O.
  7. 7 . A compound of Formula (IV):
  8. 8 . The compound according to claim 2 , wherein the deuterium and carbon-13 enrichment is no less than 1% at the specified position.
  9. 9 . The compound according to claim 2 , wherein the deuterium and carbon-13 enrichment is no less than 100% at the specified position.
  10. 10 . The compound according to claim 2 , wherein the carbon-14 enrichment is no less than one part per million at the specified position.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. national stage filing under 35 U.S.C. § 371 from International Application No. PCT/CA2020/051211, filed on Sep. 9, 2020, and published as WO2021/046640 on Mar. 18, 2021, which claims the benefit of priority to U.S. Provisional Application Nos. 62/898,221, filed Sep. 10, 2019, and 63/037,768, filed Jun. 11, 2020, the contents of which are incorporated herein by reference in their entirety. FIELD OF THE DISCLOSURE The present disclosure relates to new cannabinoid derivatives and precursors and catalytic asymmetric processes for their preparation. The disclosure also relates to pharmaceutical compositions and pharmaceutical and analytical uses of the new cannabinoid derivatives. BACKGROUND OF THE DISCLOSURE A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid receptors that alter neurotransmitter release in the brain. Cannabinoids include the endocannabinoids produced naturally in the body by animals; phytocannabinoids found in cannabis and perrottetinenes found in liverworts. The most notable cannabinoids are tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and Cannabidiol (CBD). There are more than 100 different cannabinoids isolated from cannabis, exhibiting varying effects. Cannabidiol (CBD) is the non-psychoactive and primary medicinal component of the cannabis plant. As such, CBD has significant medicinal benefits. It has been shown to counteract the psychoactive effect of tetrahydrocannabinol (THC), the other main component of cannabis. Hence, over the years a variety of CBD-rich strains of cannabis has been developed and used medicinally for treating inflammation, AIDS, ALS, Alzheimer's disease, anorexia, anxiety, arthritis, asthma, cancer, depression, diabetes, epilepsy, glaucoma, migraine, nausea, neuropathic pain, Parkinson's disease, just to name a few. In addition, there are numerous clinical trials being conducted worldwide for pharmaceutical applications of CBD, THC, Cannabidivarin (CBDV), Tetrahydrocannabidivarin (THV) and other cannabinoids for these and numerous other illnesses. Cannabinoids contain natural distribution of hydrogen isotopes. That is hydrogen accounts for 99.9844% and deuterium accounts for 0.0156%. Increased levels of deuterium incorporation may produce detectable deuterium kinetic isotope effects that could affect pharmacokinetic, pharmacological and therapeutic profiles in comparison with cannabinoids having naturally occurring levels of deuterium. SUMMARY OF THE DISCLOSURE The present disclosure, in some aspects, describes an approach to developing a method for the catalytic asymmetric synthesis of deuterated cannabinoids and their precursors. The processes focus on the use of commercially available chemicals and the use of these chemicals to prepare stable precursors that can be transformed into the desired deuterated cannabinoid products on demand. The approach can also be used to prepare cannabinoids containing other isotopes, such as carbon-13 and carbon-14. In various aspects, the disclosure relates to the preparation of new precursors, and the use of such precursor compounds for the preparation of isotope labelled cannabinoid products using chiral and achiral catalysts and catalytic processes. The deuterium, carbon-13 and carbon-14 containing compounds can be prepared and purified prior to transformation to the desired individual deuterated cannabinoid products. The precursors are air-stable and shelf-stable compounds that can be stored, transported and converted into the desired isotope labelled cannabinoid products on demand. In some embodiments, the deuterated cannabinoid compounds of the disclosure may expose a user to a maximum of about 0.000005% D2O or about 0.00001% DHO. These levels of deuterium are much lower than the minimum levels known to cause toxicity. Hence, the deuterium enriched compounds disclosed in the present disclosure should not cause any additional toxicity due to the formation of D2O and DHO upon drug metabolism. In the embodiments of the disclosure, the deuterated cannabinoid compounds of the present disclosure maintain the beneficial aspects of the corresponding non-deuterated compounds while substantially increasing the maximum dose, decreasing toxicity, increasing the half-life, lowering the plasma concentration of the minimum efficacious dose, lowering the dose, and lowering the probability of drug-drug interactions. In an embodiment of the disclosure, the deuterium, carbon-13 and carbon-14 enrichment is no less than about 1% at the specified position. In another embodiment, the deuterium, carbon-13 and carbon-14 enrichment is no less than about 5% at the specified position. In another embodiment, the deuterium, carbon-13 and carbon-14 enrichment is no less than about 10% at the specified position. In another embodiment, the deuterium, carbon-13 and carbon-14 enrichment is no less than about 20% at the specified