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US-12617747-B2 - Cannabinoid analogs and methods for their preparation

US12617747B2US 12617747 B2US12617747 B2US 12617747B2US-12617747-B2

Abstract

Provided herein are cannabinoid analogs, including halogenated cannabinoid analogs, hydroxylated cannabinoid analogs, deuterated cannabinoid analogs, and tritiated cannabinoid analogs. The cannabinoid analogs can be prepared by partial or total expression in modified host cells, such as recombinantly modified yeast cells, optionally in combination with chemical synthetic steps.

Inventors

  • Philip J. Barr
  • Charles K. Marlowe
  • Jianping Sun
  • James T. Kealey

Assignees

  • INMED PHARMACEUTICALS INC.

Dates

Publication Date
20260505
Application Date
20191031

Claims (16)

  1. 1 . A pharmaceutical composition comprising a compound according to Formula I: or a salt or cannabinoid derivative thereof, wherein: R 1 is selected from the group consisting of C 1 -C 20 haloalkyl, C 1 -C 20 hydroxyalkyl, C 2 -C 20 alkenyl, deuterated C 1 -C 20 alkyl, and tritiated C 1 -C 20 alkyl, R 2 is selected from the group consisting of COOR 2a and H, R 2a is selected from the group consisting of H and C 1 -C 6 alkyl, and R 3 is a prenyl moiety and the prenyl moiety is 3,7-dimethylocta-2,6-dien-1-yl; wherein the cannabinoid derivative is selected from the group consisting of: wherein R is H or CH 3 ; or wherein the cannabinoid derivative is and R 1 is C 1 -C 20 haloalkyl or C 2 -C 20 alkenyl; and a pharmaceutically acceptable excipient.
  2. 2 . The pharmaceutical composition of claim 1 , where in the compound or a salt or cannabinoid derivative thereof, R 1 C 2 -C 10 alkenyl.
  3. 3 . The pharmaceutical composition of claim 1 , where in the compound or a salt or cannabinoid derivative thereof, R 1 is C 1 -C 10 haloalkyl.
  4. 4 . The pharmaceutical composition of claim 3 where in the compound or a salt or cannabinoid derivative thereof, R 1 is selected from the group consisting of fluoropentyl, fluoroethyl, fluoropropyl, fluorobutyl, fluorohexyl, fluorooctyl, and fluorononyl.
  5. 5 . The pharmaceutical composition of claim 3 , where in the compound or a salt or cannabinoid derivative thereof, R 1 is selected from the group consisting of 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl, and 3-fluoropentyl.
  6. 6 . The pharmaceutical composition of claim 3 , where in the compound or a salt or cannabinoid derivative thereof, R 1 is C 1 -C 10 chloroalkyl.
  7. 7 . The pharmaceutical composition of claim 1 , where in the compound or a salt or cannabinoid derivative thereof, R 1 is C 1 -C 10 hydroxyalkyl when the cannabinoid derivative is not
  8. 8 . The pharmaceutical composition of claim 1 , where in the compound or a salt or cannabinoid derivative thereof, R 2 is selected from the group consisting of COOH and H.
  9. 9 . The pharmaceutical composition of claim 1 , wherein the compound according to Formula (I) is according to Formula Ia: or a salt or cannabinoid derivative thereof.
  10. 10 . The pharmaceutical composition of claim 1 , wherein the compound of Formula (I) is a cannabinoid derivative thereof, or a salt thereof.
  11. 11 . The pharmaceutical composition of claim 1 , wherein the cannabinoid derivative or salt thereof is selected from the group consisting of: or wherein the cannabinoid derivative is and R 1 is C 1 -C 20 haloalkyl or C 2 -C 20 alkenyl; and wherein R is H.
  12. 12 . The pharmaceutical composition of claim 1 , wherein the cannabinoid derivative or salt thereof is selected from the group consisting of: wherein R is H or CH 3 ; or wherein the cannabinoid derivative is and R 1 is C 1 -C 20 haloalkyl or C 2 -C 20 alkenyl.
  13. 13 . The pharmaceutical composition of claim 1 , the salt is a pharmaceutically acceptable salt thereof.
  14. 14 . The pharmaceutical composition of claim 3 , where in the compound or a salt or cannabinoid derivative thereof, R 1 is C 1 -C 10 bromoalkyl.
  15. 15 . The pharmaceutical composition of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: and the cannabinoid derivative is selected from the group consisting of
  16. 16 . A method for treating a disease or condition mediated by cannabinoid receptor activity, the method comprising administering an effective amount of the pharmaceutical composition of claim 1 , comprising a) a cannabinoid derivative, or a pharmaceutically acceptable salt thereof.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Pat. Appl. No. 62/753,708, filed on Oct. 31, 2018, and U.S. Provisional Pat. Appl. No. 62/767,447, filed on Nov. 14, 2018, which applications are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION Cannabis sativa varieties have been cultivated and utilized extensively throughout the world for a number of applications. Stems, branches, and leaves are used in fibers and fiber-based products; sprouts and seeds as food; seeds for inexpensive oils; flowers for aromatic, recreational, ritual and medicinal purposes; and flowers and roots for nutritional and additional medicinal and pharmaceutical applications. Indeed, many controlled clinical studies and anecdotal or open-label studies in humans have been documented that demonstrate beneficial effects of both plant extracts and purified C. sativa plant compounds in many human medical conditions. Beneficial activities of the cannabinoid family of compounds described from human studies range from neurological to mood/behavior disorders, and to gastrointestinal disorders as well as sleeping, appetite and fatigue problems. Other uses or potential uses include the treatment of various microbial and viral infections and the treatment of a number of cancers. BRIEF SUMMARY OF THE INVENTION Provided herein are compounds according to Formula I: and salts and cannabinoid derivatives thereof, wherein:R1 is selected from the group consisting of C1-C20 haloalkyl, C1-C20 hydroxyalkyl, deuterated C1-C20 alkyl, tritiated C1-C20 alkyl, and C2-C20 alkenyl,R2 is selected from the group consisting of COOR2a and H,R2a is selected from the group consisting of C1-C6 alkyl and H, andR3 is selected from the group consisting of H and a prenyl moiety. In some embodiments, the cannabinoid derivative is a cannabidiolic acid analog, a cannabidiol analog, a Δ9-tetrahydrocannabinolic acid analog, a Δ8-tetrahydrocannabinolic acid analog, a cannabichromenic acid analog, a cannabichromene analog, a cannabinol analog, a cannabinodiol analog, a cannabinolic acid analog, a cannabivarin analog, a cannabivarinic acid analog, a Δ9-tetrahydrocannabivarin analog, a Δ8-tetrahydrocannabivarin analog, a Δ9-tetrahydrocannabivarinic acid analog, a Δ8-tetrahydrocannabivarinic acid analog, a cannabigerovarin analog, a cannabigerovarinic acid analog, a cannabichromevarin analog, a cannabichromevarinic acid analog, a cannabidivarin analog, a cannabidivarinic acid analog, a cannabitriol analog, or a cannabicyclol analog. Also provided herein are methods of producing compounds according to Formula IV: or a salt thereof, wherein R1 is selected from the group consisting of C1-C20 haloalkyl, C1-C20 hydroxyalkyl, deuterated C1-C20 alkyl, tritiated C1-C20 alkyl, and C2-C20 alkenyl;the method comprising culturing a modified recombinant host cell in a medium comprising a thioester according to Formula II; wherein R4 is selected from the group consisting of a coenzyme A (CoA) moiety, a pantetheine moiety, and a cysteamine moiety,wherein the modified recombinant host cell comprises i. a first polynucleotide that encodes a synthase that converts the thioester according to Formula II and malonyl CoA to a tetraketide according to Formula III: andii. a second polynucleotide that encodes a 2-alkyl-4,6-dihydroxybenzoic acid cyclase that converts the tetraketide according to Formula III to the compound of Formula IV,and wherein the modified recombinant host cell is cultured under conditions in which products encoded by the first and second polynucleotides are expressed and the compound according to Formula IV is produced. Compounds of Formula IV can be converted to a number of neutral and acidic cannabinoid analogs via the methods described herein. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows one example of an enzymatic route for preparation of cannabinoid analogs according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION The present disclosure provides new cannabinoid compounds which are useful in a number of human therapeutic indications including neurological conditions, mood/behavior disorders, infections, and cancers. Also provided are methods for the production of pharmaceutical grade cannabinoids using sustainable, modern biopharmaceutical preparation methods. I. DEFINITIONS Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of ordinary skill in the art to which the present application pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. As used herein, the terms “cannabinoid,” “cannabinoid compound,” and “cannabinoid product” are us