Allyl-derivatives of cannabinoids

Abstract

The disclosure relates to derivatives as well as oduction-processes of allyl-derivatives of cannabinoids. Also disclosed are medical uses of said derivatives. (Formula I)

Description

[0001] Allyl-derivatives of cannabinoids

[0002] The disclosure relates to derivatives as well as production-processes of allyl-derivatives of cannabinoids. Also disclosed are medical uses of said derivatives. of the Disclosure

[0003] Cannabinoids are terpene phenols found in flowering Cannabinaceae plants of the genus Cannabis, namely in the species Cannabis sativa, Cannabis indica, and Cannabis ruderalis and are subdivided into 12 classes: cannabigerols (CBG), cannabichromenes (CBC), cannabidiols (CBD), cannabinodiols (CBND), tetrahydrocannabinols (THC), cannabinols (CBN), cannabitriols (CBT), cannabielsoins (CBE), isocannabinoids, cannabicyclols (CBL), cannabicitrans (CBT) and cannabichromanones (CBCN).

[0004] Cannabinoids have found wide applications, mainly in the medical field, as food additives and for cosmetic use. For example, cannabidiol has been proposed for the treatment of anxiety, addiction, psychosis, movement disorders, and pain (Kirkland et al., Psychiatry Research. 308: 114347; Black et al., The Lancet. Psychiatry. 6 (12): 995-1010; VanDolah et al., Mayo Clinic Proceedings. 94 (9): 1840-1851 ; Prud'homme et al., Substance Abuse. 9: 33-38). Distinct physiological effects are caused by binding of the cannabinoids to the cannabinoid receptors CB1 and CB2 of the endocannabinoid system.

[0005] Both CBD and A9-THC are used as pharmaceuticals for modulating appetite, pain, mood and memory (effected at the CB1 receptor) and for influencing the immune system (effected at the CB2 receptor). However, the psychoactive, intoxicating effect is not preferred when THC-deriva- tives are used in therapeutic settings. Accordingly, there is a need for novel THC-derivatives, which possess only mild or ideally no psychoactive and intoxicating effects, while providing and / or retaining one or more of the wanted beneficial effects facilitated by binding to the CB1- receptor and / or the CB2-receptor.

[0006] Currently known THC-derivatives display a mixed effect spectrum comprising both wanted and unwanted physiological effects. Accordingly, there is also a need for THC-derivatives which essentially display a single or main effect, also referred to as mono-therapeutic compounds.

[0007] The above-mentioned problems are solved by the subject-matter described here below.

[0008] September 9, 2024 1 / 61 Summary of the invention

[0009] A first aspect of this disclosure relates to a compound according to Formula I wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to a) R1is allyl and R2is H, b) R1is H and R2is allyl, c) R1is H and R2is 1-propenyl, 2-butenyl, 2-pentenyl, or 2,4-hexadienyl, d) R1is H and R2is 3-hydroxy-propyl, e) R1is H and R2is butyryl aldehyde, f) R1is H and R2is propionyl acid, g) R1is H and R2is 2-oxopropyl, and h) wherein R1and R2together form a ring structure selected from the group consisting of

[0010] September 9, 2024 2 / 61 i) R1is (C=O)OCH3and R2is allyl, wherein R3is selected from propyl, pentyl, heptyl,

[0011] This disclosure thus provides synthetic access to hitherto unknown C-allyl-A9-tetrahydrocanna- binol derivatives (C-allyl-A9-THC), C-allyl-A8-tetrahydrocannabinol derivatives (C-allyl-A8-THC), C-allyl-hexahydrocannabinol derivatives (C-allyl-HHC), as well as C-allyl-cannabinol derivatives (C-allyl-CBN). Disclosed are also the respective intermediate compounds, i.e. O-allyl-deriva- tives, which are used to achieve the final C-allyl derivatives by Claisen rearrangement.

[0012] The disclosed compounds are derivatives with reduced or absent psychoactive, intoxicating effects. The compound according to Formula I is stable and suitable for shipping and storage purposes for extended periods of time and in the absence of refrigeration conditions.

[0013] It shall be understood that the compound according to Formula I has two chiral C-atoms (at the

[0014] 6a and 10a positions), provided that the ring A is selected from ,

[0015] . If the ring A is aromatic, the indicated chiral centers will disappear, and there will be no H atoms at the 6a and 10a positions.

[0016] A second aspect of the disclosure relates to a process for the synthesis of the compounds i) to viii), the compounds i) to viii) being i) 1-(Allyloxy)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene (O-Allyl-CBN); ii) 2-Allyl-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol (C-Allyl-CBN); iii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,10, 10a-tetrahydro-6H- benzo[c]chromene (O-Allyl-A8-THC); iv) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,10, 10a-tetrahydro-6H-benzo[c]chromen- 1-ol (C-Allyl-A8-THC); v) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen-1-ol (O-Allyl-A9-THC); vi) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-

[0017] September 9, 2024 3 / 61 1-ol (C-Allyl-A9-THC); vii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,9, 10,10a-hexahydro-6H- benzo[c]chromene (O-Allyl-HHC); or viii) (6aR, 10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,9, 10, 10a-hexahydro-6H- benzo[c]chromen-1-ol (C-Allyl-HHC), the process comprising the steps of: a. Providing a starting compound selected from the group of A9-THC, A8-THC, HHC, and CBN, and dissolving the starting compound in a solvent; b. Reacting the starting compound with allyl-bromide to obtain an intermediate product; c. Extracting the intermediate product; d. Washing and drying the intermediate product; e. Optionally heating the intermediate product; f. Optionally obtaining a second product; and g. Optionally isolating the second product.

[0018] In a third aspect this disclosure relates to a pharmaceutical composition comprising the compounds according to this disclosure.

[0019] In a fourth aspect, this disclosure relates to compounds according to this disclosure for use in medicine, or the pharmaceutical composition according to this disclosure for use in medicine.

[0020] In a fifth aspect this disclosure relates to compounds according to this disclosure for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, Inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof.

[0021] In a related aspect this disclosure relates to the pharmaceutical composition according to this disclosure for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation,

[0022] September 9, 2024 4 / 61 Inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof.

[0023] In a sixth aspect this disclosure relates to a kit comprising the compounds according to this disclosure, or the pharmaceutical composition according to this disclosure, further comprising at least one object selected from the group consisting of an applicator, a package leaflet, a trans- dermal patch, a second active agent, and a treatment schedule, as well as combinations thereof.

[0024] In a further aspect this disclosure relates to a compound according to Formula XX

[0025] XX, wherein R1= methyl, ethyl, or propyl; wherein R2= methyl, ethyl, or propyl; wherein R3= propyl, pentyl, or heptyl.

[0026] This disclosure thus provides synthetic access to hitherto unknown O-allyl-cannabidiol deriva- fives.

[0027] In summary, this disclosure provides synthetic access to hitherto unknown cannabinoids, without the requirement of chromatographic steps for purification. Whereas in the art, providing chemically pure cannabinoids typically requires cumbersome and resource-intensive chromatographic purification.

[0028] September 9, 2024 5 / 61 Detailed description

[0029] Compounds

[0030] A first aspect of this disclosure relates to a compound according to Formula I wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to i): a) R1is allyl and R2is H, b) R1is H and R2is allyl, c) R1is H and R2is 1-propenyl, 2-butenyl, 2-pentenyl, or 2,4-hexadienyl, d) R1is H and R2is 3-hydroxy-propyl, e) R1is H and R2is butyryl aldehyde, f) R1is H and R2is propionyl acid, g) R1is H and R2is 2-oxopropyl, and h) wherein R1and R2together form a ring structure selected from the group consisting of

[0031] September 9, 2024 6 / 61 i) R1is (C=O)OCH3and R2is allyl, wherein R3is selected from propyl, pentyl, heptyl,

[0032] In one embodiment, this disclosure relates to a compound according to Formula I wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to b): a) R1is allyl and R2is H, b) R1is H and R2is allyl, wherein R3is selected from propyl, pentyl, heptyl,

[0033] In one embodiment, this disclosure relates to a compound according to Formula I

[0034] September 9, 2024 7 / 61

[0035] wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to i): a) R1is allyl and R2is H, b) R1is H and R2is allyl, c) R1is H and R2is 1-propenyl, 2-butenyl, 2-pentenyl, or 2,4-hexadienyl, d) R1is H and R2is 3-hydroxy-propyl, e) R1is H and R2is butyryl aldehyde, f) R1is H and R2is propionyl acid, g) R1is H and R2is 2-oxopropyl, and h) wherein R1and R2together form a ring structure selected from the group consisting of i) R1is (C=O)OCH3and R2is allyl, wherein R3is pentyl.

[0036] In one embodiment, a compound is provided being either

[0037] September 9, 2024 8 / 61 i) 1-(Allyloxy)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene (O-Allyl-CBN); ii) 2-Allyl-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol (C-Allyl-CBN); iii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7, 10,10a-tetrahydro-6H- benzo[c]chromene (O-Allyl-A8-THC); iv) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1- ol (C-Allyl-A8-THC); v) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8, 10a-tetrahydro-6H-benzo[c]chromen- 1-ol (O-Allyl-A9-THC); vi) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (C-Allyl-A9-THC); vii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10, 10a-hexahydro-6H- benzo[c]chromene (O-Allyl-HHC); or viii) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydro-6H- benzo[c]chromen-1-ol (C-Allyl-HHC). In one embodiment, this disclosure provides a compound according to any one of formula II to formula V:

[0038] September 9, 2024 9 / 61

[0039]

[0040] In one embodiment, the compound may be selected from the group consisting of the A8-THC- or A9-THC-derivatives of formula VI to XVI:

[0041] September 9, 2024 10 / 61 wherein R is selected from -H, -CH3, -CH2-CH3, or -CH=CH-CH3. x,

[0042] September 9, 2024 11 / 61

[0043]

[0044] September 9, 2024 12 / 61 XIV,

[0045] XVI.

[0046] In a further aspect this disclosure relates to a compound according to Formula XX

[0047] XX, wherein R1= methyl, ethyl, or propyl;

[0048] September 9, 2024 13 / 61 wherein R2= methyl, ethyl, or propyl; wherein R3= propyl, pentyl, or heptyl.

[0049] In one embodiment, this disclosure provides a compound according to formula XXI

[0050] XXI.

[0051] In one embodiment, the compounds according to this disclosure are characterized by one or more of the following features: a. having a reduced psychoactive effect as compared to A9-Tetrahydrocannabinol (A9- THC); b. having an elevated effect selected from the group consisting of pain relief, appetite stimulation, anti-inflammatory properties, muscle relaxation, anxiety reduction, and antiemetic effect reduction, as well as combinations thereof, as compared to A9-Tetrahydro- cannabinol (A9-THC); c. having an increased lipophilicity as compared to A9-Tetrahydrocannabinol (A9-THC).

[0052] Process

[0053] A second aspect of the disclosure relates to a process for the synthesis of the compounds i) to viii), the compounds i) to viii) being i) 1-(Allyloxy)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene (O-Allyl-CBN); ii) 2-Allyl-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol (C-Allyl-CBN); iii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene (O-Allyl-A8-THC);

[0054] September 9, 2024 14 / 61 iv) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen- 1-ol (C-Allyl-A8-THC); v) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen-1-ol (O-Allyl-A9-THC); vi) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen- 1-ol (C-Allyl-A9-THC); vii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydro-6H- benzo[c]chromene (O-Allyl-HHC); or viii) (6aR, 10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,9, 10, 10a-hexahydro-6H- benzo[c]chromen-1-ol (C-Allyl-HHC), the process comprising the steps of: a. Providing a starting compound selected from the group of A9-THC, A8-THC, HHC, and CBN, and dissolving the starting compound in a solvent; b. Reacting the starting compound with allyl-bromide to obtain an intermediate product; c. Extracting the intermediate product; d. Washing and drying the intermediate product; e. Optionally heating the intermediate product; f. Optionally obtaining a second product; and g. Optionally isolating the second product.

[0055] In one embodiment, the process comprises the steps of: a. Providing a starting compound selected from the group of A9-THC, A8-THC, HHC, and CBN, and dissolving the starting compound in a solvent to obtain a solution; b. Reacting the solution with allyl-bromide to obtain an intermediate product; c. Extracting the intermediate product to obtain one or more extract portions, and combining the one or more extract portions to obtain a combined extract; d. Washing and drying the combined extract, to obtain a washed and dried intermediate

[0056] September 9, 2024 15 / 61 product; e. Optionally heating the washed and dried intermediate product; f. Optionally obtaining a second product; and g. Optionally isolating the second product.

[0057] Step b. realizes the manufacture of, respectively, the O-allyl-A9-THC-, the O-allyl-A8-THC-, the O-allyl-HHC, or the O-allyl-CBN derivative according to this disclosure, depending on the chosen starting compound selected from the group of A9-THC, A8-THC, HHC, and CBN in step a.

[0058] Step f. realizes the manufacture of, respectively, the C-allyl-A9-THC-, the C-allyl- A8-THC-, the C-allyl-HHC, or the C-allyl-CBN derivative according to this disclosure, depending on the chosen starting compound selected from the group of A9-THC, A8-THC, HHC, and CBN in step a.

[0059] In one embodiment, providing a starting compound comprises providing the starting compound in pure form, e.g., crystalline form, or in an amorphous form. In one embodiment, dissolving the starting compound in a solvent comprises choosing an appropriate polar, aprotic solvent which facilitates the subsequent reactions. In one embodiment, the solvent is chosen from the group of polar (hydrophilic) aprotic solvents, such as, e.g., DMF (dimethylformamide), DMSO (dimethyl sulfoxide), acetone, acetonitrile, dichloromethane, ethyl acetate, pyridine, sulfolane, and tetrahydrofuran (THF).

[0060] If this disclosure refers to a step of "reacting" the starting compound or any other compound, as well as heating the intermediate product, with a chemical agent and / or under the influence of thermal energy, optionally in a suitable solvent, it shall be understood that each step or sequence of steps is carried out for a time sufficient to effect (i.e. allow) the underlying reaction (to take place) of at least a portion of the starting compound(s) into the target (or intermediate) compound. Preferably, the time is sufficient to allow the underlying reaction to take place and to reach chemical equilibrium between the starting compound(s) and the target (or intermediate) compounds at the respectively chosen reaction or treatment conditions. Analogously, the skilled person understands and knows how to carry out the addition of chemical (re)agents under e.g. stirring and / or maintaining a preferred temperature to optimize and / or maximize the yields of the target compounds. Furthermore, the skilled person understands and knows how to carry out the work-up of reaction batches, e.g. adding water and / or combining with an aqueous HCI solution for neutralization purposes, extraction using organic solvents, washing steps with e.g. aqueous HCI solution or with saturated NaCI solution, drying over Na2SC>4, filtration and concentration, to optimize and / or maximize the yields of the target compounds.

[0061] September 9, 2024 16 / 61 In one embodiment, reacting the starting compound with allyl-bromide to obtain an intermediate product comprises adding allyl-bromide to the dissolved starting compound, subsequently adding a chemical base under vigorous stirring of the solution of the starting compound and the allyl-bromide in the solvent. In one embodiment, the reaction step b. is performed at a temperature range of 10 to 40 °C, preferably 15 to 35 °C, more preferably 20 to 30 °C, for 2 to 40 hours, preferably 5 to 30 hours, more preferably 10 to 20 hours.

[0062] In one embodiment, the chemical base is chosen from potassium carbonate or sodium carbonate. In one embodiment the chemical base used is potassium tert-butoxide. Potassium tert- butoxide was found to be superior over potassium carbonate and afforded nearly complete conversion of the starting compound into the intermediate product.

[0063] In one embodiment, extracting the intermediate product comprises adding water to the reaction mixture and stirring the reaction mixture for 30 to 120 minutes at a temperature range of 10 to 40 °C, preferably 15 to 35 °C, more preferably 20 to 30 °C, and subsequently extracting the reaction mixture with an extraction solvent. Preferably, the reaction mixture is extracted with extraction solvent two to six times, preferably four times, to obtain extract portions. In one embodiment, the extraction solvent is chosen from dichloromethane, diethyl ether, or tetrahydrofuran (THF).

[0064] In one embodiment, washing and drying the intermediate product comprises combining the extract portions, washing with saturated NaHCCh solution and brine, drying over Na2SC>4, subsequent filtration of the extract portions, and concentration of the combined extract portions. In one embodiment, concentration of the combined extract portions comprises removal of the extraction solvent from the extract portions to obtain the intermediate product in pure, e.g., crystalline, form, or as an oil.

[0065] In one embodiment the step of heating the intermediate product, i.e. , heating step e. may be performed under an inert gas atmosphere, chosen from, e.g., nitrogen (N2) or argon. The step of heating the intermediate product may be performed in the absence of a solvent.

[0066] In one embodiment the heating step e. is carried out at temperatures from 150 to 200 °C, or from 160 to 190 °C, or from 175 to 180 °C. In one embodiment the heating step e. is carried out for 4 to 10 h, or for 5 to 9 h, or for 5 to 8 h. In one embodiment the heating step e. is carried out under a N2 atmosphere at 160 to 190 °C for 5 to 8 h. In one embodiment the heating step e. is carried out in the presence of a Lewis acid catalyst, such as, e.g., boron trifluoride (BF3), titanium tetrachloride (TiCI4), or aluminum chloride (AICI3). In one embodiment the heating step e. is carried out to enable and / or facilitate a Claisen rearrangement.

[0067] September 9, 2024 17 / 61 The Claisen rearrangement is an organic reaction named after the German chemist Rainer Ludwig Claisen. It involves the conversion of allyl vinyl ethers into y,b-unsaturated carbonyl compounds through a sigmatropic rearrangement. This rearrangement is typically initiated by heating the allyl vinyl ether in the presence of a Lewis acid catalyst.

[0068] In one embodiment the heating step e. is carried out to perform a Claisen-lreland rearrangement of the intermediate compound to obtain structures wherein R1and R2together form a ring structure selected from the group consisting of

[0069] Step f. affords the compounds C-allyl-A9-THC-, C-allyl- A8-THC-, C-allyl-HHC, and C-allyl-CBN according to this disclosure, all of which have a hydroxyl group at the position 1 according to III- PAC nomenclature. Said phenolic hydroxyl group lends itself for further derivatization and may be reacted and thus functionalized to obtain a formate or a carbonate derivative.

[0070] A related aspect of the disclosure relates to a process for the synthesis of the compounds XX, the process comprising the steps of: a. Providing a starting compound XX’, and dissolving the starting compound XX’ in a solvent;

[0071] XX’, wherein R1= methyl, ethyl, or propyl, wherein R2= methyl, ethyl, or propyl, and wherein R3= propyl, pentyl, or heptyl

[0072] September 9, 2024 18 / 61 b. Reacting the starting compound XX’ with allyl-bromide to obtain an intermediate product; c. Extracting the intermediate product; d. Washing and drying the intermediate product; e. Optionally heating the intermediate product; f. Optionally obtaining a second product; and g. Optionally isolating the second product.

[0073] In one embodiment, the process for the synthesis of the compounds XX comprises the steps of: a. Providing a starting compound XX’, and dissolving the starting compound XX’ in a solvent to obtain a solution; b. Reacting the solution with allyl-bromide to obtain an intermediate product; c. Extracting the intermediate product to obtain one or more extract portions, and combining the one or more extract portions to obtain a combined extract; d. Washing and drying the combined extract, to obtain a washed and dried intermediate product; e. Optionally heating the washed and dried intermediate product; f. Optionally obtaining a second product; and g. Optionally isolating the second product.

[0074] Step b. realizes the manufacture of compounds XX.

[0075] Step d. affords compounds XX in pure form.

[0076] Step f. realizes the manufacture of the C-allyl derivates of compounds XX, optionally after a Claisen rearrangement.

[0077] Pharmaceutical composition

[0078] The compounds of the present disclosure may be formulated as a pharmaceutical composition for the administration selected from the group consisting of oral administration, sublingual administration, buccal administration, rectal administration, intravenous (IV) administration,

[0079] September 9, 2024 19 / 61 intramuscular (IM) administration, subcutaneous (SC) administration, inhalative administration, transdermal administration, topical administration, intranasal administration and intraocular administration, as well as combinations thereof.

[0080] In one aspect, this disclosure provides a pharmaceutical composition comprising a compound according to this disclosure.

[0081] In one aspect, the pharmaceutical composition further comprises at least one excipient selected from the group consisting of fillers such as lactose, microcrystalline cellulose, dicalcium phosphate, mannitol, starches, e.g., corn starch; optionally a binder, e.g., starch paste, povidone (polyvinylpyrrolidone), hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose sodium; optionally a disintegrant, e.g., croscarmellose sodium, crospovidone, sodium starch glycolate, crosslinked polyvinylpyrrolidone (PVP), microcrystalline cellulose; optionally a glidant, e.g., magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate, stearic acid; optionally a coating, e.g., hydroxypropyl methylcellulose (HPMC), ethyl cellulose, shellac, polyvinyl alcohol (PVA), gelatin; optionally a preservative, e.g., benzalkonium chloride, methylparaben, propylparaben, sorbic acid, benzyl alcohol; optionally a colorant, e.g., iron oxides, titanium dioxide, indigo carmine, sunset yellow, al- lura red; optionally a flavoring, e.g., aspartame, sucrose, sorbitol, sodium saccharin, peppermint oil; optionally a solubilizer, e.g., polysorbate 80, propylene glycol, ethanol, cyclodextrins, polyethylene glycol (PEG); optionally a buffer system, e.g., citric acid and sodium citrate, hydrogen phosphate and dihydrogen phosphate, acetic acid and sodium acetate.

[0082] In one embodiment, the pharmaceutical composition comprises at least one excipient selected from the group consisting of fillers, such as lactose, microcrystalline cellulose, dicalcium phosphate, mannitol, starches, e.g., corn starch.

[0083] September 9, 2024 20 / 61 In one embodiment, the pharmaceutical composition comprises a binder, e.g., starch paste, povidone (polyvinylpyrrolidone), hydroxypropyl cellulose, methylcellulose, and carboxymethyl cellulose sodium.

[0084] In one embodiment, the pharmaceutical composition comprises a disintegrant, e.g., croscarmel- lose sodium, crospovidone, sodium starch glycolate, crosslinked polyvinylpyrrolidone (PVP), and microcrystalline cellulose.

[0085] In one embodiment, the pharmaceutical composition comprises a glidant, e.g., magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate, and stearic acid.

[0086] In one embodiment, the pharmaceutical composition comprises a coating, e.g., hydroxypropyl methylcellulose (HPMC), ethyl cellulose, shellac, polyvinyl alcohol (PVA), and gelatin.

[0087] In one embodiment, the pharmaceutical composition comprises a preservative, e.g., benzalkonium chloride, methyl paraben, propylparaben, sorbic acid, and benzyl alcohol.

[0088] In one embodiment, the pharmaceutical composition comprises a colorant, e.g., iron oxides, i.e. Fe2C>3, FeO and Fe3C>4, titanium dioxide, indigo carmine, sunset yellow, and allura red.

[0089] In one embodiment, the pharmaceutical composition comprises a flavoring, e.g., aspartame, sucrose, sorbitol, sodium saccharin, and peppermint oil.

[0090] In one embodiment, the pharmaceutical composition comprises a solubilizer, e.g., polysorbate 80, propylene glycol, ethanol, cyclodextrins, and polyethylene glycol (PEG).

[0091] In one embodiment, the pharmaceutical composition comprises a buffer system, e.g., citric acid and sodium citrate, hydrogen phosphate and dihydrogen phosphate, and acetic acid and sodium acetate.

[0092] Definitions

[0093] Pain Management: The compounds of the present disclosure have analgesic properties and can be effective in managing various types of pain, including neuropathic pain, cancer-related pain, and chronic pain conditions.

[0094] Nausea and Vomiting: The compounds of the present disclosure have antiemetic effects, making it useful in managing nausea and vomiting associated with chemotherapy, radiation therapy, and certain medical conditions, such as AIDS.

[0095] Appetite Stimulation: The compounds of the present disclosure can stimulate appetite, making it

[0096] September 9, 2024 21 / 61 beneficial for patients suffering from appetite loss and weight loss associated with conditions, such as HIV / AIDS or cancer, as well as for individuals undergoing chemotherapy.

[0097] Muscle Spasticity: The compounds of the present disclosure may help reduce muscle spasms and spasticity, making it potentially useful for conditions such as multiple sclerosis (MS) and spinal cord injuries.

[0098] Glaucoma: The compounds of the present disclosure have been investigated for its potential to lower intraocular pressure, which is beneficial for individuals with glaucoma, although its effects may be temporary and require frequent dosing.

[0099] Inflammatory Bowel Disease (IBD): The compounds of the present disclosure may have antiinflammatory effects that could be beneficial in managing symptoms of inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis.

[0100] Sleep Disorders: The compounds of the present disclosure may have sedative effects and could be useful in managing certain sleep disorders like insomnia, although long-term use may disrupt sleep patterns.

[0101] Neurological Disorders: The compounds of the present disclosure may have neuroprotective properties and could be beneficial in the treatment of neurological conditions, such as Parkinson's disease, Alzheimer's disease, and epilepsy.

[0102] Anxiety and post-traumatic stress disorder (PTSD): The compounds of the present disclosure may have anxiolytic effects and could potentially be helpful in managing anxiety disorders and PTSD.

[0103] Medical use

[0104] In one aspect, this disclosure provides a compound according to this disclosure for use in medicine.

[0105] In one aspect, this disclosure provides a pharmaceutical composition comprising a compound according to this disclosure for use in medicine.

[0106] In one embodiment, this disclosure relates to a compound according to this disclosure for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, Inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and

[0107] September 9, 2024 22 / 61 TR0011 P-WG nausea and / or vomiting, and combinations thereof.

[0108] In one embodiment, this disclosure relates to a pharmaceutical composition comprising a compound according to this disclosure for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, Inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof.

[0109] In one embodiment, this disclosure relates to a compound according to this disclosure for use in the treatment of nausea and vomiting associated with chemotherapy and for appetite stimulation in AIDS patients experiencing weight loss.

[0110] In one embodiment, this disclosure relates to a compound according to this disclosure for use in the treatment of nausea and vomiting associated with chemotherapy in a patient group which has not responded to conventional antiemetic therapies.

[0111] In one embodiment, this disclosure relates to a compound according to this disclosure for use in the treatment of spasticity due to multiple sclerosis (MS), wherein the compound is formulated as an oromucosal spray.

[0112] In one embodiment, this disclosure relates to a compound according to this disclosure for use in the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. Lennox-Gastaut syndrome and Dravet syndrome are two rare forms of epilepsy.

[0113] In one embodiment, this disclosure relates to a compound according to this disclosure for use in the treatment of spasticity and neuropathic pain, optionally including pain management, wherein the compound is formulated as buccal spray.

[0114] In one embodiment, this disclosure relates to a compound according to this disclosure for use in therapy related to pain management, wherein the compound is formulated into and / or provided in the form of transdermal patches. Transdermal patches may be designed in such a way to provide for controlled release of the compound for the purpose of pain management and other therapeutic purposes.

[0115] In one embodiment, this disclosure relates to a compound according to Formula I for use in medicine

[0116] September 9, 2024 23 / 61

[0117] wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to i): a) R1is allyl and R2is H, b) R1is H and R2is allyl, c) R1is H and R2is 1-propenyl, 2-butenyl, 2-pentenyl, or 2,4-hexadienyl, d) R1is H and R2is 3-hydroxy-propyl, e) R1is H and R2is butyryl aldehyde, f) R1is H and R2is propionyl acid, g) R1is H and R2is 2-oxopropyl, and h) wherein R1and R2together form a ring structure selected from the group consisting of i) R1is (C=O)OCH3and R2is allyl,

[0118] September 9, 2024 24 / 61 wherein R3is selected from propyl, pentyl, heptyl,

[0119] In one embodiment, this disclosure relates to a compound according to Formula I for use in medicine wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to b): a) R1is allyl and R2is H, b) R1is H and R2is allyl, wherein R3is selected from propyl, pentyl, heptyl,

[0120] In one embodiment, this disclosure relates to a compound according to Formula I for use in medicine

[0121] September 9, 2024 25 / 61

[0122] wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to i): a) R1is allyl and R2is H, b) R1is H and R2is allyl, c) R1is H and R2is 1-propenyl, 2-butenyl, 2-pentenyl, or 2,4-hexadienyl, d) R1is H and R2is 3-hydroxy-propyl, e) R1is H and R2is butyryl aldehyde, f) R1is H and R2is propionyl acid, g) R1is H and R2is 2-oxopropyl, and h) wherein R1and R2together form a ring structure selected from the group consisting of i) R1is (C=O)OCH3and R2is allyl, wherein R3is pentyl.

[0123] In one embodiment, this disclosure provides a compound for use in medicine, wherein the

[0124] September 9, 2024 26 / 61 compound is either i) 1-(Allyloxy)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene (O-Allyl-CBN); ii) 2-Allyl-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol (C-Allyl-CBN); iii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene (O-Allyl-A8-THC); iv) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1- ol (C-Allyl-A8-THC); v) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen- 1-ol (O-Allyl-A9-THC); vi) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (C-Allyl-A9-THC); vii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydro-6H- benzo[c]chromene (O-Allyl-HHC); or viii) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydro-6H- benzo[c]chromen-1-ol (C-Allyl-HHC).

[0125] In one embodiment, this disclosure provides a compound according to any one of formula II to formula V for use in medicine:

[0126] September 9, 2024 27 / 61

[0127]

[0128] V.

[0129] In one embodiment, this disclosure provides a compound for use in medicine, wherein the compound is selected from the group consisting of the A8-THC- or A9-THC-derivatives of formula VI to XVI:

[0130] September 9, 2024 28 / 61 wherein R is selected from -H, -CH3, -CH2-CH3, or -CH=CH-CH3.

[0131] September 9, 2024 29 / 61

[0132]

[0133] September 9, 2024 30 / 61 XIII,

[0134] XVI.

[0135] In one embodiment, this disclosure relates to a compound according to Formula I for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof,

[0136] September 9, 2024 31 / 61

[0137] wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to i): a) R1is allyl and R2is H, b) R1is H and R2is allyl, c) R1is H and R2is 1-propenyl, 2-butenyl, 2-pentenyl, or 2,4-hexadienyl, d) R1is H and R2is 3-hydroxy-propyl, e) R1is H and R2is butyryl aldehyde, f) R1is H and R2is propionyl acid, g) R1is H and R2is 2-oxopropyl, and h) wherein R1and R2together form a ring structure selected from the group consisting of i) R1is (C=O)OCH3and R2is allyl,

[0138] September 9, 2024 32 / 61 wherein R3is selected from propyl, pentyl, heptyl,

[0139] In one embodiment, this disclosure relates to a compound according to Formula I for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disor- ders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof, wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to b): a) R1is allyl and R2is H, b) R1is H and R2is allyl, wherein R3is selected from propyl, pentyl, heptyl,

[0140] In one embodiment, this disclosure relates to a compound according to Formula I for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological

[0141] September 9, 2024 33 / 61 disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof, wherein ring A is selected from wherein R1and R2are chosen in combination according to any one of the following options a) to i): a) R1is allyl and R2is H, b) R1is H and R2is allyl, c) R1is H and R2is 1-propenyl, 2-butenyl, 2-pentenyl, or 2,4-hexadienyl, d) R1is H and R2is 3-hydroxy-propyl, e) R1is H and R2is butyryl aldehyde, f) R1is H and R2is propionyl acid, g) R1is H and R2is 2-oxopropyl, and h) wherein R1and R2together form a ring structure selected from the group consisting of

[0142] September 9, 2024 34 / 61 i) R1is (C=O)OCH3and R2is allyl, wherein R3is pentyl.

[0143] In one embodiment, this disclosure relates to a compound for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof, wherein the compound provided is either i) 1-(Allyloxy)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene (O-Allyl-CBN); ii) 2-Allyl-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol (C-Allyl-CBN); iii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7, 10,10a-tetrahydro-6H- benzo[c]chromene (O-Allyl-A8-THC); iv) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1- ol (C-Allyl-A8-THC); v) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8, 10a-tetrahydro-6H-benzo[c]chromen- 1-ol (O-Allyl-A9-THC); vi) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (C-Allyl-A9-THC); vii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10, 10a-hexahydro-6H- benzo[c]chromene (O-Allyl-HHC); or viii) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydro-6H- benzo[c]chromen-1-ol (C-Allyl-HHC).

[0144] In one embodiment, this disclosure relates to a compound according to any one of formula II to formula V for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof:

[0145] September 9, 2024 35 / 61

[0146]

[0147] In one embodiment, this disclosure relates to a compound selected from the group consisting of

[0148] 10 the A8-THC- or A9-THC-derivatives of formula VI to XVI for use in the treatment of a condition

[0149] September 9, 2024 36 / 61 selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof: wherein R is selected from -H, -CH3, -CH2-CH3, or -CH=CH-CH3.

[0150] IX,

[0151] September 9, 2024 37 / 61

[0152]

[0153] September 9, 2024 38 / 61 XIII,

[0154] XVI.

[0155] In one embodiment, this disclosure relates to a compound according to Formula XX for use in medicine

[0156] September 9, 2024 39 / 61

[0157] wherein R1= methyl, ethyl, or propyl; wherein R2= methyl, ethyl, or propyl; wherein R3= propyl, pentyl, or heptyl.

[0158] In one embodiment, this disclosure relates to a compound according to Formula XXI for use in medicine

[0159] XXI. Kit

[0160] In one aspect, this disclosure relates to a kit comprising the compound according to this disclosure, or the pharmaceutical composition according to this disclosure, further comprising at least one object selected from the group consisting of an applicator, a package leaflet, a transdermal patch, a second active agent, and a treatment schedule, as well as combinations thereof.

[0161] September 9, 2024 40 / 61 Abbreviations

[0162] Abbreviation Trivial name;

[0163] IIIPAC name

[0164] CBD Cannabidiol

[0165] 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3- diol

[0166] CBDA Cannabidiolic acid

[0167] 2, 4-dihydroxy-3-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6- pentylbenzoic acid

[0168] CBN Cannabinol;

[0169] 6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene

[0170] A8-THC A8-Tetrahydrocannabinol;

[0171] (6aR, 10aR)-6,6,9-trimethyl-3-pentyl-6a,7, 10,10a-tetrahydro-6H- benzo[c]chromene

[0172] A9-THC A9-Tetrahydrocannabinol;

[0173] (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen

[0174] HHC Hexahydrocannabinol;

[0175] (6aR, 10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,9, 10, 10a-hexahydro-6H- benzo[c]chromene

[0176] Examples

[0177] Synthesis and compound characterization

[0178] All reactions were performed under an atmosphere of nitrogen using solvents dried by standard procedures. Reaction progress was monitored by TLC on Polygram SIL G / UV254 silica gel plates from Macherey & Nagel and on Silicagel plates 60 RP-18 F254 from Supelco. Detection of spots was effected by charring with sulfuric acid (5% in ethanol), staining by spraying the

[0179] September 9, 2024 41 / 61 plates with an alkaline aqueous solution of potassium permanganate, staining plates in a iodine chamber or by inspection of the TLC plates under UV light (254 nm).

[0180] Preparative chromatography was performed on silica gel (0.032-0.063 mm) from Macherey & Nagel.

[0181] NMR spectra were recorded with the following spectrometers: Bruker Avance III HD 400 (1 H: 400.2 MHz; 13C: 100.6 MHz), Bruker Avance III HDX 600 (1 H: 600.2 MHz; 13C: 150.9 MHz) and Bruker Avance III HDX 700 (1 H: 700.3 MHz; 13C: 176.1 MHz); and calibrated for the solvent signal (1H: CDCfe: 6 = 7.26 ppm; acetone-cfe: 5 = 2.05 ppm; dichlormethane-cfe: 5 = 5.32 ppm; DMSO-cfe: 5 = 2.50 ppm;13C: CDCh: 6 =77.16 ppm; acetone-cfe: 5 = 29.92 ppm; dichlor- methane-cfe: 5 = 54.0 ppm; DMSO-cfe: 5 = 39.51 ppm).

[0182] ESI-TOF-HRM spectrometry was performed on a Bruker MAXIS 4G spectrometer.

[0183] Elemental analyses were obtained from a HEKAtech Euro EA 3000 apparatus.

[0184] Optical rotations were determined with a Perkin-Elmer Polarimeter 341 in a 10 cm cuvette at 20 °C with a wavelength of 589 nm (Na-lamp).

[0185] Melting points were measured with a Buchi Melting Point M-560 apparatus.

[0186] Example 1. Preparation of CBN-derivatives

[0187] 1-(Allyloxy)-6,6,9-trirnethyl-3-pentyl-6H-benzofc1chromene (O-Allyl-CBN)

[0188] Cannabinol (CBN) (0.7 g, 2.2 mmol) and allyl bromide (0.93 g, 3.8 mmol) were dissolved in DMF (10 ml). At room temperature K2CO3 (1.13 g, 8.2 mmol) was added in one portion under vigorous stirring and stirring at room temperature was continued until TLC (petrol ether / ethyl acetate 10 / 1) showed complete conversion of THC to a faster moving product (16 h). Water (0.5 ml, 27 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was poured into water (80 ml) and extracted with dichloromethane. The combined organic layers were successively washed with saturated NaHCCfe solution and brine and dried

[0189] September 9, 2024 42 / 61 over Na2SO4. Filtration and concentration of the solution afforded O-allyl-CBN (0.71 g, 92%) as a slightly yellow oil.

[0190] HRMS m / z for [M+CH3]+calculated: 351.23186; found: 351.23197.

[0191] 1H-NMR (CDCI3) significant peaks 8=8.24 (br.s, 1 H, H-10), 7.17-6.96 (m, 2H, H-7,8), 6.40 (br.s, 1 H, H-2), 6.36 (br.s, 1 H, H-4), 6.11-6.04 (m, 1 H, HC=), 5.46-5.42 (m, 1 H, =CH2a), 5.26-5.23 (m, 1 H, =CH2b), 4.56 (dd, 2H, OCH2), 2.47 (t, 2H, H-1 ’), 2.28 (s, 3H, CH3), 1.51 (s, 6H, 2 x CH3), 1.26-1.21 (m, 6H, H-2’, 3’4’), 0.81 (t, 3H, H-5’).

[0192] 13C-NMR (CDCI3) significant peaks 8=156.3 (C-1), 154,5 (C-4a), 144.4 (C-10a), 136.9 (C-3),

[0193] 136.5 (C-9), 133.4 (HC=), 127.7 (C-8), 127.5 (C-10b), 127.4 (C-7), 122.3 (C-10), 117.3 (=CH2), 111.2 (C-4), 110.3 (C-6a), 105.6 C-2), 77.4 (C-6), 69.6 (OCH2), 36.1 (C-T), 31.6, 30.7 (C-2’, 3’), 27.1 (2 X CH3), 22.6 (C-4’), 21.5 (CH3), 14.1 (C-5’).

[0194] 2-Allyl-6,6,9-trimethyl-3-pentyl-6H-benzofc1chromen-1-ol (C-Allyl-CBN)

[0195] O-allyl-CBN (0.35 g, 1.0 mmol) was heated under N2to 185°C for 9 h to afford C-allyl-CBN (0.34 g, 97%) as a yellowish oil.

[0196] HRMS m / z for [M-H]’ calculated: 349.21730; found: 349.21810

[0197] 1H-NMR (CDCI3): 8=8.03 (s, 1 H, OH), 7.17-6.93 (m, 3H, H-7,8, 10), 6.41-6.27 (m, 1 H, =CH2a), 6.24 (s, 1 H, H-4), 6.12-6.08 (m, 1 H, HC=), 5.02-4.94 (m, 1 H, =CH2b), 3.14 (q, 1 H, =C-CH2a), 2.63 (q, 1 H, =C-CH2b), 2.39 (t, 2H, H-1’), 2.30 (s, 3H, CH3), 1.56-1.47 (m, 2H, H-2’), 1.52, 1.51 (2 s, 6H, 2XCH3), 1.31-1.20 (m, 4H, H-3’,4’), 0.82 (t, 3H, H-5’).

[0198] 13C-NMR (CDCI3): 8=156.4 (C-1), 153.2 (C-4a), 139.3 (C-10a), 136.8 (C-3), 130.1 (C-6a), 127.5 (4C, C-2, 8, 9, HC=), 126.1 (C-10), 122.4 (C-7), 118.9 (C-10b), 109.3 (H2C=), 105.2 (C-4), 80.5 (C-6), 25.3 (C-4’), 33.5 (C-3’), 31.7 (C-2’), 29.3 (CH^1), 27.5 (2C, CH3), 22.6 (C-T), 22.3 (CH3), 14.1 (C-5’).

[0199] September 9, 2024 43 / 61 Example 2. Preparation of A8-THC-derivatives

[0200] Method A: (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H- benzoldchromene (O-Allyl-A8-THC)

[0201] C2iH30O2(314,47) C24H34O2 (354,53)

[0202] A8-Tetrahydrocannabinol (18.3 g, 58.2 mmol) and allyl bromide (16.94 g, 70 mmol) were dissolved in DMF (100 ml). At room temperature K2CO3 (20.7 g, 150 mmol) was added in two portions under vigorous stirring and stirring at room temperature was continued until TLC (petrol ether / ethyl acetate 10 / 1) showed complete conversion of THC to a faster moving product (16 h). The suspension was filtered through a glass filter and the filtrate was concentrated under vacuum at the rotary evaporator (bath temperature 60°C). The concentrated solution was poured into water (200 ml) and extracted with ethyl acetate. The combined organic layers were successively washed with saturated NaHCCh solution and brine and dried over Na2SO4. Filtration and concentration of the solution afforded O-allyl-A8-THC (18.2 g, 88%) as a colorless oil.

[0203] [a]D20= -560.7 (c 1.1 , CHCh).

[0204] HRMS m / z for [M+H]+calculated: 355.26371 ; found: 355.26321.

[0205] 1H-NMR (CDCI3) 8=6.24 (d, 1 H, H-4), 6.17 (d, 1 H, H-2), 6.04-5.96 (m, 1 H HC=), 5.36-5.31 (m, 2H, H-8, =CH2a), 5,21-5.18 (m, 1 H, =CH2b), 4.45 (dd, 2H, OCH2), 3.17 (dd, 1 H, H-10a), 2.66-

[0206] 2.60 (m, 1 H, H-6a), 2.42 (t, 2H, H-T), 2.08-2.04 (m, 1 H, H-7a), 1.75-1.68 (m, 3H, H-7b, H-2’),

[0207] 1.61 (s, 3H, CH3-9), 1.30 (s, 3H, CH3-6), 1.30-1.20 (m, 4H, H-3’,4’), 1.02 (s, 3H, CH3-6), 0.82 (t, 3H, H-5’).

[0208] 13C-NMR (CDCI3) 8=157.9 (C-1), 154.4 (C-4a), 142.5 (C-3), 135.1 (C-9), 133.7 (=CH), 119.2 (C- 8), 118.9 (=CH2), 112.2 (C-10b), 110.4 (C-2), 104.3 (C-4), 68.9 (OCH2), 45.2 (C-6a), 36.4 (C- T), 36.0 (C-10), 31.8 (C-3’), 31.7 (C-4’), 30.8 (C-2’), 28.4 (C-10a), 27.8 (C-4’), 23.6 (CH3), 22.5 (CH3), 19.4 (CH3), 14.1 (C-5’).

[0209] Method B: (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-

[0210] September 9, 2024 44 / 61

[0211]

[0212] C2I H30O2(314,47) C24H34O2 (354,53)

[0213] A8-Tetrahydrocannabinol (2.01 g, 6.4 mmol) and potassium t-butanoate (0.9 g, 8.0 mmol) in DMF (8 ml) were stirred under nitrogen at room temperature for 15 minutes. Allyl bromide (1.1 g, 9.0 mmol) was dropped in with cooling so that the temperature did not exceed 40°C. The mixture was stirred at room temperature until TLC (petrol ether / ethyl acetate 10 / 1) showed complete conversion of THC to a faster moving product (2 h). The mixture was poured into water (100 ml) and extracted with dichloromethane. The combined organic phases were washed with saturated aqueous NaHCCh solution and brine and dried over Na2SO4. Filtration, concentration and storage under vacuum (10-2torr) overnight afforded O-allyl-A8-THC (2.2 g, 99%) as a colorless oil.

[0214] (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahvdro-6H-benzofc1chromen-1-ol (C-

[0215] Allyl-A8-THC)

[0216] C24H34O2 (354,53) C24H34O2 (354,53)

[0217] O-allyl-A8-THC (1.0 g, 2.8 mmol) was heated under N2 to 185-190°C for 4 h to afford C-allyl-A8- THC in quantitative yield as a colorless oil.

[0218] [a]D20= -303.3 (c 1.0, CHCh)

[0219] HRMS m / z for [M-H]’ calculated: 353.24806; found: 353.24860.

[0220] 1H-NMR (CDCI3) 8=6.23 (s, 1 H, H-4), 5.96-5.86 (m, 1 H, -CH=), 5,35 (d, 1 H, H-8), 5.11-5.04 (m, 2H, =CH2), 3.29-3.28 (m, 2H, CH2-C=), 3,15-1.10 (m, 1 H H-10a), 2.68-2.60 (m, 2H, H-T), 2.44- 2.38 (m, 2H, H-9a,6a), 2.08-2.04 (m, 1 H, H-7a), 1.78-1.70 (m, 3H, H-7b,9b,10b), 1.62 (s, 3H,

[0221] September 9, 2024 45 / 61 CH3), 1.43-1.41 (m, 1 H, H-2’), 1.30 (s, 3H, CH3), 1.24-1.21 (m, 4H, H-4’,3’), 1.02 (s, 3H, CH3), 0.81 (t, 3H, H-5’).

[0222] 13C-NMR (CDCI3) 8=154.3 (C-1), 153.0 (C-4a), 140.6 (C-3), 136.8 (-HC=), 134.9 (C-2), 119.4 (C-8), 116.4 (=CH2), 114.0 (C-9), 111.6 (C-10b), 110.8 (C-4), 76.5 (C-6), 45.2 (C-6a), 36.2 (C- 10), 33.7 (C-T), 31.9 (C-2’), 30.7 (CH2-allyl), 28.1 (C-3’), 27.6 (CH3), 23.6 (CH3), 22.6 (C-4’), 18.5 (CH3), 14.1 (C-5’).

[0223] Example 3. Preparation of A9-THC-derivatives

[0224] (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahvdro-6H-benzofc1chromene

[0225] (O-Allyl-A9-THC)

[0226] C21 H30O2 (314,47) C24H34O2 (354,53)

[0227] A9-Tetrahydrocannabinol (1.0 g, 3.2 mmol) and allyl bromide (1.4 g, 5.7 mmol) were dissolved in DMF (20 ml). At room temperature K2CO3(1.57 g, 11.4 mmol) was added in one portion under vigorous stirring and stirring at room temperature was continued until TLC (petrol ether / ethyl acetate 10 / 1) showed complete conversion of THC to a faster moving product (14 h). The suspension was filtered through a glass filter and the filtrate was concentrated under vacuum at the rotary evaporator (bath temperature 60°C). The concentrated solution was poured into water (80 ml) and extracted with ethyl acetate. The combined organic layers were successively washed with saturated NaHCO3solution and brine and dried over Na2SC>4. Filtration and concentration of the solution afforded O-allyl-A9-THC (1.1 g, 97%) as a colorless oil.

[0228] [a]D20= -150.0 (c 1.2, CHCI3).

[0229] HRMS m / z for [M+H]+calculated: 355.26371 ; found: 355.26246.

[0230] 1H-NMR (CDCI3) 8=6.26 (d, 1 H, H-4), 6.17 (d, 1 H, H-2), 6.06-5.99 (m, 1 H HC=), 5.41-5.36 (m, 1 H, H-9), 5.21-5.18 (m, 1 H, =CH2), 4.49 (d, 2H, OCH2), 3.14 (dd, 1 H, H-10a), 2.42 (t, 2H, H-1’), 2.08-2.06 (m, 3H, H-6a,8), 1.84-1.81 (m, 1 H, H-7a), 1.58 s, CH3), 1.61-1.58 (m, 2H, H-2’), 1.35 (s, 3H, CH3), 1.30-1.19 (m, 4H, H-3’,4’), 1.01 (s, 3H, CH3), 0.81 (t, 3H, H-5’).

[0231] September 9, 2024 46 / 6113C-NMR (CDCh) 8=157.4 (C-1), 154.5 (C-4a), 142.4 (C-3), 133.6 (=CH), 133.2 (C-9), 125.1 (C- 10), 117.0 (=CH2), 110.7 (C-10b), 110.4 (C-2), 104.2 (C-4), 77.1 (C-6a), 68.9 (OCH2), 45.9 (C- 6a), 36.4 (C-T), 36.0 (C-8), 31.8, 31.7, 30.8 (C-2’, 3, 4’), 27.8 (CH3), 23.6 (CH3), 19.4 (CH3), 14.1 (C-5’).

[0232] (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahvdro-6H-benzofc1chromen-1-ol (C- Allyl-A9-THC).

[0233] O-allyl-A9-THC (1.0 g, 3.4 mmol) was heated under N2 to 160-170°C for 5 h to afford C-allyl-A9- THC (0.95 g, 95%) as a yellowish oil.

[0234] [a]D20= -170.0 (c 0.5, CHCh)

[0235] HRMS m / z for [M-H]’ calculated: 353.24806; found: 353.24872.

[0236] 1H-NMR (CDCh) 8=6.22 (s, 1 H, H-4), 5.93-5.86 (m, 2H, H-10, CH=), 5.11-5.04 (m, 2H, =CH2), 3.32-3.28 (m, 3H, H-10a, CH2-C=), 2.48-2.35 (m, 3H, H-6a,H-1’), 2.08 (br s, 2H, H-8), 1.86-1.80 (m, 1 H, H-7), 1.60 (s, 3H, CH3), 1.47-1.32 (m, 7H, CH3, H-2’,3’), 1.00 (s, 3H, CH3), 0.80 (t, 3H, H-5’).

[0237] 13C-NMR (CDCh) 8=153.5 (C-1), 152.9 (C-4a), 140.7 (C-3), 139.9 (-HC=), 134.3 (C-9), 124.1 (C-10), 118.2 (=CH2), 114.1 (C-2), 110.7 (C-4), 110.0 (C-10b), 76.8 (C-6), 48.1 (C-6a), 33.9 (C- 10a), 33.7 (C-1’), 31.9 (CH2al|y'), 31.3, 30.9 (C-2’, 3’), 23.4 (CH3), 19.2 (CH3), 14.1 (C-5’).

[0238] Example 4. Preparation of HHC-derivatives

[0239] (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,9, 10,10a-hexahydro-6H-

[0240] September 9, 2024 47 / 61 benzo[c1chromene (O-Allyl-HHC)

[0241] C21H32O2 (316,49) C24H36O2 (356,55)

[0242] Hexahydrocannabinol (5:1 mixture of 9R / 9S isomers) (1.1 g, 3.5 mmol) and allyl bromide (0.96 g, 7.9 mmol) were dissolved in DMF (15 ml). At room temperature K2CO3 (1.57 g, 11.4 mmol) was added in one portion under vigorous stirring and stirring at room temperature was continued until TLC (petrol ether / ethyl acetate 10 / 1) showed complete conversion of THC to a faster moving product (16 h). The suspension was filtered through a glass filter and the filtrate was concentrated under vacuum at the rotary evaporator (bath temperature 60°C). The concentrated solution was poured into water (80 ml) and extracted with ethyl acetate. The combined organic layers were successively washed with saturated NaHCCh solution and brine and dried over Na2SC>4. Filtration and concentration of the solution afforded O-allyl-HHC (5:1 mixture of 9R / 9S isomers) (1.17 g, 97%) as a colorless oil.

[0243] HRMS m / z for [M+H]+calculated: 355.26371 ; found: 355.26246.

[0244] 1H-NMR (CDCh) significant peaks 8=6.21 (d, 1 H, H-2), 6.15 (d, 1 H, H-4), 6.13-5.96 (m, 1 H HC=), 5.39-5.15 (m, 2H, =CH2), 4.44 (q, 2H, (R)-OCH2), 4.40 (q, 2H, (S)-OCH2), 2.41-2.34 (m, 1 H, H-10a), 2.02-2.01 (m, 2H, (S)-H-10), 1.78-1.74 (m, 2H, (R)-H-10), 1.58-1.49 (m, 1 H, (R)-H- 9), 1.39-1.35 (m, 1 H, (S)-H-9), 1.26 (d, 3H, (R)-CH3), 1.24 (d, 3H, (S)-CH3), 0.85-0.76 (m, 3H, H-5’), 0.46 (q, 3H, (S)-CH3).

[0245] 13C-NMR (CDCh) significant peaks 8=157.9 ((R)-C-1), 157.8 ((S)-C-1), 142.3 ((R)-C-3), 142.2 ((S)-C-3), 133.7 (=CH), 116.8 ((S)-H2C=), 116.6 ((R)-H2C=), 110.3 (C-4), 104.3 (C-4a), 68.9 ((S)-OCH2), 68.8 ((R)-OCH2), 50.3 ((S)-C-6a), 49.4 ((R)-C-6a), 22.9 ((S)-CH3), 22.6 ((R)-CH3), 14.1 (C-5’).

[0246] (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10, 10a-hexahvdro-6H-benzofc1chromen-1-

[0247] September 9, 2024 48 / 61 ol (C-Allyl-HHC).

[0248] O-allyl-HHC (0.9 g, 2.5 mmol) was heated under N2 to 185°C for 6 h to afford C-allyl-HHC (0.85 g, 94%) as a yellowish oil.

[0249] HRMS m / z for [M-H]’ calculated: 355.26425; found: 355.26441

[0250] 1H-NMR (CDCh) significant peaks 8=7.18 (s, 1 H, OH), 5.92-5.81 (m, 1 H, HC=), 5.10-5.0 (m, 2H, (R)-H2C=), 4.96-4.81 (m, 2H, (S)-H2C=), 3.30-3.25 (2H, CH2-C=), 2.44-2.34 (m, 1 H, H-10a), 1.28 (s, 3H, (R)-CH3), 1.25 (s, 3H, (S)-CH3), 0.85-0.77 (m, 6H, CH3, H-5’).

[0251] 13C-NMR (CDCh) significant peaks 8=137.3 ((S)-HC=), 136.9 ((R)-HC=), 116.3 ((S)-=CH2),

[0252] 116.2 ((R)-=CH2), 110.6 (C-4), 50.2 ((R)-C-10), 49.4 ((S)-C-10), 30.6 (H2Cal|y'), 28.0, 27.6 (CH3),

[0253] 23.2 ((S)-CH3), 22.6 (R)-CH3), 14.1 (C-5’)

[0254] Example 5. Preparation of a A8-THC carbonate derivative

[0255] (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzofc1chromen-1-yl methyl carbonate

[0256] C?r.H3CO4(412,57)

[0257] C-Allyl-A8-THC (35.5 g) was dissolved in 200 ml dichloromethane and was contacted sequentially with 21.0 ml triethylamine (TEA) and 0.5 g 4-dimethylaminopyridine (DMAP) under vigorous stirring and in an inert atmosphere. After stirring for 15 minutes, 9.27 ml methyl chloroformate (MCF) were added dropwise at a rate which provides for gentle boiling of the dichloromethane solvent under reflux conditions. The reaction was monitored by TLC using a

[0258] September 9, 2024 49 / 61 MeOH:AcOH 19:1 (v / v) mixture. Upon apparent completion of the reaction, the mixture was quenched with 10 ml methanol and then washed with ice cold 3% aqueous HCI solution. The organic phase was separated and sequentially washed with aqueous saturated NaHCOs solution and dilute brine solution which affords the 2-allyl- 1 -methyl carbonate A8-THC derivative. The organic solution was passed through silica gel (0.032-0.063 mm) from Macherey & Nagel under removal of a forerun and the product run was concentrated by evaporation followed by subsequent degassing. The target compound was obtained in greater than 99% purity.

[0259] 1H NMR (CDCI3): 5=6.54 (s, 1 H, H-4), 5.78-5.71 (m, 1 H, HC=), 5.34 (s, 1 H, H-8), 4.89-4.84 (m, 2H =CH2), 3.76 (s, 3H, OCH3), 3.30-3.11 (ddd, 2H, CH2-C=), 2.71-2.70 (m, 1 H, H-10a), 2.63- 2.37 (m, 4H, H-6a, 10, T), 2.07-2.03 (m, 1 H, H-10), 1.84-1.68 (m, 2H, H-7), 1.50-1.44 (m, H-2’), 1.29 (s, 6H, CH3), 1.29-1.26 (m, 4H, H-3’, 4’), 1.02 (s, 3H, CH3), 0.81 (t, 3H, H-5’).

[0260] 13C NMR (CDCI3): 5=153.4 (O-C=O), 152.7 (C-4a), 148.9 (C-1), 141.5 (C-3), 136.5 (HC=), 134.3 (C-9), 121.7 (C-2), 119.5 (C-4), 117.0 (C-10b), 116.1 (C-8), 114.9 (H2C=), 77.4 (C-6), 55.5 (OCH3), 44.9 (C-6a), 36.1 (C-10), 32.7 (C-T), 31.9 (C-10a), 31.0 (CH2allyl), 30.6 (C-3’), 30.4 (C- 2’), 23.5 (CH3), 22.6 (C-4’), 18.5 (CH3), 14.1 (C-5’).

[0261] HRMS m / z for [MH]+calculated: 413.26918, found: 413.26895

[0262] Example 6. Preparation of O-Allyl-O-acetyl-CBDA-methyl-ester

[0263] C25H34O5(414,54) ^28^38^5 (454,61 )

[0264] 2O-Acetyl-CBDA-methylester (7.1 g, 17 mmol) and allyl bromide (2.66 g, 22 mmol) were dissolved in DMF (40 ml). At room temperature K2CO3(3.45 g, 25 mmol) was added in one portion under vigorous stirring and stirring at room temperature was continued until TLC (petrol

[0265] September 9, 2024 50 / 61 ether / ethyl acetate 10 / 1) showed complete conversion of the starting material into a faster moving product (16 h). The suspension was filtered through a glass filter and the filtrate was concentrated under vacuum at the rotary evaporator (bath temperature 60 °C). The concentrated solution was poured into water (100 ml) and extracted with ethyl acetate. The combined organic layers were successively washed with saturated NaHCCh solution and brine and dried over Na2SC>4. Filtration and concentration of the solution afforded O-allyl-O-acetyl-CBDA-methyl ester (7.76 g, quant.) as a slightly yellow oil.

[0266] HRMS m / z for [MH]+calculated: 455.27975, found: 455.28091

[0267] 1H NMR (CDCI3): 5=6.37 (s, 1 H, H-5), 6.00-5.86 (m, 1 H, HC=), 5.36-5.29 (m, 2H, =CH2), 5.19- 5.10 (m, 3H, H-6’, =CH2), 4.40-4.37 (m, 2H, OCH2), 3.76 (s, 3H, COOCH3), 2.95-2.89 (m, 1 H, H- 3’), 2.47-2.39 (m, 1 H, H-2’), 2.09-2.07 (m, 1 H, H-4’), 1.93-1.89 (m, 1 H, H-4’), 1.69-1 ,66 (m, 1 H, H-3’), 1.58 (s, 3H, CH3), 1.51-1.43 (m, 2H, H-2”), 1.50 (s, 6H, CH3), 1.20-1.15 (m, 4H, H-3”, 4”), 0.81 (t, 3H, H-5”).

[0268] 13C NMR (CDCI3): 5=170.4 (C=O), 169.3 (C=O), 149.9, 140.1 , 132.3, 125.3, 124.7, 116.6, 109.1 (Cq), 133.3 (HC=), 125.4 (C-6’), 116.7 (C-5), 69.1 (OCH2), 52.0 (OCH3), 44.6 (C-2’), 33.8, 31.8, 30.9, 30.8, 29.5, 22.5 (CH2), 23.5, 22.5, 19.7 (CH3), 14.0 (C-5”).

[0269] The synthesis of the starting material 2O-Acetyl-CBDA-methylester has been described in the art, e.g., WO 2023 / 099549 A1 , which synthesis is hereby incorporated by reference.

[0270] September 9, 2024 51 / 61

Claims

Claimswherein R1and R2are chosen in combination according to any one of the following options a) to a) R1is allyl and R2is H, b) R1is H and R2is allyl, c) R1is H and R2is 1-propenyl, 2-butenyl, 2-pentenyl, or 2,4-hexadienyl, d) R1is H and R2is 3-hydroxy-propyl, e) R1is H and R2is butyryl aldehyde, f) R1is H and R2is propionyl acid, g) R1is H and R2is 2-oxopropyl, and h) wherein R1and R2together form a ring structure selected from the group consisting ofSeptember 9, 2024 52 / 61i) R1is (C=O)OCH3and R2is allyl, wherein R3is selected from propyl, pentyl, heptyl,2. The compound according to claim 1 , being either i) 1-(Allyloxy)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene; ii) 2-Allyl-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol; iii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,10, 10a-tetrahydro-6H- benzo[c]chromene; iv) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,10, 10a-tetrahydro-6H-benzo[c]chromen- 1-ol; v) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen- 1 -ol ; vi) (6aR,10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen- 1-ol; vii) (6aR,10aR)-1-(allyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,9, 10,10a-hexahydro-6H- benzo[c]chromene; or viii) (6aR, 10aR)-2-allyl-6,6,9-trimethyl-3-pentyl-6a,7,8,9, 10, 10a-hexahydro-6H- benzo[c]chromen- 1 -ol .

3. The compound according to any of claims 1 or 2, selected from formula II to formula V:IISeptember 9, 2024 53 / 614. The compound according to claim 1 , selected from formula VI to formula XVI:wherein R is selected from -H, -CH3, -CH2-CH3, or -CH=CH-CH3.VI,September 9, 2024 54 / 61x,September 9, 2024 55 / 61September 9, 2024 56 / 61XIV,XVI.

5. The compound according to any of the claims 1 to 4, characterized by one or more of the following features: a. having a reduced psychoactive effect as compared to A9-Tetrahydrocannabinol (A9- THC); b. having an elevated effect selected from the group consisting of pain relief, appetite stimulation, anti-inflammatory properties, muscle relaxation, anxiety reduction, and antiemetic effect reduction, as well as combinations thereof, as compared to A9-Tetrahydro- cannabinol (A9-THC); c. having an increased lipophilicity as compared to A9-Tetrahydrocannabinol (A9-THC).

6. Process for the synthesis of the compounds according to claim 2, comprising the steps of: a. Providing a starting compound selected from the group of A9-THC, A8-THC, HHC, and CBN, and dissolving the starting compound in a solvent;September 9, 2024 57 / 61b. Reacting the starting compound with allyl-bromide to obtain an intermediate product; c. Extracting the intermediate product; d. Washing and drying the intermediate product; e. Optionally heating the intermediate product; f. Optionally obtaining a second product; and g. Optionally isolating the second product.

7. Pharmaceutical composition comprising a compound according to any of the claims 1 to 4.

8. The pharmaceutical composition of claim 7, further comprising- at least one excipient selected from the group consisting of fillers such as lactose, microcrystalline cellulose, dicalcium phosphate, mannitol, starches, e.g., corn starch;- optionally a binder, e.g., starch paste, povidone (polyvinylpyrrolidone), hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose sodium;- optionally a disintegrant, e.g., croscarmellose sodium, crospovidone, sodium starch glycolate, crosslinked polyvinylpyrrolidone (PVP), microcrystalline cellulose;- optionally a glidant, e.g., magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate, stearic acid;- optionally a coating, e.g., hydroxypropyl methylcellulose (HPMC), ethyl cellulose, shellac, polyvinyl alcohol (PVA), gelatin;- optionally a preservative, e.g., benzalkonium chloride, methylparaben, propylparaben, sorbic acid, benzyl alcohol;- optionally a colorant, e.g., iron oxides, titanium dioxide, indigo carmine, sunset yellow, allura red;- optionally a flavoring, e.g., aspartame, sucrose, sorbitol, sodium saccharin, peppermint oil; optionally a solubilizer, e.g., polysorbate 80, propylene glycol, ethanol, cyclodextrins, polyethylene glycol (PEG);September 9, 2024 58 / 61optionally a buffer system, e.g., citric acid and sodium citrate, hydrogen phosphate and dihydrogen phosphate, acetic acid and sodium acetate.

9. Compound according to any one of claims 1 to 4 for use in medicine, or the pharmaceutical composition according to any of claims 7 and 8 for use in medicine.

10. Compound according to any one of claims 1 to 4 for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, Inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof, or the pharmaceutical composition according to any of claims 6 and 7, for use in the treatment of a condition selected from the group consisting of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorder and / or depression, neurological disorders, sleep disorders, pain, anorexia and / or appetite loss, inflammation, Inflammatory Bowel Disease (IBD), muscle tension, muscle spasticity, spasms and / or cramps, glaucoma, and nausea and / or vomiting, and combinations thereof.

11. Kit comprising the compound according to any one of claims 1 to 4, or the pharmaceutical composition according to any of claims 7 and 8, further comprising at least one object selected from the group consisting of an applicator, a package leaflet, a transdermal patch, a second active agent, and a treatment schedule, as well as combinations thereof.

12. A compound according to Formula XXXX,September 9, 2024 59 / 61wherein R1= methyl, ethyl, or propyl; wherein R2= methyl, ethyl, or propyl; wherein R3= propyl, pentyl, or heptyl13. The compound according to claim 11 , selected from formula XXIXXI.

14. Pharmaceutical composition comprising a compound according to claim 12 or claim 13.

15. Compound according to claim 12 or claim 13 for use in medicine, or the pharmaceutical composition according to claim 14 for use in medicine.September 9, 2024 60 / 61

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