Cannabinoid derivatives as pharmaceutically active compounds and methods for their preparation

Abstract

The present invention relates to a class of cannabinoid derivatives as pharmaceutically active compounds and methods for their preparation. The cannabinoid derivatives of the present invention are analogs of cannabidiol (CBD). CBD is a non-psychotropic cannabinoid that has been used to treat a variety of diseases and disorders. While such treatments are promising, there remains a need in the art for more effective treatments, which the cannabinoid derivatives of the present invention address.

Description

[Technical Field]

[0001] The present invention relates to a class of cannabinoid derivatives as pharmaceutically active compounds and to methods for their preparation.

[0002] The cannabinoid derivatives of the present invention are analogs of cannabidiol (CBD). CBD is a non-psychotropic cannabinoid that has been used to treat a variety of diseases and disorders. While such treatments are promising, there remains a need in the art for more effective treatments, which the cannabinoid derivatives of the present invention provide. [Background technology]

[0003] Cannabinoids are natural and synthetic compounds structurally or pharmacologically related to the constituents of the cannabis plant or to the endogenous agonists (endocannabinoids) of the cannabinoid receptors CB1 or CB2. The only way these compounds are naturally produced is by the cannabis plant. Cannabis is a genus of flowering plants in the Cannabaceae family that includes the species Cannabis sativa, Cannabis indica, and Cannabis ruderalis (sometimes considered part of Cannabis).

[0004] The cannabis plant contains an extremely complex mixture of compounds. At least 568 unique molecules have been identified. These compounds include cannabinoids, terpenoids, sugars, fatty acids, flavonoids, other hydrocarbons, nitrogenous compounds, and amino acids.

[0005] Cannabinoids exert their physiological effects through various receptors, including, but not limited to, adrenergic receptors, cannabinoid receptors (CB1 and CB2), GPR55, GPR3, or GPR5. The major cannabinoids present in the cannabis plant are the cannabinoid acids Δ9-tetrahydrocannabinolic acid (Δ9-THCA) and cannabidiolic acid (CBDA), with smaller amounts of each neutral (decarboxylated) cannabinoid. In addition, cannabis may contain lower levels of other minor cannabinoids.

[0006] There are currently four approved cannabinoid-based pharmaceutical products on the market: dronabinol (Marinol®), a synthetic tetrahydrocannabinol (THC) approved for the treatment of appetite loss in AIDS and severe nausea and vomiting caused by cancer chemotherapy; nabilone (Cesamet®), a synthetic cannabinoid and THC analogue approved for the treatment of nausea and vomiting caused by cytotoxic chemotherapy unresponsive to conventional antiemetics; nabiximols (Sativex®), a mixture of two cannabis plant extracts approved for the treatment of neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis; and highly purified plant-based CBD (Epidiolex®), approved in the United States for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in children over the age of two and adults.

[0007] As can be seen from the above, cannabinoids are a set of compounds that can be obtained naturally from the cannabis plant or produced semi-synthetically or synthetically by chemical synthesis.

[0008] Over 100 different cannabinoids have been identified. These cannabinoids are divided into various groups: phytocannabinoids; endocannabinoids and synthetic cannabinoids (which may be new cannabinoids, i.e., synthetically produced versions of phytocannabinoids or endocannabinoids). Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3-15, details the cannabinoids known to date.

[0009] Cannabidiol (CBD) is the major cannabinoid component of Cannabis species, such as the cannabis plant (hemp). Unlike other cannabinoids, such as THC, cannabidiol does not bind to CB1 or CB2 receptors, or its binding to these receptors induces only minimal pharmacological effects. Therefore, cannabidiol does not induce central or peripheral nervous system effects mediated by CB1 or CB2 receptors. CBD has little or no psychotropic (cannabis-like) activity, and its molecular structure and properties differ significantly from other cannabinoids.

[0010] Cannabidiol administration has been the subject of research in an effort to provide alternative treatments for a variety of diseases and disorders that may respond to such treatment.

[0011] The synthetic production of 7-hydroxy-cannabidiol (7-OH CBD), a metabolite of CBD, is disclosed in WO 01 / 95899. This compound was tested in models of inflammation and found to be effective. The application then suggests that this compound may be useful as an analgesic, anxiolytic, anticonvulsant, neuroprotective, antipsychotic, and anti-inflammatory agent based on the mechanisms that this compound exhibits in models of inflammation.

[0012] The present invention relates to new cannabinoid compounds that are biologically active and therefore useful in the treatment of diseases. Such new compounds may be administered by a variety of routes, including, but not limited to, oral, transdermal, buccal, nasal, pulmonary, rectal, or ophthalmic administration. Such compounds may be used to treat or prevent medical conditions such as epilepsy, pain, inflammation, and cancer. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] WO 01 / 95899 [Non-patent literature]

[0014] [Non-Patent Document 1] Handbook of Cannabis, Roger Pertwee, chapter 1, pages 3-15 [Non-patent document 2] The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986 Summary of the Invention [Means for solving the problem]

[0015] According to a first aspect of the present invention, a compound of general formula I

[0016] [ka]

[0017] [Wherein, X is either CH2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(0)iPr; NBz or NH, and Y is either H or OH.] or a salt thereof is provided.

[0018] According to a second aspect of the present invention, a compound of general formula II

[0019] [ka]

[0020] [Wherein, X is either CH2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(0)iPr; NBz or NH, and Y is either H or OH.] or a salt thereof is provided.

[0021] According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of general formula I or formula II.

[0022] Preferably, the pharmaceutical composition is selected from tablets, capsules, granules, oral liquids, powders for inhalation, sprinkles, oral solutions and suspensions.

[0023] Preferably, the pharmaceutical composition comprises one or more additives selected from carriers, oils, disintegrants, lubricants, stabilizers, flavorings, antioxidants, diluents and other pharmaceutically active compounds.

[0024] According to a fourth aspect of the present invention there is provided a compound of general formula I or formula II for use as a medicament.

[0025] According to a fifth aspect of the present invention there is provided a compound of general formula I or formula II for use in the treatment of epilepsy.

[0026] According to a sixth aspect of the present invention, there is provided a method comprising administering a pharmaceutical formulation comprising a compound of general formula I or formula II.

[0027] According to a seventh aspect of the present invention, there is provided a process for the production of compounds of general formula I or formula II, comprising the step of reacting resorcinol units of structures 1a-j by Friedel-Crafts 1,4-addition to produce compounds of structures 2a-2j or 3a-3j, followed by the subsequent step of producing compounds of general formula I or formula II via an intermediate.

[0028] According to an eighth aspect of the present invention, there is provided an intermediate formed during the production of a compound of general formula I or formula II.

[0029] definition "Cannabinoids" is a group of compounds that includes endocannabinoids, phytocannabinoids, and cannabinoids that are neither endocannabinoids nor phytocannabinoids, hereinafter referred to as "syntho-cannabinoids."

[0030] "Endocannabinoids" are endogenous cannabinoids that are high-affinity ligands for CB1 and CB2 receptors.

[0031] "Phytocannabinoids" are naturally occurring cannabinoids found in the cannabis plant. Phytocannabinoids may be present in extracts containing botanical drug substances, either isolated or synthetically reproduced.

[0032] "Synthocannabinoids" are compounds not found endogenously or in the cannabis plant. Examples include WIN 55212 and rimonabant.

[0033] An "isolated phytocannabinoid" is a cannabinoid that has been extracted from the cannabis plant and purified to the extent that all further components, such as minor and non-major cannabinoids and non-cannabinoid fractions, have been removed.

[0034] A "synthetic cannabinoid" is a cannabinoid produced by chemical synthesis. The term includes modifying an isolated plant cannabinoid, for example, by forming a pharmaceutically acceptable salt thereof.

[0035] "Substantially pure" cannabinoids are defined as cannabinoids present at greater than 95% (w / w) purity, more preferably greater than 96% (w / w) to 97% (w / w) to 98% (w / w) to 99% (w / w) or greater. [Brief explanation of the drawings]

[0036] [Figure 1] FIG. 1 shows the data obtained in the experiment. [Figure 2] FIG. 2 shows the data obtained in the experiment. [Figure 3] FIG. 3 shows the data obtained in the experiment. [Figure 4] FIG. 4 shows the data obtained in the experiment. DETAILED DESCRIPTION OF THE INVENTION

[0037] The following describes the production of the new cannabinoid derivatives claimed in this invention. The structures and absolute configurations of the compounds produced were determined by X-ray crystallography using a molybdenum X-ray source. [Example]

[0038] Example 1 How CBD derivatives are typically produced This example describes a novel synthetic methodology used to generate new analogs of conventional CBD that exhibit pharmacological activity. Scheme 1 below describes the initial reactions used to generate the primary intermediates, and Scheme 2 describes the generation of conventional CBD derivatives formed via multiple intermediates. Scheme 1: Friedel-Crafts 1,4-addition reaction

[0039] [ka]

[0040] wherein R1 = H or OMe, and X = CH2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(0)iPr; NBz or NH.

[0041] The resorcinol units in structures 1a-1j (shown below) underwent a Friedel-Crafts 1,4-addition reaction shown in Scheme 1 to give compounds of structures 2a-2j, shown below.

[0042] Various catalysts were tested. Silylated Jorgensen-Hayashi catalysts gave poor yields but excellent selectivity. MacMillan catalysts gave better yields but poorer enantioselectivities. Structures 1a~j

[0043] [ka]

[0044] Structure 2a~j

[0045] [ka]

[0046] Structure 3a~j

[0047] [ka]

[0048] Compounds of structure 2a-2j or 3a-3j (shown above) were then reacted as shown in Scheme 2 below to give two different conventional CBD derivatives 11a-11j or 12a-12j.

[0049] Compounds 13 and 14 were further generated by deprotection of derivatives 11c-j and 12c-j. Scheme 2: Synthesis of conventional CBD analogues

[0050] [ka]

[0051] Synthesis of intermediates 4a-4j or 5a-5j: Intermediates 2a-2j or 3a-3j were brominated with N-bromosuccinimide (NBS) to prepare aryl bromide compounds 4a-4j or 5a-5j shown below. Structure 4a~4j

[0052] [ka]

[0053] Structure 5a~5j

[0054] [ka]

[0055] Synthesis of intermediates 6a-6j or 7a-7j Intermediates 4a-4j or 5a-5j were O-demethylated with boron tribromide in the presence of dichloromethane to give the deprotected chiral resorcinol compounds depicted as 6a-6j or 7a-7j as illustrated below. Structure 6a~6j

[0056] [ka]

[0057] Structure 7a~7j

[0058] [ka]

[0059] Synthesis of intermediates 9a to 9j (excluding 9f) or 10a to 10j (excluding 10f) Brominated intermediates 6a-6j or 7a-7j were coupled with menthadienol (shown as structure 8 in Scheme 2) in the presence of boron trifluoride diethyl etherate to give intermediates 9a-9j (excluding 9f, which is not feasible) or 10a-10j (excluding 10f, which is not feasible), the structures of which are depicted below. Structures 9a-j (but 9f is not feasible)

[0060] [ka]

[0061] Structures 10a-j (but 10f is not feasible)

[0062] [ka]

[0063] Synthesis of conventional CBD derivatives 11a-11j (excluding 11f) or 12a-12j (excluding 12f) 9a-9j (except 9f) or 10a-10j (except 10f) were debrominated with acetic acid and hydrogen bromide to give the conventional CBD derivatives 11a-11j (except 11f) or 12a-12j (except 12f) shown below. Structures 11a-j (but 11f is not feasible)

[0064] [ka]

[0065] Structures 12a-j (but 12f is not feasible)

[0066] [ka]

[0067] Furthermore, the N-protected moieties of compounds 11c to 11j (excluding 11f) and 12c to 12j (excluding 12f) can be deprotected to give two NH derivatives, compounds 13 and 14, shown below. Structures 13 and 14

[0068] [ka]

[0069] Example 2 Unusual methods for producing CBD derivatives This example describes a novel synthetic methodology used to generate novel, unusual CBD analogs that exhibit pharmacological activity. Scheme 1, illustrated in Example 1, describes the initial reactions used to generate primary intermediates 2a-2j and 3a-3j, and Scheme 3 describes the generation of unusual CBD derivatives formed via multiple intermediates. Scheme 3: Synthesis of unusual CBD analogues

[0070] [ka]

[0071] Synthesis of Intermediates 15a to 15j or 16a to 16j Intermediates 2a-2j or 3a-3j were O-demethylated with boron tribromide in the presence of dichloromethane to give the deprotected chiral resorcinol compounds depicted below as 15a-15j or 16a-16j. Structure 15a~j

[0072] [ka]

[0073] Structure 16a~j

[0074] [ka]

[0075] Synthesis of unusual CBD derivatives 17a-17j or 18a-18j Coupling of intermediates 15a-15j or 16a-16j with menthadienol (shown as structure 8 in Scheme 3) in the presence of boron trifluoride diethyl etherate gave the unusual CBD derivatives 17a-17j or 18a-18j, as illustrated below. Structure 17a~17j

[0076] [ka]

[0077] Structures 18a to 18j

[0078] [ka]

[0079] Synthesis of compounds 19-22 Deprotection of 17c-17j or 18c-18j produced compounds 19-22, as shown below. Structures 19, 20, 21, 22

[0080] [ka]

[0081] Conclusion: It would be beneficial to utilize new synthetic routes to generate new cannabidiol analogs and their intermediates.

[0082] Compounds of general formulas I and II are detailed below and are equivalent to compounds of structures 11a-11j (excluding 11f), 12a-12j (excluding 12f), 17a-17j, and 17a-17j. Such compounds may provide improved or novel therapeutic treatment options.

[0083] Deprotection of certain compounds has been found to yield additional new molecules that offer further improved or novel therapeutic benefits. Such compounds include 13, 14, 19, 20, 21, and 22.

[0084] [ka]

[0085] In the formula, X is either CH2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(0)iPr; NBz or NH, and Y is either H or OH.

[0086] [ka]

[0087] In the formula, X is either CH2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(0)iPr; NBz or NH, and Y is either H or OH.

[0088] Example 3 Evaluation of cannabinoid derivatives for anticonvulsant activity using the maximal electroshock seizure threshold (MEST) test in mice The efficacy of exemplary cannabinoid derivatives according to Formula I and Formula II was tested in a mouse model of generalized seizures, the Maximum Electroshock Seizure Threshold (MEST) test.

[0089] The maximal electroshock seizure threshold (MEST) test is widely used preclinically to assess the proconvulsant or anticonvulsant properties of test compounds (Loscher et al., 1991).

[0090] In the MEST test, the ability of a drug to alter the seizure threshold current required to induce a hindlimb tonic extensor seizure is measured according to the "up and down" method of shock titration (Kimball et al., 1957). An increase in the seizure threshold indicates an anticonvulsant effect. Antiepileptic drugs with clinically proven efficacy against generalized tonic-clonic seizures, including sodium channel blockers (e.g., lamotrigine), all exhibit anticonvulsant properties in this test in mice.

[0091] Conversely, a reduction in the seizure threshold, as observed with known convulsants such as picrotoxin, indicates a proconvulsant effect.

[0092] The MEST determines the ability of test compounds to alter the stimulus intensity, expressed as current (mA), required to induce the presence of tonic hindlimb extensor spasms. The current (CC) required to produce tonic hindlimb extension in 50% of the animals in the treatment group is 50 The seizure threshold of the treatment group was determined from the results of the presence (+) or absence (0) of tonic hindlimb extensor spasms observed in the CC group, and the effect was then compared to that of the vehicle control group. 50 was compared against.

[0093] method Research details: Naive mice were allowed to acclimate to the treatment room in their home cages with free access to food and water for up to 7 days.

[0094] All animals were weighed at the start of the study and randomly assigned to treatment groups based on the average distribution of body weights across groups. All animals received either vehicle, 200 mg / kg test compound, or 2.5 mg / kg diazepam via intraperitoneal (ip) injection at 10 mL / kg.

[0095] Animals were individually judged for the production of tonic hindlimb extensor convulsions in response to a single electric shock 60 minutes after vehicle administration, 30-120 minutes (depending on the compound) after test compound administration, and 30 minutes after diazepam administration.

[0096] The first animal in the treatment group was given the expected or estimated CC 50 A current shock was administered, with subsequent animals receiving either a decreasing or increasing current depending on the outcome of the seizure in the preceding animal.

[0097] The data generated from each treatment group were used to calculate the CC for the treatment group. 50 Values ​​were calculated ±SEM.

[0098] Test Compound: Solvent: (5% ethanol, 5% solutol solution in 90% saline) was prepared as follows: 2 mL ethanol, 2 mL solutol were warmed to 60° C. in 36 mL saline (1:1:18).

[0099] Positive control: diazepam 2.5 mg / kg was used.

[0100] The test compounds used were 12a, 12b, 18a and 18b. Test compounds were administered at 200 mg / kg (ip) in a 1:1:18 ethanol:solutol:saline formulation.

[0101] Sample Collection: Each animal was humanely killed immediately after the production of convulsions by destruction of the brain by a blow to the skull, followed by decapitation to ensure permanent cessation of circulation, under the Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collections were performed after decapitation.

[0102] Blood was collected into lithium-heparin tubes and centrifuged at 1500 x g for 10 minutes at 4°C. The resulting plasma was removed (>100 μL) and divided into two aliquots in 0.5 mL Eppendorf tubes containing 10 μL of ascorbic acid (100 mg / mL) for stabilization. Brains were removed, washed with saline, and divided into two equal halves. Each half was placed into a separate 2 mL screw-cap cryovial, weighed, and frozen on dry ice.

[0103] statistical analysis Data for each treatment group was recorded as the number of +s and 0s at each current level used, and this information was then used to calculate CC 50 The value (current required for 50% of the animals to exhibit seizure behavior) ± standard error is calculated.

[0104] The effect of the test compound was also evaluated by comparing CC from the vehicle control group. 50 The change was calculated as a percentage of the change in

[0105] Significant differences between drug-treated animals and controls were determined according to Litchfield and Wilcoxon (1949).

[0106] result Figures 1-4 and Tables 1-4 describe the data generated in this experiment.

[0107] In the solvent group, CC 50 The value was calculated to be 21mA.

[0108] In the diazepam (2.5 mg / kg) treatment group, which was administered intravenously 30 minutes before the test, CC 50 The value was 35 mA. This result was statistically significant (p<0.001) compared to the vehicle control.

[0109] In the test compound-treated groups administered ip 30-120 min before testing, all four compounds showed statistically significant CC increases compared with vehicle. 50 The value was obtained.

[0110] Such data indicate that these compounds are therapeutically beneficial.

[0111] [Table 1]

[0112] [Table 2]

[0113] [Table 3]

[0114] [Table 4]

[0115] conclusion These data demonstrate therapeutic efficacy for compounds of Formula I and Formula II.

[0116] These data are significant because they provide previously unknown evidence that these new cannabinoid derivatives may have therapeutic value.

[0117] The compounds tested were those detailed as Compound 12a, Compound 12b, Compound 18a and Compound 18b. Such compounds are examples of cannabinoid derivatives of general formula I and formula II.

[0118] Apparently, such therapeutic efficacy can be attributed to the cannabinoid derivatives of general formula I and formula II of the present invention, since all the compounds showed efficacy in the MEST test.

Claims

1. Compounds of general formula I 【Chemistry 1】 [Wherein X is CH 2 ;O; or NH, and Y is either H or OH.] Or its salt.

2. Compounds of general formula II 【Chemistry 2】 [Wherein X is CH 2 ;O; or NH, and Y is either H or OH.] Or its salt.

3. A pharmaceutical composition comprising a compound according to claim 1 or 2.

4. 4. The pharmaceutical composition according to claim 3, which is selected from tablets, capsules, granules, powders for inhalation, sprinkles, oral solutions and suspensions.

5. 5. The pharmaceutical composition of claim 3 or claim 4, further comprising one or more additives selected from carriers, oils, disintegrants, lubricants, stabilizers, flavorings, antioxidants, diluents and other pharmaceutically active compounds.

6. 6. A pharmaceutical composition according to any one of claims 3 to 5 for use in the treatment of epilepsy.

7. 7. A pharmaceutical composition according to any one of claims 3 to 6 for the treatment of a mammal in need thereof.

8. 1. A process for the production of compounds of general formula I or general formula II, comprising the step of reacting resorcinol units of structure 1a-e or 1g-j by Friedel-Crafts 1,4-addition to produce compounds of structure 2a-e or 2g-j or 3a-e or 3g-j, followed by the subsequent step of producing compounds of general formula I or general formula II according to claim 1 or 2. 【Transformation 3】

9. Compounds 2a-e, 2g-j, 3a-e, 3g-j, 4a-e, 4g-j, 5a-e, 5g-j, 6a-e, 6g-j, 7a-e, 7g-j, 9a-e, 9g-j, 10a-e, 10g-j, 15a-e, 15g-j, 16a-e or 16g-j. 【Chemistry 4】

10. Compounds 11c to e, 11g to j, 12c to e, 12g to j, 17c to e, 17g to j, 18c to e or 18g to j. 【Transformation 5】

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