CANNABINOID DERIVATIVES AS PHARMACEUTICALLY ACTIVE COMPOUNDS AND METHODS OF PREPARATION THEREOF

Abstract

The present invention relates to a group of cannabinoid derivatives as pharmaceutically active compounds and methods of preparation thereof. The cannabinoid derivatives of the invention are analogues of cannabidiol (CBD). CBD is a non-psychoactive cannabinoid which has been used to treat various diseases and disorders. While such treatments hold promise, there remains a need in the art for more effective treatments and this has been brought about by way of the cannabinoid derivatives of the invention

Claims

1. A compound of the general Formula I or a salt thereof ##STR00039## where X is either CH.sub.2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(O)iPr; NBz or NH and Y is either H or OH.

2. A compound of general Formula II or a salt thereof ##STR00040## where X is either CH.sub.2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(O)iPr; NBz or NH and Y is either H or OH.

3. A pharmaceutical composition comprising a compound of claim 1 or salt thereof.

4. A pharmaceutical composition as claimed in claim 3, wherein the pharmaceutical composition is selected from a tablet, a capsule, a granule, a powder for inhalation, a sprinkle, an oral solution and a suspension.

5. A pharmaceutical composition as claimed in claim 3, wherein the composition additionally comprises one or more of: an excipient selected among a carrier, an oil, a disintegrant, a lubricant, a stabilizer, a flavouring agent, an antioxidant, a diluent and another pharmaceutically effective compound.

6. (canceled)

7. A method of treating epilepsy in a mammal in need thereof comprising administering a pharmaceutical preparation comprising a compound of claim 1 or salt thereof.

8. (canceled)

9. A process for the production of a compound of general Formula I comprising reacting a resorcinol unit of Structure 1a-j via a Friedel-Crafts 1,4-addition to produce compounds of Structures 2a to 2j or 3a to 3j followed by subsequent steps to produce the compounds of general Formula I via intermediates.

10. An intermediate formed in the process of the production of a compound of general Formula I.

11. A pharmaceutical composition comprising a compound of claim 2 or salt thereof.

12. A pharmaceutical composition as claimed in claim 11, wherein the pharmaceutical composition is selected from a tablet, a capsule, a granule, a powder for inhalation, a sprinkle, an oral solution and a suspension.

13. A pharmaceutical composition as claimed in claim 11, wherein the composition additionally comprises one or more of: an excipient selected among a carrier, an oil, a disintegrant, a lubricant, a stabilizer, a flavouring agent, an antioxidant, a diluent and another pharmaceutically effective compound.

14. A method of treating epilepsy in a mammal in need thereof comprising administering a pharmaceutical preparation comprising a compound of claim 2 or a salt thereof.

15. A process for the production of a compound of general Formula II comprising reacting a resorcinol unit of Structure 1a-j via a Friedel-Crafts 1,4-addition to produce compounds of Structures 2a to 2j or 3a to 3j followed by subsequent steps to produce the compounds of general Formula II via intermediates.

16. An intermediate formed in the process of the production of a compound of general Formula II.

Description

Example 1: Method of Manufacture of Normal CBD Derivatives

[0031] This example describes a novel method of synthesis which was used to produce novel analogues of normal CBD which demonstrated pharmacological activity. Scheme 1 below describes the initial reaction which was used to produce the primary intermediate and Scheme 2 describes the production of the normal CBD derivatives which were formed via a number of intermediates.

##STR00003##

Where R.sub.1=H or OMe and X=CH.sub.2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(O)iPr; NBz or NH

[0032] The resorcinol unit, in Structures la to 1j (shown below), underwent a Friedel-Crafts 1,4-addition reaction as shown in Scheme 1 to produce compounds of Structures 2a to 2j described below.

[0033] Various catalysts were tested. Silylated Jorgensen-Hayashi type gave poor yields but excellent selectivity. MacMillan-type catalysts gave better yields but poorer enantioselectivities.

##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##

[0034] The compound of Structures 2a to 2j or 3a to 3j (shown above) were then reacted as shown in Scheme 2 below to derive two different normal CBD derivatives 11a to 11j or 12a to 12j.

[0035] Deprotection of the derivatives 11c-j and 12 c-j further produced compounds 13 and 14.

##STR00009##

Synthesis of Intermediates 4a to 4j or 5a to 5j

[0036] Intermediates 2a-2j or 3a-3j were brominated with N-bromosuccinimide (NBS) to create arylbromide system compounds 4a-4j or 5a-5j shown below.

##STR00010## ##STR00011## ##STR00012## ##STR00013##

Synthesis of Intermediates 6a to 6j or 7a to 7j

[0037] Intermediates 4a-4j or 5a-5j were O-demethylated with boron tribromide in the presence of dichloromethane which resulted in the deprotected chiral resorcinol compounds as described in 6a to 6j or 7a to 7j depicted below.

##STR00014## ##STR00015## ##STR00016## ##STR00017##

Synthesis of Intermediates 9a to 9j (except 9f) or 10a to 10j (except 10f)

[0038] Coupling of the brominated intermediates of 6a-6j or 7a-7j with menthadienol (shown as structure 8 in Scheme 2) in the presence of boron trifluoride diethyl etherate produced the intermediates 9a to 9j (except 9f which is not possible) or 10a to 10j (except 10f which is not possible). These structures are depicted below.

##STR00018## ##STR00019## ##STR00020## ##STR00021##

Synthesis of Normal CBD Derivatives 11a to 11j (Except 11f) or 12a to 12j (except 12f)

[0039] 9a to 9j (except 9f) or 10a to 10j (except 10f) were debrominated with acetic acid and hydrogen bromide to produce the normal CBD derivatives 11a to 11j (except 11f) or 12a to 12j (except 12f) shown below.

##STR00022## ##STR00023## ##STR00024##

[0040] Furthermore, the N-protected moieties compounds 11c-11j (except 11f) and 12c to 12j (except 12f) can be deprotected to give the two NH derivatives, compounds 13 and 14, shown below.

##STR00025##

Example 2: Method of Manufacture of Abnormal CBD Derivatives

[0041] This example describes a novel method of synthesis which was used to produce novel analogues of abnormal CBD which demonstrated pharmacological activity. Scheme 1 depicted in Example 1 describes the initial reaction which was used to produce the primary intermediates 2a to 2j and 3a to 3j and Scheme 3 describes the production of the abnormal CBD derivatives which were formed via a number of intermediates.

##STR00026##

Synthesis of Intermediates 15a to 15j or 16a to 16j

[0042] Intermediates 2a to 2j or 3a to 3j were O-demethylated with boron tribromide in the presence of dichloromethane which resulted in the deprotected chiral resorcinol compounds as described in 15a to 15j or 16a to 16j below.

##STR00027## ##STR00028## ##STR00029##

Synthesis of Abnormal CBD Derivatives 17a to 17j or 18a to 18j

[0043] Coupling of the intermediates of 15a-15j or 16a-16j with menthadienol (shown as structure 8 in Scheme 3) in the presence of boron trifluoride diethyl etherate produced the abnormal CBD derivatives 17a to 17j or 18a to 18j depicted below.

##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035##

Synthesis of Compounds 19 to 22

[0044] Deprotection of 17c to 17j or 18c to 18j produced the compounds 19 to 22 described below.

##STR00036##

Conclusion

[0045] The application of the novel routes of synthesis to produce novel cannabidiol analogues and their intermediates is of benefit.

[0046] Compounds of the general formulas I and II are as detailed below and are equivalent to the compounds of structures 11a to 11j (except 11f), 12a to 12j (except 11f), 17a to 17j and 17a to 17j. Such compounds may provide improved or new therapeutic treatment options.

[0047] Deprotection of particular compounds has been found to produce additional novel molecules which provide additional improved or new therapeutic benefit. Such compounds include 13, 14, 19, 20, 21 and 22.

##STR00037##

where X is either CH.sub.2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(O)iPr; NBz or NH and Y is either H or OH.

##STR00038##

where X is either CH.sub.2; O; NBoc; NFMoc; NZ; NTs; NAc; NC(O)iPr; NBz or NH and Y is either H or OH.

Example 3: Evaluation of Cannabinoid Derivatives for Anticonvulsant Activity using the Maximal Electroshock Seizure Threshold (MEST) Test in the Mouse

[0048] The efficacy of exemplary cannabinoid derivatives according to Formula I and Formula II were tested in a mouse model of generalised seizure, the maximal electroshock seizure threshold (MEST) test.

[0049] The maximal electroshock seizure threshold (MEST) test is widely utilized preclinically to evaluate pro- or anti-convulsant properties of test compounds (Loscher et al., 1991).

[0050] In the MEST test the ability of a drug to alter the seizure threshold current required to induce hind limb tonic extensor convulsions is measured according to an “up and down” method of shock titration (Kimball et al., 1957). An increase in seizure threshold is indicative of anti-convulsant effect. Antiepileptic drugs including the sodium channel blockers (e.g. lamotrigine) with clinically proven efficacy against generalised tonic-clonic seizures all exhibit anti-convulsant properties in this test in the mouse.

[0051] Conversely, a reduction in seizure threshold is indicative of a pro-convulsant effect as observed with known convulsant agents such as picrotoxin.

[0052] The ability of a test compound to alter the stimulus intensity, expressed as current (mA), required to induce the presence of tonic hind limb extensor convulsions, is assessed in the MEST. The outcome of the presence (+) or absence (0) of tonic hind limb extensor convulsions observed from a current to produce tonic hind limb extension in 50% of animals in the treatment group (CC.sub.50) determines the seizure threshold for the treatment group and the effects were then compared to the CC.sub.50 of the vehicle control group.

Methods

Study Details

[0053] Naïve mice were acclimatised to the procedure room in their home cages for up to 7 days, with food and water available ad libitum.

[0054] All animals were weighed at the beginning of the study and randomly assigned to treatment groups based on a mean distribution of body weight across groups. All animals were dosed at 10 mL/kg via intraperitoneal (i.p) injection, with either vehicle, test compound at 200 mg/kg, or diazepam at 2.5 mg/kg.

[0055] Animals were individually assessed for the production of a tonic hind limb extensor convulsion at 60 min post-dose for vehicle, 30-120 min post-dose for test compound (dependant on compound) and 30 min post-dose for diazepam, from a single electroshock.

[0056] The first animal within a treatment group was given a shock at the expected or estimated CC.sub.50 current. For subsequent animals, the current was lowered or raised depending on the convulsions outcome from the preceding animal.

[0057] Data generated from each treatment group were used to calculate the CC.sub.50±SEM values for the treatment group.

Test Compounds

[0058] Vehicle: (5% ethanol, 5% solutol in 90% Saline) was prepared as follows: 2 mL of ethanol, 2 mL of solutol were warmed to 60° C., in 36 mL of saline (1:1:18).

[0059] Positive control: diazepam was used at 2.5 mg/kg.

[0060] The test compounds used were 12a, 12b, 18a and 18b. Test compounds were administered at 200 mg/kg (i.p.) in a 1:1:18 ethanol:solutol:saline formulation.

Sample Collection

[0061] Each animal was humanely killed immediately after production of a convulsion by destruction of the brain from striking the cranium, followed by the confirmation of permanent cessation of the circulation from decapitation under The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collection were performed following decapitation.

[0062] Blood was collected in Lithium-heparin tubes and centrifuged at 4° C. for 10 minutes at 1500×g. The resulting plasma was removed (>100 μL) and split into 2 aliquots of 0.5 mL Eppendorf tubes containing 10 μL of ascorbic acid (100 mg/mL) for stabilisation. Brains were removed, washed in saline and halved. Each half was placed into separate 2 mL screw cap cryovials, weighed and frozen on cardice.

Statistical analysis

[0063] The data for each treatment group were recorded as the number of +'s and 0's at each current level employed and this information is then used to calculate the CC.sub.50 value (current required for 50% of the animals to show seizure behaviour)±standard error.

[0064] Test compound effects were also calculated as percentage change in CC.sub.50 from the vehicle control group.

[0065] Significant difference between drug-treated animals and controls were assessed according to Litchfield and Wilcoxon (1949).

Results

[0066] FIGS. 1 to 4 and Tables 1 to 4 describe the data produced in this experiment.

[0067] In the vehicle group, the CC.sub.50 value was calculated to be 21 mA.

[0068] In the diazepam (2.5 mg/kg) treated group, administered i.p. 30 minutes before the test, the CC.sub.50 value was 35 mA. This result was statistically significant (p<0.001) compared to the vehicle control.

[0069] In the test compound treatment groups, administered i.p. between 30 and 120 minutes before the test, all four compounds produced a statistically significant CC.sub.50 value compared to vehicle.

[0070] Such data are indicative that these compounds will be of therapeutic benefit.

TABLE-US-00001 TABLE 1 Evaluation of effect of Compound 12a in the MEST test Test time % change Dose post dose CC.sub.50 +/− Sig- from Treatment (mg/kg) (min) N SEM nificance vehicle Vehicle — 60 12 21.0 +/− 0.5 — — Diazepam 2.5 30 12 35.0 +/− 1.1 P < 0.001  66% Compound 200 60 8 54.0 +/− 0.2 P < 0.001 157% 12a

TABLE-US-00002 TABLE 2 Evaluation of effect of Compound 12b in the MEST test Test time % change Dose post dose CC.sub.50 +/− Sig- from Treatment (mg/kg) (min) N SEM nificance vehicle Vehicle — 60 12 21.0 +/− 0.5 — — Diazepam 2.5 30 12 35.0 +/− 1.1 P < 0.001  66% Compound 200 30 12 43.8 +/− 0.2 P < 0.001 109% 12b

TABLE-US-00003 TABLE 3 Evaluation of effect of Compound 18a in the MEST test Test time % change Dose post dose CC.sub.50 +/− Sig- from Treatment (mg/kg) (min) N SEM nificance vehicle Vehicle — 60 12 21.0 +/− 0.5 — — Diazepam 2.5 30 12 35.0 +/− 1.1 P < 0.001 66% Compound 200 120 12 41.8 +/− 0.5 P < 0.001 99% 18a

TABLE-US-00004 TABLE 4 Evaluation of effect of Compound 18b in the MEST test Test time % change Dose post dose CC.sub.50 +/− Sig- from Treatment (mg/kg) (min) N SEM nificance vehicle Vehicle — 60 12 21.0 +/− 0.5 — — Diazepam 2.5 30 12 35.0 +/− 1.1 P < 0.001 66% Compound 200 120 12 40.3 +/− 0.8 P < 0.001 92% 18b

Conclusions

[0071] These data demonstrate a therapeutic effect for the compounds of Formula I and Formula II.

[0072] These data are significant as they provide heretofore unknown evidence that these novel cannabinoid derivatives may be of therapeutic value.

[0073] The compounds tested were those detailed as Compound 12a, Compound 12b, Compound 18a and Compound 18b. Such compounds are examples of the cannabinoid derivatives of general Formula I and Formula II.

[0074] Clearly as all compounds showed efficacy in the MEST test such therapeutic efficacy can be attributed to the cannabinoid derivatives of general Formula I and Formula II of the invention.