Derivatives of cannabidiol-c4 for the treatment of epilepsy

Patent metadata

Field	Value
Publication number	US-2024254072-A1
Application number	US-202218560337-A
Country	US
Kind code	A1
Filing date	May 11, 2022
Priority date	May 12, 2021
Publication date	Aug 1, 2024
Grant date	—

Abstract

The present invention relates to compounds that are pharmaceutically active and methods of preparation thereof. The compounds of the invention are 7-hydroxy-cannabidol-C4 (7-OH-CBD-C4) and 7-carboxy-cannabidiol-C4 (7-COOH-CBD-C4). The compounds of the invention are related to 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 compounds of the invention.

First claim

1 . A compound of formula (I), or a salt thereof:

2 . The compound of claim 1 as a pure, isolated or synthetic compound.

3 . A pharmaceutical composition comprising a compound of formula (I) or a salt thereof.

4 . The pharmaceutical composition of claim 3 in a form selected from a liquid, a solution, a suspension, an emulsion, a syrup, an electuary, a mouthwash, a drop, a tablet, a granule, a powder, a lozenge, a pastille, a capsule, a cachet, a pill, an ampoule, a bolus, a suppository, a pessary, a tincture, a gel, a paste, an ointment, a cream, a lotion, an oil, a foam, a spray, and an aerosol.

5 . The pharmaceutical composition of claim 3 or claim 4 comprising one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

6 . A compound of formula (I), or a salt thereof, for use a medicament.

7 . The compound for use of claim 6 , wherein the medicament is a medicament for treating epilepsy.

8 . The compound for use of claim 6 or claim 7 , wherein the medicament is a medicament for treating generalised seizures, focal-onset seizures, or tonic-clonic seizures.

9 . A compound of formula (I), or a salt thereof, for use in a method of treatment.

10 . The compound for use of claim 9 , wherein the method of treatment is a method of treating epilepsy.

11 . The compound for use of claim 9 or claim 10 , wherein the method of treatment is a method of treating generalised seizures, focal-onset seizures, or tonic-clonic seizures.

12 . The compound for use of any of claims 9 to 11 , wherein the compound is used in combination with one or more concomitant anti-epileptic drugs (AEDs).

13 . The compound for use of claim 12 , wherein the AEDs are selected from rufinamide; lamotrigine; topiramate; felbamate, stiripentol, clobazam and valproic acid.

14 . The compound for use of any of claims 9 to 13 , wherein the dose of the compound is between 1 and 2,000 mg/day, such as between 20 and 1,000 mg/day, such as between 50 and 500 mg/day.

15 . A method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I) or a salt thereof.

16 . The method of treatment of claim 15 , wherein the method of treatment is a method of treating epilepsy.

17 . The method of treatment of claim 15 or 16 , wherein the method of treatment is a method of treating generalised seizures, focal-onset seizures, or tonic-clonic seizures.

18 . A process for the production of a compound of formula (I) comprising the following steps:
i) treating 3,5-dimethoxybenzyl bromide with a propyl Grignard reagent to produce 1-butyl-3,5-dimethoxybenzene; ii) treating 1-butyl-3,5-dimethoxybenzene with a demethylation reagent to produce 5-butylbenzene-1,3-diol; iii) coupling 5-butylbenzene-1,3-diol with (R)-isolimonenediol 7-O-acetate in the presence of acid to produce 7-acetoxy-CBD-C4; and iv) treating 7-acetoxy-CBD-C4 with a reducing agent to produce the compound of formula (I).

19 . The method of claim 18 , wherein the Grignard reagents is selected from n-propylmagnesium chloride and n-propylmagnesium bromide, such as n-propylmagnesium chloride.

20 . The method of claim 18 or claim 19 , wherein the demethylation reagent is selected from boron tribromide, beryllium dichloride, aluminium trichloride, trimethylsilyliodide and pyridine hydrochloride; such as boron tribromide.

21 . The method of any of claims 18 to 20 , wherein the acid is selected from p-toluenesulfonic acid and aluminium trichloride, such as catalytic p-toluenesulfonic acid.

22 . The method of any of claims 18 to 21 , wherein the reducing agent is selected from lithium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride (red-Al), diborane and sodium borohydride; such as sodium borohydride.

23 . An intermediate formed in the process of the production of a compound of formula (I), wherein the intermediate is selected from:

24 . A compound of formula (II) or a salt thereof:

25 . The compound of claim 24 as a pure, isolated or synthetic compound.

26 . A pharmaceutical composition comprising a compound of formula (II) or a salt thereof.

27 . The pharmaceutical composition of claim 26 in a form selected from a liquid, a solution, a suspension, an emulsion, a syrup, an electuary, a mouthwash, a drop, a tablet, a granule, a powder, a lozenge, a pastille, a capsule, a cachet, a pill, an ampoule, a bolus, a suppository, a pessary, a tincture, a gel, a paste, an ointment, a cream, a lotion, an oil, a foam, a spray, and an aerosol.

28 . The pharmaceutical composition of claim 26 or claim 27 comprising one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

29 . A compound of formula (II), or a salt thereof, for use a medicament.

30 . The compound for use of claim 29 , wherein the medicament is a medicament for treating epilepsy.

31 . The compound for use of claim 29 or claim 30 , wherein the medicament is a medicament for treating generalised seizures, focal-onset seizures, or tonic-clonic seizures.

32 . A compound of formula (II), or a salt thereof, for use in a method of treatment.

33 . The compound for use of claim 32 , wherein the method of treatment is a method of treating epilepsy.

34 . The compound for use of claim 32 or claim 33 , wherein the method of treatment is a method of treating generalised seizures, focal-onset seizures, or tonic-clonic seizures.

35 . The compound for use of any of claims 32 to 34 wherein the compound is used in combination with one or more concomitant anti-epileptic drugs (AEDs).

36 . The compound for use of claim 35 , wherein the AEDs are selected from rufinamide; lamotrigine; topiramate; felbamate, stiripentol, clobazam and valproic acid.

37 . The compound for use of any of claims 32 to 36 , wherein the dose of the compound is between 1 and 2,000 mg/day, such as between 20 and 1,000 mg/day, such as between 50 and 500 mg/day.

38 . A method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I) or a salt thereof.

39 . The method of treatment of claim 38 , wherein the method of treatment is a method of treating epilepsy.

40 . The method of treatment of claim 38 or 39 , wherein the method of treatment is a method of treating generalised seizures, focal-onset seizures, or tonic-clonic seizures.

Assignees

• Gw Pharma Ltd

Inventors

• Silcock Alan James
• Tse Karen Ka-Yen

Classifications

• C07C39/23 Primary

  polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/658

  o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title