JP7637241B2 - Silicon-Based Tetrahydrocannabinol Derivatives and Compositions Thereof - Google Patents

Description

Tetrahydrocannabinol (THC) is a phytocannabinoid known to have anti-inflammatory activity.

It is the primary psychoactive cannabinoid known to bind to cannabinoid receptors (CB1 and CB2) and reduce pain, inflammation, and hyperalgesia (see, e.g., Citti et al., Sci. Rep. 9, 20335 (2019); Karsak et al., Science, 316,1494 (2007); Richardson et al., Pain, 75, 111 (1998)). Tetrahydrocannabinol is the designated name for (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, shown below:

Citti et al., Sci. Rep. 9, 20335 (2019) Karsak et al., Science, 316,1494 (2007) Richardson et al., Pain, 75, 111 (1998) Karsak et al., Science, 316, 1494-1497 (2007)

Topical formulations of tetrahydrocannabinol have been reported to reduce allergic inflammation (Karsak et al., Science, 316, 1494-1497 (2007)). Pure tetrahydrocannabinol has poor stability in air, light, acidic media, and elevated temperatures, but derivatives of tetrahydrocannabinol with improved stability would be attractive. Also desirable would be derivatives with lower surface tension that could allow for the formation of thin films, either directly or by increasing solubility in low surface tension fluids such as silicones.

The silicon-based tetrahydrocannabinol derivative according to one embodiment of the present disclosure has the formula (I):

contains silicon-based functional groups containing Si-O-Si bonds bonded to tetrahydrocannabinol molecules.

A topical or dermatological formulation according to one embodiment of the present disclosure comprises a base formulation and a compound of formula (I):

and at least one silicon-based tetrahydrocannabinol derivative containing at least one silicon-based functional group containing a Si-O-Si bond bonded to a tetrahydrocannabinol molecule having the formula:

The present disclosure relates to compositions containing derivatives of tetrahydrocannabinol (THC) containing silicon-containing functional groups, and methods for their preparation, that are useful in a variety of applications, including the formulation of topical pharmaceuticals and personal care products. The silicon-containing tetrahydrocannabinol derivatives described herein are unique hybrid organosilicon compounds formed by attaching tetrahydrocannabinol to a siloxane backbone, also described as molecules containing one silicon-based functional group containing a Si-O-Si bond attached to a tetrahydrocannabinol molecule. Although the binding affinity of the compounds described herein to cannabinoid receptors has not yet been studied, they are expected to provide improved stability and solubility, and to release free tetrahydrocannabinol uniformly and over a long period of time.

As used herein, the terms tetrahydrocannabinol and THC are intended to encompass all isomers of tetrahydrocannabinol, including those found in nature or synthetically developed.

Preferred embodiments of the compounds of the present disclosure include trisiloxanyl derivatives of tetrahydrocannabinol in which the siloxane-based groups are attached through the phenolic hydroxyl groups of the tetrahydrocannabinol molecule to form Si-O-C bonds.

Silicon-based tetrahydrocannabinol derivatives include tetrahydrocannabinol molecules, such as those shown in formula (I), having a silicon-based group as a functional group. Most preferably, the silicon-based group is a siloxanyl group or a trialkoxysilane-containing group.

Preferred tetrahydrocannabinol derivatives described herein have a structure according to formula (I) above, in which the phenolic hydroxyl group is bonded to a siloxane moiety containing two or more silicon atoms, preferably three or more silicon atoms, and most preferably about 3 to about 10 silicon atoms.

Tetrahydrocannabinol derivatives according to embodiments of the present invention have the general formula (A). In this formula, R can be, for example, but not limited to, SiMe( _{OSiMe3 ) 2} , _{SiMe2 ( OSiMe2 )4CH2CH2CH2CH3 , SiMe2OSiMe3} , and _{SiMe2OSiMe2C6H5} , where _" Me" is a methyl group. However, compounds having formula (A) within the scope of the present disclosure are not limited to these substituents, and _{other silicon - containing} functional groups having Si-O-Si bonds known in the art or to be developed may also be suitable for R.

Substituents containing a single silicon atom without an oxane (oxygen) bridge between two or more silicon atoms are not within the scope of this disclosure, as such tetrahydrocannabinol derivatives are unable to provide acceptable film-forming properties. For example, simple trialkylsilyl derivatives, as well as derivatives containing only alkyl, aryl, hydrogen, halogen, vinyl, allyl, and/or alkoxy substituents on the silicon, are not within the scope of this disclosure, as they are not effective for the intended purpose.

Other compounds within the scope of the present disclosure include polydimethylsiloxanes in which tetrahydrocannabinol is substituted in place _of methyl groups on the polydimethylsiloxane through the phenolic oxygen, for example, _Me3Si ( _OSiMe2 ) _m (OSiMeTHC) _nSiMe3 , where "THC" represents tetrahydrocannabinol, Me is a methyl group, and m and n are integers. Preferably, m is 1 to about 100 and n is 1 to about 10.

Silicon-based tetrahydrocannabinol derivatives according to embodiments of the present disclosure include a wide variety of derivatized compounds, including most preferred compounds such as (tetrahydrocannabinoloxy)heptamethyltrisiloxane (formula (II)), tetrahydrocannabinoloxy-terminated polydimethylsiloxane (formula (III)), and tetrahydrocannabinoloxypropyl-terminated polydimethylsiloxane (formula (IV)) shown below, where m and n are integers, preferably m is 1 to about 100 and n is 1 to about 10.

Compounds according to embodiments of the present disclosure may contain a direct ether bond (direct Si-O bond) between the silicon-containing functional group and the phenolic hydroxyl group of the tetrahydrocannabinol molecule, or may contain an alkyl group spacer between the phenolic hydroxyl group on the tetrahydrocannabinol and the silicon-based functional group, for example, compounds of formula _{( A} ) where _R is _{CH2SiMe2OSiMe3} or _{CH2SiMe2OSiMe2C6H5 .} The spacer is not limited to _CH2 , but may also be a longer alkyl chain containing up to _about 11 carbon atoms, for example _{( CH2} ) ₃ , with _CH2 being a preferred embodiment as well.

Compounds according to embodiments of the present disclosure that contain an alkyl group spacer between the phenolic hydroxyl group on the tetrahydrocannabinol and the silicon-based functional group may have the following general formula (B): where R' is a silicon-based group and x is an integer ranging from 1 to about 11, preferably 1 (methyl) to ₃ ( _propyl ). Most preferably, the silicon-based group is a siloxanyl group or a trialkoxysilane-containing group. R' may be, for example, without _limitation , _SiMe (OSiMe3) ₂ , _{SiMe2 ( OSiMe2 ) 4CH2CH2CH2CH3} , _SiMe2OSiMe3 , or _{SiMe2OSiMe2C6H5 , where} Me is _methyl .

The direct Si-O bonds of tetrahydrocannabinol derivatives such as those shown in formula (A) may result in reduced allergic inflammation by releasing free tetrahydrocannabinol over an extended period of time through slow hydrolysis. The Si-O bonds on tetrahydrocannabinol derivatives are not stable when exposed to moisture, which results in slow decomposition of the compound to form free tetrahydrocannabinol and low molecular weight siloxanes. Silane-based tetrahydrocannabinol derivatives are predicted to be stable when stored in air and protected from moisture. They are predicted to exhibit biological activity in pharmaceutical applications through direct or slow hydrolysis to form underivatized THC.

Unlike many silicones and silicone derivatives, these compounds are easily incorporated into topical or dermatological products, including anti-inflammatory and soothing formulations, due to their solubility in a range of polar compounds, such as castor oil and various cosmetic or dermatological vehicles. They may also act as co-solvents for silicones. Furthermore, due to such solubility, these derivatives may be useful as compatibilizers for other bioactive substances, such as unmodified cannabidiol and tetrahydrocannabinol compounds, among other possible applications.

The tetrahydrocannabinol derivatives described herein may be prepared by a variety of synthetic routes. According to one embodiment of the present disclosure, these compounds may be prepared by reacting the hydroxyl groups on the benzenoid ring of tetrahydrocannabinol with an allyl halide in a solvent to form an allyloxytetrahydrocannabinol intermediate, which is then hydrosilylated with a silane compound and a catalyst to form a silicon-based tetrahydrocannabinol derivative with a spacer. It is also within the scope of the present disclosure to form Si-O bonds directly on the hydroxyl groups of tetrahydrocannabinol by reacting the hydroxyl groups (C-OH) with a chlorine-containing siloxane compound (-Si-Cl) in the presence of a base acceptor, or by dehydrocoupling the hydroxyl groups with a hydride-containing siloxane compound (-Si-H). Another possible synthetic route to form a direct Si-O bond is to form an alkali metal alkoxide intermediate (-C-O-Na) and reacting this intermediate with either a Si-Cl-containing siloxane compound or a Si-H-containing siloxane compound. The reaction to form the hydrocarbon crosslinks proceeds by the addition of hydride-containing siloxanes (-Si-H) across the C=C double bond via a hydrosilylation reaction.

The silane compound used in the above reaction may be any of a wide variety of silicon-based compounds, preferably including alkylsilanes, alkoxysilanes, alkylsiloxanes and alkoxysiloxanes, as well as their derivatized or functionalized counterparts. In general, it is preferred to have two or more silicon atoms in the substitution to provide suitable solubility and application properties for topical creams and ointments. Examples include, but are not limited to, bis(trimethylsiloxy)methylsilane, bis(trimethylsiloxy)ethylsilane, bis(trimethylsiloxy)propylsilane, bis(triethylsiloxy)methylsilane, bis(triethylsiloxy)ethylsilane, bis(triethylsiloxy)propylsilane, triethoxysilane, trimethoxysilane, tripropylsilane, bis(tripropylsiloxy)methylsilane, bis(tripropylsiloxy)ethylsilane, bis(tripropylsiloxy)propylsilane, and similar compounds.

Also useful as silane compounds herein are polymeric silicon-containing molecules having similar reactive capabilities to the silane monomer structures listed above, such as polydimethylsiloxane, polydiethylsiloxane, polydipropylsiloxane, polymethylethylsilane, polymethylpropylsiloxane, and other polyalkyl or polyalkenylsiloxanes, as known in the art or to be developed. Although the chain length can vary, the molecular weight (Mn) of the polymeric silane compound used to form the polymeric silicon-based derivative group on the tetrahydrocannabinol is preferably from 100 to about 5000, and most preferably from about 500 to about 2000. It should be noted that variations in molecular weight above and below this range are within the scope of the present disclosure, and that components having different chain lengths may contribute to changes in properties accordingly. For example, generally, lower molecular weight chains will tend to be more emollient in nature, while higher molecular weight chains will tend to be more inherent in that they last longer on the skin and are less likely to wash off.

It should also be understood that the derivatives described herein may be produced using pure tetrahydrocannabinol. Alternatively, the derivatives may be formed and provided as components of phytocannabinoid and/or other phytochemical mixtures. For example, tetrahydrocannabinol derivatives of cannabis extracts may be formed without isolating the pure tetrahydrocannabinol component. Additionally, compositions according to the present invention may contain one or more of the derivatives described herein and one or more phytochemicals extracted from cannabis.

The silicon-based tetrahydrocannabinols described herein may be used in a variety of topical and dermatological compositions, including those having silicon compounds or silicone-based polymers in the base formulation, preferably since the derivatives promote compatibility and solubility in such compounds in the formulation. However, the present disclosure is not limited to these compositions and may include any topical or dermatological composition in which silicon-based tetrahydrocannabinol derivatives are useful. The cosmetic and topical compositions of the present disclosure include a base formulation, which may be any suitable topical or dermatological base formulation as described above, and at least one silicon-based tetrahydrocannabinol derivative as described herein. Silicon-based tetrahydrocannabinol derivatives include tetrahydrocannabinol molecules or commercially available or naturally occurring derivatives thereof, and include silicon-based functional groups bonded to the tetrahydrocannabinol molecule (or its derivatives) via oxygen atoms in the benzenoid ring.

When incorporated into such formulations, the silicon-based tetrahydrocannabinol derivatives are preferably present in an amount of about 0.01 weight percent to about 20 weight percent, preferably about 0.5 weight percent to about 5 weight percent, and most preferably about 0.5 to about 1.0 weight percent, based on the weight of the formulation.

The invention will now be described with reference to the following non-limiting examples.

Synthesis of 1,1,1,3,5,5,5-heptamethyl-3-(((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)trisiloxane (II)

Sodium (0.55 g, 0.02 mol) and tetrahydrofuran (13.42 g) are charged to the reactor. A solution of tetrahydrocannabinol (6.29 g, 0.02 mol) in tetrahydrofuran (37.98 g) is added dropwise over 30 minutes while maintaining the pot temperature below 70° C. The resulting reaction mixture is stirred at 50-60° C. until all the sodium is consumed. Bis(trimethylsiloxy)methylsilane (6.77 g, 0.03 mol) is added dropwise over 10 minutes at 70° C. and the reaction mixture is then heated at 110-120° C. for 10 hours. The reaction mixture is filtered through silica gel (40 g) and washed with tetrahydrofuran (400 g). The filtrate is concentrated in vacuo. The residue contains the product and unreacted tetrahydrocannabinol and is analyzed by ¹ H NMR and FTIR.

Synthesis of 1-butyl-1,1,3,3,5,5,7,7,9,9-decamethyl-9-(((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)pentasiloxane (III)

Sodium (0.55 g, 0.02 mol) and tetrahydrofuran (13.42 g) are charged to the reactor. A solution of tetrahydrocannabinol (6.29 g, 0.02 mol) in tetrahydrofuran (37.98 g) is added dropwise over 30 minutes while maintaining the pot temperature below 70° C. The resulting reaction mixture is stirred at 50-60° C. until all of the sodium is consumed. 1-Butyl-1,1,3,3,5,5,7,7,9,9-decamethylpentasiloxane (12.39 g, 0.03 mol) is added dropwise over 10 minutes at 70° C. and the reaction mixture is then heated at 110-120° C. for 10 hours. The reaction mixture is filtered through silica gel (40 g) and washed with tetrahydrofuran (400 g). The filtrate is concentrated in vacuo. The residue contains the product and unreacted tetrahydrocannabinol and is analyzed by ¹ H NMR and FTIR.

Tetrahydrocannabinol oxypropyl terminated polydimethylsiloxane(IV)

Allyloxytetrahydrocannabinol (70.9 g, 0.2 mol) and toluene (50 mL) are charged to a reactor. The resulting mixture is heated to 80-90° C. Once the pot temperature reaches 80-90° C., Karstedt's catalyst (2% Pt concentration in xylene, 0.5 mL) is added. Hydride-terminated polydimethylsiloxane (Mn-1050, 105 g) is added dropwise while controlling the exotherm, and the reaction mixture is then heated at 85-115° C. until FTIR indicates that all the Si-H has been consumed. Activated charcoal is added to the mixture and stirred overnight. The mixture is filtered and the filtrate is concentrated in vacuo. The residue contains the product and unreacted tetrahydrocannabinol and is analyzed by ¹ H NMR and FTIR.

It will be appreciated by those skilled in the art that modifications may be made to the above-described embodiments without departing from the broad inventive concept thereof. Based on this disclosure, one skilled in the art will further appreciate that the relative proportions of the components exemplified above may be varied without departing from the spirit and scope of the invention. It is therefore understood that the invention is not limited to the particular embodiments disclosed, but is intended to include modifications within the spirit and scope of the invention as defined by the appended claims.

Claims (11)

Formula (A):
_{A silicon - based} tetrahydrocannabinol _derivative having the formula: (wherein R _{is SiMe ( OSiMe3 ) 2} , _SiMe2 ( _OSiMe2 ) _{4CH2CH2CH2CH3} , _{SiMe2OSiMe3 , SiMe2OSiMe2C6H5} , _{CH2SiMe2OSiMe3} , or _{CH2SiMe2OSiMe2C6H5 ,} and Me represents _a methyl group _{) .} Formula (B):
_{A silicon} based tetrahydrocannabinol derivative having the formula: (wherein R' is SiMe _{( OSiMe3 ) 2} , _SiMe2 ( _{OSiMe2 ) 4CH2CH2CH2CH3} , _SiMe2OSiMe3 , or _{SiMe2OSiMe2C6H5} , Me represents a methyl group, and x is _an integer in the range of 1 to _{11 .} Formula (II):
2. The silicon-based tetrahydrocannabinol derivative of claim 1, having the formula: (wherein Me represents a methyl group). Formula (III):
2. The silicon-based tetrahydrocannabinol derivative of claim 1, having the formula: Formula (IV):
(wherein Me represents a methyl group, m is an integer from 1 to 100, and n is an integer from 1 to 10 ) . A topical or dermatological composition comprising a base formulation and at least one silicon-based tetrahydrocannabinol derivative according to any one of claims 1 to 5 . 10. A method for making the silicon based tetrahydrocannabinol derivative of claim 2 or 5 , comprising reacting tetrahydrocannabinol with an allyl halide in a solvent to form an allyloxytetrahydrocannabinol intermediate, and reacting the allyloxytetrahydrocannabinol intermediate with a silane compound and a catalyst to form the silicon based tetrahydrocannabinol derivative. A method for making the silicon-based tetrahydrocannabinol derivatives of claim 1, comprising the step of forming a silylated alkyl ether on the tetrahydrocannabinol molecule by reacting a chlorine-containing siloxane compound with a hydroxyl group in the presence of a base acceptor. A method for making the silicon-based tetrahydrocannabinol derivatives of claim 1, comprising forming a silylated alkyl ether on a tetrahydrocannabinol molecule by dehydrocoupling a hydride-containing siloxane. A method for making the silicon-based tetrahydrocannabinol derivatives of claim 1, comprising forming an intermediate alkali metal alkoxide followed by reaction with a silicon hydride or silicon-chlorine containing compound to form a silylated alkyl ether on the tetrahydrocannabinol molecule. 10. A composition comprising a silicon-based tetrahydrocannabinol derivative according to claim 1, 2 or 5 and at least one phytochemical extracted from cannabis.