CN116685595A - Silicon-based tetrahydrocannabinol derivatives and compositions thereof - Google Patents

Abstract

Silicon-based tetrahydrocannabinol derivatives and methods for synthesizing the same are provided, wherein the derivatives comprise tetrahydrocannabinol molecules and at least one silicon-based group containing a Si-O-Si bond. The derivatives are useful in topical and dermatological compositions, have potentially beneficial topical properties, and can increase the solubility and compatibility of topical and dermatological formulations containing silicon-based materials.

Description

Silicon-based tetrahydrocannabinol derivatives and compositions thereof

Background of the invention

Tetrahydrocannabinol (THC) is a phytocannabinoid known to have anti-inflammatory activity. It is the major psychoactive cannabinoid that can bind to cannabinoid receptors (CB1 and CB2) to 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)). THC is (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol The assigned name of the , as follows:

Topical formulations of THC have been reported to reduce allergic inflammation (Karsak et al., Science, 316, 1494-1497 (2007)). Pure THC is less stable in air, light, acidic media and high temperature, but derivatives of THC are more stable and attractive. Derivatives with lower surface tension are also desirable, capable of forming thin films either directly or through increased solubility in low surface tension fluids such as silicones.

Contents of the invention

According to one embodiment of the invention, the silicon-based THC derivative comprises a silicon-based functional group containing Si-O-Si bonds, said silicon-based functional group being bound to a THC molecule having the formula (I):

According to one embodiment of the invention, a topical or dermatological formulation comprises a base formulation and at least one silicon-based THC derivative comprising at least one Si-O-Si-containing A bonded silicon-based functional group that binds to a THC molecule having the formula (I):

Detailed description of the invention

The present invention relates to compositions comprising tetrahydrocannabinol (THC) derivatives containing silicon-containing functional groups, which are beneficial for various applications, including the formulation of topical pharmaceutical products and personal care products, and methods for their preparation. The silicon-containing THC derivatives described herein are unique hybrid organosilicon compounds formed by attaching THC to a siloxane backbone, which is also described as containing Molecules of silicon-based functional groups of Si-O-Si bonds, which are bonded to THC molecules. Although the binding affinities of the compounds described herein to cannabinoid receptors have not been studied, they are expected to offer increased stability and solubility and a uniform release of free THC over an extended period of time.

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

Preferred embodiments of the compounds of the present invention include trisiloxane derivatives of THC, wherein the siloxane groups are bonded via the phenolic hydroxyl groups of the THC molecule, thereby forming Si-O-C bonds.

Silicon-based THC derivatives include THC molecules, as shown in formula (I), having silicon-based groups as functional groups. Most preferably, the silicon-based groups are siloxane groups or trialkoxysilane-containing groups.

Preferred THC derivatives described herein have the structure of formula (I) above, wherein the phenolic hydroxyl group is bonded to a siloxane moiety containing two or more silicon atoms, preferably three one or more silicon atoms, most preferably from about 3 to about 10 silicon atoms.

The THC derivatives according to the embodiments of the present invention have the general formula (A). In this formula, R can be, for example but not limited to, SiMe(OSiMe ₃ ) ₂ , SiMe ₂ (OSiMe ₂ ) ₄ CH ₂ CH ₂ CH ₂ CH ₃ , SiMe ₂ OSiMe ₃ and SiMe ₂ OSiMe ₂ C ₆ H ₅ , where "Me" is methyl. However, compounds of formula (A) within the scope of the present invention are not limited to these substituents, and other silicon-containing functional groups with Si-O-Si bonds known in the art or to be developed will also be suitable for R.

Substituents containing a single silicon atom without an oxane (oxygen) bridge between two or more silicon atoms are outside the scope of this invention as such THC derivatives do not provide acceptable film forming properties . For example, simple trialkylsilyl derivatives, and derivatives containing only alkyl, aryl, hydrogen, halogen, vinyl, allyl and/or alkoxy substituents on the silicon are not within the scope of the present invention. within the scope of these, as these are not effective for their intended purpose.

Other compounds within the scope of the present invention include dimethicones in which tetrahydrocannabinol replaces the methyl group on the dimethicone via the phenolic oxygen, such as Me ₃ Si(OSiMe ₂ ) _m (OSiMeTHC ) _n SiMe ₃ , where "THC" stands for tetrahydrocannabinol, Me is methyl, 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 invention include a variety of derivative compounds, including most preferred compounds such as (tetrahydrocannabinoloxy)heptamethyltrisiloxane (formula (II)), tetrahydrocannabinol Hydrocannabinoloxy-terminated polydimethylsiloxane (formula (III)) and tetrahydrocannabinoloxypropyl-terminated polydimethylsiloxane (formula (IV)), as shown below, wherein 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 invention may contain a direct ether bond (direct Si-O bond) between the silicon-containing functional group and the phenolic hydroxyl group of the THC molecule, or may An alkyl spacer is contained between the functional groups, for example, R in the formula (A) is CH ₂ SiMe ₂ OSiMe ₃ or CH ₂ SiMe ₂ OSiMe ₂ C ₆ H ₅ . The spacer is not limited to _CH2 , but may also be a longer alkyl chain containing up to about 11 carbon atoms, such as ( _CH2 ) ₃ , which along with _CH2 is also a preferred embodiment.

According to an embodiment of the present invention, the compound containing an alkyl spacer between the phenolic hydroxyl group of THC and the silicon-based functional group may have the following general formula (B), wherein R' is a silicon-based group, and x is 1 An integer of up to about 11, preferably 1 (methyl) to 3 (propyl). Most preferably, the silicon-based groups are siloxane groups or trialkoxysilane-containing groups. R' can be, for example but not limited to, SiMe(OSiMe ₃ ) ₂ , SiMe ₂ (OSiMe ₂ ) ₄ CH ₂ CH ₂ CH ₂ CH ₃ , SiMe ₂ OSiMe ₃ or SiMe ₂ OSiMe ₂ C ₆ H ₅ , where Me is methyl.

The direct Si-O bond of the THC derivative as represented by formula (A) can release free THC over a long period of time through slow hydrolysis resulting in reduced allergic inflammation. The Si-O bonds on THC derivatives are unstable when exposed to moisture, which causes the compound to slowly decompose to form free THC and low molecular weight siloxanes. The silyl THC derivatives are expected to be stable when stored in air and protected from moisture. They are expected to exhibit biological activity directly in pharmaceutical applications, or through slow hydrolysis to form unactivated THC.

Unlike many silicones and silicone derivatives, these compounds are readily incorporated into topical or dermatological products due to their solubility in a range of polar compounds such as castor oil and various cosmetic or dermatological vehicles , including anti-inflammatory and demulcent agents. They also act as co-solvents for silicones. Furthermore, due to this solubility, these derivatives could be used as compatibilizers for other biologically active substances, such as unmodified cannabidiol and THC compounds, among other possible applications.

The THC derivatives described herein can be prepared by various synthetic routes. According to one embodiment of the present invention, the compound can be formed by reacting the hydroxyl group on the benzene ring of THC with an allyl halide in a solvent to form an allyloxytetrahydrocannabinol intermediate, and then use The silane compound and the catalyst hydrosilylate the intermediate to form a silicon-based tetrahydrocannabinol derivative with a spacer. By reacting a hydroxyl group (C-OH) with a chlorine-containing siloxane compound (-Si-Cl) in the presence of a base acceptor, or by deactivation of a hydroxyl group with a hydride-containing siloxane compound (-Si-H) Hydrogen coupling, formation of direct Si-O bonds on the hydroxyl groups of THC is also within the scope of the present invention. Another possible synthetic route to form a direct Si-O bond is to form an alkali metal alkoxide intermediate (-C-O-Na) and react this intermediate with a Si-Cl or Si-H containing siloxane compound . The reaction to form a hydrocarbon bridge is carried out by adding a hydride-containing siloxane (-Si-H) to the C=C double bond through a hydrosilylation reaction.

The silane compound used in the above reaction can be any of a variety of silicon-based compounds, preferably including alkylsilanes, alkoxysilanes, alkylsiloxanes and alkoxysiloxanes and their derivatization or functionalization the counterpart of . In general, two or more silicon atoms in the substituent are preferred in order to provide solubility and spreading properties suitable for topical creams and ointments. Examples include, but are not limited to, bis(trimethylsiloxy)methylsilane, bis(trimethylsiloxy)ethylsilane, bis(trimethylsiloxy)propylsilane, bis(trimethylsiloxy)propylsilane, Ethylsiloxy)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 in this context are silicon-containing polymeric molecules having similar reactivity to the above-mentioned silane monomer structures, such as polydimethylsiloxane, polydiethylsiloxane, polydipropylsiloxane Oxane, polymethylethylsilane, polymethylpropylsiloxane and other polyalkyl or polyalkenylsiloxanes known in the art or to be developed. The chain length can vary, but the molecular weight (Mn) of the polymeric silane compound used to form the polymeric silyl derivative groups on the THC preferably ranges from 100 to about 5000, 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 invention, and components with different chain lengths may provide different properties accordingly. For example, in general, lower molecular weight chains tend to be more emollient in nature, while higher molecular weight chains tend to be more substantive, longer-wearing and more emollient on the skin. Wash-off resistant.

It should also be understood that the derivatives described herein may be prepared using pure THC. Alternatively, the derivatives may be formed and provided as components of phytocannabinoids and/or other phytochemical mixtures. For example, THC derivatives of cannabis extracts can be formed without isolating the pure THC components. Furthermore, the composition according to the invention may contain one or more derivatives as described herein and one or more phytochemicals extracted from cannabis.

The silicon-based THC described herein can be used in a variety of topical and dermatological compositions, including those preferably having silicon compounds or silicone-based polymers in the base formulation because the derivatives facilitate formulation compatibility and solubility of such compounds in However, the present invention is not limited to those compositions and may include any topical or dermatological composition in which the silicon-based THC derivatives are useful. The cosmetic and topical compositions of the present invention comprise a base formulation which may be any suitable topical or dermatological base as described above and at least one silicon-based THC derivative as described herein preparation. Silicon-based THC derivatives include the THC molecule or its commercial or natural derivatives and include a silicon-based functional group bonded to the THC molecule (or its derivatives) through the oxygen atom of the benzene ring .

When incorporated into such formulations, the silicon-based THC derivatives are present (based on the weight of the formulation) in an amount of, preferably, from about 0.01% by weight to about 20% by weight, preferably, from about 0.5% by weight to about 5% by weight. % by weight, most preferably, from about 0.5% by weight to about 1.0% by weight.

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

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

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

Example 2: 1-butyl-1,1,3,3,5,5,7,7,9,9-decamethyl-9-(((6aR,10aR)-6,6,9-trimethyl Synthesis of 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) were added to the reactor. A solution of THC (6.29 g, 0.02 mol) in THF (37.98 g) was added dropwise over 30 min while maintaining the pot temperature below 70°C. The resulting reaction mixture was stirred at 50-60°C until all sodium was consumed. At 70°C, 1-butyl-1,1,3,3,5,5,7,7,9,9-decamethylpentasiloxane (12.39 g, 0.03 mol) was added dropwise within 10 min, The reaction mixture was then heated at 110-120 °C for 10 h. The reaction mixture was filtered through silica gel (40 g) and washed with tetrahydrofuran (400 g). The filtrate was concentrated in vacuo. The residue, containing product and unreacted THC, was analyzed by ¹ H NMR and FTIR.

Example 3: Tetrahydrocannabinoloxypropyl-terminated polydimethylsiloxane (IV)

Allyloxytetrahydrocannabinol (70.9 g, 0.2 mol) and toluene (50 mL) were charged to the reactor. The resulting mixture was heated to 80-90°C. When the pot temperature reached 80-90°C, Karstedt's catalyst (2% Pt in xylene, 0.5 mL) was added. Hydride-terminated polydimethylsiloxane (Mn-1050, 105 g) was added dropwise while controlling the exotherm, and the reaction mixture was heated at 85-115 °C until FTIR indicated that all Si-H had been consumed . Activated charcoal was added to the mixture and stirred overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue contained product and unreacted THC and was analyzed by ¹ HNMR and FTIR.

It will be appreciated by those skilled in the art that changes may be made in the above-described embodiments without departing from their broad inventive concepts. In addition, based on the present invention, those skilled in the art will further recognize that the relative proportions of the above-mentioned components can be changed without departing from the spirit and scope of the present invention. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.

Claims (18)

1. A silicon-based tetrahydrocannabinol derivative comprising a silicon-based functional group containing a Si-O-Si bond, the silicon-based functional group is combined with a THC molecule having formula (I): 2. The silicon-based THC derivative according to claim 1, wherein the silicon-based functional group is combined with the THC molecule through the phenolic oxygen atom on the benzene ring. 3. The silicon-based tetrahydrocannabinol derivative according to claim 1, wherein the silicon-based functional group is a siloxane group or a trialkoxysilane-containing group. 4. The silicon-based tetrahydrocannabinol derivative according to claim 1, wherein the silicon-based functional group contains at least two silicon atoms. 5. The silicon-based tetrahydrocannabinol derivative according to claim 1, having the formula (A), wherein R is SiMe(OSiMe ₃ ) ₂ , SiMe ₂ (OSiMe ₂ ) ₄ CH ₂ CH ₂ CH ₂ CH ₃ , SiMe ₂ OSiMe ₃ , SiMe ₂ OSiMe ₂ C ₆ H ₅ , CH ₂ SiMe ₂ OSiMe ₃ or CH ₂ SiMe ₂ OSiMe ₂ C ₆ H ₅ , where Me represents methyl: 6. The silicon-based THC derivative according to claim 1, having formula (B), wherein R' is SiMe(OSiMe ₃ ) ₂ , SiMe ₂ (OSiMe ₂ ) ₄ CH ₂ CH ₂ CH ₂ CH ₃ , SiMe ₂ OSiMe ₃ or SiMe ₂ OSiMe ₂ C ₆ H ₅ , Me represents methyl, and x is an integer from 1 to about 11: 7. Silicon-based tetrahydrocannabinol derivatives according to claim 1, having the formula (II), wherein Me represents methyl: 8. The silicon-based tetrahydrocannabinol derivative according to claim 1, having the formula (III): 9. The silicon-based tetrahydrocannabinol derivative according to claim 1, having the formula (IV), wherein Me represents a methyl group, m is an integer from 1 to about 100, and n is an integer from 1 to about 10: 10. A topical or dermatological composition comprising a base formulation and at least one silicon-based THC derivative, wherein at least one silicon-based THC derivative comprises A silicon-based functional group that combines with a THC molecule of formula (I): 11. The topical or dermatological composition according to claim 10, wherein the silicon-based functional group is combined with the THC molecule through the phenolic oxygen atom on the benzene ring. 12. The topical or dermatological composition according to claim 10, wherein the silicon-based functional group is a siloxane group or a trialkoxysilane-containing group. 13. The topical or dermatological composition according to claim 10, wherein said silicon-based functional group contains at least two silicon atoms. 14. A process for preparing the silicon-based THC derivatives of claim 1, comprising reacting THC with an allyl halide in a solvent to form an allyloxy THC intermediate body, and reacting the allyloxy-tetrahydrocannabinol intermediate with a silane compound and a catalyst to form the silicon-based tetrahydrocannabinol derivative. 15. A process for the preparation of silicon-based THC derivatives as claimed in claim 1, comprising forming on the THC molecule by reacting a chlorine-containing siloxane compound with hydroxyl groups in the presence of a base acceptor. Silanized alkyl ethers. 16. A process for the preparation of silicon-based THC derivatives as claimed in claim 1, comprising forming silanized alkyl groups on THC molecules by dehydrocoupling hydride-containing siloxanes ether. 17. A process for preparing the silicon-based tetrahydrocannabinol derivatives of claim 1, comprising forming an intermediate alkali metal alkoxide and then reacting it with a silicon hydride- or silicon-chloride-containing compound, in A silanized alkyl ether is formed on the THC molecule. 18. A composition comprising the silicon-based THC derivative according to claim 1 and at least one phytochemical extracted from cannabis.