Note: Descriptions are shown in the official language in which they were submitted.
WO 2022/125095
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TITLE OF THE INVENTION
100011 Silicon-based Tetrahydrocannabinol Derivatives and
Compositions Thereof
BACKGROUND OF THE INVENTION
100021 Tetrahydrocannabinol (THC) is a phytocannabinoid which is
known to have anti-
inflammatory activity. It is the primary psychoactive cannabinoid and is known
to bind to
cannabinoid receptors (CB1 and CB2) to reduce pain, inflammation, and
hyperalgesia (see, for
example, Citti et alõS'ci. 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-trimethy1-3-penty1-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-
01, shown
below:
ri OH
_____________________________________ 0
(I)
100031 Topical formulations of tetrahydrocannabinol have been
reported to reduce allergic
inflammation (Karsak et al, Science, 316, 1494-1497 (2007)). Pure
tetrahydrocannabinol has
low stability in air, light, acid media, and at high temperature, but
derivatives of
tetrahydrocannabinol with increased in stability would be attractive Also
desirable would be
derivatives having lower surface tension, which would enable the formation of
thin films either
directly or by enhancing solubility in low surface tension fluids, such as
silicones.
BRIEF SUMMARY OF THE INVENTION
100041 A silicon-based tetrahydrocannabinol derivative according
to an embodiment of
the disclosure contains a silicon-based functional group containing Si-O-Si
bonds which is bound
to a tetrahydrocannabinol molecule having Formula (I):
9H
___________________________________ r=-=
(I)
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[0005] A topical or dermatological formulation according to an
embodiment of the
disclosure contains a base formulation and at least one silicon-based
tetrahydrocannabinol
derivative comprising at least one silicon-based functional group containing
Si-O-Si bonds
which is bound to a tetrahydrocannabinol molecule having Formula (I).
OH
H I
(I)
DETAILED DESCRIPTION OF THE INVENTION
[0006] The disclosure relates to compositions containing derivatives
of tetrahydrocannabinol
(THC) containing a silicon-containing functional group which are beneficial
for various
applications, including the formulation of topical medicinal products and
personal care products,
and methods for their preparation. The silicon-containing tetrahydrocannabinol
derivatives
described herein are unique hybrid organosilicon compounds formed by attaching
tetrahydrocannabinol to a siloxane backbone, also described as a molecule
comprising one
silicon-based functional group containing Si-O-Si bonds which is bound to a
tetrahydrocannabinol molecule. Although the binding affinity for cannabinoid
acceptors of the
compounds described herein has not yet been studied, they are expected to
provide increased
stability and solubility and to release the free tetrahydrocannabinol
uniformly and over a
prolonged period.
[0007] As used herein, the terms tetrahydrocannabinol and THC are
intended to encompass
all isomers of tetrahydrocannabinol, including those found naturally or
developed synthetically.
[0008] Preferred embodiments of the compounds of the disclosure
include trisiloxanyl
derivatives of tetrahydrocannabinol in which a siloxane-based group is bound
through the
phenolic hydroxyl group of the tetrahydrocannabinol molecule, forming an Si-O-
C bond.
10009] The silicon-based tetrahydrocannabinol derivatives include a
tetrahydrocannabinol
molecule, such as 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.
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[0010] Preferred tetrahydrocannabinol derivatives described herein
have a structure in
accordance with Formula (I) above in which the phenolic hydroxyl group is
bound to a siloxane
moiety containing two or more silicon atoms, preferably three or more silicon
atoms, most
preferably about 3 to about 10 silicon atoms.
[0011] Tetrahydrocannabinol derivatives according to embodiments of
the invention have
general formula (A). In this formula, R may be, for example and without
limitation,
SiMe(OSiMe3)2, SiMe2(0SiMe2)4CH2CH2CH2CH3, SiMe20SiMe3, and SiMe20SiMe2C6H5,
in
which "Me" is a methyl group. However, compounds having formula (A) that are
within the
scope of the disclosure are not limited to these substituents, and other
silicon-containing
functional groups having Si-O-Si bonds that are known in the art or to be
developed would also
be suitable for R.
[0012] Substituents containing a single silicon atom without an
oxane (oxygen) bridge
between two or more silicon atoms are not within the scope of the disclosure
because such
tetrahydrocannabinol derivatives fail 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 the disclosure as these are not effective for the intended purpose.
..----.. ,.
L."..õ OR
H 1
õ,---
0 (A)
[0013] Other compounds within the scope of the disclosure include
polydimethylsiloxanes in
which the tetrahydrocannabinol substitutes through the phenolic oxygen in
place of a methyl
group on a polydimethylsiloxane, such as Me3Si(OSiMe2)40SiMeTHC)nSiMe3, in
which
"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.
[0014] The silicon-based tetrahydrocannabinol derivatives according
to embodiments of the
disclosure include a wide variety of derivatized compounds, including most
preferred
compounds such as, for example,
(tetrahydrocannabinoloxy)heptamethyltrisiloxane (formula
(II)), tetrahydrocannabinoloxy-terminated polydimethylsiloxane (formula
(III)), and
-,
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tetrahydrocannabinoloxypropyl-terminated polydimethylsiloxane (formula (IV)),
shown below,
in which m and n are integers; preferably m is 1 to about 100 and n is 1 to
about 10.
OSime3
0-SLOSiNAe- )
H
(n)
\
,Si, Si, 1Si
01010/1
.õH
,
(III)
Me
Me3Si(OSiMe2)m(OS)n0SiMe3
0
0 (IV)
[0015] Compounds according to embodiments of the disclosure may
contain a direct ether
linkage between the silicon-containing functional group and the phenolic
hydroxyl group of the
tetrahydrocannabinol molecule (direct Si-0 bond) or may contain an alkyl group
spacer between
the phenolic hydroxyl group on tetrahydrocannabinol and the silicon-based
functional group,
such as compounds in which R in formula (A) is CH2SiMe20SiMe3 or
CH2SiMe20SiMe2C6H5.
The spacer is not limited to CH2, and 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.
[0016] Compounds according to embodiments of the disclosure which
contain an alkyl group
spacer between the phenolic hydroxyl group on tetrahydrocannabinol and the
silicon-based
functional group may have general formula (B) below, in which R' is a silicon-
based group and
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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 and without limitation, SiMe(OSiMe3)2, SiMe2(0SiMe2)4CH2CH2CH2CH3,
SiMe2OSiMe3, or SiMe20SiMe2C6H5, in which Me is methyl.
H 0(CH2)xR'
(B)
[0017] Direct Si-0 linkage of the tetrahydrocannabinol derivatives,
such as shown in formula
(A), may result in diminished allergic inflammation by releasing free
tetrahydrocannabinol over
a prolonged period by slow hydrolysis. The Si-0 bond on tetrahydrocannabinol
derivatives is
not stable when exposed to moisture, which results in slow decomposition of
compounds to form
free tetrahydrocannabinol and low molecular weight siloxanes The silane-based
tetrahydrocannabinol derivatives are anticipated to be stable when stored in
air and protected
from moisture. They are anticipated to show bioactivity in medicinal
applications either directly
or by slow hydrolysis to form underivatized THC.
[0018] Unlike many silicones and silicone derivatives, these
compounds are easily
incorporated into topical or dermatological products, including anti-
inflammatory and palliative
formulations, due to their solubility in a range of polar compounds such as
castor oil and a
variety of cosmetic or dermatological vehicles. They may also act as co-
solvents for silicones.
Further, due to such solubility, these derivatives may be useful as
compatibilizers for other
bioactives, such as unmodified cannabidiol and tetrahydrocannabinol compounds,
among other
possible applications.
[0019] The tetrahydrocannabinol derivatives described herein may be
prepared by various
synthetic pathways. In accordance with one embodiment of the disclosure, the
compounds may
be prepared by reacting the hydroxyl group on the benzenoid ring of
tetrahydrocannabinol with
an allylic halide in a solvent to form an allyloxytetrahydrocannabinol
intermediate, and then
hydrosilylating the intermediate with a silane compound and catalyst to form a
silicon-based
tetrahydrocannabinol derivative with a spacer. It is also within the scope of
this disclosure to
form a direct Si-0 linkage on the hydroxyl group of tetrahydrocannabinol by
reacting the
hydroxyl group (C-OH) with a chlorine-containing siloxane compound (-Si-C1) in
the presence
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of a base acceptor, or by the dehydrogenative coupling of the hydroxyl group
with a hydride-
containing siloxane compound (-Si-H). Another possible synthetic route to form
the direct Si-0
linkage is the formation of an alkali metal alkoxide intermediate (-C-O-Na)
and reacting the
intermediate with either a Si-C1 or Si-H containing siloxane compound Reaction
to form a
hydrocarbon bridge proceeds by the addition of a hydride containing siloxane (-
Si __ H) across a
C=C double bond by a hydrosilylati on reaction.
[0020] The silane compounds used in the reactions described above
may be any of a wide
variety of silicon-based compounds, and preferably include alkylsilanes,
alkoxysilanes,
alkylsiloxanes and alkoxysiloxanes and their derivatized or functionalized
counterparts. In
general, it is preferred to have two or more silicon atoms in the substitution
in order to provide
solubility and spreading characteristics suitable for topical creams and
ointments. Examples
include, without limitation, bis(trimethylsiloxy)methylsilane,
bis(trimethylsiloxy)ethylsilane,
bis(trimethylsiloxy)propylsilane, bis(triethylsiloxy)methylsilane,
bis(triethylsiloxy)ethylsilane,
bis(triethylsiloxy)propylsilane, triethoxysilane, trimethoxysilane, tripropyl
silane,
bis(tripropylsiloxy)methylsilane, bis(tripropylsiloxy)ethylsilane,
bis(tripropylsiloxy)propylsilane
and similar compounds.
[0021] Also useful as silane compounds herein are polymeric silicon-
containing molecules
having similar reactive capabilities as the silane monomeric structures noted
above, such as
polydimethyl siloxane, polydiethyl siloxane, polydipropyl siloxane,
polymethylethyl silane,
polymethylpropylsiloxane, and other polyalkyl- or polyalkenyl-siloxanes as are
known in the art
or to be developed. Chain lengths may vary, but it is preferred that the
molecular weight (Mn) of
polymeric silane compounds used to form polymeric silicon-based derivative
groups on
tetrahydrocannabinol be 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 disclosure and that the components having different
chain lengths may
contribute varying properties accordingly. For example, generally, lower
molecular weight
chains would tend to be more emollient in nature, while higher molecular
weight chains would
tend to be more substantive in terms of being longer-wearing on skin and more
resistant to wash-
off.
[0022] 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 a
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component of phytocannabinoid and/or other phytochemical mixtures. For
example, the
tetrahydrocannabinol derivative of cannabis extracts may be formed without
isolating the pure
tetrahydrocannabinol component. Further, compositions according to the
invention may contain
one or more of the derivatives described herein and one or more phytochemicals
extracted from
cannabis.
[0023] The silicon-based tetrahydrocannabinols described herein may
be used in various
topical and dermatological compositions, including preferably those which have
silicon
compounds or silicone-based polymers in the base formulation because the
derivatives facilitate
compatibility and solubility in such compounds within formulations. However,
the disclosure is
not limited to those compositions and may include any topical or
dermatological composition in
which the 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. The silicon-based
tetrahydrocannabinol
derivatives include a tetrahydrocannabinol molecule or a commercial or natural
derivative
thereof and include a silicon-based functional group bonded to the
tetrahydrocannabinol
molecule (or the derivative thereof) through the oxygen atom of the benzenoid
ring.
[0024] When incorporated in such formulations, it is preferred that
the silicon-based
tetrahydrocannabinol derivative is present in an amount of about 0.01 percent
by weight to about
20 percent by weight, preferably about 0.5 percent by weight to about 5 weight
percent and most
preferably about 0.5 to about 1.0 percent by weight based on the weight of the
formulation.
[0025] The invention will now be described in connection with the
following, non-limiting
examples.
Example 1: Synthesis of 1,1, 1,3,5,5,5-heptamethy1-3-(((6aR,10aR)-6,6,9-
trimethy1-3 -pentyl-
6a,7,8,10a-tetrahy dro-6H-benzo[c]chromen-l-yl)oxy)trisiloxane (II)
OSiMe3
H
OH pSMe3
CY' 'OSIMe3
Na H-S:¨ ,H
õ
H µOSMe3
,
[0026] Sodium (0.55g, 0.02 mol) and tetrahydrofuran (13.42g) are
charged to a reactor. A
solution of tetrahydrocannabinol (6.29g, 0.02 mol) in tetrahydrofuran (37.98g)
is added dropwise
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over 30 min while keeping pot temperature below 70 C. The resulting reaction
mixture is
stirred at 50-60 C until all sodium has been consumed.
Bis(trimethylsiloxy)methylsilane
(6.77g, 0.03 mol) is added dropwise over 10 min at 70 C, then the reaction
mixture is heated at
110-120 C for 10h. The reaction mixture is filtered through silica gel (40g)
and washed with
tetrahydrofuran (400g). The filtrate is concentrated in vacuo. The residue
contains the product
and unreacted tetrahydrocannabinol and is analyzed by 1H NMR and FTIR.
Example 2: Synthesis of 1-buty1-1,1,3,3,5,5,7,7,9,9-decamethy1-9-(((6aR,10aR)-
6,6,9-trimethyl-
3 -penty1-6a,7, 8,10a-tetrahy dro-6H-b enzo [c] chromen-1 -
yl)oxy)pentasiloxane (III)
OH
[.
( 1\ I.
,H _________________________ .õH . Na -F- 3
101/(..iH
\ H
(III)
[0027] Sodium (0.55g, 0.02 mol) and tetrahydrofuran (13.42g) are
charged to a reactor. A
solution of tetrahydrocannabinol (6.29g, 0.02 mol) in tetrahydrofuran (37.98g)
is added dropwise
over 30 min while keeping pot temperature below 70 C. The resulting reaction
mixture is
stirred at 50-60 C until all sodium has been consumed. 1-Buty1-
1,1,3,3,5,5,7,7,9,9-
decamethylpentasiloxane (12.39g, 0.03 mol) is added dropwise over 10 min at 70
C, then the
reaction mixture is heated at 110-120 C for 10h. The reaction mixture is
filtered through silica
gel (40g) and washed with tetrahydrofuran (400g). The filtrate is concentrated
in mem ). The
residue contains the product and unreacted tetrahydrocannabinol and is
analyzed by 1H NMR
and FTIR.
Example 3: Tetrahydrocannabinoloxypropyl -terminated polydimethylsiloxane (IV)
ik.4e
Me3S(OSIIVie2)m(01)nOSityle3
1
Me3Si(OSiMe2)m(OSiMeH)nOSUvle3 Pt õ,1--1
_
__________________________________ 0-
, 0-- -
(IV)
[0028] Allyloxytetrahydrocannabinol (70.9g, 0.2 mol) and toluene
(50mL) are charged to a
reactor. The resulting mixture is heated to 80-90 C. Karstedt catalyst (2% Pt
concentration in
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xylene, 0.5 mL) is added when pot temperature reaches 80-90 C. Hydride-
terminated
polydimethylsiloxane (Mn-1050, 105g) is added dropwise while controlling the
exotherm, then
the reaction mixture is heated at 85-115 'V until FTIR indicates that all 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 1-1-1 NMR and FTIR.
[0029]
It will be appreciated by those skilled in the art that changes could be
made to the
embodiment described above without departing from the broad inventive concepts
thereof Also,
based on this disclosure, a person of ordinary skill in the art would further
recognize that the
relative proportions of the components illustrated above could be varied
without departing from
the spirit and scope of the invention. It is understood, therefore, that this
invention is not limited
to that particular embodiment disclosed, but it is intended to cover
modifications within the spirit
and scope of the present invention as defined by the appended claims.
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