CN116685595A - 硅基四氢***酚衍生物及其组合物 - Google Patents
硅基四氢***酚衍生物及其组合物 Download PDFInfo
- Publication number
- CN116685595A CN116685595A CN202080107856.2A CN202080107856A CN116685595A CN 116685595 A CN116685595 A CN 116685595A CN 202080107856 A CN202080107856 A CN 202080107856A CN 116685595 A CN116685595 A CN 116685595A
- Authority
- CN
- China
- Prior art keywords
- silicon
- tetrahydrocannabinol
- derivative
- osime
- sime
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical class C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 title claims abstract description 87
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229910052710 silicon Inorganic materials 0.000 title claims abstract description 60
- 239000010703 silicon Substances 0.000 title claims abstract description 59
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229960004242 dronabinol Drugs 0.000 claims abstract description 50
- 230000000699 topical effect Effects 0.000 claims abstract description 15
- 238000009472 formulation Methods 0.000 claims abstract description 12
- 229910002808 Si–O–Si Inorganic materials 0.000 claims abstract description 7
- -1 allylic halide Chemical class 0.000 claims description 30
- 125000000524 functional group Chemical group 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 7
- 125000005373 siloxane group Chemical group [SiH2](O*)* 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 4
- 150000004678 hydrides Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229910000077 silane Inorganic materials 0.000 claims description 4
- 235000017807 phytochemicals Nutrition 0.000 claims description 3
- 229930000223 plant secondary metabolite Natural products 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 150000005215 alkyl ethers Chemical class 0.000 claims 3
- 240000004308 marijuana Species 0.000 claims 1
- 229910052990 silicon hydride Inorganic materials 0.000 claims 1
- FDNAPBUWERUEDA-UHFFFAOYSA-N silicon tetrachloride Chemical compound Cl[Si](Cl)(Cl)Cl FDNAPBUWERUEDA-UHFFFAOYSA-N 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 239000002210 silicon-based material Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 7
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 229910018557 Si O Inorganic materials 0.000 description 5
- 229920001296 polysiloxane Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 239000004205 dimethyl polysiloxane Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 2
- 108050007331 Cannabinoid receptor Proteins 0.000 description 2
- 241000218236 Cannabis Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000009285 allergic inflammation Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000006459 hydrosilylation reaction Methods 0.000 description 2
- SWGZAKPJNWCPRY-UHFFFAOYSA-N methyl-bis(trimethylsilyloxy)silicon Chemical compound C[Si](C)(C)O[Si](C)O[Si](C)(C)C SWGZAKPJNWCPRY-UHFFFAOYSA-N 0.000 description 2
- 150000004756 silanes Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 description 2
- ZQTYRTSKQFQYPQ-UHFFFAOYSA-N trisiloxane Chemical class [SiH3]O[SiH2]O[SiH3] ZQTYRTSKQFQYPQ-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- UFGHYRMVKCEZHO-UHFFFAOYSA-N C[SiH]([Si](C)(C)C)[Si](C)(C)C Chemical compound C[SiH]([Si](C)(C)C)[Si](C)(C)C UFGHYRMVKCEZHO-UHFFFAOYSA-N 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- FOLNDEOXOGUWTR-UHFFFAOYSA-N [ethyl(trimethylsilyloxy)silyl]oxy-trimethylsilane Chemical compound C[Si](C)(C)O[SiH](CC)O[Si](C)(C)C FOLNDEOXOGUWTR-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001343 alkyl silanes Chemical class 0.000 description 1
- 125000005376 alkyl siloxane group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- FYBYQXQHBHTWLP-UHFFFAOYSA-N bis(silyloxysilyloxy)silane Chemical compound [SiH3]O[SiH2]O[SiH2]O[SiH2]O[SiH3] FYBYQXQHBHTWLP-UHFFFAOYSA-N 0.000 description 1
- CUNJTLKUJLNNOJ-UHFFFAOYSA-N butyl-[[[dimethylsilyloxy(dimethyl)silyl]oxy-dimethylsilyl]oxy-dimethylsilyl]oxy-dimethylsilane Chemical compound CCCC[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[SiH](C)C CUNJTLKUJLNNOJ-UHFFFAOYSA-N 0.000 description 1
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical class OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000003961 organosilicon compounds Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003377 silicon compounds Chemical class 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- QQQSFSZALRVCSZ-UHFFFAOYSA-N triethoxysilane Chemical compound CCO[SiH](OCC)OCC QQQSFSZALRVCSZ-UHFFFAOYSA-N 0.000 description 1
- DHMBAQQIVDNJQY-UHFFFAOYSA-N triethyl-[ethyl(triethylsilyloxy)silyl]oxysilane Chemical compound CC[Si](CC)(CC)O[SiH](CC)O[Si](CC)(CC)CC DHMBAQQIVDNJQY-UHFFFAOYSA-N 0.000 description 1
- LLVYBYXTNXKYKA-UHFFFAOYSA-N triethyl-[methyl(triethylsilyloxy)silyl]oxysilane Chemical compound CC[Si](CC)(CC)O[SiH](C)O[Si](CC)(CC)CC LLVYBYXTNXKYKA-UHFFFAOYSA-N 0.000 description 1
- XWQDJMSZBLQFDS-UHFFFAOYSA-N triethyl-[propyl(triethylsilyloxy)silyl]oxysilane Chemical compound CCC[SiH](O[Si](CC)(CC)CC)O[Si](CC)(CC)CC XWQDJMSZBLQFDS-UHFFFAOYSA-N 0.000 description 1
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 description 1
- PMFSLPPNQCIHBT-UHFFFAOYSA-N trimethyl-[propyl(trimethylsilyloxy)silyl]oxysilane Chemical compound CCC[SiH](O[Si](C)(C)C)O[Si](C)(C)C PMFSLPPNQCIHBT-UHFFFAOYSA-N 0.000 description 1
- ZHOVAWFVVBWEGQ-UHFFFAOYSA-N tripropylsilane Chemical compound CCC[SiH](CCC)CCC ZHOVAWFVVBWEGQ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/695—Silicon compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/58—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing atoms other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur or phosphorus
- A61K8/585—Organosilicon compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/89—Polysiloxanes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0834—Compounds having one or more O-Si linkage
- C07F7/0838—Compounds with one or more Si-O-Si sequences
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/10—General cosmetic use
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Birds (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
提供硅基四氢***酚衍生物及其合成方法，其中所述衍生物包含四氢***酚分子和至少一个含有Si‑O‑Si键的硅基基团。所述衍生物可用于局部用和皮肤病用组合物，具有潜在的有益的局部用性质，并能提高含有硅基材料的局部用和皮肤病用制剂的溶解性和相容性。
Description
发明背景
四氢***酚(THC)是已知具有抗炎活性的植物***素。它是主要的精神活性***素，可以与***素受体(CB1和CB2)结合以减少疼痛、炎症和痛觉过敏(参见,例如,Citti等人,Sci.Rep.9,20335(2019)；Karsak等人,Science,316,1494(2007)；Richardson等人,Pain,75,111(1998))。四氢***酚是(6aR,10aR)-6,6,9-三甲基-3-戊基-6a,7,8,10a-四氢-6H-苯并[c]色烯-1-酚的指定名称，如下所示：
据报道，四氢***酚的局部用制剂可减少过敏性炎症(Karsak等人,Science,316,1494-1497(2007))。纯四氢***酚在空气、光照、酸性介质和高温下的稳定性较低，但是四氢***酚的衍生物具有更高的稳定性，具有吸引力。具有较低表面张力的衍生物亦是理想的，其能够直接或通过提高在低表面张力流体(例如硅酮)中的溶解度来形成薄膜。
发明内容
根据本发明的一个实施方案，硅基四氢***酚衍生物包含含有Si-O-Si键的硅基官能团，所述硅基官能团与具有式(I)的四氢***酚分子结合：
根据本发明的一个实施方案，局部用或皮肤病用制剂包含基础制剂和至少一种硅基四氢***酚衍生物，所述硅基四氢***酚衍生物包含至少一个含有Si-O-Si键的硅基官能团，所述硅基官能团与具有式(I)的四氢***酚分子结合：
发明的详细描述
本发明涉及包含含有含硅官能团的四氢***酚(THC)衍生物的组合物，其对各种应用，包括局部用药物产品和个人护理产品的制剂有益，本发明还涉及其制备方法。本文所述的含硅四氢***酚衍生物是通过将四氢***酚连接到硅氧烷主链上而形成的独特杂化有机硅化合物，所述硅氧烷主链也被描述为包含含有Si-O-Si键的硅基官能团的分子，所述硅基官能团与四氢***酚分子结合。尽管尚未研究本文所述化合物对***素受体的结合亲和力，但预计它们有望提供更高的稳定性和溶解性，并在较长的时间内均匀释放游离的四氢***酚。
如本文所用，术语四氢***酚和THC旨在包括四氢***酚的所有异构体，包括那些天然发现的或合成开发的异构体。
本发明化合物的优选实施例包括四氢***酚的三硅氧烷衍生物，其中硅氧烷基团通过四氢***酚分子的酚羟基结合，从而形成Si-O-C键。
硅基四氢***酚衍生物包括四氢***酚分子，如式(I)所示，具有硅基基团作为官能团。最优选地，所述硅基基团是硅氧烷基团或含三烷氧基硅烷的基团。
本文所述的优选四氢***酚衍生物具有上述式(I)的结构，其中所述酚羟基与硅氧烷部分结合，所述硅氧烷部分含有两个或更多个硅原子，优选三个或更多个硅原子，最优选约3至约10个硅原子。
根据本发明实施例的四氢***酚衍生物具有通式(A)。在该式中，R可以是，例如但不限于，SiMe(OSiMe3)2、SiMe2(OSiMe2)4CH2CH2CH2CH3、SiMe2OSiMe3和SiMe2OSiMe2C6H5，其中“Me”是甲基。然而，在本发明范围内具有式(A)的化合物并不限于这些取代基，并且本领域已知或待开发的其它具有Si-O-Si键的含硅官能团也将适合用于R。
含有单个硅原子且在两个或更多个硅原子之间没有氧烷(氧)桥的取代基不在本发明的范围内，因为这样的四氢***酚衍生物不能提供可接受的成膜性能。例如，简单的三烷基硅(trialkylsilyl)衍生物，以及硅上仅含有烷基、芳基、氢、卤素、乙烯基、烯丙基和/或烷氧基取代基的衍生物都不在本发明的范围内，因为这些不能有效地实现预期目的。
本发明内容范围内的其他化合物包括聚二甲基硅氧烷，其中四氢***酚通过酚的氧取代聚二甲基硅氧烷上的甲基，例如Me3Si(OSiMe2)m(OSiMeTHC)nSiMe3，其中“THC”代表四氢***酚，Me是甲基，m和n是整数。优选地，m是1至约100，n是1至约10。
根据本发明实施例的硅基四氢***酚衍生物包括多种衍生化合物，包括最优选的化合物，例如(四氢***酚氧基)七甲基三硅氧烷(式(II))、四氢***酚氧基封端的聚二甲基硅氧烷(式(III))和四氢***酚氧基丙基封端的聚二甲基硅氧烷(式(IV))，如下所示，其中m和n是整数；优选地，m是1至约100，n是1至约10。
根据本发明实施例的化合物可以在含硅官能团和四氢***酚分子的酚羟基之间含有直接的醚键(直接的Si-O键)，或者可以在四氢***酚的酚羟基和硅基官能团之间含有烷基间隔物，如式(A)中的R是CH2SiMe2OSiMe3或CH2SiMe2OSiMe2C6H5。所述间隔物不限于CH2，也可以是含有最多约11个碳原子的较长烷基链，如(CH2)3，其与CH2一起，也是优选的实施例。
根据本发明的实施例，在四氢***酚的酚羟基与硅基官能团之间含有烷基间隔物的化合物可具有以下通式(B)，其中R’是硅基基团，且x是1至约11的整数，优选1(甲基)至3(丙基)。最优选地，所述硅基基团是硅氧烷基团或含三烷氧基硅烷的基团。R’可以是，例如但不限于，SiMe(OSiMe3)2、SiMe2(OSiMe2)4CH2CH2CH2CH3、SiMe2OSiMe3或SiMe2OSiMe2C6H5，其中Me是甲基。
如式(A)所示的四氢***酚衍生物的直接Si-O键可通过缓慢水解在长时间内释放游离四氢***酚而导致过敏性炎症减少。四氢***酚衍生物上的Si-O键在受潮时不稳定，这导致化合物缓慢分解形成游离的四氢***酚和低分子量的硅氧烷。预计硅烷基四氢***酚衍生物储存在空气中并防止潮湿时是稳定的。预计它们将直接在药物应用中显示生物活性，或通过缓慢水解形成未活化的THC显示生物活性。
与许多有机硅和有机硅衍生物不同，由于这些化合物在一系列极性化合物(例如蓖麻油和各种化妆品或皮肤病载体)中的溶解性，它们容易被纳入局部用或皮肤病用产品中，包括抗炎和缓和制剂。它们还可以作为有机硅的共溶剂。此外，由于这种溶解性，这些衍生物可以被用作其他生物活性物质，例如未改性的***二酚和四氢***酚化合物的相容剂，以及其他可能的应用。
本文所述的四氢***酚衍生物可以通过各种合成途径制备。根据本发明的一个实施方案，所述化合物可以通过使四氢***酚的苯环上的羟基与烯丙基卤化物在溶剂中反应，形成烯丙基氧基四氢***酚中间体，然后用硅烷化合物和催化剂将中间体氢化硅烷化，形成具有间隔物的硅基四氢***酚衍生物来制备。通过使羟基(C-OH)与含氯的硅氧烷化合物(-Si-Cl)在碱受体存在下反应，或通过羟基与含氢化物的硅氧烷化合物(-Si-H)的脱氢偶联，在四氢***酚的羟基上形成直接的Si-O键也在本发明的范围内。另一种可能的形成直接Si-O键的合成途径是形成碱金属烷氧化物中间体(-C-O-Na)，并使该中间体与含Si-Cl或Si-H的硅氧烷化合物反应。形成烃桥(hydrocarbon bridge)的反应是通过氢化硅烷化反应在C＝C双键上加成含氢化物的硅氧烷(-Si-H)进行的。
用于上述反应的硅烷化合物可以是各种硅基化合物中的任何一种，优选地包括烷基硅烷、烷氧基硅烷、烷基硅氧烷和烷氧基硅氧烷及其衍生或官能化的对应物。一般来说，优选取代基中有两个或更多个硅原子的，以便提供适合于局部乳膏和软膏的溶解性和铺展性。例子包括但不限于双(三甲基硅氧烷基)甲基硅烷、双(三甲基硅氧烷基)乙基硅烷、双(三甲基硅氧烷基)丙基硅烷、双(三乙基硅氧烷基)甲基硅烷、双(三乙基硅氧烷基)乙基硅烷、双(三乙基硅氧烷基)丙基硅烷、三乙氧基硅烷、三甲氧基硅烷、三丙基硅烷、双(丙三基硅氧烷基)甲基硅烷、双(三丙基硅氧烷基)乙基硅烷、双(三丙基硅氧烷基)丙基硅烷和类似化合物。
在本文中，也可用作硅烷化合物的是具有与上述硅烷单体结构类似反应能力的含硅聚合分子，例如聚二甲基硅氧烷、聚二乙基硅氧烷、聚二丙基硅氧烷、聚甲基乙基硅烷、聚甲基丙基硅氧烷和其他本领域已知或待开发的聚烷基或聚烯基硅氧烷。链长可以变化，但用于在四氢***酚上形成聚合硅基衍生物基团的聚合硅烷化合物的分子量(Mn)优选是100至约5000，最优选是约500至约2000。应当注意的是，高于和低于该范围的分子量变化在本发明的范围内，并且具有不同链长的组分可以相应地提供不同的性能。例如，一般来说，较低分子量的链在性质上倾向于更润肤，而较高分子量的链倾向于更实质的(substantive)，在皮肤上的附着时间更长(longer-wearing)且更耐洗脱。
还应理解的是，本文所述的衍生物可使用纯四氢***酚制备。或者，所述衍生物可以作为植物***素和/或其他植物化学混合物的组分形成和提供。例如，***提取物的四氢***酚衍生物可以在不分离纯四氢***酚组分的情况下形成。此外，根据本发明的组合物可以含有一种或多种本文所述的衍生物和一种或多种从***中提取的植物化学物质。
本文所述的硅基四氢***酚可用于各种局部用和皮肤病用组合物中，包括优选那些在基础制剂中具有硅化合物或硅酮基聚合物的，因为所述衍生物有利于制剂中此类化合物的相容性和溶解性。然而，本发明不限于那些组合物，并且可以包括硅基四氢***酚衍生物可用于的任何局部用或皮肤病用组合物。本发明的化妆品和局部用组合物包括基础制剂和至少一种如本文所述的硅基四氢***酚衍生物，所述基础制剂可以是如上所述的任何合适局部用或皮肤病用的基础制剂。硅基四氢***酚衍生物包括四氢***酚分子或其商业的或天然的衍生物，并且包括通过苯环的氧原子与四氢***酚分子(或其衍生物)键合的硅基官能团。
当被纳入此类制剂中时，硅基四氢***酚衍生物的存在量(基于制剂重量)是，优选地，约0.01％重量至约20％重量，优选地，约0.5％重量至约5％重量，最优选地，约0.5％重量至约1.0％重量。
现在将结合以下非限制性实施例描述本发明。
实施例1：1,1,1,3,5,5,5-七甲基-3-(((6aR,10aR)-6,6,9-三甲基-3-戊基-6a,7,
8,10a-四氢-6H-苯并[c]色烯-1-基)氧基)三硅氧烷的合成(II)
将钠(0.55g,0.02mol)和四氢呋喃(13.42g)加入到反应器中。在30min内滴加在四氢呋喃(37.98g)中的四氢***酚(6.29g,0.02mol)溶液，同时保持锅内温度低于70℃。将所得的反应混合物在50-60℃下搅拌，直到所有的钠都被消耗掉。在70℃下，在10min内滴加双(三甲基硅氧烷基)甲基硅烷(6.77g,0.03mol)，然后将反应混合物在110-120℃下加热10h。将反应混合物经硅胶(40g)过滤并用四氢呋喃(400g)洗涤。滤液在真空中浓缩。残余物含有产物和未反应的四氢***酚，用1H NMR和FTIR分析。
实施例2：1-丁基-1,1,3,3,5,5,7,7,9,9-十甲基-9-(((6aR,10aR)-6,6,9-三甲
基-3-戊基-6a,7,8,10a-四氢-6H-苯并[c]色烯-1-基)氧基)五硅氧烷的合成(III)
将钠(0.55g,0.02mol)和四氢呋喃(13.42g)加入到反应器中。在30min内滴加在四氢呋喃(37.98g)中的四氢***酚(6.29g,0.02mol)溶液，同时保持锅内温度低于70℃。将所得的反应混合物在50-60℃下搅拌，直到所有的钠都被消耗掉。在70℃下，在10min内滴加1-丁基-1,1,3,3,5,5,7,7,9,9-十甲基五硅氧烷(12.39g，0.03mol)，然后将反应混合物在110-120℃下加热10h。将反应混合物经硅胶(40g)过滤并用四氢呋喃(400g)洗涤。滤液在真空中浓缩。残余物含有产物和未反应的四氢***酚，用1H NMR和FTIR分析。
实施例3：四氢***酚氧丙基封端的聚二甲基硅氧烷(IV)
将烯丙基氧基四氢***酚(70.9g,0.2mol)和甲苯(50mL)加入到反应器中。将所得混合物加热至80-90℃。当锅内温度达到80-90℃时，加入Karstedt催化剂(二甲苯中2％浓度的Pt,0.5mL)。在控制放热的同时滴加氢化物封端的聚二甲基硅氧烷(Mn-1050,105g)，然后将反应混合物在85-115℃下加热，直到FTIR表明所有Si-H都已被消耗。将活性炭加入混合物中，搅拌过夜。过滤混合物并在真空中浓缩滤液。残余物含有产物和未反应的四氢***酚，用1HNMR和FTIR分析。
本领域技术人员应当理解，可以在不脱离其广泛的发明构思的情况下对上述实施例进行改变。此外，基于本发明，本领域普通技术人员将进一步认识到，在不脱离本发明的精神和范围的情况下，可以改变上述组分的相对比例。因此，应当理解的是，本发明不限于所公开的特定实施例，而是旨在涵盖由所附权利要求限定的本发明的精神和范围内的修改。
Claims (18)
1.一种包含含有Si-O-Si键的硅基官能团的硅基四氢***酚衍生物，所述硅基官能团与具有式(I)的四氢***酚分子结合：
2.根据权利要求1所述的硅基四氢***酚衍生物，其特征在于，所述硅基官能团通过苯环上的酚氧原子与所述四氢***酚分子结合。
3.根据权利要求1所述的硅基四氢***酚衍生物，其特征在于，所述硅基官能团为硅氧烷基团或含三烷氧基硅烷的基团。
4.根据权利要求1所述的硅基四氢***酚衍生物，其特征在于，所述硅基官能团含有至少两个硅原子。
5.根据权利要求1所述的硅基四氢***酚衍生物，具有式(A)，其中R为SiMe(OSiMe3)2、SiMe2(OSiMe2)4CH2CH2CH2CH3、SiMe2OSiMe3、SiMe2OSiMe2C6H5、CH2SiMe2OSiMe3或CH2SiMe2OSiMe2C6H5，其中Me代表甲基：
6.根据权利要求1所述的硅基四氢***酚衍生物，具有式(B)，其中R’是SiMe(OSiMe3)2、SiMe2(OSiMe2)4CH2CH2CH2CH3、SiMe2OSiMe3或SiMe2OSiMe2C6H5，Me代表甲基，x是1至约11的整数：
7.根据权利要求1所述的硅基四氢***酚衍生物，具有式(II)，其中Me代表甲基：
8.根据权利要求1所述的硅基四氢***酚衍生物，具有式(III)：
9.根据权利要求1所述的硅基四氢***酚衍生物，具有式(IV)，其中Me代表甲基，m是1至约100的整数，n是1至约10的整数：
10.一种局部用或皮肤病用组合物，其包含基础制剂和至少一种硅基四氢***酚衍生物，其中至少一种硅基四氢***酚衍生物包含含有Si-O-Si键的硅基官能团，所述硅基官能团与具有式(I)的四氢***酚分子结合：
11.根据权利要求10所述的局部用或皮肤病用组合物，其特征在于，所述硅基官能团通过所述苯环上的酚氧原子与所述四氢***酚分子结合。
12.根据权利要求10所述的局部用或皮肤病用组合物，其特征在于，所述硅基官能团为硅氧烷基团或含三烷氧基硅烷的基团。
13.根据权利要求10所述的局部用或皮肤病用组合物，其特征在于，所述硅基官能团含有至少两个硅原子。
14.一种制备权利要求1所述的硅基四氢***酚衍生物的方法，包括使四氢***酚与烯丙基卤化物在溶剂中反应，形成烯丙基氧基四氢***酚中间体，并使所述烯丙基氧基四氢***酚中间体与硅烷化合物和催化剂反应，形成所述硅基四氢***酚衍生物。
15.一种制备权利要求1所述的硅基四氢***酚衍生物的方法，包括通过使含氯的硅氧烷化合物与羟基在碱受体存在下反应，在四氢***酚分子上形成硅烷化的烷基醚。
16.一种制备权利要求1所述的硅基四氢***酚衍生物的方法，包括通过使含氢化物的硅氧烷脱氢偶联，在四氢***酚分子上形成硅烷化的烷基醚。
17.一种制备权利要求1所述的硅基四氢***酚衍生物的方法，包括通过形成中间体碱金属烷氧化物，然后使其与含硅氢化物或含硅氯的化合物反应，在四氢***酚分子上形成硅烷化的烷基醚。
18.一种包含根据权利要求1所述的硅基四氢***酚衍生物和至少一种从***中提取的植物化学物质的组合物。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2020/064235 WO2022125095A1 (en) | 2020-12-10 | 2020-12-10 | Silicon-based tetrahydrocannabinol derivatives and compositions thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116685595A true CN116685595A (zh) | 2023-09-01 |
Family
ID=74125705
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202080107856.2A Pending CN116685595A (zh) | 2020-12-10 | 2020-12-10 | 硅基四氢***酚衍生物及其组合物 |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP4259065A1 (zh) |
| JP (1) | JP2023554329A (zh) |
| KR (1) | KR20230143137A (zh) |
| CN (1) | CN116685595A (zh) |
| CA (1) | CA3201704A1 (zh) |
| WO (1) | WO2022125095A1 (zh) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2854896A1 (fr) * | 2003-05-16 | 2004-11-19 | Mayoly Spindler Lab | Nouveaux tensioactifs, compositions les comprenant |
| WO2009018389A1 (en) * | 2007-07-30 | 2009-02-05 | Alltranz Inc. | Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same |
| WO2018148787A1 (en) * | 2017-02-15 | 2018-08-23 | Botanix Pharmaceuticals Ltd | Formulations of cannabinoids for the treatment of psoriasis |
| WO2018148785A1 (en) * | 2017-02-15 | 2018-08-23 | Botanix Pharmaceuticals Ltd | Formulations of cannabinoids for the treatment of dermatitis and inflammatory skin diseases |
| US20200325091A1 (en) * | 2019-04-15 | 2020-10-15 | Trustees Of Boston University | One-step flow-mediated synthesis of cannabidiol (cbd) and derivatives |
| CN112047973A (zh) * | 2019-06-06 | 2020-12-08 | 上海科技大学 | 一种***素类化合物，其制备方法、组合物和用途 |
-
2020
- 2020-12-10 CN CN202080107856.2A patent/CN116685595A/zh active Pending
- 2020-12-10 WO PCT/US2020/064235 patent/WO2022125095A1/en active Application Filing
- 2020-12-10 CA CA3201704A patent/CA3201704A1/en active Pending
- 2020-12-10 JP JP2023535575A patent/JP2023554329A/ja active Pending
- 2020-12-10 KR KR1020237023201A patent/KR20230143137A/ko unknown
- 2020-12-10 EP EP20835965.3A patent/EP4259065A1/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2854896A1 (fr) * | 2003-05-16 | 2004-11-19 | Mayoly Spindler Lab | Nouveaux tensioactifs, compositions les comprenant |
| WO2009018389A1 (en) * | 2007-07-30 | 2009-02-05 | Alltranz Inc. | Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same |
| WO2018148787A1 (en) * | 2017-02-15 | 2018-08-23 | Botanix Pharmaceuticals Ltd | Formulations of cannabinoids for the treatment of psoriasis |
| WO2018148785A1 (en) * | 2017-02-15 | 2018-08-23 | Botanix Pharmaceuticals Ltd | Formulations of cannabinoids for the treatment of dermatitis and inflammatory skin diseases |
| US20200325091A1 (en) * | 2019-04-15 | 2020-10-15 | Trustees Of Boston University | One-step flow-mediated synthesis of cannabidiol (cbd) and derivatives |
| CN112047973A (zh) * | 2019-06-06 | 2020-12-08 | 上海科技大学 | 一种***素类化合物，其制备方法、组合物和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20230143137A (ko) | 2023-10-11 |
| JP2023554329A (ja) | 2023-12-27 |
| WO2022125095A1 (en) | 2022-06-16 |
| CA3201704A1 (en) | 2022-06-16 |
| EP4259065A1 (en) | 2023-10-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3328450A (en) | Silylalkyl phenols | |
| US5347028A (en) | Highly functionalized polycyclosiloxanes and their polymerization into thermally reversible living rubbers | |
| EP1871779A2 (en) | Process for making si-h functional siloxane oligomer | |
| US5296624A (en) | Preparation of sterically-hindered organosilanes | |
| US4536265A (en) | Siloxane polyphotoinitiators of the substituted acetophenone type | |
| KR20090024827A (ko) | 신규 에폭시 화합물 및 그 제조방법 | |
| CA2210586A1 (en) | Cyclic silane esters and solvolysis products thereof, and processes for the preparation of the cyclic silane esters and the solvolysis products | |
| US5153332A (en) | Organocyclosiloxane and method for its preparation | |
| US5136064A (en) | Olefinic and acetylenic azasilacyclopentanes | |
| US11667655B2 (en) | Silicon-based tetrahydrocannabinol derivatives and compositions thereof | |
| CN116685595A (zh) | 硅基四氢***酚衍生物及其组合物 | |
| JPH05271249A (ja) | ハイドロシリレーション法 | |
| US5693735A (en) | Trimethylsiloxy group-containing polysiloxane and a process for producing the same | |
| US5086127A (en) | Silicone UV absorbers containing silane units | |
| CA2084733A1 (en) | Siloxy-functional cyclopolysiloxanes | |
| US5239099A (en) | Azasilacycloalkyl functional alkoxysilanes and azasilacycloalkyl functional tetramethyldisiloxanes | |
| US5290841A (en) | Organocyclosiloxane and method for its preparation | |
| EP1149837A2 (en) | Organosilicon compounds | |
| JP4178266B2 (ja) | アルキルポリエーテルシロキサン | |
| US5449734A (en) | Curable composition | |
| US5239085A (en) | Organocyclosiloxane and method for its preparation | |
| US4623741A (en) | Chlorosilane compounds | |
| JP7156759B2 (ja) | ケイ素ベースのカンナビジオール誘導体及びその組成物 | |
| US6118014A (en) | Organofunctional cocyclic siloxanes | |
| WO2005000856A2 (en) | Siloxane compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |