CN116983265B - Embedding system of dihydro cannabidiol-2, 6-dioxopiperazine formate and preparation method and application thereof - Google Patents
Embedding system of dihydro cannabidiol-2, 6-dioxopiperazine formate and preparation method and application thereof Download PDFInfo
- Publication number
- CN116983265B CN116983265B CN202311265862.2A CN202311265862A CN116983265B CN 116983265 B CN116983265 B CN 116983265B CN 202311265862 A CN202311265862 A CN 202311265862A CN 116983265 B CN116983265 B CN 116983265B
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- China
- Prior art keywords
- dihydrocannabidiol
- dioxopiperazine
- formate
- cannabidiol
- organic solvent
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- 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.)
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- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 title claims abstract description 53
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- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 claims abstract description 94
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 claims abstract description 25
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229950011318 cannabidiol Drugs 0.000 claims abstract description 23
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 claims abstract description 23
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- 238000000034 method Methods 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
The invention discloses an embedding system of dihydro cannabidiol-2, 6-dioxopiperazine formate and a preparation method and application thereof, wherein the preparation method comprises the following steps: mixing cannabidiol, an organic solvent A and a catalytic system to obtain dihydro cannabidiol; mixing the dihydrocannabidiol, an organic solvent B, 4-ethyl-2, 3-dioxo-1-piperazine formyl chloride and an alkaline reagent to obtain the dihydrocannabidiol-2, 6-dioxopiperazine formate; dissolving the dihydrocannabidiol-2, 6-dioxopiperazine formate in an organic solvent C to obtain an oil solution, mixing the oil solution with a cellulose nanocrystalline suspension, and shearing to obtain an embedding system of the dihydrocannabidiol-2, 6-dioxopiperazine formate. The dihydro cannabidiol-2, 6-dioxopiperazine formate and the embedding system thereof have good stability, can be used for preparing nerve cell protection medicines and hypoglycemic medicines, and have practical application value in medicine production.
Description
Technical Field
The invention belongs to the technical field of chemical industry, and particularly relates to an embedding system of dihydro cannabidiol-2, 6-dioxopiperazine formate, a preparation method and application thereof.
Background
Industrial cannabis is a Sang Keda cannabis plant, has important medicinal value, and the terpenoid secondary metabolite, namely cannabinoid, has various biological activities. Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the higher content components of cannabinoids. While tetrahydrocannabinol is useful in the treatment of emesis caused by cancer, it is prohibited in many countries because of its addictive nature. Unlike tetrahydrocannabinol, cannabidiol has no mental addiction, and has anticonvulsant, sedative-hypnotic, anxiolytic, antipsychotic, antiinflammatory and neuroprotective effects, and is a natural active ingredient with great application prospect in the fields of medicine, cosmetics and food.
Current studies have shown that cannabidiol can produce tetrahydrocannabinol in artificial gastric juice containing ethanol (Zhang Xuran, fan Dekai, sun Wuxing, etc., CBD and water-soluble CBD are stable in artificial gastric juice, intestinal juice for green technology, 2020, 8:5). Additional studies have shown that cannabidiol can be converted to tetrahydrocannabinol under acidic conditions (Michal P. Dybowski, andrzej L. Dawidowicz, rafal Typek, michal Rombel Conversion of Cannabidiol (CBD) to Δ9-tetrahydrocanabinol (Δ9-THC) during protein precipitations prior to plasma samples analysis by chromatography-Troubles with reliable CBD quantitation when acidic precipitation agents are applied Talanta, 2020, 220: 121390). Therefore, the possibility of formation of tetrahydrocannabinol is eliminated, the key for guaranteeing the use safety of tetrahydrocannabinol is provided, and the application scene of tetrahydrocannabinol can be greatly expanded. The dihydrocannabidiol is used as a derivative of cannabidiol, is not present in cannabidiol extract, and cannot be converted into tetrahydrocannabidiol in vivo or by other synthetic means, and has better safety than cannabidiol.
Therefore, the designed and synthesized dihydrocannabidiol derivative based on the cannabidiol structure can be used as an important way for obtaining the compound with good stability and activity, and has important significance for preparing novel medicines.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides an embedding system of dihydro cannabidiol-2, 6-dioxopiperazine formate, and a preparation method and application thereof. The research shows that the dihydro cannabidiol-2, 6-dioxopiperazine formate and the embedding system thereof have better nerve cell protection effect and blood sugar reducing effect.
In a first aspect of the present invention, there is provided a method for preparing an embedding system of dihydrocannabidiol-2, 6-dioxopiperazine carboxylic acid ester, the method comprising the steps of:
(1) Preparation of dihydrocannabidiol-2, 6-dioxopiperazine formate:
a: mixing cannabidiol, an organic solvent A and a catalytic system to obtain dihydro cannabidiol;
b: mixing the dihydrocannabidiol, an organic solvent B, 4-ethyl-2, 3-dioxo-1-piperazine formyl chloride and an alkaline reagent to obtain dihydrocannabidiol-2, 6-dioxopiperazine formate;
(2) Preparing an embedding system:
and dissolving the dihydrocannabidiol-2, 6-dioxopiperazine formate in an organic solvent C to obtain an oil solution, mixing the oil solution with a cellulose nanocrystalline suspension, and shearing to obtain an embedding system of the dihydrocannabidiol-2, 6-dioxopiperazine formate.
Further, the structure of the dihydrocannabidiol-2, 6-dioxopiperazine formate is shown as a formula I:
。
further, the organic solvent A is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene, in particular dichloromethane.
Further, the catalytic system is a catalyst and/or hydrogen.
Further, the catalyst is a metal catalyst and/or a carbon carrier.
Further, the pressure of the hydrogen gas is 1-5 MPa, specifically 1, 2,3, 4, 5 MPa, especially 2 MPa.
Further, the metal catalyst is selected from one or more of platinum (Pt), palladium (Pd), rhodium (Rh), molybdenum (Mo), tin (Sn) and uranium (Ur), in particular palladium.
Further, the carbon support is selected from one or more of activated carbon (C), carbon nanotubes, activated carbon fibers, graphene, and carbon black, in particular activated carbon.
In some embodiments of the invention, the catalytic system is a 10% palladium on carbon catalyst.
Further, the mass ratio of cannabidiol to the catalytic system is 10-30:1, specifically 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1.
In some embodiments of the invention, the mass ratio of cannabidiol to catalytic system is 20:1.
Further, in the step A, the reaction time is 4-12 h, especially 6 h.
Further, the organic solvent B is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene, in particular dichloromethane.
Further, the molar ratio of the dihydrocannabidiol to the 4-ethyl-2, 3-dioxo-1-piperazine formyl chloride is 1:2-4, such as 1:2, 1:3, and 1:4.
In some embodiments of the invention, the molar ratio of dihydrocannabidiol to 4-ethyl-2, 3-dioxo-1-piperazine carbonyl chloride is 1:3.
Further, the alkaline reagent is selected from one or more of triethylamine, dimethylamine, diethylamine, di-N-propylamine, diisopropylamine, N-ethylmethylamine, di-N-butylamine, diisobutylamine, di-sec-butylamine, di-tert-butylamine, dipentamine, di-N-octylamine, diallylamine, dicyclohexylamine and diphenylamine, in particular triethylamine.
Further, the molar ratio of the dihydrocannabidiol to the alkaline agent is 1:2-4, such as 1:2, 1:3, 1:4.
In some embodiments of the invention, the molar ratio of the dihydrocannabidiol to the alkaline agent is 1:3.
Further, in step B, the reaction time is 6-24 h, especially 12-h.
Further, in the step B, the reaction is performed at room temperature.
Further, the organic solvent C is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene, especially propylene glycol.
Further, the oil solution has a mass concentration of 0.1-5%, such as 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5%, especially 2%.
Further, the mass concentration of the cellulose nanocrystal suspension is 0.01-2%, such as 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2%, especially 0.2%.
Further, the volume ratio of the oil solution to the cellulose nanocrystal suspension is 1:0.1-5, such as 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, especially 1:1.
Further, the shearing method is selected from one or more of ultrasonic shearing, mechanical shearing, laser shearing, thermal shearing and water jet shearing, and particularly ultrasonic shearing.
Further, the parameters of the ultrasonic shearing are as follows: the ultrasonic power is 100-1000W (such as 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000W), and the ultrasonic time is 1-10 min (such as 1, 2,3, 4, 5, 6, 7, 8, 9, 10 min).
In some embodiments of the invention, the parameters of the ultrasonic shearing are: the ultrasonic power is 400W and the ultrasonic time is 5min.
In some embodiments of the present invention, the step (1) specifically includes: mixing cannabidiol, dichloromethane and 10% Pd/C, replacing nitrogen for 3 times, replacing hydrogen for 3 times, reacting for 6 hours under 2Mpa hydrogen, filtering, concentrating by rotary evaporation, and separating and purifying by column chromatography to obtain the dihydrocannabidiol; mixing the dihydrocannabidiol, 4-ethyl-2, 3-dioxo-1-piperazine formyl chloride, triethylamine and dichloromethane, reacting for 12 hours at room temperature, concentrating by rotary evaporation, dissolving with dichloromethane, washing with water, drying with anhydrous magnesium sulfate, rotary evaporation, and separating and purifying by column chromatography to obtain the dihydrocannabidiol-2, 6-dioxopiperazine formate.
In some embodiments of the present invention, the step (2) specifically includes: dissolving dihydrocannabidiol-2, 6-dioxopiperazine formate in propylene glycol to obtain an oil solution of the dihydrocannabidiol-2, 6-dioxopiperazine formate; and carrying out ultrasonic shearing on the oil solution of the dihydrocannabidiol-2, 6-dioxopiperazine formate and the cellulose nanocrystalline suspension to obtain an embedding system of the dihydrocannabidiol-2, 6-dioxopiperazine formate.
In a second aspect of the present invention, there is provided an embedding system of dihydrocannabidiol-2, 6-dioxopiperazine formate prepared by the preparation method as described in the first aspect.
In a third aspect of the present invention, there is provided a process for the preparation of dihydrocannabidiol-2, 6-dioxopiperazine formate as described in the first aspect.
In a fourth aspect of the present invention, there is provided a dihydrocannabidiol-2, 6-dioxopiperazine carboxylate prepared by the preparation method as described in the third aspect.
In a fifth aspect, the invention provides an embedding system of dihydrocannabidiol-2, 6-dioxopiperazine formate as described in the second aspect for preparing a hypoglycemic drug.
In a sixth aspect, the present invention provides the use of an embedding system of dihydrocannabidiol-2, 6-dioxopiperazine carboxylate as described in the second aspect for the preparation of a neuroprotective medicament.
In a seventh aspect, the invention provides an application of the dihydrocannabidiol-2, 6-dioxopiperazine formate in preparing hypoglycemic drugs.
In an eighth aspect of the invention, there is provided the use of a dihydrocannabidiol-2, 6-dioxopiperazine carboxylate as described in the fourth aspect in the preparation of a medicament for neuroprotection.
In a ninth aspect of the present invention, there is provided a pharmaceutical composition comprising the dihydrocannabidiol-2, 6-dioxopiperazine carboxylate as described in the fourth aspect, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an embedding system of the dihydrocannabidiol-2, 6-dioxopiperazine formate as described in the second aspect.
Further, the pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials.
Further, the pharmaceutically acceptable auxiliary materials comprise excipient, diluent, filler and the like.
Further, the dosage form of the pharmaceutical composition is powder or granule.
The invention has the following beneficial effects:
(1) The dihydro cannabidiol-2, 6-dioxopiperazine formate and the embedding system thereof have good stability, have a protective effect on nerve cell injury and a relieving effect on insulin resistance, can be used for preparing nerve cell protective medicaments and hypoglycemic medicaments, and have practical application values in medical production.
(2) The preparation method of the dihydro cannabidiol-2, 6-dioxopiperazine formate and the embedding system thereof has the advantages of simple operation, low raw material cost, mild reaction, low energy consumption and high yield.
Detailed Description
Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention relates.
In the present invention, the structural formula and chinese name of the compound used are as follows:
in the invention, the term Pickering emulsion, also called Pickering emulsion, is a novel emulsion which uses solid particles to replace the traditional organic surfactant to stabilize an emulsion system.
In the present invention, the term "room temperature" means that the temperature of an item is close to or the same as the temperature of a space, such as the location of a fume hood in which the item is located. Typically, room temperature is about 20 ℃ to about 30 ℃, or about 22 ℃ to 27 ℃, or about 25 ℃.
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
EXAMPLE 1 preparation of Dihydrocannabidiol derivatives and embedding System therefor
1.1 preparation of the Dihydrocannabidiol derivatives
1.1.1 Synthesis routes to the Dihydrocannabidiol-2, 6-dioxopiperazine formate
31.4 g (0.1 mol) cannabidiol, 1.57g 10% Pd/C and 200ml anhydrous dichloromethane were added to a 500 mL reactor, nitrogen was replaced 3 times, hydrogen was replaced 3 times, and the reaction was stirred under 2MPa hydrogen for 6 hours. The reaction solution is reactedFiltering, rotary evaporating, concentrating, separating and purifying by column chromatography to obtain colorless liquid 25.8 g with 82% yield.
3.07 g (15 mmol) of 4-ethyl-2, 3-dioxo-1-piperazine formyl chloride and 20 mL of anhydrous dichloromethane are added into a 50 mL three-necked flask, stirred, 1.57g (5 mmol) of dihydrocannabidiol is added, 1.51g (15 mmol) of triethylamine is added, stirred and reacted for 12 hours at room temperature, concentrated by rotary evaporation, dissolved by dichloromethane, washed by water, dried by anhydrous magnesium sulfate, rotary evaporated, separated and purified by column chromatography to obtain 2.58g of colorless liquid with the yield of 79%.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 8.26 (s, 2H), 7.54 (s, 2H), 7.15 (d,J= 1.7 Hz, 2H), 7.04 (s, 2H), 5.22 (d,J= 2.7 Hz, 1H), 3.59 – 3.48 (m, 1H), 2.67 (dd,J= 9.0, 6.7 Hz, 2H), 1.89 – 1.63 (m, 6H), 1.52 (dqd,J= 13.0, 6.5, 3.1 Hz, 1H), 1.41 – 1.28 (m, 7H), 0.93 – 0.85 (m, 6H), 0.70 (d,J= 6.9 Hz, 3H)。 13 C NMR (126 MHz, Chloroform-d) δ 148.9, 147.0, 143.4, 137.4, 135.3, 131.1, 127.3, 123.0, 117.4, 43.6, 37.7, 35.1, 31.3, 30.3, 27.9, 22.8, 22.4, 21.9, 21.6, 15.9, 13.9。
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 653.3545 and measured 653.3543.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol-2, 6-dioxopiperazine formate.
1.1.2 synthetic routes to the Dihydrocannabidiol dioctanoate
2.43 g (15 mmol) octanoyl chloride and 20 mL anhydrous dichloromethane are added into a 50 mL three-necked flask, stirred, 1.57g (5 mmol) dihydrocannabidiol, 1.18g (15 mmol) pyridine are added, stirred at room temperature, reacted for 9 hours, concentrated by rotary evaporation, dissolved by dichloromethane, washed by water, dried by anhydrous magnesium sulfate, rotary evaporated, separated and purified by column chromatography, and colorless liquid is obtained.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 6.70 (s, 2H), 5.14 (d,J= 2.4 Hz, 1H), 3.46 – 3.36 (m, 1H), 2.55 (m,J= 9.2, 6.6 Hz, 4H), 2.44 (t,J= 7.5 Hz, 4H), 2.31 (m,J= 29.1, 7.6 Hz, 1H), 1.79 – 1.65 (m, 8H), 1.68 – 1.55 (m, 9H), 1.00 – 0.92 (m, 2H), 0.91 – 0.86 (m, 21H), 0.82 (d,J= 7.0 Hz, 4H), 0.75 (d,J= 6.8 Hz, 3H).
13 C NMR (126 MHz, Chloroform-d)) δ 171.9, 150.0, 141.9, 132.8, 126.4, 125.1, 42.7, 37.5, 35.3, 34.3, 31.7, 30.5, 29.2, 29.0, 27.9, 26.9, 24.7, 24.2, 23.4, 22.6, 22.5, 21.6, 16.1, 14.1.
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 568.4570 and measured 568.4573.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol dioctanoate.
1.1.3 synthetic routes to the dihydrocannabidiol diisononanoate
2.64 g (15 mmol) isononyl chloride and 20 mL anhydrous dichloromethane are added into a 50 mL three-necked flask, stirred, 1.57g (5 mmol) of dihydrocannabidiol, 1.18g (15 mmol) of pyridine are added, stirred at room temperature, reacted for 9 hours, concentrated by rotary evaporation, dissolved by dichloromethane, washed by water, dried by anhydrous magnesium sulfate, rotary evaporated, separated and purified by column chromatography, and colorless liquid is obtained.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 6.62 (s, 2H), 5.07 (s, 1H), 3.38 – 3.31 (m, 1H), 2.52 – 2.43 (m, 3H), 1.31 – 1.20 (m, 10H), 1.12 (m,J= 14.0, 6.5, 2.4 Hz, 3H), 1.01 (dd,J= 6.6, 2.5 Hz, 8H), 0.90 – 0.84 (m, 26H), 0.83 – 0.80 (m, 4H), 0.75 (d,J= 6.9 Hz, 3H), 0.69 (m,J= 6.9, 2.2 Hz, 3H).
13 C NMR (126 MHz, Chloroform-d)) δ 171.1, 150.0, 141.9, 132.7, 126.3, 125.0, 50.7, 43.8, 42.7, 37.6, 35.2, 31.5, 31.1, 30.9, 30.4, 30.0, 30.0, 27.9, 26.9, 23.4, 22.7, 22.5, 21.5, 14.0.
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 597.4883 and measured 597.4884.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol diisononanoate.
1.1.4 synthetic routes to the dihydrocannabidiol dipelargonate
2.65 g (15 mmol) of nonanoyl chloride and 20 mL of anhydrous dichloromethane are added into a 50 mL round bottom flask and stirred, 1.57g (5 mmol) of dihydrocannabidiol and 1.18g (15 mmol) of pyridine are added, stirring is carried out at room temperature, the reaction is carried out for 12 hours, rotary evaporation concentration, dichloromethane dissolution, water washing, anhydrous magnesium sulfate drying, rotary evaporation and column chromatography separation and purification are carried out, and colorless liquid is obtained.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 6.60 (t,J= 1.0 Hz, 2H), 6.19 (d,J= 9.1, 1.3 Hz, 1H), 3.42 (m,J= 10.1, 9.2, 2.3, 1.0 Hz, 1H), 2.61 – 2.47 (m, 6H), 2.16 – 2.03 (m, 2H), 1.82 – 1.45 (m, 13H), 1.43 – 1.18 (m, 24H), 0.89 (s, 15H).
13 C NMR (125 MHz, Chloroform-d)) δ 171.8, 151.2, 143.2, 138.7, 124.1, 120.2, 115.2, 44.8, 35.8, 35.7, 34.4, 31.3, 31.0, 30.8, 30.7, 29.6, 29.3, 29.2, 24.7, 24.1, 23.4, 22.6, 22.5, 20.0, 14.0 .
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 597.4883 and measured 597.4889.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol dipelargonate.
1.1.5 synthetic route to dihydrocannabidiol diacetate
1.53 g (15 mmol) of acetic anhydride and 20 mL of anhydrous dichloromethane are added into a 50 mL three-necked flask, stirred, 1.57g (5 mmol) of dihydrocannabidiol and 1.18g (15 mmol) of pyridine are added, stirred at room temperature, reacted for 9 hours, concentrated by rotary evaporation, dissolved by dichloromethane, washed by water, dried by anhydrous magnesium sulfate, purified by rotary evaporation, and separated by column chromatography, thus obtaining colorless liquid.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 6.58 (t,J= 1.0 Hz, 2H), 6.19 (d,J= 9.1, 1.3 Hz, 1H), 3.42 (m,J= 10.1, 9.2, 2.8, 0.9 Hz, 1H), 2.57 (tt,J= 7.7, 1.1 Hz, 2H), 2.50 (s, 5H), 2.17 – 2.02 (m, 2H), 1.83 – 1.46 (m, 10H), 1.43 – 1.27 (m, 4H), 0.92 – 0.86 (m, 9H).
13 C NMR (125 MHz, Chloroform-d)) δ 168.1, 151.8, 143.1, 138.7, 124.1, 121.2, 115.6, 44.8, 35.8, 35.7, 31.3, 31.0, 30.8, 29.2, 24.1, 23.4, 22.5, 20.7, 20.0, 14.0.
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 401.2692 and measured 401.2689.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol diacetate.
1.1.6 synthetic route to Dihydrocannabidiol Di-p-methylbenzoate
2.31 g (15 mmol) of p-methylbenzoyl chloride and 20 mL of anhydrous dichloromethane are added into a 50 mL three-necked flask, stirred, 1.57g (5 mmol) of dihydrocannabidiol and 1.51g of triethylamine (15 mmol) are added, stirred at room temperature for reaction for 6 hours, washed with water, dried over anhydrous magnesium sulfate, distilled, separated and purified by column chromatography, and colorless liquid is obtained.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-dδ 8.21 – 8.16 (m, 4H), 7.52 – 7.49 (m, 4H), 6.89 (d,J= 3.4 Hz, 2H), 5.24 (t,J= 1.9 Hz, 1H), 2.68 – 2.54 (m, 2H), 2.33(s, 6H) 2.03-1.88(m, 2H), 1.73 – 1.49 (m, 10H), 1.39 – 1.26 (m, 4H), 0.95 – 0.76 (m, 9H)
13 C NMR (126 MHz, Chloroform-d) δ 165.0, 150.3, 142.3, 135.3, 133.6, 131.5, 130.1, 128.9, 128.5, 127.1, 124.7, 43.2, 37.7, 35.3, 31.6, 30.5, 27.9, 26.9, 23.0, 22.5, 21.8, 16.3, 14.0.
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 553.3318 and measured 553.3320.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol di-p-methyl benzoate.
1.2 Preparation method of embedding system of dihydrocannabidiol derivative
The dihydrocannabidiol-2, 6-dioxopiperazine formate was dissolved in propylene glycol to prepare an oil solution of the dihydrocannabidiol-2, 6-dioxopiperazine formate at a concentration of 2% (w/v). The oil solution of the dihydrocannabidiol-2, 6-dioxopiperazine formate and the 0.2% (w/v) cellulose nanocrystalline suspension are subjected to ultrasonic shearing in a ratio of 1:1, so as to obtain the Pickering emulsion embedding the dihydrocannabidiol-2, 6-dioxopiperazine formate. The configuration parameters are as follows: ultrasonic power 400W, ultrasonic time 5min.
The embedding system of other dihydrocannabidiol derivatives (such as dihydrocannabidiol di-p-methyl benzoate, dihydrocannabidiol diisononanoate, dihydrocannabidiol dioctanoate, dihydrocannabidiol diacetate and dihydrocannabidiol dipelargonoate) is prepared by the same method as above.
EXAMPLE 2 determination of neuronal injury protection effect of Dihydrocannabidiol derivatives
The dihydrocannabidiol-2, 6-dioxopiperazine formate (prepared in example 1) and its analogues (e.g., cannabidiol-2-imidazole-1-formate, cannabidiol-2-propionate, cannabidiol-2-butyrate, cannabidiol-2-nicotinate, cannabidiol-2- (N-acetyl) piperidine, cannabidiol-2-pyrrolidone, cannabidiol-2-piperazine) were dissolved in DMSO under aseptic conditions to prepare a 10 mM mother liquor. Human neuroblastoma cells SH-SY5Y are inoculated into 96-well plates, the compounds are respectively added into culture media, diluted to 5.0, 2.5, 1.0, 0.5, 0.25 and 0.1 mu M, 5 compound holes are set in each group, after 24 hours of culture, a cell damage model is constructed by stimulation of hydrogen peroxide, after 24 hours of continuous culture, 10 mu L of CCK-8 reagent is added into each hole, and the culture is continued for 2 hours. The experiment was carried out in a normal control group and in a SH-SY5Y cell damage group caused by hydrogen peroxide. The cell viability was calculated by measuring OD values in 96-well plates on an enzyme-labeled instrument at a wavelength of 450 nm.
Cell viability (%) = (treatment OD-blank OD)/(control OD-blank OD) ×100%.
The test results are shown in Table 1.
TABLE 1 protection of nerve cell injury by Hydrogen peroxide by different Compounds
Note that: in the SH-SY5Y cell damage caused by hydrogen peroxide as a model, the cell survival rate (%) of a normal control group is 100, and the cell survival rate (%) of the SH-SY5Y cell damage group is 68.67 +/-2.82.
From the results shown in Table 1, it can be seen that the dihydrocannabidiol-2, 6-dioxopiperazine formate has the effect of antagonizing the oxidative stress of hydrogen peroxide on SH-SY5Y cells, and can improve the cell survival rate. And the activity of the dihydro cannabidiol-2, 6-dioxopiperazine formate is higher than that of the analogue thereof under the same concentration. The research results show that the dihydrocannabidiol-2, 6-dioxopiperazine formate has a protective effect on nerve cell injury.
EXAMPLE 3 determination of neuronal injury protection effect of Dihydrocannabidiol derivatives and their embedding System
The dihydrocannabidiol-2, 6-dioxopiperazine formate and its embedding system (prepared in example 1), other dihydrocannabidiol derivatives and its embedding system (such as dihydrocannabidiol di-p-methylbenzoate, dihydrocannabidiol diisopelargonate, dihydrocannabidiol dioctanoate, dihydrocannabidiol diacetate, dihydrocannabidiol dipelargonate), CBD, cannabidiol-2-piperazine were dissolved in DMSO under aseptic conditions to prepare 10 mM mother liquor. Human neuroblastoma cells SH-SY5Y are inoculated into a 96-well plate, the above compounds and Pickering emulsion thereof are respectively added into a culture medium, diluted into 10.0, 2.5, 0.5 and 0.1 mu M of each group of 6 compound wells, after 24 hours of culture, a cell injury model is constructed by stimulation of hydrogen peroxide, after the culture is continued for 24 hours, 10 mu L of CCK-8 reagent is added into each well, and the culture is continued for 2 hours. The experiment was carried out in a normal control group and in a SH-SY5Y cell damage group caused by hydrogen peroxide. The cell viability was calculated by measuring OD values in 96-well plates on an enzyme-labeled instrument at a wavelength of 450 nm.
Cell viability (%) = (treatment OD-blank OD)/(control OD-blank OD) ×100%.
The test results are shown in Table 2.
TABLE 2 protection of different compounds and their embedding systems against SH-SY5Y cell damage by hydrogen peroxide
Note that: in the SH-SY5Y cell damage caused by hydrogen peroxide as a model, the cell survival rate (%) of a normal control group is 100+/-0, and the cell survival rate (%) of the SH-SY5Y cell damage group is 65 67+/-2.82 a 。
As can be seen from the results in Table 2, the CBD and the dihydrocannabidiol derivative and the embedding system thereof have the protection effect on SH-SY5Y cell damage caused by hydrogen peroxide, and the cytoprotection effect of the dihydrocannabidiol derivative and the embedding system thereof is best at 0.5 mu M. After embedding, the cytoprotective activity of the dihydrocannabidiol-2, 6-dioxopiperazine formate is obviously improved. The activity of the dihydrocannabidiol di-p-methyl benzoate after embedding is obviously improved, and the activity of the dihydrocannabidiol diisopelargonate, the dihydrocannabidiol dioctanoate, the dihydrocannabidiol diacetate and the dihydrocannabidiol dinonoate after embedding also has certain cytoprotective effect, but has no obvious difference with the activity before embedding, and even certain derivatives are reduced relative to the activity before embedding. The research results show that the dihydrocannabidiol derivative and the embedding system thereof have a certain effect of relieving SH-SY5Y cell damage caused by hydrogen peroxide, and the protection effect of the dihydrocannabidiol-2, 6-dioxopiperazine formate on SH-SY5Y cell damage caused by hydrogen peroxide after being embedded is obviously improved.
EXAMPLE 4 determination of insulin resistance of Dihydrocannabidiol derivatives and embedding System thereof
The dihydrocannabidiol-2, 6-dioxopiperazine formate and its embedding system (prepared in example 1), other dihydrocannabidiol derivatives and its embedding system (such as dihydrocannabidiol di-p-methylbenzoate, dihydrocannabidiol diisopelargonate, dihydrocannabidiol dioctanoate, dihydrocannabidiol diacetate, dihydrocannabidiol dipelargonate), CBD, cannabidiol-2-piperazine were dissolved in DMSO under aseptic conditions to prepare 10 mM mother liquor. Inoculating human liver cancer cell HepG2 into 96-well plate, constructing insulin resistance model by high-concentration insulin induction, culturing for 24 hr, and mixing the above compounds and Pick thereofThe culture medium was added to the ng emulsion and diluted to 10.0, 2.5, 0.5 and 0.1. Mu.M, each group was further incubated for 24 hours in 6 duplicate wells, and after further incubation, 5. Mu.L of the supernatant was aspirated from each well, 195. Mu.L of glucose content assay working solution was added and incubated for 20 minutes at 37 ℃. Experimental setup of insulin resistance model group, metformin (10 -3 M) positive control group and compound experimental group. The OD value was measured by placing the 96-well plate on an enzyme-labeled instrument at 550 nm wavelength, and the glucose consumption was calculated.
Glucose consumption (μm) =5550- (OD-0.0554 per group)/0.0002.
The test results are shown in Table 3.
TABLE 3 hypoglycemic effects of different Compounds and their embedding systems on insulin-resistant liver cancer cell model
Note that: in the modified insulin resistance model, the glucose consumption of the insulin resistance model group is: 3122.18 + -183.29 a The method comprises the steps of carrying out a first treatment on the surface of the The metformin positive group was: 3845.57 + -103.96 g 。
As can be seen from the results in Table 3, the above-mentioned dihydrocannabidiol derivatives and the embedding system thereof all have the effect of reducing glucose in insulin resistant HepG2 cells, and the compound has the best effect of reducing glucose at 0.5. Mu.M. Among the above compounds, 0.5. Mu.M of the embedded dihydrocannabidiol-2, 6-dioxopiperazine formate had the highest hypoglycemic activity, which was closest to that of the positive control group, namely dihydrocannabidiol di-p-methylbenzoate, dihydrocannabidiol diisononanoate, dihydrocannabidiol dioctanoate, dihydrocannabidiol diacetate and dihydrocannabidiol dipelargonoate, had a certain hypoglycemic effect after embedding, but was not significantly different from that before embedding, even if some derivatives had decreased activity relative to that before embedding. The research results show that the dihydrocannabidiol derivative and the embedding system thereof have a certain relieving effect on the insulin resistance of HepG2 cells, and the relieving effect on the insulin resistance of the HepG2 cells is obviously improved after the dihydrocannabidiol-2, 6-dioxopiperazine formate is embedded.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (15)
1. The preparation method of the embedding system of the dihydrocannabidiol-2, 6-dioxopiperazine formate is characterized by comprising the following steps:
(1) Preparation of dihydrocannabidiol-2, 6-dioxopiperazine formate:
a: mixing cannabidiol, an organic solvent A and a catalytic system to obtain dihydro cannabidiol;
b: mixing the dihydrocannabidiol, an organic solvent B, 4-ethyl-2, 3-dioxo-1-piperazine formyl chloride and an alkaline reagent to obtain dihydrocannabidiol-2, 6-dioxopiperazine formate;
(2) Preparing an embedding system:
dissolving the dihydrocannabidiol-2, 6-dioxopiperazine formate in an organic solvent C to obtain an oil solution, mixing the oil solution with a cellulose nanocrystalline suspension, and shearing to obtain an embedding system of the dihydrocannabidiol-2, 6-dioxopiperazine formate;
the structure of the dihydrocannabidiol-2, 6-dioxopiperazine formate is shown in formula I:
；
the organic solvent A is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene;
the catalyst system is 10% palladium/carbon catalyst and hydrogen;
the organic solvent B is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene;
the alkaline reagent is selected from one or more of triethylamine, dimethylamine, diethylamine, di-N-propylamine, diisopropylamine, N-ethylmethylamine, di-N-butylamine, diisobutylamine, di-sec-butylamine, di-tert-butylamine, dipentamine, di-N-octylamine, diallylamine, dicyclohexylamine and diphenylamine;
the organic solvent C is propylene glycol;
the shearing method is ultrasonic shearing.
2. The process of claim 1, wherein the organic solvent a is methylene chloride.
3. The preparation method according to claim 1, wherein the mass ratio of cannabidiol to the catalytic system is 10-30:1.
4. The method according to claim 1, wherein the hydrogen gas has a pressure of 1 to 5 MPa.
5. The process according to claim 1, wherein the organic solvent B is methylene chloride.
6. The process according to claim 1, wherein the molar ratio of dihydrocannabidiol to 4-ethyl-2, 3-dioxo-1-piperazinecarboxchloride is 1:2-4.
7. The method according to claim 1, wherein the basic reagent is triethylamine.
8. The method according to claim 1, wherein the molar ratio of the dihydrocannabidiol to the alkaline agent is 1:2-4.
9. The preparation method according to claim 1, wherein the mass concentration of the oil solution is 0.1-5%.
10. The method of claim 1, wherein the volume ratio of the oil solution to the suspension of cellulose nanocrystals is 1:0.1-5.
11. The method according to claim 1, wherein the ultrasonic shearing parameters are: the ultrasonic power is 100-1000W, and the ultrasonic time is 1-10 min.
12. An embedding system of dihydrocannabidiol-2, 6-dioxopiperazine carboxylic acid ester prepared by the method of any one of claims 1-11.
13. Use of the embedding system of dihydrocannabidiol-2, 6-dioxopiperazine carboxylate as defined in claim 12 for the preparation of a hypoglycemic agent.
14. The application of the dihydrocannabidiol-2, 6-dioxopiperazine formate in preparing hypoglycemic drugs is characterized in that the structure of the dihydrocannabidiol-2, 6-dioxopiperazine formate is shown as a formula I:
。
15. a pharmaceutical composition comprising dihydrocannabidiol-2, 6-dioxopiperazine carboxylate, or a pharmaceutically acceptable salt thereof, or an entrapment system for dihydrocannabidiol-2, 6-dioxopiperazine formate according to claim 12;
the structure of the dihydrocannabidiol-2, 6-dioxopiperazine formate is shown in formula I:
。
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| CN114292241A (en) * | 2022-03-07 | 2022-04-08 | 中国农业科学院农产品加工研究所 | Cannabidiol-2-dioxopiperazinoate and application thereof |
| CN115052868A (en) * | 2020-02-06 | 2022-09-13 | 伦敦制药与研究公司 | Cannabinoid sulfate, and salts and uses thereof |
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| WO2008107879A1 (en) * | 2007-03-05 | 2008-09-12 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Novel cannabidiol derivatives and their use as anti-inflammatory agents |
| CN115052868A (en) * | 2020-02-06 | 2022-09-13 | 伦敦制药与研究公司 | Cannabinoid sulfate, and salts and uses thereof |
| WO2021245676A1 (en) * | 2020-06-03 | 2021-12-09 | Epm (Ip), Inc. | Cannabidiolic acid (cbda) derivatives and uses thereof |
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