CN114315680B - Cannabidiol-2-pyrrolidine acid ester and application thereof - Google Patents
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Abstract
The invention discloses cannabidiol-2-pyrrolidine acid ester and application thereof, in particular to a compound shown in a formula I, a stereoisomer or pharmaceutically acceptable salt thereof, the cannabidiol-2-pyrrolidine acid ester has good stability, has a protection effect on nerve cell injury and skin cell injury, can induce apoptosis of human breast cancer cells, has practical application value in the production of medicines and cosmetics,
formula I.
Description
Technical Field
The invention belongs to the technical field of chemical engineering, and particularly relates to a novel cannabidiol derivative, and a preparation method and application thereof.
Background
Industrial cannabis sativa is a plant of the genus cannabis of the family Moraceae, and has significant medicinal value, and its terpenoid secondary metabolite, cannabinoid, has various biological activities. Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are high-content components of cannabinoids. While tetrahydrocannabinol is useful in the treatment of cancer-induced emesis, its use is banned in many countries due to its addictive nature. Unlike tetrahydrocannabinol, cannabidiol has no mental addiction, has anticonvulsant, sedative hypnotic, anxiolytic, antipsychotic, anti-inflammatory and neuroprotective effects, and becomes a natural active ingredient with great application prospects in the fields of medicines, cosmetics and foods.
The existing research shows that cannabidiol can generate tetrahydrocannabinol (Zhang, Van der Ke, Sunwuxing, etc. CBD and water-soluble CBD in artificial gastric juice and intestinal juice stability research green technology, 2020, 8: 5) in artificial gastric juice and intestinal juice. Another study showed that cannabidiol can be converted to tetrahydrocannabinol under acidic conditions (Michal P. Dybowski, Andrzej L. Dawidowcz, Rafal type, Michal Rombel. Conversion of Cannabidiol (CBD) to Δ 9-tetrahydrocannabinol (Δ 9-THC) during protein prediction enzymes from plant samples analysis by chromatography-hydrogenation with regenerated CBD catalysis, Talan, 2020, 220: 121390). Therefore, the possibility of reducing formation of tetrahydrocannabinol in the process of cannabidiol entering gastrointestinal tracts or other acidic environments is a key for guaranteeing the use safety of the cannabidiol, and the application scenes of the cannabidiol can be greatly expanded.
Based on the structure of cannabidiol, the cannabidiol derivative is designed and synthesized, can be used as an important way for obtaining a compound with good stability and activity, and has important significance for preparing novel medicines and cosmetics.
Most of the existing cannabidiol derivatives pay attention to the biological activity, for example, CN113336705A discloses a cannabidiol-2-imidazole-1-formate and application thereof, however, whether the risk of converting the prodrugs into tetrahydrocannabinol is unknown, and the drug development requirements cannot be met.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a novel cannabidiol derivative and a preparation method thereof. The invention also provides the compound, pharmaceutically acceptable salts or solvates thereof, a pharmaceutical composition containing the compound, and applications of the compound and the pharmaceutical composition in preparing nerve cell protection medicaments, breast cancer resisting medicaments and skin cell protection cosmetics.
The compounds of the invention have the structure shown in formula I:
formula I
The preparation method of the cannabidiol derivative provided by the invention comprises the following steps: cannabidiol with a structure shown in a formula II and (S) - (-) -N- (trifluoroacetyl) pyrrolidine-2-carbonyl chloride with a structure shown in a formula III react in the presence of a solvent to obtain a compound with a structure shown in a formula I.
The preparation method according to a preferred embodiment of the present invention has at least the following advantageous effects:
(1) the invention provides a novel cannabidiol derivative, which is cannabidiol-2-pyrrolidinoate, has good stability, has a protection effect on nerve cell injury, has an inhibition effect on breast cells, has a protection effect on skin injury cells, can be prepared into neuroprotective drugs, anti-breast cancer drugs and skin cell protection cosmetics, and has practical application values in the production of medicines and cosmetics.
(2) According to the preparation method provided by the invention, cannabidiol with a structure shown in a formula II and (S) - (-) -N- (trifluoroacetyl) pyrrolidine-2-carbonyl chloride with a structure shown in a formula III are used as raw materials, no catalyst is used, and a solvent is a common solvent, so that the raw materials are cheap and easy to obtain.
(3) The preparation method provided by the invention has the advantages of mild conditions and low energy consumption.
(4) The preparation method provided by the invention has the advantages that the yield of the main product reaches 61.1%, and the yield is higher.
In some embodiments of the invention, the methods of preparation comprise the following synthetic routes:
in some embodiments of the invention, the solvent is anhydrous acetonitrile.
In some embodiments of the invention, the molar ratio of cannabidiol, (S) - (-) -N- (trifluoroacetyl) pyrrolidine-2-carbonyl chloride is 1: 1.
In some embodiments of the present invention, the preparation method specifically comprises heating and refluxing the reaction mixture for 9 hours, concentrating by rotary evaporation, dissolving with dichloromethane, washing with water, drying with anhydrous magnesium sulfate, rotary evaporation, and separating and purifying by column chromatography.
The invention also provides a pharmaceutical composition, which comprises the cannabidiol-2-pyrrolidinoate or the pharmaceutically acceptable salt thereof or the solvate of the compound, and one or more excipients, diluents, fillers and the like;
preferably, the pharmaceutical composition is formulated in the form of powder or granules.
The invention also provides application of the cannabidiol-2-pyrrolidinoate or pharmaceutically acceptable salts thereof or solvates of the compounds, or a pharmaceutical composition containing the compounds in preparation of nerve cell protective drugs, breast cancer resistant drugs and skin cell protective cosmetics.
Further, the nerve cell is a glial cell BV 2; or the breast cancer cell is human breast cancer cell MDA-MB-231; or the skin cell is human immortalized epidermal cell HaCaT.
Drawings
FIG. 1 shows the chemical structure of cannabidiol-2-pyrrolidinate analogs (cannabidiol, cannabidiol-2-propionate, cannabidiol-2-butyrate, cannabidiol-2-imidazole-1-carboxylate);
FIG. 2 is a liquid chromatogram of a sample mixture of tetrahydrocannabinol and cannabidiol;
FIG. 3 is a liquid chromatogram for detecting cannabidiol derivative stability;
FIG. 4 is a liquid chromatogram of cannabidiol-2-pyrrolidinate conversion risk experiment at 0 hour;
FIG. 5 is a 24-hour liquid chromatogram of a cannabidiol-2-pyrrolidinate conversion risk experiment;
FIG. 6 shows a liquid chromatogram of 0 hour of cannabidiol-2-propionate conversion risk experiment;
FIG. 7 shows a 24-hour liquid chromatogram of a cannabidiol-2-propionate conversion risk experiment;
FIG. 8 is a 0-hour liquid chromatogram of a cannabidiol-2-butyrate conversion risk experiment;
FIG. 9 shows a 24-hour liquid chromatogram of a cannabidiol-2-butyrate conversion risk experiment;
FIG. 10 is a liquid chromatogram of cannabidiol-2-imidazole-1-carboxylate conversion risk experiment at 0 hr;
FIG. 11 liquid chromatogram of cannabidiol-2-imidazole-1-carboxylate conversion risk experiment for 24 hours.
Detailed Description
The conception and the resulting technical effects of the present invention will be further described with reference to specific embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention. The method is a conventional method unless otherwise specified. The materials are commercially available from the open literature unless otherwise specified.
Example 1 preparation of cannabidiol-2-pyrrolidinoate
The synthetic route is shown as the following formula:
adding 1.15 g (5 mmol) of (S) - (-) -N- (trifluoroacetyl) pyrrolidine-2-carbonyl chloride and 20 mL of anhydrous acetonitrile into a 50 mL three-necked bottle, stirring, adding 1.57 g (5 mmol) of cannabidiol and 1mL of pyridine, stirring, heating, refluxing for 9 hours, carrying out rotary evaporation concentration, dissolving with dichloromethane, washing with water, drying with anhydrous magnesium sulfate, carrying out rotary evaporation, and carrying out column chromatography separation and purification to obtain 1.55g of colorless liquid, wherein the yield is 61.1%.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1H NMR (300 MHz, DMSO-d 6) δ: 8.66 (s, 2H), 6.01 (s, 2H), 5.08 (s, 1H), 4.44 (d, J = 24.0 Hz, 2H), 4.03(q, J = 7.0 Hz, 1H), 3.80 (s, 1H), 3.38 (s, 1H), 3.02 (t, J = 10.5 Hz, 1H), 2.28 (d, J = 6.0 Hz, 2H), 2.05-1.88 (m, 3H), 1.66-1.44 (m, 11H),1.20 (t, J = 13.5 Hz, 6H), 0.86 (t, J = 7.5 Hz, 3H)。
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H]+: the theoretical value is 508.26692, and the actual value is 508.26865.
The results of the nuclear magnetic hydrogen spectrum and high-resolution mass spectrum detection show that the preparation method provided by the invention can be used for effectively preparing the cannabidiol-2-pyrrolidine acid ester.
Example 2 determination of the conversion Risk of cannabidiol-2-pyrrolidinoate
An appropriate amount of the compound cannabidiol-2-pyrrolidinoate and its analogues (cannabidiol-2-propionate, cannabidiol-2-butyrate, cannabidiol-2-imidazole-1-formate) obtained in example 1 was taken, dissolved in 20 mL of 95% ethanol solution, adjusted to pH 1.68 with 37% hydrochloric acid, taken 20 μ L and added with methanol to 1mL, and the mixture was loaded onto a machine and sampled every 2 hours. The control solutions were 100. mu.g/mL tetrahydrocannabinol methanol solution and 100. mu.g/mL cannabidiol methanol solution. Liquid phase conditions: the chromatographic column is Agilent ZORBAX SB-C18, and the elution conditions are 0.1% formic acid solution: acetonitrile =25:75, time 30 min, wavelength 220 nm, sample size 1 μ L. The results are expressed as changes in peak area. FIG. 2 is a liquid chromatogram of a sample mixture of tetrahydrocannabinol and cannabidiol.
As can be seen from the results in fig. 3 and fig. 4 to 11, the compounds of the present invention did not see conversion to tetrahydrocannabinol under the experimental conditions; the analogues of cannabidiol-2-propionate and cannabidiol-2-imidazole-1-formate have no conversion to tetrahydrocannabinol under the experimental conditions, but the conversion to cannabidiol is found in the experiment; the analog cannabidiol-2-butyrate was found to convert to tetrahydrocannabinol and also to cannabidiol under the experimental conditions. The research results show that the compound of the invention has good stability and no risk of conversion to tetrahydrocannabinol.
Example 3 determination of the neuronal injury protection Effect of cannabidiol-2-pyrrolidinoate
Cannabidiol-2-pyrrolidinate, a compound obtained in example 1, and its analogues (cannabidiol, cannabidiol-2-propionate, cannabidiol-2-butyrate, cannabidiol-2-imidazole-1-carboxylate) were dissolved in DMSO under sterile conditions to prepare a 20 mM stock solution. Glial cells BV2 were inoculated into 96-well plates, which were stimulated with glutamate and corticosterone, respectively, to construct a cell injury model, after 12 hours of culture, cannabidiol and the compound obtained in example 1 were added to the culture medium, diluted to 5.0, 2.5, 1.0, 0.5, 0.25, 0.1. mu.M, 5 duplicate wells per group were set, culture was continued for 72 hours, 20. mu.L of MTT reagent was added to each well, and culture was continued for 0.5 hours. MTT working solution was discarded, 150. mu.l DMSO was added to each well, and the mixture was mixed by shaking gently at room temperature for 10 minutes. The experiment was carried out on a normal control group, a glutamic acid-induced BV2 cell injury group and a corticosterone-induced BV2 cell injury group. The 96-well plate was placed in an microplate reader at a wavelength of 450 nm to measure the OD value, and the cell survival rate was calculated.
Cell survival (%) = (each treatment group OD-blank OD)/(control group OD-blank OD) × 100%.
The test results are shown in tables 1 and 2.
TABLE 1 protective Effect of Compounds on glutamate induced neuronal injury
Note: in a model of BV2 cell damage caused by glutamic acid, the cell survival rate (%) of a normal control group is 100.12 +/-0.42; the cell survival rate (%) of BV2 cell injury group was 61.49. + -. 0.64.
TABLE 2 protective Effect of Compounds on Cortisol-induced nerve cell Damage
Note: in a BV2 cell damage caused by corticosterone as a model, the cell survival rate (%) of a normal control group is 100.14 +/-0.55; the cell survival rate (%) of the BV2 cell injury group was 62.96. + -. 0.71.
As can be seen from the results in table 1, the compounds of the present invention have an antagonistic effect against the cytotoxicity of glutamic acid against BV2, and as can be seen from the results in table 2, the compounds of the present invention have an antagonistic effect against the cytotoxicity of corticosterone against BV2, and can improve the cell survival rate, and the activity of the compounds of the present invention at the same concentration is equivalent to that of the analogues cannabidiol-2-propionate, cannabidiol-2-butyrate, and cannabidiol-2-imidazole-1-carboxylate, higher than that of the analogues cannabidiol. The research results show that the compound has good protection effect on nerve cell damage.
Example 4 determination of anti-Breast cancer Effect of cannabidiol-2-pyrrolidinoate
Cannabidiol-2-pyrrolidinate, a compound obtained in example 1, and its analogues (cannabidiol, cannabidiol-2-propionate, cannabidiol-2-butyrate, cannabidiol-2-imidazole-1-carboxylate) were dissolved in DMSO under sterile conditions to prepare a 20 mM stock solution. Human breast cancer cells MDA-MB-231 are inoculated to a 6-well plate, 3 multiple wells are set for each group, the culture is carried out for 12 hours, after the cells adhere to the wall, a culture medium is added to dilute the cells into drug treatment groups with the concentration of 5.0, 2.5 and 1.0 mu M, and the drug treatment groups are cultured for 29 hours. The experiment was set as a normal control group. Cells are digested by trypsin without EDTA, washed for 2 times by PBS, 100 mu L of binding buffer solution is used for resuspending the cells, the cells are transferred into a flow tube, then 5 mu L of Annexin V-FITC and 5 mu L of PI staining solution are respectively added, the cells are incubated for 15 minutes in the dark at room temperature, and finally 400 mu L of binding buffer solution is added and mixed evenly. And (5) checking on the computer, and processing data by software.
The test results are shown in Table 3.
TABLE 3 apoptosis rate of Compounds on human Breast cancer cells MDA-MB-231
Note: the apoptosis rate (%) of the control group was 2.22. + -. 0.07.
As can be seen from the results in table 3, the compounds of the present invention induced apoptosis in human breast cancer cells MDA-MB-231, and at the same concentration, the activity of the compounds of the present invention was comparable to, and higher than, the analogues cannabidiol-2-propionate, cannabidiol-2-butyrate, cannabidiol-2-imidazole-1-carboxylate. The research results show that the compound has good breast cancer resistance.
Example 5 determination of the protective action of cannabidiol-2-pyrrolidinoate against skin cell damage
Cannabidiol-2-pyrrolidinate, a compound obtained in example 1, and its analogues (cannabidiol, cannabidiol-2-propionate, cannabidiol-2-butyrate, cannabidiol-2-imidazole-1-carboxylate) were dissolved in DMSO under sterile conditions to prepare a 20 mM stock solution. Human immortalized epidermal cells HaCaT were inoculated into 96-well plates with H2O2Cell injury model was constructed by stimulation, and after culturing for 29 hours, the compound obtained in example 1 and its analogue were added to the medium, diluted to 10.0, 5.0, 2.5, 1.0, 0.5 μ M, and 5 wells per group were set, culturing was continued for 29 hours, 16 μ L of MTT reagent was added to each well, and culturing was continued for 9 hours. MTT working solution was discarded, 160. mu.L DMSO was added to each well, and the mixture was shaken gently in a shaker at room temperature for 10 minutes and mixed well. The experiment was set as a normal control group H2O2The resulting HaCaT cell injury group. The 96-well plate was placed in an microplate reader at a wavelength of 450 nm to measure the OD value, and the cell survival rate was calculated.
Cell survival (%) = (each treatment group OD-blank OD)/(control group OD-blank OD) × 100%.
The test results are shown in Table 4.
TABLE 4 Compound vs. H2O2Protective effects of HaCaT cell damage caused by HaCaT
Note: the cell survival rate (%) of the normal control group was 100.12. + -. 0.98; cell survival (%) of HaCaT cell injury group was 56.67. + -. 0.82.
As can be seen from the results in Table 4, the compounds of the present invention have antagonistic H activity2O2The compound has the effect of oxidative damage to HaCaT cells and can improve the cell survival rate, and the activity of the compound is equivalent to that of analogues of cannabidiol-2-propionate and cannabidiol-2-butyrate and higher than that of analogues of cannabidiol and cannabidiol-2-imidazole-1-formate under the equivalent concentration. The research results show that the compound has good protective effect on skin cell damage.
Although the present invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it is not limited to the above-described embodiments, but may be modified or improved on the basis of the present invention, as will be apparent to those skilled in the art. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. The cannabidiol derivative is cannabidiol-2-pyrrolidine acid ester and pharmaceutically acceptable salts thereof, wherein the chemical structural formula of the cannabidiol-2-pyrrolidine acid ester is shown as a formula I:
formula I.
2. The cannabidiol derivative of claim 1, wherein the cannabidiol-2-pyrrolidinate has the following nuclear magnetic hydrogen spectrum characterization:1H NMR (300 MHz, DMSO-d 6) δ: 8.66 (s, 2H), 6.01 (s, 2H), 5.08 (s, 1H), 4.44 (d, J = 24.0 Hz, 2H), 4.03(q, J = 7.0 Hz, 1H), 3.80 (s, 1H), 3.38 (s, 1H), 3.02 (t, J = 10.5 Hz, 1H), 2.28 (d, J = 6.0 Hz, 2H), 2.05-1.88 (m, 3H), 1.66-1.44 (m, 11H),1.20 (t, J = 13.5 Hz, 6H), 0.86 (t, J = 7.5 Hz, 3H)。
3. cannabidiol derivative according to claim 1 or 2, wherein cannabidiol-2-pyrrolidinoate has the following high resolution mass spectral characterization: HRMS [ M + H ] +: theoretical value is 508.26692, found 508.26865.
4. A process for the preparation of cannabidiol derivatives as claimed in any one of claims 1 to 3, comprising the following reaction scheme:
the method comprises the following steps: cannabidiol with a structure shown in a formula II and (S) - (-) -N- (trifluoroacetyl) pyrrolidine-2-carbonyl chloride with a structure shown in a formula III react in the presence of a solvent to obtain a compound with a structure shown in a formula I.
5. The process according to claim 4, wherein the reaction mixture is heated under reflux for 9 hours, concentrated by rotary evaporation, dissolved in methylene chloride, washed with water, dried over anhydrous magnesium sulfate, rotary evaporated, and purified by column chromatography.
6. The application of the cannabidiol derivative in the preparation of the nerve cell protection medicine is characterized in that the derivative is cannabidiol-2-pyrrolidine acid ester or pharmaceutically acceptable salt thereof, wherein the chemical structural formula of the cannabidiol-2-pyrrolidine acid ester is shown as a formula I:
formula I.
7. The application of the cannabidiol derivative in preparing the anti-breast cancer medicine is characterized in that the derivative is cannabidiol-2-pyrrolidine acid ester or pharmaceutically acceptable salt thereof, wherein the chemical structural formula of the cannabidiol-2-pyrrolidine acid ester is shown as a formula I:
formula I.
8. The application of the cannabidiol derivative in the preparation of the skin cell protection cosmetics is characterized in that the derivative is cannabidiol-2-pyrrolidine acid ester or pharmaceutically acceptable salt thereof, wherein the chemical structural formula of the cannabidiol-2-pyrrolidine acid ester is shown as a formula I:
formula I.
9. The use according to any one of claims 6 to 8, wherein the neural cell is glial cell BV 2;
or the breast cancer cell is human breast cancer cell MDA-MB-231;
or the skin cell is a human immortalized epidermal cell HaCaT.
10. Use of a pharmaceutical composition comprising, as active ingredient, the cannabidiol derivative according to claim 1, together with one or more excipients, for the preparation of a neuroprotective drug, an anti-breast cancer drug or a skin cytoprotective cosmetic.
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