WO2023207460A1 - Dérivé de cannabidiol, son procédé de préparation et son utilisation - Google Patents

Dérivé de cannabidiol, son procédé de préparation et son utilisation Download PDF

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WO2023207460A1
WO2023207460A1 PCT/CN2023/083791 CN2023083791W WO2023207460A1 WO 2023207460 A1 WO2023207460 A1 WO 2023207460A1 CN 2023083791 W CN2023083791 W CN 2023083791W WO 2023207460 A1 WO2023207460 A1 WO 2023207460A1
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cancer
compound
disease
group
parkinson
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Chinese (zh)
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谭昕
王曙宾
蓝蓝
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汉义生物科技（北京）有限公司
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C51/41—Preparation of salts of carboxylic acids
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to the technical field of chemical medicine, specifically to a cannabidiol derivative and its preparation method and application, especially its application in the prevention and treatment of neurological diseases (such as epilepsy and Parkinson's disease).
  • neurological diseases such as epilepsy and Parkinson's disease.
  • Cannabinoids are a class of secondary metabolites unique to cannabis plants containing alkyl and monoterpene group structures. More than a hundred cannabinoids have been isolated from cannabis plants, mainly including ⁇ -9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabichromene (CBC), cannabigerol (CBG), Cannabidiol (CBN), etc., among which CBD has the highest content. Research shows that cannabinoids have a wide range of pharmacological effects.
  • THC ⁇ -9-tetrahydrocannabinol
  • CBD cannabidiol
  • CBD cannabigerol
  • CBD Cannabidiol
  • Cannabidiol (CBD)
  • chemical name is 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-5-pentyl -1,3-Benzodiphenol, CAS registration number: 13956-29-1
  • chemical structure is as follows:
  • CBD has anti-spasmodic, anti-anxiety, anti-inflammatory, antioxidant and other pharmacological effects, and can be used for drug development.
  • high-purity CBD is a white or light yellow crystal with a melting point of 66-67°C. It is almost insoluble in water or 10% sodium hydroxide solution, and is easily soluble in ethanol, methanol, ether, benzene, chloroform and petroleum ether. and other organic solvents. CBD has poor water solubility and low bioavailability, which greatly limits the application of CBD in medicine and other fields.
  • the present invention provides a cannabidiol derivative and its preparation method and application, especially its application in the prevention and treatment of neurological diseases (such as epilepsy and Parkinson's disease).
  • neurological diseases such as epilepsy and Parkinson's disease.
  • X 3 and X 4 are independently selected from:
  • R 1 and R 2 are independently selected from: OH, alkoxy, and amino acid residues
  • R 3 is selected from: OH, alkoxy group, amino acid residue
  • general formula (I) is optionally substituted by 1 or more D atoms.
  • X 1 and X 2 are independently selected from: single bond, C 1-6 linear or branched alkylene, especially C 1-3 linear alkyl; in one embodiment of the invention, 1 is methylene; in one embodiment of the invention, X 2 is methylene.
  • X3 is
  • X 4 is
  • R 1 is selected from: OH, C 1-6 alkoxy (such as methoxy, ethoxy), amino acid residue (that is, the remaining part of the amino group of the amino acid lacking a hydrogen atom, such as ); In some embodiments of the invention, R 1 is OH, methoxy or ethoxy.
  • R 2 is selected from: OH, C 1-6 alkoxy (such as methoxy, ethoxy), amino acid residue (that is, the remaining part of the amino acid lacking a hydrogen atom, such as ); In some embodiments of the invention, R 2 is OH, methoxy or ethoxy.
  • R3 is OH
  • R 3 is alkoxy, such as C 1-6 alkoxy, such as methoxy or ethoxy.
  • R 3 is an amino acid residue, that is, the remaining part of the amino acid lacking a hydrogen atom, for example
  • the above compounds have the following structures:
  • X 1 , X 2 , X 3 , X 4 , R 1 , R 2 and R 3 have the corresponding definitions as described in the first aspect of the present invention.
  • the above-mentioned stereoisomers have the following structures:
  • a salt or co-crystal of the compound described in the first aspect or the stereoisomer described in the second aspect especially a pharmaceutically acceptable salt or co-crystal.
  • the salt is a base addition salt, which can be formed from a metal or an amine and a compound, in particular an alkali metal salt, an alkaline earth metal salt, such as a sodium salt, a potassium salt, a magnesium salt, a calcium salt, especially a sodium salt.
  • a base addition salt which can be formed from a metal or an amine and a compound, in particular an alkali metal salt, an alkaline earth metal salt, such as a sodium salt, a potassium salt, a magnesium salt, a calcium salt, especially a sodium salt.
  • prodrugs, solvates, and metabolites of the compounds described in the first aspect are provided.
  • a method for preparing the compound described in the first aspect is provided.
  • the preparation method may include the following reaction steps:
  • R 3 ' is an alkoxy group, such as C 1-6 alkoxy group, such as methoxy group or ethoxy group.
  • the preparation method may also include separately or simultaneously (at this time and represent the same substance) and The reaction is A step of;
  • R 1 ' and R 2 ' are alkoxy groups, such as C 1-6 alkoxy groups, such as methoxy group and ethoxy group;
  • R 4 and R 5 are leaving groups, such as -F, -Cl, -Br, -I,
  • the preparation method may also include the following reaction steps:
  • the base in the above reaction step is an alkali metal hydroxide, such as sodium hydroxide.
  • the acid in the above reaction step is an inorganic acid, such as hydrochloric acid.
  • the temperature of the above reaction is 20-30°C, such as room temperature.
  • the preparation method may also include the following reaction steps:
  • the base in the above reaction step is an alkali metal hydroxide, such as sodium hydroxide.
  • the acid in the above reaction step is an inorganic acid, such as hydrochloric acid.
  • the temperature of the above reaction is 80-95°C, such as 90°C.
  • a pharmaceutical composition which contains the compound described in the first aspect of the present invention, or its pharmaceutically acceptable salt or co-crystal, stereoisomer, prodrug, solvate, metabolite product, and one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients can be selected from: fillers, binders, lubricants, disintegrants, antioxidants, buffers, suspending agents, solubilizers, thickeners, stabilizers and preservatives, etc. one or more of them.
  • the pharmaceutical composition may be administered gastrointestinally or parenterally, such as by intravenous, intramuscular, intradermal and subcutaneous routes.
  • the pharmaceutical composition can be prepared into the following dosage forms: tablets, pills, powders, granules, capsules, lozenges, syrups, gels, emulsions, suspensions, controlled release preparations, aerosols, Powder spray, film, injection, intravenous drip, transdermal absorption preparation, ointment, lotion, adhesive preparation, suppository, nasal preparation, lung preparation, etc.
  • various dosage forms of the above pharmaceutical compositions can be prepared according to conventional production methods in the pharmaceutical field.
  • the pharmaceutical composition may also contain one or more other active ingredients for the same or different indications.
  • the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt or co-crystal, stereoisomer, prodrug, solvate, metabolite thereof, or the compound described in the sixth aspect.
  • the above-mentioned diseases are selected from: one or more of neurological diseases, cancer, autoimmune diseases, cardiovascular diseases, pain, inflammation, liver damage, especially neurological diseases, and more particularly epilepsy.
  • neurological diseases include, but are not limited to, epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies, Huntington's disease, anxiety disorders, depression, and the like.
  • epilepsy can be acute epilepsy, chronic epilepsy, especially chronic epilepsy.
  • cancers include, but are not limited to, breast cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, gastric cancer, gastroesophageal adenocarcinoma, esophageal cancer, small bowel cancer, cardia cancer, endometrial cancer, ovarian cancer, fallopian tube cancer , vulvar cancer, testicular cancer, prostate cancer, leukemia, glioma, etc.
  • autoimmune diseases include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, Crohn's disease, autoimmune hepatitis, and the like.
  • a method for preventing and/or treating diseases which includes administering the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt or co-existant thereof, to a subject in need thereof. Crystals, stereoisomers, prodrugs, solvates, metabolites, or steps of the pharmaceutical composition described in the sixth aspect.
  • the above-mentioned diseases are selected from: one or more of neurological diseases, cancer, autoimmune diseases, cardiovascular diseases, pain, inflammation, liver damage, especially neurological diseases, and more particularly epilepsy.
  • neurological diseases include, but are not limited to, epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies, Huntington's disease, anxiety disorders, depression, and the like.
  • epilepsy can be acute epilepsy, chronic epilepsy, especially chronic epilepsy.
  • cancers include, but are not limited to, breast cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, gastric cancer, gastroesophageal adenocarcinoma, esophageal cancer, small bowel cancer, cardia cancer, endometrial cancer, ovarian cancer, fallopian tube cancer , vulvar cancer, testicular cancer, prostate cancer, leukemia, glioma, etc.
  • autoimmune diseases include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, Crohn's disease, autoimmune hepatitis, and the like.
  • the subject may be a mammal, such as a human, a gorilla, a monkey, a dog, a rabbit, a mouse, etc., especially a human.
  • the inventor of the present invention carried out structural modifications on the basis of cannabidiol and screened a series of synthetic derivatives to obtain the compounds of the present invention.
  • Animal test results show that these compounds can effectively shorten the duration of epileptic seizures in experimental animals and improve experiments.
  • Symptoms of epileptic seizures in animals can also reduce the balance beam score of Parkinson's model animals, increase dopamine levels and the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the brain, and can be used for epilepsy, Parkinson's disease, etc.
  • TH tyrosine hydroxylase
  • Figure 1 shows the results of seizure duration detection in rats with PTZ-ignited epilepsy before and after treatment.
  • Figure 2 shows the behavioral seizure index Ono’s grading of rats with PTZ-ignited epilepsy before and after treatment.
  • Figure 3 shows the results of seizure latency detection in rats with PTZ-ignited epilepsy before and after treatment.
  • Figure 4 shows the PAGE gel image of apoptosis-related proteins Bax and Bcl-2 in rat hippocampus tissue.
  • Figure 5 shows the changes in apoptosis-related proteins Bax and Bcl-2 in rat hippocampus tissue.
  • Figure 6 shows the detection results of ⁇ -aminobutyric acid content in rat brain tissue homogenate.
  • Figure 7 shows the detection results of glycine content in rat brain tissue homogenate.
  • Figure 8 shows the detection results of glutamate content in rat brain tissue homogenate.
  • Figure 9 shows the detection results of aspartic acid content in rat brain tissue homogenate.
  • Figure 10 shows a microscopic image of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the brain.
  • alkyl refers to a hydrocarbon group formed by losing one hydrogen atom from an alkane molecule. It can be a straight chain or a branched chain and is connected to other parts of the molecule by a single bond.
  • Alkyl groups as used herein generally contain 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, preferably 1 to 6 carbon atoms atoms (i.e., C 1 -C 6 alkyl).
  • alkyl group examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl base, n-hexyl base, isohexyl base, etc.
  • alkylene refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule. It can be a straight chain or a branched chain and is connected to other parts of the molecule with a single bond.
  • Typical alkylene groups herein have 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, preferably 1 to 6 carbon atoms, Examples of alkylene groups include methylene (-CH 2 -), ethylene, propylene, butylene, and the like.
  • alkoxy refers to a substituent in which a hydrogen in a hydroxyl group is replaced by an alkyl group.
  • Alkoxy as used in this article
  • the radicals typically contain 1 to 12 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, preferably 1 to 6 carbon atoms (i.e., C 1 - C 6 alkoxy).
  • Examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
  • pharmaceutically acceptable salts includes acid addition salts and base addition salts.
  • co-crystal refers to the combination of the compound of the present invention with other physiologically acceptable acids, bases, and nonionic compounds through non-covalent bonds such as hydrogen bonds, van der Waals forces, ⁇ - ⁇ stacking interactions, and halogen bonds. formed crystal.
  • stereoisomer includes enantiomeric, diastereomeric and geometric isomeric forms.
  • solvate refers to the physical association of a compound of the invention with one or more solvent molecules. This physical bonding includes various degrees of ionic and covalent bonding, including hydrogen bonding. Under certain circumstances, solvates can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phase and isolatable solvates. Representative solvates include ethanolates, methanolates, etc.
  • metabolite refers to the products resulting from the chemical degradation of the compounds of the present invention under physiological conditions in the body.
  • prodrug refers to a form of a compound of formula I suitable for administration to a patient without undue toxicity, irritation, allergic reactions, etc. and effective for its intended purpose, including acetal, ester and zwitterionic forms.
  • the prodrug is transformed in vivo, eg by hydrolysis in the blood, to give the parent compound.
  • D refers to deuterium
  • substituted by deuterium refers to replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.
  • subject refers to any animal or cells thereof that is subjected to the methods described herein, whether in vitro or in situ.
  • the aforementioned animals include mammals, such as rats, mice, guinea pigs, rabbits, dogs, monkeys, orangutans or humans, especially humans.
  • treatment means preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, arresting and/or stopping one or more clinical symptoms of a disease after the onset of the disease.
  • prevention refers to treatment to avoid, minimize, or make the onset or progression of a disease more difficult before it occurs.
  • Salt formation Dissolve the above product 5 with 30ml ethanol, add 0.8g saturated aqueous solution of NaHCO 3 , heat and stir for half an hour, fully react to form sodium salt, concentrate and evaporate to dryness, remove residual water with ethanol twice, evaporate to dryness, and pump with oil pump Dry; add 30 ml of absolute ethanol to the obtained solid, ultrasonic, filter out the insoluble matter (excess sodium bicarbonate) through diatomaceous earth, concentrate the mother liquor and spin dry to obtain 1.8g of light yellow foamy solid product (purity >93%); take 1.2g was recrystallized from ethanol and ethyl acetate to obtain 550mg of white solid product with purity >95%.
  • Salt formation Dissolve the above product 6 with 20ml ethanol, add 0.4g NaHCO 3 saturated aqueous solution, heat and stir for half an hour, fully react to form sodium salt, concentrate and evaporate to dryness, remove residual water with ethanol twice, evaporate to dryness, and pump with oil pump Dry; add 20 ml of absolute ethanol to the obtained solid, fully dissolve it with ultrasonic, filter out the insoluble matter (excess sodium bicarbonate) through diatomaceous earth, concentrate the mother liquor and spin it to dryness to obtain 320 mg of brown solid product (purity >95%).
  • PTZ was purchased from Sigma Company; sodium valproate was purchased from Sigma Company; absolute ethanol was purchased from Sinopharm Chemical Reagent Co., Ltd.
  • the experimental animals were randomly divided into 4 groups: model group, positive drug group, compound 1 group, and compound 2 group, with 8 animals in each group.
  • the model group was administered an equal volume of physiological saline; the positive drug group (sodium valproate was administered intragastrically at 100 mg/kg); the compound group 1 (compound E1 prepared in Example 1 was administered intragastrically, 100 mg/kg); the compound group 2 (example 2 The prepared compound E2 was administered orally, 100 mg/kg).
  • the prepared PTZ solution was injected intraperitoneally 1 hour after oral administration, and the injection dose was 35 mg/kg. Observe the behavioral changes of rats within 30 minutes after injection of PTZ.
  • the behavioral seizure indicators before and after administration were recorded according to Ono’s classification, and the seizure latency, seizure grade and seizure duration were recorded.
  • the brains and hippocampus of the experimental animals were collected and frozen at -80°C.
  • WB detects the expression of apoptosis-related proteins Bax and Bcl-2 in rat hippocampus tissue:
  • the corresponding protein concentration ( ⁇ g/ ⁇ l) can be found on the standard curve.
  • Multiplied by the sample dilution factor (10) is the actual concentration of the sample (unit: ⁇ g/ ⁇ l).
  • the loading amount per well is approximately 25 ⁇ g of protein, and the loading amount can be increased according to experimental requirements.
  • Add the required protein to an appropriate amount of loading buffer, bath in boiling water for 10 minutes, centrifuge and load the supernatant.
  • the stacking gel runs at 80V for 20 minutes, and the separating gel runs at 120V for 60 minutes.
  • the voltage and time can be adjusted according to specific experimental requirements.
  • Film transfer is divided into wet transfer and semi-dry transfer. Semi-dry transfer was selected for this experiment.
  • the sandwich arrangement is: /filter paper/gel/membrane/filter paper. After being soaked with electroporation buffer, it is placed directly between the positive and negative electrodes of the electroporation instrument. Glue on the negative electrode and place the membrane on the positive electrode.
  • the semi-dry electroporation buffer is different from the wet electroporation buffer.
  • the recommended buffer is: 48mM Tris, 39mM glycine, 0.04% SDS, and 20% methanol. Transfer film at 25V for 30 minutes. Before transferring, soak the PVDF membrane in methanol for 1-2 minutes (soak the NC membrane in electroporation solution for 10-20 minutes), and then incubate it in ice-cold electroporation buffer for 5 minutes. The gel also needs to be in ice-cold electroporation buffer. Equilibrate for 3-5 minutes, otherwise the strips will be deformed during transfer.
  • Ponceau staining working solution 2% Ponceau stock solution diluted 1:10, that is, add 9 times ddH 2 O.
  • Staining method Wash the membrane once in TBST, then place it in Ponceau red staining working solution, shake at room temperature for 5 minutes, wash the membrane with a large amount of water until the water becomes clear, and the colorless protein band is clear (the membrane can also be used Re-wash with TBST or water before dyeing)
  • the PVDF membrane needs to be reactivated with methanol, washed with TBST and then blocked.
  • Blocking Block with 5% skimmed milk powder (BSA for detecting phosphorylated proteins) at room temperature for 1 hour or at 4°C overnight.
  • BSA skimmed milk powder
  • ECL chemiluminescence detection Prepare ECL luminescent liquid. According to the dosage, take equal amounts of ECL luminescent liquid A and B and mix well. Add to the front of the film in a dark room to avoid light for 5 minutes. Pour away the developing liquid, carefully absorb the developing liquid with paper, and cover it with a flat layer of transparent paper. Place it into the imaging system and scan it.
  • Ono s grading records the highest grade of epileptic seizures in rats.
  • epileptic seizures are a progressive process, and the highest seizure grade will have a duration during the epileptic seizure. It is recommended that the duration of each episode grade be recorded subsequently.
  • the experimental results showed that the apoptosis-related Bax protein was highly expressed in the hippocampus tissue of rats in the model group, while the positive drug group and the model group had lower expression of the apoptosis-related Bax protein, which was statistically significant. Moreover, Bax protein expression was also down-regulated in the compound group compared with the model group.
  • excitatory amino acids glutamic acid and aspartic acid
  • inhibitory neurotransmitters ⁇ -aminobutyric acid and glycine in brain tissue homogenate were detected by ELISA detection kit.
  • the ELISA experimental results showed that the brain tissue homogenate of the model group contained low levels of ⁇ -aminobutyric acid and glycine, while glutamic acid and High aspartic acid content.
  • the positive drug and compound group showed a decrease in the expression of excitatory amino acids, with statistical significance in each group; compared with the model group, the expression of inhibitory neurotransmitters ⁇ -aminobutyric acid and glycine increased, and has statistical significane.
  • the duration of epileptic seizures in the compound group was significantly reduced on the 7th and 14th days of treatment, with significant differences.
  • the duration of epileptic seizures was in the order of compound E1>compound E2; on the 14th day of treatment, the duration of epileptic seizures was in the order of compound E2>compound E1.
  • MPTP was purchased from Sigma Company; amantadine was purchased from Sigma Company; absolute ethanol was purchased from Sinopharm Chemical Reagent Co., Ltd.
  • the experimental animals were randomly divided into 4 groups: blank group, model group, positive drug group, and compound group, with 8 animals in each group.
  • the positive drug group was orally administered amantadine (40 mg/kg), and the compound group (100 mg/kg) was orally administered the determined drug dose of compound E2 (prepared in Example 2) once a day for 14 consecutive days.
  • a wooden bar with a length of 80cm and a width of 2.5cm is fixed horizontally at a height of 10cm from the table, and then the animals are allowed to walk on the wooden bar.
  • mice were quickly sacrificed, the brains were removed and the cerebral cortex (CP) of the mice was isolated. After exposing the striatum of the mouse brain, the striatum was weighed, PBS was added according to the proportion, and then ground and homogenized. The supernatant was then separated to detect dopamine content in the striatum.
  • CP cerebral cortex
  • the corresponding protein concentration ( ⁇ g/ ⁇ l) can be found on the standard curve, and multiplied by the sample dilution factor (10) is the actual concentration of the sample (unit: ⁇ g/ ⁇ l);
  • Use HCl to adjust the pH of the solution to 7.4 and dilute the volume to 1L. After filtering, sterilize by autoclaving at room temperature. save.
  • Citric acid C 6 H 8 O 7 ⁇ H 2 O molecular weight 210.14; 0.1mol/L solution is 21.01 g/L.
  • tissue blocks When cutting tissue, you should use a sharp knife or scissors. When cutting tissue blocks, start from the root of the knife and pull backward to cut through the tissue.
  • the thickness of the tissue block is about 0.2-0.3cm, and the appropriate size is 1.5cm ⁇ 1.5cm ⁇ 0.3cm.
  • the tissue blocks were fixed in 10% formalin for 48 hours.
  • tissue block Place the tissue block into an equal volume mixture of pure ethanol and xylene for 2 hours, then into pure xylene for two hours, and again into pure xylene for two hours; after the material is made transparent, it will show the effect of dehydration in the previous step. If dehydration Thoroughly, the tissue will appear transparent. If there is white cloud in the tissue, it means that the dehydration is not clean and must be reworked, but the effect of reworking is often not good. When using xylene transparent, you should avoid its volatilization and absorption of moisture in the air, and keep it in an anhydrous state.
  • Wax dipping must be done in a constant temperature oven. First, soak the tissue material block in a mixture of equal amounts of molten paraffin and xylene for 1-2 hours, and then move it into two molten paraffin liquids and soak it for about 3 hours each.
  • Embedding involves wrapping a wax-soaked tissue block in paraffin.
  • the specific method is: first prepare the carton, pour the melted wax into the box, quickly use pre-warmed tweezers to pick up the tissue block and lay it flat on the bottom of the carton, with the cut side facing down, then gently lift the carton and place it flat.
  • cold water after the paraffin on the surface solidifies, immediately press the carton into the water to allow it to cool and solidify quickly, and take it out after 30 minutes.
  • the dewaxed sections were soaked in 100% alcohol, 95% alcohol, 85% alcohol, and 75% alcohol for 5 min respectively, and rinsed with tap water for 10 min.
  • the Parkinson's model was prepared in mice by intraperitoneal injection of MPTP, and behavioral evaluation was carried out through balance beam scoring. Seven days after MPTP was injected intraperitoneally, balance beam scoring was performed. Except for the blank group, no modeling was performed, and the balance beam score was 0. The scores of mice in other groups were All scores were 5-6, and each group had P ⁇ 0.05 compared with the blank group, which was statistically significant, proving the success of the model.
  • the balance beam score of the model group was 4-5 points, and the balance beam score of the positive drug was between 2-3 points.
  • the balance beam score of the other compound treatment groups was 3-4 points.
  • Dopamine as a neurotransmitter, regulates various physiological functions of the central nervous system.
  • the dopamine content in the striatum of the treated mouse Parkinson's model was measured. Determine the effect of drug treatment on Parkinson's disease model.
  • the degree of dopamine decline in the model was judged by comparing the dopamine content of each group with the blank group. Except for the positive drug group, the dopamine content of each group decreased significantly, P ⁇ 0.05, which was statistically significant.
  • the dopamine content of the compound group was compared with the model group.
  • the dopamine content was increased compared with the model group, P ⁇ 0.01, which was statistically significant, indicating that each drug group had the effect of increasing the dopamine content in the brain.
  • the striatal dopamine content was in the order of blank group>positive drug group>compound group>model group.
  • Tyrosine hydroxylase is a monooxygenase. It is the rate-limiting enzyme that catalyzes the first step in the series of reactions of the organism's own synthesis of L-dopamine (DA). It is only expressed in the cytoplasm. . Neurons are rich in TH. Because the midbrain lacks dopamine- ⁇ -hydroxylase, the TH immunoreactive neurons in the midbrain are DA neurons, which can be used as a marker of dopamine neurons in the brain.
  • the body uses L-tyrosine to survive levodopa under the catalysis of tyrosine hydroxylase, and levodopa decarboxylizes under the catalysis of aromatic decarboxylase to finally generate levodopamine. Due to the important position of tyrosine hydroxylase in the synthesis of dopamine, the lack of its function or insufficient expression directly affects the synthesis and secretion of dopamine. Dopamine is an important neurotransmitter. Inability to synthesize or secrete dopamine by dopaminergic neurons can lead to Parkinson's disease.
  • mice Parkinson's model caused by intraperitoneal injection of MPTP
  • the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the mice decreased, P ⁇ 0.05, which is statistically significant. significance.
  • the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the positive drug group showed a significant increase, indicating that the modeling success.
  • the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the brain was increased in both the compound group and the model group.
  • the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the compound group was compared with the model group, P ⁇ 0.01, and it was statistically significant.
  • mice Parkinson model was established by intraperitoneal injection of MPTP (25 mg/kg) once a day for 7 consecutive days, and the mouse Parkinson model was screened through balance beam scoring.
  • the model mice were treated by oral administration through the positive drug and compound groups.
  • the balance beam scores of each group after treatment were analyzed, the dopamine content in the striatum was detected by ELISA, and the substantia nigra of the brain was detected by immunohistochemistry (SubN) in the tyrosine hydroxylase (TH) cell positivity rate and other detection methods, identify the compound and blank group, the difference between the model group, and then perform statistical analysis to analyze the effectiveness of the compound group.
  • SubN immunohistochemistry
  • TH tyrosine hydroxylase
  • the positive rate of the positive drug group and the compound group compared with the model group among which the tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the compound group Compared with the model group, the positive rate was P ⁇ 0.01, and it was statistically significant.

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Abstract

Sont divulgués un dérivé de cannabidiol, son procédé de préparation et son utilisation, en particulier, son utilisation dans la prévention et le traitement de maladies du système nerveux (telles que l'épilepsie et la maladie de Parkinson). Le dérivé de cannabidiol sus-mentionné est obtenu par criblage à partir d'une série de dérivés synthétiques. Des résultats d'expériences menées sur animaux montrent que ces composés peuvent raccourcir de manière efficace la durée de crises épileptiques et soulager leurs symptômes chez des animaux expérimentaux, et peuvent également réduire les scores de faisceau d'équilibre de modèles animaux de la maladie de Parkinson et augmenter le niveau de dopamine et le taux de cellules tyrosine hydroxylase positives dans la substantia nigra, de telle sorte qu'ils peuvent être utilisés pour le développement et la recherche de médicaments pour diverses maladies telles que l'épilepsie et la maladie de Parkinson, et ont une valeur d'application relativement bonne.
PCT/CN2023/083791 2022-04-29 2023-03-24 Dérivé de cannabidiol, son procédé de préparation et son utilisation WO2023207460A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020031179A1 (fr) * 2018-08-06 2020-02-13 Beetlebung Pharma Ltd. Procédés de synthèse de composés cannabinoïdes
CN111848365A (zh) * 2020-07-16 2020-10-30 云南自由贸易试验区睿之成医药科技有限公司 一种大麻二酚的合成方法
WO2021007663A1 (fr) * 2019-07-12 2021-01-21 Canopy Growth Corporation Dérivés cannabinoïdes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020031179A1 (fr) * 2018-08-06 2020-02-13 Beetlebung Pharma Ltd. Procédés de synthèse de composés cannabinoïdes
WO2021007663A1 (fr) * 2019-07-12 2021-01-21 Canopy Growth Corporation Dérivés cannabinoïdes
CN111848365A (zh) * 2020-07-16 2020-10-30 云南自由贸易试验区睿之成医药科技有限公司 一种大麻二酚的合成方法

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