WO2023103733A1 - 一种大麻二酚衍生物及其制备方法和应用 - Google Patents
一种大麻二酚衍生物及其制备方法和应用 Download PDFInfo
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- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the invention relates to the technical field of chemistry and medicine, in particular to a cannabidiol derivative and its preparation method and application, especially the application in the prevention and treatment of nervous system diseases (such as epilepsy and Parkinson's disease).
- nervous system diseases such as epilepsy and Parkinson's disease.
- Cannabinoids are a class of secondary metabolites unique to cannabis plants containing alkyl and monoterpene groups. At present, more than one hundred cannabinoids have been isolated from cannabis plants, mainly including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabichromene (CBC), cannabigerol (CBG), Cannabinol (CBN), etc., among which THC and CBD have the highest content. Studies have shown that cannabinoids have a wide range of pharmacological effects.
- THC delta-9-tetrahydrocannabinol
- CBD cannabidiol
- CBD cannabichromene
- CBD cannabigerol
- CBD Cannabinol
- Cannabidiol (CBD), chemical name 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-5-pentyl -1,3-benzenediol, CAS registration number: 13956-29-1, the chemical structure is as follows:
- CBD has pharmacological effects such as anti-spasmodic, anti-anxiety, anti-inflammatory, and anti-oxidative, 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, almost insoluble in water or 10% sodium hydroxide solution, and 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 the application in the prevention and treatment of nervous system diseases (such as epilepsy and Parkinson's disease).
- nervous system diseases such as epilepsy and Parkinson's disease.
- X 3 selected from:
- R is selected from: H, alkyl, cycloalkyl
- R 2 is selected from: OH, alkoxy
- n is an integer of 1-5 (eg 1, 2, 3, 4, 5);
- R is selected from: H,
- R is selected from: H, alkyl, cycloalkyl
- R is selected from: OH, alkoxy
- n is an integer of 1-5 (eg, 1, 2, 3, 4, 5).
- X 1 is selected from: single bond, C1-6 straight chain or branched chain alkylene, especially C1-3 straight chain alkyl; in one embodiment of the present invention, X 1 is methylene.
- R can be selected from: H, methyl, isopropyl, sec-butyl, isobutyl, In one embodiment of the invention, R 7 is
- X 3 is
- n 1
- R 1 is H.
- R 2 is selected from: OH, C1-6 alkoxy; in some embodiments of the present invention, R 2 is OH, methoxy or ethoxy.
- the above compound has the following structure:
- R3 is H.
- R 3 is
- X 4 is selected from: single bond, C1-6 straight chain or branched chain alkylene, especially C1-3 straight chain alkyl; in one embodiment of the present invention, X 4 is methylene.
- R can be selected from: H, methyl, isopropyl, sec-butyl, isobutyl, In one embodiment of the invention, R 8 is
- X 6 is
- n 1
- R4 is H.
- R 5 is selected from: OH, C1-6 alkoxy; in some embodiments of the present invention, R 5 is OH, methoxy or ethoxy.
- the above compound has the following structure:
- the above compound has the following structure:
- the above compound has the following structure:
- X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , and n have the corresponding definitions as described in the first aspect of the present invention.
- the above stereoisomers have the following structures:
- the salt of the compound of the first aspect or the stereoisomer of the second aspect especially a pharmaceutically acceptable salt.
- the salts are base addition salts, which may be formed with metals or amines and compounds, especially alkali metal salts, alkaline earth metal salts, eg sodium, potassium, magnesium, calcium salts.
- the salt is N-(2-aminoethyl)-2-aminoethyl
- esters, prodrugs, and solvates of the compounds described in the first aspect are provided.
- R 3 is H
- the preparation method may comprise the following reaction steps:
- R 2 ' is an alkoxy group, such as a C1-6 alkoxy group, such as a methoxy group.
- the preparation method may also include the following reaction steps:
- the alkali in the above reaction step is an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide.
- the acid in the above reaction step is an inorganic acid, such as hydrochloric acid.
- the preparation method may also include the following reaction steps:
- R 9 is an alkyl group, such as a C1-6 alkyl group, such as a methyl group;
- R 10 is a leaving group, such as -F, -Cl, -Br, -I, (-OTs), (-OMs), (-OBs), (-OTf).
- the alkali in the above reaction step is an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide.
- the acid in the above reaction step is an inorganic acid, such as hydrochloric acid.
- R 3 is The method of preparation may include separately or simultaneously (at this time and represent the same substance) as the steps of the reaction;
- R 2 ′ and R 5 ′ are alkoxy groups, such as C1-6 alkoxy groups, such as methoxy groups.
- a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate thereof, and a One or more pharmaceutically acceptable excipients.
- auxiliary materials can be selected from: fillers, binders, lubricants, disintegrants, antioxidants, buffers, suspending agents, solubilizers, thickeners, stabilizers and preservatives, etc. one or more of.
- the pharmaceutical composition can be administered gastrointestinally or parenterally, such as intravenously, intramuscularly, intradermally and subcutaneously.
- 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, Film preparations, injections, intravenous drips, transdermal preparations, ointments, lotions, adhesive preparations, suppositories, nasal preparations, lung preparations, etc.
- various dosage forms of the above pharmaceutical composition can be prepared according to conventional production methods in the field of pharmacy.
- 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 its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and the pharmaceutical composition described in the sixth aspect.
- the above diseases are selected from one or more of nervous system diseases, cancer, autoimmune diseases, cardiovascular diseases, pain, inflammation, liver damage, especially nervous system diseases.
- 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 may 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 intestine 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 comprises administering the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereo Isomer, ester, prodrug, solvate, or the step of the pharmaceutical composition described in the sixth aspect.
- the above diseases are selected from one or more of nervous system diseases, cancer, autoimmune diseases, cardiovascular diseases, pain, inflammation, liver damage, especially nervous system diseases.
- 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 may 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 intestine 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, for example, a human, an orangutan, a monkey, a dog, a rabbit, a mouse, etc., especially a human.
- the inventors of the present invention carried out structural modification on the basis of cannabidiol, and screened the compounds of the present invention in a series of synthetic derivatives. The results of animal experiments showed that these compounds can effectively shorten the duration of epileptic seizures in experimental animals and improve the experimental results.
- Epilepsy symptoms in animals reduce the balance beam score of Parkinson's model animals, increase the dopamine level and the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN), and can be used for epilepsy, Parkinson's disease and other diseases.
- Drug development and research have better application value.
- Figure 1 shows the detection results of seizure duration in PTZ-ignited epileptic rats before and after treatment.
- Figure 2 shows the Ono's grading of the behavioral seizure index of PTZ-ignited epileptic rats before and after treatment.
- Figure 3 shows the detection results of seizure latency in PTZ-ignited epileptic rats before and after treatment.
- Figure 4 shows the PAGE gel images of apoptosis-related proteins Bax and Bcl-2 in rat hippocampal tissue.
- Figure 5 shows the changes of apoptosis-related proteins Bax and Bcl-2 in rat hippocampus.
- 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 glutamic acid content in rat brain tissue homogenate.
- Figure 9 shows the detection results of aspartic acid content in rat brain tissue homogenate.
- Figure 10 shows the behavioral balance beam scoring results of the Parkinson's model.
- Figure 11 shows the test results of striatal dopamine content after Parkinson's model treatment.
- Figure 12 shows the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN).
- Figure 13 shows microscopic images of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN).
- alkyl refers to a hydrocarbon group derived from an alkane molecule by the loss of one hydrogen atom, which may be straight or branched and which is attached to the rest 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 atom (ie, C 1 -C 6 alkyl).
- alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl base, n-hexyl, isohexyl, etc.
- aralkyl e.g. C 7 -C 18 aralkyl, e.g.
- alkylene refers to a hydrocarbon group (divalent alkyl group) formed by the loss of two hydrogen atoms from an alkane molecule, which may be straight or branched and which is connected to the rest of the molecule by a single bond.
- Typical alkylene groups herein are 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, preferably containing 1 to 6 carbon atoms, Examples of alkylene groups are methylene ( -CH2- ), ethylene, propylene, butylene and the like.
- alkoxy refers to a substituent formed by replacing hydrogen in a hydroxy group with an alkyl group.
- Alkoxy groups as used herein typically contain 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 atom (ie, C 1 -C 6 alkoxy).
- Examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and the like.
- cycloalkyl refers to an alicyclic hydrocarbon, such as containing 1 to 4 monocyclic and/or condensed rings, containing 3-18 carbon atoms, preferably 3-10 (eg 3, 4, 5, 6, 7 , 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.
- aryl refers to any functional group or substituent derived from a simple aromatic ring, including monocyclic aryl groups and/or fused ring aryl groups, such as those containing 1-3 rings, single Cyclic or fused ring and having 6-18 (eg 6, 8, 10, 12, 14, 16, 18) carbon ring atoms.
- the aryl group used herein is usually an aryl group containing 1-2 rings, monocyclic or condensed rings and having 6-12 carbon ring atoms (ie, C 6 -C 12 aryl group), wherein the carbon atom
- the H on can be substituted, for example by alkyl, halogen and the like. Examples of the aryl group include, but are not limited to, phenyl, p-hydroxyphenyl, and the like.
- heterocyclyl refers to a 3 to 18 membered non-aromatic ring group comprising 2 to 17 carbon atoms and 1 to 10 heteroatoms.
- a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can contain fused, spirocyclic, or bridged ring systems.
- a heterocyclyl group can be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl).
- pharmaceutically acceptable salt includes acid addition salts and base addition salts.
- stereoisomers includes the existence of enantiomers, diastereomers and geometric isomers.
- solvate refers to a physical association of a compound of the invention with one or more solvent molecules. This physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be isolated, for example 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, and the like.
- prodrug refers to a form of the compound of formula I which is suitable for administration to a patient without undue toxicity, irritation, allergic response, etc. and which is effective for the purpose for which it is used, including acetal, ester and zwitterionic forms. Prodrugs are transformed in vivo, eg, by hydrolysis in blood, to yield the parent compound.
- subject refers to any animal or cell thereof, whether in vitro or in situ, that is subjected to the methods described herein.
- the aforementioned animals include mammals, for example, rats, mice, guinea pigs, rabbits, dogs, monkeys, orangutans or humans, especially humans.
- treating refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, arresting and/or stopping one or more clinical symptoms of a disease after onset of the disease.
- prevention refers to avoiding, minimizing or making the onset or progression of a disease difficult by treatment, before the onset of the disease occurs.
- Embodiment 1 the preparation of compound E1
- CBD (20g, 64mmol, 1eq) was dissolved in 400ml butanone, cesium carbonate (31g, 96mmol, 1.5eq) was added, heated to 80°C for 2h. 12.6 g (0.082 mol, 1.3 eq) of methyl bromoacetate was added and reacted overnight.
- methyl bromoacetate (5g) and cesium carbonate (15g) react for 2h, filter the reaction solution, add ethyl acetate (100ml) after concentration, wash with 2N hydrochloric acid, wash with saturated sodium chloride, collect the organic phase, anhydrous sulfuric acid Drying over sodium and concentration gave the crude product as a brown oil (30 g).
- Column chromatography n-hexane/dichloromethane 20:1-1:1) gave compound 1 (11 g) and compound 5 (10.5 g) as yellow oil.
- reaction solution Concentrate the reaction solution, add 100ml of ethyl acetate, adjust the pH to 2 with 2N hydrochloric acid, separate the layers, wash the organic phase with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 5.5g of a yellow oily crude product.
- the crude product was subjected to column chromatography (dichloro/methanol: 150/1-50/1) to obtain compound 4 (3.4 g) as a yellow oil.
- Embodiment 2 the synthesis of compound E2
- PTZ was purchased from Sigma; sodium valproate was purchased from Sigma; 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 groups are randomized. Start the treatment, all Wistar rats are weighed, and the intragastric dosage is calculated.
- the model group was given an equal volume of normal saline; the positive drug group (sodium valproate was given 100 mg/kg by stomach); the compound 1 group (compound E1 prepared in Example 1 was given by stomach, 100 mg/kg); the compound 2 group (the Compound E2 prepared in 2, intragastric administration, 100mg/kg).
- the prepared PTZ solution was intraperitoneally injected 1 hour after intragastric administration, and the injection dose was 35 mg/kg.
- the behavioral changes of the rats were observed within 30 min after the injection of PTZ.
- the behavioral onset indicators before and after administration were recorded according to Ono's classification, and the onset latency, onset classification and onset duration were recorded.
- the brain and hippocampus of the experimental animals were collected and frozen at -80°C.
- 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).
- the loading amount of each well is about 25 ⁇ g protein, and the loading amount can be increased according to the experimental requirements.
- the protein quantification results take the required protein and add an appropriate amount of loading buffer, centrifuge in a boiling water bath for 10 minutes, and take the supernatant for loading. Put the prepared PAGE gel into the electrophoresis tank, add an appropriate amount of electrophoresis buffer, remove the comb and gently blow the sample hole with a gun to avoid residual gel residue in the hole affecting sample loading. Slowly add the prepared sample into the corresponding hole with a sample gun, and be careful not to overflow the sample hole.
- the concentrated gel is 80V for 20 minutes, and the separating gel is 120V for 60 minutes.
- the voltage and time can be adjusted according to specific experimental requirements.
- the membrane transfer is divided into wet transfer and semi-dry transfer, and semi-dry transfer was selected in this experiment.
- the sandwich arrangement is: /filter paper/glue/membrane/filter paper, soaked with electrotransfer buffer, and placed directly between the positive and negative electrodes of the electrotransfer instrument.
- the glue is placed on the negative electrode and the membrane is placed on the positive electrode.
- the semi-dry electrotransfer buffer is different from the wet electrotransfer buffer, the recommended ones are: 48mM Tris, 39mM glycine, 0.04% SDS, 20% methanol. 25V transfer film for 30 minutes. Soak the PVDF membrane in methanol for 1-2 minutes before transferring the membrane (soak the NC membrane in the electrotransfer solution for 10-20 minutes), and then incubate in the ice-cold electrotransfer buffer for 5 minutes. The gel also needs to be in the ice-cold electrotransfer buffer Equilibrate for 3-5 minutes, otherwise the strips will be deformed when transferred to the membrane.
- Staining method Wash the membrane once in TBST, then place it in Ponceau staining solution, shake and stain at room temperature for 5 minutes, wash the membrane with a large amount of water until the water becomes clear and the colorless protein bands are clear, (the membrane can also be used TBST or water re-washing before staining) PVDF membrane needs to be reactivated with methanol and then washed with TBST before blocking.
- Blocking block with 5% skimmed milk powder (BSA for detection of phosphorylated protein) at room temperature for 1 hour or overnight at 4°C.
- BSA skimmed milk powder
- ECL chemiluminescent detection prepare ECL luminescent liquid, mix equal amounts of ECL luminescent liquid A and B according to the dosage, add it to the front of the membrane in a dark room for 5 minutes to avoid light. Pour off the chromogenic solution, carefully absorb the chromogenic solution with paper, and cover it with a flat layer of transparent paper. Put it in the imaging system and scan it.
- the experimental operation and method refer to the kit instructions.
- the duration of PTZ ignited epileptic seizures before and after treatment by comparing the data, it was found that the duration of each group before treatment did not change, and the duration of seizures was about 350s; as the treatment stage entered, there were significant differences among the groups, and the positive drug group was in The onset duration decreased on the 7th and 14th day of treatment, and it was statistically significant.
- the other compound groups also showed a significant decrease in seizure duration on day 7 of treatment and before treatment, which was statistically significant; among them, compound 2 had a statistically significant decrease in seizure duration on day 14 of follow-up treatment and on day 7 of treatment. There is no change in the onset duration of compound 1 on the 14th day of treatment and the 7th day of treatment.
- Ono s grading records the highest grade of epileptic seizures in rats.
- epileptic seizures are a progressive process, and the highest seizure grades will have a duration during the epileptic seizures. Subsequent recording of the duration of each seizure grade is recommended.
- the experimental results showed that the apoptosis-promoting Bax protein was highly expressed in the hippocampal tissue of the rats in the model group, while the apoptosis-promoting Bax protein was lower in the positive drug group and the model group, and the expression was statistically significant.
- the expression of Bax protein was significantly down-regulated in both compound E1 and compound E2 with statistical significance.
- 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 results of ELISA experiments showed that the content of ⁇ -aminobutyric acid and glycine in the brain tissue homogenate of the model group was low, and the content of glutamic acid and aspartic acid was high.
- the duration of seizures in the two compound groups on the 7th and 14th days of treatment were significantly reduced, and there were significant differences.
- the duration of seizures was in the order of compound E2>compound E1; on the 14th day of treatment, the duration of seizures was in the order of compound E2>compound E1.
- Embodiment 4 research on the treatment of Parkinson's
- mice SPF grade, weighing 18-20 g, 6-8 weeks old, male, were purchased from Shanghai Slack Experimental Animal Co., Ltd.
- the temperature of the feeding environment was kept at 22 ⁇ 1°C, the humidity was kept at 65-70%, the light/dark light cycle was 12 hours, and water was freely available.
- MPTP was purchased from Sigma; amantadine was purchased from Sigma; absolute ethanol was purchased from Sinopharm Chemical Reagent Co., Ltd.
- the experimental animals were randomly divided into 5 groups: blank group, model group, positive drug group, compound 1 group, and compound 2 group, with 8 animals in each group.
- a wooden bar with a length of 80 cm and a width of 2.5 cm is fixed horizontally at a height of 10 cm from the table top, and then the animals are allowed to walk on the wooden bar.
- mice After the mice were sacrificed quickly, the brains of the mice were removed, and the cerebral cortex (CP) of the mice was isolated. After exposing the striatum of the mouse brain, take the striatum and weigh it, add PBS according to the proportion, and grind and homogenate. Then the supernatant was separated to detect the content of dopamine 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);
- Citric acid C 6 H 8 O 7 ⁇ H 2 O molecular weight 210.14; 0.1 mol/L solution is 21.01 g/L.
- tissue block When cutting the tissue block, pull the cut tissue backwards from the root of the knife.
- the thickness of the tissue block is about 0.2-0.3 cm, and the size is preferably 1.5 cm ⁇ 1.5 cm ⁇ 0.3 cm.
- the tissue blocks were fixed in 10% formalin for 48 hours.
- Ethanol with different concentrations is dehydrated step by step, 50%, 70%, 85%, 95% until pure alcohol (absolute ethanol), each stage for 2 hours. Dehydration must be carried out in a bottle with a cover to prevent high-concentration ethanol from absorbing moisture in the air, resulting in a decrease in concentration and incomplete dehydration. Materials that need to be preserved can be dehydrated to 70% ethanol and stay there. For long-term preservation, an equal amount of glycerin can be added.
- tissue block Place the tissue block in an equal-volume mixture of pure ethanol and xylene for 2 hours, then into pure xylene for 2 hours, and again in pure xylene for 2 hours; the material will be transparent to show the effect of the previous step of dehydration, if dehydration Thoroughly, the tissue will show a transparent state, such as white clouds in the tissue, indicating that the dehydration is not clean, and rework is required, but the effect of rework is often not good.
- xylene for transparency it should avoid volatilization and absorption of moisture in the air, and keep it in an anhydrous state.
- Dip wax must be carried out in a constant temperature box. First place the tissue material block in an equal mixture of molten paraffin and xylene to immerse for 1-2 hours, then move it into two melted paraffin liquids and immerse for about 3 hours each.
- Embedding is the encapsulation of 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 place it flat on the bottom of the carton, with the cut side facing down, then gently lift the carton and place it flat on the bottom of the carton. In cold water, after the surface paraffin solidifies, immediately press the carton into the water to make it cool and solidify rapidly, and take it out after 30 minutes.
- the wax blocks were placed in a -20°C refrigerator for at least 30 minutes to increase the hardness.
- the dewaxed sections were soaked in 100% alcohol, 95% alcohol, 85% alcohol, and 75% alcohol for 5 minutes respectively, and rinsed with tap water for 10 minutes.
- the slides were placed in 3% H2O2 and incubated in a wet box for 10 min to eliminate the activity of endogenous peroxidase. Wash with 0.02M PBS for 3 min ⁇ 3 times.
- DAB staining when the color change of the section is observed, immediately wash away the staining solution with tap water.
- mice were prepared by intraperitoneal injection of MPTP for Parkinson's model, and the behavioral evaluation was carried out by the balance beam score. Seven days after the intraperitoneal injection of MPTP, the balance beam score was performed. All scores are 5-6 points, each group compared with the blank group P ⁇ 0.05, which is statistically significant and proves that the model is successful.
- 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 beam score for the other compound treatment groups was 3-4.
- the positive drug group and each group of compounds showed a significant downward trend, P ⁇ 0.05, which was statistically significant.
- Parkinson's model As a neurotransmitter, dopamine regulates various physiological functions of the central nervous system, and the content of dopamine in the striatum of Parkinson's model in treated mice was detected. To judge the effect of drug treatment on Parkinson's model.
- the degree of dopamine decline in the model was judged by comparing the dopamine content of each group and the blank group. Except for the positive drug group, the dopamine content of the other groups all decreased significantly, P ⁇ 0.05, which was statistically significant.
- the content of dopamine in striatum was blank group>positive drug group>compound 1 group>compound 2 group>model group.
- Tyrosine hydroxylase is a monooxygenase, which 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), and is only expressed in the cytoplasm .
- DA L-Dopamine
- the content of TH in neurons is abundant, because the midbrain lacks dopamine- ⁇ -hydroxylase, so the neurons positive for TH immune response in the midbrain are DA neurons, which can be used as a sign of dopamine neurons in the brain.
- the body uses L-tyrosine to survive levodopa under the catalysis of tyrosine hydroxylase, and levodopa is decarboxylated under the catalysis of aromatic decarboxylase to finally generate L-dopamine. Due to the important position of tyrosine hydroxylase in the synthesis of dopamine, the loss or insufficient expression of its function directly affects the synthesis and secretion of dopamine. Dopamine is an important neurotransmitter, and the failure of dopaminergic neurons to synthesize or insufficient secretion of dopamine will lead to Parkinson's disease.
- the results of this experiment showed that in the mouse Parkinson's model induced by intraperitoneal injection of MPTP, the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the mouse decreased, P ⁇ 0.05, which was statistically significant. significance.
- the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the positive drug group was significantly higher than that of the model group, indicating that the modeling was successful.
- the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the brain substantia nigra (SubN) of each compound group was compared, and all of them increased.
- the positive rate of tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the compound 1 group was compared with that of the model group, P ⁇ 0.01, and it was statistically significant.
- the mouse Parkinson's model was established by intraperitoneal injection of MPTP (25mg/kg) once a day for 7 consecutive days, and the mouse Parkinson's model was screened by the balance beam score.
- the model mice were treated by intragastric administration of positive drugs and various compounds.
- 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 (SubN) in tyrosine hydroxylase (TH) cell positive rate and other detection methods, identify each compound and blank group, model group difference, then carry out statistical analysis, the effectiveness of each compound is analyzed.
- SubN substantia nigra
- TH tyrosine hydroxylase
- the dopamine content of the model group was compared with other compound groups, and the dopamine content of each group was higher than that of the model group, P ⁇ 0.01, which was statistically significant.
- the positive rate of the positive drug group and each compound comparison model group wherein the tyrosine hydroxylase (TH) cells in the substantia nigra (SubN) of the compound 1 group
- the positive rate was compared with the model group, P ⁇ 0.01, and it was statistically significant.
- each compound group has a certain therapeutic effect compared with the model group. Compared with each detection index, compound 1 has a better therapeutic effect.
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Abstract
Description
Ono’s分级 | 发作表现 |
0 | 无惊厥 |
1 | 点头或头部抽搐 |
2 | 全身肌肉阵挛 |
3 | 头部抽搐加前肢阵挛 |
4 | 阵挛惊厥加后肢站立 |
5 | 跌倒 |
6 | 全身强直-阵挛性惊厥 |
孔号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
蛋白标准液(μl) | 0 | 2 | 4 | 6 | 8 | 12 | 16 | 20 |
去离子水(μl) | 20 | 18 | 16 | 14 | 12 | 8 | 4 | 0 |
蛋白浓度(μg/μl) | 0 | 0.05 | 0.1 | 0.15 | 0.2 | 0.3 | 0.4 | 0.5 |
分组 | 治疗前持续时间/s | 治疗7天持续时间/s | 治疗14天持续时间/s |
模型组 | 338.33±27.16 | 327.50±12.01 | 311.83±29.02 |
阳性药物组 | 347.25±44.10 | 200.29±18.43 | 178.71±16.96 |
化合物1组 | 359.83±14.41 | 290.50±66.93 | 299.67±39.25 |
化合物2组 | 358.57±40.33 | 280.17±65.01 | 250.33±48.64 |
分组 | 治疗前Ono’s分级 | 治疗7天Ono’s分级 | 治疗14天Ono’s分级 |
模型组 | 3.67±0.52 | 3.50±0.55 | 3.67±0.52 |
阳性药物组 | 3.38±0.52 | 3.43±0.53 | 3.57±0.79 |
化合物1组 | 3.17±0.41 | 3.33±0.52 | 3.33±0.52 |
化合物2组 | 3.29±0.49 | 3.17±0.41 | 3.50±0.84 |
分组 | 治疗前潜伏期/s | 治疗7天潜伏期/s | 治疗14天潜伏期/s |
模型组 | 99.14±15.52 | 87.67±16.82 | 90.00±22.73 |
阳性药物组 | 97.38±15.86 | 87.00±13.90 | 84.43±14.77 |
化合物1组 | 85.75±21.45 | 82.83±20.90 | 87.00±20.96 |
化合物2组 | 99.00±1914 | 80.50±17.51 | 81.17±21.31 |
孔号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
蛋白标准液(μl) | 0 | 2 | 4 | 6 | 8 | 12 | 16 | 20 |
去离子水(μl) | 20 | 18 | 16 | 14 | 12 | 8 | 4 | 0 |
蛋白浓度(μg/μl) | 0 | 0.05 | 0.1 | 0.15 | 0.2 | 0.3 | 0.4 | 0.5 |
分组 | 造模后 | 治疗后 |
空白组 | 0 | 0 |
模型组 | 4.63±0.52*** | 4.50±0.53 |
阳性药物组 | 4.75±0.46*** | 2.13±0.83### |
化合物1组 | 4.63±0.52*** | 3.75±0.89# |
化合物2组 | 4.13±0.35*** | 3.50±0.93## |
分组 | DA(ng/mg) |
空白组 | 0.71±0.16 |
模型组 | 0.30±0.07*** |
阳性药物组 | 0.61±0.12### |
化合物1组 | 0.45±0.09## |
化合物2组 | 0.38±0.08# |
分组 | TH细胞阳性率(%) |
空白组 | 34.27±5.08 |
模型组 | 12.74±1.71*** |
阳性药物组 | 20.82±5.77## |
化合物1组 | 16.92±3.13## |
化合物2组 | 15.18±3.37 |
Claims (10)
- 一种化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物,所述化合物具有如下结构:其中,X 1和X 2独立地选自:单键、取代或未取代的亚烷基、被一个或多个-C(=O)O-间隔的亚烷基、被一个或多个-OC(=O)-间隔的亚烷基、被一个或多个-C(=O)NH-间隔的亚烷基;R 1选自:H、烷基、环烷基;R 2选自:OH、烷氧基;n为1-5的整数;其中,X 4和X 5独立地选自:单键、取代或未取代的亚烷基、被一个或多个-C(=O)O-间隔的亚烷基、被一个或多个-OC(=O)-间隔的亚烷基、被一个或多个-C(=O)NH-间隔的亚烷基;R 4选自:H、烷基、环烷基;R 5选自:OH、烷氧基;m为1-5的整数。
- 如权利要求1所述的化合物,其特征在于,X 1和X 4独立地选自:单键、C1-6直链或支链亚烷基;优选地,X 1为亚甲基;优选地,X 4为亚甲基。
- 如权利要求1所述的化合物,其特征在于,R 2和R 5独立地选自:OH、C1-6烷氧基;优选地,R 2为OH、甲氧基或乙氧基;优选地,R 5为OH、甲氧基或乙氧基。
- 一种药物组合物,其包含权利要求1-8任一项所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物,以及一种或多种药学上可接受的辅料。
- 权利要求1-8任一项所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物在制备预防和/或治疗疾病的药物中的应用,其中,所述疾病选自:神经系统疾病、癌症、自身免疫性疾病、心血管疾病、疼痛、炎症、肝损伤中的一种或多种;优选地,所述神经系统疾病选自:癫痫、多发性硬化症、帕金森氏病、阿尔茨海默症、路易体痴呆、亨廷顿病、焦虑症、抑郁症;优选地,所述癌症选自:乳腺癌、肺癌、结直肠癌、肝癌、胰腺癌、胃癌、胃食管腺癌、食管癌、小肠癌、贲门癌、子宫内膜癌、卵巢癌、输卵管癌、外阴癌、睾丸癌、前列腺癌、白血病、神经胶质瘤;优选地,所述自身免疫性疾病选自:系统性红斑狼疮、类风湿关节炎、多发性硬化症、溃疡性结肠炎、克罗恩氏病、自身免疫性肝炎。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101815697A (zh) * | 2007-07-30 | 2010-08-25 | 奥特兰兹公司 | 大麻二酚前药、包括大麻二酚前药的组合物及其使用方法 |
WO2017132526A1 (en) * | 2016-01-29 | 2017-08-03 | University Of Mississippi | Biologically active cannabidiol analogs |
CN109311838A (zh) * | 2016-04-15 | 2019-02-05 | 蒂温诺特技术有限公司 | 大麻素前药的生物合成 |
WO2021000053A1 (en) * | 2019-07-04 | 2021-01-07 | Canopy Growth Corporation | Cannabinoid derivatives |
WO2021007662A1 (en) * | 2019-07-12 | 2021-01-21 | Canopy Growth Corporation | Cannabinoid derivatives |
WO2021062231A2 (en) * | 2019-09-26 | 2021-04-01 | Firstlight Pharmaceuticals Llc | Cannabinoid prodrug compounds |
WO2022213931A1 (zh) * | 2021-04-06 | 2022-10-13 | 山东绿叶制药有限公司 | 大麻二酚前药及其药物组合物和应用 |
-
2021
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- 2022-11-17 WO PCT/CN2022/132572 patent/WO2023103733A1/zh active Application Filing
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101815697A (zh) * | 2007-07-30 | 2010-08-25 | 奥特兰兹公司 | 大麻二酚前药、包括大麻二酚前药的组合物及其使用方法 |
WO2017132526A1 (en) * | 2016-01-29 | 2017-08-03 | University Of Mississippi | Biologically active cannabidiol analogs |
CN109311838A (zh) * | 2016-04-15 | 2019-02-05 | 蒂温诺特技术有限公司 | 大麻素前药的生物合成 |
WO2021000053A1 (en) * | 2019-07-04 | 2021-01-07 | Canopy Growth Corporation | Cannabinoid derivatives |
WO2021007662A1 (en) * | 2019-07-12 | 2021-01-21 | Canopy Growth Corporation | Cannabinoid derivatives |
WO2021062231A2 (en) * | 2019-09-26 | 2021-04-01 | Firstlight Pharmaceuticals Llc | Cannabinoid prodrug compounds |
WO2022213931A1 (zh) * | 2021-04-06 | 2022-10-13 | 山东绿叶制药有限公司 | 大麻二酚前药及其药物组合物和应用 |
Non-Patent Citations (1)
Title |
---|
no. 13956-29-1 |
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