WO2009026817A1 - Compounds and composition used for inhibitting pge2 released from cmec - Google Patents

Compounds and composition used for inhibitting pge2 released from cmec Download PDF

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WO2009026817A1
WO2009026817A1 PCT/CN2008/071910 CN2008071910W WO2009026817A1 WO 2009026817 A1 WO2009026817 A1 WO 2009026817A1 CN 2008071910 W CN2008071910 W CN 2008071910W WO 2009026817 A1 WO2009026817 A1 WO 2009026817A1
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weight
parts
composition
acid
pharmaceutical composition
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PCT/CN2008/071910
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French (fr)
Chinese (zh)
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Hairu Huo
Lanfang Li
Shuying Guo
Tingliang Jiang
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Tang Foundation For The Research Of Traditional Chinese Medicines
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a chemical pharmaceutical composition derived from a composition of the Chinese medicine classic Decoction of Cinnamon Twigs, or Guizgi Tang, which is capable of allyl b enzenes compounds, which is capable of Inhibition of secretion of prostaglandin E2 by cerebral vascular endothelial cells can be used to prevent fever and strokes such as stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis and congenital dementia, as well as antipyretic. Background technique
  • Prostaglandin E2 is a well-recognized central heating medium and an important inflammatory factor. Many cells (including cerebral vascular endothelial cells) can induce excessive PGE2 under the stimulation of internal and external pathogenic factors. Tissue damage, apoptosis or proliferation, causing various diseases and diseases.
  • a series of compounds refers to a series of compounds having the same parent core and different functional groups.
  • the chemical entity of the Chinese medicine has a powder of the decoction piece, various crude extracts of the decoction piece, an active chemical part and a chemical monomer, and also a composition of the Chinese and Western medicine.
  • the chemical entity of a western medicine chemical has a single chemical monomer or a combination of several chemical monomers; the chemical entity of the biological drug is a product mainly composed of a certain biological substance.
  • no series of compounds have been seen, and a series of compounds with a certain number and a clear ratio have not been seen as a medicinal chemical entity.
  • PubMed PubMed
  • CNKI United States, Britain and Japan
  • other related drug regulatory authorities have not seen the composition of the series as a drug.
  • Decoction refers to all the traditional Chinese medicines used for clinical formulation and for the production of proprietary Chinese medicines, including cuts, segments, silks, blocks, netted flowers, leaves, seeds, fruits, and after processing. Processed products. Summary of the invention
  • PGE2 prostaglandin E2
  • Another object of the present invention is to provide a pharmaceutical composition for use in the antipyretic of mammals including humans.
  • compositions of the present invention further comprise a pharmaceutically acceptable carrier.
  • the carrier includes powders, liquids, and gases.
  • the invention further relates to the use of the pharmaceutical composition for the manufacture of a medicament for inhibiting the secretion of prostaglandin E2 from mammalian cells, including human brain vascular endothelial cells.
  • the invention further relates to the use of the pharmaceutical composition for the preparation of a medicament for use in antipyretics.
  • the invention further relates to a method of inhibiting secretion of prostaglandin E2 from a mammal, including human brain vascular endothelial cells, comprising administering to a patient a pharmaceutically effective amount of a pharmaceutical composition of the invention.
  • the invention further relates to a method of treatment of a mammal, including human fever, comprising administering to the patient a pharmaceutically effective amount of a pharmaceutical composition of the invention.
  • the present invention further provides a compound selected from the group consisting of 2-methoxycinnamaldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol or cinnamic acid in the preparation of a blood vessel for inhibiting mammals including human brain Use of a drug that secretes prostaglandin E2 by endothelial cells.
  • the invention further provides the use of a compound selected from the group consisting of 2-methoxycinnamic aldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol or cinnamic acid for the preparation of antipyretic drugs.
  • the formulation of the present invention is derived from the 2-methoxy-3-phenyl-2-propenal of the traditional Chinese medicine Guizhi Decoction, and the 2-methoxy-3-phenyl-3-propenal (o-methoxy-3-phenyl) -2-propenol), 2-methoxy-3-phenyl-2-propenoic acid, 3-phenyl-2-propenal, 3-phenyl-2-propenol
  • phenylpropene compounds such as 3-phenyl-2-propenoic acid, have different inhibitory effects on the secretion of PGE2 by cerebral vascular endothelial cells.
  • the above six phenyl propylene compounds are disposed in the following weight ratio: 1-methoxycinnamic aldehyde 1 part, 2-methoxycinnacol 0.01-0.1 part, 2-methoxycinnamic acid 0.05- 0.15 parts, cinnamic aldehyde 10-20 parts, cinnamyl alcohol 4-8
  • a composition obtained by mixing a mixture of cinnamic acid and 0.05-0.1 parts has a synergistic effect on the inhibition of secretion of prostaglandin E2 by cerebral vascular endothelial cells.
  • the component of the composition of the invention is 2-methoxy-3-phenyl-2-propenal, 2-methoxy-3-phenyl-2-propenol, 2-methoxy-3-phenyl-2-propenoic acid, phenyl aldehyde (3-phenyl-2-propenal), cinnabarin (3-phenyl-2-propenol) cinnamic acid (3 -phenyl-2-propenoic acid) is a compound of known structure.
  • compositions of the invention can be mixed according to methods of the prior art.
  • the compositions of the invention may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to provide a suitable administration form or dosage for use as a human medicament. form.
  • the compound composition of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as orally, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum. Oral administration is preferred.
  • the dosage form can be a liquid dosage form or a solid dosage form.
  • the liquid dosage form may be a true solution, a colloid, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form.
  • Other dosage forms such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and the like.
  • the compounds or compositions of the present invention may be formulated as common preparations, as sustained release preparations, as controlled release preparations, as targeted preparations, and as various microparticle delivery systems.
  • a carrier for example, a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannose, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannose, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch syrup, dextrin, syrup, honey, glucose solution, gum arabic, gelatin syrup, sodium carboxymethyl cellulose , shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and tannic acid, calcium carbonate, polyoxyethylene sorbus Sugar alcohol fatty acid ester, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.
  • disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.
  • absorption enhancer For example, quaternary ammonium salts, sodium lauryl sulfate, etc.
  • lubricants such as talc, silica, corn starch,
  • Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • a carrier for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, Ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, and the like.
  • a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.
  • binders such as gum arabic, tragacanth, gelatin, Ethanol, honey, liquid sugar, rice paste or batter
  • disintegrating agents such as agar powder, dried starch, alginate, sodium dode
  • the active ingredient compound of the present invention is mixed as an effective component with the above various carriers, and the mixture thus obtained is placed in a hard gelatin capsule or soft capsule.
  • the invention can also be turned into
  • the compound is prepared into a microcapsule, suspended in an aqueous medium to form a suspension, and can also be used in a hard capsule.
  • the compound of the present invention can be formulated into a liquid preparation such as a solution, a suspension, a solution, or an emulsion.
  • the preparation may be aqueous or non-aqueous, and may contain one and/or more pharmaceutically acceptable substances.
  • Carrier, diluent, binder, lubricant, preservative, surfactant or dispersant may be aqueous or non-aqueous, and may contain one and/or more pharmaceutically acceptable substances.
  • Carrier, diluent, binder, lubricant, preservative, surfactant or dispersant may be aqueous or non-aqueous, and may
  • the diluent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like.
  • a conventional cosolvent, a buffer, a P H conditioner, or the like may be added. These excipients are commonly used in the art.
  • a coloring agent a preservative, a flavor, a flavoring agent, a sweetener or the like may be added to the pharmaceutical preparation as needed.
  • the therapeutic effect can be enhanced, and the pharmaceutical or pharmaceutical composition prepared by the compound or composition of the present invention can be administered by any known administration method.
  • the dose of the compound of the present invention and the pharmaceutical composition to be administered depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, personality and individual response of the patient or animal, the route of administration, and the number of administrations.
  • the therapeutic dose of the present invention can vary widely.
  • the dose of the chemical component used in the present invention can be appropriately adjusted according to the actual amount of the compound contained in the final preparation of the compound composition of the present invention to achieve the therapeutically effective amount thereof, and the treatment of the present invention is completed. purpose.
  • a suitable daily dosage range for the compounds of the invention is used in an amount of from 1 to 80 mg/kg body weight, preferably from 3 to 20 mg/kg body weight.
  • the above dosages may be administered in the form of a single dose or divided into several, for example two, three or four doses. This is limited by the clinical experience of the administering physician and the dosing regimen including the use of other therapeutic means.
  • the present invention is a composition obtained by mixing six benzene propylene series compounds, and a series of compounds as active substances, which are new chemical entities or mixtures of new Chinese medicines.
  • the present invention is directed to PGE2, an important cytokine produced by brain vascular endothelial cells in the basic pathological processes of brain and brain vascular tissue damage, apoptosis or proliferation, so it is pleiotropic for a variety of related diseases.
  • the present invention also has an effect on inhibiting fever in mammals including humans.
  • the chemical composition of the invention is clear, the compatibility ratio is clear, the quality is controllable, and the composition of the active ingredient group of the traditional Chinese medicine is also exhibited.
  • the present invention can be formulated into oral and parenteral injection forms for use in acute and chronic patients.
  • Figure 1 is a graph showing the effect of the pharmaceutical composition group (23 mg/kg) of the present invention on the body temperature of a pyrolyzed rat.
  • Figure 2 is a graph showing the effect of intravenous administration of the pharmaceutical composition group of the present invention on the body temperature of a pyrolyzed rat.
  • Fig. 3 is a graph showing the effect of different combinations of the pharmaceutical compositions of the present invention on the temperature of yeast heating after 2 hours.
  • Figure 4 is a graph showing the effect of different combinations of the pharmaceutical compositions of the present invention on the yeast body temperature after 4 hours of oral administration.
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the technical solutions of the present invention will be described in detail with reference to the accompanying drawings and embodiments.
  • Example 1 Obtainment of phenyl propylene compound from Guizhi Decoction
  • 2-methoxycinnamic aldehyde and 2-methoxy cinnabar are separately isolated from the decoction extract of Decoction of Cinnamon Twigs, or Guizgi Tang.
  • the active ingredients of alcohol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol, cinnamic acid, etc. are shown in Table 1.
  • the recipe of Guizhi Decoction consists of 9 grams of Guizhi, 9 grams of peony, 9 grams of ginger, 4 jujubes, and 6 grams of licorice. Table 1. Yield of benzene propylene in 6 kinds of compounds in Guizhi Decoction
  • ratio # is based on the yield of 2-methoxycinnamic aldehyde (ratio 1) to calculate the ratio of the yield of other compounds, and adjust the range determined by the actual ratio.
  • SD rats anesthesia, o o decapitation, cerebral cortex, homogenate, filter with different pore sizes, collection of blood vessels, washing, collagenase digestion, pipetting, washing, enrichment, inoculation
  • Immunohistochemistry and cell morphology were identified as vascular endothelial cells. For experimental use.
  • the cultured cerebrovascular endothelial cells were seeded in a 96-well culture plate at a rate of 2 ⁇ 10 4 cells per well. After incubating in an incubator until they became fused, 2-methoxycinnamic aldehyde and 2-methoxy cinnabar were added respectively.
  • each compound dose is 12.5 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / mL 100 g / Ml 200 g/ml; then add the inflammatory factor interleukin-1 ⁇ 30ng/ml to stimulate the cerebral vascular endothelial cells, continue to culture, 12 hours later, take the culture solution (extracellular fluid), using the PGE2-ELISA assay kit, detection Prostaglandin E2 content (pg/ml) in extracellular fluid.
  • the half-inhibitory concentration (IC50) of each compound on the secretion of prostaglandin E2 secreted by cerebrovascular endothelial cells was calculated by the probability unit method. The results are shown in Table 2.
  • the phenylpropene compound in the composition of the present invention is used in combination with different ratios to inhibit the secretion of prostaglandin ⁇ 2 by vascular endothelial cells stimulated by interleukin-1 ⁇ (IL-1 ⁇ ).
  • IL-1 ⁇ interleukin-1 ⁇
  • composition of the present invention in a ratio of 1: 0.04 : 0.09 : 15.4 : 6.3 : 0.08 parts by weight
  • the effect of the composition on inhibiting the release of PGE2 is the result of a synergy between the six components.
  • Example 4 is as follows: 0.01: 0.05: 10.0: 4.0: 0.05 parts by weight Compositions
  • IL-1 ⁇ irritation + phenyl propylene composition 30ng/ml, 12.5 ⁇ g/ml 7.013 + 1.036
  • IL-1 ⁇ irritant + phenyl propylene composition 30ng/ml, 25.0 ⁇ g/ml 6.323 + 0.915
  • IL-1 ⁇ irritation + phenyl propylene composition 30ng/ml, 50.0 ⁇ g/ml 6.072 + 0.904
  • IL-1 ⁇ irritant + styrene composition 30 ng/ml, 200 ⁇ g/ml 5.137 + 0.939 IC50 66.49 ⁇ g/ml of phenylpropene composition (1: 0.01: 0.05: 10.0: 4.0: 0.05)
  • the extended equivalent line method was applied to calculate 2-methoxycinnamic aldehyde and 2-methoxy cinnabar.
  • Example 5 Composition according to 1:0.10: 0.15: 20.0: 8.0: 0.10 parts by weight of the composition
  • the IC50 of the phenylpropene composition (1: 0.10: 0.15: 20.0: 8.0: 0.10) was 52.62 ⁇ g/ml.
  • the extended equivalent line method was used to calculate the comparison of 2-methoxycinnamic aldehyde and 2-methoxycin
  • Example 6 Effect of Oral Administration of the Composition of the Invention on Body Temperature Curve of Pyrogens
  • the animals in the pyrogen group were given a fresh yeast suspension of 20% of the pyrogen, subcutaneously injected with 2 ml/100 g of body weight, and the rectal temperature was measured 3.5 h after the heat, and the non-fever was removed.
  • the molding administration group orally administered the composition of the present invention wherein the composition has a weight ratio of the composition of each single compound: 2-methoxycinnamic aldehyde: cinnamaldehyde: 2-methoxycinnacol: cinnamyl alcohol: 2 -Methoxy cinnamic acid: cinnamic acid was 1.00: 15.40: 0.04: 6.30: 0.09: 0.07), and the dose was 23 mg/kg ; the model control group was given an equal volume of distilled water.
  • Figure 2 also shows the test of the phenyl propylene compound group of Guizhi Decoction. Each dose group inhibited the effects of fever. Effect of intravenous administration of the composition group of the present invention on body temperature of a rat with heat
  • the difference in body temperature after drug administration refers to the temperature detection point of each group and before administration (ie 4 hours after the yeast is heated) The difference in body temperature.
  • Example 8 Guizhi Tang phenyl propylene compound in different proportions combined with oral administration on the body temperature of febrile animals Male Wistar rats were weighed and weighed 160g ⁇ 180g. After adjusting to laboratory conditions for 2 days, the anus temperature was measured, once in the afternoon and the next morning.
  • the anus temperature was measured again in the morning, and the average temperature of the anus was taken. Only 20% of the fresh yeast suspension of the pyrogen was administered, and 2 ml/100 g of body weight was injected subcutaneously. The anus temperature was measured 3.5 hours after the fever, and the non-fever was excluded. They were randomly divided into 6 groups: one group was the model control group, and the other 6 groups were the model administration group (see Table 9 for the number of animals in each group). The phenylpropene series of compounds consisting of different proportions were administered orally (see Table 8 for the composition ratio of each group); the model control group was given an equal volume of distilled water. The rectal temperature was measured at 2 hours and 4 hours after administration, and the difference in body temperature before administration (3.5 hours of heating) was calculated and statistically processed (t test).
  • the preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin ⁇ 2. And diseases such as congenital dementia or antipyretic.
  • Example 10
  • the drug of the present invention was prepared according to the method of Example 9, except that 100 g of 2-methoxycinnamic aldehyde, 1 g of 2-methoxycinnacol, 5 g of 2-methoxycinnamic acid, and cinnamaldehyde were taken. 1000 g, 800 g of cinnamyl alcohol, 5 g of cinnamic acid, 3 to 6 times of calcium carbonate, calcium phosphate or ⁇ -cyclodextrin, granulated, tableted, coated, made into tablets 18180 pieces, each piece A composition containing six phenyl propylene species, 125 mg, for oral use.
  • the preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin ⁇ 2. And diseases such as congenital dementia or antipyretic.
  • Example 11 The drug of the present invention was prepared according to the method of Example 9, except that 100 g of 2-methoxycinnamic aldehyde, 10 g of 2-methoxycinnacol, 15 g of 2-methoxycinnamic acid, and cinnamaldehyde were taken.
  • Example 12 2000 g, 400 g of cinnamyl alcohol, 10 g of cinnamic acid, and polyoxyethylene hydrogenated castor oil were added to make 9090 bottles of injection, and each bottle contained 125 mg of styrene-based composition for injection.
  • the preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin E2. Detoxification with diseases such as congenital dementia.
  • Example 12 Example 12
  • the preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin ⁇ 2. And diseases such as congenital dementia or antipyretic.
  • Example 13
  • the preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin ⁇ 2. And diseases such as congenital dementia or antipyretic.
  • Example 14
  • Example 9 500 g of 2-methoxycinnamic aldehyde obtained in Example 9 was obtained by a method well known to those skilled in the art: 2-methoxycinnacol 50 g: 2-methoxycinnamic acid 100: Cinnamaldehyde 15500 g: Cinnamon 6500 g: Cinnamic acid is mixed for 100 g. 3 to 6 times of calcium carbonate, calcium phosphate or ⁇ -cyclodextrin is added, granulated, and filled into hard capsules, each of which contains 250 mg of a composition of 6 kinds of phenyl propylene for oral use.
  • Example 15 500 g of 2-methoxycinnamic aldehyde obtained in Example 9 was obtained by a method well known to those skilled in the art: 2-methoxycinnacol 50 g: 2-methoxycinnamic acid 100: Cinnamaldehyde 15500 g: Cinnamon 6500 g: Cinnamic acid is mixed for 100

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Abstract

2-methoxy cinnamaldehyde, 2-methoxy cinnamyl alcohol, 2-methoxy cinnamic acid, cinnamaldehyde, cinnamyl alcohol, cinnamic acid and the composition containing said compounds are disclosed. They are used to prepare the medicine for inhibiting PGE2 released from CMEC in mammal, including human. They are also used to prepare the medicine for antipyretic.

Description

抑制脑血管内皮细胞分泌前列腺素 E2或解热的化合物及其组合物 技术领域 Compound for inhibiting secretion of prostaglandin E 2 or antipyretic by brain vascular endothelial cells and compositions thereof
本发明涉及一种化学药物组合物， 该组合物源自中药经典名方桂枝汤（Decoction of Cinnamon Twigs, or Guizgi Tang)的苯丙稀类化合物 (allyl b enzenes compounds)的组合物， 该组合物能抑制脑血管内皮细胞分泌前列腺素 E2， 可用于防治发热以及脑中风、 缺血 性脑损伤、 蛛网膜下腔出血、 高血压、 脑血管硬化和先天性痴呆等病变， 以及解热。 背景技术  The present invention relates to a chemical pharmaceutical composition derived from a composition of the Chinese medicine classic Decoction of Cinnamon Twigs, or Guizgi Tang, which is capable of allyl b enzenes compounds, which is capable of Inhibition of secretion of prostaglandin E2 by cerebral vascular endothelial cells can be used to prevent fever and strokes such as stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis and congenital dementia, as well as antipyretic. Background technique
前列腺素 E2 (Prostaglandin E2, PGE2) 系本领域公认的中枢发热介质和重要的炎症 因子， 机体许多细胞 (包括脑血管内皮细胞)在内外致病因子刺激下， 都能诱生过量的 PGE2, 造成组织损伤、 凋亡或增殖， 引起各种病变和疾病。 已有的研究表明， 脑血管 内皮细胞诱生的 PGE2可扩张局部血管， 易化水肿形成， 促进血管新生和动脉硬化， 与 发热、 疼痛、 中风、 缺血性脑损伤、 蛛网膜下腔出血、 高血压、 脑血管硬化和先天性痴 呆的发生发展有关 (Simmons DL., Botting RM., Hla Τ·: Cyclooxygenase isozymes: The biology and Prostaglandin synthesis and inhibition. Pharmacol. Rev. 2004; 56: 387-437)。 寻 找脑血管内皮细胞合成分泌前列腺素 E2的阻断剂，是近几年人们才开始研究防治上述有 关疾病的新的靶标。但目前除了对现有的环氧酶抑制剂作了初步筛选、发现对乙酰氨基 酚等对脑血管内皮合成分泌有一定抑制作用外，尚未有选择性的新药问世 (Kis B.， Snipes JA., Simandle SA., Busija DW.: Acetaminophen-sensitive prostaglandin production in rat cerebral endothelial cells. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005; 288: R897-R902 术语 Prostaglandin E2 (PGE2) is a well-recognized central heating medium and an important inflammatory factor. Many cells (including cerebral vascular endothelial cells) can induce excessive PGE2 under the stimulation of internal and external pathogenic factors. Tissue damage, apoptosis or proliferation, causing various diseases and diseases. Previous studies have shown that PGE2 induced by cerebral vascular endothelial cells can expand local blood vessels, facilitate edema formation, promote angiogenesis and arteriosclerosis, and with fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, Hypertension, cerebral arteriosclerosis, and the development of congenital dementia (Simmons DL., Botting RM., Hla Τ: Cyclooxygenase isozymes: The biology and Prostaglandin synthesis and inhibition. Pharmacol. Rev. 2004; 56: 387-437) . It is in recent years that people have begun to study new targets for the prevention and treatment of the aforementioned diseases, in order to find a blocker for the synthesis of prostaglandin E 2 secreted by brain vascular endothelial cells. However, in addition to the preliminary screening of existing epoxidase inhibitors, and the discovery that acetaminophen has a certain inhibitory effect on the synthesis and secretion of cerebral vascular endothelium, there is no selective new drug available (Kis B., Snipes JA. , Simandle SA., Busija DW.: Acetaminophen-sensitive prostaglandin production in rat cerebral endothelial cells. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005; 288: R897-R902 Terminology
系列化合物 (series compounds), 是指化学结构上有相同母核、 具有不同官能团的系 列化合物。  A series of compounds refers to a series of compounds having the same parent core and different functional groups.
药物化学实体： 关于药物的化学实体， 中药的化学实体有饮片的粉末、 饮片的各类 粗提物、 活性化学部位和化学单体， 也包括中西药物的组合物。西药化学药的化学实体 有单一化学单体或几个化学单体的组合物；生物药物的化学实体是以某一生物物质为主 的产物。 迄今尚未见以系列化合物、 更未见以若干数目、 明确比值的系列化合物组合作 为药物化学实体的。在本领域中， PubMed、 CNKI和美英日等国药典及其相关药品监管 部门所公开的信息均未见有系列化物的组合物作为药品的记载。  Medicinal chemical entity: Regarding the chemical entity of the drug, the chemical entity of the Chinese medicine has a powder of the decoction piece, various crude extracts of the decoction piece, an active chemical part and a chemical monomer, and also a composition of the Chinese and Western medicine. The chemical entity of a western medicine chemical has a single chemical monomer or a combination of several chemical monomers; the chemical entity of the biological drug is a product mainly composed of a certain biological substance. To date, no series of compounds have been seen, and a series of compounds with a certain number and a clear ratio have not been seen as a medicinal chemical entity. In the field, the information published by PubMed, CNKI, and the United States, Britain and Japan, and other related drug regulatory authorities have not seen the composition of the series as a drug.
饮片： 饮片泛指所有用于临床调配处方以及供中成药生产所使用的中药， 包括药材 切制后的片、 段、 丝、 块， 净制后的花， 叶， 种子， 果实， 和炮制后的炮制品。 发明内容 Pieces of decoction: Decoction refers to all the traditional Chinese medicines used for clinical formulation and for the production of proprietary Chinese medicines, including cuts, segments, silks, blocks, netted flowers, leaves, seeds, fruits, and after processing. Processed products. Summary of the invention
本发明的目的在于提供一种药物组合物， 该药物组合物能够抑制哺乳动物包括人脑 血管内皮细胞分泌前列腺素 E2 (PGE2 )。  It is an object of the present invention to provide a pharmaceutical composition capable of inhibiting secretion of prostaglandin E2 (PGE2) by mammalian cells including human brain vascular endothelial cells.
本发明的另一目的在于提供一种药物组合物， 该药物组合物用于哺乳动物包括人的 解热。  Another object of the present invention is to provide a pharmaceutical composition for use in the antipyretic of mammals including humans.
为了完成本发明的目的， 本发明技术方案为：  In order to accomplish the object of the present invention, the technical solution of the present invention is:
一种药物组合物， 其特征在于所述的药物组合物由以下组分组成： 0.5〜1.5 重量 份 2-甲氧基桂皮醛、 0.01〜0.1重量份 2-甲氧基桂皮醇、 0.05〜0.15重量份 2-甲氧基桂 皮酸、 10〜20重量份桂皮醛、 4〜8重量份桂皮醇、 0.05〜0.1重量份桂皮酸。  A pharmaceutical composition characterized in that the pharmaceutical composition consists of: 0.5 to 1.5 parts by weight of 2-methoxycinnamaldehyde, 0.01 to 0.1 part by weight of 2-methoxycinnacol, 0.05 to 0.15 Parts by weight of 2-methoxycinnamic acid, 10 to 20 parts by weight of cinnamaldehyde, 4 to 8 parts by weight of cinnamyl alcohol, and 0.05 to 0.1 part by weight of cinnamic acid.
优选的是 1重量份 2-甲氧基桂皮醛、 0.01〜0.1重量份 2-甲氧基桂皮醇、 0.05〜0.15 重量份 2-甲氧基桂皮酸、 10〜20重量份桂皮醛、 4〜8重量份桂皮醇、 0.05〜0.1重量份 桂皮酸。  Preferably, 1 part by weight of 2-methoxycinnamic aldehyde, 0.01 to 0.1 part by weight of 2-methoxycinnacol, 0.05 to 0.15 part by weight of 2-methoxycinnamic acid, 10 to 20 parts by weight of cinnamaldehyde, 4~ 8 parts by weight of cinnamyl alcohol, 0.05 to 0.1 parts by weight of cinnamic acid.
更优选的是 1重量份 2-甲氧基桂皮醛、 0.04〜0.01重量份 2-甲氧基桂皮醇、 0.05〜 0.09重量份 2-甲氧基桂皮酸、 10〜15.5重量份桂皮醛、 4〜6.5重量份桂皮醇、 0.05〜0.07 重量份桂皮酸。  More preferably, 1 part by weight of 2-methoxycinnamic aldehyde, 0.04 to 0.01 part by weight of 2-methoxycinnacol, 0.05 to 0.09 part by weight of 2-methoxycinnamic acid, 10 to 15.5 parts by weight of cinnamaldehyde, 4 ～6.5 parts by weight of cinnamyl alcohol, 0.05 to 0.07 parts by weight of cinnamic acid.
本发明药物组合物进一步包括药学上可接受的载体。所述的载体包括粉体、液体和 气体。  The pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable carrier. The carrier includes powders, liquids, and gases.
本发明还涉及该药物组合物在制备用于抑制哺乳动物包括人脑血管内皮细胞分泌 前列腺素 E2的药物中的用途。  The invention further relates to the use of the pharmaceutical composition for the manufacture of a medicament for inhibiting the secretion of prostaglandin E2 from mammalian cells, including human brain vascular endothelial cells.
本发明进一步涉及该药物组合物在制备用于解热药物中的用途。  The invention further relates to the use of the pharmaceutical composition for the preparation of a medicament for use in antipyretics.
本发明还涉及抑制哺乳动物包括人脑血管内皮细胞分泌前列腺素 E2的方法， 包括 向患者使用药物有效剂量的本发明所述的药物组合物。  The invention further relates to a method of inhibiting secretion of prostaglandin E2 from a mammal, including human brain vascular endothelial cells, comprising administering to a patient a pharmaceutically effective amount of a pharmaceutical composition of the invention.
本发明进一步涉及哺乳动物包括人发热的治疗方法，其中包括向患者使用药物有效 剂量的本发明所述的药物组合物。  The invention further relates to a method of treatment of a mammal, including human fever, comprising administering to the patient a pharmaceutically effective amount of a pharmaceutical composition of the invention.
本发明进一步提供选自 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮 醛、桂皮醇或者桂皮酸化合物在制备用于抑制哺乳动物包括人脑血管内皮细胞分泌前列 腺素 E2的药物中的用途。  The present invention further provides a compound selected from the group consisting of 2-methoxycinnamaldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol or cinnamic acid in the preparation of a blood vessel for inhibiting mammals including human brain Use of a drug that secretes prostaglandin E2 by endothelial cells.
本发明进一步提供选自 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮 醛、 桂皮醇或者桂皮酸的化合物在制备解热药物中的用途。  The invention further provides the use of a compound selected from the group consisting of 2-methoxycinnamic aldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol or cinnamic acid for the preparation of antipyretic drugs.
换言之 ， 本发 明 的配方源 自 中 药桂枝汤 的 2- 甲 氧基桂皮醛 (o-methoxy-3-phenyl-2-propenal)、 2-甲氧基桂皮酉享 (o-methoxy-3-phenyl-2-propenol)、 2- 甲氧基桂皮酸 (o-methoxy-3-phenyl-2-propenoic acid) 桂皮醛 (3-phenyl-2-propenal)、 桂皮 醇 (3-phenyl-2-propenol)、 桂皮酸 (3-phenyl-2-propenoic acid)等 6种的苯丙烯类化合物对 脑血管内皮细胞分泌释放 PGE2具有不同程度的抑制作用。  In other words, the formulation of the present invention is derived from the 2-methoxy-3-phenyl-2-propenal of the traditional Chinese medicine Guizhi Decoction, and the 2-methoxy-3-phenyl-3-propenal (o-methoxy-3-phenyl) -2-propenol), 2-methoxy-3-phenyl-2-propenoic acid, 3-phenyl-2-propenal, 3-phenyl-2-propenol Six kinds of phenylpropene compounds, such as 3-phenyl-2-propenoic acid, have different inhibitory effects on the secretion of PGE2 by cerebral vascular endothelial cells.
本发明是将上述 6种苯丙烯类化合物， 按下述重量比配置： 2-甲氧基桂皮醛 1份、 2-甲氧基桂皮醇 0.01-0.1份、 2-甲氧基桂皮酸 0.05-0.15份、桂皮醛 10-20份、桂皮醇 4-8 份、 桂皮酸 0.05-0.1份等混合成的组合物， 对脑血管内皮细胞分泌前列腺素 E2的抑制 呈协同作用。 In the present invention, the above six phenyl propylene compounds are disposed in the following weight ratio: 1-methoxycinnamic aldehyde 1 part, 2-methoxycinnacol 0.01-0.1 part, 2-methoxycinnamic acid 0.05- 0.15 parts, cinnamic aldehyde 10-20 parts, cinnamyl alcohol 4-8 A composition obtained by mixing a mixture of cinnamic acid and 0.05-0.1 parts has a synergistic effect on the inhibition of secretion of prostaglandin E2 by cerebral vascular endothelial cells.
本发明组合物中的组分 2-甲氧基桂皮醛 (o-methoxy-3-phenyl-2-propenal)、 2-甲氧基 桂 皮 醇 （o-methoxy-3-phenyl-2-propenol) 、 2- 甲 氧 基 桂 皮 酸 (o-methoxy-3-phenyl-2-propenoic acid) 、 桂皮醛 (3-phenyl-2-propenal) 、 桂皮酉享 (3-phenyl-2-propenol) 桂皮酸 (3-phenyl-2-propenoic acid)为公知结构的化合物。  The component of the composition of the invention is 2-methoxy-3-phenyl-2-propenal, 2-methoxy-3-phenyl-2-propenol, 2-methoxy-3-phenyl-2-propenoic acid, phenyl aldehyde (3-phenyl-2-propenal), cinnabarin (3-phenyl-2-propenol) cinnamic acid (3 -phenyl-2-propenoic acid) is a compound of known structure.
本发明化合物组合物可根据现有技术的方法进行混合。 用于此目的时， 如果需要， 可将本发明的组合物与一种或多种固体或液体药物赋形剂和 /或辅剂结合， 制成可做为人用药使用的适当的施用形式或剂量形式。  The compound compositions of the invention can be mixed according to methods of the prior art. For this purpose, if desired, the compositions of the invention may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to provide a suitable administration form or dosage for use as a human medicament. form.
本发明化合物组合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为 肠道或非肠道， 如口服、 肌肉、 皮下、 鼻腔、 口腔粘膜、 皮肤、 腹膜或直肠等， 优选口 服。  The compound composition of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as orally, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum. Oral administration is preferred.
给药剂型可以是液体剂型、 固体剂型。 如液体剂型可以是真溶液类、 胶体类、 微粒 剂型、 乳剂剂型、 混悬剂型。 其它剂型例如片剂、 胶囊、 滴丸、 气雾剂、 丸剂、 粉剂、 溶液剂、 混悬剂、 乳剂、 颗粒剂、 栓剂、 等。  The dosage form can be a liquid dosage form or a solid dosage form. For example, the liquid dosage form may be a true solution, a colloid, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form. Other dosage forms such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and the like.
本发明涉及的化合物或者组合物可以制成普通制剂、也可以是缓释制剂、控释制剂、 靶向制剂及各种微粒给药系统。  The compounds or compositions of the present invention may be formulated as common preparations, as sustained release preparations, as controlled release preparations, as targeted preparations, and as various microparticle delivery systems.
为了将单位给药剂型制成片剂， 可以广泛使用本领域公知的各种载体。关于载体的 例子是， 例如稀释剂与吸收剂， 如淀粉、 糊精、硫酸钙、 乳糖、甘露糖、 蔗糖、 氯化钠、 葡萄糖、 尿素、 碳酸钙、 白陶土、 微晶纤维素、 硅酸铝等； 湿润剂与粘合剂， 如水、 甘 油、 聚乙二醇、 乙醇、 丙醇、 淀粉浆、 糊精、 糖浆、 蜂蜜、 葡萄糖溶液、 阿拉伯胶浆、 明胶浆、 羧甲基纤维素钠、 紫胶、 甲基纤维素、 磷酸钾、 聚乙烯吡咯烷酮等； 崩解剂， 例如干燥淀粉、 海藻酸盐、 琼脂粉、 褐藻淀粉、 碳酸氢钠与枸橼酸、 碳酸钙、 聚氧乙烯 山梨糖醇脂肪酸酯、 十二烷基磺酸钠、 甲基纤维素、 乙基纤维素等； 崩解抑制剂， 例如 蔗糖、 三硬脂酸甘油酯、 可可脂、 氢化油等； 吸收促进剂， 例如季铵盐、 十二烷基硫酸 钠等； 润滑剂， 例如滑石粉、 二氧化硅、 玉米淀粉、 硬脂酸盐、 硼酸、 液体石蜡、 聚乙 二醇等。 其它载体如聚丙稀酸树脂类、 脂质体， 水溶性载体如 PEG4000和 PEG6000、 PVP等。 还可以将片剂进一步制成包衣片， 例如糖包衣片、 薄膜包衣片、 肠溶包衣片， 或双层片和多层片。  In order to form a unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannose, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid. Aluminum, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch syrup, dextrin, syrup, honey, glucose solution, gum arabic, gelatin syrup, sodium carboxymethyl cellulose , shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and tannic acid, calcium carbonate, polyoxyethylene sorbus Sugar alcohol fatty acid ester, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.; absorption enhancer For example, quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants such as talc, silica, corn starch, stearates, boric acid, liquid paraffin, polyethylene glycol . Other carriers such as polyacrylic resins, liposomes, water-soluble carriers such as PEG4000 and PEG6000, PVP and the like. Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
例如为了将给药单元制成丸剂， 可以广泛使用本领域公知的各种载体。关于载体的 例子是， 例如稀释剂与吸收剂， 如葡萄糖、 乳糖、 淀粉、 可可脂、 氢化植物油、 聚乙烯 吡咯烷酮、 高岭土、 滑石粉等； 粘合剂， 如阿拉伯胶、 黄蓍胶、 明胶、 乙醇、 蜂蜜、 液 糖、 米糊或面糊等； 崩解剂， 如琼脂粉、 干燥淀粉、 海藻酸盐、 十二烷基磺酸钠、 甲基 纤维素、 乙基纤维素等。  For example, in order to prepare a drug delivery unit into a pellet, various carriers known in the art can be widely used. Examples of the carrier are, for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, Ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, and the like.
例如， 为了将给药单元制成胶囊， 将有效成分本发明化合物作为有效组分与上述的 各种载体混合， 并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将本发明化 合物制成微囊剂， 混悬于水性介质中形成混悬剂， 亦可装入硬胶囊中应用。 例如， 将本发明化合物制成液体制剂， 如溶液剂、 混悬剂、 溶液剂、 乳剂， 这种制 剂可以是含水或非水的， 可含一种和 /或多种药效学上可接受的载体、 稀释剂、 粘合剂、 润滑剂、 防腐剂、 表面活性剂或分散剂。 如稀释剂可选自水、 乙醇、 聚乙二醇、 1， 3- 丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。此外， 还可以添加常规的助溶剂、 缓冲剂、 PH调节剂等。 这些辅料是本领域常用的。 For example, in order to encapsulate the administration unit, the active ingredient compound of the present invention is mixed as an effective component with the above various carriers, and the mixture thus obtained is placed in a hard gelatin capsule or soft capsule. The invention can also be turned into The compound is prepared into a microcapsule, suspended in an aqueous medium to form a suspension, and can also be used in a hard capsule. For example, the compound of the present invention can be formulated into a liquid preparation such as a solution, a suspension, a solution, or an emulsion. The preparation may be aqueous or non-aqueous, and may contain one and/or more pharmaceutically acceptable substances. Carrier, diluent, binder, lubricant, preservative, surfactant or dispersant. For example, the diluent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. Further, a conventional cosolvent, a buffer, a P H conditioner, or the like may be added. These excipients are commonly used in the art.
此外， 根据需要， 也可以向药物制剂中添加着色剂、 防腐剂、 香料、 矫味剂、 甜味 剂或其它材料。  Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetener or the like may be added to the pharmaceutical preparation as needed.
为达到用药目的， 增强治疗效果， 本发明化合物或者组合物制成的药物或药物组合 物可用任何公知的给药方法给药。  For the purpose of administration, the therapeutic effect can be enhanced, and the pharmaceutical or pharmaceutical composition prepared by the compound or composition of the present invention can be administered by any known administration method.
本发明化合物、药物组合物的给药剂量取决于许多因素， 例如所要预防或治疗疾病 的性质和严重程度， 患者或动物的性别、 年龄、 体重、 性格及个体反应， 给药途径、 给 药次数、 治疗目的， 因此本发明的治疗剂量可以有大范围的变化。 一般来讲， 本发明中 化学成分的使用剂量可以根据本发明化合物组合物中最后的制剂中所含有的化合物实 际数量， 加以适当的调整， 以达到其治疗有效量的要求， 完成本发明的治疗目的。  The dose of the compound of the present invention and the pharmaceutical composition to be administered depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, personality and individual response of the patient or animal, the route of administration, and the number of administrations. For therapeutic purposes, the therapeutic dose of the present invention can vary widely. In general, the dose of the chemical component used in the present invention can be appropriately adjusted according to the actual amount of the compound contained in the final preparation of the compound composition of the present invention to achieve the therapeutically effective amount thereof, and the treatment of the present invention is completed. purpose.
本发明化合物的每天的合适剂量范围。 本发明的组合物的用量为 l-80mg/Kg体重， 优选为 3-20mg/Kg体重。 上述剂量可以单一剂量形式或分成几个， 例如二、三、 四个剂 量形式给药。 这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。  A suitable daily dosage range for the compounds of the invention. The composition of the present invention is used in an amount of from 1 to 80 mg/kg body weight, preferably from 3 to 20 mg/kg body weight. The above dosages may be administered in the form of a single dose or divided into several, for example two, three or four doses. This is limited by the clinical experience of the administering physician and the dosing regimen including the use of other therapeutic means.
本发明的特点与优点： ①本发明是由 6个苯丙烯类系列化合物混和而成的组合物， 以系列化合物作为活性物质， 是中药新药一类新的化学实体或者混合物。②本发明针对 的是引起脑和脑血管组织损伤、凋亡或增殖等基本病理过程中、 由脑血管内皮细胞产生 的一种重要细胞因子 --PGE2,故对多种相关疾病具有多效性，本发明还对抑制哺乳动物 包括人发热的有作用。③本发明的化学成分明确， 配伍比例清楚， 质量可控性强， 又体 现了中药系活性成分群组成的特点。④本发明可制成口服和非口服注射剂型， 供急、慢 性患者使用。 附图说明  Features and advantages of the present invention: 1. The present invention is a composition obtained by mixing six benzene propylene series compounds, and a series of compounds as active substances, which are new chemical entities or mixtures of new Chinese medicines. 2 The present invention is directed to PGE2, an important cytokine produced by brain vascular endothelial cells in the basic pathological processes of brain and brain vascular tissue damage, apoptosis or proliferation, so it is pleiotropic for a variety of related diseases. The present invention also has an effect on inhibiting fever in mammals including humans. 3 The chemical composition of the invention is clear, the compatibility ratio is clear, the quality is controllable, and the composition of the active ingredient group of the traditional Chinese medicine is also exhibited. 4 The present invention can be formulated into oral and parenteral injection forms for use in acute and chronic patients. DRAWINGS
图 1 是本发明药物组合物组 (23mg/kg)对致热大鼠体温的影响。  Figure 1 is a graph showing the effect of the pharmaceutical composition group (23 mg/kg) of the present invention on the body temperature of a pyrolyzed rat.
图 2是本发明药物组合物组组静脉给药对致热大鼠体温的影响。  Figure 2 is a graph showing the effect of intravenous administration of the pharmaceutical composition group of the present invention on the body temperature of a pyrolyzed rat.
图 3是本发明药物组合物不同组合口伺 2小时后对酵母致热体温的影响。  Fig. 3 is a graph showing the effect of different combinations of the pharmaceutical compositions of the present invention on the temperature of yeast heating after 2 hours.
图 4是本发明药物组合物不同组合口伺 4小时后对酵母致热体温的影响。 具体实施方式 以下将结合附图和实施例详细说明本发明的技术方案。 实施例 1 桂枝汤苯丙烯类化合物的获得 Figure 4 is a graph showing the effect of different combinations of the pharmaceutical compositions of the present invention on the yeast body temperature after 4 hours of oral administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the technical solutions of the present invention will be described in detail with reference to the accompanying drawings and embodiments. Example 1 Obtainment of phenyl propylene compound from Guizhi Decoction
根据本领域技术人员熟知的方法， 从中药经典方剂桂枝汤 （Decoction of Cinnamon Twigs, or Guizgi Tang)的水煎提取物中多次分离获得 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮醛、 桂皮醇、 桂皮酸等活性成分， 得率如表 1所示。  According to the method well known to those skilled in the art, 2-methoxycinnamic aldehyde and 2-methoxy cinnabar are separately isolated from the decoction extract of Decoction of Cinnamon Twigs, or Guizgi Tang. The active ingredients of alcohol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol, cinnamic acid, etc., are shown in Table 1.
桂枝汤的配方由桂枝 9克、 芍药 9克、 生姜 9克、 大枣 4枚、 甘草 6克组成。 表 1. 桂枝汤中苯丙烯类 6种化合物的得率  The recipe of Guizhi Decoction consists of 9 grams of Guizhi, 9 grams of peony, 9 grams of ginger, 4 jujubes, and 6 grams of licorice. Table 1. Yield of benzene propylene in 6 kinds of compounds in Guizhi Decoction
活性化合物 得率 (％) 得率范围 相互比值范围 # Active compound yield (%) yield range mutual ratio range #
2-甲氧基桂皮醛 0.3416, 0.8540, 0.4270, 0.2135, 0.6405 0.854—0.213 12-methoxycinnamic aldehyde 0.3416, 0.8540, 0.4270, 0.2135, 0.6405 0.854—0.213 1
2-甲氧基桂皮醇 0.0288, 0.0194, 0.0096, 0.0384, 0.0153 0.038—0.009 2-methoxycinnacol 0.0288, 0.0194, 0.0096, 0.0384, 0.0153 0.038—0.009
2-甲氧基桂皮酸 0.0388, 0.0192, 0.0656, 0.0307, 0.0576  2-methoxycinnamic acid 0.0388, 0.0192, 0.0656, 0.0307, 0.0576
桂皮醛 6.5778, 5.2606, 13.151, 3.2879, 9.8637  Cinnamaldehyde 6.5778, 5.2606, 13.151, 3.2879, 9.8637
桂皮醇 5.3802, 2.7026, 1.3450, 2.1521, 4.0351 4— -8 桂皮酸 0.0576, 0.0307, 0.0388, 0.0656, 0.0192  Cinnamyl 5.3802, 2.7026, 1.3450, 2.1521, 4.0351 4-8 cinnamic acid 0.0576, 0.0307, 0.0388, 0.0656, 0.0192
#是以 2-甲氧基桂皮醛的得率为基准 (比值为 1)计算其他化合物得率与之的比值， 并以实际比值作调整所确定的范围。  # is based on the yield of 2-methoxycinnamic aldehyde (ratio 1) to calculate the ratio of the yield of other compounds, and adjust the range determined by the actual ratio.
脑微血管内皮细胞的获取： 取雄性幼年 o o  Acquisition of brain microvascular endothelial cells: taking male infants o o
SD大鼠， 麻醉， o o断头， 取大脑皮质， 匀浆， 不同孔径的滤网过滤， 收集血管段， 洗涤， 胶原酶消化， 吹打、 洗涤、 富集， 接种于明 o o  SD rats, anesthesia, o o decapitation, cerebral cortex, homogenate, filter with different pore sizes, collection of blood vessels, washing, collagenase digestion, pipetting, washing, enrichment, inoculation
胶覆盖的培养瓶， C02 培养箱培养， 换液传代， 以第八因子相关抗 o O Glue-coated culture flask, C02 incubator culture, liquid exchange passage, with factor VIII related anti-o
寸原作免疫组化和细 胞形态鉴定， 确定为血管内皮细胞。 供实验用。  Immunohistochemistry and cell morphology were identified as vascular endothelial cells. For experimental use.
o o o o o 实施例 2 o  o o o o o Example 2 o
o O O 本发明组合物中的苯丙烯类化合物分别对白介素 -1 β (IL-1 β )刺激脑血管内皮细胞 o o o 分泌前列腺素 Ε2的抑制作用  o O O The inhibitory effect of phenylpropenes in the composition of the present invention on interleukin-1β (IL-1β)-stimulated secretion of prostaglandin 脑2 by cerebral vascular endothelial cells o o o
取培养的脑血管内皮细胞， 接种于 96孔培养板内， 每孔 2 χ104细胞， 在培养箱培 养至长成融合状态后， 分别加入 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮醛、桂皮醇、桂皮酸等 6个化合物， 每种化合物的剂量均为 12.5 μ g/ml、 25 μ g/ml、 50 μ g/mL 100 g/ml 200 g/ml; 继而加入致炎因子白介素 -1 β 30ng/ml激惹脑血管内 皮细胞， 继续培养， 12小时后， 取培养液 (细胞外液)， 使用 PGE2-ELISA测定试剂盒， 检测细胞外液中的前列腺素 E2含量 (pg/ml)。 并以概率单位法计算出每个化合物对脑血 管内皮细胞分泌释放前列腺素 E2的半数抑制浓度 (IC50)。 结果如表 2所示。 The cultured cerebrovascular endothelial cells were seeded in a 96-well culture plate at a rate of 2 χ 10 4 cells per well. After incubating in an incubator until they became fused, 2-methoxycinnamic aldehyde and 2-methoxy cinnabar were added respectively. 6 compounds such as alcohol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol, cinnamic acid, etc., each compound dose is 12.5 μg / ml, 25 μ g / ml, 50 μ g / mL 100 g / Ml 200 g/ml; then add the inflammatory factor interleukin-1 β 30ng/ml to stimulate the cerebral vascular endothelial cells, continue to culture, 12 hours later, take the culture solution (extracellular fluid), using the PGE2-ELISA assay kit, detection Prostaglandin E2 content (pg/ml) in extracellular fluid. The half-inhibitory concentration (IC50) of each compound on the secretion of prostaglandin E2 secreted by cerebrovascular endothelial cells was calculated by the probability unit method. The results are shown in Table 2.
从表 2结果可知， 6种苯丙烯类化合物对脑血管内皮细胞分泌释放前列腺素 E2均 有不同程度的抑制作用。 其中， 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 桂皮醛、 桂皮醇作 用较强。依作用强弱依次为： 桂皮醛 >2-甲氧基桂皮醛 >桂皮醇 >2-甲氧基桂皮醇 >桂皮酸 >2-甲氧基桂皮酸。 表 2. 六个苯丙烯类化合物对 IL-1 β 刺激的脑血管内皮细胞释放 PGE2的影响 注： 与 IL-Ι β 组比较， *Ρ<0.05， **Ρ<0.01 From the results in Table 2, it can be seen that the six phenyl propylene compounds have different inhibitory effects on the secretion of prostaglandin E2 by cerebral vascular endothelial cells. Among them, 2-methoxycinnamic aldehyde, 2-methoxycinnacol, cinnamaldehyde and cinnamyl alcohol have strong effects. According to the strength of the action, it is: cinnamaldehyde > 2-methoxycinnamic aldehyde > cinnamyl alcohol > 2-methoxycinnamic alcohol > cinnamic acid > 2-methoxycinnamic acid. Table 2. Effect of six phenylpropenes on release of PGE2 from IL-1β-stimulated cerebrovascular endothelial cells Note: *Ρ<0.05, **Ρ<0.01 compared with IL-Ιβ group
IL-1 0  IL-1 0
药物浓度 （y g/ml)  Drug concentration (y g/ml)
浓度  Concentration
Figure imgf000007_0001
实施例 3
Figure imgf000007_0001
Example 3
本发明组合物中苯丙烯类化合物按不同配比联合应用， 对白介素 -1 β (IL-1 β )刺激脑 血管内皮细胞分泌前列腺素 Ε2的抑制作用  The phenylpropene compound in the composition of the present invention is used in combination with different ratios to inhibit the secretion of prostaglandin Ε2 by vascular endothelial cells stimulated by interleukin-1β (IL-1 β).
按 1 ： 0.04 ： 0.09 ： 15.4 ： 6.3 ： 0.08 重量份配比的本发明组合物  Composition of the present invention in a ratio of 1: 0.04 : 0.09 : 15.4 : 6.3 : 0.08 parts by weight
以上述 6个苯丙烯类化合物在桂枝汤中所测含量 (得率)比值， 取其中位数， 将 2-甲 氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮醛、 桂皮醇、 桂皮酸等 6种化合 物依次按 1 ： 0.04 ： 0.09 ： 15.4 ： 6.3 ： 0.08 进行混合， 将此混合的组合物按实施例 2所述的方法， 观察它对白介素 -1 β (IL-1 β )刺激脑血管内皮细胞分泌前列腺素 Ε2的抑 制作用。  Taking the ratio of the content (yield ratio) of the above six phenylpropene compounds in Guizhi Decoction, taking the median, 2-methoxycinnamic aldehyde, 2-methoxycinnacol, 2-methoxycin Six compounds, such as acid, cinnamaldehyde, cinnamyl alcohol, and cinnamic acid, were sequentially mixed at 1: 0.04 : 0.09 : 15.4 : 6.3 : 0.08 , and the mixed composition was observed as described in Example 2 to observe the interleukin. -1 β (IL-1 β ) stimulates the inhibition of secretion of prostaglandin 2 by cerebral vascular endothelial cells.
结果如表 3所示， 按 6种苯丙烯类化合物在桂枝汤中含量比例混合的组合物,处理 IL-2 P 激惹的脑血管内皮细胞， 对其分泌释放 PGE2 的半数抑制浓度 (IC50)为 48.79 g/ml ， 比其组合的各个单一化合物的 IC50为低，说明组合物的作用强度高于任 何一个单一化合物。 表 3. 不同比例的苯丙烯类组合物对 IL- Ι β刺激的脑血管内皮细胞释放 PGE2的影响 -1 组别 细胞外液 PGE2含 The results are shown in Table 3. The composition of the six phenylpropene compounds in the proportion of Guizhi Decoction was used to treat the IL-2P-irritated cerebrovascular endothelial cells, and the half-inhibitory concentration of PGE2 secreted and released (IC50). ) is 48.79 g/ml, which is lower than the IC50 of each single compound in combination, indicating that the composition has a higher intensity of action than any single compound. Table 3. Effect of different proportions of phenylpropene composition on release of PGE2 from IL-Ιβ-stimulated cerebrovascular endothelial cells-1 Group of extracellular fluid PGE2
(Pg/ml) 对照组 3.561士 0.821 单纯 IL- 1 β 激惹组 30ng/ml 7.577士 1.517 IL- Ι β 激惹 + 苯乙烯类组合物 30ng/ml, 12.5 μ g/ml 6.886 + 0.955 IL- Ι β 激惹 + 苯乙烯类组合物 30ng/ml, 25 μ g/ml 6.195 + 0.852 IL- Ι β 激惹 + 苯乙烯类组合物 30ng/ml, 50 μ g/ml 5.731士 0.636 IL- Ι β 激惹 + 苯乙烯类组合物 30ng/ml, 100 μ g/ml 5.299士 0.737 IL- Ι β 激惹 + 苯乙烯类组合物 30ng/ml, 200 μ g/ml 4.821士 1.106 苯乙烯类组合物的 IC50 48.79 μ g/ml 应用扩展的等效线法 (isobole equation) , 计算比较了 2-甲氧基桂皮醛、 2-甲氧基桂皮 醇、 2-甲氧基桂皮酸、 桂皮醛、 桂皮醇、 桂皮酸及其组合物的 IC50的相互关系， Q值 为 0.92 ((2值<1为协同作用、 Q值 =1为相加作用、 （2值>1为拮抗作用)， 表明联合应用 后的组合物抑制 PGE2释放的效应， 是 6个成分间的协同作用的结果。 实施例 4 按 1： 0.01： 0.05： 10.0： 4.0： 0.05 重量份配比的组合物  (Pg/ml) Control group 3.561 ± 0.821 IL - 1 β stimulation group 30 ng / ml 7.577 ± 1.517 IL - Ι β irritation + styrene composition 30 ng / ml, 12.5 μ g / ml 6.886 + 0.955 IL- Ι β irritant + styrene composition 30 ng/ml, 25 μg/ml 6.195 + 0.852 IL- Ι β irritant + styrene composition 30 ng/ml, 50 μg/ml 5.731 ± 0.636 IL- Ι β Irritant + styrene composition 30ng/ml, 100 μg/ml 5.299士 0.737 IL- Ι β irritant + styrene composition 30ng/ml, 200 μg/ml 4.821 ± 1.106 styrene composition IC50 48.79 μ g/ml Calculate and compare 2-methoxycinnamic aldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol using the extended isobole equation. The IC50 relationship between cinnamic acid and its composition, the Q value is 0.92 ((2 values <1 for synergy, Q = 1 for additive effect, (2 value > 1 for antagonism), indicating joint application The effect of the composition on inhibiting the release of PGE2 is the result of a synergy between the six components. Example 4 is as follows: 0.01: 0.05: 10.0: 4.0: 0.05 parts by weight Compositions
将市售的 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮醛、 桂皮醇、 桂皮酸等 6种化合物依次按相互的最小比例范围 (1 ： 0.01 ： 0.05 ： 10.0 ： 4.0 ： 0.05 进行混合， 制成组合物， 按实施例 3的方法， 观察它对白介素 -1 β 刺激脑血管内皮细胞 分泌前列腺素 Ε2的抑制作用。结果如表 4所示，其分泌释放 PGE2的半数抑制浓度 (IC50) 为 66.49 μ g/ml 。 表 4. 不同比例的本发明组合物对 IL- 1 β 刺激的脑血管内皮细胞释放 PGE2的影响 -2 组别 剂量 细胞外液 PGE2含  6 kinds of compounds such as 2-methoxycinnamic aldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol and cinnamic acid are sequentially placed in the minimum ratio range of each other (1: 0.01 : 0.05 : 10.0 : 4.0 : 0.05 The mixture was prepared to prepare a composition, and the inhibitory effect of interleukin-1 β on the secretion of prostaglandin 2 by cerebral vascular endothelial cells was observed by the method of Example 3. The results are shown in Table 4. The half-inhibitory concentration (IC50) of secreted and released PGE2 was 66.49 μg/ml. Table 4. Effect of different proportions of the composition of the present invention on release of PGE2 by IL-1β-stimulated cerebrovascular endothelial cells-2 Group dose Extracellular fluid PGE2 contains
(Pg/ml) 对照组 —— 3.780士 0.933 单纯 IL- 1 β 激惹组 30ng/ml 7.736士 1.457 (Pg/ml) Control group - 3.780 ± 0.933 Simple IL-1β challenge group 30ng/ml 7.736士 1.457
IL- 1 β 激惹 +苯丙烯类组合物 30ng/ml, 12.5 μ g/ml 7.013 + 1.036IL-1β irritation + phenyl propylene composition 30ng/ml, 12.5 μg/ml 7.013 + 1.036
IL- 1 β 激惹 +苯丙烯类组合物 30ng/ml, 25.0 μ g/ml 6.323 + 0.915IL-1β irritant + phenyl propylene composition 30ng/ml, 25.0 μg/ml 6.323 + 0.915
IL- 1 β 激惹 +苯丙烯类组合物 30ng/ml, 50.0 μ g/ml 6.072 + 0.904IL-1β irritation + phenyl propylene composition 30ng/ml, 50.0 μg/ml 6.072 + 0.904
IL- 1 β 激惹 +苯丙烯类组合物 30ng/ml, 100 μ g/ml 5.401士 0.811IL-1β irritation + phenyl propylene composition 30ng/ml, 100 μg/ml 5.401 ± 0.811
IL- 1 β 激惹 +苯丙烯类组合物 30ng/ml, 200 μ g/ml 5.137 + 0.939 苯丙烯类组合物 (1： 0.01： 0.05： 10.0： 4.0： 0.05 ) 的 IC50 66.49 μ g/ml 应用扩展的等效线法， 计算比较了 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂 皮酸、 桂皮醛、 桂皮醇、 桂皮酸及其组合物的 IC50的相互关系， Q值为 0.999， 表明联 合应用后的组合物抑制 PGE2释放的效应， 是 6个成分间的协同作用的结果， 但已接近 相加的作用。 实施例 5 按 1： 0.10： 0.15： 20.0： 8.0： 0.10 重量份配比的组合物 IL-1β irritant + styrene composition 30 ng/ml, 200 μg/ml 5.137 + 0.939 IC50 66.49 μg/ml of phenylpropene composition (1: 0.01: 0.05: 10.0: 4.0: 0.05) The extended equivalent line method was applied to calculate 2-methoxycinnamic aldehyde and 2-methoxy cinnabar. The IC50 relationship of alcohol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol, cinnamic acid and their compositions, Q value of 0.999, indicating that the combined application inhibits the release of PGE2, which is 6 components. The result of synergy, but is close to the additive effect. Example 5 Composition according to 1:0.10: 0.15: 20.0: 8.0: 0.10 parts by weight of the composition
将 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮醛、 桂皮醇、 桂皮酸 等 6种化合物依次按相互的最大比例范围 (1： 0.10： 0.15： 20.0： 8.0： 0.10 ) 进行混合， 制成组合物，按实施例 3的方法，观察它对白介素 -1 β 刺激脑血管内皮细胞分泌前列腺 素 Ε2 的抑制作用。 结果如表 5 所示， 其分泌释放 PGE2 的半数抑制浓度 (IC50)为 52.62 μ g/ml 。 表 5. 不同比例的苯丙烯类组合物对 IL-Ι β 刺激的脑血管内皮细胞释放 PGE2的影响 -3 组别 剂 细胞外液 PGE2含量 (pg/ml) 对照组 3.492士 0.832 单纯 IL-1 0 激惹组 30ng/ml 7.578士 1.318 IL-1 0 激惹 +苯丙烯类组合物 30ng/ml, 6.665士 0.099  6 kinds of compounds such as 2-methoxycinnamaldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol and cinnamic acid are sequentially in the maximum ratio range of each other (1: 0.10: 0.15) : 20.0: 8.0: 0.10) The mixture was prepared to prepare a composition, and the inhibitory effect of interleukin-1β on the secretion of prostaglandin 2 by cerebral vascular endothelial cells was observed by the method of Example 3. The results are shown in Table 5, and the half-inhibitory concentration (IC50) of the secreted PGE2 released was 52.62 μ g/ml. Table 5. Effect of different proportions of phenylpropene composition on release of PGE2 from IL-Ιβ-stimulated cerebrovascular endothelial cells-3 PGE2 content in extracellular fluid of group (pg/ml) Control group 3.492±0.832 Simple IL-1 0 irritating group 30ng/ml 7.578±1.318 IL-1 0 irritating + styrene composition 30ng/ml, 6.665士0.099
12.5 μ g/ml  12.5 μ g/ml
IL-1 0 激惹 +苯丙烯类组合物 30ng/ml, 5.989士 0.908  IL-1 0 irritant + phenyl propylene composition 30ng/ml, 5.989士 0.908
25.0 g/ml  25.0 g/ml
IL-1 0 激惹 +苯丙烯类组合物 30ng/ml, 5.535士 0.577  IL-1 0 irritant + phenyl propylene composition 30ng/ml, 5.535 士 0.577
50.0 μ g/ml  50.0 μg/ml
IL-1 0 激惹 +苯丙烯类组合物 30ng/ml, 5.125士 0.603  IL-1 0 irritant + phenyl propylene composition 30ng/ml, 5.125 士 0.603
100 g/ml  100 g/ml
IL-1 0 激惹 +苯丙烯类组合物 30ng/ml, 4.537士 0.889  IL-1 0 irritant + phenyl propylene composition 30ng/ml, 4.537士 0.889
200 μ g/ml  200 μ g/ml
苯丙烯类组合物 (1： 0.10： 0.15： 20.0： 8.0： 0.10 ) 的 IC50 52.62 μ g/ml 应用扩展的等效线法， 计算比较了 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂 皮酸、 桂皮醛、 桂皮醇、 桂皮酸及其组合物的 IC50的相互关系， Q值为 0.997， 表明联 合应用后的组合物抑制 PGE2释放的效应， 是 6个成分间的协同作用的结果， 但也已接 近相加的作用。  The IC50 of the phenylpropene composition (1: 0.10: 0.15: 20.0: 8.0: 0.10) was 52.62 μg/ml. The extended equivalent line method was used to calculate the comparison of 2-methoxycinnamic aldehyde and 2-methoxycin The IC50 relationship of alcohol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol, cinnamic acid and their compositions, Q value of 0.997, indicating that the combined application inhibits the release of PGE2, which is 6 components. The result of synergy between the two, but it is also close to the additive effect.
经上述实施例 1-5结果表明， 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮醛、 桂皮醇、 桂皮酸等 6种化合物按一定比例联合应用， 具有协同效果， 而其相互 配伍比值应在 1 : 0.01-0.10 ： 0.05-0.15 ： 10.0-20.0 ： 4.0-8.0 ： 0.05-0.10之内。  According to the results of the above Examples 1-5, 6 kinds of compounds such as 2-methoxycinnamaldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol and cinnamic acid are combined in a certain ratio. Application, with synergistic effect, and their mutual compatibility ratio should be within 1: 0.01-0.10: 0.05-0.15: 10.0-20.0: 4.0-8.0: 0.05-0.10.
实施例 6 本发明组合物口伺给药对致热动物体温曲线的影响 取雄性 SD大鼠， 体重 160g-180g， 适应实验室条件 2天后， 测肛温， 上下午各一 次， 次晨再次测肛温， 取肛温均值， 剔去异常肛温大鼠， 随机分为正常和致热二组， 致 热组动物每只给予致热剂 20 %的鲜酵母混悬液， 皮下注射 2ml/100g体重， 致热后 3.5h 再测肛温， 剔除不发热的， 随机分为造模对照组 (12只动物)和造模给药组 (10只动物)。 造模给药组口伺一次给予本发明组合物， 其中该组合物各单一化合物的组成的重量比： 2-甲氧基桂皮醛： 桂皮醛： 2-甲氧基桂皮醇： 桂皮醇： 2-甲氧基桂皮酸： 桂皮酸为 1.00: 15.40： 0.04： 6.30： 0.09： 0.07)， 剂量为 23mg/kg; 造模对照组口伺给予等体积的蒸馏 水。 Example 6 Effect of Oral Administration of the Composition of the Invention on Body Temperature Curve of Pyrogens Male Sprague-Dawley rats weighing 160g-180g, adapted to laboratory conditions for 2 days, measured rectal temperature, once in the afternoon and afternoon, again measured the rectal temperature in the morning, took the average temperature of the anus, and removed the abnormal anal temperature rats, randomly divided into In the normal and pyrogenic groups, the animals in the pyrogen group were given a fresh yeast suspension of 20% of the pyrogen, subcutaneously injected with 2 ml/100 g of body weight, and the rectal temperature was measured 3.5 h after the heat, and the non-fever was removed. For the modeling control group (12 animals) and the model administration group (10 animals). The molding administration group orally administered the composition of the present invention, wherein the composition has a weight ratio of the composition of each single compound: 2-methoxycinnamic aldehyde: cinnamaldehyde: 2-methoxycinnacol: cinnamyl alcohol: 2 -Methoxy cinnamic acid: cinnamic acid was 1.00: 15.40: 0.04: 6.30: 0.09: 0.07), and the dose was 23 mg/kg ; the model control group was given an equal volume of distilled water.
另设正常组 (8 只动物)， 也分别给予等量蒸馏水。 以后， 每小时测肛温一次。 计算 测定点与致热后 3.5小时 (给药时)的体温差值， 进行统计学 (t检验)， 再减去正常组的体 温波动差值， 参见图 1， 实验结果见表 6。 表 6. 本发明组合物 (23mg/kg)口伺对致热大鼠体温的影响  A normal group (8 animals) was also set, and an equal amount of distilled water was also given. In the future, the anus temperature is measured every hour. Calculate the difference in body temperature between the measurement point and 3.5 hours after administration (during administration), perform statistical (t test), and subtract the difference in body temperature fluctuation of the normal group. See Figure 1, and the experimental results are shown in Table 6. Table 6. Effect of the composition of the present invention (23 mg/kg) on the body temperature of a pyrolyzed rat
组 别 动 基础体温 致热 3.5小时 药后的体温变化差值 （°C)  Group basal body temperature, heat, 3.5 hours, difference in body temperature after drug (°C)
物 (°C) 体温 (°c) 1 h 2 h 正常对照 37.40±0.15 37.61 ±0.20 0.36±0.41 0.46±0.31 0.70 ±0.23 造模对照 10 37.46 ±0.25 39.10±0.32 0.70±0.34 0.83 ±0.34 0.98 ±0.41  (°C) Body temperature (°c) 1 h 2 h Normal control 37.40±0.15 37.61 ±0.20 0.36±0.41 0.46±0.31 0.70 ±0.23 Model control 10 37.46 ±0.25 39.10±0.32 0.70±0.34 0.83 ±0.34 0.98 ±0.41
10 37.62±0.17 39.31 ±0.25 0.40 ±0.29 0.53 ±0.39* 0.42 ±0.34* 注： 差值是指该时间点的体温与给药前 (即 3.5小时的检测值)的增加值 从表 6和图 1可见， 23mg/kg的本发明组合物， 在酵母致大鼠发热过程中的 3.5小 时， 一次口伺给药， 1小时后即能阻断其继续升温， 3小时后阻断升温作用己非常显著。 表明口伺本发明组合物能抑制发热动物的体温升高。 实施例 7 本发明组合物静脉给药对致热动物体温曲线的影响  10 37.62±0.17 39.31 ±0.25 0.40 ±0.29 0.53 ±0.39* 0.42 ±0.34* Note: The difference is the increase in body temperature at the time point and the pre-dose (ie 3.5-hour test value) from Table 6 and Figure 1. It can be seen that the composition of the present invention at 23 mg/kg is administered once in a period of 3.5 hours during the fever of the rat-induced rat, and can be stopped after 1 hour, and the temperature rise is markedly significant after 3 hours. . It is indicated that the composition of the present invention can inhibit the increase in body temperature of a febrile animal. Example 7 Effect of Intravenous Administration of the Composition of the Invention on Body Temperature Curve of a Thermogenic Animal
取 Wistar雄性大鼠， 体重 200克左右， 适应实验室条件 2天后， 测肛温， 上下午各 一次， 次晨再次测肛温， 取肛温均值， 剔去异常肛温大鼠， 随机分为正常和致热二组， 致热组动物每只给予致热剂 15 %的鲜酵母混悬液， 皮下注射 2ml/100g体重， 致热后 4h 再测肛温， 剔除不发热的， 随机分为造模对照组和造模给药组。造模给药组又随机分为 大、 中和小剂量给药组， 静脉注射本发明组合物， 该市售的组合物各单一化合物组成的 重量比： 2-甲氧基桂皮醛： 桂皮醛： 2-甲氧基桂皮醇： 桂皮醇： 2-甲氧基桂皮酸： 桂皮 酸为 1.00： 15.40： 0.04： 6.30： 0.09： 0.07。 各个组分分别采用市售的产品。 剂量分别 为 22.9mg/kg、 11.5mg/kg和 5.7mg/kg; 造模对照和正常对照组相应分别静脉给予等体 积的助溶剂生理盐水 (0.0025 %吐温 80的生理盐水)或生理盐水。 以后， 每半小时或 1小 时测定各动物的肛温。 计算测定点与致热后 4小时 (给药时)的体温差值， 进行统计学处 理 （t检验)， 再减去正常组的体温波动差值。 Take Wistar male rats, weighing about 200 grams, after adjusting to laboratory conditions for 2 days, measure the rectal temperature, once in the afternoon and the next morning, measure the rectal temperature again in the morning, take the average temperature of the anus, and remove the abnormal anal temperature rats, randomly divided into In the normal and pyrogenic groups, the pyrogen group animals were given 15% fresh yeast suspension for the heat agent, subcutaneously injected with 2ml/100g body weight, and the anus temperature was measured 4h after the heat was taken, and the non-fever was removed. Molding control group and model administration group. The model administration group was further divided into large, medium and small dose groups, and the composition of the present invention was intravenously administered. The weight ratio of each single compound of the commercially available composition: 2-methoxycinnamic aldehyde: cinnamaldehyde : 2-methoxycinnacol: Cinnamon: 2-methoxycinnamic acid: cinnamic acid 1.00: 15.40: 0.04: 6.30: 0.09: 0.07. Commercially available products were used for each component. The doses were 22.9 mg/kg, 11.5 mg/kg, and 5.7 mg/kg, respectively; the model control and the normal control group were intravenously given an equal volume of the co-solvent physiological saline (0.0025% Tween 80 physiological saline) or physiological saline, respectively. Thereafter, the anal temperature of each animal was measured every half hour or one hour. Calculate the difference in body temperature between the measurement point and 4 hours after the heat (during administration), and perform statistical analysis. (t test), then subtract the difference in body temperature fluctuations of the normal group.
结果如表 7和图 2所示， 以 15 %酵母混悬液 2ml/100g体重的剂量皮下注射， 4小 时后能引起大鼠体温升高， 平均约升高 0.96°C， 于此时静脉一次给予 22.9mg/kg〜 5.7mg/kg体重剂量的桂枝汤苯丙烯类化合物组， 药后 1.5小时开始， 酵母的升温作用受 到抑制， 到药后 2〜3小时， 有显著抑制作用， 其中以所试的高剂量 (22.9mg/kg剂量组) 尤为明显。  The results are shown in Table 7 and Figure 2. Subcutaneous injection at a dose of 2 ml/100 g body weight of 15% yeast suspension can cause an increase in body temperature in rats after 4 hours, with an average increase of 0.96 ° C. The phenyl propylene compound group of Guizhi Tang was administered at a dose of 22.9 mg/kg to 5.7 mg/kg body weight. The heating effect of the yeast was inhibited at 1.5 hours after the drug was administered, and the inhibitory effect was significantly inhibited 2 to 3 hours after the drug. The high doses tested (22.9 mg/kg dose group) are particularly evident.
鉴于正常对照组大鼠在实验观测期间也有体温波动， 以此作为 "实验本底" ， 实验 各组扣除了 "实验本底"所作的图 2亦显示了桂枝汤苯丙烯类化合物组所试各剂量组 抑制发热的作用。 本发明组合物组静脉给药对致热大鼠体温的影响  In view of the fact that the rats in the normal control group also had body temperature fluctuation during the experimental observation, as the "experimental background", the experimental group deducted the "experimental background". Figure 2 also shows the test of the phenyl propylene compound group of Guizhi Decoction. Each dose group inhibited the effects of fever. Effect of intravenous administration of the composition group of the present invention on body temperature of a rat with heat
组 别 动物 基础体温 致热后 4小时 药后的体温变化差值 (°C)  Group animal basal body temperature 4 hours after heating, the difference in body temperature after the drug (°C)
数 (°C) 体温 (°c) 1.5小时 2.0小时 3.0小时 正常对照 8 38.01 ±0.25 38.29 + 0.26 0.30 ±0.40 0.18 ±0.21 0.26 ±0.29 造模对照 11 38.21 ±0.20 39.13 ±0.29 0.80 ±0.27 0.70 ±0.22 0.80±0.31 Number (°C) Body temperature (°c) 1.5 hours 2.0 hours 3.0 hours Normal control 8 38.01 ±0.25 38.29 + 0.26 0.30 ±0.40 0.18 ±0.21 0.26 ±0.29 Model control 11 38.21 ±0.20 39.13 ±0.29 0.80 ±0.27 0.70 ±0.22 0.80±0.31
22.9mg/kg 7 38.24+0.30 39.29 ±0.29 0.61 ±0.23 0.33 ±0.34** 0.16 + 0.44**22.9mg/kg 7 38.24+0.30 39.29 ±0.29 0.61 ±0.23 0.33 ±0.34** 0.16 + 0.44**
11.5mg/kg 9 38.34±0.32 39.11 ±0.34 0.56±0.49 0.44 ±0.36 0.44 ±0.21*11.5mg/kg 9 38.34±0.32 39.11 ±0.34 0.56±0.49 0.44 ±0.36 0.44 ±0.21*
5.7mg/kg 8 38.18 ±0.29 39.16±0.31 0.54±0.29 0.41 ±0.32 0.45 ±0.42* 注： 药后的体温变化差值， 是指各组体温检测点与给药前 (即酵母致热后 4小时)的 体温差值。 *,与造模对照组相比， p<0.05; **,与造模对照组相比， p<001 实施例 8 桂枝汤苯丙烯类化合物不同比例组合口伺给药对发热动物体温影响的比较 取雄性 Wistar大鼠， 体重 160g〜180g， 适应实验室条件 2天后， 测肛温， 上下午 各一次， 次晨再次测肛温， 取肛温均值， 剔去异常肛温大鼠， 每只给予致热剂 20 %的 鲜酵母混悬液， 2ml/100g体重皮下注射。 致热后 3.5h再测肛温， 剔除不发热的， 随机 分为 6组： 一组为造模对照组， 另 6组为造模给药组 (各组动物数见表 9)， 分别一次口 伺给予由不同比例组成的苯丙烯类系列化合物组 (各组的组成比例见下表 8); 造模对照 组口伺给予等体积的蒸馏水。 测定给药后 2小时和 4小时的肛温， 计算与给药前 (致热 3.5小时)的体温差值， 进行统计学处理 （t检验)。 5.7mg/kg 8 38.18 ±0.29 39.16±0.31 0.54±0.29 0.41 ±0.32 0.45 ±0.42* Note: The difference in body temperature after drug administration refers to the temperature detection point of each group and before administration (ie 4 hours after the yeast is heated) The difference in body temperature. *, compared with the model control group, p < 0.05; **, compared with the model control group, p < 001 Example 8 Guizhi Tang phenyl propylene compound in different proportions combined with oral administration on the body temperature of febrile animals Male Wistar rats were weighed and weighed 160g~180g. After adjusting to laboratory conditions for 2 days, the anus temperature was measured, once in the afternoon and the next morning. The anus temperature was measured again in the morning, and the average temperature of the anus was taken. Only 20% of the fresh yeast suspension of the pyrogen was administered, and 2 ml/100 g of body weight was injected subcutaneously. The anus temperature was measured 3.5 hours after the fever, and the non-fever was excluded. They were randomly divided into 6 groups: one group was the model control group, and the other 6 groups were the model administration group (see Table 9 for the number of animals in each group). The phenylpropene series of compounds consisting of different proportions were administered orally (see Table 8 for the composition ratio of each group); the model control group was given an equal volume of distilled water. The rectal temperature was measured at 2 hours and 4 hours after administration, and the difference in body temperature before administration (3.5 hours of heating) was calculated and statistically processed (t test).
参见表 9和图 3， 图 4， 结果表明， 不同组合比例的桂枝汤苯丙烯类化合物组 1次 口伺给酵母致大鼠， 均能不同程度地抑制其诱致的体温升高， 作用似以给药三组为中心 由强变弱， 其中第三和第四给药组在药后 2小时或 4小时， 与造模对照相比， p值小于 0.05， 有显著差异。  Referring to Table 9 and Figure 3, Figure 4, the results show that the phenylpropene compound group of different combinations of Guizhi Decoction can inhibit the induced body temperature increase in different degrees. The strength was weakened by the three groups of administration, and the third and fourth administration groups had a p value of less than 0.05 compared with the model control at 2 hours or 4 hours after the medicine, and there was a significant difference.
结果提示， 解热作用与其组合的比例有关。 表 8. 本发明组合物的组成比例 (以邻甲氧基桂皮醛为基准)及其给药剂量  The results suggest that the antipyretic effect is related to the proportion of the combination. Table 8. Composition ratio of the composition of the present invention (based on o-methoxycinnamic aldehyde) and its dosage
化合物名称 给药 1组 给药 2组 给药 3组 给药 4组 给药 5组 Compound name Administration 1 group Administration 2 groups Administration 3 groups Administration 4 groups Administration 5 groups
2-甲氧基桂皮醛 1.0 1.0 1.0 1.0 1.0 τΐ55555ίίίίί、造给给给给给 * * * * * 桂皮醛 25.0 20.0 15.4 10.0 2.0 模组药药药药药 2-甲氧基桂皮醇 0.001 0.10 0.04 0.01 0.5 对别 24351 桂皮醇 12.0 8.0 6.30 4.0 1.02-methoxycinnamic aldehyde 1.0 1.0 1.0 1.0 1.0 Ϊ́ΐ55555 4 造 * * * * * * * Cinnamaldehyde 25.0 20.0 15.4 10.0 2.0 Module medicine medicine 2-methoxycinnacol 0.001 0.10 0.04 0.01 0.5 Pair 24351 Cinnamyl alcohol 12.0 8.0 6.30 4.0 1.0
2-甲召氧基桂皮酸 0.005 0.15 0.09 0.05 0.75 桂皮酸 0.0045 0.10 0.07 0.05 0.50 给药剂量 (mg/kg) 45.82 45.82 45.82 45.33 46.00 说明： 表中数字是指各组中每个化合物用量的比值， 如在 1组中， 若用 2-甲氧基桂 皮醛 lg， 桂皮醛则用 25g， 2-甲氧基桂皮醇 O.OOlg, 以此类推， 按此 6个单体混合成的 系列化合组为第一组； 该组口伺给予致热大鼠的总剂量为 45.82mg/kg体重。 余同。 表 9. 本发明组合物给药后 2小时和 4小时对致热大鼠体温的影响 2-A call oxycinnamic acid 0.005 0.15 0.09 0.05 0.75 cinnamic acid 0.0045 0.10 0.07 0.05 0.50 Dosage (mg/kg) 45.82 45.82 45.82 45.33 46.00 Description: The figures in the table refer to the ratio of the amount of each compound in each group. For example, in group 1, if 2-methoxycinsanaldehyde lg, cinnamaldehyde is used, 25g, 2-methoxycinnacol O.OOlg, and so on, according to the series of 6 monomers mixed together The first group; the total dose of this group of oral administration rats was 45.82 mg / kg body weight. Yu Tong. Table 9. Effect of 2 hours and 4 hours after administration of the composition of the present invention on body temperature of a pyrolyzed rat
动物 基础肛温 给药前肛温 给药后 2小时体 给药后 4小时体 数 (。C) (。C) 温变化值 (°c) 温变化值 (°c) Animal Basic anal temperature Pre-administration anal temperature 2 hours after administration Body volume 4 hours after administration (.C) (C) Temperature change value (°c) Temperature change value (°c)
11 37.81+0.20 39·25±0·37 0.90+0.35 1.00+0.3611 37.81+0.20 39·25±0·37 0.90+0.35 1.00+0.36
10 37.76+0.29 39.21+0.28 0.62+0.33 0.78+0.3510 37.76+0.29 39.21+0.28 0.62+0.33 0.78+0.35
9 37·68±0·20 39.22+0.29 0.58+0.45 0.74+0.449 37·68±0·20 39.22+0.29 0.58+0.45 0.74+0.44
9 37.92+0.31 39.31+0.35 0·54±0·27* 0.70+0.439 37.92+0.31 39.31+0.35 0·54±0·27* 0.70+0.43
9 37.97+0.19 39.36+0.33 0.74+0.62 0.62+0.46*9 37.97+0.19 39.36+0.33 0.74+0.62 0.62+0.46*
9 37.93+0.09 39·21±0·44 0.80+0.37 0·71±0·43 实施例 9 9 37.93+0.09 39·21±0·44 0.80+0.37 0·71±0·43 Example 9
取 2-甲氧基桂皮醛 100克、 2-甲氧基桂皮醇 5(1〜10)克、 2-甲氧基桂皮酸 9(5〜15) 克、 桂皮醛 1525(1000〜2000)克、 桂皮醇 627(400〜800)克、 桂皮酸 6.8(5〜10)克， 在胶 体磨中研磨均匀， 得原料药， 加入聚乙二醇 400适量， 采用本领域技术人员熟知的方法 制成药物软胶囊 9090粒， 每粒胶囊含 6种苯丙烯类的组合物 250毫克， 供口服使用。 该制剂可作为脑血管内皮细胞分泌释放 PGE2的抑制剂， 也可用于前列腺素 Ε2局部过 度分泌诱致的发热、 疼痛、 中风、 缺血性脑损伤、 蛛网膜下腔出血、 高血压、 脑血管硬 化和先天性痴呆等疾患或解热。 实施例 10  Take 100 g of 2-methoxycinnamic aldehyde, 5 (1~10) g of 2-methoxycinnacol, 9 (5~15) g of 2-methoxycinnamic acid, 1525 (1000~2000) g of cinnamaldehyde Cinnamyl 627 (400~800) g, cinnamic acid 6.8 (5~10) g, uniformly ground in a colloid mill to obtain a drug substance, added with an appropriate amount of polyethylene glycol 400, and prepared by a method well known to those skilled in the art. The drug soft capsules are 9090 capsules, and each capsule contains 250 kinds of benzene propylene composition 250 mg for oral use. The preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin Ε2. And diseases such as congenital dementia or antipyretic. Example 10
按照实施例 9 的方法制备本发明所说的药物，不同的是取 2-甲氧基桂皮醛 100克、 2-甲氧基桂皮醇 1克、 2-甲氧基桂皮酸 5克、 桂皮醛 1000克、 桂皮醇 800克、 桂皮酸 5 克，加入 3〜6倍的碳酸钙、磷酸钙或 β -环糊精等，制粒，压片，包衣，制成片剂 18180 片， 每片含 6种苯丙烯类的组合物 125毫克， 供口服使用。该制剂可作为脑血管内皮细 胞分泌释放 PGE2的抑制剂， 也可用于前列腺素 Ε2局部过度分泌诱致的发热、 疼痛、 中风、 缺血性脑损伤、 蛛网膜下腔出血、 高血压、 脑血管硬化和先天性痴呆等疾患或解 热。 实施例 11 按照实施例 9 的方法制备本发明所说的药物，不同的是取 2-甲氧基桂皮醛 100克、 2-甲氧基桂皮醇 10克、 2-甲氧基桂皮酸 15克、 桂皮醛 2000克、 桂皮醇 400克、 桂皮 酸 10克， 加入聚氧乙烯氢化蓖麻油， 制成注射剂 9090瓶， 每瓶含 6种苯丙烯类的组合 物 125毫克， 供注射使用。 该制剂可作为脑血管内皮细胞分泌释放 PGE2的抑制剂， 也 可用于前列腺素 E2局部过度分泌诱致的发热、 疼痛、 中风、 缺血性脑损伤、 蛛网膜下 腔出血、 高血压、 脑血管硬化和先天性痴呆等疾患解热。 实施例 12 The drug of the present invention was prepared according to the method of Example 9, except that 100 g of 2-methoxycinnamic aldehyde, 1 g of 2-methoxycinnacol, 5 g of 2-methoxycinnamic acid, and cinnamaldehyde were taken. 1000 g, 800 g of cinnamyl alcohol, 5 g of cinnamic acid, 3 to 6 times of calcium carbonate, calcium phosphate or β-cyclodextrin, granulated, tableted, coated, made into tablets 18180 pieces, each piece A composition containing six phenyl propylene species, 125 mg, for oral use. The preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin Ε2. And diseases such as congenital dementia or antipyretic. Example 11 The drug of the present invention was prepared according to the method of Example 9, except that 100 g of 2-methoxycinnamic aldehyde, 10 g of 2-methoxycinnacol, 15 g of 2-methoxycinnamic acid, and cinnamaldehyde were taken. 2000 g, 400 g of cinnamyl alcohol, 10 g of cinnamic acid, and polyoxyethylene hydrogenated castor oil were added to make 9090 bottles of injection, and each bottle contained 125 mg of styrene-based composition for injection. The preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin E2. Detoxification with diseases such as congenital dementia. Example 12
采用本领域技术人员熟知的方法， 将市售的 2-甲氧基桂皮醛 10克 ： 2-甲氧基桂 皮醇 0.5克： 2-甲氧基桂皮酸 10克： 桂皮醛 155克： 桂皮醇 65克： 桂皮酸为 1克混 合。 加入 3〜6倍的碳酸钙、 磷酸钙或 β -环糊精等， 制粒， 装入硬胶囊， 每粒胶囊含 6 种苯丙烯类的组合物 250 毫克， 供口服使用。 该制剂可作为脑血管内皮细胞分泌释放 PGE2的抑制剂， 也可用于前列腺素 Ε2局部过度分泌诱致的发热、 疼痛、 中风、 缺血 性脑损伤、 蛛网膜下腔出血、 高血压、 脑血管硬化和先天性痴呆等疾患或解热。 实施例 13  Commercially available 2-methoxycinnamic aldehyde 10 g: 2-methoxycinnamicol 0.5 g: 2-methoxycinnamic acid 10 g: Cinnamaldehyde 155 g: Cinnamyl alcohol using a method well known to those skilled in the art 65 g: 1 gram of cinnamic acid is mixed. 3 to 6 times of calcium carbonate, calcium phosphate or β-cyclodextrin is added, granulated, and filled into hard capsules, each capsule containing 60 phenacene-based compositions of 250 mg for oral use. The preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin Ε2. And diseases such as congenital dementia or antipyretic. Example 13
采用本领域技术人员熟知的方法， 取市售的 2-甲氧基桂皮醛 15克 ： 2-甲氧基桂皮 醇 1克： 2-甲氧基桂皮酸 0.5克： 桂皮醛 155克： 桂皮醇 50克： 桂皮酸为 0.5克。 融 入适量栓剂， 如基质 S-40, 制成栓剂， 每粒含 6种苯丙烯类的组合物 250毫克， 供直 肠腔内使用。 该制剂可作为脑血管内皮细胞分泌释放 PGE2的抑制剂， 也可用于前列腺 素 Ε2局部过度分泌诱致的发热、 疼痛、 中风、 缺血性脑损伤、 蛛网膜下腔出血、 高血 压、 脑血管硬化和先天性痴呆等疾患或解热。 实施例 14  Commercially available 2-methoxycinnamic aldehyde 15 g: 2-methoxycinnacol 1 g: 2-methoxycinnamic acid 0.5 g: Cinnamaldehyde 155 g: Cinnabarol using a method well known to those skilled in the art 50 g: cinnamic acid is 0.5 g. Inject a suitable amount of suppository, such as matrix S-40, into a suppository, containing 250 mg of each of the six phenylpropene compositions for intrarectal use. The preparation can be used as an inhibitor of PGE2 secreted by cerebral vascular endothelial cells, and can also be used for fever, pain, stroke, ischemic brain injury, subarachnoid hemorrhage, hypertension, cerebral arteriosclerosis induced by local excessive secretion of prostaglandin Ε2. And diseases such as congenital dementia or antipyretic. Example 14
采用本领域技术人员熟知的方法， 将经实施例 9得到的 2-甲氧基桂皮醛 500克 ： 2-甲氧基桂皮醇 50克： 2-甲氧基桂皮酸 100: 桂皮醛 15500克： 桂皮醇 6500克： 桂 皮酸为 100克进行混合。加入 3〜6倍的碳酸钙、 磷酸钙或 β -环糊精等， 制粒， 装入硬 胶囊， 每粒胶囊含 6种苯丙烯类的组合物 250毫克， 供口服使用。 实施例 15  500 g of 2-methoxycinnamic aldehyde obtained in Example 9 was obtained by a method well known to those skilled in the art: 2-methoxycinnacol 50 g: 2-methoxycinnamic acid 100: Cinnamaldehyde 15500 g: Cinnamon 6500 g: Cinnamic acid is mixed for 100 g. 3 to 6 times of calcium carbonate, calcium phosphate or β-cyclodextrin is added, granulated, and filled into hard capsules, each of which contains 250 mg of a composition of 6 kinds of phenyl propylene for oral use. Example 15
采用本领域技术人员熟知的方法， 取市售的 2-甲氧基桂皮醛 100克、 2-甲氧基桂皮 醇 10克、 2-甲氧基桂皮酸 15克、 桂皮醛 2000克、 桂皮醇 400克、 桂皮酸 5克， 在胶 体磨中研磨， 混合均匀， 得原料药。 加入聚乙二醇 400适量， 采用本领域技术人员熟知 的方法制成药物软胶囊， 每粒胶囊含本发明所述的组合物 250毫克。  Commercially available 100 g of 2-methoxycinnamic aldehyde, 10 g of 2-methoxycinnacol, 15 g of 2-methoxycinnamic acid, 2000 g of cinnamaldehyde, and cinnamyl alcohol were prepared by methods well known to those skilled in the art. 400 g, 5 g of cinnamic acid, ground in a colloid mill, and uniformly mixed to obtain a drug substance. A suitable amount of polyethylene glycol 400 is added, and a soft capsule of the drug is prepared by a method well known to those skilled in the art, each capsule containing 250 mg of the composition of the present invention.

Claims

权利要求书: Claims:
1、 一种药物组合物， 其特征在于所述的药物组合物由以下组分组成： 0.5〜1.5 重量份 2-甲氧基桂皮醛、 0.01〜0.1重量份 2-甲氧基桂皮醇、 0.05〜0.15重量 份 2-甲氧基桂皮酸、 10〜20重量份桂皮醛、 4〜8重量份桂皮醇、 0.05〜0.1 重量份桂皮酸。 A pharmaceutical composition characterized in that the pharmaceutical composition is composed of the following components: 0.5 to 1.5 parts by weight of 2-methoxycinnamaldehyde, 0.01 to 0.1 part by weight of 2-methoxycinnacol, 0.05 ~ 0.15 parts by weight of 2-methoxycinnamic acid, 10 to 20 parts by weight of cinnamaldehyde, 4 to 8 parts by weight of cinnamyl alcohol, and 0.05 to 0.1 parts by weight of cinnamic acid.
2、 根据权利要求 1所述的药物组合物， 其特征在于 1重量份 2-甲氧基桂皮醛、 0.01〜0.1重量份 2-甲氧基桂皮醇、 0.05〜0.15重量份 2-甲氧基桂皮酸、 10〜 20重量份桂皮醛、 4〜8重量份桂皮醇、 0.05〜0.1重量份桂皮酸。  The pharmaceutical composition according to Claim 1, which is characterized in that it is 1 part by weight of 2-methoxycinnamaldehyde, 0.01 to 0.1 part by weight of 2-methoxycinnacol, and 0.05 to 0.15 part by weight of 2-methoxy group. Cassia acid, 10 to 20 parts by weight of cinnamaldehyde, 4 to 8 parts by weight of cinnamyl alcohol, 0.05 to 0.1 part by weight of cinnamic acid.
3、 根据权利要求 1所述的药物组合物， 其特征在于 1重量份 2-甲氧基桂皮醛、 0.04-0.01重量份 2-甲氧基桂皮醇、 0.05-0.09重量份 2-甲氧基桂皮酸、 10〜 15.5重量份桂皮醛、 4〜6.5重量份桂皮醇、 0.05〜0.07重量份桂皮酸。  The pharmaceutical composition according to Claim 1, which is characterized in that it is 1 part by weight of 2-methoxycinnamaldehyde, 0.04-0.01 part by weight of 2-methoxycinnacol, and 0.05-0.09 part by weight of 2-methoxy group. Cassia acid, 10 to 15.5 parts by weight of cinnamaldehyde, 4 to 6.5 parts by weight of cinnamyl alcohol, 0.05 to 0.07 parts by weight of cinnamic acid.
4、 根据权利要求 1- 3 任何一项所述的药物组合物，其中进一步包括药学上可接 受的载体。  4. A pharmaceutical composition according to any one of claims 1 to 3 which further comprises a pharmaceutically acceptable carrier.
5、 如权利要求 1所述的药物组合物在制备用于抑制哺乳动物包括人脑血管内皮 细胞分泌前列腺素 E2的药物中的用途。 5. The pharmaceutical composition as claimed in claim 1 in the manufacture of a medicament for inhibiting the secretion of a mammal, including human brain microvascular endothelial cells prostaglandin E 2 in.
6、 如权利要求 1所述的药物组合物在制备用于解热药物中的用途。  6. Use of a pharmaceutical composition according to claim 1 for the preparation of a medicament for use in antipyretics.
7、 选自 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮醛、 桂皮醇 或者桂皮酸的化合物在制备用于抑制哺乳动物包括人脑血管内皮细胞分泌前 列腺素 E2的药物中的用途。 7. A compound selected from the group consisting of 2-methoxycinnamic aldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol or cinnamic acid for the preparation of a vascular endothelium for inhibiting mammalian, including human brain Use of a drug that secretes prostaglandin E 2 by a cell.
8、 选自 2-甲氧基桂皮醛、 2-甲氧基桂皮醇、 2-甲氧基桂皮酸、 桂皮醛、 桂皮醇 或者桂皮酸的化合物在制备解热药物中的用途。  8. Use of a compound selected from the group consisting of 2-methoxycinnamic aldehyde, 2-methoxycinnacol, 2-methoxycinnamic acid, cinnamaldehyde, cinnamyl alcohol or cinnamic acid for the preparation of an antipyretic drug.
9、 抑制哺乳动物包括人脑血管内皮细胞分泌前列腺素 E2的方法， 包括向患者使 用药物有效剂量的如权利要求 1所述的药物组合物。 9, The method of inhibiting a mammal, including human cerebrovascular endothelial cells prostaglandin E 2, comprising an effective dose of drug to a patient as claimed in claim 1 of the pharmaceutical composition.
10、 哺乳动物包括人发热的治疗方法， 其中包括向患者使用药物有效剂量的 如权利要求 1所述的药物组合物。  10. A method of treating a mammal, including a human fever, comprising administering to the patient a pharmaceutically effective amount of the pharmaceutical composition of claim 1.
PCT/CN2008/071910 2007-08-23 2008-08-07 Compounds and composition used for inhibitting pge2 released from cmec WO2009026817A1 (en)

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