CN110882239B - Analgesic use of terpene lactones - Google Patents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- 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]
Abstract
The invention belongs to the technical field of medical compounds, and particularly relates to analgesic application of terpene lactone compounds. The invention provides application of terpene lactone compounds shown in a formula I in preparing a medicament, wherein the medicament is used for preventing and/or treating pain or diseases or symptoms related to the pain. The compounds of formula I and pharmaceutical compositions thereof of the present invention are useful for the prevention and/or treatment of pain or pain-associated diseases or conditions. Furthermore, the compounds of formula I and pharmaceutical compositions thereof may also be used for the prevention and/or treatment of pain or diseases or conditions associated with pain while simultaneously spasmolytic, e.g. for analgesia while simultaneously spasmolytic.
Description
The present application claims the priority of the prior application with patent application number 201811051396.7 entitled "analgesic use of terpene lactones" filed on the national intellectual property office of china on the day 9, month 10 in 2018. The entire content of this prior application is incorporated by reference into this application.
Technical Field
The invention belongs to the technical field of medical compounds, and particularly relates to analgesic application of terpene lactone compounds.
Background
Pain is a complex physiological and psychological activity and is one of the most common symptoms in clinical practice. Some of the long-term intense pain has become an intolerable affliction.
Pain is a protective response to the body after being subjected to noxious stimuli, often accompanied by emotional activities such as fear, tension, uneasiness, etc. Pain is a symptom of some diseases and can cause pain. Besides the pain and emotional discomfort, the severe pain can also cause physiological dysfunction, cause insomnia and even induce shock to endanger life. Therefore, it is necessary to use analgesics appropriately in clinical practice to relieve severe pain and prevent shock, and it is of great importance in the treatment of diseases and wound care.
The analgesic mainly acts on the central nervous system, selectively inhibits and relieves various pains, relieves fear, tension and uneasiness caused by the pains, relieves pains without influencing other feelings such as perception and hearing, and can keep consciousness.
Therefore, there is a need to develop natural active ingredients and derivatives thereof for the prevention and/or treatment of pain or diseases or conditions associated with pain, e.g. for analgesia.
Disclosure of Invention
In order to improve the problems, the invention provides application of a terpene lactone compound shown in the following formula I in preparing a medicament, wherein the medicament is used for preventing and/or treating pain or diseases or symptoms related to the pain.
According to an embodiment of the invention, the medicament may be for analgesia.
According to an embodiment of the invention, the medicament is for spasmolysis and for the prevention and/or treatment of pain or a disease or condition associated with pain.
According to an embodiment of the invention, the medicament is for spasmolysis and analgesia.
Wherein each R is1Identical or different, independently of one another, from H, unsubstituted or optionally substituted by one or more RaSubstituted of the following groups: c1-40Alkyl radical, C1-40An alkoxy group;
each RaIdentical or different, independently of one another, from the group formed by-F, -Cl, -Br, -I, -OH, -SH, -CN, -O, -NO2、-NH2；
Each R2Same or different, independently from each other selected from H, C1-40Alkyl radical, C1-40An alkoxy group.
According to an embodiment of the invention, each R is1Identical or different, independently of one another, from H, unsubstituted or optionally substituted by one or more RaSubstituted of the following groups: c1-6Alkyl radical, C1-6An alkoxy group;
wherein each R isaIdentical or different, independently of one another, from the group consisting of-F, -Cl, -Br, -I, -OH, -SH, -CN, -O and-NO2、-NH2；
Each R2Same or different, independently from each other selected from H, C1-6Alkyl radical, C1-6An alkoxy group.
As a specific example, the terpene lactone compound may be selected from the compounds of formula II shown below:
According to the present invention, the drug may be prepared in liquid, solid or gaseous formulations, and may be administered orally or parenterally; oral formulations include, but are not limited to, tablets, pills, powders, liquids, or foods. Formulations for parenteral administration include, but are not limited to, injections, topical formulations or sprays; the topical formulation is for example selected from a cream or an ointment;
according to the invention, the compound of formula I is administered in an amount of 0.001mg/kg to 100 g/kg.
It is to be noted that the above-mentioned dosage is not a limiting range, and the dosage may vary depending on the severity of the symptoms to be alleviated and on factors such as the disease state, age, sex and body weight of the subject.
As examples, the compound of formula I may be administered in an amount of 0.001mg/kg to 10mg/kg, such as 0.001mg/kg, 0.002mg/kg, 0.003mg/kg, 0.0038mg/kg, 0.004mg/kg, 0.005mg/kg, 0.006mg/kg, 0.007mg/kg, 0.008mg/kg, 0.009mg/kg, 0.01mg/kg, 0.013mg/kg, 0.02mg/kg, 0.03mg/kg, 0.04mg/kg, 0.05mg/kg, 0.06mg/kg, 0.07mg/kg, 0.08mg/kg, 0.09mg/kg, 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.9 mg/kg, 1mg/kg, 1.2mg/kg, 1.3 mg/kg, 1mg/kg, 1.4 mg/kg, 1mg/kg, 1.1mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10 mg/kg.
As an example, the compound of formula I may be administered in a dose of 1.3g/kg to 100g/kg, such as 1.3g/kg, 1.5g/kg, 2.5g/kg, 5.8g/kg, 7.6g/kg, 10g/kg, 12g/kg, 20.5g/kg, 31g/kg, 40g/kg, 50g/kg, 70g/kg, 90g/kg, 100 g/kg.
The present invention also provides a pharmaceutical composition for preventing and/or treating pain or a disease or disorder associated with pain, for example, for analgesia, comprising the terpene lactone compounds.
The invention also provides a pharmaceutical composition for spasmolysis and for the prevention and/or treatment of pain or a disease or condition associated with pain, comprising said terpene lactone compound.
The invention also provides a pharmaceutical composition for spasmolysis and analgesia, which comprises the terpene lactone compound.
According to the present invention, the pharmaceutical composition may comprise one, two or more of pharmaceutical excipients such as carriers, excipients, e.g. solvents, propellants, solubilizers, solubilizing agents, co-solvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, permeation enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickening agents, encapsulation agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, and the like.
According to the present invention, the pharmaceutical composition may further comprise one, two or more of other compounds useful for the prevention and/or treatment of pain or a disease or condition associated with pain, e.g. useful for analgesia.
According to the invention, the pharmaceutical composition may also comprise one, two or more of other compounds for spasmolysis.
The present invention also provides a method for preventing and/or treating pain or a disease or disorder associated with pain, for example, for analgesia, comprising administering the above terpene lactone compounds or pharmaceutical compositions to a patient in need of treatment.
The present invention also provides a method for spasmolytic and prevention and/or treatment of pain or a disease or condition associated with pain, such as spasmolytic and analgesic, comprising administering to a patient in need thereof a terpene lactone compound as described above or a pharmaceutical composition thereof.
According to the present invention, diseases or conditions associated with pain include, but are not limited to, fear, stress, restlessness, physiological dysfunction, insomnia, shock, death.
The present invention is not particularly limited with respect to the method for preparing the compound of formula II. It will be appreciated by those skilled in the art that the compounds of formula II of the present invention may be obtained by preparative methods known in the art (e.g., extraction, isolation, etc.).
For example, the preparation method of the compound of formula II comprises the following steps:
1) extraction: extracting the crushed valerian medicinal material by using an organic solvent;
2) and (3) extraction: concentrating the extracting solution, extracting with a non-polar organic solvent, and collecting the extract;
3) separation: separating the extractive solution by column chromatography, performing gradient elution with eluent suitable for the column chromatography, checking the obtained eluate by thin layer chromatography, mixing eluates containing the bis-sesquiterpene lactone compound shown in formula I, concentrating under reduced pressure to obtain crude product, dissolving the crude product with nonpolar organic solvent, performing column chromatography for 1-3 times, eluting, concentrating the eluate, and drying to obtain pure product.
It will be appreciated that other compounds within the scope of formula I may be prepared by those skilled in the art starting from compounds of formula II according to known methods including, but not limited to: one, two or more of alkylation, etherification, reduction, oxidation, halogenation, cyanation, amination, hydrolysis, condensation and the like.
Advantageous effects
To date, the prior art has not found that the compounds of formula I can be used for analgesia. The inventors have surprisingly found that the compounds of formula I of the present invention and pharmaceutical compositions thereof can be used for the prevention and/or treatment of pain or diseases or conditions associated with pain. To this end, it will be appreciated that the compounds of formula I, which play a role in pain or pain-related diseases or conditions, may serve as active ingredients of analgesic drugs, which will provide further options for the development of analgesic drugs. Furthermore, the compounds of formula I and pharmaceutical compositions thereof may also be used for the prevention and/or treatment of pain or diseases or conditions associated with pain while spasmolytic, e.g. for analgesia while spasmolytic. In addition, the preparation method of the compound of the formula I is simple, the raw materials are cheap and easy to obtain, and the cost for preparing the analgesic drug from the compound of the formula I is reduced. In addition, the medicine prepared from the compound of the formula I has the characteristics of wide applicable population and safety.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination should fall within the scope of the present specification.
The term "C1-40Alkyl "is understood to preferably mean a linear or branched, saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms, preferably C1-10An alkyl group. "C1-10Alkyl "is understood to preferably mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a 2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a 2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group, or isomers thereof. In particular, the radicals have 1,2, 3, 4, 5, 6 carbon atoms ("C) 1-6Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1, 2 or 3 carbon atoms ("C)1-3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "C1-40Alkoxy "is to be understood as meaning" C1-40alkyl-O' where C1-40Alkyl groups have the definitions described above.
Detailed Description
The present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
EXAMPLE 1 preparation of Compound of formula II
1) Extraction: pulverizing 20kg of rhizoma et radix Valerianae, extracting with 50% ethanol (50% ethanol water solution) under reflux for 2 times (2 hr each time), with the dosage of 120kg of ethanol each time.
2) And (3) extraction: mixing the ethanol extractive solutions, concentrating under reduced pressure to obtain fluid extract with relative density of 1.20, adding n-hexane for extraction, and collecting n-hexane extractive solution.
3) Separation: weighing 700g of 200-mesh 300-mesh silica gel, loading the silica gel into a column by a dry method, eluting and balancing by petroleum ether (60-90 ℃), and passing the extract serving as a sample solution through a silica gel chromatographic column to ensure that the effective components of the sample solution are completely adsorbed on the silica gel. Then eluting with mixed solvent of petroleum ether (60-90 deg.C) and ethyl acetate at a volume ratio of 99:1, and examining the obtained eluate by thin layer chromatography under 254nm ultraviolet light, wherein the developing solvent used in the thin layer chromatography is petroleum ether and ethyl acetate (7: 1). When the target component appears in the elution fractions, using a mixed solvent of petroleum ether (60-90 ℃) and ethyl acetate with a volume ratio of 98:2 as an eluent for elution until the target component cannot be detected in the elution fractions, combining the elution fractions with the volume ratio of 98:2, and concentrating by using a rotary evaporator to obtain a crude product;
dissolving the crude product with n-hexane, performing column chromatography for 2 times, eluting, concentrating the eluate, and drying to obtain pure product.
HPLC detection shows that the product purity is 98.8%, the yield is 5.39g, and the content of the sesterterpene lactone compound with the structure shown as formula II in the valerian medicinal material is 0.045%, so that the transfer rate is calculated as follows: 5.39 × 98.8%/20000 × 0.045% ═ 59.2%.
The detection conditions of the high performance liquid chromatography are as follows: ODS 24.6 × 250mm, 5 μm analytical column; column temperature: 30 ℃; mobile phase: acetonitrile-deionized water (70:30, V/V), flow rate: 0.6ml/min, detection wavelength 268nm, sample size 20 uL.
Example 2 structural identification and resolution of Compounds of formula II
1) A light yellow oil.
2)UV(λMeOH max) The spectrum, 269nm, indicates the presence of a conjugated system.
3)IR(νmaxKBr)cm-1：3443.84,2929.24,2871.71,1735.32,1677.59,1622.83,1453.35,1376.10；
The above data indicate the presence of methyl, methylene, carbonyl, ethylenic, etc. functional groups in this structure.
4)EI-MS(me/z)：291.29，279.25，263.31，234.16，219.04(100％)，204.98，190.95，178.96，173.06，148.92，144.99，130.92，119.11，107.15，104.92，90.99，76.95，64.99，54.94；
MALDI-TOF MS(me/z)：315.1，299.1，273.0，257.0，235.0。
In the spectrum, 219.04 (100%) but no molecular ion peak is given.
5)1H-NMR(CDCL3，500MHz)δppm：9.28(s，1H)，6.35(d，J＝9.5Hz，1H)，5.35(dd，J＝5.5Hz，J＝11.5Hz，2H)，4.18(d，J＝12.0Hz，1H)，4.15(d，J＝12.0Hz，1H)，2.91(m，1H)，2.85(dd，1H)，2.26(m，1H，C14-H)，2.02(t，2H，C12-H)，2.00(s，3H)，1.28(s，3H，C20-CH3)，1.18(s，3H，C11-CH3)，1.19(s，3H，C11-CH3)，1.02(s，3H，C16-CH3)，1.03(s，3H，C16-CH3)；
In the spectrum, 9.28ppm gives a signal of an s peak of H, which is a 24-bit aldehyde group H signal; at 6.35ppm, a d-peak signal with H and a coupling constant of 9.5Hz is given as a 6-alkene H signal; at 5.35ppm, a single H is given, and the dd peak signals with coupling constants of 5.5 and 11.5Hz are respectively the 2-position alkene H signals; at 4.18ppm, a signal of d-peak with a coupling constant of 12.0Hz and a signal of 23-bit H is given; at 4.12ppm, an H is given, and the coupling constants are respectively a d peak signal of 12.0Hz and a 23-bit H signal; at 2.88ppm, an H, m peak signal is given, which is a 13-bit H signal; at 2.84ppm, giving a single H, a dd peak signal with a coupling constant of 12.0Hz, which is the 4-bit H signal; at 2.02ppm, 3H, s peak signals are given, which are-OCOCH 3A group H signal; at 1.28ppm, 3H, s peak signals are given, 20-bit CH3A group H signal; at 1.19ppm, 3H, s peak signals are given, 11-bit gem CH3A group H signal; at 1.18ppmGiving 3H, s peak signals as 11-bit gem CH3A group H signal; at 1.03ppm, 3H, s peak signals are given, 16-bit gem CH3A group H signal; at 1.02ppm, 3H, s peak signals are given, and the signal is 16-bit gem CH3A group H signal;
6)13C-NMR(CDCL3125MHz) δ ppm: 193.80(d, C-24, aldyl carbon), 170.89(s, -OCOCH)3Carbon mesocarbonyl), 175.32(s, C-22, -O-C ═ O), 155.88(d, C-6, ═ CH), 142.64(s, C-5, ═ C-), 132.94(s, C-1, ═ C-), 130.23(d, C-2, ═ CH), 85.59(s, C-20, -O-C-), 60.76(t, C-23, -OCH)2)，48.87(d，C-13，-C-COO)，41.37(d，C-19，-CH-)，40.65(t，C-21，-CH2-)，40.43(d，C-14，-CH-)，37.01(d，C-8，-CH-)，35.03(d，C-10，-CH2)，29.85(q，C20-CH3)，29.05(s，C11)，28.52(q，C11-CH3)，28.38(q，C16-CH3)，27.77(t，C-3，-CH2)，26.52(t，C-7，-CH2)，25.31，24.38(t，C-9，-CH2)，23.94(d，C-17，-CH)，23.75(t，C-18，-CH2)，23.31(t，C-4，-CH2)，21.07(t，C-15，-CH2)，20.96(q，C-23-OCOCH3)，20.55(t，C-12，-CH2)，15.86(q，C11-CH3)，15.81(q，C16-CH3)；
The spectrum gave 31 signals, of which 193.80(d, C-24, aldehydic carbon), 170.89(s, -OCOCH)3Middle acyl carbon), 175.32(s, C-22, -O-C ═ O) signal is weak, is the carbonyl carbon signal; 155.88(d, C-6, ═ CH) is a proton signal containing H and 142.64(s, C-5, ═ C-) is a quaternary carbon signal, both are carbon signals on the ethylenic double bond, and there is a conjugated system with the group; 132.94(s, C-1, ═ C-) is the quaternary carbon signal and 130.23(d, C-2, ═ CH) is the signal containing the H proton, both of which are the carbon signals on the ethylenic double bonds; 85.59(s, C-20, -O-C-) is an oxygen-containing saturated quaternary carbon signal, 60.76(t, C-23, -OCH) 2) Is an oxygen-containing saturated secondary carbon signal; 48.87(d, C-13, -C-COO) is a tertiary carbon signal containing an electron withdrawing group; 41.37(d, C-19, -CH-), 40.65(t, C-21, -CH)2-)，40.43(d，C-14，-CH-)，37.01(d，C-8，-CH-)，35.03(d，C-10，-CH2)，29.85(q，C20-CH3) Is a primary carbon signal, 29.05(s, C11), 28.52(q, C11-CH)3) Primary carbon signal, 28.38(q, C16-CH)3) Is a primary carbon signal, 27.77(t, C-3, -CH)2)，26.52(t，C-7，-CH2)，25.31，24.38(t，C-9，-CH2)，23.94(d，C-17，-CH)，23.75(t，C-18，-CH2)，23.31(t，C-4，-CH2)，21.07(t，C-15，-CH2)，20.96(q，C-23-OCOCH3) Is a primary carbon signal, 20.55(t, C-12, -CH)2)，15.86(q，C11-CH3) Primary carbon signal, 15.81(q, C16-CH)3) Is a primary carbon signal.
7) In the H-H cosy spectrum, there is a correlation between 6.35(d, J ═ 9.5Hz, 1H, C6-H) and 1.48(m, 1H), 5.35(dd, J ═ 5.5Hz, J ═ 11.5Hz, 1H, C2-H) and 2.36, 2.00, 2.88, 2.84(dd, 1H, C4-H) and 5.35(dd, J ═ 5.5Hz, J ═ 11.5Hz, 1H, C2-H), 2.91(m, 1H, C13-H) and 2.26(m, 1H, C14-H), 2.02(t, 2H, C12-H).
8) In the HMQC spectrum, 9.28(s, 1H) and 193.80(d, C-24, aldehyde-based carbon), 6.35(d, J-9.5 Hz, 1H) and 155.88(d, C-6, ═ CH), 5.35(dd, J-5.5 Hz, J-11.5 Hz, 2H) and 130.23(d, C-2, ═ CH), 4.18(d, J-12.0 Hz, 1H) and 4.12(d, J-12.0 Hz, 1H) and 60.76(t, C-23, -OCH) are given2) 2.91(m, 1H) and 48.87(d, C-13, -CH-COO), 2.85(dd, 1H) and 23.94(d, C-17, -CH), 2.00(s, 3H) and 20.96(q, C-23-OCOCH) 3) 1.02(s, 3H) and 15.81(q, C16-CH)3) 1.03(s, 3H) and 28.38(q, C16-CH)3) 1.18(s, 3H) and 15.86(q, C11-CH)3) 1.19(s, 3H) and 28.52(q, C11-CH)3) 1.28(s, 3H) and 29.85(q, C20-CH)3) Etc.
9) In the HMBC spectrum, 9.28(s, 1H) and 155.88(d, C-6, ═ CH), 142.64(s, C-5, ═ C-), 23.31(t, C-4, — CH), are given2) Correlation; 6.35(d, J ═ 9.5Hz, 1H) and 193.80(d, C-24, aldehyde carbon), 142.64(s, C-5 ═ C-), 23.31(t, C-4, -CH-)2) And (4) correlating. 5.35(dd, J-5.5 Hz, J-11.5 Hz, 1H) and 60.76(t, C-23, -OCH)2)，35.03(t，C-10，-CH2-)，27.77(t，C-3，-CH2) Correlation; 4.18(d, J ═ 12.0Hz, 1H) and 4.12(d, J ═ 12.0Hz, 1H) with 170.89(s, -OCOCH)3Middle acyl carbon), 130.23(d, C-2, ═ CH), 35.03(t, C-10, -CH)2-) are related. 2.91(m, 1H) and 26.52(t, C-12, -CH)2-) are related; 1.28(s, 3H, C20-CH)3) And 41.37(d, C-19, -CH-), 40.65(t, C-21, -CH-)2-), 85.59(s, C-20, -O-C-). 1.18(s, 3H, C11-CH)3) And 1.19(s, 3H, C11-CH)3) And 37.01(d, C-8, -CH-), 20.55(t, C-12, -CH-)2) 29.05(s, C11). 1.02(s, 3H, C16-CH)3) And 1.03(s, 3H, C16-CH)3) And 21.07(t, C-15, -CH)2) 23.94(d, C-17, -CH). 27.77(t, C-3, -CH) 2) In relation to 5.35(dd, J ═ 5.5Hz, J ═ 11.5Hz, 1H), 2.84(dd, 1H, C4-H), 1.48(m, 1H) in relation to 142.64(s, C-5 ═ C-), 37.01(d, C-8, -CH-).
By combining the above analysis, the molecular formula is C31H46O5The structure of the compound is shown in a formula II, the structure is formed by connecting 2 sesquiterpenes, one sesquiterpene lactone structure is a variant sesquiterpene lactone structure, and the biogenic pathway conforms to the isoprene rule.
EXAMPLE 3 analgesic Effect of Compounds of formula II
The analgesic effect of the compound of formula II on mice was evaluated using a hot plate assay. SPF-grade NIH mice, female, were first screened, fasted for 12 hours, placed on a hotplate apparatus (adjusted to a temperature of 55 + -0.5 deg.C), and the time required for the mouse to sit on the hotplate (called the pain threshold) for the mouse to lick, less than 5 seconds or more than 30 seconds, and discarded when the skipper was skipped. The screened qualified mice were randomly divided into 3 groups, namely a blank control group, a compound of formula II dose group 1(0.6mg/kg), and a compound of formula II dose group 2(1.2 mg/kg). Each dose group of the compound of formula II was administered three days in advance, and the mice were administered with a volume of 0.2mL/10g body weight. Fasting is carried out for 12h before the last administration, pain threshold values of 30min, 60min, 90min and 120min are measured after administration, and the pain threshold values are calculated according to 60 seconds after the administration of the medicine, so that the mice are prevented from being scalded. The results are shown in table 1 below.
TABLE 1 Effect of Compounds of formula II on Hot plate pain threshold in mice
P < 0.01 compared to basal pain threshold, # P < 0.01, # P < 0.05 compared to placebo.
As can be seen from Table 1, the pain threshold of the mice is obviously improved after the compound of the formula II is administered, and the compound of the formula II has obvious analgesic effect on the pain of the mice caused by a hot plate method.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (2)
1. Use of a terpene lactone compound of formula I below in the preparation of a medicament for analgesia, wherein the medicament is for the analgesia:
wherein R is1Is selected from C1-3An alkyl group.
2. The use of claim 1, wherein the terpene lactone compound is a compound of formula II:
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998013054A1 (en) * | 1996-09-28 | 1998-04-02 | Essential Nutrition Ltd. | A method for producing an extract from valeriana officinalis containing high levels of valerenic acid |
| CN102526135A (en) * | 2011-11-23 | 2012-07-04 | 武汉联合药业有限责任公司 | Valerian preparation and preparation method thereof |
| CN103951648A (en) * | 2014-04-30 | 2014-07-30 | 武汉联合药业有限责任公司 | Sesterterpene lactone compound |
| CN104042609A (en) * | 2014-04-30 | 2014-09-17 | 武汉联合药业有限责任公司 | Application of sesterterpene lactone compound in preparation of spasmolytic medicine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998013054A1 (en) * | 1996-09-28 | 1998-04-02 | Essential Nutrition Ltd. | A method for producing an extract from valeriana officinalis containing high levels of valerenic acid |
| CN102526135A (en) * | 2011-11-23 | 2012-07-04 | 武汉联合药业有限责任公司 | Valerian preparation and preparation method thereof |
| CN103951648A (en) * | 2014-04-30 | 2014-07-30 | 武汉联合药业有限责任公司 | Sesterterpene lactone compound |
| CN104042609A (en) * | 2014-04-30 | 2014-09-17 | 武汉联合药业有限责任公司 | Application of sesterterpene lactone compound in preparation of spasmolytic medicine |
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