CN112245416A - Application of pinnatifone A in preparation of drugs with sedative and hypnotic effects and drug composition - Google Patents
Application of pinnatifone A in preparation of drugs with sedative and hypnotic effects and drug composition Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 28
- 229940079593 drug Drugs 0.000 title claims abstract description 21
- 230000000147 hypnotic effect Effects 0.000 title claims abstract description 13
- 239000000932 sedative agent Substances 0.000 title claims abstract description 11
- 230000001624 sedative effect Effects 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 10
- 239000000203 mixture Substances 0.000 title description 3
- AJWBFJHTFGRNDG-GBJTYRQASA-N eremophilane Chemical compound C1CC[C@H](C)[C@@]2(C)C[C@H](C(C)C)CC[C@H]21 AJWBFJHTFGRNDG-GBJTYRQASA-N 0.000 claims abstract description 30
- LKBQARGGDFBGFF-UHFFFAOYSA-N eremophilane Natural products CC1C(O)CCC2C(=O)CC(CC12C)C(=C)C LKBQARGGDFBGFF-UHFFFAOYSA-N 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 6
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- 239000003795 chemical substances by application Substances 0.000 claims description 3
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- -1 sesquiterpene compound Chemical class 0.000 abstract description 21
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- 238000002474 experimental method Methods 0.000 abstract description 13
- 241001465754 Metazoa Species 0.000 abstract description 5
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- 241000699670 Mus sp. Species 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
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- 230000004622 sleep time Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 6
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- 229960001412 pentobarbital Drugs 0.000 description 6
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
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- 239000007924 injection Substances 0.000 description 4
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- 229910002027 silica gel Inorganic materials 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229960003529 diazepam Drugs 0.000 description 3
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000721671 Ludwigia Species 0.000 description 2
- 241000207834 Oleaceae Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
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- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- 229940125717 barbiturate Drugs 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940053999 hypnotics and sedatives melatonin receptor agonists Drugs 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/743—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups having unsaturation outside the rings, e.g. humulones, lupulones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
Abstract
The invention discloses an application of eremophilane type sesquiterpenoids pinnatiolone A in preparing drugs with sedative and hypnotic effects, wherein the structural formula of the compound is as follows:
Description
Technical Field
The invention relates to the field of natural medicines, in particular to application of an eremophilane type sesquiterpene compound Pinnatiofone A in preparation of medicines with sedative and hypnotic effects and a pharmaceutical composition.
Background
Insomnia is a disease in which sleep is insufficient due to failure to fall asleep or to maintain a sleep state due to environmental factors, individual factors, physical factors, mental factors, emotional factors, and the like. Also known as falling asleep and maintaining sleep disorders. Insomnia is mainly manifested by too little sleep time, insufficient sleep depth, fatigue after waking up, inability to recover physical strength and energy through sleep, difficulty in falling asleep repeatedly at night, and the like. With the modern fast-paced lifestyle and the increase of social pressure, more and more people have insomnia with different degrees. The sleep quality problem not only affects the daily living state of people, but also increases the risk of suffering from mental diseases along with the deepening of the insomnia degree. Therefore, improving sleep state, improving sleep quality level, and solving a series of sleep disorders become problems to be urgently needed to be solved in modern clinical medicine, and effective improvement of sleep conditions will bring positive social significance.
Modern medical methods for treating insomnia can be broadly divided into drug therapy and non-drug therapy. Benzodiazepine receptor agonists, melatonin receptor agonists, barbiturates and other sedative drugs are commonly used in drug therapy. The hypnotic drugs can inhibit cerebral cortex and central nerve, and a small amount of drugs can achieve the effects of calming nerves and helping sleep. However, there are cases where side effects are accompanied by muscle weakness and drowsiness in a person, and temporary memory loss may occur for a certain period of time, and long-term administration of hypnotics may cause dependence, and if it is interrupted suddenly, withdrawal syndrome may occur. Non-drug treatment mainly comprises psychotherapy, cognitive behavioral therapy, music therapy and the like, but the treatment method is relatively limited by the public and the curative effect is uncertain. Therefore, the development of the medicine for treating insomnia, which has no toxic or side effect, is convenient to take and is economical and practical, has become a hot spot of modern medicine development.
Disclosure of Invention
The invention aims to solve at least one technical problem in the prior art and provides application of an eremophilane type sesquiterpene compound Pinnatiofone A.
The technical solution of the invention is as follows:
the application of eremophilane sesquiterpenoids pinnatiolone A in the preparation of drugs with sedative and hypnotic effects,
the structural formula of the compound Pinnatiofone A is as follows:
the invention also discloses a pharmaceutical composition comprising the compound pinnatifone A as claimed in claim 1 and/or a stereoisomer thereof and/or a pharmaceutically acceptable salt thereof and/or an isotopic compound thereof, and a pharmaceutically acceptable carrier or diluent.
Preferably, the content of the compound Pinnatiofone A is 1-99.5 wt%, and the balance is pharmaceutically acceptable auxiliary materials.
Preferably, the content of the compound Pinnatiofone A is 3-30 wt%, and the balance is pharmaceutically acceptable auxiliary materials.
Preferably, the adjuvant includes at least one of a filler, a binder, a wetting agent, a disintegrant, and a surfactant.
Preferably, the pharmaceutical composition is an oral preparation, in particular one of tablets, capsules, pills and granules.
Preferably, the oral preparation is administered in a dose of 5-200mg/kg of compound Pinnatiofone A.
The invention has at least one of the following beneficial effects: experiments prove that the eremophilane sesquiterpene compound Pinnatiofone A has good sedative and hypnotic effects through the influence of the eremophilane sesquiterpene compound Pinnatiofone A on the sleep induction of mice by the aid of pentobarbital sodium in subthreshold doses, the influence of the eremophilane pentobarbital sodium in suprathreshold doses on the sleep-in incubation period and the sleep time of the mice and the influence on the autonomic activity of the mice. The invention finds that the eremophilane sesquiterpenoid Pinnatifolone A has definite function, good effect and no toxic or side effect, and can be used as a potential sedative hypnotic drug.
Detailed Description
The invention provides an application of eremophilane sesquiterpenoids pinnatiolone A in preparing drugs with sedative and hypnotic effects,
the structural formula of the compound is:
the invention also discloses a pharmaceutical composition, which comprises the compound, the stereoisomer or the pharmaceutically acceptable salt and the isotopic compound thereof, and a pharmaceutical carrier or diluent; specifically, the pharmaceutically acceptable salt may be a salt introduced at the hydroxyl group and/or the carbonyl group thereof, such as a sodium salt, a potassium salt, and a sulfonate compound.
The stereoisomers of the compounds may be in the following configurations;
the first configuration:
configuration II:
the third configuration:
the configuration is four:
the fifth configuration:
the content of the eremophilane type sesquiterpenoids pinnatiolone A in the pharmaceutical composition is 1-99.5%, 3-30%, 40%, 50%, 95%, and the balance is pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise at least one of a filling agent, a bonding agent, a wetting agent, a disintegrating agent and a surfactant.
The pharmaceutical composition can be oral dosage forms commonly used in the field, such as (capsule hard capsule, soft capsule), tablet (plain tablet, sugar-coated tablet, film coating), pill (pellet, dripping pill), granule, tablet, etc.
The dose of the oral preparation is 5-200mg/kg of eremophilane sesquiterpenoid Pinnatifolone A, specifically, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 30, 50, 100, 200mg/kg, but not limited thereto.
The carrier or excipient, in particular carrier or diluent, is one or more selected from solid, semi-solid and liquid diluents, fillers and pharmaceutical product adjuvants. The medicament of the present invention is used in the form of a dose per unit body weight. The pharmaceutical compositions of the present invention may also be administered to a patient in need of treatment in the form of an injection. For injection, the composition can be made into sterilized aqueous or oily solution, sterile powder for injection, liposome or emulsion.
This section will describe in detail specific embodiments of the invention.
It should be noted that: the eremophilane sesquiterpenoid compound Pinnatiofone A can be extracted and separated from plants in the genus of clove in the family of Oleaceae, and can also be prepared by synthesis or other methods. The eremophilane sesquiterpenoid Pinnatifolone A can also be obtained by commercial purchase, and the extraction method is reported in the literature.
The eremophilane sesquiterpenoids pinnatiolone A in the invention is extracted and separated from traditional Chinese medicines in the laboratory: molecular formula C15H20O3Molecular weight is 248.14, chemical designation: 1, 7-naphtalenedione, 2,3,4,4a,8,8a-hexahydro-6-hydroxy-4a,5-dimethyl-3- (1-methyhethyl).
The compound monomer in the following specific examples is extracted and separated from traditional Chinese medicines in the laboratory, and the solution specifically adopted is a suspension prepared by 0.5 wt% of CMC-Na (sodium carboxymethylcellulose).
The following compound monomers were prepared as follows: taking dry stems and branches of Ludwigia philippinensis of Ludwigia of Oleaceae, crushing into coarse powder, weighing about 10kg of medicinal materials, adding 8 times of 70% ethanol, soaking overnight, extracting for 3 times by reflux, filtering the extract while the extract is hot, combining the three filtrates, concentrating under reduced pressure at 50 ℃ by using a rotary evaporator to obtain viscous liquid, dispersing by using a proper amount of water, sequentially extracting by using petroleum ether, dichloromethane, ethyl acetate and n-butanol to respectively obtain a petroleum ether extraction part, a dichloromethane extraction part, an ethyl acetate extraction part, an n-butanol extraction part and a water part, concentrating and drying each part, weighing, and storing in a brown dryer for later use.
About 105g of a dichloromethane extraction site was taken, and the ratio of dichloromethane: after methanol (2: 1) is dissolved, the solution is added into 200g of silica gel (100-200 meshes) for adsorption, after drying, the solution is added into a glass chromatographic column which is filled in advance by a silica gel wet method, and petroleum ether with different proportions is used: eluting with acetone (1: 100-100: 0) and methanol, detecting the eluate with silica gel GF254 and/or silica gel G thin layer plate, and mixing the eluates with similar spots to obtain 6 mixed eluates labeled as Y-1, Y-2, Y-3, Y-4, Y-5 and Y-6. Taking the flow part Y-2, continuously carrying out chromatographic separation by using a silica gel column, and carrying out chromatographic separation by using petroleum ether with different proportions: eluting with acetone (1: 100-100: 0), collecting eluate, mixing fractions with the same spots, recrystallizing with acetone for multiple times to obtain compound, detecting with high performance liquid area normalization method to obtain purity of above 95%, simultaneously measuring with nuclear magnetism H, nuclear magnetism C and mass spectrometry, and analyzing structure and comparing with literature to determine that the compound is Pinnatiolone A (9.4 g).
The following specific examples employ sodium pentobarbital as a modeling agent for experimental animals.
In order to better understand the invention, the pharmaceutical research is combined to show that the eremophilane type sesquiterpene compound Pinnatiofone A has the effects of sedation and hypnosis, and 3 behavioral models are selected to comprehensively evaluate the effects of the eremophilane type sesquiterpene compound Pinnatiofone A. In the table, "+" indicates that p < 0.01, and "+" indicates that p.ltoreq.0.05. Wherein p is less than or equal to 0.05, representing statistical difference significance. p < 0.01 indicates that the statistical difference is very significant.
Example 1
Effect of erimophilane type sesquiterpene compound Pinnatifolone a on the induction of sleep in mice by subthreshold dose of sodium pentobarbital.
Experimental animals: male mice of Kunming strain, SPF grade, weighing 28-32g, were purchased from Schlekshirta laboratory animals Ltd, Hunan, SCXK (Hunan) 2016-0002.
The experimental method comprises the following steps: one week after the mice are adaptively raised, the mice are randomly divided into a normal group, an eremophilane type sesquiterpene compound Pinnatiofone A low (4.5mg/kg), a medium (9mg/kg), a high (18mg/kg) dose group and a positive drug group, and the mice are respectively subjected to intragastric administration of a diazepam solution by 2mg/kg, and 15 mice are respectively treated. And (3) feeding distilled water with equal volume into the gavage of a normal group, wherein the feeding volume is 0.1ml/10g, after the single feeding is carried out for 30min, injecting sodium pentobarbital (30mg/kg) with subthreshold dose found by an experiment into the abdominal cavity of each mouse, wherein the volume is 0.2ml, adopting a double-blind experiment, leading an observer to not know the fed substances of each group of animals before the experiment, observing the mice, recording the occurrence of sleep when the righting reflex disappears for more than 1min, recording the number of the mice falling asleep within 30min, and calculating the falling asleep rate.
TABLE 1 Effect of eremophilane type sesquiterpene Compound Pinnatifolone A on subthreshold dose of sodium pentobarbital to induce sleep in mice
Note: p <0.05 compared to blank.
The results show (table 1) that the group of positive drugs, the group of middle and high doses of eremophilane sesquiterpene compound pinnatifoline a, significantly increased the sleep of the mice compared to the blank control group, and had statistical significance.
Example 2
Effect of erimophilane-type sesquiterpene compound Pinnatifolone a on suprathreshold dose of sodium pentobarbital to induce sleep latency and sleep time in mice.
The experimental animals were the same as in example 1.
The experimental method comprises the following steps: one week after the mice are adaptively raised, the mice are randomly divided into a normal group, an eremophilane type sesquiterpene compound Pinnatiofone A low (4.5mg/kg), a medium (9mg/kg), a high (18mg/kg) dose group and a positive drug group, and the mice are respectively subjected to intragastric administration of a diazepam solution by 2mg/kg, and 15 mice are respectively treated. And (3) feeding distilled water with equal volume to 0.1ml/10g into the gavage of a normal group, carrying out intraperitoneal injection on pentobarbital sodium (45mg/kg) according to the optimal sleep dose found in a pre-experiment after single administration for 30min by each mouse, observing the mice by adopting a double-blind experiment, and recording the sleep latency (the time from the injection to the disappearance of righting reflex) and the sleep time (the time from the disappearance of righting reflex to the recovery) before an observer does not know the drug administered by each group of animals before the experiment.
TABLE 2 Effect of eremophilane type sesquiterpene compound Pinnatifolone A on the induction of sleep latency and sleep time in mice by suprathreshold dose of sodium pentobarbital ((
n＝15)
Note: p <0.05, compared to the blank group, P < 0.01.
Compared with a blank control group (table 2), the positive medicine can obviously prolong the sleep time of the mice and shorten the sleep latency; compared with a blank control group, the eremophilane type sesquiterpenoids pinnatiolone A high and medium dose group can obviously prolong the sleep time of mice and shorten the sleep latency.
Example 3
Effect of eremophilane type sesquiterpene compound pinnatiolone a on the autonomic activity of mice.
The experimental animals were the same as in example 1.
The experimental method comprises the following steps: one week after the mice are adaptively raised, the mice are randomly divided into a normal group, an eremophilane type sesquiterpene compound Pinnatiofone A low (4.5mg/kg), a medium (9mg/kg), a high (18mg/kg) dose group and a positive drug group, and the mice are respectively subjected to intragastric administration of a diazepam solution by 2mg/kg, and 15 mice are respectively treated. And (3) feeding distilled water with equal volume by normal intragastric administration, wherein the administration volume is 0.1ml/10g, performing an experiment by using an autonomous activity computer online processing system after 30min of single administration, starting a test after 2min adaptation, and detecting the movement distance, the movement speed and the movement time of the mouse, wherein the test time is 4 min. The ambient was kept quiet during the test.
TABLE 3 Effect of eremophilane type sesquiterpene Compound Pinnatifolione A on the autonomous Activity of mice: (
n＝15)
Note: p <0.05, compared to the blank group, P < 0.01.
Compared with a blank control group, the positive medicine group can obviously shorten the movement path, the movement speed and the movement time of the mouse, the high and medium dose groups of the eremophilane type sesquiterpene compound can obviously shorten the movement path and the movement speed of the mouse, and the high, medium and low dose groups of the eremophilane type sesquiterpene compound can obviously shorten the movement time of the mouse.
In the above examples 1-3, to prove that the above verification results are accurate and reliable, the statistical calculation and analysis of the samples are performed during the verification, specifically, the data is statistically analyzed by SPSS 17.0, the measurement data is expressed by means of the mean ± standard deviation (x ± s), the mean comparison between two groups of samples is performed by t-test, the mean comparison between multiple groups of samples is performed by means of the single variance analysis (LSD method), and the Tamhane's T2 method is used when the variance is irregular. P <0.05 is statistically significant for the difference. In the figure, "+" indicates that p < 0.01, and "+" indicates that p.ltoreq.0.05.
In conclusion, animal experiments prove that the eremophilane type sesquiterpenoid pinnatiolone A has obvious sedative and hypnotic effects. Therefore, the eremophilane sesquiterpenoids Pinnatifolone A can be used as a new candidate drug with sedative and hypnotic effects.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
In the description of the embodiments of the present invention, it should be understood that "-" and "-" indicate the same range of two numerical values, and the range includes the endpoints. For example: "A-B" means a range of greater than or equal to A and less than or equal to B. "A to B" means a range of not less than A and not more than B.
In the description of the embodiments of the present invention, the term "and/or" herein is only one kind of association relationship describing an associated object, and means that there may be three kinds of relationships, for example, a and/or B, and may mean: a exists alone, A and B exist simultaneously, and B exists alone. In addition, the character "/" herein generally indicates that the former and latter related objects are in an "or" relationship.
The above description is only a preferred embodiment of the present invention, and the technical solutions that achieve the objects of the present invention by basically the same means are all within the protection scope of the present invention.
Claims (7)
1. The application of eremophilane sesquiterpenoids pinnatiolone A in the preparation of drugs with sedative and hypnotic effects,
the structural formula of the compound Pinnatiofone A is as follows:
2. a pharmaceutical composition characterized by: comprising the compound pinnatifone a and/or a stereoisomer thereof and/or a pharmaceutically acceptable salt thereof and/or an isotopic compound thereof according to claim 1, and a pharmaceutically acceptable carrier or diluent.
3. A pharmaceutical composition according to claim 2, wherein: the content of the compound Pinnatiofone A is 1-99.5%, and the balance is pharmaceutically acceptable auxiliary materials.
4. A pharmaceutical composition according to claim 2, wherein: the content of the compound Pinnatiofone A is 3-30%, and the balance is pharmaceutically acceptable auxiliary materials.
5. A pharmaceutical composition according to claim 3 or 4, wherein: the auxiliary materials comprise at least one of a filling agent, a bonding agent, a wetting agent, a disintegrating agent and a surfactant.
6. A pharmaceutical composition according to claim 2, wherein: the pharmaceutical composition is an oral preparation, and specifically is one of tablets, capsules, pills and granules.
7. A pharmaceutical composition according to claim 6, wherein: the dosage of the oral preparation is 5-200mg/kg of compound Pinnatiofone A.
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