CN104958297A - Medicine composition for anesthesia and sedation hypnosis and application of medicine composition for anesthesia and sedation hypnosis - Google Patents
Medicine composition for anesthesia and sedation hypnosis and application of medicine composition for anesthesia and sedation hypnosis Download PDFInfo
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- CN104958297A CN104958297A CN201510297056.2A CN201510297056A CN104958297A CN 104958297 A CN104958297 A CN 104958297A CN 201510297056 A CN201510297056 A CN 201510297056A CN 104958297 A CN104958297 A CN 104958297A
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- 239000003814 drug Substances 0.000 title claims abstract description 15
- 206010002091 Anaesthesia Diseases 0.000 title abstract description 12
- 230000037005 anaesthesia Effects 0.000 title abstract description 12
- 206010039897 Sedation Diseases 0.000 title abstract description 7
- 230000036280 sedation Effects 0.000 title abstract description 7
- 229940079593 drug Drugs 0.000 title abstract description 6
- 230000000147 hypnotic effect Effects 0.000 title abstract 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 42
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and discloses a medicine composition for anesthesia and sedation hypnosis and an application of the medicine composition for anesthesia and sedation hypnosis. The composition is prepared by an active ingredient and a pharmaceutically acceptable auxiliary material; and the active ingredient comprises 1-azetidine-3-yl-4-propionyl piperazine. The medicine composition is obvious in effect when being used for anesthesia and sedation hypnosis.
Description
Technical field
The invention belongs to medical art, in particular to a kind of pharmaceutical composition for anaesthetizing tranquilizing soporific and application thereof.
Background technology
In anaesthesia technology, according to the difference of medical care precess and needs of patients, the depth state of anesthesia and degree are also not quite similar, and not only comprise surgery anesthesia, and analgesia anesthesia, also comprise effective sedation anesthesia, treatment of insomnia patients also belongs to the one of sedation anesthesia.Insomnia falls asleep and has a sleepless night to maintain sleep quality caused by difficulty or quantity does not reach normal physiological demand and affects a kind of subjective experience of social function on daytime, is modal sleep disordered illness.The national prevalences such as accelerate and today of intensified competition in social rhythm, insomnia is a kind of very general phenomenon, and insomnia's prevalence is very high, America and Europe, at about 20%-30%, have 10%-20% in China.Insomnia can cause absent minded, hypomnesis, judgment and routine work ability to decline, and severe patient merges anxiety, force and the symptom such as depression.In addition insomnia or the independent hazard factor of coronary heart disease and symtomatic diabetes.A variety of causes can cause insomnia, as transience Nervous and Mental Factors, environmental factors, psychological factor, long campaigns night shift, live irregular etc.
Diagnostic criteria:
1, patient main suit has insomnia to include to sleep difficulty (lie in bed and do not fall asleep for 30 minutes), Yi Xing, frequent awakening (every night more than 2 times), dreaminess, early awakening or again falls asleep more than 30 minutes after waking up, and total sleep time was less than 6 hours.Have above-mentioned situation more than 1, simultaneously with dreaminess, wake up after the malaise symptoms such as dizzy, weak.
2, social function to have dizziness, the symptom such as weak, deficient in energy, tired, drowsy and absent minded impaired daytime, and severe patient occurs that cognitive competence declines thus affects working and learning.
3, above-mentioned situation at least 3 times weekly, continues at least 1 month.
4, the insomnia secondary that various nerve, spirit and physical disease cause is got rid of.
5, polysomnogram is as the objective indicator Sleep latency of insomnia more than 30 minutes, and the actual length of one's sleep is less than 6 hours every night, and awaken night is time more than 30 minutes.
Transience is divided into have a sleepless night (in 1 week) according to the insomnia persistent period, acute insomnia (1 week-1 month), subacute insomnia (1-6 month), chronic insomnia (continuing more than 6 months).
At present, the drug treatment of insomnia is a lot, mainly comprise first generation barbiturates, second filial generation Benzodiazepines, anxiolytic drugs, antidepressant drug etc. at present, although at present common drug have certain effect to shorten time for falling asleep, reduce awakening time and number of times, the effect of increase total sleep time, but the untoward reaction such as easily form drug dependence, drug withdrawal knock-on, next day is dizzy, unable, Repiration can be suppressed, for life-time service side effect and erious adverse reaction time serious.Therefore, find and develop the lower sedative hypnotic of a kind of toxic and side effects, this seems particularly very always.
CN101316846A discloses aza Tetramethylene. compound and preparation method thereof, and discloses the purposes of described compound in treatment functional gastrointestinal disease, IBS and functional dyspepsia.At present, this compounds of bibliographical information is not still had to have the biological activity of tranquilizing soporific.
Summary of the invention
The object of the invention is to, by studying the biological activity of native compound monomer, provide a kind of medicine for narcohypnosis.This medicine for active component, can be used for epilepsy and neurasthenic treatment with 1-azetidine-3-base-4-propiono piperazine (QSK-02).
In order to realize object of the present invention, inventor for index, compares diazepam and QSK-02 to the impact of sedative-hypnotic effect with the dropping asleep latency of mice autonomic activities and injection pentobarbital sodium HD and prolonged sleep time.Result shows, QSK-02 group and positive drug group diazepam stand number of times and movable number of times significantly lower than blank group (
p<0.05 or
p<0.01); Meanwhile, the dropping asleep latency of diazepam group and QSK-02 group, the prolonged sleep time than blank group obviously shorten (
p<0.01); Above result shows that QSK-02 has ideal anesthesia sedative-hypnotic effect.
Based on above-mentioned result of the test, technical scheme provided by the invention is summarized as follows:
For a pharmaceutical composition for narcohypnosis, be prepared from by active component and pharmaceutically acceptable adjuvant, described active component comprises 1-azetidine-3-base-4-propiono piperazine.Preferably, as mentioned above for the pharmaceutical composition of tranquilizing soporific, wherein said active component is made up of as sole component 1-azetidine-3-base-4-propiono piperazine.The structural formula of this compound 1-azetidine-3-base-4-propiono piperazine (QSK-02) as shown in Figure 1.
Pharmaceutical composition for narcohypnosis of the present invention; wherein 1-azetidine-3-base-4-propiono piperazine has carried out relevant animal test as active component in gavage mode; result medicine is remarkable through gastrointestinal absorption, and therefore described pharmaceutical composition can be oral formulations.Wherein said oral formulations comprises tablet, capsule, granule, drop pill, oral liquid.It should be noted that; according to the common process of formulation art; those skilled in the art is easy to acceptable adjuvant on 1-azetidine-3-base-4-propiono piperazine and pharmaceutics to be prepared into conventional oral formulations, as oral liquid, granule, tablet, capsule.Wherein, on pharmaceutics, acceptable adjuvant comprises filler, disintegrating agent, binding agent, correctives, lubricant etc.Described filler is selected from following one or more: pregelatinized Starch, lactose, mannitol and microcrystalline Cellulose; Described disintegrating agent is selected from following one or more: carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose; Described binding agent is selected from following one or more: starch slurry, hydroxypropyl cellulose solution, povidone solution; Described lubricant is selected from following one or both: magnesium stearate, Pulvis Talci.
In addition, the present invention also provides a kind of compound novelty teabag, that is: 1-azetidine-3-base-4-propiono piperazine is for the preparation of the application in the medicine of narcohypnosis.
Compared with prior art, the 1-azetidine-3-base-4-propiono piperazine that the present invention relates to, for the Be very effective of tranquilizing soporific, is expected to the new drug be developed to for epilepsy and neurasthenia treating.
Accompanying drawing explanation
Fig. 1 is the structural formula of 1-azetidine-3-base-4-propiono piperazine (QSK-02);
Detailed description of the invention
Be below the specific embodiment that the present invention relates to, technical scheme of the present invention is done to describing further, but protection scope of the present invention be not limited to these embodiments.Every do not deviate from the present invention's design change or equivalent substituting include within protection scope of the present invention.
Embodiment 1:QSK-02 tests the impact of mice nonalcoholic fatty liver model
Cleaning grade Kunming mouse 36, male and female half and half, body weight (20 ± 2) g, be divided into blank group, diazepam positive controls (2mg/kg), QSK-02 group (50mg/kg) at random, every day 1 time, continuous 3 days, gavage volume 20ml/kg, blank group equivalent distilled water gavage.Stand number of times and the movable number of times of 5min put into case with mice autonomic activities instrument record mice after second day administration 60 min after.After last administration 60min, each group of mice equal lumbar injection pentobarbital sodium 50mg/kg, sleep is index with righting reflex loss, more than 30s person is kept with the downward posture of animal back, be judged as righting reflex loss, record injection pentobarbital sodium after to mice sleeping duration as dropping asleep latency, and observed and recorded righting reflex loss to awakening time as the prolonged sleep time.
Test statistics result according to table 1 can be found out, diazepam group and QSK-02 group stand number of times and movable number of times significantly lower than blank group (
p<0.05 or
p<0.01); In addition, the dropping asleep latency of diazepam group and QSK-02 group, the prolonged sleep time than blank group obviously shorten (
p<0.01); Above result shows that QSK-02 has ideal sedative-hypnotic effect.
Table 1 is respectively organized mice autonomic activities and is compared the length of one's sleep
| Group | Number of animals (n) | Autonomic activities | Autonomic activities | The length of one's sleep (min) | The length of one's sleep (min) |
| To stand number of times | Movable number of times | Dropping asleep latency | The prolonged sleep time | ||
| Blank group | 12 | 59.4±4.6 | 16.7±4.9 | 4.5±0.9 | 35.1±10.3 |
| Diazepam group | 12 | 31.6±8.2 ** | 10.2±3.5 * | 2.6±0.6 ** | 163.3±37.5 ** |
| QSK-02 group | 12 | 42.0±9.3 ** | 9.6±2.7 ** | 3.1±0.4 ** | 141.7±25.8 ** |
Compare with blank group,
* p< 0.05,
* p< 0.01.
The preparation of embodiment 2:1-azetidine-3-base-4-propiono piperazine
(a) 1-[1-(diphenyl methyl) azetidine-3-base] piperazine
In 60 DEG C of stirred under nitrogen 1-(diphenyl methyl) azetidine-3-methylmethane sulphonic acid esters (see J.Org.Chem.; 56; 1991; 6729; 25 grams, 78.6 mMs), the mixture overnight of piperazine (67.7 grams, 0.79 mole) and anhydrous acetonitrile.Cooling mixture, distributes between water and dichloromethane.Organic layers with water and salt water washing.Solution is dry through Na2SO4, then evaporation of solvent.Residue by silicagel column chromatography purification (methanol dichloromethane 5: 95).Obtain 1-[1-(diphenyl methyl) azetidine-3-base] piperazine 17.5 grams (72%) of yellow oily.1HNMR(400MHz，CDCl3)：2.1-2.4(m，4H)，2.8-2.9(m，2H)，3.0(m，4H)，3.4-3.5(m，2H)，3.7-3.9(m，1H)，4.4(s，1H)，7.2-7.4(m，10H)；LCMS：m/z 308(M+1)+。
(b) 1-[1-(diphenyl methyl) azetidine-3-base]-4-propiono piperazine
Stirred at ambient temperature 1-[1-(diphenyl methyl) azetidine-3-base] piperazine (250 milligrams; 0.81 mM), K2CO3 (146 milligrams; 1.1 mMs), the mixture of propiono chlorine (98 milligrams, 1.1 mMs) and acetonitrile (6 milliliters) 16 hours.Mixture filters through the post that is separated, evaporation of solvent.Residue is dissolved in dichloromethane, solution NaHCO3 solution washing.The organic facies post that is separated is separated, then evaporation of solvent.Obtain 1-[1-(diphenyl methyl) azetidine-3-the base]-4-propiono piperazine 216 milligrams (73%) of oily.1HNMR(500MHz，CDCl3)：1.1-1.2(t，3H)，2.2-2.4(m，6H)，2.9(t，2H)，3.0(m，1H)，3.4-3.5(m，4H)，3.6(b，2H)，4.4(s，1H)，7.2(m，2H)，7.3(m，4H)，7.4(m，4H)；LCMS：m/z 364(M+1)+。
(c) 1-azetidine-3-base-4-propiono piperazine
By 1-[1-(diphenyl methyl) azetidine-3-base]-4-propiono piperazine (0.22 gram; 0.59 mM) be dissolved in the mixture of ethanol (9 milliliters) and acetic acid (0.2 milliliter), add palladium dydroxide/carbon (83 milligrams) to gained solution.Under room temperature hydrogen, (5 bar) stirs the mixture 23 hours, then by the post filtering catalyst that is separated, then uses washing with alcohol.Evaporation of solvent, is dissolved in residue in methanol (1 milliliter).Solution filters through cation exchange column (Isolute SCX-2,10 grams).Pillar THF washs, the methanol-eluted fractions that then product ammonia is saturated.Evaporation of solvent, obtains the title compound 0.13 gram (100%) of oily.1H NMR(500MHz，CD3OD)：1.1(t，3H)，2.3-2.5(m，6H)，3.4(m，1H)，3.6(m，4H)，3.9-4.0(m，4H)。
Claims (5)
1. for a pharmaceutical composition for narcohypnosis, be prepared from by active component and pharmaceutically acceptable adjuvant, it is characterized in that: described active component comprises 1-azetidine-3-base-4-propiono piperazine.
2. according to claim 1 for the pharmaceutical composition of narcohypnosis, it is characterized in that: described active component is made up of as sole component 1-azetidine-3-base-4-propiono piperazine.
3. according to claim 1 or 2 for the pharmaceutical composition of narcohypnosis, it is characterized in that: described pharmaceutical composition is oral formulations.
4. according to claim 3 for the pharmaceutical composition of narcohypnosis, it is characterized in that: described oral formulations comprises oral liquid, drop pill, tablet, capsule, granule.
5.1-azetidine-3-base-4-propiono piperazine is for the preparation of the application in the medicine of narcohypnosis.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1520409A (en) * | 2001-07-09 | 2004-08-11 | ������ҩ������˾ | Piperazine oxime derivatives having Nk-1 receptor antagonistic activity |
| CN1856309A (en) * | 2003-09-26 | 2006-11-01 | 索尔瓦药物有限公司 | Hexa- and octahydro-pyrido[1,2-a] pyrazine derivatives with NK1 antagonistic activity |
| CN101316846A (en) * | 2005-09-29 | 2008-12-03 | 阿尔比里奥公司 | Novel azetidine compounds useful in the treatment of functional gastrointestinal disorders, IBS and functional dyspepsia |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1520409A (en) * | 2001-07-09 | 2004-08-11 | ������ҩ������˾ | Piperazine oxime derivatives having Nk-1 receptor antagonistic activity |
| CN1856309A (en) * | 2003-09-26 | 2006-11-01 | 索尔瓦药物有限公司 | Hexa- and octahydro-pyrido[1,2-a] pyrazine derivatives with NK1 antagonistic activity |
| CN101316846A (en) * | 2005-09-29 | 2008-12-03 | 阿尔比里奥公司 | Novel azetidine compounds useful in the treatment of functional gastrointestinal disorders, IBS and functional dyspepsia |
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