CN106963766A - A kind of azaspiro ketone pharmaceutical composition and preparation method thereof - Google Patents
A kind of azaspiro ketone pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
A kind of azaspiro ketone pharmaceutical composition and preparation method thereof, the azaspiro ketone pharmaceutical composition inclusion compound I and/or its citrate, compound ii and/or its citrate and compound III and/or its citrate, it has antianxiety, antidepressant effect, and adverse reaction is small；Product purity prepared by the preparation method is high, and relevant content of material is low.
Description
Technical field
The present invention relates to a kind of azaspiro ketone pharmaceutical composition and preparation method thereof.
Background technology
Tandospirone belongs to azaspiro ketone medicine, and [4 [(2- is phonetic by 4- by entitled (3a α, 4 β, 7 β, the 7a α)-hexahydro -2- of chemistry
Piperidinyl) -1- (piperazinyl)-butyl] -1,3 (2H)-diketone of -4,7- methylene -1H- iso-indoles.It is a kind of 5-hydroxytryptamine receptor
Activator, belongs to the 3rd generation anxiolytic, is mainly used in the disease for treating anxiety or other companion's anxiety states.Tandospirone can
Height selectively with integrated distribution emotion maincenter hippocampus, in every, the cerebral limbic system such as interpeduncular nucleus, amygdaloid nucleus and seam gland
The 5-HT of core1AAcceptor is combined, exciting 5-HT1AAutoreceptor, plays angst resistance effect.Tandospirone can also play one simultaneously
Fixed antidepressant effect.
Compared to it with analog derivative buspirone, Tandospirone has higher selective angst resistance effect, this work
With close with diazepam, but the toxic side effect in terms of nervimotion Sexual dysfunction and drug abuse is smaller than diazepam.
Due to the specificity of mechanism of action, when Tandospirone is used clinically for treatment anxiety disorder, with drug safety height, side effect
Less, sedative-hypnotic effect is weak, without relaxed muscle effect, no dependence and drug withdrawal give up after phenomenon, prolonged application in vivo without
The advantages of accumulation.Proved through long-term clinical practice, Tandospirone is to the anxiety state caused by various neurosises, light modest depression
Disease, and a variety of physical diseases anxiety and/or depressive state that for example hypertension, peptic ulcer etc. occur together have good treatment
Effect, hence it is evident that improve patient mental and somatization.As the basic medication of body and mind comorbidity, the potential applicability in clinical practice of Tandospirone is wide
It is wealthy.
At present, it is clinically many to be treated using the citrate (i.e. tandospirone citrate) of Tandospirone.1451
There are 150 (10.3%) adverse reaction occur in example patient, main adverse reaction there are drowsiness 43 (3.0%), lurched
16 (1.1%), nauseous 13 (0.9%), taediumvitae l1 (0.8%), unhappy 11 (0.8%), loss of appetite 10
Example (0.7%), also a few patients occur with the elevated dysfunction of liver of AST, ALT, jaundice etc..At present temporarily without pertinent literature report
The reason for road causes above-mentioned adverse reaction.
The content of the invention
The inventors discovered that, the quality of tandospirone citrate is controlled, the adverse reaction to reducing tandospirone citrate
Incidence, improve its antianxiety and antidepressant effect is significant.
The present invention provides a kind of tandospirone citrate composition and preparation method thereof, and said composition includes a certain amount ofization
((3a α, 4 β, 7 β, 7a α)-tetrahydrochysene -2- [4- [4- (2- pyrimidine radicals) -1- piperazinyls] butyl] -4,7- methylene -1H- is different for compound I
Indoles -1,3 (2H)-diketone) and/or its citrate, compound ii ([[(2- is phonetic by 4- by 4- by (3aR, 4R, 7S, 7aS)-hexahydro -2-
Piperidinyl) -1- piperazinyls] butyl] -1,3 (2H)-diketone of -4,7- methylene -1H- iso-indoles) and/or its citrate and change
((3aR, 4S, 7R, 7aS)-tetrahydrochysene -2- [4- [4- (2- pyrimidine radicals) -1- piperazinyls] the butyl] -4,7- methylene -1H- of compound III
Iso-indoles -1,3 (2H)-diketone) and/or its citrate, the structural formula of chemical compounds I, II and III is as follows：
The tandospirone citrate composition has antianxiety, antidepressant effect, and adverse reaction is small；The preparation method
Prepared product purity is high, and relevant content of material is low.
The present invention provides a kind of tandospirone citrate composition, it is characterised in that the composition includes weight percent
Content is 0-0.5% chemical compounds I and/or its citrate, 0-0.4% compound ii and/or its citrate and 0-
0.2% compound III and/or its citrate.
Preferably, the content of chemical compounds I and/or its citrate is 0.001-0.4%, more preferably 0.001-0.2%.
Preferably, the content of compound ii and/or its citrate is 0-0.3%, more preferably 0-0.2%.
Preferably, compound III and/or the content of its citrate are 0-0.1%, more preferably 0-0.05%.
Preferably, compound III and/or the content of its citrate are 0 in above-mentioned tandospirone citrate composition.
Preferably, the content of compound ii and/or its citrate is 0 in above-mentioned tandospirone citrate composition.
Preferably, the content of tandospirone citrate is more than 98% in above-mentioned tandospirone citrate composition, more excellent
Elect more than 98.5%, more preferably more than 99% as.
The preparation method of the tandospirone citrate composition of the present invention, including by cis- outer-two rings [2.2.1] heptane -2,
The process that 3- dicarboximides (IV) are purified：
The purification procedures include cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides being dissolved in after solvent to be analysed again
The step of going out.
Preferably, above-mentioned purification procedures are molten including being added into cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide
Agent, is heated, and is cooled down, and is filtered, and is dried, and produces cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide.
It is highly preferred that above-mentioned purification procedures comprise the following steps：
(A) solvent is added into cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide, heats, be cooled to 50 ± 5
DEG C, then it is cooled to 35 ± 5 DEG C, room temperature is cooled to, is filtered, is dried, the cis- outer formyl of-two rings [2.2.1] heptane -2,3- bis- is produced
Imines；Or
(B) solvent is added into cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide, heats, be cooled to room temperature,
- 10 ± 5 DEG C are cooled to again, and filtering adds solvent into filter cake, heats, is cooled to room temperature, is cooled to 5 ± 5 DEG C, filters, and does
It is dry, produce cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide.
Preferably, above-mentioned solvent is selected from water, alcohols, ketone, ethers, esters, halogenated hydrocarbon, amide-type, sulfoxide type solvents
At least one of.
Preferably, above-mentioned alcohols solvent be preferably methanol, ethanol, propyl alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol,
N-amyl alcohol, isoamyl alcohol, n-hexyl alcohol etc..
Preferably, above-mentioned ketones solvent is preferably acetone, butanone, cyclohexanone etc..
Preferably, above-mentioned ether solvent is preferably ether, isopropyl ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, methyl tertbutyl
Ether etc..
Preferably, above-mentioned esters solvent is preferably methyl acetate, ethyl acetate, propyl acetate, butyl acetate, propionic acid first
Ester, ethyl propionate, propyl propionate, butyl propionate etc..
Preferably, above-mentioned halogenated hydrocarbon solvent is preferably dichloromethane, chloroform, tetrachloromethane etc..
Preferably, above-mentioned amide solvent is preferably DMF, DMAC etc..
Preferably, above-mentioned sulfoxide type solvents are preferably DMSO.
Preferably, above-mentioned solvent is selected from least one of water, ethanol, methanol, isopropanol, butanol, acetone, butanone.
It is further preferred that above-mentioned solvent is the mixing selected from methanol, ethanol, isopropanol, butanol, acetone, ethanol and water
Solution, the mixed solution of methanol and water, the mixed solution of isopropanol and water, the mixed solution of butanol and water, acetone and water it is mixed
Close any one in solution.
It is further preferred that above-mentioned solvent is selected from ethanol：Water=0.1~10:1st, methanol：Water=0.1~10:1st, isopropyl
Alcohol：Water=0.1~10:1st, butanol：Water=0.1~10:1st, acetone：Water=0.2~5:Mixed solvent in 1.
It is further preferred that above-mentioned solvent be selected from：Ethanol：Water=0.5~4:1st, methanol：Water=3~9:1st, isopropyl
Alcohol：Water=0.2~2:1st, butanol：Water=0.15~5:1st, acetone：Water=1:Mixed solvent in 1.
Preferably, above-mentioned preparation method comprises the following steps：By 1- (2- pyrimidine radicals) piperazine, 1,4- dibromobutanes, carbonic acid
Potassium, benzyltriethylammoinium chloride and toluene, which are added in reactor, to react, and then adds cis- outer-two rings of the purifying
[2.2.1] heptane -2,3- dicarboximide is reacted, and reaction solution purify to obtain free alkali, citric acid is added and enters
Row reaction, produces product.
Preferably, above-mentioned reaction solution purification procedures comprise the following steps：The reaction solution is added to the water, point liquid will
Organic layer is acidified to pH≤3.5, separates water layer, adds organic solvent washing, point liquid, regulation water layer pH value to more than 9, filtering,
It is dried to obtain free alkali.Wherein, it is conventional acid or alkaline examination for being acidified or adjusting the reagent of water layer pH value to more than 9
Agent, such as hydrochloric acid, sulfuric acid, nitric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus；It is described to have
Machine solvent is conventional organic solvent, such as ethyl acetate, methyl acetate, dichloromethane, chloroform, tetrahydrofuran, ether, methyl- tert
Butyl ether.
It is highly preferred that above-mentioned preparation method comprises the following steps：By 1- (2- pyrimidine radicals) piperazine, 1,4- dibromobutanes, carbon
Sour potassium, benzyltriethylammoinium chloride and toluene are added in reactor, back flow reaction 3-4 hours, add the cis- of the purifying
- two rings [2.2.1] heptane -2,3- dicarboximide, flows back 4-5 hours, reaction solution is cooled to after room temperature and is added to the water outside, point
Liquid, organic layer adds hydrochloric acid solution and is acidified to pH≤3.5, separates water layer, adds organic solvent washing, separates water layer and adds activity
Charcoal, filtering, filtrate adjusts pH value to more than 9 with sodium hydroxide solution, and filtering is dried to obtain free alkali, adds citric acid and ethanol
Mixed solution, flow back 0.5-1 hour, cool down, filtering adds the 5-10 times of ethanol measured into filter cake, backflow 0.5-1 hours,
Cooling, filtering, is dried to obtain product.
Preferably, above-mentioned citric acid is monohydrate form.
The present invention also provides use of the above-mentioned tandospirone citrate composition in antidepression and/or anxiolytic drugs is prepared
On the way.
Preferably, above-mentioned antidepression and/or anxiolytic drugs also include pharmaceutically acceptable auxiliary material or complementary composition.
Preferably, above-mentioned antidepression and/or the formulation of anxiolytic drugs include liquid preparation, gaseous formulation, solid pharmaceutical preparation
And semisolid preparation, preferred fragrance aqua, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, ball
The common formulations such as agent, tablet, capsule, granule, film, ointment, suppository, paste, more preferably capsule, tablet, particle
Agent etc..
The present invention also provide above-mentioned tandospirone citrate composition treatment antidepression and/or antianxiety in purposes with
And treatment method.
The present inventor by carrying out in-depth study to relevant material in tandospirone citrate, surprisingly, it was found that
The tandospirone citrate composition of the application is in addition to anxiolytic effect, and its clinical antidepressants effect is significantly improved,
Adverse reaction is substantially reduced.The purification procedures of cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides of intermediate of the present invention
Environmental protection, safety, the reagent of low toxicity/nontoxic have been used, and there is high yield, high-purity.Improving in the middle of the key
On the basis of body purity, using the preparation method of the application, without the intermediate product of separation reaction generation, industry is substantially increased
Production efficiency, shortens the production cycle, and prepared product purity is high, and relevant content of material is low.
Embodiment
The embodiment to the present invention is described in detail below.It should be appreciated that described herein specific
Being given for example only property of embodiment the present invention will be described, be not intended to limit the invention.
Embodiment 1：
1st, the preparation of cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides
Method according to report in document (Chinese New Products .2014,8,13) prepares cis- outer-two rings
[2.2.1] heptane -2,3- dicarboximide, it is 2.7% to measure its relevant content of material through HPLC.Wherein, HPLC (efficient liquid phases
Chromatogram) test condition is：The use of octadecylsilane chemically bonded silica is filler, 0.01mol/L potassium dihydrogen phosphates (are used
10% sodium hydroxide solution adjusts pH to 7.5)-acetonitrile (80:20) it is mobile phase, Detection wavelength is 243nm, and the result purity of survey is
97.3%.
2nd, the purifying of cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides
(i) cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide 100.0g of the preparation of above-mentioned steps 1 is weighed, is added
The mixed solvent of 400mL ethanol and 400mL water, is heated to after solvent refluxing, stirring 1h, is cooled to 50 ± 5 DEG C of stirring 1h, then drop
Temperature is cooled to room temperature and places 2~3h, filtering collects filter cake, 45 ± 5 DEG C are dried under reduced pressure 3~4h, i.e., naturally to 35 ± 5 DEG C of stirring 1h
Obtain cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide 98.5g, yield 98.5%.HPLC measures purity and is more than
99.5%, testing conditions with above-mentioned steps 1, wherein, (the cis- outer formyl of-two rings [2.2.1] hept- 5- alkene -2,3- bis- is sub- for impurity 1
Amine) content is 0.18%, impurity 2 (cis- in-two rings [2.2.1] heptane -2,3- dicarboximide) content is 0.12%, impurity 3
(- two rings [2.2.1] hept- 5- alkene -2,3- dicarboximides in cis-) content is 0.009%.
(ii) cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide, inventory are prepared according to the method for above-mentioned (i)
It is 100g, actual conditions and relevant material testing result are referring to table 1.
Table 1, process for purification and result
Note：Solvent ratios are volume ratio in table；" -- " represents not detect.
3rd, the preparation of tandospirone citrate composition
By 1- (2- pyrimidine radicals) piperazine 164g, Isosorbide-5-Nitrae-dibromobutane 227g, potassium carbonate 345g, benzyltriethylammoinium chloride
20g, toluene 2L is added in reactor, is stirred at reflux reaction 3-4 hours, adds the cis- of the middle purifying of 165g above-mentioned steps 2 (i)
- two rings [2.2.1] heptane -2,3- dicarboximide, is stirred at reflux 4-5 hours outside, and reaction solution, which is cooled to after room temperature, is added to water
In, stir, stand, point liquid, organic layer adds hydrochloric acid solution acidifying, to pH≤3.5, separates water layer, add ethyl acetate washing,
Separate water layer and add proper amount of active carbon, be sufficiently stirred for, filter, filtrate adjusts pH value to more than 9 with sodium hydroxide solution, filters, and does
It is dry to obtain free alkali, citric acid 210g and ethanol 2L mixed solution is added, is stirred at reflux 0.5-1 hours, is cooled to room temperature, mistake
Filter, the 5-10 times of ethanol measured is added into filter cake, is stirred at reflux 0.5-1 hours, is cooled to room temperature, filters, is dried to obtain product
530g, yield 92%.
Products therefrom is subjected to HPLC detections, test condition is：The use of octadecylsilane chemically bonded silica is filler,
0.01mol/L potassium dihydrogen phosphates (adjusting pH to 7.5 with 10% sodium hydroxide solution)-acetonitrile (60:40) it is mobile phase, detection
Wavelength is 243nm.Measure in tandospirone citrate composition, the content of tandospirone citrate is more than 98.5%；Chemical combination
The citrate content of thing I is 0.07%, and the content of the citrate of compound ii is 0.002%, the citric acid of compound III
The content of salt is 0.001%.
Embodiment 2
Cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides prepared using under 1-5 condition entries in table 1 is originals
Material, prepares tandospirone citrate composition, is detected through HPLC, the content of tandospirone citrate exists according to the method described above
More than 98.0%, relevant content of material is shown in Table 2.
Table 2, testing result
Note：" -- " represents not detect.
As shown in the above, cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide of the intermediate of embodiment 1,2
Purification procedures used environmental protection, safety, the reagent of low toxicity/nontoxic, and there is high yield, high-purity；In addition, smooth
The preparation of spiral shell one compositions is spent using the technique of one pot of two step, without the intermediate product of separation reaction generation, substantially increases work
Industry production efficiency, shortens relevant content of material in production cycle, and the product prepared by the inventive method low.
Embodiment 3：
1st, the step 1 of the preparation be the same as Example 1 of cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides.
2nd, the purifying of cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides
(i) cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide 100.0g of the preparation of above-mentioned steps 1 is weighed, is added
The mixed solvent of 400mL ethanol and 400mL water, is heated to solvent refluxing, stirs 1h, room temperature is naturally cooled to, in -10 ± 5 DEG C
2~3h is placed, suction filtration adds the mixed solvent of 200mL ethanol and 200mL water into filter cake, is heated to solvent refluxing, stirs
1h, naturally cools to room temperature, and 2~3h is placed in 5 ± 5 DEG C, and filtering, by filtration cakes torrefaction, produces cis- outer-two rings [2.2.1] heptan
Alkane -2,3- dicarboximide 99.5g, yield 99.5%.HPLC measures purity more than 99.5%, testing conditions be the same as Example 1
Step 1, wherein, the content of impurity 1 (cis- outer-two rings [2.2.1] hept- 5- alkene -2,3- dicarboximide) is 0.13%, is not examined
Go out impurity 2 and impurity 3.
(ii) cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide is prepared according to the method described above, and inventory is
100g, actual conditions and relevant material testing result are referring to table 3.Shown according to testing result, the inventive method products obtained therefrom
Impurity 1, impurity 2, the total content of impurity 3 are not higher than 0.2%.
Table 3, process for purification and result
Note：Mixed solvent ratio is volume ratio in table；" -- " represents not detect.
3rd, the preparation of tandospirone citrate composition
By 1- (2- pyrimidine radicals) piperazine 164g, Isosorbide-5-Nitrae-dibromobutane 227g, potassium carbonate 410g, benzyltriethylammoinium chloride
22g, toluene 2.5L is added in reactor, is stirred at reflux reaction 3-4 hours, adds purifying in 165g above-mentioned steps 2 (i)
Cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide, is stirred at reflux 4-5 hours, reaction solution is cooled to after room temperature and is added to
In water, stir, stand, point liquid, organic layer adds hydrochloric acid solution and is acidified to pH≤3.5, separate water layer, add dichloromethane and wash
Wash, separate water layer and add proper amount of active carbon, be sufficiently stirred for, filter, filtrate adjusts pH value to more than 9 with sodium hydroxide solution, filters,
Free alkali is dried to obtain, citric acid 210g and ethanol 2.5L mixed solution is added, is stirred at reflux 0.5-1 hours, is cooled to room temperature,
Filtering, the 5-10 times of ethanol measured is added into filter cake, is stirred at reflux 0.5-1 hours, is cooled to room temperature, filters, is dried to obtain product
541g, yield 94%.
Products therefrom is subjected to HPLC detections, test condition is identical with the step 3 of embodiment 1, measures the smooth degree spiral shell of citric acid
In one compositions, the content of tandospirone citrate is more than 98.5%；The content of the citrate of chemical compounds I is 0.05%,
Compound II citrates and compound III citrates are not detected.
Embodiment 4
Cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides prepared using in table 3 under each condition entry is originals
Material, prepares tandospirone citrate composition, is detected through HPLC, the content of tandospirone citrate exists according to the method described above
More than 98.5%, wherein in numbering 3-5 composition, the content of tandospirone citrate is more than 99.0%.Relevant material
Content is shown in Table 4.
Table 4, testing result
Note：" -- " is expressed as detection.
As shown in the above, embodiment 3,4 intermediates cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide
Environmental protection, safety, the reagent of low toxicity/nontoxic have been used in purification procedures, and there is high yield, high-purity；In addition, smooth
The preparation of spiral shell one compositions is spent using the technique of one pot of two step, without the intermediate product of separation reaction generation, substantially increases work
Industry production efficiency, shortens the production cycle, and relevant content of material is low in the product prepared by the inventive method.
Comparative example 1
1st, the step 1 of the preparation be the same as Example 1 of cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides.
2nd, the preparation of tandospirone citrate composition
Cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide prepared by above-mentioned steps 1 is as raw material, inventory
For 165g, tandospirone citrate composition 485g is prepared according to the method for the step 3 of embodiment 1.HPLC testing conditions are same
The step 3 of embodiment 1, the content for measuring the citrate of chemical compounds I is 0.62%, and the content of the citrate of compound ii is
0.46%, the content of the citrate of compound III is 0.25%.
From embodiment 1-4 and the result of comparative example 1, the smooth degree spiral shell of citric acid can be effectively improved by the inventive method
The content of ketone, control is about material in the range of relatively low limitation.
Embodiment 5：Pharmaceutical composition of the present invention
After the tandospirone citrate composition that embodiment 3 is prepared is mixed with starch by equal increments method, then
Mixed with microcrystalline cellulose, granulation is encapsulated to produce capsule.
Embodiment 6：Pharmaceutical composition of the present invention
Supplementary material is crossed into 100 mesh sieves respectively.By the tandospirone citrate group of 1 group of 4 table of embodiment, 4 numbering of amount to be prepared
Compound is mixed with low-substituted hydroxypropyl methylcellulose by equal increments method, sequentially adds mannitol, lactose starch, is finally added
Enter orange flavor and magnesium stearate, tabletting after being well mixed produces sublingual tablets.
Embodiment 7：Pharmaceutical composition of the present invention
By tandospirone citrate composition, the hydroxypropyl methyl cellulose of 2 groups of 4 table of embodiment, 4 numbering of amount to be prepared
Well mixed with lactose, sieving adds 75% ethanol solution softwood, crosses 20 mesh sieve series wet granulars, in 50 DEG C or so drying, 20
Mesh sieve whole grain, adds magnesium stearate and talcum powder, and tabletting after being well mixed produces sustained-release tablet.
Embodiment 8：Pharmaceutical composition of the present invention
By the tandospirone citrate composition of 3 groups of 4 table of embodiment, 4 numbering of amount to be prepared, microcrystalline cellulose, lactose and
After sodium carboxymethyl starch is mixed in granulator, ethanol softwood is added, after vacuum drying, sieving is arranged, and pack produces particle
Agent.
Embodiment 9：Pharmaceutical composition of the present invention
By the tandospirone citrate composition of 4 groups of 4 table of embodiment, 4 numbering of amount to be prepared, microcrystalline cellulose, lactose and
After sodium carboxymethyl starch is mixed in granulator, ethanol softwood is added, after vacuum drying, sieving is arranged, and adds stearic acid
Tabletting after magnesium is well mixed, produces tablet.
Beneficial effects of the present invention are further illustrated below by way of pharmacodynamics test and clinical test：
Medicament composition capsule agent, the tandospirone citrate of each group is made according to the methods described of embodiment 5 in following each groups
Composition is made by the following method：Original quality group is made by comparative example 1, and Quality advance group 1 is by the 2nd in the table 2 of embodiment 2
Group is made, and Quality advance group 2 is made by the 3rd group in the table 2 of embodiment 2, and Quality advance group 3 is by the 6th group in the table 4 of embodiment 4
It is made, Quality advance group 4 is made by the 5th group in the table 4 of embodiment 4.
Experiment 1：The clinical test of pesticide effectiveness
Use the clinical examination that pharmaceutical composition of the present invention carries out polycentric random, double blinding, placebo parallel control is studied
Test, patient's sum is 120 people, be randomly divided into 3 groups, the age, inclusion criteria was the slight anxious patients to moderate from 24 to 65 years old
And meet with disease of digestive system, mucosal lesion or easy bleeding, more than 50 years old age wherein at least one condition.In research
Period patient is prohibited from using other sedatives, anti-inflammatory agent, muscle relaxant, depressor, antipsychotic drug, antidepressants or antianxiety
Medicine.Each group takes placebo, original quality group and (contains the citrate of 0.62% chemical compounds I, the Chinese holly of 0.46% compound ii respectively
Same regimen acid salt, the citrate of 0.25% compound III), Quality advance group 3 citrate of 0.05% chemical compounds I (contain).Medication
After 30 days, curative effect (antianxiety curative effect carries out evaluation analysis according to Hamilton anxiety scale) and adverse reaction evaluation are carried out.Its
In, the effective percentage of placebo is 10%, and adverse reaction rate is 5%；The effective percentage of original quality group is 65%, bad anti-
It is 35% to answer incidence；The effective percentage of Quality advance group 3 is 75%, and adverse reaction rate is 15%.
Clinical observation result shows, original quality group and Quality advance group are respectively provided with obvious curative effect, and Quality advance group
Rate of adverse reactions be significantly lower than original quality group, illustrate Quality advance group not only with anxiolytic effect, it is not
Good reaction also has obvious reduction.
Experiment 2：Hepatotoxicity wind agitation is tested
The serious adverse reaction of tandospirone citrate composition, which is used for a long time, includes the damage to liver, below by small
The long term administration of mouse tests to investigate degree of impairment of the tandospirone citrate composition to liver of different quality group.
120 18~22g of body weight male ICR mouse is randomly divided into 6 groups, every group 20, each administration group is as shown in table 5
Medicine and dosage continuous gavage be administered 28 days, blank group physiological saline gavage, takes fasting 12h before blood, the 29th by 1 times/day
It takes two parts of blood by eyeball rear vein beard, and transaminase AST and concentration of ALT in serum are determined respectively.
Test data mean+SDRepresent, data analysis is carried out with SPSS softwares.Compare between group
Using one-way analysis of variance (One-Way ANOVA), with P<0.05 and P<0.01 is with significant difference.
The influence of table 5, long term administration to liver function
Compared with blank control group：#P<0.05,##P<0.01；Compared with original quality group：*P<0.05, * * P<0.01.
Result of the test shows, is administered alone daily using routine dose, and original quality group is compared with blank group, mice serum
Middle AST and concentration of ALT significantly raise (##P<0.01)；And use the tandospirone citrate composition after Quality advance to give daily
Medicine, compared with original quality group, AST and concentration of ALT rising condition are significantly reduced in mice serum, especially Quality advance group
2、3、4(**P<0.01)；And AST and ALT concentration is with citrate, the compound ii of chemical compounds I in Quality advance group
Citrate and compound III citrate content reduction and reduce, show use quality improve after the smooth degree of citric acid
Spiral shell one compositions significantly reduce its toxicity to liver, and drug safety is higher.
Experiment 3：Antidepression animal model experiment
(1) Tail suspension test (antidepression experiment)
84 mouse are randomly divided into 7 groups, every group 12, gastric infusion is grouped once by the medicine in table 6.Each group mouse
1h after administration, will paste hang upside down at the tail point 1cm of mouse, make it be in hang state, head by the feet on hook with immobilization with adhesive tape
Apart from experimental bench about 15cm, operation one every time records the desperate row of mouse in 6min using animal behavior video analytic system
For the accumulative dead time (s) after analysis in 4min.Judge that motionless standard stops struggling for mouse, it is static in the state of hanging by the feet
It is motionless.
Test data mean+SDRepresent, data analysis is carried out with SPSS softwares.Compare between group
Using one-way analysis of variance (One-Way ANOVA), with P<0.05 and P<0.01 is with significant difference.
Table 6, Tail suspension test result
Compared with blank control group：#P<0.05,##P<0.01；Compared with original quality group：*P<0.05,**P<0.01.
Test result indicates that, compared with blank control group, accumulative dead time of positive drug group mouse significantly reduce (##P<
0.01)；The mouse accumulative dead time of original quality group and Quality advance group 1,2,3,4 is both less than blank control group, illustrates original
Beginning quality group has certain antidepressant effect with Quality advance group；Compared with original quality group, the mouse of Quality advance group 2,3,4
The accumulative dead time significantly reduce (* * P<0.01), show that Quality advance group antidepressant effect is better than original quality group；By matter
Measure raising group 3 and 4 results are understood, the mouse accumulative dead time is reduced with the increase of the citrate content of chemical compounds I,
Less than Quality advance group 1 and 2, show in the range of the application, the antidepressant effect of tandospirone citrate composition is with chemical combination
The increase of the citrate content of thing I and improve.
(2) mouse forced swimming test (antidepression experiment)
84 mouse are randomly divided into 7 groups, every group 12, medicine is grouped gastric infusion once according to the form below.Each group mouse
1h after administration, mouse is respectively put into high 20cm, diameter 10cm lucite cylinder, contained in lucite cylinder into 25 ± 1 DEG C
Water, height 15cm, operation one every time, and use the swimming row of mouse in animal behavior video analytic system record 6min
For, after analysis in 4min mouse forced swimming test accumulative dead time (s).Dead time is judged as that animal stops earning in water
Prick, in floating state, only tiny limb motion is to keep head to float on the surface.
Test data mean+SDRepresent, data analysis is carried out with SPSS softwares.Compare between group
Using one-way analysis of variance (One-Way ANOVA), with P<0.05 and P<0.01 is with significant difference.
Table 7, mouse forced swimming test result
Compared with blank control group：#P<0.05,##P<0.01；Compared with original quality group：*P<0.05,**P<0.01.
Test result indicates that, compared with blank control group, accumulative dead time of positive drug group mouse significantly reduce (##P<
0.01)；The mouse accumulative dead time of original quality group and Quality advance group 1,2,3,4 is both less than blank control group, illustrates original
Beginning quality group has certain antidepressant effect with Quality advance group；Compared with original quality group, the mouse of Quality advance group 2,3,4
The accumulative dead time significantly reduce (* * P<0.01)；From the result of Quality advance group 3 and 4, mouse add up the dead time with
The reduction of the citrate content of chemical compounds I and increase, and less than Quality advance group 1, show in the range of the application, citron
The antidepressant effect of sour Tandospirone composition improves with the increase of the citrate content of chemical compounds I.
The studies above result shows, by the control of each index components, in the framework of the present definition, can effectively carry
The drug effect of high tandospirone citrate, reduces toxic side effect.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
Claims (10)
1. a kind of tandospirone citrate composition, it is characterised in that the composition is 0-0.5% comprising weight percentage
Chemical compounds I and/or its citrate, 0-0.4% compound ii and/or its citrate and 0-0.2% compound
III and/or its citrate；The content of chemical compounds I and/or its citrate is preferably 0.001-0.4%, more preferably
0.001-0.2%；The content of compound ii and/or its citrate is preferably 0-0.3%, more preferably 0-0.2%；Compound
III and/or the content of its citrate be preferably 0-0.1%, more preferably 0-0.05%,
2. tandospirone citrate composition according to claim 1, it is characterised in that compound III in the composition
And/or the content of its citrate is 0.
3. tandospirone citrate composition according to claim 1 or 2, it is characterised in that chemical combination in the composition
The content of thing II and/or its citrate is 0.
4. the tandospirone citrate composition according to any one of claim 1-3, it is characterised in that the composition
The content of middle tandospirone citrate is more than 98%；Preferably more than 98.5%；More preferably more than 99%.
5. the preparation method of tandospirone citrate composition any one of claim 1-4, it is characterised in that including inciting somebody to action
The process that cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides (IV) are purified：
The purification procedures include cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides being dissolved in what is separated out again after solvent
Step.Preferably, the purification procedures include adding solvent into cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide,
Heating, is cooled down, and is filtered, and is dried, and produces cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide.
6. preparation method according to claim 5, it is characterised in that the purification procedures include following two methods：
(A) solvent is added into cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide, heated, be cooled to 50 ± 5 DEG C, then
35 ± 5 DEG C are cooled to, room temperature is cooled to, filtered, is dried, cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide is produced；
Or
(B) solvent is added into cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide, heats, be cooled to room temperature, then drop
Temperature is to -10 ± 5 DEG C, and filtering adds solvent into filter cake, heats, is cooled to room temperature, is cooled to 5 ± 5 DEG C, filters, and dries,
Produce cis- outer-two rings [2.2.1] heptane -2,3- dicarboximides.
7. the preparation method according to claim 5 or 6, it is characterised in that comprise the following steps：By 1- (2- pyrimidine radicals) piperazine
Piperazine, Isosorbide-5-Nitrae-dibromobutane, potassium carbonate, benzyltriethylammoinium chloride and toluene, which are added in reactor, to react, and then adds described
Cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide of purifying is reacted, and reaction solution purify to be dissociated
Alkali, adds citric acid and is reacted, produce product.Preferably, the reaction solution purification procedures comprise the following steps：Will be described
Reaction solution is added to the water, point liquid, and organic layer is acidified into pH≤3.5, separates water layer, adds organic solvent washing, and point liquid is adjusted
Layer pH value of economizing on water is to more than 9, and filtering is dried to obtain free alkali.
8. the preparation method according to any one of claim 5-7, it is characterised in that comprise the following steps：By 1-, (2- is phonetic
Piperidinyl) piperazine, Isosorbide-5-Nitrae-dibromobutane, potassium carbonate, benzyltriethylammoinium chloride and toluene is added in reactor, back flow reaction 3-
4 hours, cis- outer-two rings [2.2.1] heptane -2,3- dicarboximide of the purifying is added, is flowed back 4-5 hours, reaction solution is cold
But to being added to the water after room temperature, point liquid, organic layer adds hydrochloric acid solution acidifying, to pH≤3.5, separates water layer, adds organic
Solvent is washed, and is separated water layer and is added activated carbon, filtering, filtrate is adjusted pH value to more than 9, filtered with sodium hydroxide solution, dry
To free alkali, the mixed solution of citric acid and ethanol is added, is flowed back 0.5-1 hours, is cooled down, filtering adds 5-10 into filter cake
The ethanol of amount, flows back 0.5-1 hours again, cools down, and filtering is dried to obtain product.
9. the preparation method according to claim 5 or 6, it is characterised in that the solvent is selected from：Water, alcohols, ketone, ether
At least one of class, esters, halogenated hydrocarbon, amide-type, sulfoxide type solvents；Preferably, the alcohols solvent be preferably methanol,
Ethanol, propyl alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, n-hexyl alcohol etc.；Preferably, the ketone
Solvent is preferably acetone, butanone, cyclohexanone etc.；Preferably, the ether solvent is preferably ether, isopropyl ether, tetrahydrofuran, 1,
4- dioxane, methyl tertiary butyl ether(MTBE) etc.；Preferably, the esters solvent is preferably methyl acetate, ethyl acetate, acetic acid third
Ester, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate etc.；Preferably, the halogenated hydrocarbon solvent is preferred
For dichloromethane, chloroform, tetrachloromethane etc.；Preferably, the amide solvent is preferably DMF, DMAC etc.；Preferably, it is described
Sulfoxide type solvents are preferably DMSO；Preferably, the solvent is selected from water, ethanol, methanol, isopropanol, butanol, acetone, butanone
At least one of；Mixed solution, first more preferably selected from methanol, ethanol, isopropanol, butanol, acetone, ethanol and water
In the mixed solution of alcohol and water, the mixed solution of isopropanol and water, the mixed solution of butanol and water, the mixed solution of acetone and water
Any one；More preferably it is selected from ethanol：Water=0.1~10:1st, methanol：Water=0.1~10:1st, isopropanol：Water=
0.1~10:1st, butanol：Water=0.1~10:1st, acetone：Water=0.2~5:Mixed solvent in 1；It is still more preferably choosing
From：Ethanol：Water=0.5~4:1st, methanol：Water=3~9:1st, isopropanol：Water=0.2~2:1st, butanol：Water=0.15~5:1、
Acetone：Water=1:Mixed solvent in 1.
10. tandospirone citrate composition any one of claim 1-4 is preparing antidepression and/or anxiolytic drugs
In purposes；Preferably, the antidepression and/or anxiolytic drugs also include pharmaceutically acceptable auxiliary material or it is complementary into
Point；Preferably, the antidepression and/or the formulation of anxiolytic drugs include liquid preparation, gaseous formulation, solid pharmaceutical preparation and half admittedly
Body preparation, preferred fragrance aqua, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, piece
The common formulations such as agent, capsule, granule, film, ointment, suppository, paste, more preferably capsule, tablet, granule.
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| WO2021129340A1 (en) * | 2019-12-25 | 2021-07-01 | 四川科瑞德制药股份有限公司 | Tandospirone pharmaceutical composition, preparation method therefor and use thereof |
| CN115611866A (en) * | 2022-10-31 | 2023-01-17 | 南京海纳医药科技股份有限公司 | Preparation method of tandospirone citrate |
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| CN115611866B (en) * | 2022-10-31 | 2024-04-23 | 南京海纳医药科技股份有限公司 | Preparation method of tandospirone citrate |
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