CN106800550A - A kind of 5 receptor serotonin agonists - Google Patents
A kind of 5 receptor serotonin agonists Download PDFInfo
- Publication number
- CN106800550A CN106800550A CN201610719746.7A CN201610719746A CN106800550A CN 106800550 A CN106800550 A CN 106800550A CN 201610719746 A CN201610719746 A CN 201610719746A CN 106800550 A CN106800550 A CN 106800550A
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- Prior art keywords
- maleic acid
- tandospirone
- preparation
- solvent
- compound
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- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a kind of 5 receptor serotonin agonist.Specifically provide a kind of maleic acid Tandospirone compound.Present invention also offers the preparation method of the compound, and pharmaceutical composition and purposes containing the compound.The maleic acid Tandospirone that the present invention is provided exists in the form of crystal, and its is stable in properties, and water-soluble good, bioavilability is significantly improved, and a kind of effective solution route is provided to improve Drug safety and validity；In addition, the preparation process is simple of the compounds of this invention, high income, it is adaptable to industrialized production.
Description
The application is Chinese No. 201510835073.7 divisional application of application for a patent for invention, and the applying date of this application is
On November 25th, 2015, a kind of entitled 5-hydroxytryptamine receptor activator.
Technical field
The present invention relates to a kind of Tandospirone compound, the maleate of Tandospirone is related generally to, and in particular to the change
The crystal form of compound, and the preparation method of the compound crystal, pharmaceutical composition and purposes.
Background technology
Tandospirone chemical entitled (3a α, 4 β, 7 β, 7a α)-hexahydro -2- [4 [4- (2- pyrimidine radicals) -1- (piperazinyl) -
Butyl] -4,7- methylene -1H- iso-indoles -1,3 (2H)-diketone belong to azaspiro ketone medicine, earliest by SUMITOMO CHEMICAL pharmacy strain
Formula commercial firm is developed, and listing was approved in Japan in 1996.Tandospirone is the 3rd generation anxiolytic, is mainly used in treatment burnt
Worry or the disease of other companion's anxiety states.Different from traditional anxiolytic drugs, it is that a kind of serotonin of high selectivity is received
Body activator, by 5-HT1AThe selective binding of acceptor, suppresses hyperfunction serotonin energy nervous activity, so as to play anti-
Anxiety is acted on.Compared to original shape medicine azaspiro ketone and with analog derivative buspirone, it has selective antianxiety higher
Effect, this effect is close with diazepam, but in the toxic and side effect of the aspect such as nervimotion Sexual dysfunction and drug abuse
It is smaller than diazepam.Due to the specificity of mechanism of action, it has, and drug safety is high, side reaction is few, without relaxed muscle and calmness
The advantages of effect, no dependence and drug withdrawal give up phenomenon, prolonged application without accumulation in vivo, is suitable to long-term prescription.
Now there are some researches show, Tandospirone and its salt in addition to angst resistance effect, in the treatment of other the nervous system diseases
Or auxiliary therapy aspect also has extraordinary application.Tandospirone and its salt have antidepressant effect, for being mixed with Jiao
Consider and depressed patient is evident in efficacy, and vegetative nerve symptom can be improved by antianxiety and antidepressant effects, such as intestines swash
Invite syndrome, functional dyspepsia FD, postoperative nausea and vomiting etc..It still treats that Central nervous system is ataxic to be had
Effect medicine, can be obviously improved patient's cerebellar ataxia symptom.It can also be effectively improved suffers from neurasthenia, senile dementia or essence
The memory of the illness patients such as god's division, treatment increases rheological properties memory disorders, significantly improves declarative memory, logic memory and spoken language
Paired-association etc..For some physical diseases such as hypertension, coronary heart disease, diabetes, peptic ulcer etc., combination Tandospirone can
To play fabulous auxiliary therapy effect.Additionally, research show as 5-hydroxytryptamine receptor activator Tandospirone and its
Salt also has the activity of drop intraocular pressure, can be used for treatment because endothelial cell proliferation, inflammation, vascular permeability are improved or blood vessel life
Into etc. the eye disease that causes, such as diabetic retinopathy, AMD, macular edema, glaucoma
Etc..Tandospirone and its salt have extraordinary clinical treatment advantage and wide market prospects.
In clinical application, the drug molecule for having nearly half is all exist in a salt form and be administered.Use oppositely charged
Molecule or ion and medicine into salt, medicine some undesirable physical chemistry or biopharmaceutical properties can be effectively improved, such as
Change the solubility of medicine, reduce hygroscopicity, improve stability, change fusing point, improve grinding performance, be easy to prepare purifying, carry
High osmosis, raising bioavilability, the compliance that improves, reduction adverse reaction etc..The poorly water-soluble of Tandospirone, into after salt
Its water-soluble and physical and chemical stability can be effectively improved, bioavilability is improved, therefore, Tandospirone salt is in medical application
In often than its original shape medicine Tandospirone have bigger advantage, be conducive to having given play to greatest extent the effect of medicine.Mesh
It is preceding it is on the market be the citrate of Tandospirone, i.e. tandospirone citrate, generally with tablet or the shape of capsule
Formula is widely used in the treatment of anxiety disorder or relevant disease, the clinical application research with comparative maturity.Even so, in ophthalmology
In the application of disease, document report tandospirone citrate because its alkali can to eye caused by strong impulse, so exploitation
Will not generally consider to select its citrate first during ophthalmic preparation.In consideration of it, the exploitation other types of salt of Tandospirone has
Clinical drug value very high, such as maleate.
Maleic acid is a kind of conventional organic acid, is worth with Clinical practice very high, can be solved into salt with alkaline drug
Indissoluble sex chromosome mosaicism.At present, for the research of Tandospirone salt, in patent US4507303, US4818756, CN101362751A etc.
Report the preparation method of tandospirone citrate.In addition, in patent CN101880274A, US4507303, EP0082402 etc.
Disclose the preparation method of hydrochloric acid Tandospirone.In with regard to presently disclosed document, yet there are no on Tandospirone maleate shape
The preparation method of formula and/or the relevant report of crystal formation.
It is well known that for medicine, the compound of different salifie forms may have a different crystal formations, it is same into
Salt form compound there is likely to be polymorphic.And different crystal formations be possible to different colors, fusing point, stability,
Apparent solubility, rate of dissolution etc., these properties can directly influence stability, solubility, hygroscopicity, the life of pharmaceutical preparation
Thing availability etc., and thus cause the difference of drug quality and clinical drug effect.Therefore, for the various crystal salts of Tandospirone
It is significantly to prepare with research.
The content of the invention
It is an object of the invention to provide stable in properties, water-soluble good maleic acid Tandospirone compound.
Present invention also offers the preparation method of maleic acid Tandospirone compound, pharmaceutical composition and purposes.
The invention provides a kind of preparation method of maleic acid Tandospirone, it includes following operational sequence：
A, Tandospirone and maleic acid are taken, add solvent, stirring, completely, reaction solution is standby for question response；
B, reaction solution naturally cool to room temperature, separate solid, dry, and obtain final product maleic acid Tandospirone.
Further, in step A, Tandospirone is less than or equal to 1 with the mol ratio of maleic acid:1, Tandospirone and solvent
Mass volume ratio be 1:1~30kg/L, the solvent is any one or its combination of water, rudimentary organic solvent, wherein, institute
State alcohols, ethers, ketone, esters solvent of the rudimentary organic solvent for acetonitrile or carbon number less than 7.
Wherein, Tandospirone is preferably 1 with the mol ratio of maleic acid:(1~3).
Wherein, Tandospirone is preferably 1 with the mass volume ratio of solvent:3~25kg/L.
Wherein, the solvent is preferably methyl alcohol, ethanol, isopropanol, butanol, acetone, butanone, cyclohexanone, water, tetrahydrochysene furan
Mutter, any one or its combination of dioxane, acetonitrile, ethyl acetate, butyl acetate, ethyl butyrate, ether, isopropyl ether.
Further, course of reaction is suitably heated in step A, and preferably heating-up temperature is room temperature to solvent refluxing, more preferably
30 DEG C to solvent refluxing.
The invention provides a kind of maleic acid Tandospirone compound, the compound is characterised by that it is with crystal formation II
Form is present, when the compounds of this invention crystal formation II carries out X-ray powder diffraction using Cu K α radiations source, its X-ray powder diffraction
In figure, the 2 θ angles of diffraction have characteristic absorption peak at 7.2 ± 0.2,14.4 ± 0.2,21.8 ± 0.2 degree.
Further, in the X-ray powder diffraction figure of the compound crystal form II, the 2 θ angles of diffraction also 20.3 ± 0.2,
21.3 ± 0.2 degree have characteristic absorption peak.
Further, in the X-ray powder diffraction figure of the maleic acid Tandospirone crystal formation II, 2 θ angle of diffraction features
The main peaks of relative intensity I% >=5% at peak have：
Further, in the X-ray powder diffraction of the compound crystal form, with x-ray powder substantially as shown in Figure 1
Diffraction pattern.
The structural formula of the compounds of this invention is：
Wherein, the fusing point of the compound is 159.0~160.5 DEG C.
Present invention also offers the preparation method of above-mentioned maleic acid Tandospirone compound, it includes following operational sequence：
A, maleic acid Tandospirone is taken, add solvent, heating for dissolving is obtained maleic acid Tandospirone solution；
B, room temperature crystallization is naturally cooled to, separate crystal, dried, obtain final product maleic acid Tandospirone crystal formation II.
Further, in step a, heating for dissolving temperature be 30 DEG C to solvent refluxing, maleic acid Tandospirone and solvent
Mass volume ratio is 1:1~30g/mL, the solvent is selected from any one or its combination of water, acetonitrile, tetrahydrofuran.
Wherein, heating for dissolving temperature is preferably 45 DEG C to solvent refluxing.
Wherein, maleic acid Tandospirone is preferably 1 with the mass volume ratio of solvent:1~25g/mL, more preferably 1:3~
20g/mL。
Wherein, the mixed solution of the preferred acetonitrile of the solvent, acetonitrile and water, the mixed solution of tetrahydrofuran and water, acetonitrile
Any one of the mixed solution of mixed solution, acetonitrile and tetrahydrofuran and water with tetrahydrofuran.
Present invention also offers a kind of pharmaceutical composition, it is to live with above-mentioned maleic acid Tandospirone compound crystal form II
Property composition, adds the preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
Pharmaceutically acceptable carrier of the present invention, the conventional figuration for preparing above-mentioned preparation being well known in the art
Agent or auxiliary material.Oral formulations or the conventional excipient of external preparation or auxiliary material include but are not limited to filler (diluent), profit
Lubrication prescription (glidant or antitack agent), dispersant, wetting agent, adhesive, conditioning agent, solubilizer, antioxidant, bacteriostatic agent, emulsification
Agent, disintegrant etc..Adhesive such as syrup, Arabic gum, gelatin, starch slurry, PVP, cellulose derivative etc.；Filling
Agent such as lactose, dextrin, starch and its derivative, cellulose derivative, inorganic calcium salt, mannitol, agar powder etc.；Lubricant
Such as superfine silica gel powder, stearic acid and its esters, talcum powder, hydrogenated vegetable oil, polyethylene glycols；Disintegrant such as starch and its spread out
Biology, PVPP, cellulose derivative etc.；Wetting agent such as water, alcohols or other organic solvents etc..The injection
The conventional excipient of agent or auxiliary material are included but are not limited to：Antioxidant such as sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, fourth
Two phenylpropenoic acids etc.；Bacteriostatic agent such as 0.5% phenol, 0.3% cresols, 0.5% anesin etc.；Conditioning agent such as hydrochloric acid, Chinese holly
Rafter acid, potassium hydroxide (sodium), buffer etc.；Emulsifying agent such as Tween-80, lecithin, Fabaceous Lecithin etc.；Solubilizer is such as told
Temperature -80, bile, glycerine etc..Additionally, can also be by active component and pharmaceutically acceptable slow controlled release carrier, according to this area
The preparation method of known sustained-release preparation is made sustained-release preparation.
The dosage form of pharmaceutical composition of the present invention, can be that liquid preparation, gaseous formulation, solid pharmaceutical preparation and half are solid
Body preparation, preferred fragrance aqua, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, piece
The common formulations such as agent, capsule, film, ointment, suppository, paste.
Preparing treatment serotonin or/and going present invention also offers above-mentioned maleic acid Tandospirone compound crystal form II
Purposes in the medicine of methylepinephrine reuptake relevant disease.
Wherein, described medicine is the medicine for treating central nervous system disease and eye disease, preferably treats anxiety
Disease, depression, neurasthenia, post-traumatic stress disorder, premenstrual dysphoric disorder, ADHD, panic disorder,
Autism, self-closing disease, insomnia, schizophrenia, increasing rheological properties memory disorders, senile dementia, besetment and behavior syndrome,
Fat, bulimia nervosa or shortage, gilles de la Tourette's syndrome, chronic fatigue syndrome, angiokinesis sexflush, cocaine or
Alcohol addiction, sex dysfunction, borderline personality disorder, Raynaud syndrome, the urinary incontinence, pain, Parkinson's disease, epilepsy, green grass or young crops
The medicine of light eye, diabetic retinopathy, AMD or macular edema.
Further, II purposes in serotonin conditioning agent is prepared of above-mentioned maleic acid Tandospirone compound crystal form.
Wherein, the serotonin conditioning agent is the medicine for treating anxiety disorder, depression or insomnia.
The maleic acid Tandospirone compound that the present invention is provided, has filled up the blank of prior art；With existing product citron
Sour Tandospirone is compared, the maleic acid Tandospirone compound that the present invention is provided, and its is stable in properties, water-soluble good, biological profit
Expenditure is dramatically increased, and a kind of effective solution route is provided to improve Drug safety and validity；In addition, the present inventionization
The preparation process is simple of compound, high income, it is adaptable to industrialized production.
Brief description of the drawings
The X-ray powder diffraction pattern of the gained maleic acid Tandospirone crystal formation II of Fig. 1 embodiment of the present invention 3.
Specific embodiment
Raw materials used Tandospirone is obtained with reference to existing preparation technology synthesis in the present invention, for example
The method reported in the patent documents such as CN101362751A, US5521313.Certainly, in addition to being synthesized by existing method, this
Invention Tandospirone used can also be obtained by buying commercial goods.
The preparation of the maleic acid Tandospirone of embodiment 1
1kg Tandospirones and 303g maleic acids are weighed, 6L ethanol is added, solvent refluxing is heated to, stirring is complete to reaction
Afterwards, stop heating, room temperature is cooled to naturally, solid is collected by filtration, dry, obtain final product 1.30kg maleic acid Tandospirones, yield is
99.8%, mass spectrum shows its ESI m/z：383(M+)。
The preparation of the maleic acid Tandospirone of embodiment 2
Method according to embodiment 1 prepares maleic acid Tandospirone, and actual conditions is referring to table 1, the inventory of Tandospirone
It is 1kg.The results of structural analysis no significant difference of the results of structural analysis of products obtained therefrom and embodiment 1 under the conditions of each.
The preparation condition of table 1, maleic acid Tandospirone
Mixed solvent ratio is volume ratio in table.
The preparation of the maleic acid Tandospirone crystal formation II of embodiment 3
200g maleic acid Tandospirones are taken, 900mL acetonitriles and 300mL water is added, solvent refluxing, stirring to dissolving is heated to
Completely, stop heating, room temperature crystallization is cooled to naturally, crystal is collected by filtration, dry, obtain final product the 193g smooth degree of white powder maleic acid
Spiral shell ketone crystal formation II, yield is 96.5%, and mass spectrum shows its ESI m/z：383(M+), its fusing point is measured for 159.0~160.5 DEG C.
Using Cu K α radiations, the X-ray powder diffraction result of maleic acid Tandospirone crystal formation II of the invention is measured such as
Shown in Fig. 1, its associated diffraction data is shown in Table 2.
The X- powder diffraction results of table 2, crystal formation II
Wherein, the main associated diffraction data of relative intensity I% >=5% are shown in Table 3.
The X-ray powder diffraction result of table 3, crystal formation II
The preparation of the maleic acid Tandospirone crystal formation II of embodiment 4
Method according to embodiment 3 prepares maleic acid Tandospirone crystal formation II, actual conditions referring to table 4, the smooth degree of maleic acid
The inventory of spiral shell ketone is 200g.The results of structural analysis and X-ray powder diffraction pattern and reality of products obtained therefrom under terms and conditions
The no significant difference of example 3 is applied, maleic acid Tandospirone crystal formation II is determined that it is.
The preparation of table 4, maleic acid Tandospirone crystal formation II
Mixed solvent ratio is volume ratio in table.
Beneficial effects of the present invention are illustrated below by way of test example.
Test 1 dissolubility test
Test group：The maleic acid Tandospirone crystal formation II that the embodiment of the present invention 3 is prepared；
Control group：The tandospirone citrate that the method with reference to disclosed in existing document (CN101880274A) is prepared.
Test sample 2g is weighed, is placed in 25 ± 2 DEG C of 20mL water, every strength shaking in 1 minute 10 seconds, observed 3 minutes
Interior dissolving situation.As without visual visible particles of solute, that is, being considered as and being completely dissolved；If there is visual visible particles of solute,
5 times of water of volume (i.e. 10mL water) of test sample weight are added, aforementioned operation is repeated, until being completely dissolved.Record total water consumption
With the time, the results are shown in Table 5.
The dissolubility comparative result of table 5
Result of the test in table 5 shows, compared to the horse that existing tandospirone citrate product, the present invention are prepared
Carry out total water consumption of the sour Tandospirone crystal formation II in water to significantly reduce, dissolution time substantially shortens, and solubility is greatly improved.It is logical
In the case of often, good water-soluble only curative effect of medication and security provides strong guarantee, but also can reduce clinic
The stimulation produced during medication, improves the compliance of patient, and this advantage is especially prominent in the application of injection and ophthalmic preparations.
Test 2 stability tests
Test group：The maleic acid Tandospirone crystal formation II that the embodiment of the present invention 3 is prepared；
Control group：The tandospirone citrate that the method with reference to disclosed in existing document (CN101880274A) is prepared.
Study on the stability condition includes：1) thermal degradation：Test sample about 200mg is taken, is placed in 60 DEG C of drying boxes and is placed；2) light
Degraded：Test sample about 200mg is taken, is placed in the environment that illuminance is 4500 ± 5001x and is placed；3) high humidity degraded：Take test sample
About 200mg, is placed in and is placed with KNO3Room temperature is placed in the drier of saturated solution.Test sample places 10 respectively in each condition
My god, in sampling detection in the 5th day and the 10th day, and comparing with 0 day sample, result of the test is shown in Table 6.
The stability test result of table 6
Shown by the result of the test in table 6, the maleic acid Tandospirone crystal formation II that the present invention is prepared, in high temperature, height
Purity has no significant change under conditions of wet, illumination.The maleic acid Tandospirone compound that this explanation present invention is provided is not only pure
Degree is high, and stable and controllable for quality, is adapted to the manufacture and long term storage of pharmaceutical preparation.
Test 3 bioavailability studies：
Test group：The maleic acid Tandospirone crystal formation II that the embodiment of the present invention 3 is prepared；
Control group：The tandospirone citrate that the method with reference to disclosed in existing document (CN101880274A) is prepared.
Healthy male SD rat is randomly divided into 2 groups, every group 6, every group orally gives (pressed equivalent to 10mg/kg respectively
Tandospirone alkali meter) dosage tandospirone citrate and maleic acid Tandospirone crystal formation II.Given the test agent is matched somebody with somebody before administration
It is set to the aqueous solution of 1mg/mL concentration.Rat fasting 12 hours before administration, and recover feed after 4 hours in administration.Before administration
Blank blood is taken, and blood is taken in 0.25 after administration, 0.5,1,1.5,2,4,6,8,10 and 24 hours prefixed time interval eyes-affinity
0.5mL is placed in the centrifuge tube containing heparin, and 10min separated plasmas are centrifuged with 4000 turns/min, takes supernatant, smooth in measure blood plasma
The concentration of spiral shell ketone is spent, pharmacokinetic parameter is calculated, 7 are the results are shown in Table.The comparing of each group pharmacokinetic parameters uses single factor test side
Difference analyses (One-Way ANOVA), with P<0.05 or P<0.01 thinks with significant difference.
The pharmacokinetic parameters comparative result of table 7
Compare with tandospirone citrate,#P<0.05,##P<0.01。
Shown by the result of the test in table 7, compared with existing product tandospirone citrate, maleic acid Tandospirone is brilliant
Peak time (the T of type IImax) shorten 20%, Cmax (Cmax) improve more than 4 times, mean blood plasma concentration-time graph
Lower area (AUC) value improves nearly 3 times.It can be seen that, the T of the compounds of this inventionmaxValue substantially shortens, CmaxDramatically increased with AUC,
Illustrate that the compounds of this invention than existing product onset time faster, can more rapidly play a role；And with biology higher
Availability, can preferably play medicinal effects.
In sum, compared with existing product tandospirone citrate, the maleic acid Tandospirone chemical combination that the present invention is provided
Thing crystal formation II, its is stable in properties, and water-soluble good, bioavilability is significantly improved, to improve Drug safety and validity
There is provided a kind of effective solution route；In addition, the preparation process is simple of the compounds of this invention, high income, it is adaptable to industrialize
Production.
Claims (10)
1. a kind of maleic acid Tandospirone compound, it is characterised in that：The compound is present in the form of crystal formation II, describedization
In the X-ray powder diffraction figure of compound, the 2 θ angles of diffraction have characteristic absorption peak at 7.2 ± 0.2,14.4 ± 0.2,21.8 ± 0.2 degree；
The preferably 2 θ angles of diffraction also have characteristic absorption peak at 20.3 ± 0.2,21.3 ± 0.2 degree.
2. maleic acid Tandospirone compound according to claim 1, it is characterised in that：The preparation method of the compound includes
Following operational sequence：
A, maleic acid Tandospirone is taken, add solvent, heating for dissolving is obtained maleic acid Tandospirone solution；
B, room temperature crystallization is naturally cooled to, separate crystal, dried, obtain final product maleic acid Tandospirone crystal formation II；
Wherein, solvent described in step a is selected from any one or its combination of water, acetonitrile, tetrahydrofuran, preferably acetonitrile, acetonitrile and water
Mixed solution, the mixed solution of tetrahydrofuran and water, the mixed solution of acetonitrile and tetrahydrofuran, acetonitrile and tetrahydrofuran and water
Mixed solution any one.
3. the preparation method of maleic acid Tandospirone compound according to claim 2, it is characterised in that：In step a, horse
It is 1 to carry out sour Tandospirone with the mass volume ratio of solvent:1~30g/mL, preferably 1:1~25g/mL, more preferably 1:3~20g/
mL。
4. the preparation method of the maleic acid Tandospirone compound according to claim 2,3 any one, it is characterised in that：
In step a, heating for dissolving temperature is 30 DEG C to solvent refluxing, preferably 45 DEG C to solvent refluxing.
5. the preparation method of the maleic acid Tandospirone compound according to any one in claim 2-4, its feature exists
In：The preparation method of maleic acid Tandospirone in step a, including following operational sequence：
A, Tandospirone and maleic acid are taken, add solvent, stirring, completely, reaction solution is standby for question response；
B, reaction solution naturally cool to room temperature, separate solid, dry, and obtain final product maleic acid Tandospirone；
Wherein, solvent described in step A is any one or its combination of water, rudimentary organic solvent, and the rudimentary organic solvent is
Alcohols, ethers, ketone, the esters solvent of acetonitrile or carbon number less than 7；It is preferred that methyl alcohol, ethanol, isopropanol, butanol, third
Ketone, butanone, cyclohexanone, water, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, butyl acetate, ethyl butyrate, ether, isopropyl
Any one or its combination of ether.
6. the preparation method of maleic acid Tandospirone according to claim 5, it is characterised in that：In step A, Tandospirone
Mol ratio with maleic acid is less than or equal to 1:1, preferably 1:(1~3).
7. the preparation method of maleic acid Tandospirone according to claim 5, it is characterised in that：In step A, Tandospirone
It is 1 with the mass volume ratio of solvent:1~30kg/L, preferably 1:3~25kg/L.
8. the preparation method of the maleic acid Tandospirone according to claim 5-7 any one, it is characterised in that：Step A
Middle course of reaction is suitably heated, and preferably heating-up temperature is room temperature to solvent refluxing, more preferably 30 DEG C to solvent refluxing.
9. a kind of pharmaceutical composition, it is characterised in that：It is to contain maleic acid Tandospirone compound conduct described in claim 1
Active component, adds the pharmaceutical preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
10. maleic acid Tandospirone compound described in claim 1 is preparing treatment and serotonin or/and norepinephrine
Purposes in the medicine of reuptake relevant disease；Preferably, described medicine is treatment central nervous system disease and eye disease
The medicine of disease, for example, described medicine is treatment anxiety disorder, depression, neurasthenia, post-traumatic stress disorder, the moon
Premenstrual dysphoric disorder, ADHD, panic disorder, autism, self-closing disease, insomnia, schizophrenia, increasing rheological properties memory
It is obstacle, senile dementia, besetment and behavior syndrome, obesity, bulimia nervosa or shortage, gilles de la Tourette's syndrome, slow
Fatigue syndrome, angiokinesis sexflush, cocaine or alcohol addiction, sex dysfunction, borderline personality disorder, Reynolds synthesis
Disease, the urinary incontinence, pain, Parkinson's disease, epilepsy, glaucoma, diabetic retinopathy, AMD or
The medicine of macular edema.
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| CN102344442A (en) * | 2011-08-04 | 2012-02-08 | 成都科瑞德医药投资有限责任公司 | Novel crystal form of tandospirone citrate and preparation method and application thereof |
| CN103664905A (en) * | 2013-12-25 | 2014-03-26 | 成都科瑞德医药投资有限责任公司 | Tandospirone hydrochloride crystal form II and preparation method thereof |
| CN103755687A (en) * | 2013-12-25 | 2014-04-30 | 成都科瑞德医药投资有限责任公司 | Hydrochloric tandospirone crystal form I and preparation method of crystal form I |
-
2015
- 2015-11-25 CN CN201610719746.7A patent/CN106800550B/en active Active
- 2015-11-25 CN CN201510835073.7A patent/CN106749196B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344442A (en) * | 2011-08-04 | 2012-02-08 | 成都科瑞德医药投资有限责任公司 | Novel crystal form of tandospirone citrate and preparation method and application thereof |
| CN103664905A (en) * | 2013-12-25 | 2014-03-26 | 成都科瑞德医药投资有限责任公司 | Tandospirone hydrochloride crystal form II and preparation method thereof |
| CN103755687A (en) * | 2013-12-25 | 2014-04-30 | 成都科瑞德医药投资有限责任公司 | Hydrochloric tandospirone crystal form I and preparation method of crystal form I |
Non-Patent Citations (1)
| Title |
|---|
| 李晓天: "《生物药剂学与药物动力学》", 31 October 2006, 郑州大学出版社 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106800550B (en) | 2020-07-03 |
| CN106749196B (en) | 2020-07-03 |
| CN106749196A (en) | 2017-05-31 |
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