CN106467520A - A kind of oxalic acid tandospirone compound - Google Patents
A kind of oxalic acid tandospirone compound Download PDFInfo
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- CN106467520A CN106467520A CN201610720007.XA CN201610720007A CN106467520A CN 106467520 A CN106467520 A CN 106467520A CN 201610720007 A CN201610720007 A CN 201610720007A CN 106467520 A CN106467520 A CN 106467520A
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- 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
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Abstract
The invention provides a kind of oxalic acid tandospirone compound.Present invention also offers the preparation method of this oxalic acid tandospirone compound, and the pharmaceutical composition containing this compound and purposes.The oxalic acid tandospirone compound that the present invention provides presented in crystal, its stable in properties, water solublity is good, and bioavailability and safety for improving medicine provide a kind of effective solution route；In addition, the preparation process is simple of the compounds of this invention, high income is it is adaptable to industrialized production.
Description
The application is the divisional application of Chinese 201410249410.X application for a patent for invention, and the applying date of this application is
On 06 06th, 2014, a kind of invention entitled oxalic acid tandospirone compound.
Technical field
The present invention relates to a kind of oxalic acid tandospirone compound is and in particular to the crystal form of this compound, and this change
The preparation method of solvate crystal, pharmaceutical composition and purposes.
Background technology
Tandospirone belongs to azaspiro ketone medicine, chemical entitled (3a α, 4 β, 7 β, 7a α)-hexahydro -2- [4 [4- (2- pyrimidines
Base) -1- (piperazinyl)-butyl] -4,7- methylene -1H- iso-indoles -1,3 (2H)-diketone, molecular structural formula is as follows：
Tandospirone is to be developed by SUMITOMO CHEMICAL Pharmaceutical Co., Ltd earliest, is approved to list in Japan in 1996.
It is a kind of 5-hydroxytryptamine receptor agonist, belongs to the 3rd generation antianxiety drugss, is mainly used in treating anxiety or other companion's anxiety states
Disease.In intracerebral, it can with integrated distribution emotion maincenter Hippocampus, in every, the cerebral limbic system such as interpeduncular nucleus, corpus amygdaloideum
And the 5-HT of seam gland core1AReceptor-selective ground combines, by exciting 5-HT1AAutoreceptor, adjusts and is projected to sea from rapheal nuclei
The 5-hydroxy tryptamine of horse, the 5-hydroxy tryptamine effect of suppression action suppression system, play angst resistance effect.Compared to original shape medicine azepine
Spiral shell ketone and with analog derivative buspirone, it has higher selectivity angst resistance effect, and this effect is close with diazepam, but
But little than diazepam in the toxic and side effects of the aspect such as nervimotion Sexual dysfunction and drug dependence.Special due to mechanism of action
Property, when tandospirone and its salt are used clinically for treating anxiety neurosis, have that drug safety is high, side reaction is few, no lax flesh
The advantages of meat and sedation, no dependence and drug withdrawal are given up phenomenon, no accumulate in vivo after prolonged application.
There are some researches show, tandospirone and its salt in addition to effect antianxity, controlling in other nervous system disease
Treat or auxiliary therapy aspect also has goodish application.Tandospirone and its salt have certain antidepressant effect, for
It is mixed with anxiety and depressed patient's curative effect is very notable, and vegetative nerve can be improved by anxiety and antidepressant effects
Symptom, such as irritable bowel syndrome, functional dyspepsia, postoperative nausea and vomiting etc..It still treats Central nervous system
Ataxic active drug, can be obviously improved the symptom of patient's cerebellar ataxia.For silly with neurasthenia, old age
The patient of slow-witted or schizophrenia, it can also effectively improve memory, and treatment increases rheological properties dysmnesia, significantly improves schizophrenia
The declarative memory of disease patient, logical memory and spoken paired-association etc..Swash additionally, there are some researches show as 5-hydroxytryptamine receptor
The tandospirone of dynamic agent and its salt also have the activity of intraocular pressure lowering, can be used for treatment due to endothelial cell proliferation, inflammation, blood vessel
The ocular disease that permeability improves or angiogenesis etc. cause, such as diabetic retinopathy, age-related macular degeneration,
Retinal edema, glaucoma etc..It can be seen that, tandospirone and its salt have very good clinical treatment advantage and wide city
Field prospect.
In clinical application, the drug molecule having nearly half is all to exist in a salt form and be administered.Electric on the contrary with band
The molecule of lotus or ion carry out into salt with medicine, can be effectively improved some undesirable physical chemistry of medicine or biopharmacy
Matter, for example, change the dissolubility of medicine, reduce hygroscopicity, improve stability, change fusing point, improve and grind performance, be easy to prepare
Purification, raising permeability etc..The poorly water-soluble of tandospirone, can be effectively improved its water solublity after becoming salt and physical chemistry is steady
Qualitative, improve bioavailability, therefore, tandospirone salt often has more than its original shape medicine tandospirone in medical application
Advantage, is conducive to having given play to the effect of medicine to greatest extent.The predominantly citric acid smooth degree spiral shell for example sold in the market
Ketone, the form of its usual tablets or capsule is widely used in the treatment of the relevant diseases such as anxiety neurosis, has comparative maturity
Clinical application research.And in the application of ophthalmic diseasess, Tandospirone Citrate can cause strong thorn because of its alkali to eye
Swash, so would generally consider during medication to select the hydrochloric acid tandospirone that zest is little, comfort level is high.
At present, the research for tandospirone salt is concentrated mainly on citrate and hydrochlorate.For example, US4507303,
The preparation method of Tandospirone Citrate, patent is reported in the documents such as US4818756, JP60087262, CN101362751A
Three kinds of crystal formations of Tandospirone Citrate are also disclosed that in CN10234442A.In addition, the preparation method of hydrochloric acid tandospirone is also
Disclosed in existing document, such as patent CN101880274A, US4507303, EP0082402 etc..With regard to presently disclosed document
In, yet there are no any preparation method with regard to other salifie form of tandospirone and the relevant report of crystal formation.
It is known that for medicine, the compound of different salifie form is likely to be of different crystal formations, same one-tenth
The compound of salt form there is likely to be polymorphic.And different crystal formations is possible to have different colors, fusing point, stablizes
Property, apparent solubility, rate of dissolution etc., these properties can directly influence the stability of pharmaceutical preparation, dissolubility, moisture absorption
Property, bioavailability etc., and thus lead to drug quality and the difference of clinical drug effect.Therefore, for the various salt of tandospirone
And its preparation of correlation crystal formation is significantly with research.
Content of the invention
It is an object of the invention to provide stable in properties, the good oxalic acid tandospirone compound of water solublity.
Present invention also offers preparation method, pharmaceutical composition and the purposes of oxalic acid tandospirone compound.
The invention provides a kind of preparation method of oxalic acid tandospirone, it includes following operation sequence：
A, take oxalic acid to be dissolved in solvent, make oxalic acid solution, take tandospirone, add solvent, after heating for dissolving, add grass
Acid solution, completely, reactant liquor is standby for question response；
B, reactant liquor naturally cool to room temperature, standing, take precipitation, are dried, obtain final product oxalic acid tandospirone.
Further, in step a, tandospirone is less than or equal to 1 with the mol ratio of oxalic acid:1, heating for dissolving temperature be 30～
100 DEG C, reaction temperature is 30～100 DEG C, and tandospirone is 1 with the mass volume ratio of solvent:1～30kg/L, described solvent choosing
From water, acetonitrile, alcohol, ketones solvent, ether solvent, esters solvent any one or a combination thereof.
Wherein, tandospirone and the mol ratio of oxalic acid are preferably 1:(1～2).
Wherein, heating for dissolving temperature is preferably 30～90 DEG C, and reaction temperature is preferably 30～90 DEG C.
Wherein, tandospirone and the mass volume ratio of solvent are preferably 1:3～20kg/L.
Wherein, described solvent is preferably methanol, ethanol, isopropanol, acetone, water, oxolane, acetonitrile, ethyl acetate, second
Any one or a combination thereof of ether.
Further, in step b, time of repose is 1～16 hour, preferably 2～12 hours.
The invention provides a kind of oxalic acid tandospirone compound, this compound is characterised by that it is with the shape of crystal formation IV
Formula exists, and when the compounds of this invention carries out X-ray powder diffraction using Cu K α radiation source, the x-ray powder of described compound spreads out
Penetrate in figure, the 2 θ angles of diffraction are 5.4 ± 0.2,6.3 ± 0.2,8.9 ± 0.2,10.9 ± 0.2,14.7 ± 0.2,16.0 ± 0.2,
16.4 ± 0.2,22.1 ± 0.2,27.6 ± 0.2 degree have characteristic absorption peak.
Further, in the X-ray powder diffraction figure of described compound, the 2 θ angles of diffraction also 10.4 ± 0.2,12.1 ±
0.2nd, 17.2 ± 0.2,19.1 ± 0.2,22.7 ± 0.2,24.3 ± 0.2,26.4 ± 0.2,35.1 ± 0.2 degree have characteristic absorption
Peak.
Preferably, the X-ray powder diffraction of described compound is as shown in Figure 1.
The structural formula of the compounds of this invention is：
Wherein, the fusing point of described compound is 162.5～163.5 DEG C.
Present invention also offers the preparation method of above-mentioned oxalic acid tandospirone compound, it includes following operation sequence：
A, take oxalic acid tandospirone, add solvent, after heating for dissolving, prepared oxalic acid tandospirone solution；
B, naturally cool to room temperature, standing, take precipitation, be dried, obtain final product oxalic acid tandospirone crystal formation IV；Or,
C, naturally cool to and place under room temperature, then be placed at 0 ± 5 DEG C standing, take precipitation, be dried, obtain final product oxalic acid smooth degree spiral shell
Ketone crystal formation IV.
Further, in step A, heating for dissolving temperature is 30～100 DEG C, the quality volume of oxalic acid tandospirone and solvent
Than for 1:1～30g/mL, described solvent is selected from any one or a combination thereof of water, acetonitrile, oxolane.
Wherein, heating for dissolving temperature is preferably 50～90 DEG C.
Wherein, oxalic acid tandospirone and the mass volume ratio of solvent are preferably 1:1～25g/mL, more preferably 1:3～20g/
mL.
Wherein, described solvent is preferably water, acetonitrile, two or more combination any of oxolane, more preferably
For acetonitrile and the mixed solution of the mixed solution, oxolane and acetonitrile and water of the mixed solution, oxolane and acetonitrile of water
Any one.
Further, in step B, time of repose is 1～16 hour, preferably 2～12 hours；In step C, room temperature is transferred
Put 1～16 hour, preferably 2～12 hours, standing within 12 hours at 0 ± 5 DEG C, within preferably 10 hours.Above-mentioned standing
The length of time, determines that whether completely this compound crystallize, has an impact to its yield, but do not interfere with the structure of crystal formation.
Present invention also offers above-mentioned oxalic acid tandospirone compound crystal form IV is in preparation treatment 5-hydroxy tryptamine or/and nor-
Purposes in the medicine of epinephrine reuptake relevant disease.
Wherein, described medicine is the medicine for the treatment of central nervous system disease and ocular disease, preferably treats anxiety
Disease, depression, Panic disorder, autism, infantile autism, insomnia, schizophrenia, increasing rheological properties dysmnesia, neurasthenia, old age
The medicine of the diseases such as dementia, glaucoma, diabetic retinopathy, age-related macular degeneration, retinal edema.
Further, purposes in preparing 5-hydroxy tryptamine regulator for the above-mentioned oxalic acid tandospirone compound crystal form IV.
Wherein, described 5-hydroxy tryptamine regulator is the medicine for the treatment of anxiety neurosis, depression or insomnia.
Present invention also offers a kind of pharmaceutical composition, it is with above-mentioned oxalic acid tandospirone compound crystal form IV for activity
Composition, adds the preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared from.
Pharmaceutically acceptable adjuvant of the present invention or complementary composition, be known in the art for preparing above-mentioned system
The usual excipients of agent or adjuvant.The excipient that oral formulations or external preparation are commonly used or adjuvant include but are not limited to filler
(diluent), lubricant (fluidizer or antitack agent), dispersant, wetting agent, binding agent, regulator, solubilizing agent, antioxidant,
Antibacterial, emulsifying agent, disintegrating agent etc..Binding agent such as syrup, arabic gum, gelatin, starch slurry, polyvidone, cellulose family derive
Thing etc.；Filler such as Lactose, dextrin, starch and its derivant, cellulose derivative, inorganic calcium salt, Mannitol, agar powder
Etc.；Lubricant such as micropowder silica gel, stearic acid and its esters, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycols etc.；Disintegrating agent
As starch and its derivant, Crospovidone, cellulose derivative etc.；Wetting agent such as water, alcohols or other organic solvents
Etc..The excipient that described injection is commonly used or adjuvant include but are not limited to：Antioxidant for example sodium sulfite, sodium sulfite,
Sodium pyrosulfite, sodium thiosulfate etc.；Antibacterial such as phenol, benzyl alcohol, hydroxypropyl methyl ester, chlorobutanol etc.；Regulator
Example hydrochloric acid, citric acid, potassium hydroxide (sodium), buffer agent etc.；Emulsifying agent such as polyoxyethylene sorbitan monoleate, lecithin, fabaceous lecithin etc.；Increase
Solvent such as Tween 80, bile, glycerol etc..Additionally, also can by active component and pharmaceutically acceptable slow controlled release carrier, according to
The preparation method of sustained-release preparation known in the art makes sustained-release preparation.
The dosage form of compositionss of the present invention, can be liquid preparation, gaseous formulation, solid preparation and semi-solid system
Agent, preferred fragrance water preparation, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, film
The common formulations such as agent, ointment, suppository, paste.
The oxalic acid tandospirone compound that the present invention provides, has filled up the blank of prior art；With existing product citric acid
Tandospirone is compared, the oxalic acid tandospirone compound that the present invention provides, its stable in properties, and water solublity is good, for improving medicine
Bioavailability and safety provide a kind of effective solution route；In addition, the preparation process is simple of the compounds of this invention,
High income is it is adaptable to industrialized production.
Brief description
The X-ray powder diffraction pattern of Fig. 1 embodiment of the present invention 3 gained oxalic acid tandospirone crystal formation IV.
Specific embodiment
In the present invention, raw materials used tandospirone is to obtain with reference to existing preparation technology synthesis, for example
The method of report in the patent documentations such as CN101362751A, US5521313.Certainly, in addition to being synthesized by existing method, this
Tandospirone used by invention can also be obtained by buying commercial goods.
The preparation of embodiment 1 oxalic acid tandospirone
Weigh 0.66kg oxalic acid and be dissolved in 2L isopropanol, be configured to the aqueous isopropanol of oxalic acid.Weigh 2kg tandospirone, plus
Enter 10L isopropanol, be heated to 90 DEG C, after molten clear after, add oxalic acid aqueous isopropanol configure, continue stirring extremely reaction
Completely, stop heating, be naturally cooled to room temperature and place 2 hours, sucking filtration, washing, it is dried, obtains final product 2.42kg oxalic acid tandospirone, receive
Rate is 98.0%, and mass spectrum shows its ESI m/z：383(M+).
The preparation of embodiment 2 oxalic acid tandospirone
Method according to embodiment 1 prepares oxalic acid tandospirone, and, referring to table 1, the inventory of tandospirone is equal for actual conditions
For 2kg.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 of table 1 oxalic acid tandospirone
Note：In table, mixed solvent ratio is volume ratio.
The preparation of embodiment 3 oxalic acid tandospirone compound crystal form IV
Weigh 200g oxalic acid tandospirone, add 200mL water and 1000mL acetonitrile, be heated to 80 DEG C, to be dissolved complete
Quan Hou, stops heating after continuing stirring 30min, is naturally cooled to room temperature and places 12 hours, sucking filtration, and washing is dried, obtains final product 191g white
The oxalic acid tandospirone crystal formation IV of color, yield is 95.5%.Mass spectrum shows its ESI m/z：383(M+), recording its fusing point is
162.5～163.5 DEG C.
Using DX-2700 type X-ray powder diffraction instrument, sample crystalline phase is analyzed, Cu K α radiation, records oxalic acid smooth
The X-ray powder diffraction pattern of degree spiral shell ketone crystal formation IV is shown in Fig. 1, main associated diffraction data be shown in Table 2 (2 θ measurement error are ±
0.2).
The X-ray powder diffraction data of table 2 oxalic acid tandospirone crystal formation VI
The preparation of embodiment 4 oxalic acid tandospirone compound crystal form IV
Prepare oxalic acid tandospirone crystal formation IV according to method described in embodiment 3, actual conditions referring to table 3, the smooth degree of oxalic acid
The inventory of spiral shell ketone is 200g.The results of structural analysis of products obtained therefrom and X-ray powder diffraction pattern and enforcement under the conditions of each
Example 3 no significant difference, determines that it is oxalic acid tandospirone crystal formation IV.
The preparation of table 3 oxalic acid tandospirone crystal formation IV
Note：In table, mixed solvent ratio is volume ratio.
The Sublingual tablet of embodiment 5 present invention
Supplementary material is crossed respectively 100 mesh sieves.By the oxalic acid tandospirone crystal formation IV of amount to be prepared and low-substituted hydroxypropyl methyl
Cellulose is mixed by equal increments method, sequentially adds Mannitol, lactose starch, is eventually adding orange flavor and stearic acid
Magnesium, tabletting after mix homogeneously.
Below by way of test example, beneficial effects of the present invention are described.
Test example 1 solubility test
Test group：The oxalic acid tandospirone crystal formation IV that the embodiment of the present invention 3 prepares；
Matched group：The Chinese holly preparing with reference to method disclosed in existing document (CN101880274A, CN101362751A)
Rafter acid tandospirone.
Weigh test sample 2g, be placed in 25 ± 2 DEG C of 20mL water, every strength shaking in 1 minute 10 seconds, observe 3 minutes
Interior dissolving situation.As nothing visually visible particles of solute, that is, it is considered as being completely dissolved；If there being visually visible particles of solute,
Add the water (i.e. 10mL water) of 5 times of volumes of test sample weight, repeat aforementioned operation, until being completely dissolved.Record total water consumption
With the time, the results are shown in Table 4.
Table 4 dissolubility comparative study
Dissolubility test result in table 4 shows, the oxalic acid tandospirone crystal formation IV that the present invention prepares is in water
Dissolution time is substantially short than the dissolution time of existing product Tandospirone Citrate, and dissolubility is more excellent.Under normal circumstances, good water
Dissolubility is not only curative effect of medication and safety provides strong guarantee, but also can reduce the thorn producing during clinical application
Swash, improve the compliance of patient, this advantage is especially prominent in the application of injection and ophthalmic preparations.
Test example 2 stabilizing effect is tested
Test group：The oxalic acid tandospirone crystal formation IV that the embodiment of the present invention 3 prepares；
Matched group：The Chinese holly preparing with reference to method disclosed in existing document (CN101880274A, CN101362751A)
Rafter acid tandospirone.
Study on the stability condition includes：(1) thermal degradation：Take test sample about 200mg, be placed in 60 DEG C of drying baker and place；(2)
Light degradation：Take test sample about 200mg, be placed in the environment that illuminance is 4500 ± 5001x and place；(3) high humidity degraded：Take for examination
Product about 200mg, is placed in and is placed with KNO3In the exsiccator of saturated solution, room temperature is placed.Stability test the results are shown in Table 5.
Table 5 stability test result
Shown by the result of the test in table 5, the oxalic acid tandospirone crystal formation IV of present invention preparation, in high temperature, high humidity, illumination
Under conditions of purity have no significant change.As can be seen here, not only purity is high for the oxalic acid tandospirone crystal that the present invention provides, and
Stable and controllable for quality, the manufacture of suitable pharmaceutical preparation and long term storage.
In sum, compared with existing product Tandospirone Citrate, the oxalic acid tandospirone crystal formation IV that the present invention provides,
Its stable in properties, water solublity is good, and bioavailability and safety for improving medicine provide a kind of effective solution route；
In addition, the preparation process is simple of the compounds of this invention, high income is it is adaptable to industrialized production.
Claims (10)
1. a kind of oxalic acid tandospirone compound it is characterised in that：This compound is described chemical combination presented in crystal formation IV
In the X-ray powder diffraction figure of thing, the 2 θ angles of diffraction 5.4 ± 0.2,6.3 ± 0.2,8.9 ± 0.2,10.9 ± 0.2,14.7 ±
0.2nd, 16.0 ± 0.2,16.4 ± 0.2,22.1 ± 0.2,27.6 ± 0.2 degree have characteristic absorption peak；It is preferably the 2 θ angles of diffraction also to exist
10.4±0.2、12.1±0.2、17.2±0.2、19.1±0.2、22.7±0.2、24.3±0.2、26.4±0.2、35.1±
0.2 degree has characteristic absorption peak；More preferably there is X-ray powder diffraction figure substantially as shown in Figure 1.
2. according to claim 1 oxalic acid tandospirone compound it is characterised in that：The preparation method of this compound include as
Lower operation sequence：
A takes oxalic acid tandospirone, adds solvent, after heating for dissolving, prepared oxalic acid tandospirone solution；
B naturally cools to room temperature, standing, takes precipitation, is dried, obtains final product oxalic acid tandospirone crystal formation IV；Or,
C naturally cools to and places under room temperature, then is placed in standing at 0 ± 5 DEG C, takes precipitation, is dried, obtains final product oxalic acid tandospirone crystal formation
Ⅳ.
Wherein, described solvent is selected from any one or a combination thereof of water, acetonitrile, oxolane, preferably water, acetonitrile, oxolane
Two or more combination any.
3. oxalic acid tandospirone compound according to claim 2 preparation method it is characterised in that：In step A, oxalic acid
Tandospirone is 1 with the mass volume ratio of solvent:1～30g/mL, preferably 1:1～25g/mL, more preferably 1:3～20g/mL.
4. the oxalic acid tandospirone compound according to claim 2 or claim 3 preparation method it is characterised in that：
In step A, heating for dissolving temperature is 30～100 DEG C, preferably 50～90 DEG C.
5. the oxalic acid tandospirone compound according to any one in claim 2-4 preparation method it is characterised in that：
The preparation method of step A mesoxalic acid tandospirone, including following operation sequence：
A, take oxalic acid to be dissolved in solvent, make oxalic acid solution, take tandospirone, add solvent, after heating for dissolving, add oxalic acid molten
Liquid, completely, reactant liquor is standby for question response；
B, reactant liquor naturally cool to room temperature, standing, take precipitation, are dried, obtain final product oxalic acid tandospirone；
Wherein, described solvent is selected from any one or a combination thereof of water, acetonitrile, alcohol, ketones solvent, ether solvent, esters solvent；Excellent
Elect any one or a combination thereof of methanol, ethanol, isopropanol, acetone, water, oxolane, acetonitrile, ethyl acetate, ether as.
6. oxalic acid tandospirone compound according to claim 5 preparation method it is characterised in that：In step a, smooth degree
Spiral shell ketone is less than or equal to 1 with the mol ratio of oxalic acid:1, preferably 1:(1～2).
7. the oxalic acid tandospirone compound according to claim 5 or claim 6 preparation method it is characterised in that：
In step a, tandospirone is 1 with the mass volume ratio of solvent:1～30kg/L, preferably 1:3～20kg/L.
8. the oxalic acid tandospirone compound according to claim 5-7 any one preparation method it is characterised in that：Step
In rapid a, heating for dissolving temperature is 30～100 DEG C, preferably 30～90 DEG C；Further, in step a, reaction temperature is 30
～100 DEG C, preferably 30～90 DEG C.
9. a kind of pharmaceutical composition it is characterised in that：It is as work containing oxalic acid tandospirone compound described in claim 1
Property composition, adds the pharmaceutical preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared from.
10. oxalic acid tandospirone compound described in claim 1 is in preparation treatment with 5-hydroxy tryptamine or/and norepinephrine again
Purposes in the medicine of picked-up relevant disease.
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| CN201410249410.XA Pending CN105175398A (en) | 2014-06-06 | 2014-06-06 | Tandospirone oxalate compound |
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| CN109745323A (en) * | 2017-11-01 | 2019-05-14 | 四川科瑞德制药股份有限公司 | Azapirone compound improves the active purposes of parasympathetic nerve |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| US4507303A (en) * | 1981-12-22 | 1985-03-26 | Sumitomo Chemical Company, Limited | Succinimide derivatives, compositions and method of use |
| JPS5976059A (en) * | 1982-10-21 | 1984-04-28 | Sumitomo Chem Co Ltd | Cyclic imide derivative and its acid addition salt |
| CN103641817B (en) * | 2011-08-04 | 2015-05-13 | 四川科瑞德制药有限公司 | Tandospirone citrate, preparation method and applications |
| CN102344442B (en) * | 2011-08-04 | 2014-08-13 | 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 |
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| 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 |
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| CN106349225A (en) | 2017-01-25 |
| CN105175398A (en) | 2015-12-23 |
| CN106349227A (en) | 2017-01-25 |
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