CN106349226A - L-tartaric acid tandospirone compound - Google Patents
L-tartaric acid tandospirone compound Download PDFInfo
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- CN106349226A CN106349226A CN201610718991.6A CN201610718991A CN106349226A CN 106349226 A CN106349226 A CN 106349226A CN 201610718991 A CN201610718991 A CN 201610718991A CN 106349226 A CN106349226 A CN 106349226A
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- tartaric acid
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- 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
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Abstract
The invention provides an L-tartaric acid tandospirone compound. The invention further provides a preparation method, a pharmaceutical composition and application of the compound. The L-tartaric acid tandospirone compound provided by the invention exists in a crystal form, and is characterized in that the compound exists in an amorphous form and has no characteristic peaks in an X-ray powder diffraction pattern. The L-tartaric acid tandospirone compound provided by the invention has very good water solubility and stability and provides the possibility of improving the bioavailability and the safety of medicines; furthermore, the compound has a simple prepapration process and high yield and is suitable for industrial production.
Description
The application is the divisional application of Chinese No. 201410249687.2 application for a patent for invention, and the applying date of this application is
On 06 06th, 2014, a kind of invention entitled l- tartaric acid tandospirone compound.
Technical field
The present invention relates to a kind of l- tartaric acid tandospirone compound and in particular to this compound unformed, and should
The preparation method of compound, pharmaceutical composition and purposes.
Background technology
Tandospirone belongs to azaspiro ketone medicine, and [4 [(2- is phonetic for 4- for chemical entitled (3a α, 4 β, 7 β, 7a α)-hexahydro -2-
Piperidinyl) -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, tandospirone has higher selectivity angst resistance effect, this effect and diazepam
Close, but less than diazepam in the toxic and side effects of the aspect such as nervimotion Sexual dysfunction and drug dependence.Due to acting on machine
The specificity of system, when tandospirone and its salt are used clinically for treating anxiety neurosis, have that drug safety is high, side reaction is few,
The advantages of no relaxed muscle and sedation, no dependence and drug withdrawal are given up phenomenon, no accumulate in vivo after prolonged application.
Also 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 disclosed in cn10234442a.In addition, the preparation method of hydrochloric acid tandospirone also exists
Disclosed in existing document, such as patent cn101880274a, us4507303, ep0082402 etc..With regard to presently disclosed document, also
Have 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.Unformed is a kind of special crystal formation shape
State, is a kind of existence form of polymorph medicine.In the presence of medicine is with unformed form, its physicochemical property and clinical drug effect are special
Levy and be often different from general crystal formation medicine.The solid drugs of unformed state often have preferable In Vitro Dissolution and body absorption
Property, and be possible to play more preferable clinical effectiveness.Therefore, the preparation for the related crystal formation of tandospirone salt and research right and wrong
Often significant.
Content of the invention
It is an object of the invention to provide stable in properties, the good l- tartaric acid tandospirone compound of water solublity.
Present invention also offers preparation method, pharmaceutical composition and the purposes of l- tartaric acid tandospirone compound.
The invention provides a kind of preparation method of l- tartaric acid tandospirone, it includes following operation sequence:
A, take tandospirone and l- tartaric acid, add organic solvent, heating for dissolving, after question response is complete, extract reaction solution standby
With；
B, reactant liquor are evaporated to dry, obtain final product l- tartaric acid tandospirone.
Further, in step a, tandospirone is less than or equal to 1:1 with the tartaric mol ratio of l-, and heating for dissolving temperature is
30～100 DEG C, reaction temperature is 30～100 DEG C, and tandospirone is 1:1～30kg/l with the mass volume ratio of organic solvent, institute
State any one or a combination thereof that organic solvent is selected from alcohols solvent, ketones solvent, ether solvent, esters solvent, acetonitrile.
Wherein, tandospirone and the tartaric mol ratio of l- 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 organic solvent are preferably 1:3～20kg/l.
Wherein, described organic solvent be preferably methanol, ethanol, isopropanol, acetone, acetonitrile, oxolane, ethyl acetate,
Any one or a combination thereof of ether.
The invention provides a kind of l- tartaric acid tandospirone compound, this compound is characterised by that it is with unformed
Presented in, x-ray powder diffraction is carried out to this compound using cu k α radiation source, its x-ray powder diffraction in figure is no special
Levy peak；Preferably, its x-ray powder diffraction is as shown in Figure 1.
The compounds of this invention structural formula is:
Wherein, the fusing point of described compound is 92.5～97.0 DEG C.
Present invention also offers the preparation method of above-mentioned l- tartaric acid tandospirone compound, it includes following operative employee
Sequence:
A, take l- tartaric acid tandospirone, add organic solvent, after heating for dissolving, prepared l- tartaric acid tandospirone is molten
Liquid；
B, naturally cool to room temperature, standing, take precipitation, concentrating under reduced pressure, be dried, obtain final product unformed l- tartaric acid tandospirone
Compound；Or,
C, naturally cool to and place under room temperature, then be placed at -5 ± 5 DEG C standing, take precipitation, concentrating under reduced pressure, be dried, obtain final product
Unformed l- tartaric acid tandospirone compound；Or,
D, concentrating under reduced pressure desolvation, are dried, obtain final product unformed l- tartaric acid tandospirone compound.
Further, in step a, heating for dissolving temperature is 30～100 DEG C, l- tartaric acid tandospirone and organic solvent
Mass volume ratio be 1:1～30g/ml, described organic solvent be selected from alcohols solvent, ketones solvent, ether solvent, esters solvent,
Any one or a combination thereof of acetonitrile.
Wherein, heating for dissolving temperature is preferably 35～90 DEG C.
Wherein, l- tartaric acid tandospirone and the mass volume ratio of organic solvent are preferably 1:3～20g/ml.
Wherein, described organic solvent be preferably methanol, ethanol, acetone, acetonitrile, oxolane, ethyl acetate, ether appoint
One kind or a combination thereof.
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 -5 ± 5 DEG C, within preferably 8 hours.
Present invention also offers above-mentioned unformed l- tartaric acid tandospirone compound preparation treatment 5-hydroxy tryptamine or/and
Purposes in the medicine of norepinephrine 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, use in preparing 5-hydroxy tryptamine regulator for the above-mentioned unformed l- tartaric acid tandospirone compound
On the way.
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 to be with above-mentioned unformed l- tartaric acid tandospirone compound
Active component, 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..Described injection commonly use excipient 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 l- tartaric acid tandospirone compound that the present invention provides, has filled up the blank of prior art；With existing product Chinese holly
Rafter acid tandospirone is compared, the l- tartaric acid tandospirone compound that the present invention provides, its stable in properties, and water solublity is good, is
Improve the bioavailability of medicine and safety provides a kind of effective solution route；In addition, the smooth degree of l- tartaric acid of the present invention
The preparation process is simple of spiral shell assimilation compound, high income is it is adaptable to industrialized production.
Brief description
The x-ray powder diffraction spectrum of Fig. 1 embodiment of the present invention 3 gained unformed l- tartaric acid tandospirone.
The x-ray powder diffraction of gained unformed l- tartaric acid tandospirone under the conditions of Fig. 2 embodiment of the present invention 4 numbering 3
Collection of illustrative plates.
The x-ray powder diffraction of gained unformed l- tartaric acid tandospirone under the conditions of Fig. 3 embodiment of the present invention 6 numbering 5
Collection of illustrative plates.
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 l- tartaric acid tandospirone
Weigh 2kg tandospirone and 0.79kg l- tartaric acid, add 10l isopropanol, be heated to 90 DEG C, treat molten clear
Afterwards, continue stirring to reacting completely, stop heating, be evaporated to dry, obtain final product 2.77kg l- tartaric acid tandospirone, yield
For 99.5%, mass spectrum shows its esi m/z:383 (m+).
The preparation of embodiment 2 l- tartaric acid tandospirone
Method according to embodiment 1 prepares l- tartaric acid tandospirone, actual conditions referring to table 1, the feeding intake of tandospirone
Amount is 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 1l- tartaric acid tandospirone
Note: in table, mixed solvent ratio is volume ratio.
The preparation of the unformed l- tartaric acid tandospirone compound of embodiment 3
Weigh 200g l- tartaric acid tandospirone, add 1000ml ethanol, be heated to 80 DEG C, to be dissolved complete, continue
Stop heating after continuous stirring 30min, be naturally cooled to room temperature and place 2 hours, place 4 hours then at -5 ± 5 DEG C, abandoning supernatant,
Gained white depositions concentrating under reduced pressure, is dried, obtains final product 195g white powder unformed l- tartaric acid tandospirone, yield is
97.5%, mass spectrum shows its esi m/z:383 (m+), record its fusing point and be 92.5～97.0 DEG C.
Using dx-2700 type x- ray powder diffractometer, sample crystalline phase is analyzed, cu k α radiates, and records unformed
The x-ray powder diffraction spectrum of l- tartaric acid tandospirone is shown in Fig. 1, no characteristic peak in its x-ray powder diffraction.
The preparation of the unformed l- tartaric acid tandospirone compound of embodiment 4
Prepare unformed l- tartaric acid tandospirone according to method described in embodiment 3, actual conditions is referring to table 2, l- wine
The inventory of stone acid tandospirone is 200g.Data results and the x-ray powder such as fusing point of products obtained therefrom under the conditions of each
Last diffracting spectrum and embodiment 3 no significant difference, determine that it is unformed l- tartaric acid tandospirone, partly representative x-ray
Diffracting spectrum is shown in Fig. 2.From x-ray powder diffraction spectrum, no characteristic peak in this unformed powder diffraction in x-ray.
The preparation of the unformed l- tartaric acid tandospirone compound of table 2
Note: in table, mixed solvent ratio is volume ratio.
The preparation of the unformed l- tartaric acid tandospirone compound of embodiment 5
Weigh 200g l- tartaric acid tandospirone, add 600ml methanol, be heated to 90 DEG C, to be dissolved complete, continue
Stop heating after continuous stirring 30min, naturally cool to less than 25 DEG C, concentrating under reduced pressure desolvation, it is dried, obtain final product 199g white powder
The unformed l- tartaric acid tandospirone of last shape, yield is 99.5%, the data results such as fusing point of products obtained therefrom and x-ray
Powder diffraction spectrum and embodiment 3 no significant difference.
The preparation of the unformed l- tartaric acid tandospirone compound of embodiment 6
Prepare unformed l- tartaric acid tandospirone according to method described in embodiment 5, actual conditions is referring to table 3, l- wine
The inventory of stone acid tandospirone is 200g.Data results and the x-ray powder such as fusing point of products obtained therefrom under the conditions of each
Last diffracting spectrum and embodiment 3 no significant difference, determine that it is unformed l- tartaric acid tandospirone, partly representative x-ray
Diffracting spectrum is shown in Fig. 3.From x-ray powder diffraction spectrum, no characteristic peak in this unformed powder diffraction in x-ray.
The preparation of the unformed l- tartaric acid tandospirone compound of table 3
Note: in table, mixed solvent ratio is volume ratio.
The capsule of embodiment 7 present invention
After the unformed l- tartaric acid tandospirone of amount to be prepared and starch are mixed by equal increments method, then with crystallite
Cellulose mixes, and pelletizes, encapsulated obtains final product.
The Sublingual tablet of embodiment 8 present invention
Supplementary material is crossed respectively 100 mesh sieves.By the unformed l- tartaric acid tandospirone of amount to be prepared and low-substituted hydroxypropyl
Methylcellulose is mixed by equal increments method, sequentially adds Mannitol, lactose starch, is eventually adding orange flavor and Hard Fat
Sour 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 unformed l- tartaric acid tandospirone 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 unformed l- tartaric acid tandospirone that the present invention prepares is in water
In dissolution time hence it is evident that shorter than the dissolution time of existing product Tandospirone Citrate, dissolubility is more excellent.Under normal circumstances,
Good water solublity is not only curative effect of medication and safety provides strong guarantee, but also can reduce and produce during clinical application
Stimulation, 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 unformed l- tartaric acid tandospirone 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: takes test sample about 200mg, is placed in 60 DEG C of drying baker and places；(2)
Light degradation: take test sample about 200mg, be placed in the environment that illuminance is 4500 ± 500lx 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 present invention preparation unformed l- tartaric acid tandospirone, high temperature, high humidity,
Under conditions of illumination, purity has no significant change.As can be seen here, the unformed l- tartaric acid tandospirone that the present invention provides is not only
Purity is high, 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 smooth degree of unformed l- tartaric acid that the present invention provides
Spiral shell ketone, its stable in properties, water solublity is good, and the bioavailability and safety for improving medicine provides a kind of effectively solution
Approach；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 l- tartaric acid tandospirone compound it is characterised in that: this compound is presented in unformed, this change
No characteristic peak in the x-ray powder diffraction of compound；Preferably, its x-ray powder diffraction is as shown in Figure 1.
2. according to claim 1 l- tartaric acid tandospirone compound it is characterised in that: the preparation method bag of this compound
Include following operation sequence:
A takes l- tartaric acid tandospirone, adds organic solvent, after heating for dissolving, prepared l- tartaric acid tandospirone solution；
B naturally cools to room temperature, standing, takes precipitation, concentrating under reduced pressure, is dried, obtains final product unformed l- tartaric acid tandospirone chemical combination
Thing；Or,
C naturally cools to and places under room temperature, then is placed in standing at -5 ± 5 DEG C, takes precipitation, concentrating under reduced pressure, is dried, obtains final product unformed
L- tartaric acid tandospirone compound；Or,
D concentrating under reduced pressure desolvation, is dried, obtains final product unformed l- tartaric acid tandospirone compound；
Wherein, described organic solvent is selected from any one or its of alcohols solvent, ketones solvent, ether solvent, esters solvent, acetonitrile
Combination, preferably methanol, ethanol, acetone, acetonitrile, oxolane, ethyl acetate, any one or a combination thereof of ether.
3. according to claim 2 l- tartaric acid tandospirone compound preparation method it is characterised in that: in step a, l-
Tartaric acid tandospirone is 1:1～30g/ml, preferably 1:3～20g/ml with the mass volume ratio of organic solvent.
4. the preparation method according to claim 2 or l- tartaric acid tandospirone compound described in claim 3, its feature exists
In: in step a, heating for dissolving temperature is 30～100 DEG C, preferably 35～90 DEG C.
5. the preparation method of the l- tartaric acid tandospirone compound according to claim 2-4 any one, its feature exists
In: the preparation method of l- tartaric acid tandospirone in step a, including following operation sequence:
A, take tandospirone and l- tartaric acid, add organic solvent, heating for dissolving, after question response is complete, extract reaction solution standby；
B, reactant liquor are evaporated to dry, obtain final product l- tartaric acid tandospirone；
Wherein, described organic solvent is selected from any one or its of alcohols solvent, ketones solvent, ether solvent, esters solvent, acetonitrile
Combination；It is preferably any one or a combination thereof of methanol, ethanol, isopropanol, acetone, acetonitrile, oxolane, ethyl acetate, ether.
6. l- tartaric acid tandospirone compound according to claim 5 preparation method it is characterised in that: in step a,
Tandospirone is less than or equal to 1:1, preferably 1:(1～2 with the tartaric mol ratio of l-).
7. the preparation method according to claim 5 or l- tartaric acid tandospirone compound described in claim 6, its feature exists
In: in step a, tandospirone is 1:1～30kg/l, preferably 1:3～20kg/l with the mass volume ratio of organic solvent.
8. according to claim 5-7 any one l- tartaric acid tandospirone compound preparation method it is characterised in that:
In step a, reaction temperature is 30～100 DEG C, preferably 30～90 DEG C；Further, in step a, heating for dissolving temperature is
30～100 DEG C, preferably 30～90 DEG C.
9. a kind of pharmaceutical composition it is characterised in that: it is containing the l- tartaric acid tandospirone compound described in claim 1
As active component, add the pharmaceutical preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared from；Preferably, described
Preparation is liquid preparation, gaseous formulation, solid preparation and semi-solid preparation, more preferably aromatic water, solution, injection, conjunction
Agent, lotion, liniment, aerosol, spray, powder, pill, tablet, membrane, ointment, suppository, paste.
10. the l- tartaric acid tandospirone compound described in claim 1 is in preparation treatment with 5-hydroxy tryptamine or/and nor- kidney
Purposes in the medicine of parathyrine reuptake relevant disease；Preferably, described medicine is treatment central nervous system disease and eye
The medicine of disease, more preferably treatment anxiety neurosis, depression, Panic disorder, autism, infantile autism, insomnia, schizophrenia,
Increase rheological properties dysmnesia, neurasthenia, senile dementia, glaucoma, diabetic retinopathy, age-related macular degeneration,
The medicine of retinal edema disease.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101880274A (en) * | 2010-06-28 | 2010-11-10 | 北大国际医院集团西南合成制药股份有限公司 | Method for preparing tandospirone and analogues of tandospirone |
| 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 |
| 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 |
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| CN101880274A (en) * | 2010-06-28 | 2010-11-10 | 北大国际医院集团西南合成制药股份有限公司 | Method for preparing tandospirone and analogues of tandospirone |
| 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 |
| 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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| 李全林: "《新医药开发与研究（下册）》", 31 December 2008, 中国医药科技出版社 * |
| 梁文权: "《生物制剂学与药物动力学》", 30 June 2000, 人民卫生出版社 * |
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