CN106800550B - 5-hydroxytryptamine receptor agonist - Google Patents
5-hydroxytryptamine receptor agonist Download PDFInfo
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- CN106800550B CN106800550B CN201610719746.7A CN201610719746A CN106800550B CN 106800550 B CN106800550 B CN 106800550B CN 201610719746 A CN201610719746 A CN 201610719746A CN 106800550 B CN106800550 B CN 106800550B
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- tandospirone
- maleate
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Images
Classifications
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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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- 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
Abstract
The invention provides a 5-hydroxytryptamine receptor stimulant. Particularly provides a tandospirone maleate compound. The invention also provides a preparation method of the compound, a pharmaceutical composition containing the compound and application. The tandospirone maleate exists in the form of crystals, has stable property and good water solubility, obviously improves the bioavailability, and provides an effective solution for improving the safety and the effectiveness of the medicament; in addition, the compound of the invention has simple preparation process and high yield, and is suitable for industrial production.
Description
The application is a divisional application of the invention patent application No. 201510835073.7 in China, the application date of the application is 11 months and 25 days in 2015, and the name of the application is 5-hydroxytryptamine receptor agonist.
Technical Field
The invention relates to a tandospirone compound, mainly relates to a maleate of tandospirone, and particularly relates to a crystal form of the compound, and a preparation method, a pharmaceutical composition and application of the crystal of the compound.
Background
The chemical name of tandospirone is (3a α,4 β,7 β,7a α) -hexahydro-2- [4[4- (2-pyrimidinyl) -1- (piperazinyl) -butyl]-4, 7-methylene-1H-isoindole-1, 3(2H) -dione, which is an azaspirone-type drug, was first developed by Sumitomo pharmaceutical Co., Ltd., Japan and was approved for sale in Japan in 1996. Tandospirone is a 3 rd generation anxiolytic primarily used for the treatment of anxiety or other diseases with anxiety states. Unlike traditional anxiolytic drugs, it is a highly selective 5-hydroxytryptamine receptor agonist, and is useful for treating 5-HT1AThe selective combination of the receptors inhibits the hyperactive 5-hydroxytryptamine neuroactive, thereby exerting an anxiolytic effect. Compared with the crude drug azaspirone and the similar derivative buspirone, the azaspirone has higher selective anxiolytic effect which is similar to diazepam, but has less toxic and side effects on the aspects of nerve motility function damage, drug abuse and the like than the diazepam. Due to the specificity of action mechanism, it has high safety, less side effects, no muscle relaxation and sedative effects, and no dependenceAnd the medicine can be stopped to stop giving up, and the long-term application has no accumulation in vivo, and is suitable for long-term application.
The prior researches show that the tandospirone and the salt thereof have good application in the treatment or adjuvant treatment of other nervous system diseases besides the anti-anxiety function. The tandospirone and the salt thereof have antidepressant effect, have remarkable curative effect on patients with anxiety and depression, and can improve vegetative nerve symptoms such as irritable bowel syndrome, functional dyspepsia, postoperative nausea and vomiting and the like through the anxiolytic and antidepressant effects. It is also an effective drug for treating central nervous system ataxia, and can significantly improve the cerebellar ataxia symptoms of patients. It can also effectively improve the memory of patients suffering from neurasthenia, senile dementia or schizophrenia, treat age-related dysmnesia, and remarkably improve declarative memory, logic memory, spoken language pair association and the like. The tandospirone can play an excellent auxiliary treatment effect on body diseases such as hypertension, coronary heart disease, diabetes, peptic ulcer and the like. In addition, studies have shown that tandospirone and salts thereof, which are 5-hydroxytryptamine receptor agonists, also have ocular hypotensive activity and are useful for the treatment of ocular diseases caused by endothelial cell proliferation, inflammation, increased vascular permeability or angiogenesis, such as diabetic retinopathy, age-related macular degeneration, retinal edema, glaucoma, and the like. The tandospirone and the salt thereof have very good clinical treatment advantages and wide market prospect.
In clinical application, nearly half of the drug molecules are present and administered in the form of salts. The salt formed by molecules or ions with opposite charges and the medicine can effectively improve some undesirable physicochemical or biological pharmaceutical properties of the medicine, such as changing the solubility of the medicine, reducing hygroscopicity, improving stability, changing melting point, improving grinding performance, facilitating preparation and purification, improving permeability, improving bioavailability, improving compliance, reducing adverse reactions and the like. The tandospirone has poor water solubility, and the water solubility and the physical and chemical stability of the tandospirone can be effectively improved after salification, so that the tandospirone salt has more advantages than the original medicament tandospirone in medical application, and is favorable for exerting the medicament effect to the maximum extent. The citrate of tandospirone, namely tandospirone citrate, which is sold in the market at present, is generally widely applied to the treatment of anxiety disorder or related diseases in the form of tablets or capsules, and has mature clinical application research. Nevertheless, in the application of ophthalmic diseases, it is reported in literature that tandospirone citrate causes strong irritation to eyes due to its salt group, so the citrate is usually not considered to be selected first when developing ophthalmic preparations. In view of this, the development of other types of salts of tandospirone, such as maleate, has a high pharmaceutical clinical value.
Maleic acid is a common organic acid, has high clinical use value, and can form salt with an alkaline medicament to solve the problem of insolubility. At present, for the research on tandospirone salts, the preparation method of tandospirone citrate is reported in patents of US4507303, US4818756, CN101362751A and the like. In addition, patents CN101880274A, US4507303, EP0082402, etc. disclose methods for preparing tandospirone hydrochloride. No reports on the preparation method and/or the crystal form of the tandospirone maleate form are found in the currently published literature.
It is well known that for pharmaceutical agents, compounds in different salt forms may have different crystal forms, and that the same compound in salt form may also exist in polymorphic forms. Different crystal forms may have different colors, melting points, stabilities, apparent solubilities, dissolution rates, etc., which directly affect the stability, solubility, hygroscopicity, bioavailability, etc. of the pharmaceutical preparations and thus cause differences in the quality and clinical efficacy of the pharmaceutical products. Therefore, the preparation and research of various crystalline salts of tandospirone are very interesting.
Disclosure of Invention
The purpose of the present invention is to provide a tandospirone maleate compound having stable properties and good water solubility.
The invention also provides a preparation method, a pharmaceutical composition and application of the tandospirone maleate compound.
The invention provides a preparation method of tandospirone maleate, which comprises the following operation procedures:
A. taking tandospirone and maleic acid, adding a solvent, stirring, and keeping a reaction solution for later use after the reaction is complete;
B. and naturally cooling the reaction liquid to room temperature, separating the solid, and drying to obtain the tandospirone maleate.
Further, in the step A, the molar ratio of tandospirone to maleic acid is less than or equal to 1:1, the mass-to-volume ratio of tandospirone to a solvent is 1: 1-30 kg/L, the solvent is any one or combination of water and a lower organic solvent, wherein the lower organic solvent is acetonitrile or an alcohol, ether, ketone or ester solvent with the carbon atom number less than 7.
Wherein the mol ratio of tandospirone to maleic acid is preferably 1 (1-3).
Wherein the mass volume ratio of tandospirone to the solvent is preferably 1: 3-25 kg/L.
Wherein, the solvent is preferably any one of methanol, ethanol, isopropanol, butanol, acetone, butanone, cyclohexanone, water, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, butyl acetate, ethyl butyrate, diethyl ether and isopropyl ether or the combination thereof.
Further, the reaction process in step a is properly heated, preferably at a temperature ranging from room temperature to solvent reflux, more preferably from 30 ℃ to solvent reflux.
The invention provides a tandospirone maleate compound, which is characterized in that the tandospirone maleate compound exists in a form of a crystal form II, and when the crystal form II of the compound adopts a Cu K α radiation source to carry out X-ray powder diffraction, the 2 theta diffraction angle of the compound has characteristic absorption peaks at 7.2 +/-0.2, 14.4 +/-0.2 and 21.8 +/-0.2 degrees in an X-ray powder diffraction pattern.
Furthermore, in an X-ray powder diffraction pattern of the compound crystal form II, characteristic absorption peaks exist at the 2 theta diffraction angles of 20.3 +/-0.2 degrees and 21.3 +/-0.2 degrees.
Further, in an X-ray powder diffraction pattern of the tandospirone maleate crystal form II, main peaks with the relative intensity I% of characteristic peaks at 2 theta diffraction angles being more than or equal to 5% are as follows:
furthermore, the X-ray powder diffraction of the crystal form of the compound has the X-ray powder diffraction pattern characteristics which are basically shown in figure 1.
The structural formula of the compound of the invention is:
wherein the melting point of the compound is 159.0-160.5 ℃.
The invention also provides a preparation method of the tandospirone maleate compound, which comprises the following operation procedures:
a. taking tandospirone maleate, adding a solvent, and heating to dissolve to prepare a tandospirone maleate solution;
b. naturally cooling to room temperature for crystallization, separating crystals, and drying to obtain the tandospirone maleate crystal form II.
Further, in the step a, the heating and dissolving temperature is 30 ℃ to reflux of the solvent, the mass-to-volume ratio of the tandospirone maleate to the solvent is 1: 1-30 g/mL, and the solvent is any one or combination of water, acetonitrile and tetrahydrofuran.
Among them, the heating dissolution temperature is preferably 45 ℃ to the reflux of the solvent.
Wherein the mass-to-volume ratio of the tandospirone maleate to the solvent is preferably 1: 1-25 g/mL, and more preferably 1: 3-20 g/mL.
Wherein the solvent is preferably any one of acetonitrile, a mixed solution of acetonitrile and water, a mixed solution of tetrahydrofuran and water, a mixed solution of acetonitrile and tetrahydrofuran, and a mixed solution of acetonitrile, tetrahydrofuran and water.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the crystal form II of the tandospirone maleate compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The pharmaceutically acceptable carrier of the present invention is a common excipient or adjuvant well known in the art for preparing the above-mentioned preparations. The excipients or adjuvants commonly used in oral preparations or external preparations include, but are not limited to, fillers (diluents), lubricants (glidants or antiadherents), dispersants, wetting agents, binders, regulators, solubilizers, antioxidants, bacteriostats, emulsifiers, disintegrants, etc. Binders such as syrup, acacia, gelatin, starch slurry, povidone, cellulose derivatives, and the like; fillers such as lactose, dextrin, starch and its derivatives, cellulose derivatives, inorganic calcium salts, mannitol, agar powder, etc.; lubricants such as aerosil, stearic acid and its salts, talc, hydrogenated vegetable oils, polyethylene glycols and the like; disintegrants such as starch and its derivatives, crospovidone, cellulose derivatives, and the like; wetting agents such as water, alcohols or other organic solvents, and the like. Common excipients or adjuvants for such injections include, but are not limited to: antioxidants such as sodium sulfite, sodium bisulfite, sodium metabisulfite, butanedioic acid, and the like; bacteriostatic agents such as 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol, etc.; regulators such as hydrochloric acid, citric acid, potassium (sodium) hydroxide, buffers, and the like; emulsifiers such as polysorbate-80, lecithin, soybean lecithin, and the like; solubilizers such as tween-80, bile, glycerol, and the like. In addition, the active ingredient can be mixed with pharmaceutically acceptable sustained or controlled release carrier to make sustained or controlled release preparation according to the preparation method of sustained or controlled release preparation known in the art.
The preparation form of the pharmaceutical composition can be liquid preparation, gas preparation, solid preparation and semisolid preparation, and common preparation forms such as aromatic water agent, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, capsule, membrane, ointment, suppository, paste and the like are preferred.
The invention also provides application of the tandospirone maleate compound crystal form II in preparing a medicament for treating 5-hydroxytryptamine or/and norepinephrine reuptake related diseases.
Wherein said medicament is a medicament for the treatment of central nervous system disorders and ocular disorders, preferably anxiety disorders, depression, neurasthenia, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, panic disorder, autism, insomnia, schizophrenia, age-related memory disorders, senile dementia, obsessive-compulsive disorder, obesity, bulimia nervosa or deficiency, tourette's syndrome, chronic fatigue syndrome, vasomotor flushing, cocaine or alcohol addiction, sexual dysfunction, borderline personality disorder, raynaud's syndrome, urinary incontinence, pain disorders, parkinson's disease, epilepsy, glaucoma, diabetic retinopathy, age-related macular degeneration or retinal edema.
Further, the application of the crystal form II of the tandospirone maleate compound in preparing a 5-hydroxytryptamine regulator.
Wherein the 5-hydroxytryptamine regulator is a medicine for treating anxiety, depression or insomnia.
The tandospirone maleate compound provided by the invention fills the blank of the prior art; compared with the existing product tandospirone citrate, the tandospirone maleate compound provided by the invention has stable property, good water solubility and obviously increased bioavailability, and provides an effective solution for improving the safety and effectiveness of the medicament; in addition, the compound of the invention has simple preparation process and high yield, and is suitable for industrial production.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of tandospirone maleate crystal form II obtained in example 3 of the present invention.
Detailed Description
The tandospirone used as a raw material in the present invention is synthesized by referring to a conventional production process, and for example, methods reported in patent documents such as CN101362751A and US5521313 are disclosed. Of course, the tandospirone used in the present invention can be obtained by purchasing commercially available products, in addition to the synthesis by the existing methods.
Example 1 preparation of tandospirone maleate
Weighing 1kg tandospirone and 303g maleic acid, adding 6L ethanol, heating until the solvent refluxes, stirring until the reaction is finishedAnd after the reaction is completed, stopping heating, naturally cooling to room temperature, filtering, collecting solid, and drying to obtain 1.30kg of tandospirone maleate with the yield of 99.8%, wherein the mass spectrum shows that the ESI m/z: 383 (M)+)。
Example 2 preparation of tandospirone maleate
Tandospirone maleate is prepared according to the method of example 1, the specific conditions are shown in Table 1, and the feeding amount of the tandospirone is 1 kg. The structural analysis results of the products obtained under the respective conditions were not significantly different from those of example 1.
TABLE 1 preparation conditions of tandospirone maleate
The mixed solvent ratios in the table are volume ratios.
Example 3 preparation of Tandospirone maleate form II
Taking 200g tandospirone maleate, adding 900mL acetonitrile and 300mL water, heating until the solvent is refluxed, stirring until the solvent is completely dissolved, stopping heating, naturally cooling to room temperature for crystallization, filtering and collecting crystals, and drying to obtain 193g white powdery tandospirone maleate crystal form II with the yield of 96.5%, wherein the mass spectrum shows that the ESI m/z: 383 (M)+) The melting point is measured to be 159.0-160.5 ℃.
The X-ray powder diffraction result of the tandospirone maleate crystal form II is shown in figure 1 by using Cu K α radiation, and the relevant diffraction data are shown in Table 2.
TABLE 2X-powder diffraction results for form II
Wherein, the main relevant diffraction data of the relative intensity I% is more than or equal to 5% is shown in Table 3.
TABLE 3X-ray powder diffraction results for form II
Example 4 preparation of Tandospirone maleate form II
Tandospirone maleate crystal form II is prepared according to the method of example 3, the specific conditions are shown in Table 4, and the feeding amount of the tandospirone maleate is 200 g. The structural analysis result and the X-ray powder diffraction pattern of the product obtained under various conditions have no obvious difference from those of example 3, and the product is determined to be the tandospirone maleate crystal form II.
TABLE 4 preparation of Tandospirone maleate form II
The mixed solvent ratios in the table are volume ratios.
The advantageous effects of the present invention are described below by way of test examples.
Test 1 solubility test
Test groups: the crystal form II of tandospirone maleate prepared in the embodiment 3 of the invention;
control group: refer to the method disclosed in the prior document (CN101880274A) to prepare tandospirone citrate.
2g of the sample was weighed, placed in 20mL of water at 25. + -. 2 ℃ and shaken vigorously for 10 seconds every 1 minute, and the dissolution was observed within 3 minutes. If there are no visually visible solute particles, i.e. it is considered to be completely dissolved; if there are visually observable solute particles, 5 volumes of water (i.e., 10mL of water) by weight of the test article is added and the above procedure is repeated until complete dissolution occurs. The total water usage and time were recorded and the results are shown in table 5.
TABLE 5 results of solubility comparison
The test results in table 5 show that compared with the existing tandospirone citrate product, the tandospirone maleate crystal form II prepared by the invention has the advantages that the total water consumption in water is obviously reduced, the dissolving time is obviously shortened, and the solubility is greatly improved. In general, good water solubility not only provides powerful guarantee for the curative effect and safety of the medicine, but also can reduce the stimulation generated during clinical medication and improve the compliance of patients, and the advantage is particularly prominent in the application of injections and eye preparations.
Test groups: the crystal form II of tandospirone maleate prepared in the embodiment 3 of the invention;
control group: refer to the method disclosed in the prior document (CN101880274A) to prepare tandospirone citrate.
The stability examination conditions include: 1) thermal degradation: taking about 200mg of a test sample, and placing the test sample in a drying oven at 60 ℃; 2) photo-degradation: taking about 200mg of a test sample, and placing the test sample in an environment with the illumination of 4500 +/-5001 x; 3) high-humidity degradation: taking about 200mg of sample, placing in KNO3The saturated solution was placed in a desiccator at room temperature. The test samples were kept under each condition for 10 days, sampled and tested on day 5 and day 10, and compared with the day 0 samples, and the test results are shown in Table 6.
TABLE 6 stability test results
The test results in table 6 show that the purity of the tandospirone maleate crystal form II prepared by the invention has no obvious change under the conditions of high temperature, high humidity and illumination. The reason is that the tandospirone maleate compound provided by the invention has high purity, stable and controllable quality, and is suitable for the manufacture and long-term storage of pharmaceutical preparations.
Test 3 bioavailability test:
test groups: the crystal form II of tandospirone maleate prepared in the embodiment 3 of the invention;
control group: refer to the method disclosed in the prior document (CN101880274A) to prepare tandospirone citrate.
Healthy male SD rats were randomly divided into 2 groups of 6 animals each, each group being orally administered with tandospirone citrate and tandospirone maleate in a dose equivalent to 10mg/kg (as tandospirone base) respectively. The test sample was prepared as an aqueous solution at a concentration of 1mg/mL before administration. Rats were fasted for 12 hours prior to dosing and returned to food 4 hours after dosing. Blank blood was taken before administration, 0.5mL of blood was taken at the edge of the eye at preset time intervals of 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 24 hours after administration, and placed in a centrifuge tube containing heparin, plasma was separated by centrifugation at 4000 rpm for 10min, supernatant was taken, the concentration of tandospirone in plasma was measured, and pharmacokinetic parameters were calculated, the results of which are shown in table 7. Comparison of pharmacokinetic parameters for each group was considered to be significantly different using One-Way analysis of variance (One-Way ANOVA) with P <0.05 or P < 0.01.
TABLE 7 comparison of pharmacokinetic parameters
Compared with the tandospirone citrate,#P<0.05，##P<0.01。
the test results in Table 7 show that the time to peak (T) of tandospirone maleate crystal form II is longer than that of the existing product tandospirone citratemax) Shortened by 20%, and peak concentration (C)max) The improvement is over 4 times, and the area under the average blood concentration-time curve (AUC) value is improved by nearly 3 times. Thus, T of the Compound of the present inventionmaxSignificantly shorter value, CmaxAnd AUC valueThe increase shows that the compound of the invention has faster onset time and can play a role more quickly than the prior product; but also has higher bioavailability and better medicinal effect.
In conclusion, compared with the existing product tandospirone citrate, the tandospirone maleate compound crystal form II provided by the invention has the advantages of stable property, good water solubility and obviously improved bioavailability, and provides an effective solution for improving the safety and effectiveness of the medicine; in addition, the compound of the invention has simple preparation process and high yield, and is suitable for industrial production.
Claims (19)
1. A tandospirone maleate compound characterized by: the compound exists in a crystal form II, and the crystal form II has X-ray powder diffraction pattern characteristics shown in figure 1.
2. The method for preparing tandospirone maleate compound according to claim 1, characterized in that: the method comprises the following operation procedures:
a. taking tandospirone maleate, adding a solvent, and heating to dissolve to prepare a tandospirone maleate solution;
b. naturally cooling to room temperature for crystallization, separating crystals, and drying to obtain the tandospirone maleate crystal form II;
wherein, the solvent in the step a is one selected from acetonitrile, acetonitrile and water, acetonitrile and tetrahydrofuran, and a mixed solution of tetrahydrofuran, acetonitrile and water.
3. The method for preparing tandospirone maleate compound according to claim 2, characterized in that: in the step a, the mass-to-volume ratio of the tandospirone maleate to the solvent is 1: 1-30 g/mL.
4. The method for preparing tandospirone maleate compound according to claim 2, characterized in that: in the step a, the mass-to-volume ratio of the tandospirone maleate to the solvent is 1: 1-25 g/mL.
5. The method for preparing tandospirone maleate compound according to claim 2, characterized in that: in the step a, the mass-to-volume ratio of the tandospirone maleate to the solvent is 1: 3-20 g/mL.
6. The method for preparing tandospirone maleate compound according to claim 2, characterized in that: in step a, the dissolution temperature is heated to 30 ℃ until the solvent is refluxed.
7. The method for preparing tandospirone maleate compound according to claim 2, characterized in that: in step a, the dissolution temperature is heated to 45 ℃ until the solvent is refluxed.
8. The method for preparing tandospirone maleate compound according to claim 2, characterized in that: the preparation method of tandospirone maleate in the step a comprises the following operation procedures:
A. taking tandospirone and maleic acid, adding a solvent, stirring, and keeping a reaction solution for later use after the reaction is complete;
B. naturally cooling the reaction liquid to room temperature, separating the solid, and drying to obtain tandospirone maleate;
the solvent in the step A is selected from any one of methanol, ethanol, isopropanol, acetone and butanone, or selected from one of mixed solvents of acetone and diethyl ether, acetone and isopropyl ether, acetone and water, acetone and ethyl acetate, methanol and water, methanol and butyl acetate, isopropanol and water, isopropanol and ethyl acetate, isopropanol and methanol, ethanol and water, ethanol and acetone, ethanol and diethyl ether, acetonitrile and tetrahydrofuran.
9. The process for preparing tandospirone maleate compound according to claim 8, characterized in that: in step a, the molar ratio of tandospirone to maleic acid is less than or equal to 1: 1.
10. The process for preparing tandospirone maleate compound according to claim 8, characterized in that: in the step A, the molar ratio of tandospirone to maleic acid is 1 (1-3).
11. The process for preparing tandospirone maleate compound according to claim 8, characterized in that: in the step A, the mass volume ratio of tandospirone to the solvent is 1: 1-30 kg/L.
12. The process for preparing tandospirone maleate compound according to claim 8, characterized in that: in the step A, the mass-to-volume ratio of tandospirone to the solvent is 1: 3-25 kg/L.
13. The process for preparing tandospirone maleate compound according to claim 8, characterized in that: the reaction process in step A is properly heated.
14. The process for preparing tandospirone maleate compound according to claim 8, characterized in that: and C, heating the reaction process in the step A to room temperature until the solvent is refluxed.
15. The process for preparing tandospirone maleate compound according to claim 8, characterized in that: the heating temperature in the reaction process in the step A is 30 ℃ until the solvent is refluxed.
16. A pharmaceutical composition characterized by: the pharmaceutical preparation is prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components into the tandospirone maleate compound of claim 1 serving as an active ingredient.
17. Use of a tandospirone maleate compound according to claim l for the preparation of a medicament for the treatment of a disease associated with 5-hydroxytryptamine or/and norepinephrine reuptake.
18. Use of tandospirone maleate compound according to claim l7, characterized in that: the medicine is used for treating central nervous system diseases and eye diseases.
19. Use of tandospirone maleate compound according to claim l8, characterized in that: the medicament is a medicament for treating anxiety, depression, neurasthenia, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, panic disorder, autism, insomnia, schizophrenia, age-related memory disorders, senile dementia, obsessive-compulsive syndrome, obesity, bulimia or deficit of nervosa, tourette's syndrome, chronic fatigue syndrome, vasomotor flushing, cocaine or alcohol addiction, sexual dysfunction, borderline personality disorder, raynaud's syndrome, urinary incontinence, pain disorders, parkinson's disease, epilepsy, glaucoma, diabetic retinopathy, age-related macular degeneration or retinal edema.
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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| 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 |
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| CN106749196B (en) | 2020-07-03 |
| CN106749196A (en) | 2017-05-31 |
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