CN105175398A - Tandospirone oxalate compound - Google Patents
Tandospirone oxalate compound Download PDFInfo
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- CN105175398A CN105175398A CN201410249410.XA CN201410249410A CN105175398A CN 105175398 A CN105175398 A CN 105175398A CN 201410249410 A CN201410249410 A CN 201410249410A CN 105175398 A CN105175398 A CN 105175398A
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- oxalic acid
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- 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 a tandospirone oxalate compound. The invention also provides a preparation method of the tandospirone oxalate compound, a pharmaceutical composition containing the compound and a use of the compound. The tandospirone oxalate compound provided by the invention exists in a form of crystals, has stable properties and good solubility in water, and provides an effective solution way for improving the drug bioavailability and safety; and in addition, the preparation process of the compound is simple, high in yield, and suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of oxalic acid Tandospirone compound, be specifically related to the crystalline form of this compound, and the preparation method of this compound crystal, pharmaceutical composition and purposes.
Background technology
Tandospirone belongs to azaspiro ketone medicine, chemistry (3a α by name, 4 β, 7 β, 7a α)-six hydrogen-2-[4 [4-(2-pyrimidyl)-1-(piperazinyl)-butyl]-4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone, molecular structural formula is as follows:
Tandospirone is developed by SUMITOMO CHEMICAL Pharmaceutical Co., Ltd the earliest, gets permission listing in 1996 in Japan.It is a kind of 5-hydroxytryptamine receptor agonist, belong to the 3rd generation anxiolytic, be mainly used in treat anxiety or other companion anxiety states disease.In brain, it can with integrated distribution emotion maincenter hippocampus, in every, the cerebral limbic system such as interpeduncular nucleus, amygdala and the 5-HT stitching gland core
1Areceptor-selective ground combines, by exciting 5-HT
1Aautoreceptor, regulates the serotonin being projected to hippocampus from nuclei of median raphe, suppresses the serotonin effect of action suppression system, plays angst resistance effect.Compared to original shape medicine azaspiro ketone with analog derivative buspirone, it has higher selectivity angst resistance effect, and this effect is close with diazepam, but toxic side effect in nervimotion Sexual dysfunction and drug abuse etc. is less than diazepam.Due to the specificity of mechanism of action, when Tandospirone and salt thereof are used for the treatment of anxiety disorder clinically, have that drug safety is high, side reaction is few, give up phenomenon, prolonged application without relaxed muscle and sedative effect, no dependence and drug withdrawal after in vivo without advantages such as accumulations.
There are some researches show, Tandospirone and salt thereof, except effect antianxity, also have goodish application in the treatment or auxiliary therapy of other nervous system disorderss.Tandospirone and salt thereof have certain antidepressant effect, very remarkable for the patient's curative effect being mixed with anxiety and depression, and vegetative nerve symptom can be improved by anxiety and antidepressant effects, as irritable bowel syndrome, functional dyspepsia, postoperative nausea and vomiting etc.It still treats the ataxic active drug of Central nervous system, obviously can improve the symptom of patient's cerebellar ataxia.For the patient suffering from neurasthenia, senile dementia or schizophrenia, it effectively can also improve memory, and treatment increases rheological properties dysmnesia, significantly improves the declarative memory of schizophreniac, logic memory and spoken paired-association etc.In addition, there are some researches show the activity also as the Tandospirone of 5-hydroxytryptamine receptor agonist and salt thereof with intraocular pressure lowering, may be used for the eye disease for the treatment of because endothelial cell proliferation, inflammation, vascular permeability raising or vasculogenesis etc. cause, such as diabetic retinopathy, age-related macular degeneration, retinal edema, glaucoma etc.Visible, Tandospirone and salt thereof have very good clinical treatment advantage and wide market outlook.
In clinical application, the drug molecule of nearly half is had to be all exist in a salt form and administration.Salify is carried out with the molecule of oppositely charged or ion and medicine, effectively can improve medicine some undesirable physical chemistry or biopharmaceutical properties, such as, change the solubleness of medicine, reduce water absorbability, improve stability, change fusing point, improve nonferromagnetic substance, be convenient to prepare purifying, improve perviousness etc.The poorly water-soluble of Tandospirone, effectively can improve its water-soluble and physical and chemical stability after salify, improve bioavailability, therefore, Tandospirone salt often has more advantage than its original shape medicine Tandospirone in medical use, is conducive to the effect having given play to medicine to greatest extent.That such as sells in the market is mainly SM-3997, and it is widely used in the treatment of the relative diseases such as anxiety disorder usually with the form of tablet or capsule, have the clinical application research of comparative maturity.And in the application of ophthalmic diseases, SM-3997 can cause strong impulse to eye because of its alkali, so usually can consider during medication to select the hydrochloric acid Tandospirone that pungency is little, comfort level is high.
At present, the research for Tandospirone salt mainly concentrates on citrate and hydrochloride.Such as, in the documents such as US4507303, US4818756, JP60087262, CN101362751A, report the preparation method of SM-3997, in patent CN10234442A, also disclose three kinds of crystal formations of SM-3997.In addition, the preparation method of hydrochloric acid Tandospirone is also open in existing document, such as patent CN101880274A, US4507303, EP0082402 etc.Just in current disclosed document, yet there are no any about the preparation method of other salifie form of Tandospirone and the relevant report of crystal formation.
As everyone knows, for medicine, the compound of different salifie form may have different crystal formations, and the compound of same salifie form also may exist polymorphic.And different crystal formations likely has distinct colors, fusing point, stability, apparent solubility, dissolution rate etc., these character directly can have influence on the stability, solubleness, water absorbability, bioavailability etc. of pharmaceutical preparation, and cause the difference of drug quality and clinical drug effect thus.Therefore, be significantly for the various salt of Tandospirone and the preparation of relevant crystal formation thereof.
Summary of the invention
The object of the present invention is to provide stable in properties, water-soluble good oxalic acid Tandospirone compound.
Present invention also offers the preparation method of oxalic acid Tandospirone compound, pharmaceutical composition and purposes.
The invention provides a kind of preparation method of oxalic acid Tandospirone, it comprises following operation sequence:
A, get oxalic acid and be dissolved in solvent, make oxalic acid solution, get Tandospirone, add solvent, after heating for dissolving, then add oxalic acid solution, question response is complete, and reaction solution is for subsequent use;
B, reaction solution naturally cool to room temperature, leave standstill, get precipitation, dry, obtain oxalic acid Tandospirone.
Further, in step a, the mol ratio of Tandospirone and oxalic acid is less than or equal to 1:1, heating for dissolving temperature is 30 ~ 100 DEG C, temperature of reaction is 30 ~ 100 DEG C, the mass volume ratio of Tandospirone and solvent is 1:1 ~ 30kg/L, and described solvent is selected from any one or its combination of water, acetonitrile, alcohol, ketones solvent, ether solvent, esters solvent.
Wherein, the mol ratio of Tandospirone and oxalic acid is preferably 1:(1 ~ 2).
Wherein, heating for dissolving temperature is preferably 30 ~ 90 DEG C, and temperature of reaction is preferably 30 ~ 90 DEG C.
Wherein, the mass volume ratio of Tandospirone and solvent is preferably 1:3 ~ 20kg/L.
Wherein, described solvent is preferably any one or its combination of methyl alcohol, ethanol, Virahol, acetone, water, tetrahydrofuran (THF), acetonitrile, ethyl acetate, ether.
Further, in step b, time of repose is 1 ~ 16 hour, is preferably 2 ~ 12 hours.
The invention provides a kind of oxalic acid Tandospirone compound, the feature of this compound is that it exists with the form of crystalline form I, when the compounds of this invention adopts CuK α source of radiation to carry out X-ray powder diffraction, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle have charateristic avsorption band at 10.7 ± 0.2,11.8 ± 0.2,16.0 ± 0.2,16.8 ± 0.2,24.0 ± 0.2,27.0 ± 0.2 degree.
Further, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle also have charateristic avsorption band at 5.3 ± 0.2,7.4 ± 0.2,21.5 ± 0.2,27.9 ± 0.2,28.9 ± 0.2 degree.
Preferably, the X-ray powder diffraction of described compound as shown in Figure 1.
The structural formula of the compounds of this invention is:
Wherein, the fusing point of described compound is 162.0 ~ 163.0 DEG C.
Present invention also offers the preparation method of above-mentioned oxalic acid Tandospirone compound, it comprises following operation sequence:
A, get oxalic acid Tandospirone, add solvent, after heating for dissolving, obtained oxalic acid Tandospirone solution;
B, naturally cool to room temperature, leave standstill, get precipitation, dry, obtain oxalic acid Tandospirone crystalline form I; Or,
C, naturally cool to ambient temperatare and put, then leave standstill at being placed in 0 ± 5 DEG C, get precipitation, dry, obtain oxalic acid Tandospirone crystalline form I.
Further, in steps A, heating for dissolving temperature is 30 ~ 100 DEG C, and the mass volume ratio of oxalic acid Tandospirone and solvent is 1:1 ~ 30g/mL, and described solvent is selected from any one or its combination of water, alcohol, ketones solvent, ether solvent, esters solvent.
Wherein, heating for dissolving temperature is preferably 35 ~ 90 DEG C.
Wherein, the preferred 1:1 ~ 25g/mL of mass volume ratio of oxalic acid Tandospirone and solvent, more preferably 1:3 ~ 20g/mL.
Wherein, any one of the mixing solutions of the mixing solutions of the mixing solutions of the mixing solutions of the mixing solutions of described solvent preferred alcohols, alcohol and water mixed solution, acetone and water, alcohol and acetone, alcohol and ethyl acetate, alcohol and ether, acetone and alcohol and water.
Wherein, described alcohol is selected from any one or its combination of methyl alcohol, ethanol, Virahol.
Further, in step B, time of repose is 1 ~ 16 hour, is preferably 2 ~ 12 hours; In step C, ambient temperatare puts 1 ~ 16 hour, is preferably 2 ~ 12 hours, leaves standstill within 12 hours at 0 ± 5 DEG C, is preferably within 10 hours.The length of above-mentioned time of repose, determines that whether this compound crystallization is complete, has impact, but can not affect the structure of crystal formation to its yield.
Present invention also offers above-mentioned oxalic acid Tandospirone compound crystal form I preparation treatment serotonin or/and norepinephrine reuptake relative disease medicine in purposes.
Wherein, described medicine is the medicine for the treatment of central nervous system disease and eye disease, preferably treats the medicine of the diseases such as anxiety disorder, dysthymia disorders, Phobias, autism, autism, insomnia, schizophrenia, increasing rheological properties dysmnesia, neurasthenia, senile dementia, glaucoma, diabetic retinopathy, age-related macular degeneration, retinal edema.
Further, above-mentioned oxalic acid Tandospirone compound crystal form I is preparing the purposes in serotonin conditioning agent.
Wherein, described serotonin conditioning agent is the medicine for the treatment of anxiety disorder, dysthymia disorders or insomnia.
Present invention also offers a kind of pharmaceutical composition, it be with above-mentioned oxalic acid Tandospirone compound crystal form I for activeconstituents, add the preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
Pharmaceutically acceptable auxiliary material of the present invention or complementary composition are the usual excipients for the preparation of above-mentioned preparation well known in the art or auxiliary material.The vehicle that oral preparations or external preparation are commonly used or auxiliary material include but are not limited to weighting agent (thinner), lubricant (glidant or antitack agent), dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, disintegrating agent etc.Tackiness agent is as syrup, gum arabic, gelatin, starch slurry, polyvidone, cellulose derivative etc.; Weighting agent is as lactose, dextrin, starch and derivative thereof, cellulose derivative, inorganic calcium salt, N.F,USP MANNITOL, agar powder etc.; Lubricant is as micropowder silica gel, stearic acid and its esters, talcum powder, hydrogenated vegetable oil, polyethylene glycols etc.; Disintegrating agent is as starch and derivative, polyvinylpolypyrrolidone, cellulose derivative etc.; Wetting agent is as water, alcohols or other organic solvents etc.The vehicle that described injection is conventional or auxiliary material include but are not limited to: oxidation inhibitor is as S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine etc.; Fungistat is as phenol, phenylcarbinol, hydroxypropyl methyl esters, trichloro-butyl alcohol etc.; Conditioning agent example hydrochloric acid, Citric Acid, potassium hydroxide (sodium), buffer reagent etc.; Emulsifying agent is as Polysorbate 80, Yelkin TTS, fabaceous lecithin etc.; Solubilizing agent is as tween 80, bile, glycerine etc.In addition, also by activeconstituents and pharmaceutically acceptable slow controlled release carrier, sustained-release preparation can be made according to the preparation method of sustained-release preparation known in the art.
The dosage form of composition of the present invention, can be the common formulations such as liquid preparation, gaseous formulation, solid preparation and semi-solid preparation, preferred fragrance aqua, solution, injection, mixture, lotion, liniment, aerosol, sprays, powder, pill, tablet, film, ointment, suppository, paste.
Present invention also offers a kind of oxalic acid Tandospirone compound, the feature of this compound is that it exists with the form of crystal form II, when the compounds of this invention adopts CuK α source of radiation to carry out X-ray powder diffraction, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle have charateristic avsorption band at 6.3 ± 0.2,9.0 ± 0.2,11.2 ± 0.2,17.3 ± 0.2,18.1 ± 0.2,24.6 ± 0.2,25.5 ± 0.2,28.5 ± 0.2 degree.
Further, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle also have charateristic avsorption band at 7.4 ± 0.2,10.4 ± 0.2,12.3 ± 0.2,14.8 ± 0.2,21.0 ± 0.2,22.9 ± 0.2,26.5 ± 0.2,29.2 ± 0.2 degree.
Preferably, the X-ray powder diffraction of described compound as shown in Figure 8.
The structural formula of the compounds of this invention is:
Wherein, the fusing point of described compound is 161.5 ~ 162.5 DEG C.
Present invention also offers the preparation method of above-mentioned oxalic acid Tandospirone compound, it comprises following operation sequence:
A, get oxalic acid Tandospirone, add solvent, after heating for dissolving, obtained oxalic acid Tandospirone solution;
B, naturally cool to room temperature, leave standstill, get precipitation, dry, obtain oxalic acid Tandospirone crystal form II; Or,
C, naturally cool to ambient temperatare and put, then leave standstill at being placed in 0 ± 5 DEG C, get precipitation, dry, obtain oxalic acid Tandospirone crystal form II.
Further, in steps A, heating for dissolving temperature is 30 ~ 120 DEG C, and the mass volume ratio of oxalic acid Tandospirone and solvent is 1:1 ~ 30g/mL, and described solvent is selected from any one or its combination of water, alcohol.
Wherein, heating for dissolving temperature is preferably 50 ~ 100 DEG C.
Wherein, the mass volume ratio of oxalic acid Tandospirone and solvent is preferably 1:1 ~ 20g/mL, is more preferably 1:1 ~ 15g/mL.
Wherein, described solvent is preferably water.
Further, in step B, time of repose is 1 ~ 16 hour, is preferably 2 ~ 12 hours; In step C, ambient temperatare puts 1 ~ 16 hour, is preferably 2 ~ 12 hours, leaves standstill within 12 hours at 0 ± 5 DEG C, is preferably within 10 hours.The length of above-mentioned time of repose, determines that whether this compound crystallization is complete, has impact, but can not affect the structure of crystal formation to its yield.
Present invention also offers above-mentioned oxalic acid Tandospirone compound crystal form II preparation treatment serotonin or/and norepinephrine reuptake relative disease medicine in purposes.
Wherein, described medicine is the medicine for the treatment of central nervous system disease and eye disease, preferably treats the medicine of the diseases such as anxiety disorder, dysthymia disorders, Phobias, autism, autism, insomnia, schizophrenia, increasing rheological properties dysmnesia, neurasthenia, senile dementia, glaucoma, diabetic retinopathy, age-related macular degeneration, retinal edema.
Further, above-mentioned oxalic acid Tandospirone compound crystal form II is preparing the purposes in serotonin conditioning agent.
Wherein, described serotonin conditioning agent is the medicine for the treatment of anxiety disorder, dysthymia disorders or insomnia.
Present invention also offers a kind of pharmaceutical composition, it be with above-mentioned oxalic acid Tandospirone compound crystal form II for activeconstituents, add the preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
Pharmaceutically acceptable auxiliary material of the present invention or complementary composition are the usual excipients for the preparation of above-mentioned preparation well known in the art or auxiliary material.The vehicle that oral preparations or external preparation are commonly used or auxiliary material include but are not limited to weighting agent (thinner), lubricant (glidant or antitack agent), dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, disintegrating agent etc.Tackiness agent is as syrup, gum arabic, gelatin, starch slurry, polyvidone, cellulose derivative etc.; Weighting agent is as lactose, dextrin, starch and derivative thereof, cellulose derivative, inorganic calcium salt, N.F,USP MANNITOL, agar powder etc.; Lubricant is as micropowder silica gel, stearic acid and its esters, talcum powder, hydrogenated vegetable oil, polyethylene glycols etc.; Disintegrating agent is as starch and derivative, polyvinylpolypyrrolidone, cellulose derivative etc.; Wetting agent is as water, alcohols or other organic solvents etc.The vehicle that described injection is conventional or auxiliary material include but are not limited to: oxidation inhibitor is as S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine etc.; Fungistat is as phenol, phenylcarbinol, hydroxypropyl methyl esters, trichloro-butyl alcohol etc.; Conditioning agent example hydrochloric acid, Citric Acid, potassium hydroxide (sodium), buffer reagent etc.; Emulsifying agent is as Polysorbate 80, Yelkin TTS, fabaceous lecithin etc.; Solubilizing agent is as tween 80, bile, glycerine etc.In addition, also by activeconstituents and pharmaceutically acceptable slow controlled release carrier, sustained-release preparation can be made according to the preparation method of sustained-release preparation known in the art.
The dosage form of composition of the present invention, can be the common formulations such as liquid preparation, gaseous formulation, solid preparation and semi-solid preparation, preferred fragrance aqua, solution, injection, mixture, lotion, liniment, aerosol, sprays, powder, pill, tablet, film, ointment, suppository, paste.
Present invention also offers a kind of oxalic acid Tandospirone compound, the feature of this compound is that it exists with the form of crystalline form III, when the compounds of this invention adopts CuK α source of radiation to carry out X-ray powder diffraction, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle have charateristic avsorption band at 13.0 ± 0.2,15.2 ± 0.2,16.4 ± 0.2,17.6 ± 0.2,18.4 ± 0.2,20.6 ± 0.2,21.2 ± 0.2 degree.
Further, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle also have charateristic avsorption band at 5.4 ± 0.2,7.6 ± 0.2,10.9 ± 0.2,12.1 ± 0.2,19.0 ± 0.2,19.3 ± 0.2,24.3 ± 0.2,30.1 ± 0.2 degree.
Preferably, the X-ray powder diffraction of described compound as shown in Figure 9.
The structural formula of the compounds of this invention is:
Wherein, the fusing point of described compound is 161.5 ~ 163.0 DEG C.
Present invention also offers the preparation method of above-mentioned oxalic acid Tandospirone compound, it comprises following operation sequence:
A, get oxalic acid Tandospirone, add solvent, after heating for dissolving, obtained oxalic acid Tandospirone solution;
B, naturally cool to room temperature, leave standstill, get precipitation, dry, obtain oxalic acid Tandospirone crystalline form III.
Further, in steps A, heating for dissolving temperature is 30 ~ 100 DEG C, and the mass volume ratio of oxalic acid Tandospirone and solvent is 1:1 ~ 30g/mL, and described solvent is selected from any one or its combination of ketones solvent, ether solvent.
Wherein, heating for dissolving temperature is preferably 30 ~ 60 DEG C.
Wherein, the preferred 1:1 ~ 25g/mL of mass volume ratio of oxalic acid Tandospirone and solvent, more preferably 1:3 ~ 20g/mL.
Wherein, described solvent is preferably any one or its combination of acetone, ether, is more preferably the mixing solutions of acetone, acetone and ether any one.
Further, in step B, time of repose is 1 ~ 16 hour, is preferably 2 ~ 12 hours.The length of above-mentioned time of repose, determines that whether this compound crystallization is complete, has impact, but can not affect the structure of crystal formation to its yield.
Present invention also offers above-mentioned oxalic acid Tandospirone compound crystal form III preparation treatment serotonin or/and norepinephrine reuptake relative disease medicine in purposes.
Wherein, described medicine is the medicine for the treatment of central nervous system disease and eye disease, preferably treats the medicine of the diseases such as anxiety disorder, dysthymia disorders, Phobias, autism, autism, insomnia, schizophrenia, increasing rheological properties dysmnesia, neurasthenia, senile dementia, glaucoma, diabetic retinopathy, age-related macular degeneration, retinal edema.
Further, above-mentioned oxalic acid Tandospirone compound crystal form III is preparing the purposes in serotonin conditioning agent.
Wherein, described serotonin conditioning agent is the medicine for the treatment of anxiety disorder, dysthymia disorders or insomnia.
Present invention also offers a kind of pharmaceutical composition, it be with above-mentioned oxalic acid Tandospirone compound crystal form III for activeconstituents, add the preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
Pharmaceutically acceptable auxiliary material of the present invention or complementary composition are the usual excipients for the preparation of above-mentioned preparation well known in the art or auxiliary material.The vehicle that oral preparations or external preparation are commonly used or auxiliary material include but are not limited to weighting agent (thinner), lubricant (glidant or antitack agent), dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, disintegrating agent etc.Tackiness agent is as syrup, gum arabic, gelatin, starch slurry, polyvidone, cellulose derivative etc.; Weighting agent is as lactose, dextrin, starch and derivative thereof, cellulose derivative, inorganic calcium salt, N.F,USP MANNITOL, agar powder etc.; Lubricant is as micropowder silica gel, stearic acid and its esters, talcum powder, hydrogenated vegetable oil, polyethylene glycols etc.; Disintegrating agent is as starch and derivative, polyvinylpolypyrrolidone, cellulose derivative etc.; Wetting agent is as water, alcohols or other organic solvents etc.The vehicle that described injection is conventional or auxiliary material include but are not limited to: oxidation inhibitor is as S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine etc.; Fungistat is as phenol, phenylcarbinol, hydroxypropyl methyl esters, trichloro-butyl alcohol etc.; Conditioning agent example hydrochloric acid, Citric Acid, potassium hydroxide (sodium), buffer reagent etc.; Emulsifying agent is as Polysorbate 80, Yelkin TTS, fabaceous lecithin etc.; Solubilizing agent is as tween 80, bile, glycerine etc.In addition, also by activeconstituents and pharmaceutically acceptable slow controlled release carrier, sustained-release preparation can be made according to the preparation method of sustained-release preparation known in the art.
The dosage form of composition of the present invention, can be the common formulations such as liquid preparation, gaseous formulation, solid preparation and semi-solid preparation, preferred fragrance aqua, solution, injection, mixture, lotion, liniment, aerosol, sprays, powder, pill, tablet, film, ointment, suppository, paste.
Present invention also offers a kind of oxalic acid Tandospirone compound, the feature of this compound is that it exists with the form of crystalline form IV, when the compounds of this invention adopts CuK α source of radiation to carry out X-ray powder diffraction, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle have charateristic avsorption band at 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.
Further, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle also have charateristic avsorption band at 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.
Preferably, the X-ray powder diffraction of described compound as shown in figure 11.
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 comprises following operation sequence:
A, get oxalic acid Tandospirone, add solvent, after heating for dissolving, obtained oxalic acid Tandospirone solution;
B, naturally cool to room temperature, leave standstill, get precipitation, dry, obtain oxalic acid Tandospirone crystalline form IV; Or,
C, naturally cool to ambient temperatare and put, then leave standstill at being placed in 0 ± 5 DEG C, get precipitation, dry, obtain oxalic acid Tandospirone crystalline form IV.
Further, in steps A, heating for dissolving temperature is 30 ~ 100 DEG C, and the mass volume ratio of oxalic acid Tandospirone and solvent is 1:1 ~ 30g/mL, and described solvent is selected from any one or its combination of water, acetonitrile, tetrahydrofuran (THF).
Wherein, heating for dissolving temperature is preferably 50 ~ 90 DEG C.
Wherein, the mass volume ratio of oxalic acid Tandospirone and solvent is preferably 1:1 ~ 25g/mL, more preferably 1:3 ~ 20g/mL.
Wherein, described solvent is preferably two or more combination any of water, acetonitrile, tetrahydrofuran (THF), is more preferably the mixing solutions of the mixing solutions of the mixing solutions of acetonitrile and water, tetrahydrofuran (THF) and acetonitrile, tetrahydrofuran (THF) and acetonitrile and water any one.
Further, in step B, time of repose is 1 ~ 16 hour, is preferably 2 ~ 12 hours; In step C, ambient temperatare puts 1 ~ 16 hour, is preferably 2 ~ 12 hours, leaves standstill within 12 hours at 0 ± 5 DEG C, is preferably within 10 hours.The length of above-mentioned time of repose, determines that whether this compound crystallization is complete, has impact, but can not affect the structure of crystal formation to its yield.
Present invention also offers above-mentioned oxalic acid Tandospirone compound crystal form IV preparation treatment serotonin or/and norepinephrine reuptake relative disease medicine in purposes.
Wherein, described medicine is the medicine for the treatment of central nervous system disease and eye disease, preferably treats the medicine of the diseases such as anxiety disorder, dysthymia disorders, Phobias, autism, autism, insomnia, schizophrenia, increasing rheological properties dysmnesia, neurasthenia, senile dementia, glaucoma, diabetic retinopathy, age-related macular degeneration, retinal edema.
Further, above-mentioned oxalic acid Tandospirone compound crystal form IV is preparing the purposes in serotonin conditioning agent.
Wherein, described serotonin conditioning agent is the medicine for the treatment of anxiety disorder, dysthymia disorders or insomnia.
Present invention also offers a kind of pharmaceutical composition, it be with above-mentioned oxalic acid Tandospirone compound crystal form IV for activeconstituents, add the preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
Pharmaceutically acceptable auxiliary material of the present invention or complementary composition are the usual excipients for the preparation of above-mentioned preparation well known in the art or auxiliary material.The vehicle that oral preparations or external preparation are commonly used or auxiliary material include but are not limited to weighting agent (thinner), lubricant (glidant or antitack agent), dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, disintegrating agent etc.Tackiness agent is as syrup, gum arabic, gelatin, starch slurry, polyvidone, cellulose derivative etc.; Weighting agent is as lactose, dextrin, starch and derivative thereof, cellulose derivative, inorganic calcium salt, N.F,USP MANNITOL, agar powder etc.; Lubricant is as micropowder silica gel, stearic acid and its esters, talcum powder, hydrogenated vegetable oil, polyethylene glycols etc.; Disintegrating agent is as starch and derivative, polyvinylpolypyrrolidone, cellulose derivative etc.; Wetting agent is as water, alcohols or other organic solvents etc.The vehicle that described injection is conventional or auxiliary material include but are not limited to: oxidation inhibitor is as S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine etc.; Fungistat is as phenol, phenylcarbinol, hydroxypropyl methyl esters, trichloro-butyl alcohol etc.; Conditioning agent example hydrochloric acid, Citric Acid, potassium hydroxide (sodium), buffer reagent etc.; Emulsifying agent is as Polysorbate 80, Yelkin TTS, fabaceous lecithin etc.; Solubilizing agent is as tween 80, bile, glycerine etc.In addition, also by activeconstituents and pharmaceutically acceptable slow controlled release carrier, sustained-release preparation can be made according to the preparation method of sustained-release preparation known in the art.
The dosage form of composition of the present invention, can be the common formulations such as liquid preparation, gaseous formulation, solid preparation and semi-solid preparation, preferred fragrance aqua, solution, injection, mixture, lotion, liniment, aerosol, sprays, powder, pill, tablet, film, ointment, suppository, paste.
Oxalic acid Tandospirone compound provided by the invention, has filled up the blank of prior art; Compared with currently available products SM-3997, oxalic acid Tandospirone compound provided by the invention, its stable in properties, well water-soluble, for the bioavailability and security that improve medicine provide a kind of effective solution route; In addition, the preparation technology of the compounds of this invention is simple, and yield is high, is applicable to suitability for industrialized production.
Accompanying drawing explanation
The X-ray powder diffraction pattern of Fig. 1 embodiment of the present invention 3 gained oxalic acid Tandospirone crystalline form I.
The X-ray powder diffraction pattern of gained oxalic acid Tandospirone crystalline form I under Fig. 2 embodiment of the present invention 4 numbering 3 condition.
The X-ray powder diffraction pattern of gained oxalic acid Tandospirone crystalline form I under Fig. 3 embodiment of the present invention 4 numbering 6 condition.
The X-ray powder diffraction pattern of gained oxalic acid Tandospirone crystalline form I under Fig. 4 embodiment of the present invention 4 numbering 8 condition.
The X-ray powder diffraction pattern of gained oxalic acid Tandospirone crystalline form I under Fig. 5 embodiment of the present invention 4 numbering 19 condition.
The X-ray powder diffraction pattern of gained oxalic acid Tandospirone crystalline form I under Fig. 6 embodiment of the present invention 4 numbering 22 condition.
The X-ray powder diffraction pattern of gained oxalic acid Tandospirone crystalline form I under Fig. 7 embodiment of the present invention 4 numbering 28 condition.
The X-ray powder diffraction pattern of Fig. 8 embodiment of the present invention 5 gained oxalic acid Tandospirone crystal form II.
The X-ray powder diffraction pattern of Fig. 9 embodiment of the present invention 7 gained oxalic acid Tandospirone crystalline form III.
The X-ray powder diffraction pattern of gained oxalic acid Tandospirone crystalline form III under Figure 10 embodiment of the present invention 8 numbering 4 condition.
The X-ray powder diffraction pattern of Figure 11 embodiment of the present invention 9 gained oxalic acid Tandospirone crystalline form IV.
Embodiment
In the present invention, raw materials used Tandospirone obtains with reference to existing preparation technology's synthesis, the method such as, reported in the patent documentations such as CN101362751A, US5521313.Certainly, except being synthesized by existing method, the present invention's Tandospirone used also can obtain by buying commercial goods.
The preparation of embodiment 1 oxalic acid Tandospirone
Take 0.66kg oxalic acid and be dissolved in 2L Virahol, be configured to the aqueous isopropanol of oxalic acid.Take 2kg Tandospirone, add 10L Virahol, be heated to 90 DEG C, until molten clear after, add the oxalic acid aqueous isopropanol configured, continue to be stirred to and react completely, stop heating, naturally be chilled to room temperature and place 2 hours, suction filtration, washing, dry, obtain 2.42kg oxalic acid Tandospirone, yield is 98.0%, and mass spectrum shows its ESIm/z:383 (M
+).
The preparation of embodiment 2 oxalic acid Tandospirone
Prepare oxalic acid Tandospirone according to the method for embodiment 1, actual conditions is see table 1, and the charging capacity of Tandospirone is 2kg.The results of structural analysis of products obtained therefrom and the results of structural analysis no significant difference of embodiment 1 under each condition.
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 I
Take 200g oxalic acid Tandospirone, add 1000mL Virahol, be heated to 90 DEG C, completely to be dissolved, heating is stopped after continuing to stir 30min, naturally be chilled to room temperature and place 2 hours, suction filtration, washing, dry, obtain 197g white powder oxalic acid Tandospirone crystalline form I, yield is 98.5%, and mass spectrum shows its ESIm/z:383 (M
+), recording its fusing point is 162.0 ~ 163.0 DEG C.
Adopt DX-2700 type X-ray powder diffractometer to analyze sample crystalline phase, CuK α radiation, the X-ray powder diffraction pattern recording oxalic acid Tandospirone crystalline form I is shown in Fig. 1, and its diffraction data of being mainly correlated with is in table 2 (2 θ measuring error are ± 0.2).
The X-ray powder diffraction data of table 2 oxalic acid Tandospirone crystalline form I
The preparation of embodiment 4 oxalic acid Tandospirone compound crystal form I
Prepare oxalic acid Tandospirone crystalline form I according to method described in embodiment 3, actual conditions is see table 3, and the charging capacity of oxalic acid Tandospirone is 200g.The data results such as fusing point of products obtained therefrom and X-ray powder diffraction pattern and embodiment 3 no significant difference under each condition, determine that it is oxalic acid Tandospirone crystalline form I, the representative X ray diffracting spectrum of part is shown in Fig. 2 to Fig. 7.
The preparation of table 3 oxalic acid Tandospirone crystalline form I
Note: in table, mixed solvent ratio is volume ratio.
The preparation of embodiment 5 oxalic acid Tandospirone compound crystal form II
Get 200g oxalic acid Tandospirone, add 600mL water, be heated to 80 DEG C, completely to be dissolved, stop heating after continuing to stir 1h, be naturally chilled to room temperature and place 12 hours, suction filtration, washing, drying, obtain the oxalic acid Tandospirone crystal form II of 192g white, yield is 96.0%.Mass spectrum shows its ESIm/z:383 (M
+), recording its fusing point is 161.5 DEG C ~ 162.5 DEG C.
Adopt DX-2700 type X-ray powder diffractometer to analyze sample crystalline phase, CuK α radiation, the X-ray powder diffraction pattern recording oxalic acid Tandospirone crystal form II is shown in Fig. 8, and main relevant diffraction data is in table 4 (2 θ measuring error are ± 0.2).
The X-ray powder diffraction data of table 4 oxalic acid Tandospirone crystal form II
The preparation of embodiment 6 oxalic acid Tandospirone compound crystal form II
Prepare oxalic acid Tandospirone crystal form II according to method described in embodiment 5, actual conditions is see table 5, and the charging capacity of oxalic acid Tandospirone is 200g.Under each condition, the data results such as fusing point of products obtained therefrom and X-ray powder diffraction pattern and embodiment 5 no significant difference, determine that it is oxalic acid Tandospirone crystal form II.
The preparation of table 5 oxalic acid Tandospirone crystal form II
The preparation of embodiment 7 oxalic acid Tandospirone compound crystal form III
Take 200g oxalic acid Tandospirone, add 2000mL acetone and 2000mL ether, be heated to 35 DEG C, completely to be dissolved, stop heating after continuing to stir 30min, naturally be chilled to room temperature and place 4 hours, suction filtration, washing, dry, obtain 195g white powder oxalic acid Tandospirone crystalline form III, yield is 97.5%.Mass spectrum shows its ESIm/z:383 (M
+), recording its fusing point is 161.5 DEG C ~ 163.0 DEG C.
Adopt DX-2700 type X-ray powder diffractometer to analyze sample crystalline phase, CuK α radiation, the X-ray powder diffraction pattern recording oxalic acid Tandospirone crystalline form III is shown in Fig. 9, and main relevant diffraction data is in table 6 (2 θ measuring error are ± 0.2).
The X-ray powder diffraction data of table 6 oxalic acid Tandospirone crystalline form III
The preparation of embodiment 8 oxalic acid Tandospirone compound crystal form III
Prepare oxalic acid Tandospirone crystalline form III according to method described in embodiment 7, actual conditions is see table 7, and the charging capacity of oxalic acid Tandospirone is 200g.The data results such as fusing point of products obtained therefrom and X-ray powder diffraction pattern and embodiment 7 no significant difference under each condition, determine that it is oxalic acid Tandospirone crystalline form III, the representative X ray diffracting spectrum of part is shown in Figure 10.
The preparation of table 7 oxalic acid Tandospirone crystalline form III
Note: in table, mixed solvent ratio is volume ratio.
The preparation of embodiment 9 oxalic acid Tandospirone compound crystal form IV
Take 200g oxalic acid Tandospirone, add 200mL water and 1000mL acetonitrile, be heated to 80 DEG C, to be dissolved completely after, stop heating after continuing to stir 30min, naturally be chilled to room temperature and place 12 hours, suction filtration, washing, dry, obtain the oxalic acid Tandospirone crystalline form IV of 191g white, yield is 95.5%.Mass spectrum shows its ESIm/z:383 (M
+), recording its fusing point is 162.5 ~ 163.5 DEG C.
Adopt DX-2700 type X-ray powder diffractometer to analyze sample crystalline phase, CuK α radiation, the X-ray powder diffraction pattern recording oxalic acid Tandospirone crystalline form IV is shown in Figure 11, and main relevant diffraction data is in table 8 (2 θ measuring error are ± 0.2).
The X-ray powder diffraction data of table 8 oxalic acid Tandospirone crystal formation VI
The preparation of embodiment 10 oxalic acid Tandospirone compound crystal form IV
Prepare oxalic acid Tandospirone crystalline form IV according to method described in embodiment 9, actual conditions is see table 9, and the charging capacity of oxalic acid Tandospirone is 200g.Under each condition, the data results such as fusing point of products obtained therefrom and X-ray powder diffraction pattern and embodiment 9 no significant difference, determine that it is oxalic acid Tandospirone crystalline form IV.
The preparation of table 9 oxalic acid Tandospirone crystalline form IV
Note: in table, mixed solvent ratio is volume ratio.
Embodiment 11 slow releasing tablet of the present invention
The oxalic acid Tandospirone crystalline form I of amount to be prepared, Vltra tears and lactose are mixed, sieves, add 75% ethanolic soln softwood, cross 20 mesh sieve wet granulars, in about 50 DEG C oven dry, the whole grain of 20 mesh sieve, add Magnesium Stearate and talcum powder, mix rear compressing tablet.
Embodiment 12 slow releasing tablet of the present invention
The oxalic acid Tandospirone crystal form II of amount to be prepared, Vltra tears and lactose are mixed, sieves, add 75% ethanolic soln softwood, cross 20 mesh sieve wet granulars, in about 50 DEG C oven dry, the whole grain of 20 mesh sieve, add Magnesium Stearate and talcum powder, mix rear compressing tablet.
Embodiment 13 capsule of the present invention
After the oxalic acid Tandospirone crystalline form I of amount to be prepared and starch mixs by equal increments method, then mix with Microcrystalline Cellulose, granulation, encapsulated and get final product.
Embodiment 14 capsule of the present invention
After the oxalic acid Tandospirone crystal form II of amount to be prepared and starch mixs by equal increments method, then mix with Microcrystalline Cellulose, granulation, encapsulated and get final product.
Embodiment 15 capsule of the present invention
After the oxalic acid Tandospirone crystalline form III of amount to be prepared and starch mixs by equal increments method, then mix with Microcrystalline Cellulose, granulation, encapsulated and get final product.
Embodiment 16 Sublingual tablet of the present invention
Supplementary material is crossed 100 mesh sieves respectively.The oxalic acid Tandospirone crystalline form IV of amount to be prepared and low-substituted hydroxypropyl methylcellulose gum are mixed by equal increments method, then adds N.F,USP MANNITOL, lactose starch successively, finally add orange flavor and Magnesium Stearate, mix rear compressing tablet.
Below by way of test example, beneficial effect of the present invention is described.
Test example 1 solubility test
Test group 1: the oxalic acid Tandospirone crystalline form I that the embodiment of the present invention 3 prepares;
Test group 2: the oxalic acid Tandospirone crystal form II that the embodiment of the present invention 5 prepares;
Test group 3: the oxalic acid Tandospirone crystalline form III that the embodiment of the present invention 7 prepares;
Test group 4: the oxalic acid Tandospirone crystalline form IV that the embodiment of the present invention 9 prepares;
Control group: the SM-3997 prepared with reference to the disclosed method of existing document (CN101880274A, CN101362751A).
Take trial-product 2g, be placed in the 20mL water of 25 ± 2 DEG C, in powerful jolting 10 second every 1 minute, observe the dissolving situation in 3 minutes.As without visual visible particles of solute, be namely considered as dissolving completely; If there is visual visible particles of solute, then add the water (i.e. 10mL water) of 5 times of volumes of trial-product weight, repeat aforementioned operation, until dissolve completely.Record total water consumption and time, the results are shown in Table 10.
The comparative studies of table 10 solvability
Dissolubility test result in table 10 shows, four kinds of crystal formations of the oxalic acid Tandospirone compound that the present invention prepares, namely crystalline form I, crystal form II, crystalline form III and the crystalline form IV dissolution time in water is obviously short than the dissolution time of currently available products SM-3997, and solvability is more excellent.Under normal circumstances, good be not water-solublely only curative effect of medication and security provides strong guarantee, but also the stimulation produced when can reduce clinical application, improve the compliance of patient, this advantage is particularly outstanding in the application of injection and ophthalmic preparations.
Test example 2 stabilizing effect is tested
Test group 1: the oxalic acid Tandospirone crystalline form I that the embodiment of the present invention 3 prepares;
Test group 2: the oxalic acid Tandospirone crystal form II that the embodiment of the present invention 5 prepares;
Test group 3: the oxalic acid Tandospirone crystalline form III that the embodiment of the present invention 7 prepares;
Test group 4: the oxalic acid Tandospirone crystalline form IV that the embodiment of the present invention 9 prepares;
Control group: the SM-3997 prepared with reference to the disclosed method of existing document (CN101880274A, CN101362751A).
Study on the stability condition comprises: (1) thermal destruction: get trial-product and be about 200mg, is placed in 60 DEG C of loft drier and places; (2) photodegradation: get trial-product and be about 200mg, being placed in illuminance is that the environment of 4500 ± 5001x is placed; (3) high humidity degraded: get trial-product and be about 200mg, be placed in and be placed with KNO
3in the moisture eliminator of saturated solution, room temperature is placed.Stability test the results are shown in Table 11.
Table 11 stability test result
Shown by the test-results in table 11, four kinds of crystal formations of oxalic acid Tandospirone compound prepared by the present invention, i.e. crystalline form I, crystal form II, crystalline form III and crystalline form IV, under the condition of high temperature, high humidity, illumination, purity has no significant change.As can be seen here, not only purity is high for oxalic acid Tandospirone crystal provided by the invention, and stable and controllable for quality, is applicable to manufacture and the standing storage of pharmaceutical preparation.
In sum, compared with currently available products SM-3997, four kinds of crystal formations of oxalic acid Tandospirone compound provided by the invention, i.e. crystalline form I, crystal form II, crystalline form III and crystalline form IV, its stable in properties, well water-soluble, for the bioavailability and security that improve medicine provide a kind of effective solution route; In addition, the preparation technology of the compounds of this invention is simple, and yield is high, is applicable to suitability for industrialized production.
Claims (11)
1. an oxalic acid Tandospirone compound, it is characterized in that: this compound exists with the form of crystalline form I, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle have charateristic avsorption band at 10.7 ± 0.2,11.8 ± 0.2,16.0 ± 0.2,16.8 ± 0.2,24.0 ± 0.2,27.0 ± 0.2 degree; Be preferably 2 θ diffraction angle and also have charateristic avsorption band at 5.3 ± 0.2,7.4 ± 0.2,21.5 ± 0.2,27.9 ± 0.2,28.9 ± 0.2 degree; Be more preferably the X-ray powder diffraction figure had substantially as shown in Figure 1.
2. oxalic acid Tandospirone compound according to claim 1, is characterized in that: the preparation method of this compound comprises following operation sequence:
A gets oxalic acid Tandospirone, adds solvent, after heating for dissolving, and obtained oxalic acid Tandospirone solution;
B naturally cools to room temperature, leaves standstill, gets precipitation, dry, obtains oxalic acid Tandospirone crystalline form I; Or,
C naturally cools to ambient temperatare and puts, then leaves standstill at being placed in 0 ± 5 DEG C, gets precipitation, dry, obtains oxalic acid Tandospirone crystalline form I;
Wherein, described solvent is selected from any one or its combination of water, alcohol, ketones solvent, ether solvent, esters solvent, is preferably any one of mixing solutions of alcohol, alcohol and water mixed solution, the mixing solutions of acetone and water, the mixing solutions of alcohol and acetone, the mixing solutions of alcohol and ethyl acetate, the mixing solutions of alcohol and ether, acetone and alcohol and water; Wherein, described alcohol is selected from any one or its combination of methyl alcohol, ethanol, Virahol.
3. an oxalic acid Tandospirone compound, it is characterized in that: this compound exists with the form of crystal form II, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle have charateristic avsorption band at 6.3 ± 0.2,9.0 ± 0.2,11.2 ± 0.2,17.3 ± 0.2,18.1 ± 0.2,24.6 ± 0.2,25.5 ± 0.2,28.5 ± 0.2 degree; Be preferably 2 θ diffraction angle and also have charateristic avsorption band at 7.4 ± 0.2,10.4 ± 0.2,12.3 ± 0.2,14.8 ± 0.2,21.0 ± 0.2,22.9 ± 0.2,26.5 ± 0.2,29.2 ± 0.2 degree; Be more preferably the X-ray powder diffraction figure had substantially as shown in Figure 8.
4. oxalic acid Tandospirone compound according to claim 3, is characterized in that: the preparation method of this compound comprises following operation sequence:
A gets oxalic acid Tandospirone, adds solvent, after heating for dissolving, and obtained oxalic acid Tandospirone solution;
B naturally cools to room temperature, leaves standstill, gets precipitation, dry, obtains oxalic acid Tandospirone crystal form II; Or,
C naturally cools to ambient temperatare and puts, then leaves standstill at being placed in 0 ± 5 DEG C, gets precipitation, dry, obtains oxalic acid Tandospirone crystal form II;
Wherein, described solvent is selected from any one or its combination of water, alcohol, is preferably water.
5. an oxalic acid Tandospirone compound, it is characterized in that: this compound exists with the form of crystalline form III, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle have charateristic avsorption band at 13.0 ± 0.2,15.2 ± 0.2,16.4 ± 0.2,17.6 ± 0.2,18.4 ± 0.2,20.6 ± 0.2,21.2 ± 0.2 degree; Be preferably 2 θ diffraction angle and also have charateristic avsorption band at 5.4 ± 0.2,7.6 ± 0.2,10.9 ± 0.2,12.1 ± 0.2,19.0 ± 0.2,19.3 ± 0.2,24.3 ± 0.2,30.1 ± 0.2 degree; Be more preferably the X-ray powder diffraction figure had substantially as shown in Figure 9.
6. oxalic acid Tandospirone compound according to claim 5, is characterized in that: the preparation method of this compound comprises following operation sequence:
A, get oxalic acid Tandospirone, add solvent, after heating for dissolving, obtained oxalic acid Tandospirone solution;
B, naturally cool to room temperature, leave standstill, get precipitation, dry, obtain oxalic acid Tandospirone crystalline form III.
Wherein, described solvent is selected from any one or its combination of ketones solvent, ether solvent, is preferably any one or its combination of acetone, ether.
7. an oxalic acid Tandospirone compound, it is characterized in that: this compound exists with the form of crystalline form IV, in the X-ray powder diffraction figure of described compound, 2 θ diffraction angle have charateristic avsorption band at 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; Be preferably 2 θ diffraction angle and also have charateristic avsorption band at 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; Be more preferably the X-ray powder diffraction figure had substantially as shown in figure 11.
8. oxalic acid Tandospirone compound according to claim 7, is characterized in that: the preparation method of this compound comprises following operation sequence:
A gets oxalic acid Tandospirone, adds solvent, after heating for dissolving, and obtained oxalic acid Tandospirone solution;
B naturally cools to room temperature, leaves standstill, gets precipitation, dry, obtains oxalic acid Tandospirone crystalline form IV; Or,
C naturally cools to ambient temperatare and puts, then leaves standstill at being placed in 0 ± 5 DEG C, gets precipitation, dry, obtains oxalic acid Tandospirone crystalline form IV.
Wherein, described solvent is selected from any one or its combination of water, acetonitrile, tetrahydrofuran (THF), is preferably two or more combination any of water, acetonitrile, tetrahydrofuran (THF).
9. according to the oxalic acid Tandospirone compound in claim 2, claim 4, claim 6, claim 8 described in any one, it is characterized in that: the preparation method of steps A mesoxalic acid Tandospirone, comprises following operation sequence:
A, get oxalic acid and be dissolved in solvent, make oxalic acid solution, get Tandospirone, add solvent, after heating for dissolving, then add oxalic acid solution, question response is complete, and reaction solution is for subsequent use;
B, reaction solution naturally cool to room temperature, leave standstill, get precipitation, dry, obtain oxalic acid Tandospirone;
Wherein, described solvent is selected from any one or its combination of water, acetonitrile, alcohol, ketones solvent, ether solvent, esters solvent; Be preferably any one or its combination of methyl alcohol, ethanol, Virahol, acetone, water, tetrahydrofuran (THF), acetonitrile, ethyl acetate, ether.
10. a pharmaceutical composition, is characterized in that: it be containing oxalic acid Tandospirone compound described in claim 1,3,5,7 any one as activeconstituents, add the pharmaceutical preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
Oxalic acid Tandospirone compound described in 11. claim 1,3,5,7 any one preparation treatment with serotonin or/and norepinephrine reuptake relative disease medicine in purposes.
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| CN201610715858.5A CN106349225A (en) | 2014-06-06 | 2014-06-06 | Tandospirone oxalate compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019085494A1 (en) * | 2017-11-01 | 2019-05-09 | 四川科瑞德制药股份有限公司 | Use of azaperone compound in improving parasympathetic nervous activity |
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| CN106349227A (en) | 2017-01-25 |
| CN106349225A (en) | 2017-01-25 |
| CN106467520A (en) | 2017-03-01 |
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