CN105218528A - A kind of L-TARTARIC ACID Tandospirone compound - Google Patents
A kind of L-TARTARIC ACID Tandospirone compound Download PDFInfo
- Publication number
- CN105218528A CN105218528A CN201410249687.2A CN201410249687A CN105218528A CN 105218528 A CN105218528 A CN 105218528A CN 201410249687 A CN201410249687 A CN 201410249687A CN 105218528 A CN105218528 A CN 105218528A
- Authority
- CN
- China
- Prior art keywords
- tandospirone
- tartrate
- compound
- preparation
- amorphous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 229950000505 tandospirone Drugs 0.000 title claims abstract description 136
- -1 L-TARTARIC ACID Tandospirone compound Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 61
- 239000013078 crystal Substances 0.000 claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Chemical class 0.000 claims abstract description 7
- 229940095064 tartrate Drugs 0.000 claims description 80
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 51
- CEIJFEGBUDEYSX-FZDBZEDMSA-N tandospirone Chemical compound O=C([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C1=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 CEIJFEGBUDEYSX-FZDBZEDMSA-N 0.000 claims description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 20
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- 238000001035 drying Methods 0.000 claims description 17
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
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- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides L-TARTARIC ACID Tandospirone compound.Present invention also offers the preparation method of this compound, pharmaceutical composition and purposes.L-TARTARIC ACID Tandospirone compound provided by the invention exists with the form of crystal formation, and it is water-soluble and stability is all very good, for the bioavailability and security improving medicine provides possibility; In addition, the preparation technology of the compounds of this invention is simple, and yield is high, is applicable to suitability for industrialized production.
Description
Technical Field
The invention relates to an L-tandospirone tartrate compound, in particular to a crystal form of the compound, and a preparation method, a pharmaceutical composition and application of the compound crystal.
Background
Tandospirone belongs to azaspirone drugs and has the chemical name of (3a alpha, 4 beta, 7a alpha) -hexahydro-2- [4[4- (2-pyrimidinyl) -1- (piperazinyl) -butyl ] -4, 7-methylene-1H-isoindole-1, 3(2H) -diketone, and the molecular structural formula is as follows:
tandospirone was first developed by sumitomo pharmaceutical corporation of japan and was approved for sale in japan in 1996. It is a 5-hydroxytryptamine receptor agonist, belonging to 3 rd generation anxiolytic, and is mainly used for treating anxiety or other diseases accompanied with anxiety state. In the brain, it can interact with 5-HT of the limbic system of the brain, such as hippocampus, septum, interpeduncular nucleus, amygdala, etc., and the nucleus of the glandular gap, which are centrally distributed in the emotional center1AReceptors selectively bind by agonizing 5-HT1AThe autoreceptor regulates 5-hydroxytryptamine projected from the raphe nucleus to the hippocampus, inhibits the 5-hydroxytryptamine effect of the motility inhibition system, and exerts an anxiolytic effect. Compared with the proto-drug azaspirone and the buspirone of the same kind derivative, tandospirone has higher selective anxiolytic effect which is similar to diazepam, but has less toxic and side effects in the aspects of nerve motility function damage, drug abuse and the like than diazepam. Due to the specificity of action mechanism, the tandospirone and the salt thereof have the advantages of high medication safety, less side effect, no muscle relaxation and sedative effect, no dependence and withdrawal phenomenon after drug withdrawal, no accumulation in vivo after long-term application and the like when being clinically used for treating anxiety disorder.
The research also shows that the tandospirone and the salt thereof have quite good application in the treatment or adjuvant treatment of other nervous system diseases besides the anxiolytic effect. The tandospirone and the salt thereof have certain antidepressant effect, have very obvious curative effect on patients with mixed anxiety and depression, and can improve the 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 symptoms of cerebellar ataxia in patients. It is also effective in improving memory, treating age-related memory disorder, and significantly improving narrative memory, logical memory and spoken language association in patients with neurasthenia, senile dementia or schizophrenia. 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. Therefore, the tandospirone and the salt thereof have very good clinical treatment advantages and wide market prospects.
In clinical applications, approximately half of the drug molecules are present and administered in the form of salts. Salifying a drug with molecules or ions with opposite charges can effectively improve some undesirable physicochemical or biological pharmaceutical properties of the drug, such as changing the solubility of the drug, reducing hygroscopicity, improving stability, changing a melting point, improving grinding performance, facilitating preparation and purification, improving permeability and the like. The water solubility of tandospirone is poor, and the water solubility and the physical and chemical stability of 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. For example, tandospirone citrate is mainly sold in the market at present, is widely applied to treatment of related diseases such as anxiety disorder in the form of tablets or capsules, and has mature clinical application research. In the application of ophthalmic diseases, the tandospirone citrate can cause strong stimulation to eyes due to the salt group thereof, so that the tandospirone hydrochloride with small stimulation and high comfort level is generally considered to be selected when the medicine is taken.
Currently, studies on tandospirone salts are mainly focused on citrate and hydrochloride. For example, the preparation methods of tandospirone citrate are reported in documents such as US4507303, US4818756, JP60087262, CN101362751A and the like, and three crystal forms of tandospirone citrate are disclosed in patent CN 10234442A. In addition, processes for the preparation of tandospirone hydrochloride have also been disclosed in the prior art, for example, patents CN101880274A, US4507303, EP0082402, etc. As for the currently published documents, no reports on the preparation methods and crystal forms of other salt-forming forms of tandospirone are found.
It is well known that for pharmaceutical agents, compounds in different salt forms may have different crystal forms, and that compounds in the same 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. Amorphous is a particular crystalline state, and is one form of polymorphic drug. When the drug exists in an amorphous form, the physicochemical properties and clinical efficacy characteristics of the drug are different from those of the general crystal form drugs. Amorphous solid drugs tend to have better in vitro dissolution and in vivo absorption properties and may have better clinical effects. Therefore, the preparation and research of relevant crystal forms of tandospirone salts are very meaningful.
Disclosure of Invention
The invention aims to provide an L-tandospirone tartrate compound with stable property and good water solubility.
The invention also provides a preparation method, a pharmaceutical composition and application of the L-tandospirone tartrate compound.
The invention provides a preparation method of L-tandospirone tartrate, which comprises the following operation procedures:
a. taking tandospirone and L-tartaric acid, adding an organic solvent, heating for dissolving, and taking reaction liquid for later use after the reaction is completed;
b. and concentrating the reaction solution under reduced pressure to dryness to obtain the L-tandospirone tartrate.
Further, in the step a, the molar ratio of tandospirone to L-tartaric acid is less than or equal to 1:1, the heating and dissolving temperature is 30-100 ℃, the reaction temperature is 30-100 ℃, the mass-to-volume ratio of tandospirone to an organic solvent is 1: 1-30 kg/L, and the organic solvent is selected from any one of alcohol solvents, ketone solvents, ether solvents, ester solvents and acetonitrile or a combination thereof.
Wherein the mol ratio of tandospirone to L-tartaric acid is preferably 1 (1-2).
Wherein the heating and dissolving temperature is preferably 30-90 ℃, and the reaction temperature is preferably 30-90 ℃.
Wherein the mass volume ratio of tandospirone to the organic solvent is preferably 1: 3-20 kg/L.
Wherein, the organic solvent is preferably any one of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate and diethyl ether or the combination thereof.
The invention provides a tandospirone L-tartrate compound, which is characterized in that the compound exists in a form I, and when the compound is subjected to X-ray powder diffraction by using a CuKa radiation source, the compound has an X-ray powder diffraction pattern, wherein the 2 theta diffraction angles of the compound have characteristic absorption peaks at 9.4 +/-0.2, 10.7 +/-0.2, 11.9 +/-0.2, 14.0 +/-0.2, 14.6 +/-0.2, 16.8 +/-0.2, 18.2 +/-0.2 and 18.9 +/-0.2 degrees.
Furthermore, in the X-ray powder diffraction pattern of the compound, the 2 theta diffraction angle also has characteristic absorption peaks at 4.6 +/-0.2, 7.9 +/-0.2, 11.5 +/-0.2, 15.8 +/-0.2, 20.3 +/-0.2, 21.4 +/-0.2, 22.9 +/-0.2 and 24.0 +/-0.2 degrees.
Furthermore, the compound has an X-ray powder diffraction pattern with characteristic absorption peaks at the 2 theta diffraction angles of 13.2 +/-0.2, 14.9 +/-0.2, 18.5 +/-0.2, 19.4 +/-0.2, 21.0 +/-0.2, 21.6 +/-0.2 and 26.6 +/-0.2 degrees.
Preferably, the compound has an X-ray powder diffraction pattern as shown in FIG. 1.
The structural formula of the compound of the invention is:
wherein the melting point of the compound is 146.5-149.0 ℃.
The invention also provides a preparation method of the L-tandospirone tartrate compound, which comprises the following operation procedures:
A. taking L-tandospirone tartrate, adding an organic solvent, and heating to dissolve to obtain an L-tandospirone tartrate solution;
B. naturally cooling to room temperature, standing, taking precipitate, and drying to obtain crystal form I of the L-tandospirone tartrate compound; or,
C. naturally cooling to room temperature, standing at-5 +/-5 ℃, taking the precipitate, and drying to obtain the L-tandospirone tartrate compound crystal form I.
Further, in the step A, the heating and dissolving temperature is 30-100 ℃, the mass-volume ratio of the L-tandospirone tartrate to the organic solvent is 1: 1-30 g/mL, and the organic solvent is an alcohol solvent.
Wherein the heating and dissolving temperature is preferably 50-90 ℃.
Wherein the mass-volume ratio of tandospirone to the organic solvent is preferably 1: 1-25 g/mL, and more preferably 1: 3-20 g/mL.
Wherein, the organic solvent is preferably methanol, ethanol, propanol or isopropanol; more preferably isopropanol.
Further, in the step B, the standing time is 1-16 hours, preferably 2-12 hours; and C, standing at room temperature for 1-16 hours, preferably 2-12 hours, standing at-5 +/-5 ℃ for 12 hours, preferably 8 hours. The length of the standing time determines whether the compound is completely crystallized, influences the yield of the compound, but does not influence the structure of a crystal form.
The invention also provides application of the crystal form I of the L-tandospirone tartrate compound in preparing medicines for treating diseases related to 5-hydroxytryptamine or/and norepinephrine reuptake.
Wherein, the medicine is used for treating central nervous system diseases and eye diseases, preferably anxiety disorder, depression, panic disorder, autism, insomnia, schizophrenia, age-related memory disorder, neurasthenia, senile dementia, glaucoma, diabetic retinopathy, age-related macular degeneration, retinal edema and other diseases.
Further, the application of the crystal form I of the L-tandospirone tartrate compound in the preparation of 5-hydroxytryptamine regulators.
Wherein the 5-hydroxytryptamine regulator is a medicine for treating anxiety, depression or insomnia.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the crystal form I of the L-tandospirone tartrate compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The pharmaceutically acceptable auxiliary materials or auxiliary components are common excipients or auxiliary materials which are well known in the field and used for preparing the preparation. 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, sodium thiosulfate and the like; bacteriostatic agents such as phenol, benzyl alcohol, hydroxypropylmethyl, chlorobutanol, and the like; regulators such as hydrochloric acid, citric acid, potassium (sodium) hydroxide, buffers, and the like; emulsifiers such as polysorbate 80, lecithin, soy 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 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, film agent, ointment, suppository, paste and the like are preferred.
The invention also provides another L-tandospirone tartrate compound, which is characterized in that the compound exists in an amorphous form, and CuK alpha radiation source is adopted to carry out X-ray powder diffraction on the compound, wherein the X-ray powder diffraction pattern of the compound has no characteristic peak; preferably, the X-ray powder diffraction is as shown in fig. 2.
The structural formula of the compound is as follows:
wherein the melting point of the compound is 92.5-97.0 ℃.
The invention also provides a preparation method of the L-tandospirone tartrate compound, which comprises the following operation procedures:
A. taking L-tandospirone tartrate, adding an organic solvent, and heating to dissolve to obtain an L-tandospirone tartrate solution;
B. naturally cooling to room temperature, standing, collecting precipitate, concentrating under reduced pressure, and drying to obtain amorphous L-tandospirone tartrate compound; or,
C. naturally cooling to room temperature, standing at-5 + -5 deg.C, collecting precipitate, concentrating under reduced pressure, and drying to obtain amorphous L-tandospirone tartrate compound; or,
D. decompressing, concentrating, removing the solvent, and drying to obtain the amorphous L-tandospirone tartrate compound.
Further, in the step A, the heating and dissolving temperature is 30-100 ℃, the mass-volume ratio of the L-tandospirone tartrate to the organic solvent is 1: 1-30 g/mL, and the organic solvent is selected from any one or combination of an alcohol solvent, a ketone solvent, an ether solvent, an ester solvent and acetonitrile.
Wherein the heating and dissolving temperature is preferably 35-90 ℃.
Wherein the mass-volume ratio of tandospirone to the organic solvent is preferably 1: 3-20 g/mL.
Wherein, the organic solvent is preferably any one of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate and diethyl ether or the combination thereof.
Further, in the step B, the standing time is 1-16 hours, preferably 2-12 hours; and C, standing at room temperature for 1-16 hours, preferably 2-12 hours, standing at-5 +/-5 ℃ for 12 hours, preferably 8 hours.
The invention also provides application of the amorphous L-tandospirone tartrate compound in preparing a medicament for treating diseases related to 5-hydroxytryptamine or/and norepinephrine reuptake.
Wherein, the medicine is used for treating central nervous system diseases and eye diseases, preferably anxiety disorder, depression, panic disorder, autism, insomnia, schizophrenia, age-related memory disorder, neurasthenia, senile dementia, glaucoma, diabetic retinopathy, age-related macular degeneration, retinal edema and other diseases.
Further, the use of the amorphous L-tandospirone tartrate compound in the preparation of 5-hydroxytryptamine modulators.
Wherein the 5-hydroxytryptamine regulator is a medicine for treating anxiety, depression or insomnia.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the amorphous L-tandospirone tartrate compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The pharmaceutically acceptable auxiliary materials or auxiliary components are common excipients or auxiliary materials which are well known in the field and used for preparing the preparation. 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, sodium thiosulfate and the like; bacteriostatic agents such as phenol, benzyl alcohol, hydroxypropylmethyl, chlorobutanol, and the like; regulators such as hydrochloric acid, citric acid, potassium (sodium) hydroxide, buffers, and the like; emulsifiers such as polysorbate 80, lecithin, soy 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 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, film agent, ointment, suppository, paste and the like are preferred.
The L-tandospirone tartrate compound provided by the invention fills the blank in the prior art; compared with the existing product tandospirone citrate, the L-tandospirone tartrate compound provided by the invention has stable property and good water solubility, and provides an effective solution for improving the bioavailability and safety of the drug; in addition, the preparation process of the L-tandospirone tartrate compound is simple, high in yield and suitable for industrial production.
Drawings
FIG. 1X-ray powder diffraction pattern of Tandospirone L-tartrate form I obtained in example 3 of the present invention.
FIG. 2X-ray powder diffraction pattern of amorphous tandospirone L-tartrate obtained in example 6 of the present invention.
FIG. 3X-ray powder diffraction pattern of amorphous tandospirone L-tartrate obtained under the condition of example 7, number 3 of the present invention.
FIG. 4X-ray powder diffraction pattern of amorphous tandospirone L-tartrate obtained under the condition of example 9, No. 5, 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 L-tartrate
Weighing 2kg of tandospirone and 0.79 kgL-tartaric acid, adding 10L of isopropanol, heating to 90 ℃, continuing stirring until the reaction is complete after the solution is clear, stopping heating, and concentrating under reduced pressure to dryness to obtain 2.77 kgL-tandospirone tartrate, wherein the yield is 99.5%, and the mass spectrum shows that the ESIm/z: 383 (M)+)。
EXAMPLE 2 preparation of Tandospirone L-tartrate
The preparation of L-tandospirone tartrate is carried out according to the method in example 1, the specific conditions are shown in Table 1, and the feeding amount of the tandospirone tartrate is 2 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 of tandospirone L-tartrate
Note: the mixed solvent ratios in the table are volume ratios.
EXAMPLE 3 preparation of crystalline form I of Tandospirone L-tartrate compound
Weighing 200g of L-tandospirone tartrate, adding 600mL of isopropanol, heating to 90 ℃, keeping stirring for 30min after complete dissolution, naturally cooling to room temperature, standing for 12 h, performing suction filtration, washing and drying to obtain 191g of white L-tandospirone tartrate crystal form I, wherein the yield is 95.5%, and the mass spectrum shows ESIm/z: 383 (M)+) The melting point is 146.5-149.0 ℃.
An X-ray powder diffraction pattern of the L-tandospirone tartrate crystal form I is shown in figure 1 by analyzing a sample crystal phase by using a DX-2700X-ray powder diffractometer and measuring CuK alpha radiation, and main relevant diffraction data are shown in Table 2 (the 2 theta measurement error is +/-0.2).
TABLE 2X-ray powder diffraction data for Tandospirone L-tartrate form I
EXAMPLE 4 preparation of crystalline form I of Tandospirone L-tartrate compound
Weighing 200g of L-tandospirone tartrate, adding 2000mL of isopropanol, heating to 70 ℃, keeping stirring for 30min after complete dissolution, naturally cooling to room temperature, standing for 2h, standing at-5 +/-5 ℃ for 8 h, performing suction filtration, washing and drying to obtain 190g of white L-tandospirone tartrate crystal form I, wherein the yield is 95.0%. The analysis results of the data such as melting point and the like and the X-ray powder diffraction pattern of the obtained product have no obvious difference from the example 3.
EXAMPLE 5 preparation of crystalline form I of Tandospirone L-tartrate compound
Weighing 200g of L-tandospirone tartrate, adding 4000mL of isopropanol, heating to 50 ℃, keeping stirring for 30min after complete dissolution, naturally cooling to room temperature, standing for 6 h, standing at-5 +/-5 ℃ for 4 h, performing suction filtration, washing and drying to obtain 192g of white L-tandospirone tartrate crystal form I, wherein the yield is 96.0%. The analysis results of the data such as melting point and the like and the X-ray powder diffraction pattern of the obtained product have no obvious difference from the example 3.
EXAMPLE 6 preparation of amorphous Tandospirone L-tartrate Compound
Weighing 200g of L-tandospirone tartrate, adding 1000mL of ethanol, heating to 80 ℃, keeping stirring for 30min after complete dissolution, naturally cooling to room temperature, standing for 2h, standing at-5 +/-5 ℃ for 4 h, discarding supernatant, concentrating the obtained white precipitate under reduced pressure, and drying to obtain 195g of white powdery amorphous L-tandospirone tartrate, wherein the yield is 97.5%, and the mass spectrum shows ESIm/z: 383 (M)+) The melting point is 92.5 to 97.0℃。
A DX-2700X-ray powder diffractometer is adopted to analyze the crystal phase of the sample, CuK alpha radiation is carried out, and the X-ray powder diffraction spectrum of the amorphous L-tandospirone tartrate is measured and shown in figure 2, and the X-ray powder diffraction has no characteristic peak.
EXAMPLE 7 preparation of amorphous L-Tandospirone tartrate Compound
Amorphous tandospirone L-tartrate was prepared as described in example 6, with specific conditions in Table 3, and the dosages of tandospirone L-tartrate were all 200 g. The analysis results of the data such as melting point and the like of the product obtained under various conditions and the X-ray powder diffraction pattern have no obvious difference from example 6, the product is determined to be amorphous L-tandospirone tartrate, and a part of representative X-ray diffraction pattern is shown in figure 3. As can be seen from the X-ray powder diffraction pattern, the amorphous form has no characteristic peak in the X-ray powder diffraction.
TABLE 3 preparation of amorphous L-tandospirone tartrate compounds
Note: the mixed solvent ratios in the table are volume ratios.
EXAMPLE 8 preparation of amorphous Tandospirone L-tartrate Compound
Weighing 200g of L-tandospirone tartrate, adding 600mL of methanol, heating to 90 ℃, keeping stirring for 30min after complete dissolution, naturally cooling to below 25 ℃, carrying out reduced pressure concentration to remove the solvent, and drying to obtain 199g of white powdery amorphous L-tandospirone tartrate, wherein the yield is 99.5%, and the data analysis results such as the melting point and the like and the X-ray powder diffraction pattern of the obtained product have no obvious difference from those of example 6.
EXAMPLE 9 preparation of amorphous L-Tandospirone tartrate Compound
Amorphous tandospirone L-tartrate was prepared as described in example 8, with specific conditions in Table 4, and the dosages of tandospirone L-tartrate were all 200 g. The analysis results of the data such as melting point and the like of the product obtained under various conditions and the X-ray powder diffraction pattern have no obvious difference from example 6, the product is determined to be amorphous L-tandospirone tartrate, and a part of representative X-ray diffraction pattern is shown in figure 4. As can be seen from the X-ray powder diffraction pattern, the amorphous form has no characteristic peak in the X-ray powder diffraction.
TABLE 4 preparation of amorphous L-tandospirone tartrate compounds
Note: the mixed solvent ratios in the table are volume ratios.
EXAMPLE 10 sustained-Release tablets of the present invention
Uniformly mixing L-tandospirone tartrate crystal form I, hydroxypropyl methylcellulose and lactose to be prepared, sieving, adding 75% ethanol solution to prepare soft material, sieving with a 20-mesh sieve to prepare wet granules, drying at about 50 ℃, grading with a 20-mesh sieve, adding magnesium stearate and talcum powder, uniformly mixing, and tabletting.
EXAMPLE 11 capsules of the present invention
Uniformly mixing the L-tandospirone tartrate crystal form I with starch in the amount to be prepared by an equivalent incremental method, then uniformly mixing with microcrystalline cellulose, granulating, and encapsulating to obtain the composition.
EXAMPLE 12 capsules of the present invention
Uniformly mixing amorphous L-tandospirone tartrate and starch to be prepared, uniformly mixing with microcrystalline cellulose, granulating, and encapsulating.
EXAMPLE 13 Sublingual tablets of the invention
The raw and auxiliary materials are respectively sieved by a 100-mesh sieve. Uniformly mixing amorphous L-tandospirone tartrate and low-substituted hydroxypropyl methylcellulose in a to-be-prepared amount by an equivalent incremental method, sequentially adding mannitol and lactose starch, finally adding sweet orange essence and magnesium stearate, uniformly mixing and tabletting.
The advantageous effects of the present invention are described below by way of test examples.
Test example 1 solubility test
Test group 1: the crystal form I of the L-tandospirone tartrate prepared in the embodiment 3 of the invention;
test group 2: the amorphous L-tandospirone tartrate prepared in example 6 of the present invention;
control group: refer to the tandospirone citrate prepared by the method disclosed in the prior documents (CN101880274A, CN 101362751A).
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 comparative study of solubility
The solubility test results in table 5 show that the dissolution time of the crystal form I of L-tandospirone tartrate and the dissolution time of amorphous L-tandospirone tartrate in water are obviously shorter than that of the existing product tandospirone citrate, and the solubility is better. 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 example 2 stability effect test
Test group 1: the crystal form I of the L-tandospirone tartrate prepared in the embodiment 3 of the invention;
test group 2: the amorphous L-tandospirone tartrate prepared in example 6 of the present invention;
control group: refer to the tandospirone citrate prepared by the method disclosed in the prior documents (CN101880274A, CN 101362751A).
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 intensity of 4500 +/-500 lx; (3) high-humidity degradation: about 200mg of the sample was taken and placed in a desiccator containing a saturated solution of KNO3 at room temperature. The stability test results are shown in Table 6.
TABLE 6 stability test results
The test results in table 6 show that the purity of the crystal form i of L-tandospirone tartrate and the purity of amorphous L-tandospirone tartrate prepared by the invention have no obvious change under the conditions of high temperature, high humidity and illumination. Therefore, the L-tandospirone tartrate crystal form I and the amorphous L-tandospirone tartrate crystal form L are high in purity, stable and controllable in quality, and suitable for manufacturing and long-term storage of pharmaceutical preparations.
In conclusion, compared with the existing product tandospirone citrate, the L-tandospirone tartrate crystal form I and the amorphous L-tandospirone tartrate crystal form L provided by the invention have stable properties and good water solubility, and provide an effective solution for improving the bioavailability and the safety of the medicine; in addition, the compound of the invention has simple preparation process and high yield, and is suitable for industrial production.
Claims (9)
1. An L-tandospirone tartrate compound, characterized in that: the compound exists in a form of a crystal form I, and has characteristic absorption peaks at 2 theta diffraction angles of 9.4 +/-0.2, 10.7 +/-0.2, 11.9 +/-0.2, 14.0 +/-0.2, 14.6 +/-0.2, 16.8 +/-0.2, 18.2 +/-0.2 and 18.9 +/-0.2 degrees in an X-ray powder diffraction pattern; preferably, the 2 theta diffraction angle also has characteristic absorption peaks at 4.6 +/-0.2, 7.9 +/-0.2, 11.5 +/-0.2, 15.8 +/-0.2, 20.3 +/-0.2, 21.4 +/-0.2, 22.9 +/-0.2 and 24.0 +/-0.2 degrees; more preferably, the diffraction angle of 2 theta has characteristic absorption peaks at 13.2 +/-0.2, 14.9 +/-0.2, 18.5 +/-0.2, 19.4 +/-0.2, 21.0 +/-0.2, 21.6 +/-0.2 and 26.6 +/-0.2 degrees; most preferably having an X-ray powder diffraction pattern substantially as shown in figure 1.
2. The tandospirone L-tartrate compound of claim 1, wherein: the preparation method of the compound comprises the following operation procedures:
a, adding an organic solvent into L-tandospirone tartrate, and heating to dissolve to obtain an L-tandospirone tartrate solution;
naturally cooling the crystal form B to room temperature, standing, taking the precipitate, and drying to obtain the crystal form I of the L-tandospirone tartrate compound; or,
naturally cooling to room temperature, standing at-5 +/-5 ℃, taking the precipitate, and drying to obtain the L-tandospirone tartrate compound crystal form I;
wherein the organic solvent is an alcohol solvent, preferably methanol, ethanol, propanol or isopropanol; more preferably isopropanol.
3. An L-tandospirone tartrate compound, characterized in that: the compound exists in an amorphous form, and has no characteristic peak in X-ray powder diffraction; preferably, the X-ray powder diffraction is as shown in fig. 2.
4. The tandospirone L-tartrate compound of claim 3, wherein: the preparation method of the compound comprises the following operation procedures:
a, adding an organic solvent into L-tandospirone tartrate, and heating to dissolve to obtain an L-tandospirone tartrate solution;
naturally cooling to room temperature, standing, taking precipitate, concentrating under reduced pressure, and drying to obtain amorphous L-tandospirone tartrate compound; or,
naturally cooling to room temperature, standing at-5 +/-5 ℃, taking the precipitate, concentrating under reduced pressure, and drying to obtain an amorphous L-tandospirone tartrate compound; or,
d, decompressing, concentrating, removing the solvent, and drying to obtain an amorphous L-tandospirone tartrate compound;
wherein, the organic solvent is selected from any one of alcohol solvent, ketone solvent, ether solvent, ester solvent and acetonitrile or the combination thereof, preferably any one of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate and diethyl ether or the combination thereof.
5. The tandospirone L-tartrate compound according to claim 2 or claim 4, wherein: the preparation method of the L-tandospirone tartrate in the step A comprises the following operation procedures:
a. taking tandospirone and L-tartaric acid, adding an organic solvent, heating for dissolving, and taking reaction liquid for later use after the reaction is completed;
b. concentrating the reaction solution under reduced pressure to dryness to obtain L-tandospirone tartrate;
wherein the organic solvent is selected from any one of alcohol solvents, ketone solvents, ether solvents, ester solvents and acetonitrile or the combination thereof; preferably any one of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, diethyl ether, or a combination thereof.
6. A pharmaceutical composition characterized by: the pharmaceutical preparation is prepared by taking the L-tandospirone tartrate compound as claimed in claim 1 or claim 3 as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
7. The pharmaceutical composition of claim 6, wherein: the preparation is liquid preparation, gas preparation, solid preparation and semisolid preparation, preferably aromatic water agent, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, pellicle, ointment, suppository, and paste.
8. Use of the tandospirone-L-tartrate compound according to claim 1 or claim 3, for the preparation of a medicament for the treatment of a disease associated with 5-hydroxytryptamine or/and norepinephrine reuptake.
9. Use according to claim 8, characterized in that: the medicine is used for treating central nervous system diseases and eye diseases, preferably anxiety disorder, depression, panic disorder, autism, insomnia, schizophrenia, age-related memory disorder, neurasthenia, senile dementia, glaucoma, diabetic retinopathy, age-related macular degeneration and retinal edema diseases.
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| CN201410249687.2A CN105218528A (en) | 2014-06-06 | 2014-06-06 | A kind of L-TARTARIC ACID Tandospirone compound |
| CN201610718991.6A CN106349226A (en) | 2014-06-06 | 2014-06-06 | L-tartaric acid tandospirone compound |
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|---|---|---|---|---|
| CN108619100A (en) * | 2017-03-16 | 2018-10-09 | 四川科瑞德制药股份有限公司 | Azaspiroanone medicine injection and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4507303A (en) * | 1981-12-22 | 1985-03-26 | Sumitomo Chemical Company, Limited | Succinimide derivatives, compositions and method of use |
| US4598078A (en) * | 1982-10-21 | 1986-07-01 | Sumitomo Chemical Company, Limited | N-(substituted piperazinyl) alkylbicyclic succinimide derivatives |
| CN103641817A (en) * | 2011-08-04 | 2014-03-19 | 成都科瑞德医药投资有限责任公司 | Novel crystal form of tandospirone citrate, preparation method and applications |
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 | A kind of preparation method of tandospirone and its analog |
| CN103641818B (en) * | 2011-08-04 | 2015-08-12 | 四川科瑞德制药有限公司 | A kind of SM-3997 compound and its production and use |
-
2014
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4507303A (en) * | 1981-12-22 | 1985-03-26 | Sumitomo Chemical Company, Limited | Succinimide derivatives, compositions and method of use |
| US4598078A (en) * | 1982-10-21 | 1986-07-01 | Sumitomo Chemical Company, Limited | N-(substituted piperazinyl) alkylbicyclic succinimide derivatives |
| CN103641817A (en) * | 2011-08-04 | 2014-03-19 | 成都科瑞德医药投资有限责任公司 | Novel crystal form of tandospirone citrate, preparation method and applications |
| CN103755687A (en) * | 2013-12-25 | 2014-04-30 | 成都科瑞德医药投资有限责任公司 | Hydrochloric tandospirone crystal form I and preparation method of crystal form I |
Non-Patent Citations (2)
| Title |
|---|
| 四川医学院主编: "《药物化学》", 31 January 1981, 中国医药科技出版社 * |
| 本书编委会编: "《新时期食品药品规范化管理全书》", 31 January 2007, 经济日报出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108619100A (en) * | 2017-03-16 | 2018-10-09 | 四川科瑞德制药股份有限公司 | Azaspiroanone medicine injection and preparation method and application thereof |
| CN108619100B (en) * | 2017-03-16 | 2022-05-13 | 四川科瑞德制药股份有限公司 | Azaspirone medicine injection and preparation method and application thereof |
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