CN106905302B - Azaspiroanone compound and preparation method thereof - Google Patents
Azaspiroanone compound and preparation method thereof Download PDFInfo
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- CN106905302B CN106905302B CN201610720020.5A CN201610720020A CN106905302B CN 106905302 B CN106905302 B CN 106905302B CN 201610720020 A CN201610720020 A CN 201610720020A CN 106905302 B CN106905302 B CN 106905302B
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- tandospirone
- sulfate
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- preparing
- crystal form
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention provides (3a α,4 β,7 β,7a α) -hexahydro-2- [4- (2-pyrimidinyl) -1- (piperazinyl) -butyl]The invention provides an amorphous form and a crystal form I of the compound, and a preparation method, a pharmaceutical composition and a use thereof, (3a α,4 β,7 β,7a α) -hexahydro-2- [4[4- (2-pyrimidinyl) -1- (piperazinyl) -butyl ] -2]The formula of the (E) -4, 7-methylene-1H-isoindole-1, 3(2H) -dione sulfate compound is C21H29N5O2 .H2SO4. The compound has stable property, good water solubility and high bioavailability, and provides an effective solution for improving the safety and effectiveness of the medicament; in addition, the compound of the invention has simple preparation process and high yield, and is suitable for industrial production.
Description
The application is a divisional application of the invention patent application No. 201510970553.4 in China, the application date of the application is 2015, 12 and 22, and the name of the application is an azaspirone compound and a preparation method thereof.
Technical Field
The invention relates to an azaspirone compound, and in particular relates to tandospirone sulfate and a preparation method and application thereof. Belongs to the field of pharmaceutical chemistry.
Background
Tandospirone belongs to azaspirone drugs and has the chemical name of (3a α,4 β,7 β,7a α) -hexahydro-2- [4[4- (2-pyrimidinyl) -1- (piperazinyl) -butyl ] -4, 7-methylene-1H-isoindole-1, 3(2H) -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.
Currently, studies on tandospirone salts are mainly focused on citrate. For example, the preparation method of tandospirone citrate is reported in documents such as US4507303, US4818756, CN101362751A, etc. At present, reports related to tandospirone sulfate crystal forms are not 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 sulfate are very meaningful.
Disclosure of Invention
The invention aims to provide amorphous tandospirone sulfate and crystal form I with stable property and good water solubility, and a preparation method, a pharmaceutical composition and application thereof.
The invention provides an amorphous tandospirone sulfate compound which is subjected to X-ray powder diffraction by using a Cu K α radiation source and has no characteristic peak in an X-ray powder diffraction pattern, and preferably, the compound has the X-ray powder diffraction pattern characteristics basically as shown in figure 1, figure 2 or figure 3.
The structural formula of the amorphous tandospirone sulfate compound is as follows:
the invention also provides a preparation method of the amorphous tandospirone sulfate, which comprises the following operation procedures:
A. taking tandospirone, adding a solvent 1, heating for dissolving, adding a sulfuric acid solution, and keeping a reaction solution for later use after the reaction is complete;
B. concentrating the reaction solution to obtain amorphous tandospirone sulfate; alternatively, the first and second electrodes may be,
C. and after the reaction solution is concentrated, adding a solvent 2 for dissolving, and concentrating to obtain the amorphous tandospirone sulfate.
Wherein, the sulfuric acid solution in the step A is any one of a sulfuric acid aqueous solution, a sulfuric acid methanol solution and a sulfuric acid ethanol solution.
Further, the mass fraction of the sulfuric acid aqueous solution is 10% -40%, and more preferably 20% -30%.
Further, the mass fraction of the sulfuric acid methanol solution is 5% -25%, and more preferably 10% -20%.
Further, the mass fraction of the sulfuric acid ethanol solution is 5% -25%, and more preferably 10% -20%.
Further, in step a, the solvent 1 is selected from any one of an alcohol solvent, a ketone solvent, an ether solvent, an ester solvent, and acetonitrile, or a combination thereof, and preferably selected from any one of methanol, ethanol, acetone, acetonitrile, isopropanol, and tetrahydrofuran, or a combination thereof.
Further, in the step A, the heating dissolution temperature is 30 to 100 ℃, preferably 30 to 80 ℃.
Further, in the step A, the molar ratio of tandospirone to sulfuric acid is less than or equal to 1: 1.
Further, in the step A, the mass-volume ratio of the tandospirone to the solvent 1 is 1:1-30g/m L.
Further, in step a, the molar ratio of tandospirone to sulfuric acid is 1: 1-2.
Further, in the step A, the mass-volume ratio of the tandospirone to the solvent 1 is 1:3-20g/m L.
Further, in step C, the solvent 2 is selected from any one of an alcohol solvent, a ketone solvent, an ether solvent, an ester solvent, and acetonitrile, or a combination thereof, and preferably selected from any one of methanol, ethanol, acetone, acetonitrile, isopropanol, and tetrahydrofuran, or a combination thereof.
Further, in step C, the amount by volume (m L) of solvent 2 is 1 to 30 times the mass (g) of tandospirone in step A.
Further, in step C, the amount by volume (m L) of solvent 2 is 1 to 20 times the mass (g) of tandospirone in step A.
The invention also provides another method for preparing the amorphous tandospirone sulfate, which comprises the following operation procedures:
A. salifying with sulfuric acid and tandospirone to prepare tandospirone sulfate;
B. taking tandospirone sulfate, adding an organic solvent, and heating to dissolve to prepare a tandospirone sulfate solution;
C. naturally cooling to room temperature, standing, taking the precipitate, and drying to obtain amorphous tandospirone sulfate; alternatively, the first and second electrodes may be,
D. naturally cooling to room temperature, standing at-5 +/-5 ℃, taking the precipitate, and drying to obtain amorphous tandospirone sulfate; alternatively, the first and second electrodes may be,
E. naturally cooling to room temperature, concentrating to remove the solvent, and drying to obtain the amorphous tandospirone sulfate.
Further, in the step B, the heating and dissolving temperature is 30-100 ℃, the mass-volume ratio of the tandospirone sulfate to the organic solvent is 1:1-30g/m L, and the organic solvent is selected from any one or the combination of an alcohol solvent, a ketone solvent, an ether solvent, an ester solvent and acetonitrile.
Wherein the heating and dissolving temperature is preferably 35-85 ℃.
Wherein the mass-volume ratio of the tandospirone to the organic solvent is preferably 1:3-20g/m L.
Wherein, the organic solvent is preferably any one or the combination of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate and diethyl ether.
Further, in the step C, the standing time is 1-16 hours, preferably 2-12 hours; in step D, standing at room temperature for 1-16 hours, preferably 2-12 hours, and standing at-5 +/-5 ℃ for less than 12 hours, preferably less than 8 hours.
The invention also provides application of the amorphous tandospirone sulfate 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 tandospirone sulfate 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 tandospirone sulfate 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 a tandospirone sulfate crystal form I, and when a Cu K α radiation source is adopted for carrying out X-ray powder diffraction, the characteristic absorption peaks exist in an X-ray powder diffraction pattern of the crystal form I when the 2 theta diffraction angle is 15.3 +/-0.2, 21.3 +/-0.2, 22.2 +/-0.2, 23.0 +/-0.2 and 28.4 +/-0.2 degrees.
Furthermore, the 2 theta diffraction angle also has characteristic absorption peaks at 19.5 +/-0.2, 26.3 +/-0.2 and 26.6 +/-0.2 degrees.
Further, tandospirone sulfate crystalline form I has X-ray powder diffraction pattern characteristics substantially as shown in figure 4.
The structural formula of the tandospirone sulfate crystal form I is as follows:
the invention also provides a preparation method of the tandospirone sulfate crystal form I, which comprises the following operation procedures:
A. taking tandospirone, adding acetone, heating for dissolving, then adding an ether sulfate solution, and after the reaction is complete, keeping the reaction solution for later use;
B. concentrating and drying the reaction solution to obtain a crystal form I of tandospirone sulfate; alternatively, the first and second electrodes may be,
C. and naturally cooling the reaction liquid to room temperature, taking the precipitate, and drying to obtain the crystal form I of tandospirone sulfate.
Further, in the step A, the molar ratio of tandospirone to sulfuric acid is less than or equal to 1: 1.
Further, in the step A, the heating dissolution temperature is 30-45 ℃.
Further, in the step A, the mass-volume ratio of the tandospirone to the acetone is 1:1-30g/m L.
Further, in the step A, the mass fraction of the ether sulfate solution is 3% -25%.
Further, in step a, the molar ratio of tandospirone to sulfuric acid is 1: 1-2.
Further, in the step A, the mass-volume ratio of the tandospirone to the acetone is 1:3-20g/m L.
Further, in the step A, the mass fraction of the ether sulfate solution is 5-15%.
The invention also provides another method for preparing the tandospirone sulfate crystal form I, which comprises the following operation procedures:
A. salifying with sulfuric acid and tandospirone to prepare tandospirone sulfate;
B. taking tandospirone sulfate, adding an organic solvent, and heating to dissolve to prepare a tandospirone sulfate solution;
C. naturally cooling to room temperature, standing, taking the precipitate, and drying to obtain the crystal form I of tandospirone sulfate; alternatively, the first and second electrodes may be,
D. naturally cooling to room temperature, standing at-5 +/-5 ℃, taking the precipitate, and drying to obtain the tandospirone sulfate crystal form I.
Further, in the step B, the heating and dissolving temperature is 30-100 ℃, the mass-volume ratio of the tandospirone sulfate to the organic solvent is 1:1-30g/m L, and the organic solvent is an alcohol solvent or a ketone solvent.
Wherein, in the step B, the heating and dissolving temperature is preferably 50-80 ℃.
Wherein the mass-volume ratio of the tandospirone sulfate to the organic solvent is preferably 1:1-25g/m L, and more preferably 1:3-20g/m L.
Wherein the organic solvent is preferably propanol, isopropanol or methyl ethyl ketone; more preferably isopropanol or methyl ethyl ketone.
Further, in the step C, the standing time is 1-16 hours, preferably 2-12 hours; in step D, standing at room temperature for 1-16 hours, preferably 2-12 hours, and standing at-5 +/-5 ℃ for less than 12 hours, preferably less than 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 tandospirone sulfate crystal form I in preparation of 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 tandospirone sulfate in preparing 5-hydroxytryptamine regulator.
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 tandospirone sulfate crystal form I 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 tandospirone sulfate compound provided by the invention, namely amorphous tandospirone sulfate and tandospirone sulfate crystal form I, fills the blank in the prior art; compared with the existing product tandospirone citrate, the tandospirone sulfate compound provided by the invention has stable property, good water solubility and high bioavailability, and provides an effective solution for improving the safety and effectiveness of the medicament; in addition, the preparation process of the tandospirone sulfate compound is simple, high in yield and suitable for industrial production.
The present invention will be further described below by way of specific examples, however, the present invention is not limited to the following examples, which do not limit the scope of the present invention in any way. Certain changes and modifications within the scope of the claims, which may be made by one skilled in the art, are also considered to be within the scope of the invention.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of amorphous tandospirone sulfate provided in example 1 of the present invention.
FIG. 2 is an X-ray powder diffraction pattern of amorphous tandospirone sulfate provided in example 3 of the present invention.
FIG. 3 is an X-ray powder diffraction pattern of amorphous tandospirone sulfate provided in example 5 of the present invention.
Figure 4 is an X-ray powder diffraction pattern of tandospirone sulfate crystalline form I provided by example 7 of the present invention.
Detailed Description
The tandospirone used as the raw material in the invention is synthesized by referring to the existing preparation process, such as the method reported in documents of CN101362751A, US5521313 and the like. 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 amorphous Tandospirone sulfate
Weighing 500g of tandospirone, dissolving in 3.5L isopropanol, heating to 80 ℃, adding 427g of 30% sulfuric acid aqueous solution after complete dissolution, continuously stirring until complete reaction, stopping heating, concentrating the reaction solution to remove the solvent, adding 2.0L acetone for dissolution, and concentrating to dryness to obtain 620g of solid, namely amorphous tandospirone sulfate, wherein the yield is 98.7%, and mass spectrum shows that ESIm/z is 383(M +).
A DX-2700X-ray powder diffractometer is adopted to analyze the crystal phase of the sample, Cu K α is radiated, and the X-ray powder diffraction pattern of the amorphous tandospirone sulfate is shown in figure 1, and the X-ray powder diffraction has no characteristic peak.
EXAMPLE 2 preparation of amorphous Tandospirone sulfate
Amorphous tandospirone sulfate was prepared according to the procedure of example 1, with the specific conditions as shown in Table 1, and the dosages of tandospirone were all 500 g. The structural analysis result of the product obtained under each condition has no obvious difference from the structural analysis result of the example 1, and the X-ray powder diffraction pattern has no obvious difference from the example 1.
TABLE 1 preparation of amorphous tandospirone sulfate
Note: the mixed solvent ratios in the table are volume ratios.
EXAMPLE 3 preparation of amorphous Tandospirone sulfate
Weighing 200g of tandospirone sulfate, adding 1000M L ethanol, heating to 80 ℃, keeping stirring for 30min after the tandospirone sulfate is completely dissolved, stopping heating, naturally cooling to room temperature, standing for 2 hours, standing for 4 hours at minus 5 +/-5 ℃, discarding supernatant to obtain white-like precipitate, and drying to obtain 195g of white-like powdery amorphous tandospirone sulfate with the yield of 97.5 percent and the ESI M/z (M +) shown by mass spectrum.
The crystal phase of the sample is analyzed by using a DX-2700X-ray powder diffractometer, and the X-ray powder diffraction pattern of the amorphous tandospirone sulfate is shown in figure 2 after Cu K α radiation, wherein the X-ray powder diffraction has no characteristic peak, and the figure 2 has no obvious difference from the figure 1.
EXAMPLE 4 preparation of amorphous Tandospirone sulfate
Amorphous tandospirone sulfate was prepared as described in example 3, with specific conditions as shown in table 2, and the dosages of tandospirone sulfate were all 200 g. The X-ray powder diffraction pattern of the product obtained under each condition has no obvious difference from that of example 3, and the product is determined to be amorphous tandospirone sulfate.
TABLE 2 preparation of amorphous tandospirone sulfate compounds
Note: the mixed solvent ratios in the table are volume ratios.
EXAMPLE 5 preparation of amorphous Tandospirone sulfate
Weighing 200g of tandospirone sulfate, adding 600M L of methanol, heating to 70 ℃, keeping stirring for 30min after the tandospirone sulfate is completely dissolved, stopping heating, naturally cooling to below 25 ℃, concentrating to remove the solvent, and drying to obtain 199g of quasi-white powdery amorphous tandospirone sulfate with the yield of 99.5%, wherein the mass spectrum shows that ESI M/z is 383(M +).
An X-ray powder diffraction pattern of the amorphous tandospirone sulfate is shown in figure 3 by analyzing a sample crystal phase by using a DX-2700X-ray powder diffractometer and radiating Cu K α, and the X-ray powder diffraction has no characteristic peak, and the figure 3 has no obvious difference with the figure 1.
EXAMPLE 6 preparation of amorphous Tandospirone sulfate
Amorphous tandospirone sulfate was prepared as described in example 5, with specific conditions as shown in Table 3, and the dosages of tandospirone sulfate were all 200 g. The X-ray powder diffraction pattern of the product obtained under each condition has no obvious difference from that of example 5, and the product is determined to be amorphous tandospirone sulfate.
TABLE 3 preparation of amorphous tandospirone sulfate compounds
Note: the mixed solvent ratios in the table are volume ratios.
Example 7 preparation of Tandospirone sulfate form I
Weighing 5g of tandospirone, adding 25M L of acetone, heating to 35 ℃, adding 13g of 10% diethyl sulfate solution after complete dissolution, stirring until complete reaction, concentrating and drying reaction liquid to obtain 6.24g of off-white tandospirone crystal form I, wherein the yield is 99.4%, and mass spectrum shows that ESI M/z is 383(M +).
The X-ray powder diffraction pattern of the crystal form I of tandospirone sulfate is shown in figure 4 by analyzing the crystal phase of a sample by using a DX-2700X-ray powder diffractometer and radiating Cu K α, and the main relevant diffraction data are shown in Table 4 (the 2 theta measurement error is +/-0.2).
TABLE 4X-ray powder diffraction data for tandospirone sulfate form I
Example 8 preparation of Tandospirone sulfate form I
Tandospirone sulfate crystal form I was prepared according to the method of example 7, the specific conditions are shown in table 5, and the feeding amount of tandospirone was 5 g. The structural analysis result of the product obtained under each condition has no obvious difference from the structural analysis result of the example 7, and the X-ray powder diffraction pattern has no obvious difference from the example 7.
TABLE 5 preparation of tandospirone sulfate form I
Note: the mixed solvent ratios in the table are volume ratios.
EXAMPLE 9 preparation of Tandospirone sulfate form I
Weighing 200g of tandospirone sulfate, adding 600M L isopropanol, heating to 80 ℃, keeping stirring for 30min after the tandospirone sulfate is completely dissolved, stopping heating, naturally cooling to room temperature, standing for 12 hours, taking precipitate, and drying to obtain 191g of a white tandospirone sulfate crystal form I with the yield of 95.5%, wherein mass spectrum shows that ESIm/z is 383(M +), and the X-ray powder diffraction pattern of the obtained product has no obvious difference with example 7.
EXAMPLE 10 preparation of Tandospirone sulfate form I
Weighing 200g of tandospirone sulfate, adding 1000m L isopropanol, heating to 70 ℃, continuing to stir for 30min after complete dissolution, stopping heating, naturally cooling to room temperature, standing for 2 hours, standing for 8 hours at minus 5 +/-5 ℃, taking precipitate, and drying to obtain 190g of white tandospirone sulfate crystal form I, wherein the yield is 95.0%.
EXAMPLE 11 preparation of Tandospirone sulfate form I
Weighing 200g of tandospirone sulfate, adding 4000m of L methyl ethyl ketone, heating to 50 ℃, keeping stirring for 30min after the tandospirone sulfate is completely dissolved, stopping heating, naturally cooling to room temperature, standing for 6 hours, standing for 4 hours at minus 5 +/-5 ℃, taking precipitate, and drying to obtain 192g of white tandospirone sulfate crystal form I, wherein the yield is 96.0%.
EXAMPLE 12 sustained-release tablets of the present invention
Uniformly mixing the crystal form I of tandospirone sulfate, 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 13 capsules of the present invention
Uniformly mixing the tandospirone sulfate crystal form I with starch by an equivalent incremental method, then uniformly mixing with microcrystalline cellulose, granulating, and encapsulating to obtain the tamsulosin sulfate.
EXAMPLE 14 capsules of the present invention
Uniformly mixing amorphous tandospirone sulfate and starch to be prepared by an equivalent incremental method, then uniformly mixing with microcrystalline cellulose, granulating, and encapsulating to obtain the composition.
EXAMPLE 15 Sublingual tablets of the invention
The raw and auxiliary materials are respectively sieved by a 100-mesh sieve. Uniformly mixing amorphous tandospirone sulfate and low-substituted hydroxypropyl methylcellulose in the amount to be prepared by an equivalent incremental method, sequentially adding mannitol and lactose starch, finally adding sweet orange essence and magnesium stearate, uniformly mixing and tabletting.
EXAMPLE 16 topical ophthalmic formulations of the present invention
Mixing the amorphous tandospirone sulfate, sodium acetate, sodium chloride and disodium edetate to the preparation amount, adding water for injection, after sufficient dissolution, adjusting the pH to about 5.0, then adding benzalkonium chloride, and appropriately adjusting the pH of the solution to about 5.0.
The advantageous effects of the present invention are described below by way of test examples.
Test example 1: solubility test
Test group 1: the amorphous tandospirone sulfate prepared in example 1 of the invention;
test group 2: the crystal form I of tandospirone sulfate prepared in the embodiment 7 of the invention;
control group: refer to the prior literature (CN101880274A example 7) to disclose the citric acid tandospirone prepared by the method.
2g of the test sample was weighed into 10m L of 25 + -2 deg.C water for injection, shaken for 1 minute, and after visible solute particles were present, water (i.e., 10m L water) was added in an amount of 5 times the weight of the test sample, and the above procedure was repeated until completely dissolved, and the total water usage was recorded, the results are shown in Table 6.
TABLE 6 comparative solubility study
| Amorphous tandospirone sulfate | Tandospirone sulfate crystal form I | Tandospirone citrate |
| Total water consumption (times) | Total water consumption (times) | Total water consumption (times) |
| 5 | 10 | 60 |
The solubility test results in table 6 show that the amount of water required for dissolving the amorphous tandospirone sulfate and the crystal form I prepared by the invention is obviously less than that of 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 amorphous tandospirone sulfate prepared in example 1 of the invention;
test group 2: the crystal form I of tandospirone sulfate prepared in the embodiment 7 of the invention;
control group: refer to the prior literature (CN101880274A example 7) to disclose the citric acid tandospirone prepared by the method.
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: taking about 200mg of sample, placing in KNO3The saturated solution was placed in a desiccator at room temperature. The stability test results are shown in Table 7.
TABLE 7 stability test results
The test results in table 7 show that the purity of the amorphous tandospirone sulfate and the crystal form I prepared by the invention has no obvious change under the conditions of high temperature, high humidity and illumination. Therefore, the amorphous tandospirone sulfate and the crystal form I provided by the invention have high purity, stable and controllable quality, and are suitable for manufacturing and long-term storage of pharmaceutical preparations.
Test example 3: bioavailability test
Test group 1: the amorphous tandospirone sulfate prepared in example 1 of the invention;
test group 2: the crystal form I of tandospirone sulfate prepared in the embodiment 7 of the invention;
control group: refer to the prior literature (CN101880274A example 7) to disclose the citric acid tandospirone prepared by the method.
18 healthy male SD rats were randomly divided into 3 groups of 6 animals each orally administered with tandospirone sulfate form I equivalent to a dose of 10mg/kg (in terms of tandospirone base), amorphous tandospirone sulfate, and tandospirone citrate as a control group, the test samples were prepared as an aqueous solution at a concentration of 1mg/m L before administration, the rats were fasted for 12 hours before administration and returned to food 4 hours after administration, blank blood was taken before administration, and 0.5m L was taken at predetermined time intervals of 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 24 hours after administration, and placed in a centrifuge tube containing heparin, plasma was separated by centrifugation at 4000 rpm for 10min, and the supernatant was taken, and the concentration of tandospirone in plasma was measured, and pharmacokinetic parameters were calculated, and the results are shown in Table 8.
TABLE 8 comparison of pharmacokinetic parameters
| Test subject | AUC(ng·h/mL) | T1/2(h) | Tmax(h) | Cmax(ng/mL) |
| Amorphous tandospirone sulfate | 148.7±35.6 | 1.2±0.1 | 0.9±0.1 | 32.9±19.3 |
| Tandospirone sulfate crystal form I | 136.8±33.2 | 1.2±0.1 | 0.9±0.1 | 27.2±18.5 |
| Tandospirone citrate | 45.1±12.2 | 1.4±0.1 | 1.3±0.1 | 5.6±1.4 |
The test results in table 8 show that: compared with the existing product tandospirone citrate, the peak time (T) of the amorphous tandospirone sulfatemax) Shortened by 30%, and peak concentration (C)max) The improvement is nearly 6 times, and the area under the average blood concentration-time curve (AUC) value is improved by about 3.3 times; time to peak (T) of tandospirone sulfate form Imax) Shortened by 30%, and peak concentration (C)max) The increase is about 5 times, and the area under the curve (AUC) of the mean blood concentration-time is improved by more than 3 times. It can be seen that the tandospirone sulfate amorphous and crystalline form I T of the present inventionmaxSignificantly shorter value, CmaxAnd the AUC value is obviously increased, which shows that the amorphous tandospirone sulfate and the crystal form I have quicker onset time than the tandospirone citrate and can play a role more quickly; but also has higher bioavailability and better medicinal effect.
In conclusion, compared with the existing product tandospirone citrate, the tandospirone sulfate compound provided by the invention, namely amorphous tandospirone sulfate and tandospirone sulfate crystal form I, has stable property, good water solubility and remarkably improved bioavailability, and provides an effective solution for improving the effectiveness and safety of the medicament; in addition, the compound of the invention has simple preparation process and high yield, and is suitable for industrial production.
Claims (18)
1. A tandospirone sulfate crystalline form I characterized by: it has the X-ray powder diffraction pattern characteristics as shown in fig. 4.
2. The process for preparing tandospirone sulfate crystalline form I according to claim 1, characterized in that: the method comprises the following operation procedures:
A. taking tandospirone, adding acetone, heating for dissolving, then adding an ether sulfate solution, and after the reaction is complete, keeping the reaction solution for later use;
B. concentrating and drying the reaction solution to obtain a crystal form I of tandospirone sulfate; alternatively, the first and second electrodes may be,
C. and naturally cooling the reaction liquid to room temperature, taking the precipitate, and drying to obtain the crystal form I of tandospirone sulfate.
3. The process for preparing tandospirone sulfate crystalline form I according to claim 2, characterized in that: in the step A, the molar ratio of tandospirone to sulfuric acid is less than or equal to 1: 1.
4. The process for preparing tandospirone sulfate crystalline form I according to claim 2, characterized in that: in step a, the molar ratio of tandospirone to sulfuric acid is 1: (1-2).
5. The preparation method of tandospirone sulfate crystal form I according to claim 2, characterized in that in step A, the mass-to-volume ratio of tandospirone to acetone is 1:1-30g/m L.
6. The preparation method of tandospirone sulfate crystal form I according to claim 5, characterized in that in step A, the mass-to-volume ratio of tandospirone to acetone is 1:3-20g/m L.
7. The process for preparing tandospirone sulfate crystalline form I according to claim 2, characterized in that: in the step A, the heating and dissolving temperature is 30-45 ℃.
8. The process for preparing tandospirone sulfate crystalline form I according to claim 1, characterized in that: the method comprises the following operation procedures:
A. salifying with sulfuric acid and tandospirone to prepare tandospirone sulfate;
B. taking tandospirone sulfate, adding an organic solvent, and heating to dissolve to prepare a tandospirone sulfate solution;
C. naturally cooling to room temperature, standing, taking the precipitate, and drying to obtain the crystal form I of tandospirone sulfate; alternatively, the first and second electrodes may be,
D. naturally cooling to room temperature, standing at-5 +/-5 ℃, taking the precipitate, and drying to obtain the crystal form I of tandospirone sulfate;
wherein the organic solvent is propanol, isopropanol or methyl ethyl ketone.
9. The process for preparing tandospirone sulfate crystalline form I according to claim 8, characterized in that: the organic solvent is isopropanol or methyl ethyl ketone.
10. The method for preparing the tandospirone sulfate crystal form I according to claim 8, wherein in step B, the mass-to-volume ratio of the tandospirone sulfate to the organic solvent is 1:1-30g/m L.
11. The method for preparing the tandospirone sulfate crystal form I according to claim 10, wherein in step B, the mass-to-volume ratio of the tandospirone sulfate to the organic solvent is 1:1-25g/m L.
12. The method for preparing the tandospirone sulfate crystal form I according to claim 10, wherein in step B, the mass-to-volume ratio of the tandospirone sulfate to the organic solvent is 1:3-20g/m L.
13. The process for preparing tandospirone sulfate crystalline form I according to claim 8, characterized in that: in the step B, the heating and dissolving temperature is 30-100 ℃.
14. The process for preparing tandospirone sulfate crystalline form I according to claim 13, characterized in that: in the step B, the heating and dissolving temperature is 50-80 ℃.
15. A pharmaceutical composition characterized by: the pharmaceutical preparation is prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components into tandospirone sulfate as an active ingredient in claim 1; wherein the preparation can be aromatic water, solution, injection, mixture, lotion, liniment, aerosol, powder, pill, tablet, pellicle, ointment, suppository, and paste.
16. Use of crystalline form I of tandospirone sulfate according to claim 1 for the preparation of a medicament for the treatment of a disease associated with 5-hydroxytryptamine or/and norepinephrine reuptake.
17. Use of crystalline form I of tandospirone sulfate according to claim 16, characterized in that: the medicine is used for treating central nervous system diseases and eye diseases.
18. Use of crystalline form I of tandospirone sulfate according to claim 17, characterized in that: the medicine is used for treating 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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| CN102344442A (en) * | 2011-08-04 | 2012-02-08 | 成都科瑞德医药投资有限责任公司 | Novel crystal form of tandospirone citrate and preparation method and application thereof |
| CN103664905A (en) * | 2013-12-25 | 2014-03-26 | 成都科瑞德医药投资有限责任公司 | Tandospirone hydrochloride crystal form II and preparation method thereof |
| CN103755687A (en) * | 2013-12-25 | 2014-04-30 | 成都科瑞德医药投资有限责任公司 | Hydrochloric tandospirone crystal form I and preparation method of crystal form I |
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| CN1915216A (en) * | 2006-08-30 | 2007-02-21 | 四川科瑞德制药有限公司 | New usage of tandospirone and its derivative, and composition containing tandospirone |
| CN102344442A (en) * | 2011-08-04 | 2012-02-08 | 成都科瑞德医药投资有限责任公司 | Novel crystal form of tandospirone citrate and preparation method and application thereof |
| CN103664905A (en) * | 2013-12-25 | 2014-03-26 | 成都科瑞德医药投资有限责任公司 | Tandospirone hydrochloride crystal form II and preparation method thereof |
| CN103755687A (en) * | 2013-12-25 | 2014-04-30 | 成都科瑞德医药投资有限责任公司 | Hydrochloric tandospirone crystal form I and preparation method of crystal form I |
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