CN106397411A - A 5-hydroxytryptamine receptor agonist, a preparing method thereof and uses of the receptor agonist - Google Patents
A 5-hydroxytryptamine receptor agonist, a preparing method thereof and uses of the receptor agonist Download PDFInfo
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- CN106397411A CN106397411A CN201610599230.3A CN201610599230A CN106397411A CN 106397411 A CN106397411 A CN 106397411A CN 201610599230 A CN201610599230 A CN 201610599230A CN 106397411 A CN106397411 A CN 106397411A
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- 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 relates to a 5-hydroxytryptamine receptor agonist, a preparing method thereof and uses of the receptor agonist, particularly (3a[alpha],4[beta],7[beta],7a[alpha])-hexahydro-2-[4[4-(2-pyrimidinyl)-1-(piperazinyl)]-butyl]-4,7-methylene-1H-isoindole-1,3(2H)-dione citrate 4/5-hydrate, a preparing method thereof and uses of the 4/5-hydrate. The molecular formula of the 4/5-hydrate is C<21>H<29>N5O2.C6H8O<7>.(4/5)H2O. The 4/5-hydrate has advantages of high stability and good solubility, and therefore product quality control is facilitated and the 4/5-hydrate can be prepared into various dosage forms conveniently. The 4/5-hydrate has excellent compactibility and tabletting performance so that the 4/5-hydrate can be easily processed into tablets and is convenient to store and convey. The preparing method has advantages of few steps, simple and convenient operation, a high product yield, high purity, and the like and is particularly suitable for industrial application.
Description
Technical field
The present invention relates to Tandospirone Citrate 4/5 hydrate and preparation method thereof and purposes.Belong to medicinal chemistry art.
Background technology
Tandospirone, chemical name be (3a α, 4 β, 7 β, 7a α)-hexahydro -2- [4 [4- (2- pyrimidine radicals) -1- (piperazinyl) -
Butyl] -4,7- methylene -1H- iso-indoles -1,3 (2H)-diketone, its structural formula is as follows；Tandospirone is that a kind of 5-hydroxy tryptamine is subject to
Body agonist, is mainly used in the disease treating anxiety or other companion's anxiety states.
Tandospirone belongs to azaspiro ketone medicine, in intracerebral, it can with integrated distribution emotion maincenter Hippocampus, in every,
The cerebral limbic systems such as interpeduncular nucleus, corpus amygdaloideum and the 5-HT of seam gland core1AReceptor-selective ground combines, by exciting 5-HT1AFrom
Experience body, adjust the 5-hydroxy tryptamine being projected to Hippocampus from rapheal nuclei, the 5-hydroxy tryptamine effect of suppression action suppression system, play anti-
Anxiety acts on.Compared to original shape medicine azaspiro ketone with analog derivative buspirone, tandospirone has higher selectivity
Angst resistance effect, this effect is close with diazepam, but secondary in the poison of the aspect such as nervimotion Sexual dysfunction and drug dependence
Effect is but little than diazepam.Due to the specificity of mechanism of action, when tandospirone is used clinically for treating anxiety neurosis, there is use
Medicine is safe, side reaction is few, no relaxed muscle and sedation, no dependence and drug withdrawal give up phenomenon, after prolonged application
The advantages of internal no accumulation.
In addition to angst resistance effect, tandospirone also has in terms of the treatment of other nervous system disease or auxiliary therapy
There is goodish application.Tandospirone has certain antidepressant effect, to the patient's curative effect being mixed with anxiety and depression very
Significantly, and vegetative nerve symptom can be improved by anxiety and antidepressant effects, such as irritable bowel syndrome, functional digestive
Bad, postoperative nausea and vomiting etc..It still treats the ataxic active drug of Central nervous system, can be obviously improved
The symptom of patient's cerebellar ataxia.For the patient with neurasthenia, senile dementia or schizophrenia, it can also be effective
Improve memory, treatment increases rheological properties dysmnesia, significantly improves declarative memory, logical memory and the mouth of schizophrenic
Language paired-association etc..Additionally, tandospirone also has the activity of intraocular pressure lowering, can be used for treatment due to endothelial cell proliferation, inflammation
The ocular disease that disease, vascular permeability raising or angiogenesis etc. cause, such as diabetic retinopathy, age related are yellow
Speckle degeneration, retinal edema, glaucoma etc..It can be seen that, tandospirone has very high clinical value and wide city
Field prospect.
At present, it is used mostly the citrate of tandospirone in clinical treatment, also known as citrate (the i.e. smooth degree of citric acid
Spiral shell ketone).In order to ensure the steady quality of medicine and play good therapeutical effect, need medicine to have higher stability simultaneously
And good dissolubility.In the prior art, the crystal of Tandospirone Citrate is usually used.However, the crystalline substance in prior art
In type, although the dissolubility of Tandospirone Citrate crystal formation I is preferably, its stability relatively low (see：Chinese patent CN
102344442 A)；Although the stability of Tandospirone Citrate crystal formation II and crystal formation III is higher, its dissolubility is relatively poor
(see：Chinese patent CN 103641817 A and CN 103641818 A).It can be seen that, the stability of medicine and dissolubility (dissolubility)
It is the contradiction of a pair mutual restriction, that is,：The stability of medicine improves it will usually lead to the dissolubility of medicine to be deteriorated, and this is also this
Field basic general knowledge (see：Lv Yangdu hat China chief editor,《Crystal formation medicine》Section of four final stage of page 45, people's health is published
Society, 2009).For Tandospirone Citrate, researcher wishes to find stability height and the good product of dissolubility always, thus
Better ensure that the quality stability of its product and play good therapeutical effect.
Therefore, a kind of exploitation stability height and the good Tandospirone Citrate new product of dissolubility are needed badly.
Content of the invention
It is an object of the invention to provide a kind of stability height and the good Tandospirone Citrate new product of dissolubility.
The present invention provides a kind of Tandospirone Citrate 4/5 hydrate, and the molecular formula of described 4/5 hydrate is
C21H29N5O2 .C6H8O7 .4/5H2O；Wherein, C21H29N5O2For tandospirone, C6H8O7For citric acid.
Further, the structural formula of 4/5 described hydrate is：
Further, described hydrate is it is characterized in that its TGA (thermogravimetric analysiss) or DSC (differential scanning calorimetry)
There is absworption peak between 80～115 DEG C on spectrogram；Or its weightlessness about 2.44% between 80～115 DEG C.
Present invention also offers the preparation method of 4/5 hydrate described above, described preparation method comprises the following steps：
Take Tandospirone Citrate, add water, after 50 DEG C～90 DEG C dissolvings, add dissolved agent, cooling, stirring, be preferably cooled to room
After temperature stirring 0.25 hour～3 hours, stir 1 hour～4 hours at 0 DEG C～10 DEG C.Separate solid, be dried, obtain final product Chinese holly
Rafter acid tandospirone 4/5 hydrate.
Further, Tandospirone Citrate and the mass volume ratio of water are 1:5～15g/mL；Tandospirone Citrate with
The mass volume ratio of dissolved agent is 1:5～20g/mL.
Further, Tandospirone Citrate and the mass volume ratio of water are 1:6、1:7、1:8、1:9、1:10、1:11、1:
12 or 1:14g/mL.
Further, Tandospirone Citrate and the mass volume ratio of dissolved agent are 1:5.5、1:6.25、1:8、1:9、1:
10、1:12、1:15、1:17.5 or 1:18g/mL.
Further, dissolved agent includes dissolved agent A and dissolved agent B；Dissolved agent A is in acetone, ether, ethyl acetate
Any one；Any one in acetone, ether, ethyl acetate of dissolved agent B, and dissolved agent A and B is different.
Further, the volume of dissolved agent A and dissolved agent B is 1:4～4:1.
Further, baking temperature is 15 DEG C～50 DEG C, and drying time is 2 hours～10 hours.
Present invention also offers 4/5 hydrate described above is in preparation treatment or prevention 5-hydroxy tryptamine or/and nor- kidney
Purposes in the medicine of upper parathyrine reuptake relevant disease.
Further, described medicine is 5-hydroxy tryptamine regulator.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition comprises above-mentioned 4/5 hydrate as activity
Composition, also includes the adjuvant pharmaceutically commonly used or complementary composition.
The hydrate of medicine refers to that drug molecule and water of crystallization occur hydration reaction to form eutectic state of matter, belongs to many
Crystal formation category (see：Lv Yangdu hat China chief editor,《Crystal formation medicine》Page 92～page 96, People's Health Publisher, 2009).
Compared with no hydrate, the dissolubility of hydrate may improve it is also possible to reduce, such as：Amoxicillin no hydrate molten
Xie Du is 67.6%, and the dissolubility of amoxicillin monohydrate is 83.5%, and the dissolubility of amoxicillin dihydrate only has
15.8%, the dissolubility of Utimox be 95.5% (see：Lv Yangdu hat China chief editor,《Crystal formation medicine》Page 45, people
People's health publishing house, 2009).Therefore, in polyhydrate to be comformed, stability height and the good product of dissolubility are filtered out, and
It is not an easy thing.
However, Tandospirone Citrate 4/5 hydrate of the present invention, have that stability is high simultaneously and that dissolubility is good is excellent
Point, is conducive to the quality control of product, can be conveniently fabricated various dosage forms；Additionally, the Tandospirone Citrate 4/5 of the present invention
Hydrate also has superior mouldability and flakiness, is easily worked in flakes, is easy to store and transports；And, the inventive method
There is step few, easy and simple to handle, the advantages of product yield is high, purity is high, be especially suitable for the application in industry.
Described medicine is the medicine for the treatment of central nervous system disease and ocular disease, including treatment anxiety neurosis, depression
Disease, neurasthenia, post-traumatic stress disorder, premenstrual dysphoric disorder, ADHD, Panic disorder, autism,
Infantile autism, insomnia, schizophrenia, increasing rheological properties dysmnesia, senile dementia, obsessive idea and behavior syndrome, obesity, god
Become through property bulimia nerovsa or shortage, Tourette syndrome, chronic fatigue syndrome, vasomotion sexflush, cocaine or ethanol
Addiction, sexual dysfunction, borderline personality disorder, Raynaud syndrome, urinary incontinence, pain, Parkinson's disease, epilepsy, glaucoma, sugar
The medicine of multiple diseases such as urine characteristic of disease retinopathy, age-related macular degeneration or retinal edema.
Pharmaceutically acceptable adjuvant of the present invention or complementary composition, be known in the art for preparing above-mentioned system
The usual excipients of agent or adjuvant.The excipient that oral formulations or external preparation are commonly used or adjuvant include but are not limited to filler
(diluent), lubricant (fluidizer or antitack agent), dispersant, wetting agent, binding agent, regulator, solubilizing agent, antioxidant,
Antibacterial, emulsifying agent, disintegrating agent etc..Binding agent such as syrup, arabic gum, gelatin, Sorbitol, tragacanth, starch slurry, poly- dimension
Ketone, cellulose derivative (as Microcrystalline Cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methylcellulose etc.) etc.
Deng；Filler such as Lactose, dextrin, starch and its derivant, cellulose derivative, inorganic calcium salt (as calcium sulfate, calcium phosphate,
Calcium hydrogen phosphate, precipitated calcium carbonate etc.), Mannitol, agar powder etc.；Lubricant such as micropowder silica gel, stearic acid and its esters are (as firmly
Fatty acid magnesium etc.), Pulvis Talci, hydrogenated vegetable oil, polyethylene glycols etc.；Disintegrating agent such as starch and its derivant are (as carboxymethyl forms sediment
Powder sodium, Explotab, Pregelatinized Starch, modified starch, hydroxypropyl starch, corn starch etc.), Crospovidone, fiber
Plain analog derivative etc.；Wetting agent such as sodium lauryl sulphate, water, alcohols or other organic solvents etc..Note of the present invention
Penetrate the conventional excipient of agent or adjuvant includes but are not limited to：Antioxidant for example sodium sulfite, sodium sulfite, sodium pyrosulfite,
Sodium thiosulfate, dibutyl benzoic acid etc.；Antibacterial such as phenol, benzyl alcohol, cresol, hydroxypropyl methyl ester, chlorobutanol etc.；Adjust
Section agent example hydrochloric acid, citric acid, potassium hydroxide (sodium), buffer agent (including phosphoric acid dioxy sodium and disodium hydrogen phosphate etc.) etc.；Emulsifying
Agent such as polyoxyethylene sorbitan monoleate, do not have that sour Pyrusussuriensiss are smooth, pluronic gram F-68, lecithin, fabaceous lecithin etc.；Solubilizing agent such as Tween 80, gallbladder
Juice, glycerol etc..
Additionally, also can be by active component and pharmaceutically acceptable slow controlled release carrier, according to slow controlled release well known in the art
The preparation method of preparation makes sustained-release preparation.For example add blocker coating or micro- by making again after active principle microcapsules
Ball, including slow-release micro-pill or controlled release micro pill etc..Described slow controlled release carrier includes but are not limited to oil dopant, hydrophilic gel
Body or coating blocker etc., described oil dopant is selected from glyceryl monostearate, castor oil hydrogenated, Dormant oils, poly- silica
Any one or a combination thereof of alkane or dimethyl siloxane；Described hydrophilic colloid is selected from sodium carboxymethyl cellulose, hydroxy propyl cellulose
Element, hydroxypropyl methyl cellulose, PVP, any one or a combination thereof of arabic gum, tragacanth or carbopol；Described coating
Blocker is selected from ethyl cellulose (EC), hydroxypropyl methylcellulose (HMPC), Polyvinylpyrrolidone (PVP), phthalic acid
Cellulose acetate (CAP), any one or a combination thereof of acrylic resin.
The dosage form of compositionss of the present invention, can be liquid preparation, gaseous formulation, solid preparation and semi-solid system
Agent, preferred fragrance water preparation, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, glue
The common formulations such as wafer, membrane, ointment, suppository, paste.
Obviously, the above according to the present invention, according to ordinary technical knowledge and the customary means of this area, without departing from
Under the premise of the present invention above-mentioned basic fundamental thought, modification, replacement or the change of other various ways can also be made.
The specific embodiment of form by the following examples, remakes further specifically to the above of the present invention
Bright.But this scope being interpreted as the above-mentioned theme of the present invention should not be only limitted to Examples below.All based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Brief description
Fig. 1 is the TGA collection of illustrative plates of Tandospirone Citrate 4/5 hydrate of the present invention；
Fig. 2 is the DSC collection of illustrative plates of Tandospirone Citrate 4/5 hydrate of the present invention；
Fig. 3 is to prepare gained Tandospirone Citrate with reference to the open method of existing document (CN101880274A embodiment 8)
TGA collection of illustrative plates；
Fig. 4 is to prepare gained Tandospirone Citrate with reference to the open method of existing document (CN101880274A embodiment 8)
DSC collection of illustrative plates.
Specific embodiment
Used in the specific embodiment of the invention, raw material, equipment are known product, are obtained by buying commercially available prod.
Embodiment 1
Weigh 20g Tandospirone Citrate, add 140mL water, be heated to 70 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add acetone 100mL and ether 100mL, continues to be cooled to and is stirred at room temperature 1 hour, and 5 ± 5 DEG C are stirred 1 hour,
Treat that solid separates out, filter, be vacuum dried 2h at 50 DEG C, obtain final product 19.6g Tandospirone Citrate 4/5 hydrate, yield is
95.6%, purity is 99.93%.
Mass spectrum shows its ESI m/z：383.
Take product of the present invention to carry out elementary analysiss, the results are shown in Table 1.
Table 1, elementary analysiss result
| Element | N% | C% | H% |
| C21H29N5O2 ·C6H8O7 ·4/5H2O theoretical value | 11.87 | 54.96 | 6.59 |
| Product measured value of the present invention | 11.88 | 54.94 | 6.58 |
Loss on drying measures：By product of the present invention in 105 DEG C of dryings to constant weight, weight reduces 2.42%.
Water analysiss：This sample is pressed Ka Shi aquametry and is measured moisture, and result is 2.45%；Two kinds of results are basic
Unanimously, show to contain 4/5 molecular water in product of the present invention.
Heat analysis：Product of the present invention is taken to carry out TGA (thermogravimetric analysiss) and DSC (differential scanning calorimetry) test, gained is tied
Fruit is as depicted in figs. 1 and 2.TGA (the heat of existing product (method with reference to report in CN101880274A (embodiment 8) is obtained)
Weight analysis) and DSC (differential scanning calorimetry) test result is as shown in Figure 3 and Figure 4.
Result shows, in heat analysis, product of the present invention has absworption peak between 80～115 DEG C；In TGA, 80～
This product weightlessness about 2.44% in 115 DEG C.With reference to the product obtained by CN101880274A embodiment 8, do not inhale in this interval
Receipts peak and accordingly weightless step.By compareing with existing product, also illustrate that and contain water of crystallization in product of the present invention or crystallize molten
Agent, and in existing product, do not contain water of crystallization or recrystallisation solvent.
Summary result of the test, may certify that the water of crystallization containing 4/5 molecule in product of the present invention, and its structural formula is：
Embodiment 2
Weigh 20g Tandospirone Citrate, add 300mL water, be heated to 50 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add acetone 150mL and ether 250mL, continues to be cooled to and is stirred at room temperature 3 hours, and 5 ± 5 DEG C are stirred 1 hour,
Treat that solid separates out, filter, be vacuum dried 8h at 35 DEG C, obtain final product 19.8g Tandospirone Citrate 4/5 hydrate, yield is
96.6%, purity is 99.90%.
The result of the tests such as the elementary analysiss of products obtained therefrom, loss on drying, determination of water and heat analysis show, the present invention obtains
Be Tandospirone Citrate 4/5 hydrate.
Embodiment 3
Weigh 20g Tandospirone Citrate, add 100mL water, be heated to 90 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add acetone 40mL and ether 60mL, continues to be cooled to and is stirred at room temperature 15 minutes, and 5 ± 5 DEG C are stirred 4 hours,
Treat that solid separates out, filter, be vacuum dried 10h at 15 DEG C, obtain final product 19.5g Tandospirone Citrate 4/5 hydrate, yield is
95.1%, purity is 99.93%.
The result of the tests such as the elementary analysiss of products obtained therefrom, loss on drying, determination of water and heat analysis show, the present invention obtains
Be Tandospirone Citrate 4/5 hydrate.
Embodiment 4
Weigh 20g Tandospirone Citrate, add 200mL water, be heated to 80 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add acetone 200mL and ether 100mL, continues to be cooled to and is stirred at room temperature 0.5 hour, and 5 ± 5 DEG C of stirrings 3 are little
When, treat that solid separates out, filter, aeration-drying 10h at 50 DEG C, obtain final product 19.6g Tandospirone Citrate 4/5 hydrate, yield is
95.6%, purity is 99.92%.
The result of the tests such as the elementary analysiss of products obtained therefrom, loss on drying, determination of water and heat analysis show, the present invention obtains
Be Tandospirone Citrate 4/5 hydrate.
Embodiment 5
Weigh 20g Tandospirone Citrate, add 120mL water, be heated to 75 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add acetone 80mL and ethyl acetate 30mL, continues to be cooled to and is stirred at room temperature 1 hour, and 5 ± 5 DEG C of stirrings 4 are little
When, treat that solid separates out, filter, be vacuum dried 2h at 50 DEG C, obtain final product 19.9g Tandospirone Citrate 4/5 hydrate, yield is
97.1%, purity is 99.92%.
The result of the tests such as the elementary analysiss of products obtained therefrom, loss on drying, determination of water and heat analysis show, the present invention obtains
Be Tandospirone Citrate 4/5 hydrate.
Embodiment 6
Weigh 20g Tandospirone Citrate, add 240mL water, be heated to 50 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add acetone 180mL and ethyl acetate 180mL, continues to be cooled to and is stirred at room temperature 3 hours, 5 ± 5 DEG C of stirrings 1
Hour, treat that solid separates out, filter, be vacuum dried 10h at 20 DEG C, obtain final product 19.7g Tandospirone Citrate 4/5 hydrate, yield
For 96.1%, purity is 99.91%.
The result of the tests such as the elementary analysiss of products obtained therefrom, loss on drying, determination of water and heat analysis show, the present invention obtains
Be Tandospirone Citrate 4/5 hydrate.
Embodiment 7
Weigh 20g Tandospirone Citrate, add 180mL water, be heated to 90 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add acetone 140mL and ethyl acetate 100mL, continues to be cooled to and is stirred at room temperature 15 minutes, 5 ± 5 DEG C of stirrings 3
Hour, treat that solid separates out, filter, aeration-drying 8h at 50 DEG C, obtain final product 19.8g Tandospirone Citrate 4/5 hydrate, yield is
96.6%, purity is 99.92%.
The result of the tests such as the elementary analysiss of products obtained therefrom, loss on drying, determination of water and heat analysis show, the present invention obtains
Be Tandospirone Citrate 4/5 hydrate.
Embodiment 8
Weigh 20g Tandospirone Citrate, add 160mL water, be heated to 90 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add ether 80mL and ethyl acetate 80mL, continues to be cooled to and is stirred at room temperature 2 hours, and 5 ± 5 DEG C of stirrings 4 are little
When, treat that solid separates out, filter, be vacuum dried 10h at 20 DEG C, obtain final product 19.4g Tandospirone Citrate 4/5 hydrate, yield is
94.6%, purity is 99.90%.
The result of the tests such as the elementary analysiss of products obtained therefrom, loss on drying, determination of water and heat analysis show, the present invention obtains
Be Tandospirone Citrate 4/5 hydrate.
Embodiment 9
Weigh 20g Tandospirone Citrate, add 280mL water, be heated to 50 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add ether 100mL and ethyl acetate 80mL, continues to be cooled to and is stirred at room temperature 3 hours, and 5 ± 5 DEG C of stirrings 1 are little
When, treat that solid separates out, filter, be vacuum dried 2h at 50 DEG C, obtain final product 19.5g Tandospirone Citrate 4/5 hydrate, yield is
95.1%, purity is 99.91%.
The result of the tests such as the elementary analysiss of products obtained therefrom, loss on drying, determination of water and heat analysis show, the present invention obtains
Be Tandospirone Citrate 4/5 hydrate.
Embodiment 10
Weigh 20g Tandospirone Citrate, add 220mL water, be heated to 70 DEG C, to be dissolved complete, it is cooled to 40
± 5 DEG C, stirring is lower to add ether 100mL and ethyl acetate 25mL, continues to be cooled to and is stirred at room temperature 20 minutes, 5 ± 5 DEG C of stirrings
2.5 hours, treat that solid separates out, filter, be vacuum dried 5h at 45 DEG C, obtain final product 19.7g Tandospirone Citrate 4/5 hydrate, receive
Rate is 96.1%, and purity is 99.92%.
The result of the tests such as the elementary analysiss of products obtained therefrom, loss on drying, determination of water and heat analysis show, the present invention obtains
Be Tandospirone Citrate 4/5 hydrate.
Comparative experimental example：
Weigh 50g Tandospirone Citrate, add 350mL water, be heated to 100 DEG C, to be dissolved complete, continue stirring
Stop heating after 0.5 hour, in the lower stirring of 1 DEG C of cooling 1 hour, treat that solid separates out, filter, be vacuum dried 2h at 50 DEG C, obtain final product
The monohydrate of 50.3g Tandospirone Citrate, yield is 97.5%.
Mass spectrum shows its ESI m/z：383.
Take contrast test product to carry out elementary analysiss, the results are shown in Table 2：
Table 2, elementary analysiss result
| Element | N% | C% | H% |
| C21H29N5O2 .C6H8O7 .H2O theoretical value | 11.80 | 54.63 | 6.62 |
| Contrast test product measured value | 11.80 | 54.58 | 6.67 |
Loss on drying measures：By contrast test product in 105 DEG C of dryings to constant weight, weight decreases 3.03%；Moisture divides
Analysis：Contrast test product is pressed Ka Shi aquametry and is measured moisture, and result is 3.06%；Two kinds of results are basically identical, table
1 molecular water is contained in bright contrast test product.
Heat analysis：Contrast test product is taken to carry out TGA (thermogravimetric analysiss) and DSC (differential scanning calorimetry) test, result
Show, contrast test product has absworption peak between 90～120 DEG C, and contrast test product weightlessness is about in this interval
3.02%.
Summary result of the test, may certify that the water of crystallization containing 1 molecule in contrast test product, and its structural formula is：
It can be seen that, change processing step or the process conditions of preparation method, it will obtain the hydration produce different from the present invention
Product.
In order to beneficial effects of the present invention are described, the present invention provides tests below example：
Test example 1, dissolubility test
Test group：Tandospirone Citrate 4/5 hydrate of the present invention；
Existing product：The citric acid preparing with reference to method disclosed in existing document (CN101880274A embodiment 8)
Tandospirone.
Weigh test sample 2g, be placed in 25 DEG C ± 2 DEG C of 20mL water, every strength shaking in 1 minute 10 seconds；Observe 3 points
Dissolving situation in clock.As no visually visible particles of solute when, that is, be considered as being completely dissolved；If visually there being visible solute
Grain, adds 5 times amount water, repeats aforementioned operation, until being completely dissolved, records total water consumption and time；The results are shown in Table 3.
Table 3, the result of dissolubility test
Result of the test shows, compared with existing product, product dissolution time of the present invention is short, and total water consumption is few, its dissolubility
Have increased significantly, more conducively preparation uses.
Test example 2, stabilizing effect test
Test group：Tandospirone Citrate 4/5 hydrate of the present invention；
Existing product：The citric acid preparing with reference to method disclosed in existing document (CN101880274A embodiment 8)
Tandospirone.
(1) influence factor's test
Investigation condition is strong illumination (4500 ± 500lx), high temperature (60 DEG C), high humidity (relative humidity 92.5%, 25 DEG C).
Product of the present invention and existing product are placed 10 days under the conditions of different investigation respectively, was measured by sampling in 5,10 days, same batch with 0 day
Sample data is compared, and the results are shown in Table 4.
Table 4, the result of influence factor's test
Result of the test shows, Tandospirone Citrate 4/5 hydrate of the present invention, under high temperature, high humidity, illumination condition, produces
Product content and impurity have no significant change, stability more preferably, be more beneficial for realizing product quality stablize controlled；And existing product pair
Light, heat, wet less stable, particularly under strong illumination, product impurity substantially increases, and its stability is relatively poor.
(2) study on the stability under the conditions of different humidity
By Tandospirone Citrate 4/5 hydrate of the present invention and existing product, in different relative humidities (75%,
92.5%) place 10 days under, be measured by sampling respectively at 5,10 days, be compared with batch sample data with 0 day, the results are shown in Table 5.
Stability test result under the conditions of table 5, different humidity
Result of the test shows, Tandospirone Citrate 4/5 hydrate of the present invention is placed under different relative humidities
10 days, the no significant change of sample moisture, basically identical with batch sample data with 0 day, illustrate that product stability of the present invention is good
Good, store beneficial to steady in a long-term, be readily transported, and need not especially control humidity in preparation of preparation, more conducively the preparation of preparation；
And existing product moisture under above-mentioned difference relative humidities substantially increases, existing product is described to moist lability, has
Hygroscopicity.
(3) accelerated test
Take test sample aluminum-plastic composite membrane bag pack, acceleration environment (40 DEG C ± 2 DEG C of temperature, relative humidity 75 ± 5%
In constant temperature and humidity incubator) under place six months, respectively at the sampling detection of 1,2,3,6 the end of month, and with 0 month knot with batch sample
Fruit is compareed；Result of the test is shown in Table 6.
Table 6, accelerated test result
Result of the test shows, product of the present invention is placed 6 months under acceleration conditions, and sample size and moisture all no substantially become
Change, impurity level has no obvious increase, basically identical with batch sample data with 0 month, illustrates that this product is stable under acceleration conditions；And show
There is product to place under acceleration conditions 3 months, its total impurities increases 1 times, the stability of existing product is described relatively
Difference.
Moisture in above-mentioned each table refers to the moisture being measured by dry weight-loss method, and content refers to the citron by anhydride metering
The content of sour tandospirone.
The result of the test of test example 2 shows, Tandospirone Citrate 4/5 hydrate of the present invention is in high temperature, high humidity, illumination
Under the conditions of, product content no substantially reduces, and moisture no substantially changes, and impurity level has no obvious increase, has good stability, product matter
Amount is stablized controlled；And existing product is to light, heat, wet less stable, impurity increases substantially, especially under conditions of high humidity,
Existing product moisture substantially increases, and its product stability is relatively poor.
Test example 3, mouldability test
Test group：Tandospirone Citrate 4/5 hydrate of the present invention；
Existing product：The citric acid preparing with reference to method disclosed in existing document (CN101880274A embodiment 8)
Tandospirone.
Accurately weigh the test sample of 200mg, respectively under the pressing pressure of 400～1200kg by test sample processing in flakes,
And test tablet hardness；Result of the test is shown in Table 7.
Table 7, mouldability result of the test
Result of the test shows, the hardness of existing product tablet raises with the increase of pressing pressure, when pressing pressure is up to
During 1200kg, just can obtain the tablet with 8kg hardness；Compared with existing product, product of the present invention only needs the compacting pressure of half
Power can get the tablet of same rigidity.Product of the present invention just can suppress the tablet of higher hardness at low pressures, says
Bright product of the present invention has very superior mouldability and flakiness, is easily worked in flakes.
Under normal circumstances, the mouldability of product of the present invention is better, when making preparation especially tablet, its excipient and collapsing
The consumption of solution agent can accordingly reduce, and the volume of tablet also can reduce, so that oral medication is easier, significantly improves patient and comply with
Property.Additionally, the reduction of pressing pressure in blocks can also be effectively improved the disintegrating property of tablet, reduce the abrasion of press mold and drift, fall
Input of low plant maintenance usage charges etc..
In sum, Tandospirone Citrate 4/5 hydrate of the present invention, has stability high good with dissolubility simultaneously
Advantage, is conducive to the quality control of product, can be conveniently fabricated various dosage forms；Additionally, the rafter acid tandospirone of Chinese holly of the present invention
4/5 hydrate also has superior mouldability and flakiness, is easily worked in flakes, is easy to store and transports；And, side of the present invention
Method has the advantages of step is few, easy and simple to handle, and product yield is high, purity is high, is especially suitable for the application in industry.
Claims (9)
1. a kind of Tandospirone Citrate 4/5 hydrate, its structural formula is：
2. the preparation method of hydrate described in claim 1 is it is characterised in that comprise the following steps：Take Tandospirone Citrate,
Add water, after 50 DEG C～90 DEG C dissolvings, add dissolved agent, cooling, stirring, separate solid, be dried, obtain final product described citric acid
Tandospirone 4/5 hydrate.
3. preparation method according to claim 2 it is characterised in that：Tandospirone Citrate with the mass volume ratio of water is
1:5～15g/mL；Tandospirone Citrate is 1 with the mass volume ratio of dissolved agent:5～20g/mL.
4. the preparation method according to Claims 2 or 3 it is characterised in that：Tandospirone Citrate and the quality volume of water
Than for 1:6、1:7、1:8、1:9、1:10、1:11、1:12 or 1:14g/mL.
5. the preparation method according to any one of claim 2-4 it is characterised in that：Tandospirone Citrate and dissolved agent
Mass volume ratio is 1:5.5、1:6.25、1:8、1:9、1:10、1:12、1:15、1:17.5 or 1:18g/mL.
6. the preparation method according to any one of claim 2-5 it is characterised in that：Described dissolved agent include dissolved agent A and
Dissolved agent B, wherein, described dissolved agent A and B is each independently selected from acetone, ether, any one in ethyl acetate, and molten
Agent A and B is different for analysis；Preferably, the volume of described dissolved agent A and dissolved agent B is 1:4～4:1.
7. the preparation method according to any one of claim 2-6 it is characterised in that：Baking temperature is 15 DEG C～50 DEG C, does
The dry time is 2 hours～10 hours.
8. the hydrate described in claim 1 is in preparation treatment or prevention 5-hydroxy tryptamine or/and norepinephrine reuptake phase
Purposes in the medicine of related disorders；Preferably, described medicine is 5-hydroxy tryptamine regulator；It is highly preferred that described medicine is to control
Treat the medicine of central nervous system disease and ocular disease, for example, described medicine is treatment anxiety neurosis, depression, nerve decline
Weak, post-traumatic stress disorder, premenstrual dysphoric disorder, ADHD, Panic disorder, autism, infantile autism, mistake
Dormancy disease, schizophrenia, increasing rheological properties dysmnesia, senile dementia, obsessive idea and behavior syndrome, obesity, Bulimia
Cross Sheng or shortage, Tourette syndrome, chronic fatigue syndrome, vasomotion sexflush, cocaine or alcohol addiction, sexual function
Obstacle, borderline personality disorder, Raynaud syndrome, urinary incontinence, pain, Parkinson's disease, epilepsy, glaucoma, diabetic regard
The medicine of nethike embrane disease, age-related macular degeneration or retinal edema.
9. a kind of pharmaceutical composition, it is characterised in that comprising hydrate described in claim 1 as active component, also includes medicine
Conventional adjuvant or complementary composition on.
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| CN102351812A (en) * | 2008-12-01 | 2012-02-15 | 北京四环制药有限公司 | Methanesulfonic acid cinepazide crystal form III and preparation method thereof |
| CN103012430A (en) * | 2013-01-16 | 2013-04-03 | 湖北济生医药有限公司 | Mezlocillin sodium compound and medicine composition thereof |
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| CN102351812A (en) * | 2008-12-01 | 2012-02-15 | 北京四环制药有限公司 | Methanesulfonic acid cinepazide crystal form III and preparation method thereof |
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