CN106397410A - 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
- Publication number
- CN106397410A CN106397410A CN201610597515.3A CN201610597515A CN106397410A CN 106397410 A CN106397410 A CN 106397410A CN 201610597515 A CN201610597515 A CN 201610597515A CN 106397410 A CN106397410 A CN 106397410A
- Authority
- CN
- China
- Prior art keywords
- monohydrate
- water
- tandospirone citrate
- tandospirone
- preparation
- 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.)
- Granted
Links
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 monohydrate, a preparing method thereof and uses of the monohydrate. The molecular formula of the monohydrate is C<21>H<29>N5O2.C6H8O<7>.H2O. The monohydrate has advantages of high stability and good solubility, thus facilitating product quality control, increasing dissolution rates of preparations, and facilitating medicine absorption and utilization. The monohydrate can be prepared into various dosage forms conveniently, and is convenient to process, 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 monohydrate 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, from
And 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 monohydrate, and the molecular formula of described monohydrate is C21H29N5O2·
C6H8O7·H2O；Wherein, C21H29N5O2For tandospirone, C6H8O7For citric acid.
Further, the structural formula of described monohydrate is：
Further, described monohydrate is it is characterised in that its fusing point is 168.0～169.0 DEG C.
Further, described monohydrate, on the spectrogram of its TGA (thermogravimetric analysiss) or DSC (differential scanning calorimetry)
There is absworption peak between 90～120 DEG C, or weightlessness about 3.02% between 90～120 DEG C.
Further, in the X-ray powder diffraction of described monohydrate, 2 θ angle of diffraction 18.2 ± 0.2 °, 19.1 ±
There is characteristic peak at 0.2 °, 21.2 ± 0.2 °, 22.3 ± 0.2 °, 22.8 ± 0.2 °, 26.3 ± 0.2 ° and 30.6 ± 0.2 °.
Further, in the X-ray powder diffraction of described monohydrate, the relative intensity I% of 2 θ angle of diffraction characteristic peaks
>=10% main peaks are：
| 2θ | Relative intensity (I% >=10%) |
| 6.6±0.2° | 10 |
| 11.3±0.2° | 19 |
| 13.7±0.2° | 24 |
| 15.0±0.2° | 20 |
| 18.2±0.2° | 100 |
| 19.1±0.2° | 10 |
| 20.5±0.2° | 12 |
| 22.0±0.2° | 48 |
| 22.3±0.2° | 26 |
| 24.1±0.2° | 15 |
| 25.2±0.2° | 30 |
| 26.3±0.2° | 19 |
| 27.2±0.2° | 48 |
| 30.1±0.2° | 22 |
Another object of the present invention is to providing the preparation method of above-mentioned monohydrate.
Present invention also offers the preparation method of above-mentioned monohydrate, described preparation method comprises the following steps：Take citron
Sour tandospirone, adds water, after heating for dissolving, cooling, stirring, and separate solid, be dried, obtain final product Tandospirone Citrate one hydration
Thing.
Further, Tandospirone Citrate and the mass volume ratio of water are 1:3～15g/mL；Further, citric acid
Tandospirone is 1 with the mass volume ratio of water:5～10g/mL；Further, the quality volume of Tandospirone Citrate and water
Than for 1:7、1:7.5 or 1:9g/mL.
Further, the temperature of heating for dissolving is 50 DEG C～100 DEG C；The temperature of cooling condition is 1 DEG C～10 DEG C；During stirring
Between be 1 hour～8 hours.
Present invention also offers another preparation method of above-mentioned monohydrate, described another preparation method includes following step
Suddenly：Take Tandospirone Citrate, add water, form suspension solution, stirring, separate solid, be dried, obtain final product Tandospirone Citrate
Monohydrate.
Further, Tandospirone Citrate and the mass volume ratio of water are 1:1～18g/mL；Further, citric acid
Tandospirone is 1 with the mass volume ratio of water:2～15g/mL；Further, the quality volume of Tandospirone Citrate and water
Than for 1:4、1:5、1:8 or 1:10g/mL.
Further, the temperature of stirring is 5 DEG C～28 DEG C, and the time of stirring is 5 hours～40 hours.
Further, baking temperature is 15 DEG C～50 DEG C, and drying time is 2 hours～8 hours.
Present invention also offers above-mentioned monohydrate in preparation treatment or prevents 5-hydroxy tryptamine or/and norepinephrine again
Purposes in the medicine of picked-up relevant disease.
Further, described medicine is 5-hydroxy tryptamine regulator.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition is to comprise monohydrate described above to make
For active component, also contain 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, the Tandospirone Citrate monohydrate of the present invention, have the advantages that stability is high and dissolubility is good simultaneously,
Not only contribute to the quality control of product, also improve the dissolution of its preparation, be conducive to absorption and the utilization of medicine, Ke Yifang
Just make various dosage forms, be easy to store and transport；And, it is few, easy and simple to handle that the inventive method has a step, product yield
The advantages of height, purity are high, is 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 monohydrate of the present invention.
Fig. 2 is the DSC collection of illustrative plates of Tandospirone Citrate monohydrate 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.
Fig. 5 is the X-ray powder diffraction figure of Tandospirone Citrate monohydrate of the present invention.
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 prepares Tandospirone Citrate monohydrate
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
50.3g Tandospirone Citrate monohydrate, yield is 97.5%, and purity is 99.90%；Mass spectrum shows its ESI m/z：383.
Recording fusing point is：168.0～169.0 DEG C.
The Tandospirone Citrate monohydrate taking the present invention carries out elementary analysiss, the results are shown in Table 1：
Table 1, elementary analysiss result
| Element | N% | C% | H% |
| C21H29N5O2·C6H8O7·H2O theoretical value | 11.80 | 54.63 | 6.62 |
| Product measured value of the present invention | 11.80 | 54.58 | 6.67 |
Loss on drying measures：By product of the present invention in 105 DEG C of dryings to constant weight, weight decreases 3.03%；Water analysiss：
This sample is pressed Ka Shi aquametry and is measured moisture, and result is 3.06%；Two kinds of results are basically identical, show that the present invention produces
1 molecular water is contained in product.
Heat analysis：Product of the present invention is taken to carry out TGA (thermogravimetric analysiss) and DSC (differential scanning calorimetry) test, test knot
Fruit is as illustrated in fig. 1 and 2.The TGA (thermogravimetric analysiss) of existing product (with reference to CN10188027A embodiment 8) and DSC (differential scanning
Calorimetry), its test result is as shown in Figures 3 and 4.
Result shows, product of the present invention has absworption peak between 90～120 DEG C, and product of the present invention is weightless in this interval
About 3.02%, and existing product did not all have absworption peak and corresponding weightless step before 150 DEG C；By compareing with existing product,
Also illustrate that in product of the present invention and contain water of crystallization or recrystallisation solvent, and in existing product, do not contain water of crystallization or recrystallisation solvent.
Using Cu K α radiation, record the X-ray powder diffraction result of the Tandospirone Citrate monohydrate of the present invention
As shown in figure 5, its associated diffraction data is shown in Table 2.
Table 2, X-ray powder diffraction result
Wherein, the main associated diffraction data of relative intensity I% >=10% is shown in Table 3.
Table 3, X-ray powder diffraction result
Summary result of the test, may certify that the water of crystallization containing 1 molecule in product of the present invention, and its structural formula is：
Embodiment 2 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 250mL water, be heated to 90 DEG C, to be dissolved complete, continue stirring
Stop heating after 0.5 hour, in the lower stirring of 8 DEG C of coolings 6 hours, treat that solid separates out, filter, aeration-drying 6h at 40 DEG C, obtain final product
50.5g Tandospirone Citrate monohydrate, yield is 98.0%, 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 monohydrate.
Embodiment 3 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 500mL water, be heated to 50 DEG C, to be dissolved complete, continue stirring
Stop heating after 0.5 hour, in the lower stirring of 2 DEG C of coolings 4 hours, treat that solid separates out, filter, be vacuum dried 8h at 15 DEG C, obtain final product
50.4g Tandospirone Citrate monohydrate, yield is 97.8%, and 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 monohydrate.
Embodiment 4 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 375mL water, be heated to 75 DEG C, to be dissolved complete, continue stirring
Stop heating after 0.5 hour, in the lower stirring of 4 DEG C of coolings 2 hours, treat that solid separates out, filter, be vacuum dried 4h at 30 DEG C, obtain final product
50.2g Tandospirone Citrate monohydrate, yield is 97.4%, and purity is 99.89%.
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 monohydrate.
Embodiment 5 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 450mL water, be heated to 50 DEG C, to be dissolved complete, continue stirring
Stop heating after 0.5 hour, in the lower stirring of 10 DEG C of coolings 8 hours, treat that solid separates out, filter, be vacuum dried 8h at 15 DEG C, obtain final product
50.2g Tandospirone Citrate monohydrate, yield is 97.4%, and 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 monohydrate.
Embodiment 6 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 500mL water, so that solid is suspended in water at 10 DEG C and stir 24 hours,
Filter, be vacuum dried 5h at 30 DEG C, obtain final product 49.8g Tandospirone Citrate monohydrate, 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 monohydrate.
Embodiment 7 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 100mL water, so that solid is suspended in water at 28 DEG C and stir 30 hours,
Filter, be vacuum dried 6h at 15 DEG C, obtain final product 50.3g Tandospirone Citrate monohydrate, yield is 97.6%, 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 monohydrate.
Embodiment 8 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 750mL water, so that solid is suspended in water at 5 DEG C and stir 10 hours,
Filter, aeration-drying 8h at 50 DEG C, obtain final product 49.9g Tandospirone Citrate monohydrate, yield is 96.8%, 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 monohydrate.
Embodiment 9 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 400mL water, so that solid is suspended in water at 20 DEG C and stir 20 hours,
Filter, be vacuum dried 2h at 45 DEG C, obtain final product 50.1g Tandospirone Citrate monohydrate, yield is 97.2%, 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 monohydrate.
Embodiment 10 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 200mL water, so that solid is suspended in water at 25 DEG C and stir 40 hours,
Filter, be vacuum dried 8h at 15 DEG C, obtain final product 50.0g Tandospirone Citrate monohydrate, yield is 97.0%, 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 monohydrate.
Embodiment 11 prepares Tandospirone Citrate monohydrate
Weigh 50g Tandospirone Citrate, add 250mL water, so that solid is suspended in water at 15 DEG C and stir 5 hours,
Filter, be vacuum dried 6h at 25 DEG C, obtain final product 50.1g Tandospirone Citrate monohydrate, yield is 97.2%, purity is
99.89%.
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 monohydrate.
Embodiment 12 prepares capsule product
Table 4, the proportioning raw materials of capsule
| Tandospirone Citrate monohydrate | 3g |
| Starch | 200g |
| Microcrystalline Cellulose | 5g |
| Make | 1000 |
According to the proportioning of table 4, after Tandospirone Citrate monohydrate and starch are mixed by equal increments method, then with
Microcrystalline Cellulose mixes, and pelletizes, encapsulated obtains final product.
Comparative experimental example：
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%.
Mass spectrum shows its ESI m/z：383.
Take contrast test product to carry out elementary analysiss, the results are shown in Table 5.
Table 5, 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 contrast test product in 105 DEG C of dryings to constant weight, weight reduces 2.42%；Water analysiss：
Contrast test product is pressed Ka Shi aquametry and is measured moisture, and result is 2.45%；Two kinds of results are basically identical, and it is right to show
Ratio contains 4/5 molecular water in test products.
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 80～115 DEG C, and contrast test product weightlessness is about in this interval
2.44%.
Summary result of the test, may certify that the water of crystallization containing 4/5 molecule in contrast test product, its structural formula
For：
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：The Tandospirone Citrate monohydrate 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；Record total water consumption and time；The results are shown in Table 6.
Table 6, the result of dissolubility test
Dissolubility test result shows, compared with existing product, the water solublity of product of the present invention has clear improvement, more conducively
Preparation uses.
Test example 2, stabilizing effect test
Test group：The Tandospirone Citrate monohydrate 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),
The tandospirone monohydrate of the present invention and existing product are placed 10 days under the conditions of different investigation respectively, sampled in 5,10 days
Measure, be compared with batch sample data with 0 day, the results are shown in Table 7.
Table 7, the result of influence factor's test
Result of the test shows, the Tandospirone Citrate monohydrate 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 the tandospirone monohydrate of the present invention and existing product, in different relative humidities (75%, 92.5%)
Lower room temperature is placed 10 days, was measured by sampling respectively at 5,10 days, was compared with batch sample data with 0 day, the results are shown in Table 8.
Stability test result under the conditions of table 8, different humidity
Result of the test shows, the Tandospirone Citrate monohydrate of the present invention places 10 under different relative humidities
My god, 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,
Store beneficial to steady in a long-term, be readily transported, and especially need not control humidity it is easier to make preparation in preparation of preparation；And show
There is product moisture under above-mentioned difference relative humidities substantially to increase, illustrate that existing product, to moist lability, has moisture absorption
Property.
(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 9.
Table 9, accelerated test result
Result of the test shows, this product is placed 6 months under acceleration conditions, and sample size and moisture have no significant change, miscellaneous
Quality has no obvious increase, basically identical with batch sample data with 0 month, illustrates that this product is stable under acceleration conditions；And existing product
Product are placed 3 months under acceleration conditions, and its total impurities increases 1 times, illustrate that the stability of existing product is relatively poor.
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, the Tandospirone Citrate monohydrate 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, preparation Dissolution Rate Testing
Test group 1：The capsule product of the embodiment of the present invention 12；
Test group 2：Take the Tandospirone Citrate preparing according to existing document (CN101880274A embodiment 8)
(i.e. existing product), 12 methods describeds according to embodiments of the present invention make capsule, obtain the capsule of existing product.
Dissolution determination method：According to dissolution method (2010 editions two annex XC the 3rd methods of Chinese Pharmacopoeia), with
0.1mol/L hydrochloric acid solution is dissolution medium, and rotating speed 100r/min operates in accordance with the law, during through 15 minutes, takes solution 5mL, filtration, plus
Mobile phase is diluted to the solution containing Tandospirone Citrate 5 μ g in every 1mL, as need testing solution；Separately take citric acid smooth degree spiral shell
Appropriate ketone, plus mobile phase make in every 1mL contain 5 μ g solution, as reference substance solution.Measure the chromatograph under item according to chromatographic content
Condition measures, and calculates the stripping quantity of every.
Result of the test shows, in the dissolution medium of 0.1mol/L hydrochloric acid solution, test group 1, test group 2 are in 15min
Interior dissolution is respectively 90% and 70%；The result of extraction of product of the present invention is more satisfactory, raising compared with existing product
Nearly 1/3, it is significantly better than existing product.It can be seen that, the dissolution of product of the present invention is higher, is suitable for making various preparations, and it is biological
Availability high it is ensured that medication effect, more suitable for clinical practice.
In sum, the Tandospirone Citrate monohydrate of the present invention, has stability high good with dissolubility simultaneously
Advantage, not only contributes to the quality control of product, also improves the dissolution of its preparation, is conducive to absorption and the utilization of medicine,
Various dosage forms can be conveniently fabricated, be easy to store and transport；And, it is few, easy and simple to handle that the inventive method has a step, product
The advantages of high income, purity are high, is especially suitable for the application in industry.
Claims (10)
1. a kind of Tandospirone Citrate monohydrate, its structural formula is：
2. monohydrate according to claim 1 it is characterised in that in its X-ray powder diffraction 2 θ angle of diffraction exist
18.2 ± 0.2 °, 19.1 ± 0.2 °, 21.2 ± 0.2 °, 22.3 ± 0.2 °, 22.8 ± 0.2 °, 26.3 ± 0.2 ° and 30.6 ± 0.2 °
There is characteristic peak at place.
3. the preparation method of monohydrate described in claim 1 or 2 is it is characterised in that comprise the following steps：Take the smooth degree of citric acid
Spiral shell ketone, adds water, after heating for dissolving, cooling, stirring, and separate solid, be dried, obtain final product Tandospirone Citrate monohydrate.
4. preparation method according to claim 3 is it is characterised in that Tandospirone Citrate with the mass volume ratio of water is
1:3～15g/mL；Further, Tandospirone Citrate and the mass volume ratio of water are 1:5～10g/mL；Further,
Tandospirone Citrate is 1 with the mass volume ratio of water:7、1:7.5 or 1:9g/mL.
5. the preparation method according to claim 3 or 4 is it is characterised in that the temperature of heating for dissolving is 50 DEG C～100 DEG C；
The temperature of cooling condition is 1 DEG C～10 DEG C；Mixing time is 1 hour～8 hours.
6. the preparation method of monohydrate described in claim 1 or 2 is it is characterised in that comprise the following steps：Take the smooth degree of citric acid
Spiral shell ketone, adds water, forms suspension solution, stirring, separates solid, is dried, obtains final product Tandospirone Citrate monohydrate；
Preferably, Tandospirone Citrate and the mass volume ratio of water are 1:1～18g/mL；Further, citric acid smooth degree spiral shell
Ketone is 1 with the mass volume ratio of water:2～15g/mL；Further, Tandospirone Citrate and the mass volume ratio of water are 1:
4、1:5、1:8 or 1:10g/mL.
7. preparation method according to claim 6 it is characterised in that stirring temperature be 5 DEG C～28 DEG C, the time of stirring
For 5 hours～40 hours.
8. the preparation method according to claim 6 or 7 it is characterised in that：Baking temperature is 15 DEG C～50 DEG C, drying time
For 2 hours～8 hours.
9. the monohydrate described in claim 1 or 2 is taken the photograph in preparation treatment or prevention 5-hydroxy tryptamine or/and norepinephrine again
Take the purposes in the medicine of relevant disease；Preferably, described medicine is 5-hydroxy tryptamine regulator；It is highly preferred that described medicine
For the medicine for the treatment of central nervous system disease and ocular disease, for example, described medicine is treatment anxiety neurosis, depression, god
Through weak, post-traumatic stress disorder, premenstrual dysphoric disorder, ADHD, Panic disorder, autism, self-closing
Disease, insomnia, schizophrenia, increasing rheological properties dysmnesia, senile dementia, obsessive idea and behavior syndrome, obesity, nerves
Bulimia nerovsa or shortage, Tourette syndrome, chronic fatigue syndrome, vasomotion sexflush, cocaine or alcohol addiction, property
Dysfunction, borderline personality disorder, Raynaud syndrome, urinary incontinence, pain, Parkinson's disease, epilepsy, glaucoma, diabetes
The medicine of property retinopathy, age-related macular degeneration or retinal edema.
10. a kind of pharmaceutical composition is it is characterised in that comprise monohydrate described in claim 1 or 2 as active component, also
Including the adjuvant pharmaceutically commonly used or complementary composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510461017 | 2015-07-30 | ||
| CN2015104610171 | 2015-07-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106397410A true CN106397410A (en) | 2017-02-15 |
| CN106397410B CN106397410B (en) | 2021-03-26 |
Family
ID=58004223
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610597515.3A Active CN106397410B (en) | 2015-07-30 | 2016-07-27 | 5-hydroxytryptamine receptor agonist and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106397410B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005132799A (en) * | 2003-10-31 | 2005-05-26 | Mochida Pharmaceut Co Ltd | Agent for prevention/treatment of essential tremor |
| 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 | Method for preparing tandospirone and analogues of tandospirone |
| CN102276447A (en) * | 2011-06-03 | 2011-12-14 | 海南锦瑞制药股份有限公司 | Naproxen hydrate crystal, preparation method thereof and medicinal composition containing naproxen hydrate crystal and sumatriptan |
| 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 |
| 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 |
-
2016
- 2016-07-27 CN CN201610597515.3A patent/CN106397410B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005132799A (en) * | 2003-10-31 | 2005-05-26 | Mochida Pharmaceut Co Ltd | Agent for prevention/treatment of essential tremor |
| 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 |
| 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 | Method for preparing tandospirone and analogues of tandospirone |
| CN102276447A (en) * | 2011-06-03 | 2011-12-14 | 海南锦瑞制药股份有限公司 | Naproxen hydrate crystal, preparation method thereof and medicinal composition containing naproxen hydrate crystal and sumatriptan |
| 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 |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106397410B (en) | 2021-03-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103641818B (en) | A kind of SM-3997 compound and its production and use | |
| CN1320926C (en) | Ginkgo leaf extract composition and its prepn | |
| CN109369747A (en) | Icariside I compound and its derivative, pharmaceutical composition and its preparation method and application | |
| DE102016014603A1 (en) | Synthetic ayahuasca | |
| CN107108603B (en) | Mangiferin -6-O- berberine salt and preparation method thereof and purposes | |
| WO2008145064A1 (en) | The method for a sequoyitol-containing extract obtaining from the genus of trifolium, sobyean and ginkgo biloba and use thereof | |
| CN106278907B (en) | A kind of Syprine Hydrochloride compound | |
| WO2014117700A1 (en) | Protopanoxadiol derivative, preparation method thereof and application thereof | |
| CN105566314A (en) | Tizanidine hydrochloride compound | |
| CN106397412A (en) | 5-hydroxytryptamine receptor agonists, a preparing method thereof and uses of the receptor agonists | |
| CN114644642B (en) | Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition thereof | |
| CN1868520A (en) | Compound Barbados aloe soft-capsule prepn. and its preparing method | |
| CN106397410A (en) | A 5-hydroxytryptamine receptor agonist, a preparing method thereof and uses of the receptor agonist | |
| CN103641817B (en) | Tandospirone citrate, preparation method and applications | |
| CN106397411A (en) | A 5-hydroxytryptamine receptor agonist, a preparing method thereof and uses of the receptor agonist | |
| CN106397413A (en) | A 5-hydroxytryptamine receptor agonist, a preparing method thereof and uses of the receptor agonist | |
| CN105985327A (en) | Tandospirone citrate compound | |
| CN104829467A (en) | Ambroxol hydrochloride dihydrate compound | |
| CN104098575B (en) | Brilliant type of a kind of Epinastine Hydrochloride and its production and use | |
| CN1850132A (en) | Herba thesii granules and preparing method therefor | |
| CN108997468A (en) | Dandelion alkane type triterpenoid and its preparation method and application | |
| CN113603711B (en) | Bisindole alkaloid compound and preparation method and application thereof | |
| CN106349225A (en) | Tandospirone oxalate compound | |
| US20190194138A1 (en) | 7H- azulene [1,2,3-i,j] isoquinolin-7-one compound, single crystal and use thereof | |
| KR20240045217A (en) | Prenylated chalcone and flavonoid compositions for use in treating cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |