CN104447611A - Acotiamide compound - Google Patents
Acotiamide compound Download PDFInfo
- Publication number
- CN104447611A CN104447611A CN201310419631.2A CN201310419631A CN104447611A CN 104447611 A CN104447611 A CN 104447611A CN 201310419631 A CN201310419631 A CN 201310419631A CN 104447611 A CN104447611 A CN 104447611A
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- China
- Prior art keywords
- examining
- amine hydrochlorate
- trihydrate
- crystal formation
- amine
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- 0 CCCNC(C1=CSC(NC(c(c(O)c2)cc(OC)c2OC)=O)N1)=* Chemical compound CCCNC(C1=CSC(NC(c(c(O)c2)cc(OC)c2OC)=O)N1)=* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine and relates to an Acotiamide hydrochloride hydrate crystal form and a preparation method thereof. The Acotiamide hydrochloride contains trihydrate and has the advantages of chemical purity of 99.9%, the largest impurity content less than 0.1%, optical purity of 99.95%ee and good stability. The invention also relates to a use of the Acotiamide hydrochloride hydrate composition in preparation of drugs for treating stomach reception disorder.
Description
Technical field
The invention belongs to medical art, be specifically related to Ah examining for amine hydrate and preparation method thereof, the invention still further relates to the application in the medicine of the composition manufacture treatment stomach accommodation disorder using this compound.
Background technology
Digestive tract power is that neuro-muscular that is very complicated, hight coordinate is movable, mainly control with esodic nerve by spreading out of of enteric nervous system, the motion of its pushability is subject to the factors such as nerve, body fluid and regulates, comprise the neurohumors such as vagusstoff, Dopamine HCL, serotonin, motilin, act on the wriggling that one just can increase stomach and intestine.Can cause multiple symptom of digestive tract by gastrointestinal motility disorders, typical performance is stomach, oesophagus or Duodenal reflux, pyrosis, gastritis, esophagitis, functional dyspepsia, constipation, diabetic gastroparesis, postsurgical gastroparesis, idiopathic gastroparesis, anorexia nervosa and irritable bowel syndrome etc.Be clinical common one group based on the syndrome of the multiple symptom of upper digestive tract, account for the 20%-40% of digestive system, the gastric motility exception that its possible pathophysiological mechanism is relevant with delayed gastric emptying, and (or) stomach-uodenal movement is abnormal relevant.
Short gastrointestinal prokinetic agent (Prokinetics) is by increasing gastrointestinal propulsive effect motion, strengthen gastrointestinal tract contraction, promote and stimulating gastrointestinal emptying, reduce the bacterium residence time, reduce the chance that ulcer wound surface infects, alleviate the stimulation of food to stomach hole portion G cell and parietal cell, the secretion of gastric acid inhibitory, improves the symptoms such as functional dyspepsia simultaneously.Its clinical application has made gastric motility dysfunction patient obtain comparatively reasonably treating.
Conventional short gastrointestinal prokinetic agent is divided on pharmacological mechanism and target site: (1) Dopamine Receptors: block maincenter and periphery Dopamine Receptors, or act on oblongata urge vomiting chemical co-ordination district, but cause nervus centralis side effect through hemato encephalic barrier, occur extrapyramidal symptoms.As metoclopramide, domperidone, itopride and clebopride.(2) serotonin 4 acceptor: serotonin 4 acceptor of the exciting gi tract cholinergic relay cell of selectivity and myenteric nerve plexus, stimulate vagusstoff release, thus enhancing gastrointestinal motility, but to small intestine and colon substantially without effect, and do not affect gastric acid secretion.Represent medicine and have mosapride.But the constipation of these medicines to the irritable bowel syndrome being attended by colonic motor dysfunction is invalid, and do not substantially improve by strengthening stomach emptying ingest later early stage satiety and sensation of fullness, and Ah examining can improve colonic motion dysfunctions disease for amine, and at the bottom of diastole stomach, there is good effect, or have effect to alleviating stomach accommodation obstacle, for early stage satiety and sensation of fullness, there is significant improvement result, and there is higher security.
Ah examining is the medicine that the suppression vagusstoff developed jointly by Zeria and Astellas company is degraded for amine sheet, and on March 25th, 2013 goes on the market in Japan, trade(brand)name: Acofide
?, approval listing specification is 100mg.Ah examining is used for the treatment of for amine sheet the functional dyspepsia that Nonorganic lesion causes.
Ah examining for amine hydrochlorate, molecular formula: C
21h
30n
4o
5sHCl, structural formula is as follows:
Ah examining is for amine hydrochlorate structural formula
Chemical name: N-[2-(two isopropylamino) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-4-thiazole carboxamides hydrochloride
Disclose the method for synthesis Ah examining for amine hydrochlorate in patent WO1996036619, but this patent only discloses its synthetic method, characterizes for the crystalline texture of amine hydrochlorate Ah examining, therefore this area needs Ah examining for amine hydrochlorate hydrate crystal forms.
Ah the examining that the present invention obtains on the basis of great many of experiments for amine hydrochlorate hydrate crystal forms, the advantage had: purity is high, maximum contaminant is less than 1 ‰; Optical purity is high, good stability, especially to wet good stability.
Summary of the invention
One object of the present invention, discloses a kind of Ah examining for amine hydrochlorate trihydrate.
Another object of the present invention, discloses the preparation method of Ah examining for amine hydrochlorate trihydrate.
Another object of the present invention, discloses and comprises the pharmaceutical composition of Ah examining for amine hydrochlorate trihydrate.
The invention also discloses Ah examining for the application of amine hydrochlorate trihydrate in the medicine manufacturing treatment stomach accommodation disorder illness.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of Ah examining for amine hydrochlorate trihydrate crystal formation (shown in formula I)
（I）
Karl_Fischer method (Karl Fischer method) a kind ofly measures in all kinds of chemical processes of moisture in material, and, method the most accurately the most single-minded to water, has been listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.Through 6 batches of mensuration, the moisture that described invention compound contains is between 8.89%-9.04% (weight percent).Ah examining is 8.97% for the theoretical content of water in amine hydrochlorate trihydrate, can assert that invention compound contains three crystal water.
This Ah examining, for amine hydrochlorate trihydrate crystalline form I, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value as follows,
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
When infrared spectrogram measures, the correction polystyrene film of instrument, meets the regulation of Chinese Pharmacopoeia.
This crystal formation infrared spectrogram (KBr pressed disc method mensuration), at 3550 ± 5cm
-1, 3237 ± 5cm
-1, 1537 ± 5cm
-1with 1078 ± 5cm
-1there is characteristic peak at place.
The fusing point of this crystal formation is 225 DEG C-225.5 DEG C, and measure by the method for Chinese Pharmacopoeia, this is that those skilled in the art are in common knowledge.
Another object of the present invention, discloses the preparation method of Ah examining for amine hydrochlorate trihydrate crystal formation,
Specifically comprise the following steps:
By Ah examining being added in 4-5 times of (weigh-volume ratio) water for amine hydrochlorate, in the above-mentioned aqueous solution, add the dimethyl formamide (DMF) of Ah examining for amine hydrochlorate 0.5%-1%, stir 30 minutes, filter, filtrate is cooled to 10 DEG C-15 DEG C, for subsequent use.
Ah examining is cooled to 10 DEG C-15 DEG C for the mixed solution of amine hydrochlorate 18-20 times of methyl ethyl ketone-ethanol=5-6:5-4, adds above-mentioned stock solution, insulation 16-20 hour, crystallization, filter, drying obtains crystal habit hydrate.Chemical purity is up to 99.9%, and maximum contaminant is less than 1 ‰, and optical purity is up to more than 99.95%ee.
In above-mentioned preparation method, Ah examining for amine hydrochlorate 0.5%-1% dimethyl formamide (DMF) add the formation contributing to hydrate, the amount of mixed solution of methyl ethyl ketone-ethanol=5-6:5-4 and the amount of crystal water about: the mixed solution using 13-15 times of methyl ethyl ketone-ethanol=5-6:5-4, easily generates monohydrate; Use the mixed solution of 11-13 times of methyl ethyl ketone-ethanol=5-6:5-4, easily generate dihydrate.
Above-mentioned dihydrate, monohydrate easily dry out when placement, drying, and poor stability, can not ensure the quality of pharmaceutical preparation.
At 40 DEG C, under relative humidity (RH) (75%) condition, Ah examining is for the mensuration of moisture in amine hydrochlorate dihydrate, monohydrate crystal:
Ah examining used is for amine hydrochlorate, and the method synthesis that reference WO1996036619 provides, Ah the examining of synthesis is for amine hydrochlorate, and its chemical structure, through determination of elemental analysis, proves that chemical structure is correct.
Another object of the present invention, provides and comprises Ah examining that Ah examining form for amine hydrochlorate trihydrate crystal formation and one or more the pharmaceutically acceptable carriers composition for amine hydrochlorate trihydrate.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of tablet.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is the 1%-30%(weight of composition).
Present invention also offers Ah examining for the application of amine hydrochlorate trihydrate crystal formation in the medicine manufacturing treatment stomach accommodation disorder.
By abdominal cavity to male SD rat trial drug, administration collected ight soil after 60 minutes, and took dry weight.Experimental result shows: crystal formation of the present invention and A Kao show significant stool weight really for amine hydrochlorate unformed powder group to be increased, and the state of these ight soil is all normal, the no significant difference (P>0.05) between two medication groups.
Stability test
The stability of contriver to crystal formation of the present invention is studied, and investigation condition is high temperature (60 DEG C ± 2 DEG C), strong illumination (5000Lx ± 500lx), and high humidity (92.5% ± 5%) inspection target is outward appearance, content and related substance.
Result: from 0-15 days under high light, high temperature, super-humid conditions, outward appearance, related substance, content do not change, and illustrate that chemical stability is good, are applicable to manufacture and the standing storage of pharmaceutical preparation.
Embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Ah examining used in the present invention is for amine hydrochlorate, the method synthesis that reference WO1996036619 provides, Ah the examining of synthesis is for amine hydrochlorate, purity 97.9% (HPLC normalization method), optical purity 99.1%ee, its chemical structure, through determination of elemental analysis, proves that chemical structure is correct.
Results of elemental analyses:
Measured value (calculated value), C:51.66 (51.76), H:6.37 (6.39), N:11.56 (11.52),
S：6.60(6.58)，Cl：7.32(7.30) ；
Prove that chemical structure is correct.
Embodiment 1
In the 500ml reaction flask that stirring, thermometer, condenser are housed, add 60 Ke Akao for amine hydrochlorate and 300 ml waters, add 0.5 gram of dimethyl formamide (DMF), stir 30 minutes in the above-mentioned aqueous solution, filter, filtrate is cooled to 13 DEG C, for subsequent use.
The mixed solution of 1150ml methyl ethyl ketone-ethanol=5:5 is cooled to 13 DEG C, adds above-mentioned stock solution under stirring, be incubated 18 hours, crystallization, filter, drying obtains white crystals 54.3 grams.Measure 3 times through Karl_Fischer method, get average, the moisture containing 8.93% (weight percent).Purity 99.9% (HPLC normalization method), optical purity 99.96%ee (chirality HPLC).
Results of elemental analyses:
Measured value (calculated value), C:47.15 (47.10), H:6.94 (6.92), N:10.45 (10.47),
S：5.95(5.98)，Cl：6.60(6.64)
X-ray powder diffraction charateristic avsorption band (2 θ) and D value as follows.
This crystal formation infrared spectrogram (KBr pressed disc method mensuration), at 3550 ± 5cm
-1, 3237 ± 5cm
-1, 1537 ± 5cm
-1with 1078 ± 5cm
-1there is characteristic peak at place.
INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffractometer; CuKa 40Kv 100mA; 2 θ sweep limits: 0-50
°;
Embodiment 2
Containing the tablet of Ah examining for amine hydrochlorate trihydrate
Prescription: Ah examining for amine hydrochlorate trihydrate 20 grams, lactose 100 grams, W-Gum 36 grams, crystalline cellulose 30 grams, carboxy-propyl cellulose 10 grams, Magnesium Stearate 4 grams.
The above-described composition of Homogeneous phase mixing, to make the tablet of 100 millis gram/piece by mixture through the hole of 9.1 millimeters with singles hole pelleter.
Claims (6)
1. Ah examining shown in formula 1 is for amine hydrochlorate trihydrate,
（1）
Measure with Karl_Fischer method, the crystal formation of described trihydrate contains the moisture of 8.89%-9.04% (weight percent);
Described Ah examining is for the crystal formation of amine hydrochlorate trihydrate, and in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle and d value,
The error of 2 θ diffraction angle is ± 0.2.
2. Ah examining described in claim 1 is for amine hydrochlorate trihydrate crystal formation, infrared spectrogram, and pellet technique measures, and has characteristic peak at 3550 ± 5cm-1,3237 ± 5 cm-1,1537 ± 5 cm-1 and 1078 ± 5cm-1 place.
3. Ah examining described in claim 1 is for the preparation method of amine hydrochlorate trihydrate crystal formation, by Ah examining is added in 4-5 times of (weigh-volume ratio) water for amine hydrochlorate, the dimethyl formamide (DMF) of Ah examining for amine hydrochlorate 0.5%-1% is added in the above-mentioned aqueous solution, stir 30 minutes, filter, filtrate is cooled to 10 DEG C-15 DEG C, for subsequent use, then, Ah examining is cooled to 10 DEG C-15 DEG C for the mixed solution of amine hydrochlorate 18-20 times of methyl ethyl ketone-ethanol=5-6:5-4, add above-mentioned stock solution, insulation 16-20 hour, crystallization, filter, drying obtains crystal habit hydrate.
4. Ah the examining formed for amine hydrochlorate trihydrate crystal formation and one or more pharmaceutically acceptable carriers containing Ah examining described in claim 1 is for the composition of amine hydrochlorate trihydrate.
5. composition according to claim 4, is characterized in that said composition is for the preparation of tablet.
6. Ah examining described in claim 1 is for the application of amine hydrochlorate trihydrate crystal formation in the medicine manufacturing treatment stomach accommodation disorder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310419631.2A CN104447611A (en) | 2013-09-16 | 2013-09-16 | Acotiamide compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310419631.2A CN104447611A (en) | 2013-09-16 | 2013-09-16 | Acotiamide compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104447611A true CN104447611A (en) | 2015-03-25 |
Family
ID=52894437
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310419631.2A Withdrawn CN104447611A (en) | 2013-09-16 | 2013-09-16 | Acotiamide compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104447611A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104003958A (en) * | 2014-05-30 | 2014-08-27 | 杭州新博思生物医药有限公司 | Novel acotiamide hydrochloride hydrate crystal form and preparation method thereof |
| CN105237493A (en) * | 2014-07-07 | 2016-01-13 | 中美华世通生物医药科技（武汉）有限公司 | Crystalline form I of acotiamide hydrochloride hydrate, preparation method therefor and use thereof |
| CN105481791A (en) * | 2015-12-09 | 2016-04-13 | 北京科莱博医药开发有限责任公司 | Acotiamide hydrochloride dihydrate crystal, and preparation method and applications thereof |
| CN107266389A (en) * | 2017-07-11 | 2017-10-20 | 湖南七纬科技有限公司 | It is a kind of to treat medicine times semihydrate of enterogastric diseases and preparation method thereof |
| CN105753810B (en) * | 2016-04-15 | 2018-09-28 | 浙江新赛科药业有限公司 | The refined and preparation method of acotiamide hydrochloride hydrate trihydrate |
-
2013
- 2013-09-16 CN CN201310419631.2A patent/CN104447611A/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104003958A (en) * | 2014-05-30 | 2014-08-27 | 杭州新博思生物医药有限公司 | Novel acotiamide hydrochloride hydrate crystal form and preparation method thereof |
| CN105237493A (en) * | 2014-07-07 | 2016-01-13 | 中美华世通生物医药科技（武汉）有限公司 | Crystalline form I of acotiamide hydrochloride hydrate, preparation method therefor and use thereof |
| CN105481791A (en) * | 2015-12-09 | 2016-04-13 | 北京科莱博医药开发有限责任公司 | Acotiamide hydrochloride dihydrate crystal, and preparation method and applications thereof |
| CN105753810B (en) * | 2016-04-15 | 2018-09-28 | 浙江新赛科药业有限公司 | The refined and preparation method of acotiamide hydrochloride hydrate trihydrate |
| CN107266389A (en) * | 2017-07-11 | 2017-10-20 | 湖南七纬科技有限公司 | It is a kind of to treat medicine times semihydrate of enterogastric diseases and preparation method thereof |
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Legal Events
| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C04 | Withdrawal of patent application after publication (patent law 2001) | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20150325 |