CN103709150B - Tosi acid Bei Gelieting crystal formations and its production and use - Google Patents
Tosi acid Bei Gelieting crystal formations and its production and use Download PDFInfo
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- CN103709150B CN103709150B CN201210379359.5A CN201210379359A CN103709150B CN 103709150 B CN103709150 B CN 103709150B CN 201210379359 A CN201210379359 A CN 201210379359A CN 103709150 B CN103709150 B CN 103709150B
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- acid bei
- crystal formations
- tosi
- bei gelieting
- diabetes
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- 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
Abstract
Crystal formation the invention discloses a kind of Tosi acid Bei Gelieting and its production and use, its XRD spectrum characteristic peak 2 θ（±0.2°）It is 6.07,8.78,12.04,13.62,13.62,18.75,19.13,20.02 and 24.96.Stability of crystal form provided by the present invention is good.
Description
Technical field
The present invention relates to a kind of Tosi acid Bei Gelieting crystal formations II, its preparation method, its pharmaceutical composition and its pharmaceutical purpose
On the way.
Background technology
When human body lacks insulin or insulin can not effectively play a role or target tissue cell is to insulin sensitivity
Property reduce when, the glucose in blood can not be metabolized by normal mode into intracellular, cause the glucose in blood dense
Degree is abnormal to be increased, so as to trigger diabetes.
In recent years, diabetes are global 4th fatal diseases, are the 3rd lethal factors in China.The current whole world there are about
1.94 hundred million people suffer from diabetes.China there are about 25,000,000 diabetics, if adding potential crowd, by the sum that diabetes are threatened
Reach 40,000,000 people.Expect 2025, diabetes will turn into one of most disease of number of patients in the world, when the time comes world's model
Enclosing will have 3.3 hundred million people to suffer from diabetes, and diabetes mellitus in China patient will reach 50,000,000.At present, the trouble of developed country's diabetes
Sick rate has been up to 5-10%, and the illness rate of China is up to 3.2%, and this numeral is also in constantly rising.
According to pathogenesis, diabetes are broadly divided into I types i.e. IDD（IDDM）It is non-pancreas with II types
Island element dependent diabetes mellitus（NIDDM）Two kinds, in all diabetics for making a definite diagnosis, patient 90-95% suffers from II type glycosurias
Disease, and patient is usually associated with fat, physical activity deficiency（physical inactivity）, older, family's glycosuria
Medical history, glucose metabolism are damaged and have family's diabetic history etc..Research shows that normal person and type ii diabetes patient are to grape
Sugar reaction has very important difference.Normal person belongs to early stage insulin response to the reaction of blood glucose rise after the meal（early
insulin response）.The medicine of conventional treatment diabetes mainly has following a few classes in the market：GLP-1 analogs,
PPAR α/γ dual agonists, Cannabined receptor 1 (CB1) antagonist, DPP-IV inhibitor etc..
DPP-IV is a kind of internal multi-functional Second-Type cell surface glycoprotein, that is, enzyme, and its main effect is
Protein in decomposer.It is wherein, a kind of that GLP-1 (glucagon kind polypeptide-1) is called by the protein that DPP-IV is decomposed,
It is the hormone secreted by intestinal cell, and this hormone can stimulate insulin, glucagon suppression, suppress gastric emptying, makes pancreas
Island cell is lived again.But, as long as GLP-1 one is released in blood, within a few minutes, will be broken off, so can not work as
Used into medicine.Scientist then have developed the medicine for suppressing DPP-IV enzyme, and this kind of medicine can effectively suppress internal
The activity of DPP-IV enzyme, reduces its degraded to GLP-1, so as to improve the content of GLP-1 in blood plasma.
As in the market is to the solid demand of diabetes medicament, global major drugmakers accelerate grinds to such medicine
Study carefully.Up to the present, the DPP-IV inhibitor for having listed has Sitagliptin（MK-0431）And Vildagliptin（LAF-
237）.Sitagliptin（Sitagliptin, MK-0431）Developed by Merck companies, August is listed in Mexico on the 8th within 2006,
In October, 2006 obtains U.S. FDA approval.It is FDA approval listing the first be used for treat type ii diabetes (T2DM)
DPP-IV inhibitor, administering mode is oral.It can be used alone, can also be double with diformazan when effect on driving birds is not good is used alone
Guanidine, sulfonylureas or Thiazolidinediones（thiazolidinedione,TZD）Such as Pioglitazone
Or Rosiglitazone (pioglitazone)（rosiglitazone）Deng combination effectively controlling blood sugar.Recommend agent in most patients
Amount is daily 100mg.HbA1c levels can be reduced 0.6-0.8% by 8.0% during monotherapy experiment；Compared with control group,
Sitagliptin can be by HbA1c levels reduction by 0.7% or so when being combined with melbine, Glipizide or Pioglitazone.
Sitagliptin shows good oral administration biaavailability（87%）And without considering the meal time when taking；Its albumen knot
Conjunction rate（protein binding）It is relatively low（37%）, hepatic metabolism is less.About 12 hours half-life period are removed in Sitagliptin bodies.
The side reaction related to Sitagliptin mainly has nasopharyngitis（nasopharyngitis）, the infection of the upper respiratory tract and headache, clothes
Situation with rear generation gastrointestinal disturbance is actually rare.Vildagliptin (vildagliptin, LAF-237) is opened by Novartis Co., Ltd
Hair, is approved listing in 2007 in Brazil and Mexico.The medicine is a kind of DPP-IV inhibitor of high selectivity, it is oral after meeting
Absorbed rapidly（85%）, without the consideration meal time when taking.Its plasma half-life is different during various dose, 25-200mg
Half-life period about 1.5-4.5 hours during dosage, the medicine about 55% is hydrolyzed in vivo, is not hydrolyzed part and is removed by kidney.Should
Medicine can be used alone, for treating type ii diabetes（T2DM）, it is also possible to it is combined with melbine, insulin etc..
In addition, the force of on January 7th, 2008 field global R ＆ D center has submitted their DPP-IV inhibitor to U.S. FDA
The NDA of medicine alogliptin；The DPP-IV inhibitor medicine Saxagliptin of Mei-Shi Guibao is in 2009 when hundred
July obtains the approval of FDA；Other DPP-IV inhibitor medicines for coming into III phase clinic have Boehringer Ingelheim company
The PHX-1149 of BI-1356 and Phenomix companies.
WO2009094866A1（Its Chinese patent families is CN200810004727.1）Tosi acid Bei Gelieting is disclosed,
Its structure is shown below：
Relative to positive compound LAF-237, not only activity is high for Tosi acid Bei Gelieting, toxicity is relatively low, and stability
Well, its half-life period is also relatively long, therefore with more wide market potential.
Drug crystal forms are studied and the research and development of medicine solid-state have very important meaning in pharmacy industry.Drug molecule generally has not
With solid forms, including salt, polycrystalline, eutectic is amorphous, hydrate and solvate；The not isomorphous of same drug molecule
Type, in crystal structure, stability, the properties such as productibility and bioavilability might have significant difference, so that directly
Influence the curative effect and exploitability of medicine.Therefore, any one drug research and development, is required for carrying out comprehensive and systematic polymorphic sieve
Choosing, finds crystal formation as much as possible, then in-depth study is carried out to these crystal formations using various solid-state approach, so as to find most
It is adapted to the crystal formation of exploitation.
The content of the invention
It is an object of the invention to provide a kind of crystal formation II of Tosi acid Bei Gelieting, its XRD data is as shown in Figure 1.
Preparation method another object of the present invention is to provide above-mentioned Tosi acid Bei Gelieting crystal formations II, including：
1）Tosi acid Bei Gelieting is dissolved with organic solvent；
2）Anti-solvent crystallization is added, and
3）Filter to obtain target crystal formation II.
Wherein, organic solvent is 75% ethanol~98% ethanol, preferably 95% ethanol.
Wherein, anti-solvent is alkane solvents, preferably normal heptane or n-hexane.
Another object of the present invention is to provide a kind of pharmaceutical composition for treating type ii diabetes, it is effective that it contains treatment
The above-mentioned Tosi acid Bei Gelieting crystal formations II of amount are used as active ingredient and pharmaceutically acceptable carrier.
Another object of the present invention is to provide a kind of above-mentioned Tosi acid Bei Gelieting crystal formations II or treatment II type glycosurias
Purposes of the pharmaceutical composition of disease in preparing for treating type ii diabetes medicine.
Brief description of the drawings
Fig. 1 is the XRD spectrum of Tosi acid Bei Gelieting crystal formations II.
Specific embodiment
Embodiment 1
Tosi acid Bei Gelieting 2.0g and 75% ethanol 20.0ml are placed in reaction bulb, after 45 DEG C are completely dissolved, are added dropwise to
Normal heptane, stirring and crystallizing 3 hours, filtering, vacuum drying obtains the 1.0g of target crystal formation II, and its structure is confirmed through accompanying drawing 1.
Embodiment 2
Tosi acid Bei Gelieting 2.0g and 98% ethanol 50.0ml are placed in reaction bulb, after 45 DEG C are completely dissolved, are added dropwise to
Normal heptane, stirring and crystallizing 3 hours, filtering, vacuum drying obtains the 1.6g of target crystal formation II, and its structure is confirmed through accompanying drawing 1.
Embodiment 3
Tosi acid Bei Gelieting 2.0g and 95% ethanol 40.0ml are placed in reaction bulb, after 45 DEG C are completely dissolved, are added dropwise to
Normal heptane, stirring and crystallizing 3 hours, filtering, vacuum drying obtains the 1.5g of target crystal formation II, and its structure is confirmed through accompanying drawing 1.
Embodiment 4
Tosi acid Bei Gelieting 2.0g and 95% ethanol 40.0ml are placed in reaction bulb, after 45 DEG C are completely dissolved, are added dropwise to
N-hexane, stirring and crystallizing 3 hours, filtering, vacuum drying obtains the 1.4g of target crystal formation II, and its structure is confirmed through accompanying drawing 1.Experimental example
1 stability experiment
Conclusion：Crystal formation provided by the present invention II has good stability.
Claims (6)
1. a kind of Tosi acid Bei Gelieting crystal formations II, (± 0.2 °) of its XRD spectrum characteristic peak 2 θ is 6.07,8.78,12.04,
13.62nd, 13.62,18.75,19.13,20.02 and 24.96.
2. Tosi acid Bei Gelieting crystal formations II according to claim 1, its XRD spectrum is as shown in Figure 1.
3. a kind of preparation method of Tosi acid Bei Gelieting crystal formations II according to claim 2, including：
1) Tosi acid Bei Gelieting is dissolved with organic solvent；
2) anti-solvent crystallization is added, and
3) target crystal formation II is filtered to obtain,
Wherein described organic solvent is 75% ethanol~98% ethanol, and the anti-solvent is normal heptane or n-hexane.
4. the preparation method of Tosi acid Bei Gelieting crystal formations II according to claim 3, wherein the organic solvent is
95% ethanol.
5. a kind of pharmaceutical composition for treating type ii diabetes, its support as claimed in claim 1 or 2 for containing therapeutically effective amount
West acid Bei Gelieting crystal formations II are used as active ingredient and pharmaceutically acceptable carrier.
6. a kind of Tosi acid Bei Gelieting crystal formations II according to claim 1 and 2 or according to claim 5 control
Treat purposes of the pharmaceutical composition of type ii diabetes in preparing for treating type ii diabetes medicine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230059A (en) * | 2007-01-23 | 2008-07-30 | 上海恒瑞医药有限公司 | Bicycle aza alkyl derivative, preparation method and use in medicine thereof |
| CN101230058A (en) * | 2007-01-23 | 2008-07-30 | 上海恒瑞医药有限公司 | Bicycle aza alkyl derivative, preparation method and use in medicine thereof |
-
2012
- 2012-10-09 CN CN201210379359.5A patent/CN103709150B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230059A (en) * | 2007-01-23 | 2008-07-30 | 上海恒瑞医药有限公司 | Bicycle aza alkyl derivative, preparation method and use in medicine thereof |
| CN101230058A (en) * | 2007-01-23 | 2008-07-30 | 上海恒瑞医药有限公司 | Bicycle aza alkyl derivative, preparation method and use in medicine thereof |
| CN101914092A (en) * | 2007-01-23 | 2010-12-15 | 上海恒瑞医药有限公司 | Azabicyclo alkane derivative and preparation method and application thereof in medicaments |
Non-Patent Citations (1)
| Title |
|---|
| Acute and chronic administration of SHR117887，a novel and specific dipeptidyl peptidase-4 inhibitor,improves metabolic control in diabetic rodent models;Xiao LIU等;《Acta Pharmacologica Sinica》;20120730;第33卷;全文 * |
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Address after: 222006 Jiangsu province Lianyungang Kaitai Dapu Road Industrial Area Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222006 Jiangsu province Lianyungang Kaitai Dapu Road Industrial Area Applicant before: Jiangsu Hansoh Pharmaceutical Group Lianyungang Hongchuang Medical Co., Ltd. |
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Effective date of registration: 20160311 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222006 Jiangsu province Lianyungang Kaitai Dapu Road Industrial Area Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. |
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