CN104649953A - Saxagliptin sesquihydrate compound - Google Patents
Saxagliptin sesquihydrate compound Download PDFInfo
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- CN104649953A CN104649953A CN201310601775.XA CN201310601775A CN104649953A CN 104649953 A CN104649953 A CN 104649953A CN 201310601775 A CN201310601775 A CN 201310601775A CN 104649953 A CN104649953 A CN 104649953A
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- bms
- semihydrate
- times semihydrate
- diabetes
- saxagliptin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a Saxagliptin sesquihydrate and a preparation method thereof. The Saxagliptin sesquihydrate contains a semi-hydrate. The Saxagliptin sesquihydrate has the following advantages: the purity is high; the stability is good, and moisture absorption and weight gain are also not obvious even under the high-humidity condition; the dipeptidyl peptidase inhibition function of the Saxagliptin sesquihydrate is improved by near 20%. The invention also relates to clinical application of a composition of the compound in treatment of type II diabetes mellitus.
Description
Technical field
The invention belongs to medical art, be specifically related to BMS-477118 times semihydrate and preparation method thereof, the invention still further relates to the application of the composition treatment diabetes B using this hydrate.
Background technology
The metabolic disease group of diabetes to be a kind of with blood sugar increasing be principal character.Main pathophysiological basis is insulin secretion obstacle and (or) the sugar caused by insulin action deficiency, protein, fat metabolic disturbance secondary water and electrolyte metabolism is unbalance.
Diabetes can be divided into amphitypy: I type---insulin-dependent diabetes, are due to islet p-cell destruction, and insulin secretion lacks and causes hyperglycemia; II type---non-insulin-dependent diabetes mellitus (NIDDM), be that β cell function is low, Regular Insulin lacks relatively and insulin action link is unsound and hyperamization sugar level raises.According to IDF's statistics, within 2006, global diabetes (DM) patient numbers is up to 2.46 hundred million, estimates will reach 3.8 hundred million in 2025.Diabetes can make patient's lost of life, and case fatality rate increases.Therefore, the primary prevention carrying out diabetes effectively can improve quality of life and the prolongs life of the elderly.
Type II diabetes is our modal diabetes type at ordinary times, be generally acquired disposition to cause, refer to the diabetes still having to a certain degree insulin secretion, but its degree can from significant insulin resistant with insufficient insulin, to hypoinsulinism with insulin resistant.Along with going deep into diabetes study, diabetes control is turned to from simple hypoglycemic and improves insulin resistant, thus can integrated control Hazard Factor, reduce the incidence of diabetic vascular complications and relative sudden death rate, improve life in patients.Current use has become for the ofhypoglycemic medicine of insulin resistant and protection Pancreatic beta cells function the common recognition controlling type II diabetes New Policy.
Up-to-date data display, the number of the current having diabetes of China is about 9,240 ten thousand, wherein more than 20 years old city, in small towns and rich rural population, diabetes prevalence reaches 11%, in addition in addition 15% people's impaired glucose regulation.Diabetes have become China one big bus hygienic issues, but compatriots are also not high to the degree of awareness of diabetes.Although the pathogenic factor of diabetes also not last research is clear, the Hazard Factor of its morbidity are clear and definite, and wherein some factor can change.
Type II diabetes is invisible due to morbidity, and considerable patient has been made a definite diagnosis diabetes because of developing complications.The most of patients course of disease is longer, multi viscera and the system generation pathologies such as eyes, foot, kidney, heart, neural system, vascular system can be caused, often there is the infringement of the multiple internal organs of whole body in the progress along with the state of an illness, severe patient is then disabled because of diabetic complication and death.Diabetes not only cause suffering to patient, bring white elephant also to family and society.
Type II diabetes (T
2dM) major reason of morbidity and progress is the decline of islet function Progressive symmetric erythrokeratodermia, comprise Regular Insulin that β cell insulin secretion defect and the increase of α cell glucagon secretion cause and hyperglycemic-glycogenolytic factor out of proportion.For many T2DM patients, single medicine oral administration can not maintain glycemic target.The secretin secreted by gastrointestinal tract cell comprises glicentin-1 (GLP-1) and glucose dependency pancreotropic hormone release polypeptide (GIP), islet cell function can be regulated, the suppression that the glicentin strengthening the insulin secretion of glucose stimulation, increase insulin synthesis and strengthen the pancreatic alpha cells of glucose mediation discharges, improves stomach emptying and increase satiety.Because GLP-1 and GIP can by dipeptidyl peptidase (DPP-4) fast degradation, suppress DPP-4 enzyme thus extend endogenous GLP-1 and the GIP continuous action time is valued by the people as the novel targets of drug development.Thus, based on regulate α and β cell function a kind of novel mechanism ofhypoglycemic medicine---DPP-4 inhibitor arises at the historic moment.BMS-477118 (saxagliptin) is namely a kind of DPP-4 inhibitor.
GLP-1 and GIP is two kinds of important secretins, and under the stimulation of food Middle nutrition material, secretion is released into blood, by glucose-dependent fashion insulin secretion accelerating, regulates glycaemic homeostasis.GLP-1 has the characteristic of glucose dependency insulin secretion accelerating, and its promoting insulin secretion occurs when blood sugar concentration raises, and blood sugar concentration is recovered normally then to disappear.Meanwhile, GLP-1 also can promote Beta cell proliferation, suppresses its apoptosis, increases insulin synthesis, improves β cell function.But the active GLP-1 transformation period produced in body is only 1.5 ~ 2 min, and its N-terminal the first two amino acid can be lost insulin secretion accelerating activity by DPP-4 rapid cleavage, makes endogeneous activity GLP-1 cannot reach treatment concentration in vivo.BMS-477118 is a kind of potent, selective d PP-4 inhibitor, specificity can extend suppression to DPP-4 enzyme, thus extend endogenous GLP-1 and GIP continuous action time, reduce blood sugar.
At T
2in DM patient, BMS-477118 suppresses DPP-4 enzymic activity to reach 24 h.At oral glucose or after having meal, the restraining effect of BMS-477118 to DPP-4 enzyme causes the activity level of GLP-1 and GIP to increase by 2 ~ 3 times, and can reduce Glucagon concentrations, and glucose dependency ground increases pancreatic beta cell excreting insulin.
BMS-477118 has great advantage in validity and security, but in actual production process, applicant finds, there is purification difficult, foreign matter content is higher, crystal formation is by patent protection and have the problems such as certain moisture absorption weightening finish in BMS-477118 preparation technology.
The BMS-477118 times hemi-hydrate crystalline that the present inventor obtains on the basis of great many of experiments, the advantage had: purity is high, maximum contaminant is less than 1 ‰; Good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions.
Allow people surprisingly, identical prescription and technique, wait BMS-477118 times semihydrate tablet and the BMS-477118 tablet of dosage (BMS-477118 times semihydrate is converted into BMS-477118), to the promoter action of Regular Insulin, the former exceeds the latter about 10%.
Summary of the invention
One object of the present invention, discloses a kind of BMS-477118 times semihydrate.
Another object of the present invention, discloses the preparation method of BMS-477118 times semihydrate.
Another object of the present invention, discloses the drug regimen comprising BMS-477118 times semihydrate
Thing.
The invention also discloses BMS-477118 times semihydrate and prepare treatment use.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of BMS-477118 times semihydrate (shown in formula I),
(formula I)
Thermogravimetry a kind ofly measures in the chemical process 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 multiple batches of mensuration, the moisture that described invention compound contains is between 8.40%-8.60% (weight percent).In BMS-477118 times semihydrate, the theoretical content of water is 8.50%, can assert that invention compound contains a hypocrystalline water.
Wherein the measurement result of 6 batches is as follows:
This BMS-477118 times hemi-hydrate crystalline, 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), D value and relative intensity are as follows,
| No. | d（?） | 2θ | I/I 0 |
| 1 | 17.5 | 5.1 | 56 |
| 2 | 16.7 | 6.8 | 87 |
| 3 | 15.5 | 7.5 | 16 |
| 4 | 14.3 | 8.6 | 31 |
| 5 | 12.1 | 9.9 | 87 |
| 6 | 10.9 | 11.1 | 99 |
| 7 | 9.8 | 12.5 | 12 |
| 8 | 8.6 | 13.6 | 37 |
| 9 | 6.7 | 14.7 | 56 |
| 10 | 5.4 | 16.2 | 78 |
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 °.
Fusing point test: measure fusing point according to Pharmacopoeia of People's Republic of China (2010 editions, two) annex VI C first method, the fusing point recorded is 176 DEG C-179 DEG C.
Another object of the present invention, discloses the preparation method of BMS-477118 times hemi-hydrate crystalline, by being dissolved at n-hexyl alcohol-furans-heated in water solution by BMS-477118, naturally cools to room temperature, then is incubated for some time and obtains.
Specifically comprise the following steps: that BMS-477118 times semihydrate adds in the mixed solution of 8-10 times of (weight or measurement (WM) ratio) n-hexyl alcohol-furans-water=3.7-4.9:0.3-0.7:5-9, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
A large amount of experiments proves: the adding of tetrahydrofuran (THF), the proportioning of mixed solution, standing temperature and time are most important to obtaining BMS-477118 of the present invention times hemi-hydrate crystalline.
Another object of the present invention, provides the composition comprising the BMS-477118 times semihydrate that BMS-477118 times hemi-hydrate crystalline and one or more pharmaceutically acceptable carriers form.
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 oral preparations.
Allow people surprisingly, identical prescription and technique, wait BMS-477118 times semihydrate tablet and the BMS-477118 tablet of dosage (BMS-477118 times semihydrate is converted into BMS-477118), to the restraining effect of hydrochloric acid in gastric juice, the former exceeds the latter about 10%.
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 1% ~ 30%(weight of composition).
Present invention also offers BMS-477118 times semihydrate and manufacture the application in treatment type ii diabetes medicine.
To the Regular Insulin improvement result of STZ severe diabetes rat
To by giving STZ(75 mg/kg, i.v.) the severe diabetes Oral Administration in Rats carrying out modeling gives the BMS-477118 of 0.1 mg/kg and the BMS-477118 times semihydrate of Isodose, administration 2 weeks altogether, adopt euglycemic insulin clamp method, insulin sensitivity (Regular Insulin injection speed 6 mU/kg/ divides) and Insulin sensitivity (Regular Insulin injection speed 30 mU/kg/ divides) are studied.In insulin sensitivity, more known by with control group, BMS-477118 group and BMS-477118 times semihydrate group all show the obvious reduction of blood sugar, reduce degree reduction by 10% more than BMS-477118 group at the blood sugar of the rat giving BMS-477118 times semihydrate group.
stability test
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in hydrate crystal of the present invention:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), water tariff collection is constant, and explanation has good stability, and is 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.
embodiment 1
In the 10L reactor that stirring, thermometer, condenser are housed, add 350 grams of BMS-477118s and 970.0ml n-hexyl alcohol, 16.5ml tetrahydrofuran (THF), 980.0ml water, starts stirring, is heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, then leaves standstill insulation 4 hours, crystallization, filter, through indoor seasoning, obtain BMS-477118 times semihydrate white crystals 254.6 grams, fusing point is the fusing point recorded is 176 DEG C-179 DEG C, content 99.76%, single contaminant is less than 0.06%.Measure through thermogravimetry, the moisture containing 8.50% (weight percent).
Use standard and conventional technology, make the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics be 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 oral preparations, injection.Only citing is illustrated, and never means that it limits the scope of the invention by any way.
embodiment 2
Tablet containing BMS-477118 times semihydrate
Prescription: BMS-477118 times semihydrate 12.7 grams, Microcrystalline Cellulose 14 g, pregelatinized Starch 18g, carboxymethylstach sodium 5 g, lactose 240 grams, 35 grams of PEG-4000, Magnesium Stearate 6 grams, 30 grams of PVP K30s, croscarmellose sodium 35 grams, distilled water is appropriate, makes 10000.
Technique:
The preparation of label: mixed with auxiliary material by main ingredient by determined prescription, granulate, particle air seasoning below 40 DEG C, with the whole grain of l6 mesh sieve, adds Magnesium Stearate and remaining starch, compressing tablet, to obtain final product.
Sealing coat dressing: added by talcum powder in 5% polyvinylpyrrolidone (PVP) anhydrous alcohol solution, stir, is mixed with the suspension of 20% as sealing coat coating liquid.In fluidized-bed, carry out dressing, its processing condition are as follows: spray pressure 0.3 MPa, feed liquor speed 5mL/min, inlet temperature 37 DEG C, temperature out 31 DEG C, dry air flow 200m
3/ h, sealing coat weightening finish for essence blade heavy 9%.
Enteric layers dressing: No. II resin is dissolved in dehydrated alcohol, clothing liquid concentration is 10% (w/v), its processing condition except spray speed be except 4mL/min, all the other are with sealing coat coating conditions, enteric layers weightening finish for wrap isolate synusia heavy 6%.
Claims (6)
1. times semihydrate of BMS-477118 shown in formula I,
（Ⅰ）
Measure with thermogravimetry, described hydrate contains the moisture of weight percent 8.40%-8.60%;
The crystal of described BMS-477118 times semihydrate, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle, spacing (d value) and relative intensity (I/I
0),
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of times hemi-hydrate crystalline of BMS-477118 described in claim 1, by being dissolved at n-hexyl alcohol-furans-heated in water solution by BMS-477118, naturally cools to room temperature, then is incubated for some time and obtains.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that BMS-477118 times semihydrate adds in the mixed solution of 8-10 times of (weight or measurement (WM) ratio) n-hexyl alcohol-furans-water=3.7-4.9:0.3-0.7:5-9, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
4. one kind forms the composition of BMS-477118 times semihydrate containing BMS-477118 according to claim 1 times hemi-hydrate crystalline and one or more pharmaceutically acceptable carriers.
5. the composition of BMS-477118 according to claim 4 times semihydrate, is characterized in that said composition is for the preparation of oral preparations.
6. the application of times semihydrate of BMS-477118 described in claim 1 in the medicine for the treatment of diabetes B.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310601775.XA CN104649953A (en) | 2013-11-25 | 2013-11-25 | Saxagliptin sesquihydrate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310601775.XA CN104649953A (en) | 2013-11-25 | 2013-11-25 | Saxagliptin sesquihydrate compound |
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| Publication Number | Publication Date |
|---|---|
| CN104649953A true CN104649953A (en) | 2015-05-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310601775.XA Pending CN104649953A (en) | 2013-11-25 | 2013-11-25 | Saxagliptin sesquihydrate compound |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005115982A1 (en) * | 2004-05-25 | 2005-12-08 | Bristol-Myers Squibb Company | Process for producing a dipeptidyl peptidase iv inhibitor |
| CN101687793A (en) * | 2007-04-20 | 2010-03-31 | 百时美施贵宝公司 | Crystalline form of Sha Gelieting and preparation method thereof |
| CN1791401B (en) * | 2002-12-09 | 2012-10-03 | 布里斯托尔-迈尔斯斯奎布公司 | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| CN103140475A (en) * | 2010-05-05 | 2013-06-05 | 亚细亚化学工业有限公司 | Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof |
-
2013
- 2013-11-25 CN CN201310601775.XA patent/CN104649953A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1791401B (en) * | 2002-12-09 | 2012-10-03 | 布里斯托尔-迈尔斯斯奎布公司 | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| WO2005115982A1 (en) * | 2004-05-25 | 2005-12-08 | Bristol-Myers Squibb Company | Process for producing a dipeptidyl peptidase iv inhibitor |
| CN101687793A (en) * | 2007-04-20 | 2010-03-31 | 百时美施贵宝公司 | Crystalline form of Sha Gelieting and preparation method thereof |
| CN103140475A (en) * | 2010-05-05 | 2013-06-05 | 亚细亚化学工业有限公司 | Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| 吕扬，杜冠华.: "《晶型药物》", 31 October 2009 * |
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Application publication date: 20150527 |
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