CN106795159A - A kind of crystal form of cyclin dependent kinase inhibitor and preparation method thereof - Google Patents
A kind of crystal form of cyclin dependent kinase inhibitor and preparation method thereof Download PDFInfo
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- CN106795159A CN106795159A CN201680001861.9A CN201680001861A CN106795159A CN 106795159 A CN106795159 A CN 106795159A CN 201680001861 A CN201680001861 A CN 201680001861A CN 106795159 A CN106795159 A CN 106795159A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
Crystal form of a kind of cyclin dependent kinase (CDK4＆6) inhibitor and preparation method thereof is provided.Specifically; 6 acetyl group, 8 cyclopenta 5 methyl 2 ((5 (base of piperidines 4) base of pyridine 2) amino) pyrido [2 is provided; 3 d] pyrimidine 7 (8H) ketone (formula (I) compound) II types crystallization and preparation method thereof; the crystallization has X ray powder diffractions as shown in Figure 1; it possesses good chemical stability and stability of crystal form; and using low toxicity, the recrystallisation solvent of low-residual, clinical treatment can be preferably applied to.
Description
The present invention relates to 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- bases) amino) pyrido [2,3-d] pyrimidine -7 (8H) -one and its II crystal formations.Formula (I) compound that the method according to the invention is prepared can be used for the treatment of breast cancer.
Breast cancer is one of most common malignant tumour of women, high with the incidence of disease, has much invasion, but course advancement is slow, and Chinese population association 2010 year 2 month issues in Beijing on the 1st《Chinese mammary gland disease survey report》Report display, the death rate of China's urban area breast cancer increases 38.91%, breast cancer, which has become, threatens WomanHealth maximum disease, at present at least 156 kinds of breast cancer medicines for grinding and listing, wherein 68% is target therapeutic agent, and numerous studies find that tumour is unusual related to the cell cycle, and the mass mutation of mitogenic signals albumen and antimitotic signal protein defect cause Proliferative Disorders in tumour cell；Simultaneously all there is genomic instability (GIN) and genome unstability (CIN) in most of tumour, and these three basic cell cycle defects are all directly or indirectly caused by the out of control of CDKs.Cyclin dependent kinase (CDK, Cyclin Dependent Kinase) inhibitor is increasingly becoming popular target.
The a generation two generations CDK inhibitor developed at present is a lot, two generation medicines of greatest concern include the CDK4＆6 inhibitor PD-0332991 of Pfizer companies and Onyx companies joint development, its activity by suppressing CDK4＆6, suppress Rb phosphorylation, E2F-Rb compounds is detained in endochylema, block the startup of cell cycle.Clinical test results (NCT00721409) are shown, progresson free survival phase (the Progression-free survival of the patient of Letrozole single therapy, PFS) it is 7.5 months, and the patient of Letrozole and the treatment of PD-0332991 drug combinations then extends to 26.1 months its progresson free survival phase, FDA thinks that this is probably a kind of breakthrough cancer therapy drug after the term results of this medicine have been audited at the beginning of this significant advantage obtains extensive concern, 2013.
WO2014183520 discloses the CDK4＆6 inhibitor similar to PD-0332991 structures, inhibitory activity and high selectivity with significant CDK4＆6, including following compound：
But WO2014183520 does not further investigate the crystal form of the compound.It is as well known to those skilled in the art, the crystalline structure of medicinal active component often has influence on the chemical stability of the medicine, the difference of crystallization condition and condition of storage is likely to result in the change of the crystalline structure of compound, sometimes can also be along with the crystal formation for producing other forms.In general, unformed drug products do not have well-regulated crystalline structure, often with other defects, such as product stability is poor, and crystallization is thinner, and it is more difficult to filter, easily caking, poor fluidity etc..Therefore, it is necessary to improve each side's surface properties of above-claimed cpd, it would be desirable to which it is higher and possess the novel crystal forms of good chemical stability that crystal form purity is found in further investigation.
The content of the invention
The invention provides the new crystal form of 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- bases) amino) pyrido [2,3-d] pyrimidine -7 (8H) -one (as shown in formula (I)).
The series of crystallization product that compound shown in formula (I) is obtained under different crystallization conditions, X- diffraction and DSC detections have been carried out to gained crystallized product, it was found that compound shown in formula (I) is under conventional crystallization condition, a kind of crystal formation having good stability can be obtained, we are called the crystallization of II types.The DSC collection of illustrative plates of II types crystallization in the application, which is shown in 294.42 DEG C, nearby has melting endothermic peak, X-ray powder diffraction collection is as shown in Figure 1, radiated using Cu-Ka, the X-ray powder diffraction collection represented with 2 θ angles and interplanar distance (d values), wherein in 5.84 (15.12), 6.16 (14.35), 10.75 (8.22), 12.56 (7.04), 12.96 (6.82), 16.25 (5.45), 17.24 (5.14), 18.97 (4.67), 20.22 (4.39), 21.74 (4.08), 22.99 (3.87), there is characteristic peak with 25.85 (3.44).
Present invention also offers prepare 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- bases) amino) pyrido [2; 3-d] pyrimidine -7 (8H) -one the crystallization of II types method, methods described comprises the steps：
1) compound shown in any crystal formation or unformed formula (I) is added in appropriate solvent, add acid, add alkali after dissolved clarification, crystallization, the solvent is selected from the mixed solvent with water of any one or they that carbon number is less than or equal to 3 alcohols, ketone, nitrile；
2) filtering for crystallizing and wash, dry.
The acid is inorganic acid, preferably hydrochloric acid in preferred embodiments；The alkali is inorganic base, preferably sodium hydroxide or potassium hydroxide.
Step 1 in preferred embodiments) described in solvent be methanol, ethanol, isopropanol, acetone, acetonitrile or methanol/water, ethanol/water, acetone/water, acetonitrile/water, isopropanol/water；Preferred alcohol.
The method of recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, can with compound shown in raw material formula (I) after organic solvent heating for dissolving slowly cooling crystallization, after the completion of crystallization, through filtration drying, you can obtain required crystallization.Specifically, the crystalline solid of institute's leaching generally under reduced pressure, is dried in vacuo under 30~100 DEG C or so, preferably 40~60 DEG C of heating condition, and the effect of recrystallization solvent is removed with regard to that can reach.
Determined by differential scanning calorimeter (DSC), X- diffracting spectrums, crystal formation research has been carried out to compound crystalline solid shown in obtained formula (I), while the dissolvent residual crystallized to gained is detected.
The crystallization of compound II types is not contained or the only residual solvent containing lower content shown in formula (I) prepared by the method according to the present invention, meet the limitation requirement about medical product residual solvent as defined in NF, thus the crystallization of the present invention can use preferably as medicating active ingredients.
Research has shown that, the II types crystallization of compound shown in formula (I) prepared by the present invention has good stability under conditions of illumination, high temperature, high humidity, and grinding, pressure and it is heated etc. under the conditions of, stability of crystal form is good, it disclosure satisfy that the medicinal requirements of production and transport storage, stable processing technique repeats controllable, can adapt in industrialized production.
The X-ray powder diffraction collection of the crystallization of compound II types shown in Fig. 1 formulas (I).
The DSC collection of illustrative plates of the crystallization of compound II types shown in Fig. 2 formulas (I).
The present invention is explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate technical scheme, and non-limiting the spirit and scope of the invention.
Experiment tester used
1st, DSC is composed
INSTRUMENT MODEL：MettlerToledo DSC 1Staree System
Purge gass：Nitrogen
Heating rate：10.0℃/min
Temperature range：40-350℃
2nd, x-ray diffraction pattern
INSTRUMENT MODEL：Bruker D8Focus X-ray powder diffraction instrument
Ray：Monochromatic Cu-K alpha rays (λ=1.5406)
Scan mode：The θ of θ/2, scanning range：2-40°
Voltage：40KV, electric current：40mA
Embodiment 1
Take (1.0g, 2.24mmol) compound shown in formula (I) (prepared by the method provided by WO2014183520) is added in 250ml conical flasks, 40ml ethanol is added, is stirred at room temperature, watery hydrochloric acid (219mg is then instilled, 6.01mmol) (it is dissolved in 4ml water), 60 DEG C are heated to, dissolved clarification instills sodium hydroxide solution (576mg, in 14.40mmol) (being dissolved in 40ml water), it is cooled to and is stirred overnight at room temperature.Dry solid 0.88g, yield is 88.0%.The X-ray diffraction spectrogram of the crystallized sample is shown in Fig. 1.The crystallization is in about 5.84 (15.12), 6.16 (14.35), 10.75 (8.22), 12.56 (7.04), 12.96 (6.82), 16.25 (5.45), 17.24 (5.14), 18.97 (4.67), 20.22 (4.39), there is characteristic peak 21.74 (4.08), 22.99 (3.87), and 25.85 (3.44).DSC spectrograms are shown in Fig. 2, have sharp 294.42 DEG C of endothermic peak of melting, this crystal formation is defined as into II crystal formations.
Embodiment 2
Take (1.0g, 2.24mmol) compound (being prepared by embodiment 1) shown in formula (I) is added in 250ml conical flasks, add 40ml methanol, stir at room temperature, then watery hydrochloric acid (219mg, 6.01mmol) (being dissolved in 4ml water) is instilled, 60 DEG C are heated to, dissolved clarification, instills hydrogen-oxygen
Change in sodium solution (576g, 14.40mmol) (being dissolved in 40ml water), be cooled to and be stirred overnight at room temperature.Dry solid 0.86g, yield is 86.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is II crystal formations to determine product.
Embodiment 3
Take (1.0g, 2.24mmol) compound (being prepared by embodiment 1) shown in formula (I) is added in 250ml conical flasks, 40ml isopropanols are added, are stirred at room temperature, watery hydrochloric acid (219mg is then instilled, 6.01mmol) (it is dissolved in 4ml water), 60 DEG C are heated to, dissolved clarification instills sodium hydroxide solution (576mg, in 14.40mmol) (being dissolved in 40ml water), it is cooled to and is stirred overnight at room temperature.Dry solid 0.90g, yield is 90.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is II crystal formations to determine product.
Embodiment 4
Take (1.0g, 2.24mmol) compound (being prepared by embodiment 1) shown in formula (I) is added in 250ml conical flasks, 40ml acetone is added, is stirred at room temperature, watery hydrochloric acid (219mg is then instilled, 6.01mmol) (it is dissolved in 4ml water), 60 DEG C are heated to, dissolved clarification instills sodium hydroxide solution (576mg, in 14.40mmol) (being dissolved in 40ml water), it is cooled to and is stirred overnight at room temperature.Dry solid 0.86g, yield is 86.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is II crystal formations to determine product.
Embodiment 5
Take (1.0g, 2.24mmol) compound (being prepared by embodiment 1) shown in formula (I) is added in 250ml conical flasks, 40ml acetonitriles are added, are stirred at room temperature, watery hydrochloric acid (219mg is then instilled, 6.01mmol) (it is dissolved in 4ml water), 60 DEG C are heated to, dissolved clarification instills sodium hydroxide solution (576mg, in 14.40mmol) (being dissolved in 40ml water), it is cooled to and is stirred overnight at room temperature.Dry solid 0.60g, yield is 60.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is II crystal formations to determine product.
Embodiment 6
Take (1.0g, 2.24mmol) compound (being prepared by embodiment 1) shown in formula (I) is added in 250ml conical flasks, 40ml tetrahydrofurans are added, are stirred at room temperature, watery hydrochloric acid (219mg is then instilled, 6.01mmol) (it is dissolved in 4ml water), 60 DEG C are heated to, dissolved clarification instills sodium hydroxide solution (576mg, in 14.40mmol) (being dissolved in 40ml water), it is cooled to and is stirred overnight at room temperature.Dry solid 0.76g, yield is 76.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is II crystal formations to determine product.
Embodiment 7
By the II type crystallized products sample of the gained of embodiment 1, opening divides placement respectively, investigates at illumination (4500Lux), heats (40 DEG C, 60 DEG C), the stability of sample under the conditions of high humidity (RH75%, RH90%).It is 5 days and 10 days to investigate sample time, and HPLC detections purity is shown in Table 1.
The stability of compound II crystal form samples compares shown in table 1, formula (I)
Study on the stability result shows compound II types crystallized sample shown in formula (I) under conditions of opening is placed, through having good stability under illumination, high temperature and super-humid conditions.
Embodiment 8
The crystallization of compound II types shown in formula (I) it will be ground, heat and compressing tablet process as made from the method for embodiment 1, result of study shows stable crystal form, and detailed experimental data is referring to table 2 below.
The special stability study of compound II crystal formations shown in the formula of table 2. (I)
Claims (7)
- The II types crystallization of compound as shown in formula (I), it is characterised in that：Radiated using Cu-Ka, obtain the X-ray powder diffraction collection represented with 2 θ angles and interplanar distance, the crystallization has X-ray powder diffraction collection as shown in Figure 1, wherein in about 5.84 (15.12), 6.16 (14.35), 10.75 (8.22), 12.56 (7.04), 12.96 (6.82), 16.25 (5.45), 17.24 (5.14), 18.97 (4.67), 20.22 (4.39), 21.74 (4.08), there is characteristic peak 22.99 (3.87), and 25.85 (3.44)
- The method that one kind prepares the II types crystallization of the compound according to claim 1 as shown in formula (I), methods described comprises the steps：1) compound shown in any crystal formation or unformed formula (I) is added in appropriate solvent, add acid, add alkali after dissolved clarification, crystallization, the solvent is selected from the mixed solvent with water of any one or they that carbon number is less than or equal to 3 alcohols, ketone, nitrile；2) filtering for crystallizing and wash, dry.
- Preparation method according to claim 2, wherein the acid is inorganic acid, preferably hydrochloric acid.
- Preparation method according to claim 2, wherein the alkali is inorganic base, preferably sodium hydroxide or potassium hydroxide.
- Method according to claim 2, it is characterised in that step 1) described in solvent be methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran；Or methanol/water, ethanol/water, acetone/water, acetonitrile/water, isopropanol/water, tetrahydrofuran/water；Preferred alcohol.
- A kind of pharmaceutical composition, it contains the chemical combination as shown in formula (I) described in claim 1 The II types crystallization of thing and pharmaceutically acceptable carrier.
- Purposes of the pharmaceutical composition in the medicine for preparing the treatment disease relevant with cyclin dependent kinase (CDK4＆6) as described in the II types crystallization of the compound according to claim 1 shown in formula (I) or claim 6；The preferred breast cancer of disease.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2015101958794 | 2015-04-22 | ||
| CN201510195879 | 2015-04-22 | ||
| PCT/CN2016/079055 WO2016169422A1 (en) | 2015-04-22 | 2016-04-12 | Crystal form of a cyclin-dependent kinase inhibitor and the preparation method thereof |
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| CN106795159A true CN106795159A (en) | 2017-05-31 |
| CN106795159B CN106795159B (en) | 2018-12-28 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111902405A (en) * | 2018-01-29 | 2020-11-06 | 轩竹生物科技有限公司 | Crystalline forms of a targeted CDK4/6 kinase inhibitor |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105130986B (en) * | 2015-09-30 | 2017-07-18 | 广州科擎新药开发有限公司 | Pyrimidine or pyridopyridine ketone compounds and its application |
| CN107405350A (en) * | 2016-02-04 | 2017-11-28 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition containing pyridopyrimidines derivatives or its officinal salt |
| CN110092775B (en) * | 2018-01-29 | 2021-09-10 | 轩竹生物科技有限公司 | Crystalline forms of a targeted CDK4/6 kinase inhibitor |
| CN113993505B (en) * | 2019-06-20 | 2023-12-12 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014183520A1 (en) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | Thiophene miazines derivate, preparation method therefor, and medical application thereof |
| CN105130986A (en) * | 2015-09-30 | 2015-12-09 | 广州科擎新药开发有限公司 | Pyrimidine or pyridino-pyridone compound and application thereof |
| CN105622638A (en) * | 2014-10-29 | 2016-06-01 | 广州康盛贝特医药技术有限公司 | Pyrimido or pyridopyridone compound and its preparation method and use |
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| KR20060111716A (en) * | 2002-01-22 | 2006-10-27 | 워너-램버트 캄파니 엘엘씨 | 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
| EA024026B1 (en) * | 2010-11-25 | 2016-08-31 | Рациофарм Гмбх | Novel salts and polymorphic forms of afatinib |
| CN102863365B (en) * | 2011-07-07 | 2014-04-16 | 广州白云山制药股份有限公司广州白云山制药总厂 | Crystalline pharmaceutical compound and preparation method and usage thereof |
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- 2016-04-12 CN CN201680001861.9A patent/CN106795159B/en active Active
- 2016-04-12 WO PCT/CN2016/079055 patent/WO2016169422A1/en active Application Filing
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014183520A1 (en) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | Thiophene miazines derivate, preparation method therefor, and medical application thereof |
| CN105622638A (en) * | 2014-10-29 | 2016-06-01 | 广州康盛贝特医药技术有限公司 | Pyrimido or pyridopyridone compound and its preparation method and use |
| CN105130986A (en) * | 2015-09-30 | 2015-12-09 | 广州科擎新药开发有限公司 | Pyrimidine or pyridino-pyridone compound and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111902405A (en) * | 2018-01-29 | 2020-11-06 | 轩竹生物科技有限公司 | Crystalline forms of a targeted CDK4/6 kinase inhibitor |
| CN111902405B (en) * | 2018-01-29 | 2021-09-10 | 轩竹生物科技有限公司 | Crystalline forms of a targeted CDK4/6 kinase inhibitor |
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| Publication number | Publication date |
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| WO2016169422A1 (en) | 2016-10-27 |
| TWI745289B (en) | 2021-11-11 |
| CN106795159B (en) | 2018-12-28 |
| TW201638090A (en) | 2016-11-01 |
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