CN105622577A - Novel crystallographic form of ceritinib and preparation method of novel crystallographic form - Google Patents
Novel crystallographic form of ceritinib and preparation method of novel crystallographic form Download PDFInfo
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- CN105622577A CN105622577A CN201410714723.8A CN201410714723A CN105622577A CN 105622577 A CN105622577 A CN 105622577A CN 201410714723 A CN201410714723 A CN 201410714723A CN 105622577 A CN105622577 A CN 105622577A
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Abstract
The invention relates to a novel crystallographic form of ceritinib. An X-ray powder diffraction pattern of the novel crystallographic form of ceritinib is as shown in Figure 1. The invention further relates to a method for preparing the crystallographic form, and application of the crystallographic form to preparation of a medicament for treating anaplastic lymphoma kinase mediated diseases.
Description
Technical field
The present invention relates to organic chemistry filed and biomedicine field, relate to color auspicious for a kind of novel crystal forms C of Buddhist nun, Preparation Method And The Use.
Background technology
Color is auspicious for the Buddhist nun's chemistry chloro-N-of 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl phenyl)-N-2-(isopropelsulfonyl) phenyl)-2,4-diamidogen by name, and structural formula is such as shown in following formula I:
Color is auspicious for Buddhist nun (Ceritinib, original name LDK378) it is a kind of gradually changeable lymphoma enzyme (ALK) the TYR inhibitors of kinases researched and developed by Novartis (Novartis), this medicine is used for the treatment of existing progression of disease or not tolerant transitivity NSCLC patient after gram azoles is for Buddhist nun (Crizotinib) treatment in April, 2014 by FDA approval, and commodity are called Zykadia. Color is auspicious is for second ALK inhibitor of FDA approval after Buddhist nun continue gram azoles for Buddhist nun, is also second medicine giving special approval to passage listing through quadruple after Ibrutinib (Ibrutinib).
It is auspicious for Buddhist nun and preparation method thereof that patent WO2008/073687A1 discloses and protect color; in addition; WO2009120798, WO2008073687, WO2004080980; WO20140066406; WO2011140338, WO209143389, WO2008073687; the patents such as WO2009126515 also disclose the auspicious preparation method for Buddhist nun of color respectively, but its crystal formation is mentioned.
Patent application CN103282359A discloses auspicious two kinds of crystal form A and the B for Buddhist nun of color.
This patent is pointed out, the auspicious XRPD for the crystal form A of Buddhist nun of color is presented in lower group of angle of diffraction place the diffraction maximum of maximum:: 7.2 ��, 8.1 ��, 10.8 ��, 12.0 ��, 12.4 ��, 13.4 ��, 14.4 ��, 14.8 ��, 15.7 ��, 16.9 ��, 17.7 ��, 18.5 ��, 19.0 ��, 19.5 ��, 20.0 ��, 20.3 ��, 21.1 ��, 21.6 ��, 22.4 ��, 22.6 ��, 23.0 ��, 24.1 ��, 24.5 ��, 25.5 ��, 26.0 ��, 26.2 ��, 27.0 ��, 27.3 ��, 28.3 ��, 29.0 ��, 29.1 ��, 30.6 ��, 31.3 ��, 32.8 ��, 33.5 ��, 34.2 �� and 36.4 �� (2 �� degree). , being measured by differential scanning calorimetry, its fusing point is 174 DEG C. , being measured by thermogravimetric analysis, higher than 250 DEG C and at 200 DEG C, loss on drying is 0.1% to its decomposition point.
This patent is pointed out, the auspicious XRPD for the crystal form B of Buddhist nun of color is presented in lower group of angle of diffraction place the diffraction maximum of maximum:: 5.1 ��, 5.5 ��, 5.6 ��, 9.5 ��, 9.6 ��, 10.1 ��, 11.0 ��, 11.8 ��, 12.1 ��, 12.6 ��, 13.7 ��, 14.5 ��, 14.9 ��, 15.2 ��, 16.1 ��, 16.6 ��, 16.7 ��, 17.0 ��, 17.1 ��, 17.5 ��, 17.7 ��, 18.0 ��, 18.8 ��, 19.0 ��, 19.3 ��, 19.5 ��, 20.5 ��, 20.9 ��, 21.5 ��, 21.9 ��, 22.1 ��, 22.4 ��, 22.8 ��, 23.2 ��, 23.7 ��, 23.9 ��, 24.3 ��, 24.5 ��, 24.8 ��, 25.1 ��, 25.4 ��, 25.9 ��, 26.4 ��, 26.8 ��, 27.8 ��, 28.1 ��, 28.6 ��, 29.1 ��, 29.6 ��, 29.8 ��, 30.6 ��, 31.6 ��, 32.7 ��, 33.5 ��, 34.2 ��, 35.4 ��, 35.6 �� and 36.8 �� (2 �� degree). , being measured by differential scanning calorimetry, its fusing point is 162 DEG C. , being measured by thermogravimetric analysis, higher than 250 DEG C and at 200 DEG C, loss on drying is 0.05% to its decomposition point.
The present inventor is in the research auspicious process for Buddhist nun's crystal formation of color, finding and prepare the auspicious another kind of novel crystal forms for Buddhist nun of color, it has and is significantly different from existing X-ray powder diffraction feature, and preparation method is simple, chemical stability is excellent, is suitable for use in several formulations.
Summary of the invention
It is an object of the invention to provide the auspicious crystal formation for Buddhist nun of a kind of new color, temporary called after crystal C.
It is a further object of the present invention to provide the method preparing the auspicious above-mentioned novel crystal forms C for Buddhist nun of color.
The purpose of the present invention can be realized by following approach:
The auspicious feature for Buddhist nun novel crystal forms C of color of the present invention:
Color provided by the invention is auspicious for Buddhist nun novel crystal forms C, and to spend the 2 �� X-ray Powder Diffraction pattern represented at 5.6 ��, 9.5 ��, 12.6 ��, 15.2 ��, 16.2 ��, 16.6 ��, 18.8 ��, there is characteristic diffraction peak at 25.9 �� of places.
Above-mentioned color of the present invention is auspicious for Buddhist nun novel crystal forms C, still further comprises 2 �� values at 8.3 ��, 11.0 ��, 11.9 ��, 12.2 ��, 14.5 ��, 17.0 ��, 17.6 ��, 19.0 ��, 19.5 ��, 20.6 ��, 21.0 ��, 21.7 ��, 21.9 ��, 22.2 ��, 22.4 ��, 22.9 ��, 23.9 ��, 24.3 ��, 24.9 ��, 25.1 ��, 28.1 ��, 28.7 ��, 29.8 ��, 30.7 ��, the position of 31.6 �� is to there being characteristic diffraction peak.
Color provided by the invention is auspicious for Buddhist nun novel crystal forms C, and its x-ray diffraction pattern is as shown in Figure 1.
Color provided by the invention is auspicious relatively sees Fig. 2 for the x-ray diffraction pattern of crystal form A, crystal form B disclosed in Buddhist nun novel crystal forms C and patent application CN103282359A.
It is understandable that, owing to being subject to the impact of many factors (during such as the granularity of test sample, test the processing method of sample, instrument, test parameter, test operation etc.), the X-ray powder diffraction measured by same crystal formation go out peak position or peak intensity has certain difference. In X-ray powder diffraction, the experimental error of diffraction maximum 2 �� value can be �� 0.2 ��.
The differential scanning calorimetry (DSC) of the auspicious novel crystal forms C for Buddhist nun of color of the present invention, it absorbs and changes at 164 �� 2 DEG C.
Differential scanning calorimetry (DSC) figure of the auspicious novel crystal forms C for Buddhist nun of color of the present invention is as shown in Figure 3.
The auspicious infrared absorption pattern recorded for the novel crystal forms C KBr tabletting of Buddhist nun of color of the present invention, is characterized by 3418.6cm-1, 3311.0cm-1, 1597.5cm-1, 1568.7cm-1, 1508.3cm-1, there is absworption peak at place.
The auspicious infrared absorption pattern recorded for the novel crystal forms C KBr tabletting of Buddhist nun of the color of the present invention is as shown in Figure 4.
The auspicious novel crystal forms C for Buddhist nun of color of the present invention, the content (mass content) of its crystal C is generally higher than 70%, it is preferable that more than 80%, optimum more than 90%.
The preparation method that present invention also offers the auspicious novel crystal forms C for Buddhist nun of a kind of color, the method includes dissociating crystallize out by the method for alkali adjustment pH value for Buddhist nun by auspicious for color from souring soln, is separated by crystal, dry, it is thus achieved that novel crystal forms C.
In one specific embodiment, the auspicious preparation method for Buddhist nun novel crystal forms C of color comprises the following steps:
1) dissipating auspicious for color with moisture for Buddhist nun, add suitable acid or acid solution, make system dissolve, obtain the auspicious solution for Buddhist nun's salt of color, solution temperature is 0��60 DEG C, it is preferable that 5��20 DEG C;
2) auspicious for Buddhist nun's saline solution adds suitable alkali or aqueous slkali to above-mentioned color, regulate pH value, make color auspicious for Buddhist nun's crystallize out, and continue stirring 24��168h, recrystallization temperature is 0��60 DEG C, it is preferable that 5��20 DEG C, regulates pH to pH6��14, it is preferable that pH9��12;
3) crystal of precipitation is filtered or centrifugation;
4) carrying out vacuum drying by separating the crystal obtained, baking temperature is 30��150 DEG C, it is preferable that 80��120 DEG C.
In the method for the embodiment above, step 1) described in acid or acid solution include but not limited in hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, benzenesulfonic acid one or more. Step 2) described in alkali or aqueous slkali be potassium hydroxide, sodium hydroxide, Lithium hydrate, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, Disilver carbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, triethylamine, tri-n-butylamine, 4-dimethylamino pyridine, N, N-dimethylaniline, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, N-methylmorpholine, N, N-diisopropylethylamine, pyridine, 2,6-lutidines, imidazoles, N, N, N ', N ' one or more in-tetramethylethylenediamine.
It is a further object to provide the described color auspicious crystal C for Buddhist nun purposes in the medicament of the disease of preparation treatment anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase mediation.
The disease of preferably described anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase mediation is cancer.
Preferred described cancer is primary cutaneous type, non Hodgkin lymphom (non-Hodgkin'slymphoma), Inflammatory myofibroblastic tumor, neuroblastoma, sarcoma, pulmonary carcinoma, bronchogenic carcinoma, carcinoma of prostate, breast carcinoma (comprises sporadic breast carcinoma and cowden's disease (Cowdendisease) patient), cancer of pancreas, human primary gastrointestinal cancers, colon cancer, rectal cancer, colon carcinoma (coloncarcinoma), Colon and rectum adenoma, thyroid carcinoma, hepatocarcinoma, intrahepatic cholangiocarcinoma, hepatocarcinoma, adrenal carcinoma, gastric cancer, stomach cancer, glioma, gliablastoma, carcinoma of endometrium, melanoma, renal carcinoma, carcinoma of renal pelvis, bladder cancer, carcinoma of uterine body, cervical cancer, cancer of vagina, ovarian cancer, multiple myeloma, esophageal carcinoma, leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, Lymphocytic leukemia, myeloid leukemia, the brain cancer, brain cancer tumor, oral cavity and pharyngeal cancer, laryngeal carcinoma, carcinoma of small intestine and melanoma.
The auspicious stability study for Buddhist nun novel crystal forms C of color of the present invention:
Uniformly share auspicious for color to uncovered culture dish for Buddhist nun's crystal C, be positioned under the influence factors such as illumination, high temperature, high humidity, separately sampled detection, and with 0 day result compare. Result is in Table 1.
Table 1 color is auspicious for Buddhist nun's crystal C study on the stability
By above-mentioned result of the test it can be seen that the color that obtains of the present invention auspicious for Buddhist nun novel crystal forms C under the conditions such as illumination, high temperature, high humidity, purity is without large change, stable crystal form. Color provided by the invention is auspicious stable for Buddhist nun's crystal C physicochemical properties, is suitable to long storage periods and is applied to preparation.
Accompanying drawing explanation
Fig. 1 is the auspicious x-ray diffraction pattern for Buddhist nun's crystal C of color of the present invention.
Fig. 2 is that the auspicious x-ray diffraction pattern for crystal form A disclosed in Buddhist nun's crystal C and patent application CN103282359A, crystal form B of color of the present invention compares.
Fig. 3 is the auspicious crystal DSC spectrogram for Buddhist nun's crystal C of color of the present invention.
Fig. 4 is the auspicious crystal IR spectrogram for Buddhist nun's crystal C of color of the present invention.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described, it is possible to makes professional and technical personnel in the field be more completely understood by the present invention, but the scope not limited the present invention in any way.
Embodiment 1
(it is equipped with mechanical agitation to the four-hole boiling flask of 2L; thermometer; nitrogen protection; constant pressure funnel) in add color auspicious for Buddhist nun's free alkali (100.0g); it is subsequently added purified water (1L) stirring, controls system temperature 20 DEG C, add hydrochloric acid (6N; 0.22L), nitrogen protection borehole cooling to 15 DEG C. Being added drop-wise in reaction system by sodium hydroxide solution (3N, 0.53L), time for adding controls 120 minutes, starts slowly to become cloudy after dropping a period of time, comparatively fast precipitates out solid subsequently, continues stirring 168 hours after precipitating out solid. Filtering, filter cake purified water (500ml �� 3) is washed, and after vacuum takes out pressure (carrying out under nitrogen protection), is placed in vacuum drying oven by product at 80 DEG C and dries 96h, obtain color auspicious for Buddhist nun crystal C (64g, yield 72%).
Embodiment 2
(it is equipped with mechanical agitation to the four-hole boiling flask of 5L; thermometer; nitrogen protection; constant pressure funnel) in add color auspicious for Buddhist nun (200.0g); it is subsequently added purified water (2L) stirring, controls system temperature 10 DEG C, add hydrochloric acid (3N; 0.8L), nitrogen protection borehole cooling to 5 DEG C. Being added drop-wise in reaction system by potassium hydroxide solution (3N, 0.8L), time for adding controls at 60 minutes, starts slowly to become cloudy after dropping a period of time, comparatively fast precipitates out solid subsequently, at room temperature continues stirring 24 hours after precipitating out solid. Filtering, filter cake purified water (1L �� 3) is washed, and after vacuum takes out pressure (carrying out under nitrogen protection), is placed in vacuum drying oven by product at 100 DEG C and dries 2h, obtain color auspicious for Buddhist nun crystal C (176g, yield 88%).
Embodiment 3
(it is equipped with mechanical agitation to the four-hole boiling flask of 5L; thermometer; nitrogen protection; constant pressure funnel) in add color auspicious for Buddhist nun (200.0g); it is subsequently added purified water (2L) stirring, controls system temperature 5 DEG C, add sulfuric acid solution (6N; 0.22L), under nitrogen protection temperature control to 20 DEG C. Being added drop-wise in reaction system by ammonia (7N, 0.5L), time for adding controls at 180 minutes, starts slowly to become cloudy after dropping a period of time, comparatively fast precipitates out solid subsequently, continues stirring 72 hours after precipitating out solid. Filtering, filter cake purified water (1L �� 3) is washed, and after vacuum takes out pressure (carrying out under nitrogen protection), is placed in vacuum drying oven by product at 120 DEG C and dries 2h, obtain color auspicious for Buddhist nun crystal C (170g, yield 85%).
Claims (10)
1. the auspicious crystal C for Buddhist nun of color, it is characterised in that: to spend the 2 �� X-ray Powder Diffraction pattern represented at 5.6 ��, 9.5 ��, 12.6 ��, 15.2 ��, 16.2 ��, 16.6 ��, 18.8 ��, the position of 25.9 �� is to there being characteristic diffraction peak.
2. crystal C as claimed in claim 1, still further comprises 2 �� values at 8.3 ��, 11.0 ��, 11.9 ��, 12.2 ��, 14.5 ��, 17.0 ��, 17.6 ��, 19.0 ��, 19.5 ��, 20.6 ��, 21.0 ��, 21.7 ��, 21.9 ��, 22.2 ��, 22.4 ��, 22.9 ��, 23.9 ��, 24.3 ��, 24.9 ��, 25.1 ��, 28.1 ��, 28.7 ��, 29.8 ��, 30.7 ��, the position of 31.6 �� is to there being characteristic diffraction peak.
3. crystal C as claimed in claim 1, it is characterised in that: the X-ray powder diffraction figure of described crystal is as shown in Figure 1.
4. the auspicious crystal C for Buddhist nun of color as claimed in claim 1, its DSC endothermic transition is at 164 �� 2 DEG C.
5. the auspicious crystal C for Buddhist nun of color as claimed in claim 1, its infrared absorption pattern has absworption peak at 3418.6cm-1,3311.0cm-1,1597.5cm-1,1568.7cm-1,1508.3cm-1 place.
6. crystal C as claimed in claim 1, its content is more than 70%, it is preferable that more than 80%, optimum more than 90%.
7. the preparation method of the auspicious crystal C for Buddhist nun of color described in a claim 1, it is characterised in that:
1) dissipating auspicious for color with moisture for Buddhist nun, add suitable acid or acid solution, make system dissolve, obtain the auspicious solution for Buddhist nun's salt of color, solution temperature is 0��60 DEG C, it is preferable that 5��20 DEG C;
2) auspicious for Buddhist nun's saline solution adds suitable alkali or aqueous slkali to above-mentioned color, regulate pH value, make color auspicious for Buddhist nun's crystallize out, and continue stirring 24��168h, recrystallization temperature is 0��60 DEG C, it is preferable that 5��20 DEG C, regulates pH to pH6��14, it is preferable that pH9��12;
3) crystal of precipitation is filtered or centrifugation;
4) carrying out vacuum drying by separating the crystal obtained, baking temperature is 30��150 DEG C, it is preferable that 80��120 DEG C.
8. preparation method as claimed in claim 7, it is characterised in that described acid or acid solution include but not limited to one or more in hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, benzenesulfonic acid; Described alkali or aqueous slkali are potassium hydroxide, sodium hydroxide, Lithium hydrate, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, Disilver carbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, triethylamine, tri-n-butylamine, 4-dimethylamino pyridine, N, N-dimethylaniline, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, N-methylmorpholine, N, N-diisopropylethylamine, pyridine, 2,6-lutidines, imidazoles, N, N, N ', N ' one or more in-tetramethylethylenediamine.
9. the color as claimed in claim 1 auspicious crystal C for Buddhist nun purposes in the medicament of the disease of preparation treatment anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase mediation.
10. purposes as claimed in claim 9, wherein said disease is the cancer selected from lower group: primary cutaneous type, non Hodgkin lymphom (non-Hodgkin'slymphoma), Inflammatory myofibroblastic tumor, neuroblastoma, sarcoma, pulmonary carcinoma, bronchogenic carcinoma, carcinoma of prostate, breast carcinoma (comprises sporadic breast carcinoma and cowden's disease (Cowdendisease) patient), cancer of pancreas, human primary gastrointestinal cancers, colon cancer, rectal cancer, colon carcinoma (coloncarcinoma), Colon and rectum adenoma, thyroid carcinoma, hepatocarcinoma, intrahepatic cholangiocarcinoma, hepatocarcinoma, adrenal carcinoma, gastric cancer, stomach cancer, glioma, gliablastoma, carcinoma of endometrium, melanoma, renal carcinoma, carcinoma of renal pelvis, bladder cancer, carcinoma of uterine body, cervical cancer, cancer of vagina, ovarian cancer, multiple myeloma, esophageal carcinoma, leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, Lymphocytic leukemia, myeloid leukemia, the brain cancer, brain cancer tumor, oral cavity and pharyngeal cancer, laryngeal carcinoma, carcinoma of small intestine and melanoma.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2651918B1 (en) | 2010-12-17 | 2017-07-12 | Novartis AG | Crystalline forms of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
| CN108314676A (en) * | 2017-01-18 | 2018-07-24 | 上海医药工业研究院 | The aminopyridine analog derivative and its antitumor application thereof of the segment containing hydroxamic acid |
| WO2021143819A1 (en) * | 2020-01-17 | 2021-07-22 | 山东轩竹医药科技有限公司 | Crystal form of polycyclic anaplastic lymphoma kinase inhibitor |
| CN114901289A (en) * | 2019-10-28 | 2022-08-12 | 奥斯陆大学 | ALK inhibitors for the treatment of ALK negative cancers and plasma cell mediated diseases |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103282359A (en) * | 2010-12-17 | 2013-09-04 | 诺华股份有限公司 | Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
-
2014
- 2014-11-29 CN CN201410714723.8A patent/CN105622577A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103282359A (en) * | 2010-12-17 | 2013-09-04 | 诺华股份有限公司 | Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2651918B1 (en) | 2010-12-17 | 2017-07-12 | Novartis AG | Crystalline forms of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
| EP3121171B1 (en) | 2010-12-17 | 2018-08-15 | Novartis Ag | Crystalline forms of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
| CN108314676A (en) * | 2017-01-18 | 2018-07-24 | 上海医药工业研究院 | The aminopyridine analog derivative and its antitumor application thereof of the segment containing hydroxamic acid |
| CN108314676B (en) * | 2017-01-18 | 2020-07-14 | 上海医药工业研究院 | Amino pyridine derivative containing hydroxamic acid fragment and anti-tumor application thereof |
| CN114901289A (en) * | 2019-10-28 | 2022-08-12 | 奥斯陆大学 | ALK inhibitors for the treatment of ALK negative cancers and plasma cell mediated diseases |
| WO2021143819A1 (en) * | 2020-01-17 | 2021-07-22 | 山东轩竹医药科技有限公司 | Crystal form of polycyclic anaplastic lymphoma kinase inhibitor |
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