CN106029664A - Crystalline form of malate of tyrosine kinase inhibitor and preparation method therefor - Google Patents
Crystalline form of malate of tyrosine kinase inhibitor and preparation method therefor Download PDFInfo
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- CN106029664A CN106029664A CN201680000679.1A CN201680000679A CN106029664A CN 106029664 A CN106029664 A CN 106029664A CN 201680000679 A CN201680000679 A CN 201680000679A CN 106029664 A CN106029664 A CN 106029664A
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
It can be used as 5- (2- diethylin-ethyl) -2- (fluoro- 2- oxo -1 of 5- of tyrosine kinase inhibitor, 2- Dihydro-indole -3- ylidene-memyl) -3- methyl-1,5,6,7- tetrahydro-pyrroles [3,2-c] pyridine -4- ketone L MALIC ACID salt (formula (I) compound) I type crystallization and preparation method thereof. The method includes by any crystal form and unbodied formula (I) compound or its at salt raw material preferably alcohols organic solvent and water in the mixed solvent crystallization the step of.
Description
The present invention relates to a kind of crystal habit of the malate of tyrosine kinase inhibitor, particularly 5- (2- diethylin-ethyl) -2- (fluoro- 2- oxos -1 of 5-, 2- Dihydro-indole -3- ylidene-memyls) -1,5,6, the I types crystallization of 7- tetrahydrochysenes-pyrroles [3,2-c] pyridine -4- ketone L MALIC ACID salt.
In recent years, what the progress with Protocols in Molecular Biology and the molecular level from cell receptor and multiplication regulatory were recognized Tumorigenesis further gos deep into, clinic is initially entered for the treatment of target spot for cell receptor, key gene and regulatory molecule, people are referred to as " molecular targeted therapy ".These fields include EGF-R ELISA (EGFR) retarding agent, the monoclonal antibody for some specific cells marks, the medicine for some oncogenes and the cytogenetics mark of cancer, the medicine of Antineoplastic angiogenesis, anti-tumor vaccine and gene therapy with targeting etc..
Initially entering the Anticancer Effect and Mechanism of the tyrosine kinase inhibitor (TKIs) of clinic may be realized by following approach：Suppress the injury repair of tumour cell, cell division is arrested in G1 phases, induction and maintain Apoptosis, anti-angiogenesis etc..EGFR overexpressions often indicate patient's poor prognosis, shift fast, shorter to chemotherapeutics resistance, Steroid-Resistance, life cycle etc..TKIs can also be by lowering the angiogenesis factor of tumour cell and suppressing signal transductions of the EGFR to tumor vascular endothelial cell, " crosstalk " of two kinds of signal transduction pathway of EGFR and vascular endothelial growth factor receptor (VEGFR), to be clinical while suppressing both conduction paths provides rational foundation.Clinical test results show that Mutiple Targets inhibitor is better than single target spot inhibitor in terms for the treatment of, and Mutiple Targets combined occlusion signal transduction is oncotherapy and the new developing direction of drug development.
Up to the present, U.S. FDA ratifies 3 kinds of Mutiple Targets TKIs listings, such as：Sorafenib (sorafenib), ZD6474 (vandetanib) and Sunitinib (Sutent, SU-11248), wherein Sunitinib ratify to list in January, 2006, treatment GIST and advanced renal cell cancer.Due to clinically treating the medicine of advanced GIST in addition to Imatinib, not at present, the medicine for treating kidney is also seldom, so Sunitinib result is encouraging.WO2007085188 discloses a kind of compound similar with Sunitinib, and shown in such as following formula (I), it may preferably be answered
Treatment for above-mentioned tumour.
Those skilled in the art will know that, 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-mentioned product, it would be desirable to which it is higher and possess the stable novel crystal forms of good chemical that crystal form purity is found in further investigation.
The content of the invention
The invention provides 5- (2- diethylin-ethyl) -2- (the fluoro- 2- oxos -1 of 5-, 2- Dihydro-indole -3- ylidene-memyls) -1,5,6, the new crystal form of 7- tetrahydrochysenes-pyrroles [3,2-c] pyridine -4- ketone L MALIC ACIDs salt (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 specific crystallization condition of the invention, a kind of novel crystal forms can be obtained, we are called the crystallization of I types.The DSC collection of illustrative plates of I types crystallization in the application, which is shown in 240.64 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 7.34 (12.02), 10.09
(8.76), 11.06 (7.99), 12.25 (7.22), 13.03 (6.79), 14.69 (6.02), 15.11 (5.86), 15.42 (5.74), 16.00 (5.54), 17.17 (5.16), 17.72 (5.00), 19.86 (4.47), 20.35 (4.36), 21.96 (4.04), 22.77 (3.90), 23.37 (3.80), 25.33 (3.51), 25.96 (3.43), 26.52 (3.36), 28.77 (3.10), there is characteristic peak 30.17 (2.96) and 31.65 (2.83).
Present invention also offers prepare 5- (2- diethylin-ethyl) -2- (fluoro- 2- oxos -1, the 2- Dihydro-indole -3- ylidene-memyls of 5-) -1, the method for the I types crystallization of 5,6,7- tetrahydrochysenes-pyrroles [3,2-c] pyridine -4- ketone L MALIC ACIDs.This method comprises the following steps：
(1) by L MALIC ACID and 5- (2- diethylin-ethyl) -2- (fluoro- 2- oxos -1 of 5-, 2- Dihydro-indole -3- ylidene-memyls) -1,5,6,7- tetrahydrochysenes-pyrroles [3,2-c] pyridine -4- ketone, or compound shown in any crystal formation or unformed formula (I) is dissolved in the in the mixed solvent crystallization of organic solvent and water, the one or more that the organic solvent is less than or equal in 3 alcohols, ketone, nitrile, ethers or tetrahydrofuran selected from carbon number；
(2) filtering for crystallizing and wash, dry.
In a preferred embodiment of the present invention, in step (1), organic solvent is alcohols, preferably methanol, ethanol, isopropanol.
The method of recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, slowly cooling crystallization after can in a solvent being dissolved by heating with compound shown in raw material formula (I), 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 I 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 crystallization of compound I types shown in formula (I) prepared by the present invention has good stability under conditions of 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 I types shown in Fig. 1 formulas (I).
The DSC spectrograms of the crystallization of compound I 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：Mettler Toledo DSC 1StareeSystem
Purge gass：Nitrogen
Heating rate：10.0℃/min
Temperature range：40-300℃
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, 1.84mmol) compound shown in formula (I) (being prepared by method disclosed in WO2007085188) is added in 250ml single port bottles, 50ml ethanol is added, 50ml water is dissolved by heating, it is cooled to room temperature, stand crystallization, suction filtration, vacuum drying, obtain solid 0.64g, yield 64.0%.The X-ray diffraction spectrogram of the crystallized sample is shown in Fig. 1, the peak lists such as table 1 of the X-ray diffraction spectrogram.The crystallization is in about 7.34 (12.02), 10.09 (8.76), 11.06 (7.99), 12.25 (7.22), 13.03 (6.79), 14.69 (6.02), 15.11 (5.86), 15.42 (5.74), 16.00 (5.54), 17.17 (5.16), 17.72 (5.00), 19.86 (4.47), 20.35 (4.36), 21.96 (4.04), 22.77 (3.90), 23.37 (3.80), 25.33 (3.51), 25.96 (3.43), 26.52 (3.36), 28.77 (3.10), 30.17 (2.96) and there is characteristic peak at 31.65 (2.83) places.DSC spectrograms are shown in Fig. 2, there is sharp.
The peak lists of table 1, X-ray diffraction spectrogram
Embodiment 2
Take compound shown in (1.0g, 1.84mmol) formula (I) to be added in 250ml single port bottles, add 74ml ethanol, 37ml water is dissolved by heating, and is cooled to room temperature, stand crystallization, suction filtration, vacuum drying obtains solid 0.33g, yield 33.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is I crystal to determine product.
Embodiment 3
Take compound shown in (1.0g, 1.84mmol) formula (I) to be added in 250ml single port bottles, add 50ml methanol, 50ml water is dissolved by heating, and is cooled to room temperature, stand crystallization, suction filtration, vacuum drying obtains solid 0.42g, yield 42.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is I crystal to determine product.
Embodiment 4
Take compound shown in (1.0g, 1.84mmol) formula (I) to be added in 250ml single port bottles, add 60ml isopropanols, 60ml water, dissolve by heating, be cooled to room temperature, stand crystallization, suction filtration, vacuum drying, obtains solid 0.31g, yield 31.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is I crystal to determine product.
Embodiment 5
Take compound shown in (1.0g, 1.84mmol) formula (I) to be added in 250ml single port bottles, add 50ml acetone, 50ml water is dissolved by heating, and is cooled to room temperature, stand crystallization, suction filtration, vacuum drying obtains solid 0.35g, yield 35.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is I crystal to determine product.
Embodiment 6
Take compound shown in (1.0g, 1.84mmol) formula (I) to be added in 250ml single port bottles, add 60ml acetonitriles, 60ml water is dissolved by heating, and is cooled to room temperature, stand crystallization, suction filtration, vacuum drying obtains solid 0.37g, yield 37.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is I crystal to determine product.
Embodiment 7
Take compound shown in (1.0g, 1.84mmol) formula (I) to be added in 250ml single port bottles, add 50ml tetrahydrofurans, 50ml water, dissolve by heating, be cooled to room temperature, stand crystallization, suction filtration, vacuum drying, obtains solid 0.34g, yield 34.0%.Its X- diffraction and DSC collection of illustrative plates are compared through research, and it is I crystal to determine product.
Embodiment 8
By the I type crystallized products sample of the gained of embodiment 1, opening divides placement respectively, investigates the stability of the sample under the conditions of heating (40 DEG C, 60 DEG C), high humidity (RH75%, RH90%).It is 5 days and 10 days to investigate sample time, and HPLC detections purity is shown in Table 2.
The stability of compound I type crystallized samples shown in table 2, formula (I)
Study on the stability result shows, compound I types crystallized sample shown in formula (I) is under conditions of opening is placed, through the stability under high temperature and super-humid conditions it was found that, high humidity, high temperature influence little to the quality of product, illustrate that it has preferable stability.
Embodiment 9
The crystallization of compound I 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 3 below.
The special stability study of compound I crystal shown in the formula of table 3. (I)
Claims (5)
- The I 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 7.34 (12.02), 10.09 (8.76), 11.06 (7.99), 12.25 (7.22), 13.03 (6.79), 14.69 (6.02), 15.11 (5.86), 15.42 (5.74), 16.00 (5.54), 17.17 (5.16), 17.72 (5.00), 19.86 (4.47), 20.35 (4.36), 21.96 (4.04), 22.77 (3.90), 23.37 (3.80), 25.33 (3.51), 25.96 (3.43), 26.52 (3.36), 28.77 (3.10), there is characteristic peak 30.17 (2.96) and 31.65 (2.83),
- The method that one kind prepares the I types crystallization of the compound as claimed in claim 1 as shown in formula (I), methods described comprises the steps：1) by L MALIC ACID and 5- (2- diethylin-ethyl) -2- (fluoro- 2- oxos -1 of 5-, 2- Dihydro-indole -3- ylidene-memyls) -1,5,6,7- tetrahydrochysenes-pyrroles [3,2-c] pyridine -4- ketone, or the one or more that compound shown in any crystal formation or unformed formula (I) is less than or equal in 3 alcohols, ketone, nitrile, ethers or tetrahydrofuran in organic solvent and the in the mixed solvent crystallization of water, the organic solvent selected from carbon number；2) filtering for crystallizing and wash, dry.
- Method according to claim 2, it is characterised in that in step 1) described in organic solvent be preferably alcohols, further preferred methanol, ethanol, isopropanol.
- A kind of pharmaceutical composition, its I types crystallization for containing the compound as claimed in claim 1 as shown in formula (I) and pharmaceutically acceptable carrier.
- Purposes of the pharmaceutical composition in the medicine for preparing the treatment disease relevant with EGFR-TK as described in the I types crystallization of the compound according to claim 1 shown in formula (I) or claim 4；The preferred tumour of disease, more preferably non-small cell lung cancer, liver cancer, gastrointestinal stromal tumors or kidney.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015100079732 | 2015-01-07 | ||
| CN201510007973 | 2015-01-07 | ||
| PCT/CN2016/070136 WO2016110243A1 (en) | 2015-01-07 | 2016-01-05 | Crystalline form of malate of tyrosine kinase inhibitor and preparation method therefor |
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| CN107629048B (en) * | 2016-07-18 | 2020-10-20 | 江苏恒瑞医药股份有限公司 | Crystal form of malate of tyrosine kinase inhibitor and preparation method thereof |
| WO2020177678A1 (en) * | 2019-03-04 | 2020-09-10 | 江苏恒瑞医药股份有限公司 | Use of multi-target tyrosine kinase inhibitor in combination with egfr inhibitor in preparing drug for treating tumor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101007815A (en) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | Pyrrolehexa-heterocyclic compound and pharmaceutical use thereof |
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- 2016-01-05 CN CN201680000679.1A patent/CN106029664A/en active Pending
- 2016-01-05 WO PCT/CN2016/070136 patent/WO2016110243A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101007815A (en) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | Pyrrolehexa-heterocyclic compound and pharmaceutical use thereof |
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