CN104961681A - Cabozantinib mucate and crystal form there of - Google Patents
Cabozantinib mucate and crystal form there of Download PDFInfo
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- CN104961681A CN104961681A CN201410641139.4A CN201410641139A CN104961681A CN 104961681 A CN104961681 A CN 104961681A CN 201410641139 A CN201410641139 A CN 201410641139A CN 104961681 A CN104961681 A CN 104961681A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to mucate of N-(4-{[6,7-bis(methoxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dimethanamide and a crystal form thereof, and a preparation method thereof. The solubility of the mucate of a compound as shown in a formula (I) which is described in the specification is higher than the solubility of malate of the compound, which is of important significance to improvement of bioavailability, curative effect and security of the compound.
Description
Technical field
The present invention relates to chemical medicine, particularly relate to mucate and the crystal formation thereof of N-(4-{ [6,7-two (methyl oxygen base) quinolyl-4] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide.
Background technology
N-(4-{ [6, two (the methyl oxygen base) quinolyl-4 of 7-] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide, have another name called card rich for Buddhist nun (cabozantinib), researched and developed by Exelixis company and be used for the treatment of metastatic medullary thyroid carcinoma, obtain FDA approval in November, 2012, go on the market with the form of malate.The rich Buddhist nun's structure of replacing of card is as shown in formula I:
The drug molecule of nearly half is all exist in a salt form and administration.Salify can improve medicine some undesirable physical chemistry or biopharmaceutical properties, as changed the solubleness of medicine or dissolution rate, reduction draw moist, improve stability, change fusing point, improve nonferromagnetic substance, be convenient to prepare purifying, improve perviousness etc.
According in patent US7579473, compound formula I free alkali solubleness is extremely low.Therefore, Yuan Yan company in the patent CN102388024A has carried out a large amount of salt screening experiments, final selects Malate Form listing, and, which disclose malate N-1 crystal type, N-2 crystal type and armorphous.Wonderful, the present inventor has found the mucate of formula I compound in research process, and its degree of crystallinity is high, good stability, further, the malate of its solubleness ratio is higher, and for improving, the bioavailability of medicine, curative effect of medication and security are significant.
Summary of the invention
An object of the present invention is to provide the mucate of formula I compound.Preferably, the proportioning of formula I compound and glactaric acid is 1:1.Preferably, described mucate is crystal salt.
The mucate of formula I compound provided by the invention easily obtains, its preparation method, only need formula I compound and glactaric acid to be dissolved in respectively in solvent, make the two react, the mucate of formula I compound can be obtained.Described solvent can be acetonitrile, alcohols, ketone, ethers and above-mentioned solvent respectively with the mixed solvent system of water.When the two reacts in solvent system, without the need to recrystallization operation, crystallization can obtain stable salt form.
The mucate solubleness of formula I compound of the present invention is higher, is conducive to the bioavailability and the curative effect that improve medicine.
The mucate of formula I compound provided by the invention has and lower draws moist, without the need to special drying conditions in preparation process, simplifies preparation and the aftertreatment technology of medicine, is easy to suitability for industrialized production.Further, this crystal formation divides content substantially to remain unchanged at different humidity Water Under, is convenient to the long storage periods of medicine.Owing to requiring not harsh to condition of storage, greatly reduce material storing and quality control cost, there is very strong economic worth.
The mucate of formula I compound provided by the invention has satisfactory stability.Further, the mucate found at present, only has single crystal form, can reduce polymorph medicine owing to turning the brilliant change causing the efficacy and saferry of medicine.
The mucate of formula I compound provided by the invention can be used for the preparation of Therapeutic cancer medicine, especially for the preparation for the treatment of metastatic medullary thyroid carcinoma medicine.
Medicinal compositions is with the mucate of formula I compound for activeconstituents, and interpolation medicine is commonly used auxiliary material and is prepared from.
Another object of the present invention is to provide a kind of crystallized form of mucate of formula I compound, called after crystal form A in the present invention.
Crystal form A provided by the invention, is characterized in that, its X-ray powder diffraction figure is that 13.4 ° ± 0.2 °, 25.5 ° ± 0.2 °, 19.6 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 24.8 ° ± 0.2 °, 26.6 ° ± 0.2 °, 17.3 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 23.1 ° ± 0.2 °, 22.5 ° ± 0.2 °, 21.8 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form A provided by the invention, is characterized in that, its X-ray powder diffraction figure substantially as shown in Figure 1.
Further, crystal form A provided by the invention, is characterized in that, starts to occur endotherm(ic)peak near being heated to 208.8 DEG C, and its differential scanning calorimetric thermogram substantially as shown in Figure 2.
Further, crystal form A provided by the invention, is characterized in that, when being heated to 179.0 DEG C, have the weight loss gradient of about 1.50%, its thermogravimetric analysis figure substantially as shown in Figure 3.
Further, described crystal form A is anhydrous crystal forms.
Another object of the present invention is to provide the preparation method of crystal form A, it is characterized in that, its preparation method comprises makes formula I compound and glactaric acid react, and stirring and crystallizing can obtain.
Further, described reaction is carried out in a solvent, and described solvent is the mixed solvent of acetonitrile, alcohols, ethers or itself and water.
Further, described acetonitrile, alcohols, ketone, ethers respectively with the mixed system of water, meter is preferably acetonitrile by volume, and alcohols, ketone, the ratio of ethers and water is 10:1-20:1.
Further, described alcohols, is preferably methyl alcohol, described ketone, is preferably acetone, described ethers, is preferably tetrahydrofuran (THF).
Accompanying drawing explanation
Fig. 1 is the XRPD figure of mucate crystal form A
Fig. 2 is the DSC figure of mucate crystal form A
Fig. 3 is the TGA figure of mucate crystal form A
Fig. 4 be mucate crystal form A stability experiment XRPD comparison diagram (a be place before XRPD figure; B is the XRPD figure placed under 4 DEG C of conditions after 30 days; C is the XRPD figure placed under 25 DEG C/60% relative humidities after 30 days; D is the XRPD figure placed under 40 DEG C/75% relative humidities after 30 days)
Fig. 5 is the DVS figure of mucate crystal form A
Embodiment
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
DVS: dynamic water is adsorbed
NMR: nucleus magnetic resonance
X-ray powder diffraction figure of the present invention gathers on Panalytical Empyrean x-ray powder diffraction instrument.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K α
1.540598；
1.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliampere(mA)s (mA)
Divergent slit: automatically
Scan pattern: continuously
Sweep limit: from 3.0 to 40.0 degree
Sampling step length: 0.013 degree
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TA Q2000.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Thermogravimetric analysis of the present invention (TGA) figure gathers on TA Q5000.The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Dynamic water absorption (DVS) figure of the present invention gathers on the Intrinsic dynamic water adsorption instrument produced by SMS company (Surface MeasurementSystems Ltd.).The method parameter of described dynamic water adsorption instrument is as follows:
Embodiment 1
The preparation method of N-(4-{ [6,7-two (methyl oxygen base) quinolyl-4] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide mucate:
By 200mg N-(4-{ [6, two (the methyl oxygen base) quinolyl-4 of 7-] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1, the powder dissolution of 1-diformamide is in 8.0mL acetonitrile solvent system, add 84mg glactaric acid solid again in solution, magnetic agitation can obtain at ambient temperature.
The mucate product that aforesaid method prepares, its NMR appraising datum is as follows:
1H NMR(400MHz,DMSO)δ10.18(s,1H),10.05(s,1H),8.47(d,J＝5.2Hz,1H),7.76(d,J＝9.0Hz,2H),7.64(dd,J＝9.1,5.1Hz,2H),7.50(s,1H),7.39(s,1H),7.23(d,J＝9.0Hz,2H),7.15(t,J＝8.9Hz,2H),6.43(d,J＝5.2Hz,1H),4.22(s,2H),3.94(d,J＝4.8Hz,6H),3.77(s,2H),1.47(s,4H).
Embodiment 2
N-of the present invention (4-{ [6, two (the methyl oxygen base) quinolyl-4 of 7-] oxygen base } phenyl) malate solubleness comparative study in-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide mucate and CN102388024A:
Saturated solution is become to measure with pH6.5 FaSSIF (under fasted conditions simulated intestinal fluid) buffer two kinds of salt pH1.8 SGF (simulated gastric fluid).By the concentration of sample in high-performance liquid chromatogram determination saturated solution after 4 hours, experimental result is as shown in table 1:
Table 1 blocks rich for Buddhist nun's mucate and the comparative study of CN102388024A malate solubleness
Detectability: 0.03 mcg/ml
Can be found out by above-mentioned comparing result, N-of the present invention (4-{ [6 after 4 hours is placed in SGF and FaSSIF, two (the methyl oxygen base) quinolyl-4 of 7-] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide mucate is compared with CN102388024A malate, and solubleness is higher.
Embodiment 3
The preparation method of N-(4-{ [6,7-two (methyl oxygen base) quinolyl-4] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide mucate crystal form A:
By 10mg N-(4-{ [6, two (the methyl oxygen base) quinolyl-4 of 7-] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide powder dissolution is in 0.4mL methanol solvent system, add 4.2mg glactaric acid solid again, stirred at ambient temperature can obtain crystal form A.The X-ray powder diffraction data of the crystal form A that the present embodiment obtains are as shown in table 2.Its XRPD schemes as Fig. 1, and its DSC schemes as Fig. 2, and its TGA schemes as Fig. 3.
The X-ray powder diffraction data of table 2 crystal form A
| 2theta | D interval | Relative intensity % |
| 3.28 | 26.91 | 6.51 |
| 6.81 | 12.97 | 17.59 |
| 7.22 | 12.24 | 4.15 |
| 8.79 | 10.06 | 7.33 |
| 13.28 | 6.67 | 82.93 |
| 13.41 | 6.60 | 100.00 |
| 15.16 | 5.84 | 6.40 |
| 16.72 | 5.30 | 9.18 |
| 17.32 | 5.12 | 19.17 |
| 17.67 | 5.02 | 4.61 |
| 18.41 | 4.82 | 5.75 |
| 19.61 | 4.53 | 39.96 |
| 20.53 | 4.33 | 13.50 |
| 21.86 | 4.07 | 13.98 |
| 22.23 | 4.00 | 6.44 |
| 22.57 | 3.94 | 12.24 |
| 23.20 | 3.83 | 9.92 |
| 23.53 | 3.78 | 5.95 |
| 24.13 | 3.69 | 2.99 |
| 24.81 | 3.59 | 17.61 |
| 25.22 | 3.53 | 0.94 |
| 25.51 | 3.49 | 21.97 |
| 26.13 | 3.41 | 3.87 |
| 26.68 | 3.34 | 14.82 |
| 26.85 | 3.32 | 11.26 |
| 27.47 | 3.25 | 7.97 |
| 27.98 | 3.19 | 4.68 |
| 28.69 | 3.11 | 7.15 |
| 29.65 | 3.01 | 4.21 |
| 30.03 | 2.98 | 4.48 |
Embodiment 4
The preparation method of N-(4-{ [6,7-two (methyl oxygen base) quinolyl-4] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide mucate crystal form A:
By 200mg N-(4-{ [6, two (the methyl oxygen base) quinolyl-4 of 7-] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide powder dissolution is in 8.0mL methanol solvent system, add 84mg glactaric acid solid again, stirred at ambient temperature, can obtain crystal form A.The X-ray powder diffraction data of the crystal form A that the present embodiment obtains are as shown in table 3.
The X-ray powder diffraction data of table 3 crystal form A
| 2theta | D interval | Relative intensity % |
| 6.77 | 13.05 | 10.21 |
| 7.18 | 12.32 | 3.52 |
| 8.75 | 10.10 | 4.77 |
| 12.06 | 7.34 | 1.77 |
| 13.35 | 6.63 | 100.00 |
| 14.53 | 6.09 | 1.90 |
| 15.13 | 5.86 | 6.57 |
| 15.87 | 5.58 | 1.23 |
| 16.68 | 5.31 | 8.26 |
| 17.31 | 5.12 | 18.76 |
| 17.62 | 5.03 | 5.70 |
| 18.07 | 4.91 | 3.31 |
| 18.37 | 4.83 | 8.13 |
| 19.55 | 4.54 | 28.21 |
| 20.50 | 4.33 | 13.28 |
| 21.25 | 4.18 | 4.56 |
| 21.82 | 4.07 | 15.28 |
| 22.20 | 4.00 | 8.23 |
| 22.52 | 3.95 | 15.95 |
| 22.97 | 3.87 | 13.92 |
| 23.14 | 3.84 | 16.05 |
| 23.50 | 3.79 | 8.53 |
| 24.14 | 3.69 | 5.11 |
| 24.77 | 3.59 | 25.83 |
| 25.45 | 3.50 | 30.81 |
| 26.03 | 3.42 | 6.34 |
| 26.64 | 3.35 | 21.19 |
| 27.43 | 3.25 | 12.12 |
| 27.98 | 3.19 | 7.54 |
| 28.65 | 3.12 | 11.19 |
Embodiment 5
The mucate crystal form A stability study of N-(4-{ [6,7-two (methyl oxygen base) quinolyl-4] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide:
Get the mucate crystal form A sample prepared in three parts of embodiments 4 be placed in respectively 25 DEG C/60% relative humidity, 40 DEG C/75% relative humidity and 4 DEG C of condition lower open mouths place 30 days then sampling survey XRPD and purity, result is as shown in table 4.
Table 4 crystal form A stability study
Learnt by upper table, crystal form A, under the condition of 25 DEG C/60% relative humidity, 40 DEG C/75% relative humidity and 4 DEG C, is placed crystal formation after 30 days and is remained unchanged, purity reach 99.70% and more than, result shows, crystal form A of the present invention has satisfactory stability.
Embodiment 6
The mucate crystal form A of N-(4-{ [6,7-two (methyl oxygen base) quinolyl-4] oxygen base } phenyl)-N '-(4-fluorophenyl) cyclopropane-1,1-diformamide draw moist research:
Get crystal form A of the present invention to be about 10mg and to adopt dynamic water absorption (DVS) instrument to test it and draw moist.Experimental result is as shown in table 5.Draw the DVS figure of moist experiment as shown in Figure 5.
Table 5 crystal form A draw moist experiment
About drawing moist feature description and drawing defining (Chinese Pharmacopoeia version annex XIX J medicine in 2010 draws moist test direction principle, experiment condition: 25 DEG C ± 1 DEG C, 80% relative humidity) of moist weightening finish:
Deliquescence: absorb enough water and divide formation liquid
Have draw moist: draw wet weightening finish and be not less than 15%
Have draw moist: draw wet weightening finish and be less than 15% but be not less than 2%
Slightly draw moist: draw wet weightening finish and be less than 2% but be not less than 0.2%
Nothing or almost moist without drawing: draw wet weightening finish and be less than 0.2%
Result shows, after crystal form A of the present invention balances under 80% humidity, weightening finish 0.28%, slightly draws moist.
Claims (12)
1. the mucate of formula I compound:
2. the mucate of formula I compound according to claim 1, the salt described in it is crystal salt.
3. the crystal form A of formula I compound mucate according to claim 2, is characterized in that, its X-ray powder diffraction figure is that 13.4 ° ± 0.2 °, 25.5 ° ± 0.2 °, 19.6 ° ± 0.2 ° place has characteristic peak in 2theta value.
4. the crystal form A of formula I compound mucate according to claim 3, is further characterized in that, its X-ray powder diffraction figure is that 24.8 ° ± 0.2 °, 26.6 ° ± 0.2 °, 17.3 ° ± 0.2 ° place has characteristic peak in 2theta value.
5. the crystal form A of formula I compound mucate according to claim 4, is further characterized in that, its X-ray powder diffraction figure is that 23.1 ° ± 0.2 °, 22.5 ° ± 0.2 °, 21.8 ° ± 0.2 ° place has characteristic peak in 2theta value.
6. the crystal form A of formula I compound mucate according to claim 3, is characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 1.
7. prepare a method for the mucate of the formula I compound described in claims 1 to 3 any one, it comprises makes formula I compound and glactaric acid react, and stirring and crystallizing can obtain.
8. method according to claim 7, reacts described in it and carries out in a solvent, and described solvent is the mixed solvent of acetonitrile, alcohols, ethers or itself and water.
9. method according to claim 8, described alcohols is methyl alcohol, and described ketone is acetone, and described ethers is tetrahydrofuran (THF).
10. method according to claim 8, the volume ratio of wherein said acetonitrile, alcohols, ethers and water is between 10:1-20:1.
11. 1 kinds of pharmaceutical compositions, its mucate containing formula I compound described in good grounds claim 1 to 2 any one or the crystal formation according to the mucate of the formula I compound of claim 3 to 6 any one and pharmaceutically acceptable carrier.
Crystal formation or the pharmaceutical composition according to claim 7 of the mucate of 12. mucates of formula I compound according to claim 1 to 2 any one or the formula I compound according to claim 3 to 6 any one are preparing the purposes in Therapeutic cancer medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020075196A1 (en) | 2018-10-11 | 2020-04-16 | Cipla Limited | Polymorphs of n-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-n'-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide, (s)- malate, methods of production and pharmaceutical uses thereof |
| US11279675B2 (en) | 2017-05-26 | 2022-03-22 | Exelixis, Inc. | Crystalline solid forms of salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, processes for making, and methods of use |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11814356B1 (en) | 2023-03-29 | 2023-11-14 | Apotex Inc. | Salt of cabozantinib |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201036948A (en) * | 2009-01-16 | 2010-10-16 | Exelixis Inc | Malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof |
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2014
- 2014-11-13 CN CN201410641139.4A patent/CN104961681B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201036948A (en) * | 2009-01-16 | 2010-10-16 | Exelixis Inc | Malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11279675B2 (en) | 2017-05-26 | 2022-03-22 | Exelixis, Inc. | Crystalline solid forms of salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, processes for making, and methods of use |
| US11731941B2 (en) | 2017-05-26 | 2023-08-22 | Exelixis, Inc. | Crystalline solid forms of salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use |
| WO2020075196A1 (en) | 2018-10-11 | 2020-04-16 | Cipla Limited | Polymorphs of n-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-n'-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide, (s)- malate, methods of production and pharmaceutical uses thereof |
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Address after: 215123 B4-101, biological park, No. 218, Xing Hu Street, Suzhou Industrial Park, Suzhou, Jiangsu. Patentee after: Suzhou crystal cloud medicine Polytron Technologies Inc Address before: 215123 B4-101, biological park, No. 218, Xing Hu Street, Suzhou Industrial Park, Suzhou, Jiangsu. Patentee before: Crystal Pharmatech Co., Ltd. |
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