CN104961681B - The rich mucate and its crystal formation for Buddhist nun of card - Google Patents
The rich mucate and its crystal formation for Buddhist nun of card Download PDFInfo
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- CN104961681B CN104961681B CN201410641139.4A CN201410641139A CN104961681B CN 104961681 B CN104961681 B CN 104961681B CN 201410641139 A CN201410641139 A CN 201410641139A CN 104961681 B CN104961681 B CN 104961681B
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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
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Abstract
The present invention relates to the mucate and its crystal formation and preparation method of N (4 { [6,7 pairs of (methyl epoxide) quinoline 4 bases] epoxide } phenyl) N ' (4 fluorophenyl) diformamide of cyclopropane 1,1.The mucate of formula (I) compound of the invention, its solubility than malate it is higher, it is significant for improving the bioavilability of medicine, curative effect of medication and security.
Description
Technical field
The present invention relates to chemical medicine, more particularly to N- (4- { [6,7- double (methyl epoxide) quinolyl-4s] oxygen
Base } phenyl)-N '-(4- fluorophenyls) cyclopropane -1,1- diformamides mucate and its crystal formation.
Background technology
N- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) cyclopropane -1,1-
Diformamide, also known as card is rich for Buddhist nun (cabozantinib), is researched and developed for treating metastatic medullary thyroid by Exelixis companies
Sample cancer, FDA approvals are obtained in November, 2012, are listed in the form of malate.Card is rich for shown in Buddhist nun's structure such as formula (I)：
The drug molecule of nearly half is all exist in a salt form and be administered.Some are undesirable can to improve medicine into salt
Physical chemistry or biopharmaceutical properties, the solubility or dissolution rate, reduction for such as changing medicine are drawn moist, raising stability, are changed
Fusing point, improvement grind performance, are easy to prepare purifying, improve permeability etc..
According in patent US7579473, the free alkali solubility of Formula (I) is extremely low.Therefore, Yuan Yan companies are in patent
Middle CN102388024A has carried out substantial amounts of salt screening experiment, the listing of final choice Malate Form, also, the patent and discloses
Malate N-1 crystal types, N-2 crystal types and armorphous.Wonderful, the present inventor is found that in research process
The mucate of formula (I) compound, its crystallinity is high, good stability, also, its solubility than malate it is higher, for carrying
The bioavilability of medicine high, curative effect of medication and security are significant.
The content of the invention
It is an object of the present invention to provide the mucate of formula (I) compound.Preferably, formula (I) compound and glactaric acid
Proportioning is 1:1.Preferably, described mucate is crystal salt.
The mucate of formula (I) compound that the present invention is provided is readily available, its preparation method, it is only necessary to by formula (I)
Compound and glactaric acid are dissolved in solvent respectively, are reacted the two, you can obtain the mucate of formula (I) compound.It is described molten
Agent can be acetonitrile, alcohols, ketone, ethers and above-mentioned solvent respectively with the mixed solvent system of water.When the two is in solvent body
When being reacted in system, without recrystallization operation, crystallization is the salt form that can be stablized.
The glactaric acid salt solubility of formula (I) compound of the invention is higher, is conducive to improving bioavilability and the treatment of medicine
Effect.
The mucate of formula (I) compound that the present invention is provided have it is relatively low draw moist, without special in preparation process
Drying condition, simplify preparation and the aftertreatment technology of medicine, it is easy to industrialized production.Also, the crystal formation is in different humidity
Under the conditions of moisture be held essentially constant, be easy to the long-term storage of medicine.Due to not harsh to condition of storage requirement, drop significantly
Low material storing and quality control cost, with very strong economic worth.
The mucate of formula (I) compound that the present invention is provided has good stability.Also, the glactaric acid having now been found that
Salt, only has single crystal form, and can reduce polymorph medicine causes the change of the efficacy and saferry of medicine due to turning crystalline substance.
The mucate of formula (I) compound that the present invention is provided can be used for the preparation for the treatment of cancer medicine, particularly for controlling
Treat the preparation of metastatic medullary thyroid carcinoma medicine.
Pharmaceutical composition, be the mucate with formula (I) compound as active component, addition medicine often with auxiliary material prepare and
Into.
It is a further object to provide a kind of crystal form of the mucate of formula (I) compound, ordered in the present invention
Entitled crystal formation A.
The present invention provide crystal formation A, it is characterised in that its X-ray powder diffraction figure 2theta values for 13.4 ° ±
0.2 °, 25.5 ° ± 0.2 °, there is at 19.6 ° ± 0.2 ° characteristic peak.
Further, the crystal formation A that the present invention is provided, is further characterized in that, its X-ray powder diffraction figure is in 2theta values
To have characteristic peak at 24.8 ° ± 0.2 °, 26.6 ° ± 0.2 °, 17.3 ° ± 0.2 °.
Further, the crystal formation A that the present invention is provided, is further characterized in that, its X-ray powder diffraction figure is in 2theta values
To have characteristic peak at 23.1 ° ± 0.2 °, 22.5 ° ± 0.2 °, 21.8 ° ± 0.2 °.
Further, the crystal formation A that the present invention is provided, it is characterised in that its X-ray powder diffraction figure is basic such as Fig. 1 institutes
Show.
Further, the crystal formation A that the present invention is provided, it is characterised in that be heated to starting suction occur near 208.8 DEG C
Thermal spike, its differential scanning calorimetric thermogram is substantially as shown in Figure 2.
Further, the crystal formation A that the present invention is provided, it is characterised in that when being heated to 179.0 DEG C, with about
1.50% weight loss gradient, its thermogravimetric analysis figure is substantially as shown in Figure 3.
Further, the crystal formation A is anhydrous crystal forms.
It is a further object to provide the preparation method of crystal formation A, it is characterised in that its preparation method includes making formula
(I) compound reacts with glactaric acid, and stirring and crystallizing is that can obtain.
Further, the reaction is carried out in a solvent, and the solvent is acetonitrile, alcohols, ethers or it is mixed with water
Bonding solvent.
Further, described acetonitrile, alcohols, ketone, ethers respectively with the mixed system of water, count by volume preferred
It is acetonitrile, alcohols, ketone, the ratio of ethers and water is 10:1-20:1.
Further, described alcohols, preferably methyl alcohol, the ketone, preferably acetone, the ethers, preferably
Tetrahydrofuran.
Brief description of the drawings
Fig. 1 schemes for the XRPD of mucate crystal formation A
Fig. 2 schemes for the DSC of mucate crystal formation A
Fig. 3 schemes for the TGA of mucate crystal formation A
Fig. 4 for mucate crystal formation A stability experiment XRPD comparison diagrams (a be place before XRPD figure；B is in 4 DEG C of conditions
It is lower place 30 days after XRPD figure；C is the XRPD figures after being placed 30 days under 25 DEG C/60% relative humidities；D is 40
DEG C/75% relative humidities under place 30 days after XRPD figure)
Fig. 5 schemes for the DVS of mucate crystal formation A
Specific embodiment
Used abbreviation is explained as follows in the present invention：
XRPD：X-ray powder diffraction
DSC：Differential scanning calorimetric analysis
TGA：Thermogravimetric analysis
DVS：Dynamic water is adsorbed
NMR：Nuclear magnetic resonance
X-ray powder diffraction figure of the present invention is adopted on Panalytical Empyrean x-ray powder diffraction instruments
Collection.The method parameter of X-ray powder diffraction of the present invention is as follows：
X ray reflection parameter：Cu,Kα
1.540598；1.544426
The intensities of K α 2/K α 1：0.50
Voltage：45 KVs (kV)
Electric current：40 milliamperes (mA)
Divergent slit：Automatically
Scan pattern：Continuously
Sweep limits：From 3.0 to 40.0 degree
Sampling step length：0.013 degree
Differential scanning calorimetric analysis (DSC) figure of the present invention is gathered on TA Q2000.Differential of the present invention
The method parameter of scanning thermometric analysis (DSC) is as follows：
Sweep speed：10℃/min
Protective gas：Nitrogen
Thermogravimetric analysis (TGA) figure of the present invention is gathered on TA Q5000.Thermogravimetric analysis (TGA) of the present invention
Method parameter it is as follows：
Sweep speed：10℃/min
Protective gas：Nitrogen
Dynamic water of the present invention adsorbs (DVS) figure by SMS companies (Surface Measurement Systems
Ltd.) gathered on the Intrinsic dynamic water adsorption instruments of production.The method parameter of described dynamic water adsorption instrument is as follows：
Embodiment 1
N- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) cyclopropane -1,1-
The preparation method of diformamide mucate：
By 200mg N- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) ring third
Alkane -1, the powder of 1- diformamides is dissolved in 8.0mL acetonitrile solvent systems, adds 84mg glactaric acid solids in solution, in room
Magnetic agitation is that can obtain under the conditions of temperature.
The glactaric acid product salt that the above method is prepared, its NMR appraising datum is as follows：
1H NMR (400MHz, DMSO) δ 10.18 (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- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) ring third of the invention
Malate solubility comparative study in alkane -1,1- diformamides mucate and CN102388024A：
By two kinds of salt pH1.8 SGF (SGF) and pH6.5 FaSSIF (simulated intestinal fluid under fasted conditions) buffer solution
It is configured to saturated solution measure.The concentration of sample in determining saturated solution by high performance liquid chromatography after 4 hours, experiment knot
Fruit is as shown in table 1：
The card of table 1 is rich to replace Buddhist nun's mucate and CN102388024A malate solubility comparative studies
Test limit：0.03 mcg/ml
N- (the 4- of the invention after above-mentioned comparing result can be seen that and place 4 hours in SGF and FaSSIF
{ [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) cyclopropane -1,1- diformamide mucates
Compared with CN102388024A malates, solubility is higher.
Embodiment 3
N- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) cyclopropane -1,1-
The preparation method of diformamide mucate crystal formation A：
By 10mg N- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) ring third
Alkane -1,1- diformamide powder is dissolved in 0.4mL methanol solvent systems, adds 4.2mg glactaric acid solids, and stirring at room temperature is
Can obtain crystal formation A.The X-ray powder diffraction data of the crystal formation A that the present embodiment is obtained are as shown in table 2.Its XRPD figures such as Fig. 1, its
DSC figures such as Fig. 2, its TGA figure such as Fig. 3.
The X-ray powder diffraction data of the crystal formation A of table 2
| 2theta | D is spaced | 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
N- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) cyclopropane -1,1-
The preparation method of diformamide mucate crystal formation A：
By 200mg N- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) ring third
Alkane -1,1- diformamide powder is dissolved in 8.0mL methanol solvent systems, adds 84mg glactaric acid solids, stirs at room temperature, you can
Obtain crystal formation A.The X-ray powder diffraction data of the crystal formation A that the present embodiment is obtained are as shown in table 3.
The X-ray powder diffraction data of the crystal formation A of table 3
| 2theta | D is spaced | 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
N- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) cyclopropane -1,1-
The mucate crystal formation A stability studies of diformamide：
Take the mucate crystal formation A samples prepared in three parts of embodiments 4 and be respectively placed in 25 DEG C/60% relative humidity, 40
DEG C/75% relative humidity and 4 DEG C of condition lower open mouths are placed 30 days and then XRPD and purity are surveyed in sampling, as a result as shown in table 4.
The crystal formation A stability studies of table 4
Learnt by upper table, crystal formation A is in 25 DEG C/60% relative humidity, 40 DEG C/75% relative humidity and 4 DEG C of condition
Under, place 30 days after crystal formation keep it is constant, purity reach 99.70% and more than, as a result show, crystal formation A of the invention has good
Good stability.
Embodiment 6
N- (4- { [double (methyl epoxide) quinolyl-4s of 6,7-] epoxide } phenyl)-N '-(4- fluorophenyls) cyclopropane -1,1-
The mucate crystal formation A's of diformamide draws moist research：
Crystal formation A about 10mg of the invention are taken to test it and draw moist using dynamic water absorption (DVS) instrument.Experimental result such as table
Shown in 5.The DVS figures for drawing moist experiment are as shown in Figure 5.
The crystal formation A's of table 5 draws moist experiment
On draw the description of moist feature with draw moist weightening define that (Chinese Pharmacopoeia version annex XIX J medicines in 2010 draw
Moist test direction principle, experiment condition：25 DEG C ± 1 DEG C, 80% relative humidity)：
Deliquescence：Absorb enough moisture and form liquid
It is great to draw moist：Draw wet weightening not less than 15%
Have and draw moist：Draw wet weightening less than 15% but not less than 2%
Slightly draw moist：Draw wet weightening less than 2% but not less than 0.2%
Nothing is moist almost without drawing：Draw wet weightening less than 0.2%
Result shows, crystal formation A of the invention increases weight 0.28% after being balanced under 80% humidity, slightly draw moist.
Claims (9)
1. the crystal formation A of the mucate of formula (I) compound,
Characterized in that, its X-ray powder diffraction figure 2theta values be 13.4 ° ± 0.2 °, 25.5 ° ± 0.2 °, 19.6 ° ±
0.2 °, 24.8 ° ± 0.2 °, 26.6 ° ± 0.2 °, there is at 17.3 ° ± 0.2 ° characteristic peak.
2. the crystal formation A of formula (I) compound mucate according to claim 1, is further characterized in that, its x-ray powder spreads out
Penetrate figure 2theta values be 23.1 ° ± 0.2 °, 22.5 ° ± 0.2 °, 21.8 ° ± 0.2 ° place is with characteristic peak.
3. the crystal formation A of formula (I) compound mucate according to claim 2, it is characterised in that its X-ray powder diffraction
Figure is substantially consistent with Fig. 1.
4. a kind of method of the mucate of formula (I) compound prepared described in claim 1, it include making formula (I) compound with
Glactaric acid reacts, and stirring and crystallizing is that can obtain.
5. method according to claim 4, its described reaction is carried out in a solvent, and the solvent is acetonitrile, alcohols, ethers
Or its mixed solvent with water.
6. method according to claim 5, described alcohols is methyl alcohol, and the ethers is tetrahydrofuran.
7. method according to claim 6, wherein the volume ratio of the acetonitrile, alcohols, ethers and water is between 10:1-20:
1。
8. a kind of pharmaceutical composition, the crystalline substance of the mucate of its formula (I) compound for containing with good grounds claims 1 to 3 any one
Type and pharmaceutically acceptable carrier.
9. the crystal formation of the mucate of formula (I) compound according to claims 1 to 3 any one or according to claim 8
Purposes of the described pharmaceutical composition in treatment metastatic medullary thyroid carcinoma medicine is prepared.
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| CN104961681B true CN104961681B (en) | 2017-06-13 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11814356B1 (en) | 2023-03-29 | 2023-11-14 | Apotex Inc. | Salt of cabozantinib |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL3630726T3 (en) | 2017-05-26 | 2022-05-09 | Exelixis, Inc. | Crystalline solid forms of salts of n-{4-[(6,7-dimethoxyquinolin-4-yl) oxy]phenyl}-n'-(4-fluorphenyl) 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 |
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 |
-
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 (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11814356B1 (en) | 2023-03-29 | 2023-11-14 | Apotex Inc. | Salt of cabozantinib |
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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. |