CN104974139B - Methanesulfonic acid fluorine imatinib novel crystal forms and preparation method thereof and medical usage - Google Patents
Methanesulfonic acid fluorine imatinib novel crystal forms and preparation method thereof and medical usage Download PDFInfo
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- CN104974139B CN104974139B CN201410135726.6A CN201410135726A CN104974139B CN 104974139 B CN104974139 B CN 104974139B CN 201410135726 A CN201410135726 A CN 201410135726A CN 104974139 B CN104974139 B CN 104974139B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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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 discloses methanesulfonic acid fluorine imatinib novel crystal forms and preparation method thereof and medical usages.In particular it relates to a kind of novel crystal forms of methanesulfonic acid fluorine imatinib and preparation method thereof, and the compound containing therapeutically effective amount pharmaceutical composition and the application in treatment chronic myelogenous leukemia.The crystal form favorable reproducibility, stabilization are easy to get, and are very suitable to formulation application.
Description
Technical field
The present invention relates to a kind of novel crystal forms of methanesulfonic acid fluorine imatinib and preparation method thereof, and being somebody's turn to do containing therapeutically effective amount
The pharmaceutical composition of compound.
Background technique
In patient with chronic myelogenous leukemia, 95% or more is to generate BCR-ABL fusion due to chromosome translocation
Albumen leads to high expression ABL tyrosine activation enzymatic activity, generates a large amount of abnormal white cells.
In the prior art, there are recombinant interferon a-2a, cytarabine, high tricuspid for treating chronic myelogenous leukemia drug
China fir ester alkali and Imatinib.Gleevec (Imatinib) is the key agents for treating chronic myelogenous leukemia, and cure mechanism is logical
It crosses and inhibits the activity of BCR-ABL to inhibit the proliferation of cancer cell, while going back cancer cell specific induction of apoptosis；95% patient is taking medicine
It works after one to March, cancer cell is reduced, and blood cell number returns to normal value.Gleevec (Imatinib) is first and is based on
Human genome studies the drug to determine targeted kinase and adjustment signal conduction, is an important breakthrough in scientific research history.
Its sales volume in 2002 is 6.15 hundred million dollars, and 2003 annual sales amounts break through 1,000,000,000 dollars, rank among " best-selling drugs " ranks.But
Many chronic myelogenous leukemia patients that discovered in recent years takes Gleevec produce drug resistance.In most cases, drug resistance
Generation be because BCR-ABL made a variation, cause the structure of enzyme to change, prevent Gleevec is from connection.
As " me too " drug of Gleevec, methanesulfonic acid fluorine imatinib is also to design for BCR-ABL.It is compared to lattice
Column are defended, and methanesulfonic acid fluorine imatinib introduces suitable group in structure can improve binding force with kinases, and be expected to mention
Binding force of the height to kinase mutant type.Simultaneously in terms for the treatment of chronic myelogenous leukemia, the drug effect of methanesulfonic acid fluorine imatinib wants bright
It is aobvious to be higher than Gleevec, therefore there is more extensive market potential.
Summary of the invention
The purpose of the present invention is to provide a kind of crystal form D of methanesulfonic acid fluorine imatinib.
The crystal form have passed through X-ray diffraction detection, and the Cu-Ka radiation used, 2 θ ± 0.2 are 3.81,6.33,9.61,
There is diffraction maximum at 18.81,19.17,25.33 °.
Preferably, in XRD spectrum the crystal form 2 θ ± 0.2 ° be 3.81,6.33,9.61,11.11,15.34,18.81,
There is diffraction maximum at 19.17,25.33.
It is furthermore preferred that the crystal form is 3.81,6.33,9.61,11.11,11.99,12.62,15.05 in 2 θ ± 0.2 °,
There is diffraction maximum at 15.34,16.76,17.97,18.81,19.17,19.77,20.77,25.33,28.16
Another object of the present invention is to provide the preparation methods of methanesulfonic acid fluorine imatinib crystal form D, and this method is will be any
The methanesulfonic acid fluorine imatinib of solid-state form dissolves in a solvent, anti-solvent is then added under agitation, solid, filtering is precipitated
Obtain crystal form D.
Preferably, solvent used in above-mentioned preparation method is water, and anti-solvent is Isosorbide-5-Nitrae-dioxane.Specific method is, first
The methanesulfonic acid fluorine imatinib of any solid-state form is dissolved in water first, can be added using certain means during dissolution
Fast solution rate, such as heating or ultrasonic oscillation etc., are cooled to certain temperature for solution after dissolution, cooling temperature is generally
10-40 DEG C, preferably 20-30 DEG C, most preferably 25 DEG C；Then anti-solvent is added, keeps the temperature temperature stirring a period of time, generally 1-48 is small
When, preferably 20-30 hours, most preferably 24 hours；The solid that crystallization obtains to get arrive methanesulfonic acid fluorine imatinib crystal form D.
Preferably, solvent used in above-mentioned preparation method may be ethyl alcohol, and anti-solvent is isopropyl ether.Specific method be by
The methanesulfonic acid fluorine imatinib of any solid-state form is heated to certain temperature dissolution in ethanol, and heating temperature is generally 30-60 DEG C,
It is preferred that 40 DEG C -50 DEG C, most preferably 45 DEG C, keep the temperature at 45 DEG C after dissolved clarification；Then isopropyl ether is slowly added dropwise to solid is precipitated,
It crosses filter solid and obtains methanesulfonic acid fluorine imatinib crystal form D.
Another object of the present invention is to provide the pharmaceutical compositions containing methanesulfonic acid fluorine imatinib crystal form D.
Exist in addition, another object of the present invention also resides in pharmaceutical composition of the offer containing methanesulfonic acid fluorine imatinib crystal form D
The application of drug in preparation treatment chronic myelogenous leukemia.
Another object of the present invention also resides in offer and contains methanesulfonic acid fluorine imatinib crystal form D as active component and medicinal load
The pharmaceutical composition of other therapeutic components existing for body, diluent or excipient and selectivity.Composition of the invention includes suitable
In administration routes, preferably oral administration route such as oral and injections.Dosage form includes tablet, capsule, dispersing agent and suspension, preferably
Tablet and capsule.
The present invention also provides application of the methanesulfonic acid fluorine imatinib crystal form D in treatment chronic myelogenous leukemia.
Inventor passes through verification experimental verification, and methanesulfonic acid fluorine imatinib crystal form D is a kind of stable crystal form, and the sample of the crystal form exists
50 DEG C at least can there is no variations for physical state and chemical state in 10 days；The object in the case where grinding the pressure with 10MPa simultaneously
Physicochemical property is stablized, and the sample of the crystal form is soluble in water, these properties are highly beneficial to preparation.
Detailed description of the invention
Fig. 1 is the XRD spectrum of the crystal form D of methanesulfonic acid fluorine imatinib of the present invention.
Specific embodiment
Embodiment one
Methanesulfonic acid fluorine imatinib 1.0g and water 2.0ml are set in a round bottom flask, are heated to 65 DEG C, solid matter is completely molten
Solution naturally cools to 25 DEG C under stirring conditions, and Isosorbide-5-Nitrae-dioxane 20ml is added dropwise, and stirs 24 hours, and solid, filtering is precipitated
Crystal form D is obtained, through detecting, XRD spectrum is as shown in Figure 1.
Embodiment two
Methanesulfonic acid fluorine imatinib 1.0g and ethyl alcohol 3.0ml are set in a round bottom flask, are heated to 45 DEG C, solid is completely molten
Solution, isopropyl ether 2.0ml is slowly added dropwise under stirring conditions, stirs heat preservation and mixes 1 hour, and solid, filtering is precipitated, and vacuum drying obtains
Crystal form D, through detecting, XRD spectrum is nearly identical with Fig. 1, and can confirm products obtained therefrom is crystal form D.
One stable crystal form Journal of Sex Research of test example
The two batches crystal form samples are prepared, has carried out stablizing for 6 months under the conditions of 40 DEG C of temperature, humidity 75% and investigate, stability
Data such as table 1:
Stability data under the conditions of 40 DEG C of 1 temperature of table, humidity 75%
Sample is subjected to 12 months study on the stability under the conditions of 25 DEG C of temperature, humidity 60%, the results showed that the crystal form is very
Stablize, stability data such as table 2:
Stability data under the conditions of 25 DEG C of 2 temperature of table, humidity 60%
It can be seen that stability of crystal form of the present invention from sample stability investigation data to do well, be suitble to medicine quality mark
It is quasi-.
Claims (12)
1. a kind of preparation method of methanesulfonic acid fluorine imatinib crystal form D, which comprises the steps of:
1) any solid form of methanesulfonic acid fluorine imatinib salt is mixed with solvent, dissolves it all, solution is made, it is described molten
Agent is water or ethyl alcohol；
2) anti-solvent is added into the solution of preparation, the anti-solvent is Isosorbide-5-Nitrae-dioxane or isopropyl ether；
3) stirring and crystallizing obtains crystal form D；
Wherein, 2 θ ± 0.2 ° are included at least in the XRD spectrum of crystal form D are as follows: 3.81,6.33,9.61,18.81,19.17,25.33
Diffraction maximum.
2. preparation method according to claim 1, which is characterized in that in the XRD spectrum of the crystal form D include at least 2 θ ±
0.2 ° are as follows: 3.81,6.33,9.61,11.11,15.34,18.81,19.17,25.33 diffraction maximum.
3. preparation method according to claim 1, which is characterized in that include 2 θ ± 0.2 ° in the XRD spectrum of the crystal form D
Are as follows: 3.81,6.33,9.61,11.11,11.99,12.62,15.05,15.34,16.76,17.97,18.81,19.17,
19.77,20.77,25.33,28.16 diffraction maximum.
4. preparation method according to claim 1 to 3, which is characterized in that the solvent of the step 1) is water,
The anti-solvent of the step 2) is Isosorbide-5-Nitrae-dioxane, and crystallization temperature is 10-40 DEG C.
5. the preparation method according to claim 4, which is characterized in that crystallization temperature is 20-30 DEG C.
6. preparation method according to claim 5, which is characterized in that crystallization temperature is 25 DEG C.
7. preparation method according to claim 1 to 3, which is characterized in that the solvent of the step 1) is second
Alcohol, the anti-solvent of the step 2) are isopropyl ether, and crystallization temperature is 30-60 DEG C.
8. preparation method according to claim 7, which is characterized in that crystallization temperature is 40-50 DEG C.
9. preparation method according to claim 8, which is characterized in that crystallization temperature is 45 DEG C.
10. a kind of medicine of the formic acid acid fluorine imatinib crystal form D prepared comprising preparation method described in claim 1-9 any one
Compositions.
11. pharmaceutical composition according to claim 10, which is characterized in that tablet or capsule is made in the composition.
12. the methanesulfonic acid fluorine imatinib crystal form D that a kind of method described in -9 any one according to claim 1 is prepared is as work
Property ingredient preparation treatment chronic myelogenous leukemia drug in application.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1972917B (en) * | 2004-12-31 | 2010-08-25 | 孙飘扬 | Aminopyrimidine compounds and their salts, process for preparation and pharmaceutical use thereof |
| CN103509006A (en) * | 2012-06-19 | 2014-01-15 | 江苏豪森医药集团连云港宏创医药有限公司 | Flumatinib mesylate crystal form, and preparation method and use thereof |
| CN103509007A (en) * | 2012-06-19 | 2014-01-15 | 江苏豪森医药集团连云港宏创医药有限公司 | Flumatinib mesylate crystal form and preparation method and use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1972917B (en) * | 2004-12-31 | 2010-08-25 | 孙飘扬 | Aminopyrimidine compounds and their salts, process for preparation and pharmaceutical use thereof |
| CN103509006A (en) * | 2012-06-19 | 2014-01-15 | 江苏豪森医药集团连云港宏创医药有限公司 | Flumatinib mesylate crystal form, and preparation method and use thereof |
| CN103509007A (en) * | 2012-06-19 | 2014-01-15 | 江苏豪森医药集团连云港宏创医药有限公司 | Flumatinib mesylate crystal form and preparation method and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis,Crystal Structure,and Spectral Characteration of Flumatinib Mesylate;GANG Xu et al.;《Synthetic Communications》;20100805(第40期);第2564-2570页 |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL Co.,Ltd. |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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