CN104364248A - Flumatinib mesylate crystal form and preparation method and use thereof - Google Patents
Flumatinib mesylate crystal form and preparation method and use thereof Download PDFInfo
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- CN104364248A CN104364248A CN201380031403.6A CN201380031403A CN104364248A CN 104364248 A CN104364248 A CN 104364248A CN 201380031403 A CN201380031403 A CN 201380031403A CN 104364248 A CN104364248 A CN 104364248A
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- crystal formation
- methanesulfonic acid
- fluorine imatinib
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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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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Abstract
Provided is a flumatinib mesylate crystal form C, the preparation method, pharmaceutical composition thereof and the use in the preparation of medicine for treating chronic myelogenous leukemia. The crystal form C has a good stability and dissolvability.
Description
Methanesulfonic acid fluorine imatinib crystal formation and its production and use technical field
The present invention relates to a kind of methanesulfonic acid fluorine imatinib crystal formation and preparation method thereof, and the crystal formation pharmaceutical composition containing therapeutically effective amount and its application in treatment chronic myelogenous leukemia.Background technology
In patient with chronic myelogenous leukemia, have 95% above is due to chromosome translocation, generation BCR-ABL fusion proteins cause high expression ABL tyrosine activation enzymatic activity, produce a large amount of abnormal white cells.
In the prior art, there are recombinant interferon a-2a, cytarabine, homoharringtonine and Imatinib for treating chronic myelogenous leukemia medicine.Gleevec（Imatinib）It is the key agents for treating chronic myelogenous leukemia, cure mechanism is by suppressing BCR-ABL activity so as to suppress the propagation of cancer cell, while going back cancer cell specific induction of apoptosis；95% patient is worked after one to March of taking medicine, and cancer cell is reduced, and blood cell number returns to normal value.Gleevec（Imatinib）It is first medicine that targeted kinase and adjustment signal conduction are determined based on human genome research, is an important breakthrough in scientific research history.Its sales volume is 6.15 hundred million dollars within 2002, 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 generate drug resistance.As a rule, the generation of drug resistance is, because BCR-ABL is made a variation, to cause the structural change of enzyme so that Gleevec can not be in connection.The patient that many takes the medicine occurs in that drug resistance, and reason is due to the variation of BCR-ABL fusion proteins, result in the change of ABL enzymatic structures.By studying Gleevec and the crystal structure of the interaction of ABL kinases, the important combination sublocus that the kinases has a Gleevec not use is found.
WO 2006069525 (its Chinese patent families is CN 200580020883.1) discloses methanesulfonic acid fluorine imatinib, its chemical entitled 4- ((4- methyl isophthalic acid-piperazinyl）Methyl）- N- [6- methyl -5- [[4- (3- pyridine radicals) -2- pyrimidine radicals] amino] pyridine radicals -3-] -3- (trifluoromethyl)-benzamide methanesulfonate, structure is shown below：
Methanesulfonic acid fluorine imatinib introduces suitable group to improve the adhesion of compound and kinases on the architecture basics of Gleevec, while expecting to improve the adhesion with kinase mutant type.Found by the research of methanesulfonic acid fluorine imatinib Anticancer Effect and Mechanism, it is stronger than Gleevec about 30 times that methanesulfonic acid fluorine imatinib suppresses intracellular BCR-ABL tyrosinase activities.As " me too " medicine of Gleevec, methanesulfonic acid fluorine imatinib is also for BCR-ABL designs.Gleevec is compared to, methanesulfonic acid fluorine imatinib introduces suitable group in structure can improve the adhesion with kinases, and is expected to improve the adhesion to kinase mutant type.Simultaneously in terms of chronic myelogenous leukemia is treated, the drug effect of methanesulfonic acid fluorine imatinib will be apparently higher than Gleevec, therefore has more wide market potential.The content of the invention
It is an object of the invention to provide the crystal formation of methanesulfonic acid fluorine imatinib, the crystal formation is crystal formation C, and the crystal formation have passed through X-ray diffraction detection, the Cu-Ka radiation used, and 2 Θ angles of its characteristic peak are 9.60,11.12,12.78,13.34,14.94,15.24,15.48,17.38,17.70,18.74,19.24,19.72,20.10,20.52,22.08,23.30,24.08,24.52,25.76,27.18,29.18 ± 0.2.
Another object of the present invention is to provide the preparation method of above-mentioned methanesulfonic acid fluorine imatinib crystal formation, the preparation method of the crystal formation has two kinds：
(1) the fluorine imatinib of any solid-state form is placed in the in the mixed solvent of water, organic solvent and methanesulfonic acid composition, solid dissolved clarification is heated to, a certain amount of organic solvent is added, afterwards natural cooling under agitation, solid is separated out, filtration drying obtains crystal formation c.The temperature of heating be room temperature to the arbitrary temp between reflux temperature, be preferable over 50 ± 5 °C.Cooling crystallization temperature is preferably 25 °C from 0-40 °C.5-60 hours stirring and crystallizing time, it is preferable over 24 hours, resulting solid is methanesulfonic acid fluorine imatinib crystal formation C.
(2) the methanesulfonic acid fluorine imatinib of any solid-state form is dissolved by heating in aqueous solvent, protected
Hold temperature and add acetone, then natural cooling under agitation, separate out solid, filtration drying obtains crystal formation c.The temperature of heating be room temperature to the arbitrary temp between reflux temperature, be preferable over 50 ± 5 °C.Cooling crystallization temperature is preferably 25 °C from 0-40 °C.5-60 hours stirring and crystallizing time, it is preferable over 24 hours, resulting solid is methanesulfonic acid fluorine imatinib crystal formation C.
Another object of the present invention is to provide the pharmaceutical composition containing methanesulfonic acid fluorine imatinib crystal formation C, it includes methanesulfonic acid fluorine imatinib crystal formation C and one or more pharmaceutical excipients；Its existence form is selected from tablet, capsule, dispersant and supensoid agent, preferred tablet and capsule；Said composition includes being suitable to the methods of administration, preferably oral administration route such as oral and injection.
Another object of the present invention is to provide above-mentioned methanesulfonic acid fluorine imatinib crystal formation C or application of the drug regimen in treatment chronic myelogenous leukemia medicine is prepared containing above-mentioned methanesulfonic acid fluorine imatinib crystal formation C.
Methanesulfonic acid fluorine imatinib crystal formation C provided by the present invention has preferable stability and dissolubility, and the crystal formation is soluble in water, and the lg crystal form samples can be dissolved in 9ml purified waters, and this advantage studies highly beneficial to preparation prescription.Brief description of the drawings
Fig. 1:Methanesulfonic acid fluorine imatinib crystal formation C XRD spectrum.
Fig. 2:Methanesulfonic acid fluorine imatinib crystal formation C preparations（Tablet）XRD spectrum.
Fig. 3:The XRD spectrum of methanesulfonic acid fluorine imatinib crystal formation C formulation blank auxiliary materials.Embodiment
Embodiment one：By fluorine imatinib 10g, water 10ml and acetone 53ml are placed in reaction bulb, methanesulfonic acid 1.7g is added under conditions of stirring, 50 °C, solid dissolving are heated to afterwards, room temperature is naturally cooled under conditions of stirring, stirring 24 hours, separates out solid, filtering, vacuum drying obtains crystal formation C, and its XRD spectrum is as shown in Figure 1.
Embodiment two：Methanesulfonic acid fluorine imatinib 10g is added to water 12ml and acetone 120ml in the mixed solvents, 50 °C are heated to, solid all dissolves, room temperature is naturally cooled under conditions of stirring, is stirred 24 hours, filtering, vacuum drying obtains crystal formation C, and its XRD spectrum is as shown in Fig. 1.
The stability test of test example one
Three batches of crystal form samples are prepared, 6 have been carried out under the conditions of 40 °C of temperature, humidity 75%
The moon stable investigation, as a result shows that the crystal formation is highly stable, stability data such as table 1:
Stability data under the conditions of 40 °C of 1 temperature of table, humidity 75%
Sample is subjected to 12 months study on the stability under the conditions of the V of temperature 25, humidity 60%, really shows that the crystal formation is highly stable, stability data such as table 2:
The temperature 25 of table 2.Stability data under the conditions of C, humidity 60%
The preparation process stability of test example two and agent in vitro dissolution rate
The present invention has carried out preparation process stability to crystal formation c samples and agent in vitro dissolution rate is surveyed
Piece agent is prepared respectively according to preparation process, and preparation prescription is as follows:
Methanesulfonic acid fluorine imatinib 2g
Low-substituted hydroxypropyl cellulose 3g
Calcium monohydrogen phosphate 0.4g
Superfine silica gel powder 0.3g
50% ethanol water 0.8g
Sodium carboxymethyl starch 0.6g
Magnesium stearate o.ig
(one）Preparation process stability test
Pass through the prepared tablet of x-ray powder diffraction instrument detection（Collection of illustrative plates is as shown in Figure 2）With auxiliary material mixture used in preparation（Collection of illustrative plates is as shown in Figure 3）, corresponding data are contrasted, found in production process, crystal formation does not change.Specific data are as shown in table 3.
Table 3:Methanesulfonic acid fluorine imatinib crystal formation C, tablet and blank auxiliary X ray diffracting data
(two）The test of tablet dissolution in vitro
It is that raw material prepares 3 batches of formulation samples, respectively formulation samples one, formulation samples two and formulation samples three with crystal formation C made from same batch of the invention.Taken out at random from every batch of formulation samples
6 samples are taken, methanesulfonic acid fluorine imatinib dissolution data in 45 minutes are determined in simulate the gastric juice environment, as a result shows that methanesulfonic acid fluorine imatinib crystal formation C sample dissolution data are very good, has reached medicinal requirement.Specific data are as shown in table 4：
The crystal formation preparation of table 4（Tablet）In Vitro Dissolution data
Sample
Title average value
1 2 3 4 5 6
The formulation samples 3 of the formulation samples 2 of formulation samples 1 98.1% 98.3% 99.1% 97.4% 95.5% 97.9% 96.6% 96.2% 95.7% 95.2% 101.5% 100.6% 97.6% 92.9% 90.8% 102.6% 95.5% 95.4% 97.1% 95.7%
Claims (1)
- Claims:1st, methanesulfonic acid fluorine imatinib crystal formation, it is characterised in that the crystal formation is crystal formation c, itsXRD spectrum characteristic peak has 2 Θ angles (± 0.2. )：9.60,11.12,13.34,15.48,17.70,18.74,19.24,19.72,22.08,24.08,24.52,25.76,27.18,29.18.2nd, methanesulfonic acid fluorine imatinib crystal formation according to claim 1, its XRD spectrum is as shown in Figure 1.3rd, a kind of method for preparing methanesulfonic acid fluorine imatinib crystal formation according to claim 2, comprises the following steps：1. fluorine imatinib is mixed with water, organic solvent and methanesulfonic acid, being heated to certain temperature dissolves it, forms solution；2. organic solvent is added, solid precipitation is cooled to；3. filtering crystals obtain methanesulfonic acid fluorine imatinib crystal formation C.4th, a kind of method for preparing methanesulfonic acid fluorine imatinib crystal formation according to claim 2, comprises the following steps：1. any solid form of methanesulfonic acid fluorine imatinib is mixed with water and organic solvent mixed liquor, heating certain temperature dissolves it, forms solution；2. it is cooled to solid precipitation；3. filtering crystals obtain methanesulfonic acid fluorine imatinib crystal formation C.5th, the method for preparing methanesulfonic acid fluorine imatinib crystal formation according to any one of claim 3 or 4, wherein described organic solvent is acetone.6th, the method for preparing methanesulfonic acid fluorine imatinib crystal formation according to any one of claim 3 or 4, wherein described certain temperature is selected from room temperature to the arbitrary temp between reflux temperature.7th, the method according to claim 6 for preparing methanesulfonic acid fluorine imatinib crystal formation, wherein described certain temperature is selected from 50 ± 5 °C. 8th, a kind of pharmaceutical composition, it includes the sour fluorine imatinib crystal formation of formic acid according to claim 1 or 2 and one or more pharmaceutical excipients.9th, pharmaceutical composition according to claim 8, the wherein existence form of described pharmaceutical composition are selected from tablet or capsule.10th, the application of methanesulfonic acid fluorine imatinib crystal formation according to claim 1 or 2 or pharmaceutical composition according to claim 8 or claim 9 in treatment chronic myelogenous leukemia medicine is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201380031403.6A CN104364248B (en) | 2012-10-09 | 2013-09-23 | Methanesulfonic acid fluorine imatinib crystal formation and its production and use |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210379385.8A CN103709147A (en) | 2012-10-09 | 2012-10-09 | Flumatinib mesylate crystal form, preparation method thereof and applications thereof |
| CN201210379385.8 | 2012-10-09 | ||
| CN2012103793858 | 2012-10-09 | ||
| CN201380031403.6A CN104364248B (en) | 2012-10-09 | 2013-09-23 | Methanesulfonic acid fluorine imatinib crystal formation and its production and use |
| PCT/CN2013/083968 WO2014056396A1 (en) | 2012-10-09 | 2013-09-23 | Flumatinib mesylate crystal form and preparation method and use thereof |
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| CN104364248A true CN104364248A (en) | 2015-02-18 |
| CN104364248B CN104364248B (en) | 2016-12-14 |
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| CN201380031403.6A Active CN104364248B (en) | 2012-10-09 | 2013-09-23 | Methanesulfonic acid fluorine imatinib crystal formation and its production and use |
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| CN (2) | CN103709147A (en) |
| TW (1) | TWI603968B (en) |
| WO (1) | WO2014056396A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114259497A (en) * | 2016-07-26 | 2022-04-01 | 江苏豪森药业集团有限公司 | Pharmaceutical composition of aminopyrimidine compounds and preparation method thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105198860A (en) * | 2014-06-12 | 2015-12-30 | 江苏豪森药业股份有限公司 | Novel flumatinib mesylate crystal form and preparation method and application thereof |
| CN105777714B (en) * | 2016-03-11 | 2018-09-07 | 江苏豪森药业集团有限公司 | The process for purification of fluorine imatinib |
| CN107652269A (en) * | 2016-07-26 | 2018-02-02 | 江苏豪森药业集团有限公司 | Methanesulfonic acid fluorine imatinib purification of intermediate method |
| CN111505032B (en) * | 2019-01-30 | 2023-11-21 | 昆药集团股份有限公司 | Method for detecting dihydroartemisinin crystal form in dihydroartemisinin tablet |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006069525A1 (en) * | 2004-12-31 | 2006-07-06 | Piaoyang Sun | Aminopyrimidine compounds and their salts, process for preparation and pharmaceutical use thereof |
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- 2012-10-09 CN CN201210379385.8A patent/CN103709147A/en active Pending
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- 2013-09-23 WO PCT/CN2013/083968 patent/WO2014056396A1/en active Application Filing
- 2013-09-23 CN CN201380031403.6A patent/CN104364248B/en active Active
- 2013-09-30 TW TW102135288A patent/TWI603968B/en active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006069525A1 (en) * | 2004-12-31 | 2006-07-06 | Piaoyang Sun | Aminopyrimidine compounds and their salts, process for preparation and pharmaceutical use thereof |
Non-Patent Citations (1)
| Title |
|---|
| GANG XU ET AL.: "Synthesis, Crystal Structure, and Spectral Characterization of Flumatinib Mesylate", 《SYNTHETIC COMMUNICATIONS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114259497A (en) * | 2016-07-26 | 2022-04-01 | 江苏豪森药业集团有限公司 | Pharmaceutical composition of aminopyrimidine compounds and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| TWI603968B (en) | 2017-11-01 |
| WO2014056396A1 (en) | 2014-04-17 |
| CN103709147A (en) | 2014-04-09 |
| TW201414726A (en) | 2014-04-16 |
| CN104364248B (en) | 2016-12-14 |
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