CN105732589A - Phosphate of epidermal growth factor receptor inhibitor, crystal form of phosphate and preparation method - Google Patents

Phosphate of epidermal growth factor receptor inhibitor, crystal form of phosphate and preparation method Download PDF

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CN105732589A
CN105732589A CN201610075989.1A CN201610075989A CN105732589A CN 105732589 A CN105732589 A CN 105732589A CN 201610075989 A CN201610075989 A CN 201610075989A CN 105732589 A CN105732589 A CN 105732589A
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crystal form
formula
compound
phosphate
preparation
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陈敏华
张炎锋
刘凯
夏楠
张晓宇
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Crystal Pharmatech Co Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

The invention provides phosphate of an epidermal growth factor receptor inhibitor, a crystal form of the phosphate and a preparation method and relates to a phosphate crystal form A of a compound shown as the formula (I) and a preparation method of the phosphate crystal form A.The phosphate crystal form A has good solubility, low hygroscopicity, technological development and other beneficial properties.The preparation method is simple, cost is low, and significant value is achieved for optimization and development of the medicine in the future.(Please see the description for the formula (I).).

Description

The phosphate of a kind of epidermal growth factor receptor inhibitor, its crystal formation and preparation method
Technical field
The present invention relates to chemical medicine, particularly relate to N-(2-(2-dimethylaminoethyl-methylamino)-4-methoxyl group-5-(4-(1-methylindole-3-base) pyrimidine-2-base) aminophenyl) phosphate of the third-2-alkene amide, its crystal formation and preparation method.
Background technology
For Advanced Non-Small Cell adenocarcinoma of lung (NSCLC) patient, the targeted therapy that EGF-R ELISA (EGFR) and anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) suddenly change is standard regimens now.But, the curative effect of these medicines is general very of short duration, within 9-11 month, will produce drug resistance, why occur that this situation is because cancerous cell and can escape the therapeutic activity of EGFR or ALK inhibitor by suddenling change and changing growth pattern.
For the EGFR telomutation that patients with lung cancer occurs, currently without suitable medicine, it is treated.And the formula I compound (having another name called AZD9291) that Astrazeneca AB (AstraZeneca) researches and develops is a kind of oral, irreversible, third generation EGFR inhibitor, preclinical models research has remarkable result, and existing epidermal growth factor recipient tyrosine kinase inhibitor (EGFR-TKI) is had the NSCLC patient of resistance and T790M sudden change to have preferably therapeutic effect by this medicine.Formula I compound chemistry name is called N-(2-(2-dimethylaminoethyl-methylamino)-4-methoxyl group-5-(4-(1-methylindole-3-base) pyrimidine-2-base) aminophenyl) the third-2-alkene amide.
Chinese patent application CN103702990A discloses the structure of formula I compound.This patent application also discloses the polymorphic of formula I compound and mesylate thereof.
By becoming the dissolubility that salt mode improves candidate compound to become the important means in medicament research and development.Compared with the free form of medicine, suitable drug salts can improve the dissolubility of medicine, increase physical and chemical stability, and medicine also can improve the physical propertys such as its fusing point, hygroscopicity, crystalline types after becoming salt, further developing drugs dosage form is had important function.Yuan Yan company have employed the mesylate of formula I compound for clinical research.But, methanesulfonic acid bio-toxicity is high, is not suitable for patent medicine in selectable situation.(P.HeinrichStahl,CamilleG.Wermuth(Eds.).(2002).HandbookofPharmaceuticalSalts:Properties,Selection,andUse,294-302)
Thus, develop that bioavailability height, toxicity are little and applicable other medicinal salt are very necessary.
Summary of the invention
It is an object of the present invention to provide the phosphate of formula I compound.Phosphate solubility provided by the invention is high, low in hygroscopicity, and biological safety is high, fulfilling medicinal requirements, and preparation method is simple, is suitable to drug research and industrialized production.
The phosphate of formula I compound provided by the invention is crystal form, in the present invention called after crystal form A.
The X-ray powder diffraction figure of crystal form A provided by the invention is that 9.8 ° ± 0.2 °, 10.9 ° ± 0.2 °, 16.4 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, the X-ray powder diffraction figure of crystal form A provided by the invention is that 7.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, the X-ray powder diffraction figure of crystal form A provided by the invention is that 8.2 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.4 ° ± 0.2 ° place has characteristic peak in 2theta value.
In a specific embodiment, the X-ray powder diffraction figure of crystal form A provided by the invention is that 7.5 ° ± 0.2 °, 8.2 ° ± 0.2 °, 9.8 ° ± 0.2 °, 10.9 ° ± 0.2 °, 16.4 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.4 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
In another embodiment, the X-ray powder diffraction figure of crystal form A provided by the invention is substantially as shown in Figure 1.
Further, crystal form A provided by the invention starts endothermic peak occur when heating is to about 235 DEG C, and its differential scanning calorimetric thermogram is substantially as shown in Figure 2.
Further, crystal form A provided by the invention, when heating is to 200 DEG C, has the loss in weight gradient of about 1.5%, and its thermogravimetric analysis figure is as shown in Figure 3.
The preparation method that it is a further object to provide formula I compound phosphate crystal form A, including making formula I compound and phosphoric acid react in ketone, alcohols solvent, stirring and crystallizing obtains.
Further, the described alcohols solvent preferred carbon number alcohols less than 6, more preferably methanol or ethanol.
Further, the described ketones solvent preferred carbon number ketone less than 6, more preferably acetone.
Further, formula I compound is 1:1 with the mol ratio of phosphoric acid.
Formula I compound phosphate provided by the invention, particularly the phosphatic crystal form A of formula I compound can be used for treating the preparation of cancer drug, especially for the preparation for the treatment of non-small cell lung cancer drug.
Another purpose of the present invention is to provide a kind of pharmaceutical composition, and this pharmaceutical composition is with formula I compound phosphate crystal form A for active component, adds the conventional adjuvant of medicine and is prepared from.
It is a further object to provide formula I compound phosphate crystal form A or its pharmaceutical composition purposes in preparation treatment cancer drug.
The invention have the benefit that
The biological safety of formula I compound phosphate crystal form A provided by the invention is higher, overcomes the problem that mesylate toxicity is big, is particularly suited for drug development；
Drawing of formula I compound phosphate crystal form A provided by the invention is moist lower, overcomes mesylate and draws moist height and the deliquescent problem of high humility；
Formula I compound phosphate crystal form A provided by the invention is higher than the dissolubility of formula I compound as its free base, meets bioavailability and drug effect requirement.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of compound of formula I phosphate crystal form A；
Fig. 2 is the DSC figure of compound of formula I phosphate crystal form A；
Fig. 3 is the TGA figure of compound of formula I phosphate crystal form A；
Fig. 4 is compound of formula I phosphate crystal form A1HNMR schemes；
Fig. 5 is the DVS figure of compound of formula I phosphate crystal form A；
Fig. 6 is the DVS figure of compound of formula I Mesylate Form B；
The XRPD comparison diagram of 1 month stability test that Fig. 7 is compound of formula I phosphate crystal form A under different test conditions (be followed successively by the XRPD of initial sample from top to bottom, 5 DEG C, 25 DEG C/60%RH and 40 DEG C/75%RH place 1 month after the XRPD of sample)；
The XRPD comparison diagram of 3 months stability tests that Fig. 8 is compound of formula I phosphate crystal form A under different test conditions (be followed successively by the XRPD of initial sample from top to bottom, 5 DEG C, 25 DEG C/60%RH and 40 DEG C/75%RH place 3 months after the XRPD of sample).
Detailed description of the invention
Hereinafter the present invention will be expanded on further by specific embodiment, but be not limited to protection scope of the present invention.Preparation method and use instrument can be made improvements by those skilled in the art in right, and these improvement also should be regarded as protection scope of the present invention.
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
1HNMR: proton nmr spectra
DVS: dynamic water is adsorbed
X-ray powder diffraction figure of the present invention gathers on PanalyticalEmpyreanX ray powder diffractometer.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K-α radiates
Kα11.540598；Kα21.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliamperes (mA)
Sweep limits: spend from 3.0 to 40.0
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TAQ2000.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Thermogravimetric analysis of the present invention (TGA) figure gathers on TAQ5000.The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Dynamic water of the present invention absorption (DVS) figure gathers on the Intrinsic dynamic water adsorption instrument produced by SMS company (SurfaceMeasurementSystemsLtd.).The method parameter of described dynamic water adsorption instrument is as follows:
Temperature: 25 DEG C
Carrier gas, flow velocity: N2, 200 ml/min
Unit interval mass change: 0.002%/minute
RH range: 0%RH-95%RH
Embodiment 1
The preparation method of formula (I) compound phosphate crystal form A:
The formula I compound as its free base of 10.1mg is placed in the vial of 1.5mL, adding 0.5mL acetone makes it dissolve, add the phosphoric acid solution of the 0.2mol/L of 0.1mL, under the stirring of magnetic stirring apparatus (r=500r/min), at room temperature confined reaction 24 hours, crystallize, centrifugal gained solid at room temperature vacuum drying.
The phosphate product that said method prepares, its1As shown in Figure 4, appraising datum is as follows for HNMR:1nullHNMR(400MHz,DMSO)δ10.04(s,1H),9.03(s,1H),8.63(s,1H),8.33(d,J=5.3Hz,1H),8.27(d,J=7.9Hz,1H),7.91(s,1H),7.53(d,J=8.1Hz,1H),7.25(dd,J=8.7,6.3Hz,2H),7.16(t,J=7.5Hz,1H),7.03(s,1H),6.55(d,J=10.3Hz,1H),6.29(dd,J=16.9,1.9Hz,1H),5.84–5.71(m,1H),3.92(s,3H),3.88(s,3H),3.04(s,2H),2.69(s,3H),2.62(s,2H),2.41(s,6H).
After testing, the solid that the present embodiment obtains is formula (I) compound phosphate crystal form A, and its X-ray powder diffraction data are as shown in table 1.Its XRPD figure schemes such as Fig. 3 such as Fig. 1, its DSC figure such as Fig. 2, its TGA.
The X-ray powder diffraction data of table 1 crystal form A
Embodiment 2
The preparation method of formula (I) compound phosphate crystal form A:
The formula I compound as its free base of 10.2mg is placed in the vial of 1.5mL, adding 0.5mL ethanol makes it dissolve, add the phosphoric acid solution of the 0.2mol/L of 0.1mL, under the stirring of magnetic stirring apparatus (r=500r/min), at room temperature confined reaction 24 hours, crystallize, centrifugal gained solid at room temperature vacuum drying.
After testing, the solid that the present embodiment obtains is formula (I) compound phosphate crystal form A, and its X-ray powder diffraction data are as shown in table 2.
The X-ray powder diffraction data of table 2 crystal form A
2theta D interval Intensity %
7.43 11.91 31.68
8.17 10.83 28.63
8.57 10.32 16.45
9.76 9.06 100.00
10.70 8.27 57.18
11.85 7.47 7.92
12.25 7.22 13.48
12.85 6.89 3.59
13.60 6.51 22.65
15.20 5.83 15.23
16.37 5.41 35.12
16.78 5.28 19.18
17.49 5.07 17.43
19.51 4.55 41.64
21.51 4.13 24.69
22.56 3.94 20.93
23.55 3.78 13.26
24.47 3.64 37.67
25.06 3.55 31.75
25.64 3.47 16.14
29.97 2.98 2.23
Embodiment 3
The dynamic solubility comparative study of formula I compound phosphate crystal form A and free alkali:
Formula I compound phosphate crystal form A and free alkali are used H respectively2The simulated gastric fluid (simulatedgastricfluid, SGF) of O and pH1.8 is configured to saturated solution, respectively after 1 hour, adopts high performance liquid chromatography (HPLC) to measure content after 4 hours and after 24 hours.Experimental result is as shown in table 3.
Table 3
Result shows, formula (I) compound phosphate crystal form A dissolubility in water is far above its free alkali dissolubility in water, and in the process analyzed, find that free alkali exists 24 hours in SGF degrade, poor at Biomedia internal stability, it is unfavorable for patent medicine.The present invention passes through into phosphatic mode and overcomes the problem that free alkali dissolubility is low and unstable in Biomedia, has reached to improve the effect of bioavailability.
Embodiment 4
Formula I compound phosphate crystal form A and formula (I) compound methanesulfonic acid salt crystal form B draw moist comparative study:
Take Mesylate Form B in the phosphate crystal form A of the 10mg present invention, 10mg Chinese patent application CN103702990A respectively and carry out dynamic water absorption (DVS) test.The DVS of phosphate crystal form A as it is shown in figure 5, the DVS of Mesylate Form B as shown in Figure 6, result is table 4 such as.
Table 4
Sample 80% humidity weightening finish 95% humidity weightening finish
Formula (I) compound phosphate crystal form A 2.82% 3.47%
Formula (I) compound methanesulfonic acid salt crystal form B 6.16% 55.17% (deliquescence)
It is shown that the formula of the present invention (I) compound phosphate crystal form A increases weight 2.82% after balancing under 80% relative humidity, under 95% relative humidity, weightening finish 3.47% after balance, draws moist relatively low；And Chinese patent application CN103702990A Chinese style (I) compound methanesulfonic acid salt crystal form B increases weight 6.16% after balancing under 80% relative humidity, draw moist higher, and there occurs deliquescence after balance under 95% relative humidity.The present invention passes through into phosphatic mode and overcomes mesylate and draw moist problem high, deliquescent.
About draw moist feature description with draw moist weightening finish define (Chinese Pharmacopoeia version annex XIXJ medicine in 2010 draws moist test direction principle, experiment condition: 25 DEG C ± 1 DEG C, 80% relative humidity):
Deliquescence: absorb the fractal one-tenth liquid of enough water；
Great draw moist: draw wet weightening finish and be not less than 15%；
Have draw moist: drawing wet weightening finish and less than 15% but being not less than 2%；
Slightly draw moist: draw wet weightening finish and less than 2% but be not less than 0.2%；
Nothing or moist almost without drawing: drawing wet weightening finish less than 0.2%.
Embodiment 5
Formula (I) the compound phosphate crystal A present invention prepared is positioned over 5 DEG C, 25 DEG C/relative humidity 60%, and 40 DEG C/relative humidity when being 75% 3 months, respectively sample once respectively at 1,3 the end of month, high spot reviews has the stability of related substance and crystal formation, test shows that crystal form A has good stability, and HPLC purity data collects as shown in table 5, and XRPD comparison diagram is as shown in Figure 7 and Figure 8.
Table 5
5 DEG C, % 25 DEG C/60%RH, % 40 DEG C/75%RH, %
0 day 98.82 98.82 98.82
30 days 98.87 98.85 98.88
90 days 98.81 98.76 98.78
After 3 months, phosphate crystal A is all very stable for formula (I) compound.Stably refer to by the analysis means such as liquid phase, XRPD, namely do not find degraded, be also not detected by the transformation to other crystal formations.

Claims (10)

1. the phosphate crystal form A of formula I compound,
It is characterized in that, its X-ray powder diffraction figure is that 9.8 ° ± 0.2 °, 10.9 ° ± 0.2 °, 16.4 ° ± 0.2 ° place has characteristic peak in 2theta value.
2. the phosphatic crystal form A of formula I compound according to claim 1, it is characterised in that its X-ray powder diffraction figure is also that 7.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
3. the phosphatic crystal form A of formula I compound according to claim 1, it is characterised in that its X-ray powder diffraction figure is also that 8.2 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.4 ° ± 0.2 ° place has characteristic peak in 2theta value.
4. the phosphatic crystal form A of formula I compound according to any one of claim 1-3, it is characterized in that, its X-ray powder diffraction figure is that 7.5 ° ± 0.2 °, 8.2 ° ± 0.2 °, 9.8 ° ± 0.2 °, 10.9 ° ± 0.2 °, 16.4 ° ± 0.2 °, 16.7 ° ± 0..2 °, 17.4 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
5. the method for the phosphate crystal form A of the formula I compound that a kind is prepared described in any one of claim 1-4, it is characterised in that including making formula I compound and phosphoric acid react in ketone or alcohols solvent, stirring and crystallizing obtains.
6. method according to claim 5, it is characterised in that described alcohols solvent is the carbon number alcohols less than 6, described ketones solvent is the carbon number ketone less than 6.
7. method according to claim 6, it is characterised in that described alcohols solvent is methanol or ethanol, described ketones solvent is acetone.
8. the method according to any one of claim 5-7, it is characterised in that the mol ratio of formula I compound and phosphoric acid is 1:1.
9. a pharmaceutical composition, it is containing the formula I compound phosphate crystal form A described in good grounds Claims 1-4 any one and pharmaceutically acceptable carrier.
10. formula I compound phosphate crystal form A according to Claims 1-4 any one or the pharmaceutical composition according to claim 9 purposes in preparation treatment cancer drug.
CN201610075989.1A 2015-02-05 2016-02-03 Phosphate of epidermal growth factor receptor inhibitor, crystal form of phosphate and preparation method Pending CN105732589A (en)

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BR112019026483A2 (en) * 2017-06-16 2020-07-14 Beta Pharma, Inc. pharmaceutical formulation of n- (2- (2- (dimethylamine) ethoxy) -4-methoxy-5 - ((4- (1-methyl-1h-indol-3-yl) pyrimidin-2-yl) amine) phenyl) acrylamide and its salts
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CN113929663A (en) * 2020-06-29 2022-01-14 鲁南制药集团股份有限公司 AZD 9291-2-indole formate and preparation method thereof
CN113929664A (en) * 2020-07-13 2022-01-14 鲁南制药集团股份有限公司 AZD9291-3, 5-pyridine dicarboxylic acid salt and preparation method thereof
CN113968845A (en) * 2020-07-24 2022-01-25 鲁南制药集团股份有限公司 AZD 9291-gallate and preparation method thereof
WO2022105882A1 (en) * 2020-11-19 2022-05-27 上海翰森生物医药科技有限公司 Salt and crystal form of indole-containing derivative, and preparation methods therefor and applications thereof

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Application publication date: 20160706