CN104961731A

CN104961731A - Phosphate of epidermal growth factor receptor inhibitor, and crystal form and preparation method thereof

Info

Publication number: CN104961731A
Application number: CN201510059564.7A
Authority: CN
Inventors: 陈敏华; 张炎锋; 刘凯; 夏楠; 张晓宇; 王鹏; 李丕旭
Original assignee: SUZHOU PENGXU PHARMATECH Co Ltd; Crystal Pharmatech Co Ltd
Current assignee: SUZHOU PENGXU PHARMATECH Co Ltd; Crystal Pharmatech Co Ltd
Priority date: 2015-02-05
Filing date: 2015-02-05
Publication date: 2015-10-07
Also published as: CN105732589A; WO2016124137A1

Abstract

The invention relates to phosphate of a compound as shown in the formula (I) which is described in the specification, and a crystal form and a preparation method thereof. The phosphate of the compound has a stable crystal form; the crystal form has favorable performance like good solubility, low hygroscopicity and process developability; and the preparation method is simple and has low cost, so the method has an important value to optimization and development of the phosphate of the compound as a drug in the future.

Description

A kind of phosphoric acid salt of epidermal growth factor receptor inhibitor, its crystal formation and preparation method

Technical field

The present invention relates to chemical medicine, particularly relate to the phosphoric acid salt of N-(2-{2-dimethylaminoethyl-methylamino-}-4-methoxyl group-5-{ [4-(1-skatole-3-base) pyrimidine-2-base] is amino } phenyl) the third-2-alkene acid amides, 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 Nucleophosmin-anaplastic lymphoma 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, just can produce resistance, why occur that this situation is because cancer cells can by suddenling change and changing the therapeutic activity that growth pattern escapes EGFR or ALK inhibitor.

For the EGFR telomutation that patients with lung cancer occurs, suitable medicine is not had to treat it at present.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 unusual effect, and this medicine has the NSCLC patient of resistance and T790M sudden change to have preferably result for the treatment of to existing EGFR-TKI (epidermal growth factor recipient tyrosine kinase inhibitor).Formula I compound chemistry name is called N-(2-{2-dimethylaminoethyl-methylamino-}-4-methoxyl group-5-{ [4-(1-skatole-3-base) pyrimidine-2-base] is amino } phenyl) the third-2-alkene acid amides.

Patent CN103702990A discloses formula I compound structure.The polymorphic of formula I compound and mesylate thereof is also disclosed in this patent.

The solubleness improving candidate compound by salify mode has become the important means in medicament research and development.Compared with the free form of medicine, suitable medicine salt form can improve the solubleness of medicine, increase physical and chemical stability, and also can improve the physical propertiess such as its fusing point, water absorbability, crystalline types after medicine salify, to further developing drugs formulation, there is vital role.Yuan Yan company have employed the mesylate of formula I compound for clinical study.But methylsulfonic acid bio-toxicity is high, in selectable situation, be not suitable for patent medicine.Thus develop that bioavailability is high, toxicity is little and applicable other medicinal salt are very necessary.(P.Heinrich Stahl,Camille G.Wermuth(Eds.).(2002).Handbook of Pharmaceutical Salts:Properties,Selection,and Use,294-302)

Summary of the invention

An object of the present invention is to provide the phosphoric acid salt of formula I compound.Phosphate solubility provided by the invention is high, and draw moist low, biological safety is high, fulfilling medicinal requirements, and preparation method is simple, is suitable for drug research and suitability for industrialized production.

The phosphoric acid salt of formula I compound provided by the invention is crystallized form, 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 9.8 ° ± 0.2 °, 10.9 ° ± 0.2 °, 16.4 ° ± 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 7.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.5 ° ± 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 8.2 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.4 ° ± 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 235 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 200 DEG C, have the weight loss gradient of about 1.5%, its thermogravimetric analysis figure as shown in Figure 3.

Another object of the present invention is to provide the preparation method of formula I compound phosphoric acid salt crystal form A, it is characterized in that, comprise and formula I compound and phosphoric acid are reacted in ketone, alcoholic solvent, stirring and crystallizing obtains.

Further, the alcohols that the preferred carbonatoms of described alcoholic solvent is less than 6, more preferably methyl alcohol or ethanol.

Further, the ketone that the preferred carbonatoms of described ketones solvent is less than 6, more preferably acetone.

Further, the formula I compound of formation and the stoicheiometry of phosphoric acid are 1:1.

Formula I compound phosphoric acid salt provided by the invention, particularly the phosphatic crystallized form of formula I compound can be used for the preparation of Therapeutic cancer medicine, especially for the preparation for the treatment of non-small cell lung cancer drug.

Medicinal compositions is with the phosphatic crystallized form of formula I compound for activeconstituents, and interpolation medicine is commonly used auxiliary material and is prepared from.

Beneficial effect of the present invention is:

Formula I compound phosphoric acid salt biological safety provided by the invention is higher, overcomes the problem that mesylate toxicity is large, is more suitable for for drug development.

Formula I compound phosphoric acid salt provided by the invention draws moist lower, overcomes mesylate and draws moist height and the deliquescent problem of high humidity.

The free alkali solubleness of formula I compound phosphate ratio provided by the invention is improved, and meets bioavailability and drug effect requirement.

Accompanying drawing explanation

Fig. 1 is the XRPD figure of phosphoric acid salt crystal form A

Fig. 2 is the DSC figure of phosphoric acid salt crystal form A

Fig. 3 is the TGA figure of phosphoric acid salt crystal form A

Fig. 4 is phosphoric acid salt crystal form A ¹h NMR schemes

Fig. 5 is the DVS figure of phosphoric acid salt crystal form A

Fig. 6 is the DVS figure of Mesylate Form B

Embodiment

Below will set forth the present invention further by specific embodiment, but be not limited to protection scope of the present invention.Those skilled in the art can make improvements preparation method and use instrument in right, and these improvement also should be considered as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Being explained as follows of abbreviation used in the present invention:

XRPD:X ray powder diffraction

DSC: differential scanning calorimetric analysis

TGA: thermogravimetric analysis

¹h NMR: proton nmr spectra

DVS: dynamic water is adsorbed

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

Kα1 ：1.540598；Kα2 ：1.544426

K α 2/K α 1 intensity: 0.50

Voltage: 45 KVs (kV)

Electric current: 40 milliampere(mA)s (mA)

Sweep limit: from 3.0 to 40.0 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 Measurement Systems Ltd.).The method parameter of described dynamic water adsorption instrument is as follows:

Temperature: 25 DEG C

Carrier gas, flow velocity: N ₂, 200 ml/min

Unit time quality change: 0.002%/minute

RH range: 0%RH-95%RH

Embodiment 1

Method for production of phosphate salt:

Be dissolved in the acetone of 0.5mL by the formula I compound as its free base of 10.1mg, dropwise add the phosphoric acid solution of 0.1mL0.2mol/L, stirred at ambient temperature reacts and obtains phosphoric acid salt in 24 hours.

The phosphate product that aforesaid method prepares, its NMR appraising datum is as follows:

¹H NMR(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, it is crystal form A that the present embodiment obtains solid, and its X-ray powder diffraction data are as shown in table 1.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 1 crystal form A

2theta	D interval	Intensity %
			7.49	11.80	37.89
8.22	10.76	21.87
			8.63	10.25	12.84
9.82	9.01	100.00
			10.86	8.15	7.20
12.33	7.18	13.18
			13.24	6.69	3.55

13.65	6.49	19.94
			15.26	5.80	12.21
16.43	5.40	48.63
			16.77	5.29	11.93
17.48	5.07	18.35
			17.59	5.04	13.07
19.43	4.57	24.23
			19.57	4.54	37.69
19.79	4.49	22.94
			19.98	4.44	11.04
20.91	4.25	2.29
			22.16	4.01	8.13
22.48	3.95	15.64
			23.57	3.77	12.32
24.50	3.63	43.99
			24.79	3.59	14.86
25.08	3.55	40.86
			25.76	3.46	4.79
26.09	3.42	4.54
			26.46	3.37	3.61
27.46	3.25	3.38
			29.90	2.99	4.42
31.84	2.81	3.45
			32.46	2.76	3.41
33.30	2.69	3.49
			34.09	2.63	1.08

Embodiment 2

Method for production of phosphate salt:

Be dissolved in the ethanol of 0.5mL by the formula I compound as its free base of 10.2mg, dropwise add 0.1mL, the phosphoric acid solution of 0.2mol/L, stirred at ambient temperature reacts and obtains phosphoric acid salt in 24 hours.

After testing, it is crystal form A that the present embodiment obtains solid, 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 phosphoric acid salt and free alkali:

Formula I compound phosphoric acid salt and free alkali are used H respectively ₂the SGF (simulated gastric fluid, simulated gastric fluid) of O and pH 1.8 is mixed with saturated solution, respectively after 1 hour, after 4 hours and adopt high performance liquid chromatography (HPLC) to measure content after 24 hours.Experimental result is as shown in table 3.

Table 3

Result shows, the solubleness of phosphoric acid salt in water far above the solubleness of free alkali in water, and finds that free alkali exists 24 hours and degrades in SGF in the process analyzed, poor at Biomedia internal stability, is unfavorable for patent medicine.The present invention passes through into phosphatic mode and overcomes low and unstable in the Biomedia problem of free alkali solubleness, reaches the effect improving bioavailability.

Embodiment 4

Formula I compound phosphoric acid salt and mesylate draw moist comparative study:

Respectively 10mg get Mesylate Form B in phosphoric acid salt crystal form A of the present invention, patent CN103702990A carry out dynamic water absorption (DVS) test.Result is as table 4.

Table 4

Sample	80% humidity weightening finish	95% humidity weightening finish
			Phosphoric acid salt crystal form A	2.82％	3.47％

Mesylate Form B

6.16％

55.17% (deliquescence)

Result shows, after phosphoric acid salt crystal form A of the present invention balances under 80% relative humidity, weightening finish 2.82%, draws moist lower; And in patent CN103702990A Mesylate Form B balance under 80% relative humidity after weightening finish 6.16%, draw moist higher and under 95% relative humidity balance after there occurs deliquescence.The present invention passes through into phosphatic mode and overcomes mesylate and draw moist height, deliquescent problem.

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%.

Claims

1. the phosphoric acid salt of formula I compound.

It is characterized in that, described salt is crystallized form.

2. the phosphatic crystal form A of formula I compound according to claim 1, 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.

3. the phosphatic crystal form A of formula I compound according to claim 2, is further characterized in that, its X-ray powder diffraction figure is that 7.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.5 ° ± 0.2 ° place has characteristic peak in 2theta value.

4. the phosphatic crystal form A of formula I compound according to claim 3, is further characterized in that, its X-ray powder diffraction figure is that 8.2 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.4 ° ± 0.2 ° place has characteristic peak in 2theta value.

5. formula I compound phosphoric acid salt crystal form A according to claim 2, it is characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 1.

6. prepare a phosphatic method for formula I compound, it is characterized in that, comprise and formula I compound and phosphoric acid are reacted in ketone or alcoholic solvent, stirring and crystallizing obtains.

7. method according to claim 6, the alcohols that the preferred carbonatoms of described alcoholic solvent is less than 6, the ketone that the preferred carbonatoms of described ketones solvent is less than 6.

8. method according to claim 6, the formula I compound of formation and the stoicheiometry of phosphoric acid are 1:1.

9. a pharmaceutical composition, it is containing the phosphatic crystallized form of formula I compound described in good grounds claim 1 to 5 any one and pharmaceutically acceptable carrier.

10. the phosphatic crystallized form of formula I compound according to claim 1 to 5 any one or pharmaceutical composition according to claim 9 are preparing the purposes in Therapeutic cancer medicine.