CN103664738B - A kind of crystalline polymorph of carboxamide compounds L MALIC ACID salt - Google Patents

A kind of crystalline polymorph of carboxamide compounds L MALIC ACID salt Download PDF

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Publication number
CN103664738B
CN103664738B CN201210336560.5A CN201210336560A CN103664738B CN 103664738 B CN103664738 B CN 103664738B CN 201210336560 A CN201210336560 A CN 201210336560A CN 103664738 B CN103664738 B CN 103664738B
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indole
crystal form
ethyl
malic acid
tetrahydrochysene
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CN103664738A (en
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金秋
唐锋
李薇
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NANJING YOKO PHARMACEUTICAL CO Ltd
NANJING YOKO BIO-MEDICAL RESEARCH Co Ltd
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NANJING YOKO PHARMACEUTICAL CO Ltd
NANJING YOKO BIO-MEDICAL RESEARCH Co Ltd
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Priority to PCT/CN2013/083278 priority patent/WO2014040528A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention relates to compound shown in Formulas I (Z) N [2 (diethylin) ethyl] 2 methyl 7 (1,2 dihydro 5 fluorine 2 oxo 3H indole 3 subunits) 4,5, two kinds of crystal formations of 6,7 tetrahydrochysene 1H indole 3 carboxylic acid amides L malates, its preparation method and the purposes in the medicine treating excess proliferative disease or malignant tumor thereof.The invention still further relates to the Pharmaceutical composition comprising described crystal formation as active component.

Description

A kind of crystalline polymorph of carboxamide compounds L MALIC ACID salt
Technical field
The invention belongs to drug world, in particular it relates to pharmaceutically active compound (Z)-N-[2-(diethylamine Base) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole Crystalline polymorph, its preparation method of-3-carboxylic acid amides L MALIC ACID salt and be used for treating excess proliferative disease Purposes in the medicine of disease or malignant tumor.The invention still further relates to comprise medicinal as active component of described crystal formation Compositions.
Background technology
Pharmaceutically active compound (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(the 1,2-dihydro that the present invention relates to -5-fluoro-2-oxo-3H-indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides, see: Tang Feng, etc., WO2008/067756, (2008), multiple tyrosine kinase is had significant inhibitory activity, and can press down Make the propagation of multiple man-machine systems, can be used for the preparation of antitumor drug.
In organic compound, many materials often have identical chemical composition, at different thermodynamic conditions But can form different crystal structures under (temperature, pressure, pH etc.), we are referred to as homogeneity this phenomenon Polymorphism.These different crystal formations are referred to as " polymorph ".The different polymorph of material has different Lattice energy, thus it illustrates different chemically and physically characteristics when solid-state, including chemical stability, table See dissolubility, dissolution velocity, fusing point etc., these character can directly affect crude drug and preparation process and Produce, and crude drug and the stability of preparation, dissolubility and bioavailability can be affected.For the present invention Speech, this area also exists such demand: obtain the polymorphic of the high specific surface area being suitable to application.
Summary of the invention
The invention provides (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(the fluoro-2-of 1,2-dihydro-5-shown in Formulas I Oxo-3H-indole-3-subunit) crystalline polymorphs of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt Thing.
(Z) of the present invention-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H- Indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt-pepper noise polymorphs, useRadiation, 2 θ values of the characteristic peak in X-ray powder diffraction spectrogram are: 3.04, 6.18,9.34,17.60 and 26.32, the error of the 2 θ angles of diffraction is 0.2.Preferably, it has basic such as Fig. 1 Shown X-ray powder diffraction spectrogram.This Crystalline polymorph named A type.
(Z) of the present invention-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H- Indole-3-subunit) use of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt-pepper noise polymorphRadiation, 2 θ values of the characteristic peak in X-ray powder diffraction spectrogram are: 11.62, 12.58,22.40,23.50,24.12 and 25.64, the error of the 2 θ angles of diffraction is 0.2.Preferably, it has X-ray powder diffraction spectrogram the most as shown in Figure 2.The named Type B of this crystalline polymorph.
(Z) of the present invention-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H- Indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt Type B polymorph INFRARED ABSORPTION Collection of illustrative plates is at 808cm-1、1190cm-1、1368cm-1、1473cm-1、1516cm-1、1592cm-1、1625 cm-1、1655cm-1、2488cm-1、2629cm-1、2883cm-1、2946cm-1、2980cm-1、3079 cm-1、3268cm-1、3320cm-1There is absworption peak at place.Preferably, its infrared absorption pattern is basic such as Fig. 3 Shown in.
(Z) of the present invention-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H- Indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt Type B polymorph DSC heat absorption Change at 170 ± 2 DEG C.Preferably Type B polymorph DSC endothermic transition is at 170 ± 1 DEG C.
Present invention also offers the preparation method of the crystalline polymorph (A type, Type B) shown in Formulas I.
The method preparing A type crystalline polymorph: (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-bis- Hydrogen-5-fluoro-2-oxo-3H-indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides add to, in methanol, add Heat, to backflow, is gradually added the methanol solution of L MALIC ACID, is cooled to room temperature, continues stirring and crystallizing 4-12h.
Described it is cooled to room temperature, it is therefore preferable to naturally cool to room temperature.Preferably, after stirring and crystallizing 4-12h, pass through Filter, Cake Wash, 20-60 DEG C of drying under reduced pressure, prepare (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2- Dihydro-5-fluoro-2-oxo-3H-indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt A Type crystalline polymorph.
The method preparing Type B crystalline polymorph: (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-bis- Hydrogen-5-fluoro-2-oxo-3H-indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides, L MALIC ACID add Absolute methanol, ethyl acetate mixed solvent in, heat, reflux, filter, filtrate is cooled to room temperature, continue Stirring and crystallizing 4-24h.Described filtrate is cooled to room temperature, it is therefore preferable to naturally cool to room temperature.Preferably, stir After mixing crystallize 4-24h, through filtering, Cake Wash, 20-60 DEG C of drying under reduced pressure, prepare (Z)-N-[2-(diethyl Amido) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-Yin Diindyl-3-carboxylic acid amides L MALIC ACID salt Type B crystalline polymorph.
The present invention relates to crystalline polymorph A type, Type B and its mixture and at preparation treatment hyper-proliferative Purposes in the medicine of property disease or malignant tumor, and relate to the pharmaceutical composition including these crystal formations.
(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-is described in WO2008/067756 Fluoro-2-oxo-3H-indole-3-subunit) protein kinase activity has by-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides Regulation effect, can suppress the activity of multiple tyrosine kinase, by quoting, the content of the disclosure is attached to this Wen Zhong.
The present invention relates to crystalline polymorph A type and Type B and mixture thereof, further relate to include these crystal formations Pharmaceutical composition.
Term used herein " Pharmaceutical composition " refers to the crystalline polymorphs of therapeutically effective amount compound of formula I Thing (selected from A type, Type B or A type and the mixture of Type B) and other chemical composition, the most pharmaceutically Acceptable carrier and the mixture of excipient.Pharmaceutical composition is the administration to organism of the promotion compound.
" pharmaceutically acceptable carrier " refer to organism is not caused obvious zest and do not disturb to Give the biological activity of compound and the carrier of character or diluent.
" excipient " refers to join in Pharmaceutical composition with the most convenient inert material giving compound Matter.The example of excipient is including (without limitation) calcium carbonate, calcium phosphate, various saccharides and polytype shallow lake Powder, cellulose derivative, gelatin, vegetable oil and Polyethylene Glycol.
Therapeutically effective amount, can be to alleviate the disease in object or one or more diseases of disease to a certain extent Shape, make or one or more physiology of its cause of disease relevant to disease or disease or biochemical parameters partly or completely The full amount recovering outbreak probability that is normal and/or that reduce disease or disease.
The invention also discloses by (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo -3H-indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides the method for preparing its L MALIC ACID salt；And (Z) (1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-is sub-for-N-[2-(diethylin) ethyl]-2-methyl-7- Base)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides and its L MALIC ACID salt dissolubility, animal in drawing moist, water The difference of the aspect such as tumour inhibiting rate in internal plasma exposure amount (AUC), animal body.Result shows, L MALIC ACID salt There is in water more preferable dissolubility, have higher plasma exposure amount, a more preferable tumour inhibiting rate in animal body.
The present invention compares (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H- Indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt A crystal formation and B crystal form stability Difference, result display B crystal form there is more preferable stability.
The present invention determines (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H- Indole-3-subunit) fusing point of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form, result is 170～171 DEG C.
The present invention also measured weres (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo -3H-indole-3-subunit) after-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form Oral Administration in Rats Pharmacokinetics, demonstrate preferable bioavailability.
Accompanying drawing explanation
Hereinafter, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:
Fig. 1 is the present invention (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-Yin Diindyl-3-subunit) XRD figure of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt A crystal formation；
Fig. 2 is the present invention (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-Yin Diindyl-3-subunit) XRD figure of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form；
Fig. 3 is the present invention (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-Yin Diindyl-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form IR figure；
Fig. 4 is the present invention (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-Yin Diindyl-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form DSC figure；
Detailed description of the invention
The following examples are to be further illustrated by the present invention rather than limit.
Raw material sources and specification:
(Z) (1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-is sub-for-N-[2-(diethylin) ethyl]-2-methyl-7- Base)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides press literature method synthesis, see: Tang Feng, etc., WO2008/067756, (2008).
Other reagent and solvent are commercial goods, chemical pure or analytical pure, and it is chromatographically pure that HPLC measures agents useful for same.
Embodiment 1:
(Z) (1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-is sub-for-N-[2-(diethylin) ethyl]-2-methyl-7- Base)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt
By (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-, (1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-is sub- Base)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides 8.49g(20mmol) it is added to acetonitrile 500ml, dichloromethane In the mixed liquor of alkane 90ml, ultrasonic to being uniformly dispersed, add L MALIC ACID 3.22g(24mmol), nitrogen Protection, stirring is warming up to backflow, and after reaction 1h, filtered while hot, filtrate reduced in volume, to dry, adds anhydrous Ethanol 60ml, ultrasonic filters to after being uniformly dispersed, filter cake after 40 DEG C of vacuum drying the title of yellow solid Compound 10.39g(18.6mmol), yield 93%.
1H NMR(DMSO-d6) δ ppm:1.15 (6H, t, J=7.2Hz), 1.93 (2H, m), 2.36 (1H, dd,J=15.5,5.7Hz),2.47(3H,s),2.57(1H,dd,J=15.5,7.7Hz),2.83(2H,t,J=5.8 Hz),2.99(4H,q,J=7.2Hz),3.02(2H,m),3.03(2H,m),3.50(2H,q,J=6.1Hz), 4.03(1H,dd,J=7.7,5.7Hz),6.84(1H,dd,J=8.5,5.1Hz),6.91(1H,td,J=8.6,2.2 Hz),7.37(1H,dd,J=8.9,2.0Hz),7.55(1H,t,J=5.5Hz),10.01(3H,brs),10.89(1H, s),14.58(1H,s).
Embodiment 2:
(Z) (1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-is sub-for-N-[2-(diethylin) ethyl]-2-methyl-7- Base)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides (pharmaceutically active compound) and L MALIC ACID salt hygroscopic Measure
Assay method: take a certain amount of test sample and put a precise weighing (m1) tool plug glass weighing botle in, Precise weighing (m2)；(bottom placement sulfur it is placed in the thermostatic drier of suitable 25 DEG C ± 1 DEG C uncovered for weighing botle Acid ammonium saturated solution, relative humidity is 80% ± 2%), place 24 hours；Build weighing botle lid, accurate title Weight (M3).
Draw moist feature description and draw defining of wet weightening finish:
Deliquescence: absorb enough water and divide formation liquid；
Great draw moist: draw wet weightening finish the least by 15%；
Have draw moist: draw wet weightening finish less than 15% and not less than 2%；
Slightly draw moist: draw wet weightening finish less than 2% and not less than 0.2%；
Nothing or moist almost without drawing: draw wet weightening finish less than 0.2%.
Determinand Draw wet defining
Pharmaceutically active compound Moist almost without drawing
L MALIC ACID salt Moist almost without drawing
Embodiment 3:
(Z) (1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-is sub-for-N-[2-(diethylin) ethyl]-2-methyl-7- Base)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides (pharmaceutically active compound) and L MALIC ACID salt molten in water The mensuration of Xie Du
Experimental condition:
Chromatograph of liquid: Agilent 1200 highly effective liquid phase chromatographic system (diode array detector) Chemstation chromatographic work station
Chromatographic column: Aglinet C185μ250×4.6mm
Flowing phase: acetonitrile-water
Detection wavelength: 264nm
Flow velocity: 1.0ml/min
Sample size: 10 μ l
Test method:
At 25 DEG C, take and treat test product about 100mg, accurately weighed, put in 100ml measuring bottle, solubilizer [acetonitrile- Water (80:20)] appropriate, ultrasonic make dissolving, and with above-mentioned solvent dilution to scale, shake up, precision measures 10 μ l Inject chromatograph of liquid, record chromatogram；Measure peak area SComparison。
Measure purified water 10ml, be placed in 25ml eggplant type bottle, be gradually added at 25 DEG C and treat that test product is in solution Till having insoluble solid, ultrasonic 30min, filter off insoluble solid, precision measures filtrate 10 μ l and injects liquid phase Chromatograph, records chromatogram；Measure peak area STest。
Determinand Dissolubility (mg/ml) in water
Pharmaceutically active compound 0.0200
L MALIC ACID salt 38.6200
Embodiment 4:
(Z) (1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-is sub-for-N-[2-(diethylin) ethyl]-2-methyl-7- Base)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides (pharmaceutically active compound) and the animal body of L MALIC ACID salt thereof The mensuration of interior plasma exposure amount (AUC)
Testing program:
Laboratory animal: male SD rat
Dosage: 10mg/kg(is based on pharmaceutically active compound)
Salt preparation prescription: pure water dissolves
Pharmaceutically active compound preparation prescription: 0.5%CMC (carboxymethylcellulose) suspendible
Animal experiment packet and process:
Often organize each 3 male rats, body weight 180～210g.Gastric infusion blood sampling time point is: 5min, 15min, 30min, 45min, 1h, 2h, 4h, 6h, 10h and 24h, taken blood 250 μ about L in liver by orbital venous plexus In elementization test tube, centrifugal, take blood plasma 100 μ L and analyze for LC-MS.
AUC test result:
Tested material AUC(0-t)(μg/L*h)
Pharmaceutically active compound 127.9
L MALIC ACID salt 1489.4
Embodiment 5:
(Z) (1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-is sub-for-N-[2-(diethylin) ethyl]-2-methyl-7- Base)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides (pharmaceutically active compound) and L MALIC ACID salt thereof is to people's colon The curative effect of cancer HT-29 Nude Mice
Testing program:
Laboratory animal: BALB/cA-nude nude mouse, 6-7 week, ♀
Dosage: 40mg/kg(is based on pharmaceutically active compound)
L MALIC ACID salt preparation prescription: pure water dissolves
Pharmaceutically active compound preparation prescription: 0.5%CMC (carboxymethylcellulose) suspendible
Experimental procedure:
Nude mouse subcutaneous vaccination human colon carcinoma HT-29 cell, treats that tumor growth is to 150-250mm3After, will be dynamic Thing is randomly divided into 3 groups (d0), continuous gastric infusion 21 days, surveys weekly 2-3 tumor volume, records data. Gross tumor volume (V) computing formula is: V=1/2 × a × b2, wherein a, b represent length and width respectively.
Relative tumor rate of increase T/C (%)=(T-T0)/(C-C0) × 100, the tumor at the end of wherein T, C are experiment Volume；T0、C0Gross tumor volume when starting for experiment, tumour inhibiting rate=1-T/C (%).
Experimental result:
It is administered Tumour inhibiting rate (%)
Pharmaceutically active compound 40
L MALIC ACID salt 54
Embodiment 6:(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3- Subunit) preparation of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt A crystal formation:
By (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-, (1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-is sub- Base)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides 4.24g(10mmol) it is added in methanol 40mL, stirring, It is heated to backflow；Add to L MALIC ACID 2.50g, in methanol 20mL, be made into methanol solution, slowly drop to Backflow system.After completion of dropwise addition, continue stirring reaction 15min, stop heating, naturally cool to room temperature, and Continuing stirring 8h in room temperature, separate out a large amount of yellow solid, filter, filter cake is washed through dehydrated alcohol (5mL*3) Wash, 40 DEG C of vacuum drying, obtain solid 4.93g.
The XRD figure of A crystal formation is shown in Fig. 1.
Embodiment 7:(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3- Subunit) preparation of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form:
Successively by (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3- Subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides 466g (1.10mol), absolute methanol 11.65L, ethyl acetate 0.26L, L MALIC ACID 178.48g (1.33mol) are added in 20L reaction bulb, and solution stirring is warming up to backflow, instead Answer about 1h, filtered while hot.Filtrate stirring is warming up to backflow, clarifies completely to reactant liquor, closes heating, Temperature fall, to room temperature, continues stirring 12h, filters, obtain solid 564g after filter cake 40 DEG C vacuum drying.
The XRD figure of B crystal form, infrared absorption spectroscopy, DSC endothermic transition figure are shown in Fig. 2-4.
Embodiment 8:(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3- Subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt A crystal formation, the X-ray powder of B crystal form Diffraction is identified
Instrument: Rigaku company D/max-2500/PC type turns target X-ray diffractometer
Pipe pressure: 40kV
Pipe flow: 100mA
Rotary target: copper target
Beam wavelength: CuK α,
Slit system: DS:1 °；SS:1 °；RS:0.15mm
Monochromator device: graphite curved-crystal monochromator
Sweep limits: 0.00-40.00 °
Scanning speed: 10.00 °/min
A type and Type B crystal formation use Cu-K α radiation, represent spending 2 θ (error of the 2 θ angles of diffraction is for 0.2) X-ray powder diffraction spectrogram see Fig. 1 and Fig. 2 respectively, the position (2 θ) at its peak and relative peak intensities are visible Tables 1 and 2, in the table, is 1 to 12 to be classified as the most weak by peak intensity, and 13 to 32 is weak, 33 Being general to 64,65 to 87 is strong, and 88 to 100 is very strong (with reference to ZL 01817064.1).
The numerical value of A type
The numerical value of Type B
Embodiment 8 (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3- Subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt A crystal formation, the stability of B crystal form
Take and treat that test agent (A, B crystal form), in weighing botle, uncovered is placed in 85 DEG C, RH(relative humidity) > 90% Environment in, respectively at 3 days, 122 days sampling, HPLC method measure have related substance, result is:
The impact on stability of A, B crystal form
Conclusion: A crystal form samples accelerated test occurs in that two more than 0.1% newly-increased impurity after 3 days, and original Impurity has to a certain degree to be increased, and the total purity of sample declines about 1%；B crystal form sample accelerated test is after 122 days, Sample purity is declined slightly (decline degree is 0.14%), and B crystal form has more preferable stability.
Embodiment 9:(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3- Subunit) infrared spectrum (IR) of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form:
Instrument: BRUKER Vector 33 infrared spectrometer
Prepared by sample: KBr tabletting
The infrared absorption pattern of Type B crystal formation (pressing potassium bromide troche) is shown in Fig. 3, and it is at 430cm-1、450cm-1、 504cm-1、555cm-1、556cm-1、594cm-1、631cm-1、674cm-1、726cm-1、736cm-1、 772cm-1、781cm-1、789cm-1、808cm-1、820cm-1、844cm-1、892cm-1、908cm-1、 935cm-1、958cm-1、981cm-1、1008cm-1、1018cm-1、1053cm-1、1080cm-1、1103 cm-1、1134cm-1、1156cm-1、1176cm-1、1190cm-1、1234cm-1、1261cm-1、1277 cm-1、1304cm-1、1324cm-1、1368cm-1、1340cm-1、1421cm-1、1439cm-1、1456 cm-1、1473cm-1、1516cm-1、1592cm-1、1625cm-1、1655cm-1、2488cm-1、2629 cm-1、2761cm-1、2883cm-1、2946cm-1、2980cm-1、3047cm-1、3079cm-1、3268 cm-1、3320cm-1There is absworption peak at place.
Embodiment 10 (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3- Subunit) Differential scanning calorimetry (DSC) of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form:
Instrument: NETZSCH DSC 204 type differential thermal analyzer
Temperature range: 30-250 DEG C
Programming rate: 10 DEG C/min
The thermal analysis curue of Type B crystal differential scanning calorimetry is shown in Fig. 4, and its DSC endothermic transition is at 170 DEG C.
Embodiment 11 (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3- Subunit) Differential scanning calorimetry (DSC) of-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form Fusing point:
Instrument: Tianjin precision instrument factory YRT-3 type melting point apparatus
Heating rate: 1.0 DEG C/min
Type B crystalline melting point is 170～171 DEG C.
Pharmacokinetics after embodiment 12 Oral Administration in Rats B crystal form raw material
Weigh appropriate B crystal form raw material, with 10% Tween 80/0.5% benzyl alcohol/5% ethanol/84.5% normal saline It is configured to desired concn.
Healthy SD rat 12, male and female half and half, body weight 200 ~ 250g, is tested by Chinese Academy of Sciences Shanghai Animal center offer [production licence number: SCXK(Shanghai) 2007 ~ 0005, use credit number SYXK (Shanghai) 2008 ~ 0049], it is randomly divided into 2 groups.Fasting 12h before being administered, freely drinks water.With 10 and 20mg/kg Dosage gavage respectively give Type B raw material (administration volume is 10mL/kg), in be administered before and administration after 0.25, 0.5,1.0,2.0,3.0,5.0,7.0,9.0,12 and 24h through eyeball rear vein beard extracting vein blood 0.2mL, Putting in heparinised tubes, 3500rpm is centrifuged 10min, separated plasma, and-70 ° of C preserve to be measured.
Plasma sample assay method
Instrument: Synapt type quadrupole rod-flight time tandem mass spectrometer (Q-TOF MS), is furnished with electron spray electricity From source (ESI source), Waters, US；UPLC liquid chromatographic system, including binary infusion pump, certainly Dynamic injector, column oven, degasser and UV-detector, Waters, US.Data acquisition uses Waters Masslynx 4.1 software of company, data analysis uses MDF function, Metabolynx and Mass FragmentTMSoftware.
Chromatographic condition
Chromatographic column is Acquity UPLC HSS T3column(2.1 × 100mm I.D., 1.8 μm particle diameters), Waters, US；Column temperature is 40 ° of C；Flowing is acetonitrile-water mutually；Flow velocity is 0.4mL/min.
Result of study
Conclusion: after rat single oral gavage gives 10 and 20mg/kg Type B raw materials, the plasma drug level of medicine Peak time tmaxIt is respectively 3.17 and 2.67h；Reach peak concentration CmaxIt is respectively 68.5 and 454ng/mL； AUC0-tIt is respectively 349 and 2237ng h/mL；Plasma elimination half life t1/2It is respectively 2.44 and 2.10h. After dose modification, with AUC0-tCalculating, rat single oral gavage gives the exhausted of 10 and 20mg/kg Type B raw materials Bioavailability is respectively 12.9% and 41.4%.

Claims (7)

1. (Z)-N-[2-(diethylin) the ethyl]-2-methyl-7-(1 shown in a Formulas I, 2-dihydro-5-fluoro-2-oxo-3H-indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides L MALIC ACID salt B crystal form
It is characterized in that: useRadiation, it has basic X-ray powder diffraction spectrogram as shown in Fig. 2.
2. According to the B crystal form described in claim 1, it is characterised in that infrared absorption pattern is at 808cm-1、1190cm-1、1368cm-1、1473cm-1、1516cm-1、1592cm-1、1625cm-1、1655cm-1、2488cm-1、2629cm-1、2883cm-1、2946cm-1、2980cm-1、3079cm-1、3268cm-1、3320cm-1There is absworption peak at place.
3. According to the B crystal form described in claim 1, it is characterised in that infrared absorption pattern is the most as shown in Figure 3.
4. According to the B crystal form described in claim 1, it is characterised in that 170 ± 2 ° of C of DSC endothermic transition.
5. A kind of prepare any one of claim 1-4 described in the method for B crystal form, it is characterized in that: (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indole-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indole-3-carboxylic acid amides, L-malic acid add in the mixed solvent of absolute methanol, ethyl acetate, heat, reflux, filter, filtrate is cooled to room temperature, continues stirring and crystallizing 4-24h.
6. A kind of pharmaceutical composition, described pharmaceutical composition includes the B crystal form according to any one of claim 1-4 of therapeutically effective amount, and one or more pharmaceutically acceptable carrier or excipient.
7. The B crystal form according to any one of claim 1-4 purposes in the medicine of preparation treatment excess proliferative disease or malignant tumor.
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