CN103664738A - Crystalline polymorphic substance of carboxamide compound L-malate - Google Patents
Crystalline polymorphic substance of carboxamide compound L-malate Download PDFInfo
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- CN103664738A CN103664738A CN201210336560.5A CN201210336560A CN103664738A CN 103664738 A CN103664738 A CN 103664738A CN 201210336560 A CN201210336560 A CN 201210336560A CN 103664738 A CN103664738 A CN 103664738A
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- ALACGMTYNWTYRQ-FXBPSFAMSA-N CCN(CC)CCNC(C1C(CCC/C2=C(\c3cc(F)ccc3N3)/C3=O)=C2NC1C)=O Chemical compound CCN(CC)CCNC(C1C(CCC/C2=C(\c3cc(F)ccc3N3)/C3=O)=C2NC1C)=O ALACGMTYNWTYRQ-FXBPSFAMSA-N 0.000 description 1
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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
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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
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- 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 invention relates to two crystal forms of a compound (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, 2-dihydro-5-fluorine-2-oxo-3H-benzpyrole-3-subunit)-4, 5, 6, 7-tetralin-1H-benzpyrole-3-carboxamide L-malate as shown in formula I, as well as a preparation method and application thereof in a medicine for treating over-proliferation diseases or malignant tumors. The invention also relates to a medicinal composition containing the crystal forms serving as an active ingredient.
Description
Technical field
The invention belongs to pharmaceutical field, particularly, the present invention relates to pharmaceutically active compound (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5, crystalline polymorph, its preparation method of 6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt and be used for the treatment of excess proliferative disease or the medicine of malignant tumour in purposes.The invention still further relates to and comprise described crystal formation as the medicinal compositions of activeconstituents.
Background technology
The pharmaceutically active compound the present invention relates to (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, referring to: Tang Feng, etc., WO2008/067756, (2008), multiple Tyrosylprotein kinase is had to significant inhibition active, and can suppress the propagation of various human JEG-3, can be used for the preparation of antitumor drug.
In organic compound, many materials often have identical chemical constitution, under different thermodynamic condition (temperature, pressure, pH etc.), but can form different crystalline structure, and we are called polytropism this phenomenon.These different crystal formations are referred to as " polymorphic form ".The different polymorphic form of material has different lattice energies, it has shown different chemistry and physical property when solid-state thus, comprise chemical stability, apparent solubility, dissolution rate, fusing point etc., these character can directly affect processing and the production of bulk drug and preparation, and can affect stability, solubleness and the bioavailability of bulk drug and preparation.For the present invention, this area exists such demand: the polymorphic that obtains the physicochemical property excellence that is suitable for application.
Summary of the invention
The invention provides (Z)-N-[2-shown in formula I (diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4, the crystalline polymorph of 5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt.
(Z)-N-[2-of the present invention (diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt crystalline polymorph, is used
radiation, 2 θ values of the characteristic peak in X-ray powder diffraction spectrogram are: 3.04, the error of 6.18,9.34,17.60 and 26.32,2 θ diffraction angle is 0.2.Preferably, it has X-ray powder diffraction spectrogram substantially as shown in Figure 1.This crystallization polymorph called after A type.
(Z)-N-[2-of the present invention (diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt crystalline polymorph is used
radiation, 2 θ values of the characteristic peak in X-ray powder diffraction spectrogram are: 11.62, the error of 12.58,22.40,23.50,24.12 and 25.64,2 θ diffraction angle is 0.2.Preferably, it has X-ray powder diffraction spectrogram substantially as shown in Figure 2.This crystalline polymorph called after Type B.
(Z)-N-[2-of the present invention (diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt Type B polymorphic form infrared absorption pattern is at 808cm
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-1there is absorption peak at place.Preferably, its infrared absorption pattern substantially as shown in Figure 3.
(Z)-N-[2-of the present invention (diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt Type B polymorphic form DSC endothermic transition is at 170 ± 2 ℃.Preferably Type B polymorphic form DSC endothermic transition is at 170 ± 1 ℃.
The present invention also provides the preparation method of the crystalline polymorph shown in formula I (A type, Type B).
The method of preparing A type crystalline polymorph: (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides adds in methyl alcohol, is heated to reflux, and progressively adds the methanol solution of L MALIC ACID, be cooled to room temperature, continue stirring and crystallizing 4-12h.
The described room temperature that is cooled to, is preferably and naturally cools to room temperature.Preferably, after stirring and crystallizing 4-12h, through filtering, filter cake washing, 20-60 ℃ of drying under reduced pressure, makes (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt A type crystalline polymorph.
The method of preparing Type B crystalline polymorph: (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, L MALIC ACID add in the mixed solvent of anhydrous methanol, ethyl acetate, heating, backflow, filtration, filtrate are cooled to room temperature, continue stirring and crystallizing 4-24h.Described filtrate is cooled to room temperature, is preferably and naturally cools to room temperature.Preferably, after stirring and crystallizing 4-24h, through filtering, filter cake washing, 20-60 ℃ of drying under reduced pressure, makes (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-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 the purposes in the medicine of preparing overmedication proliferative disease or malignant tumour thereof, and relate to the pharmaceutical composition that comprises these crystal formations.
(Z)-N-[2-(diethylin) ethyl has been described in WO2008/067756]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides has regulating effect to protein kinase activity, the activity that can suppress multiple Tyrosylprotein kinase, is attached to the content of the disclosure herein by reference.
The present invention relates to crystalline polymorph A type and Type B and composition thereof, also relate to the pharmaceutical composition that comprises these crystal formations.
Term used herein " medicinal compositions " refers to crystalline polymorph (being selected from the mixture of A type, Type B or A type and Type B) and other chemical composition, for example mixture of pharmaceutically acceptable carrier and vehicle for the treatment of significant quantity formula I compound.Medicinal compositions be to promote the administration of compound to organism.
" pharmaceutically acceptable carrier " refers to organism do not caused obvious pungency and do not disturb the biological activity of given compound and the carrier of character or thinner.
" vehicle " refers to and joins in medicinal compositions with the further convenient inert substance that gives compound.The example of vehicle comprises (being not limited to) calcium carbonate, calcium phosphate, various saccharides and polytype starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.
Treatment significant quantity can be one or more symptoms of alleviating to a certain extent disease in object or illness, it is relevant to disease or illness to make or one or more physiology of its cause of disease or biochemical parameters are partially or completely recovered the amount of the outbreak possibility of normal and/or reduction disease or illness.
The invention also discloses the ethyl by (Z)-N-[2-(diethylin)]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides is prepared the method for its L MALIC ACID salt; And (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides and its L MALIC ACID salt difference of the aspect such as tumour inhibiting rate in plasma exposure amount (AUC), animal body in solubleness, animal body in drawing moist, water.Result shows, L MALIC ACID salt has better solubleness, has higher plasma exposure amount, a better tumour inhibiting rate in animal body in water.
The present invention has compared (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6, the difference of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt A crystal formation and B stable crystal form, result shows that B crystal formation has better stability.
The present invention has measured (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6, the fusing point of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt B crystal formation, result is 170～171 ℃.
The present invention has also measured (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6, pharmacokinetics after 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt B crystal formation Oral Administration in Rats, demonstrates good bioavailability.
Accompanying drawing explanation
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is (Z)-N-[2-of the present invention (diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6, the XRD figure of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt A crystal formation;
Fig. 2 is (Z)-N-[2-of the present invention (diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6, the XRD figure of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt B crystal formation;
Fig. 3 is (Z)-N-[2-of the present invention (diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6, the IR figure of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt B crystal formation;
Fig. 4 is (Z)-N-[2-of the present invention (diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6, the DSC figure of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt B crystal formation;
Embodiment
The following examples are further to illustrate of the present invention, rather than limit.
Raw material sources and specification:
(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5, it is synthetic that 6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides is pressed literature method, referring to: Tang Feng, Deng, 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)-N-[2-(diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt
By (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides 8.49g(20mmol) be added to acetonitrile 500ml, in the mixed solution of methylene dichloride 90ml, ultrasonic to being uniformly dispersed, add L MALIC ACID 3.22g(24mmol), nitrogen protection, stirring is warming up to backflow, after reaction 1h, filtered while hot, filtrate decompression is concentrated into dry, add dehydrated alcohol 60ml, ultrasonic to filtering after being uniformly dispersed, filter cake obtains the title compound 10.39g(18.6mmol of yellow solid after 40 ℃ of vacuum-drying), yield 93%.
1H NMR(DMSO-d
6)δppm：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=5.8Hz),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=8.6,2.2Hz),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)-N-[2-(diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (pharmaceutically active compound) and the hygroscopic mensuration of L MALIC ACID salt thereof
Measuring method: get a certain amount of trial-product and put a precise weighing (m
1) tool plug glass weighing bottle in, precise weighing (m
2); Uncovered 25 ℃ ± 1 ℃ suitable thermostatic drier interior (ammonium sulfate saturated solution is placed in bottom, and relative humidity is 80% ± 2%) that is placed in of weighing bottle, place 24 hours; Build weighing bottle lid, precise weighing (M
3).
Draw moist feature description and draw defining of wet weightening finish:
Deliquescence: absorb enough water and divide formation liquid;
Have draw moist: it is not little by 15% to draw wet weightening finish;
Have draw moist: drawing wet weightening finish and being less than 15% and be not less than 2%;
Slightly draw moist: drawing wet weightening finish and being less than 2% and be not less than 0.2%;
Nothing or almost moist without drawing: drawing wet weightening finish and being less than 0.2%.
| Determinand | Draw wet defining |
| Pharmaceutically active compound | Almost moist without drawing |
| L MALIC ACID salt | Almost moist without drawing |
Embodiment 3:
(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4, the mensuration of 5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (pharmaceutically active compound) and L MALIC ACID salt solubleness in water thereof
Test conditions:
Liquid chromatograph: Agilent 1200 highly effective liquid phase chromatographic systems (diode-array detector) chemstation chromatographic working station
Chromatographic column: Aglinet C
185 μ 250 * 4.6mm
Moving phase: acetonitrile-water
Detect wavelength: 264nm
Flow velocity: 1.0ml/min
Sample size: 10 μ l
Test method:
At 25 ℃, get and treat the about 100mg of test product, accurately weighed, put in 100ml measuring bottle, solubilizing agent [acetonitrile-water (80:20)] is appropriate, ultrasonic making dissolved, and with above-mentioned solvent cut to scale, shake up, precision measures 10 μ l injection liquid chromatographies, records color atlas; Measure peak area S
contrast.
Measure purified water 10ml, be placed in 25ml eggplant type bottle, at 25 ℃, add gradually and treat that test product is to till having insoluble solid in solution, ultrasonic 30min, elimination insoluble solid, precision measures filtrate 10 μ l injection liquid chromatographies, records color atlas; Measure peak area S
test.
| Determinand | Solubleness in water (mg/ml) |
| Pharmaceutically active compound | 0.0200 |
| L MALIC ACID salt | 38.6200 |
Embodiment 4:
(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5, the mensuration of plasma exposure amount (AUC) in the animal body of 6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (pharmaceutically active compound) and L MALIC ACID salt thereof
Testing program:
Laboratory animal: male SD rat
Dosage: 10mg/kg(is by pharmaceutically active compound)
Salt preparation prescription: pure water dissolves
Pharmaceutically active compound preparation prescription: 0.5%CMC (carboxymethylcellulose) suspendible
Animal experiment grouping and process:
Every group of 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, by eye socket venous plexus, get blood 250 μ L left and right in heparinization test tube, and centrifugal, get 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)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4, the curative effect of 5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (pharmaceutically active compound) and L MALIC ACID salt pair human colon carcinoma HT-29 Nude Mice thereof
Testing program:
Laboratory animal: BALB/cA-nude nude mouse, 6-7 week, ♀
Dosage: 40mg/kg(is by 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 150-250mm
3after, animal is divided into 3 groups (d0) at random, gastric infusion is 21 days continuously, surveys weekly knurl volume 2-3 time, record data.Gross tumor volume (V) calculation formula is: V=1/2 * a * b
2, wherein a, b represent respectively length and width.
Relative tumor proliferation rate T/C (%)=(T-T
0)/(C-C
0) * 100, gross tumor volume when wherein T, C finish for experiment; T
0, C
0gross tumor volume while starting for experiment, tumour inhibiting rate=1-T/C (%).
Experimental result:
| Administration | Tumour inhibiting rate (%) |
| Pharmaceutically active compound | 40 |
| L MALIC ACID salt | 54 |
Embodiment 6:(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6, the preparation of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt A crystal formation:
By (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides 4.24g(10mmol) be added in methyl alcohol 40mL, stir, be heated to reflux; L MALIC ACID 2.50g is added in methyl alcohol 20mL, be made into methanol solution, slowly drop to backflow system.After dropping finishes, continue stirring reaction 15min, stop heating, naturally cool to room temperature, and continue to stir 8h in room temperature, separate out a large amount of yellow solids, filter, filter cake is through dehydrated alcohol (5mL*3) washing, and 40 ℃ of vacuum-dryings, 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-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6, the preparation of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt B crystal formation:
Successively by (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides 466g (1.10mol), anhydrous methanol 11.65L, ethyl acetate 0.26L, L MALIC ACID 178.48g (1.33mol) are added in 20L reaction flask, solution stirring is warming up to backflow, reaction 1h left and right, filtered while hot.Filtrate stirring is warming up to backflow, to reaction solution, clarifies completely, closes heating, and cooling naturally, to room temperature, continues to stir 12h, filters, and obtains solid 564g after 40 ℃ of vacuum-dryings of filter cake.
The XRD figure of B crystal formation, infrared absorption spectrum, DSC endothermic transition figure are shown in Fig. 2-4.
Embodiment 8:(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4, the X-ray powder diffraction of 5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt A crystal formation, B crystal formation is identified
Instrument: the D/max-2500/PC of Rigaku company type turns target X-ray diffractometer
Pipe is pressed: 40kV
Pipe stream: 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 limit: 0.00-40.00 °
Sweep velocity: 10.00 °/min
A type and Type B crystal formation are used Cu-K α radiation, take and spend the X-ray powder diffraction spectrogram that 2 θ (error of 2 θ diffraction angle is 0.2) represent and see respectively Fig. 1 and Fig. 2, the position at its peak (2 θ) and Relative Peak intensity can be in Table 1 and table 2, in described table, by peak intensity be 1 to 12 be classified as very weak, 13 to 32 be a little less than, 33 to 64 is general, 65 to 87 is strong, and 88 to 100 is (with reference to ZL 01817064.1) very by force.
The numerical value of A type
The numerical value of Type B
Embodiment 8 (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6, the stability of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt A crystal formation, B crystal formation
Get and treat that test agent (A, B crystal formation) is in weighing bottle, be uncoveredly placed in 85 ℃, RH(relative humidity) environment of >90%, respectively at sampling in 3 days, 122 days, HPLC method was measured related substance, and result is:
A, the impact of B crystal formation on stability
Conclusion: two more than 0.1% newly-increased impurity have appearred in A crystal form samples accelerated test after 3 days, and original impurity has to a certain degree and increase, the total purity of sample 1% left and right that declines; B crystal form samples accelerated test is after 122 days, and sample purity slightly declines (decline degree is 0.14%), and B crystal formation has better stability.
Embodiment 9:(Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6, the infrared spectra (IR) of 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt B crystal formation:
Instrument: BRUKER Vector 33 infrared spectrometers
Sample preparation: KBr compressing tablet
The infrared absorption pattern of Type B crystal formation (pressing potassium bromide troche) is shown in Fig. 3, and it is at 430cm
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-1, 1176cm
-1, 1190cm
-1, 1234cm
-1, 1261cm
-1, 1277cm
-1, 1304cm
-1, 1324cm
-1, 1368cm
-1, 1340cm
-1, 1421cm
-1, 1439cm
-1, 1456cm
-1, 1473cm
-1, 1516cm
-1, 1592cm
-1, 1625cm
-1, 1655cm
-1, 2488cm
-1, 2629cm
-1, 2761cm
-1, 2883cm
-1, 2946cm
-1, 2980cm
-1, 3047cm
-1, 3079cm
-1, 3268cm
-1, 3320cm
-1there is absorption peak at place.
Embodiment 10 (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4, the hot method of differential scanning (DSC) of 5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt B crystal formation:
Instrument: NETZSCH DSC 204 type differential thermal analyzers
Temperature range: 30-250 ℃
Heat-up rate: 10 ℃/min
The thermogram of Type B crystal dsc is shown in Fig. 4, and its DSC endothermic transition is at 170 ℃.
Embodiment 11 (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4, the fusing point of the hot method of differential scanning (DSC) of 5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt B crystal formation:
Instrument: Tianjin precision instrument factory YRT-3 type melting point apparatus
Temperature rise rate: 1.0 ℃/min
Type B crystalline melting point is 170～171 ℃.
Pharmacokinetics after embodiment 12 Oral Administration in Rats B crystal formation raw materials
Take appropriate B crystal formation raw material, with 10% tween 80/0.5% phenylcarbinol/5% ethanol/84.5% physiological saline, be mixed with desired concn.
12 of healthy SD rats, male and female half and half, body weight 200 ~ 250g, provides [production licence number: SCXK(Shanghai) 2007 ~ 0005, occupancy permit SYXK(Shanghai) 2008 ~ 0049] by Chinese Academy of Sciences's Shanghai Experimental Animal Center, is divided at random 2 groups.Fasting 12h before administration, freely drinks water.Take 10 and the dosage of 20mg/kg respectively gavage give Type B raw material (administration volume is 10mL/kg), before administration and after administration 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, put in heparinization test tube, the centrifugal 10min of 3500rpm, separated plasma ,-70 ° of C preserve to be measured.
Plasma sample measuring method
Instrument: Synapt type quadrupole-flight time tandom mass spectrometer (Q-TOF MS), be furnished with electron spray ionisation source (ESI source), U.S. Waters company; UPLC liquid chromatographic system, comprises binary infusion pump, automatic sampler, column oven, de-aerator and UV-detector, U.S. Waters company.Data gathering adopts Masslynx 4.1 softwares of Waters company, and data analysis adopts MDF function, Metabolynx and MassFragment
tMsoftware.
Chromatographic condition
Chromatographic column is Acquity UPLC HSS T3column(2.1 * 100mm I.D., 1.8 μ m particle diameters), U.S. Waters company; Column temperature is 40 ° of C; Moving phase is acetonitrile-water; Flow velocity is 0.4mL/min.
Result of study
Conclusion: rat single gavage give 10 and 20mg/kg Type B raw material after, the plasma drug level peak time t of medicine
maxbe respectively 3.17 and 2.67h; Reach peak concentration C
maxbe respectively 68.5 and 454ng/mL; AUC
0-tbe respectively 349 and 2237ngh/mL; Blood plasma is eliminated transformation period t
1/2be respectively 2.44 and 2.10h.After dosage is proofreaied and correct, with AUC
0-tcalculate, rat single gavage give 10 and the absolute bioavailability of 20mg/kg Type B raw material be respectively 12.9% and 41.4%.
Claims (12)
1. (Z)-N-[2-(diethylin) ethyl shown in a formula I]-2-methyl-7-(the fluoro-2-oxo-3H-of 1,2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides L MALIC ACID salt crystalline polymorph:
2. a crystalline polymorph as claimed in claim 1, is characterized in that using
radiation, 2 θ values of the characteristic peak in X-ray powder diffraction spectrogram are: 3.04, the error of 6.18,9.34,17.60 and 26.32,2 θ diffraction angle is 0.2.
3. according to the crystalline polymorph described in claim 2, it is characterized in that using
radiation, it has X-ray powder diffraction spectrogram substantially as shown in Figure 1.
4. a method of preparing the crystalline polymorph described in any one in claim 2-3, it is characterized in that: (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides adds in methyl alcohol, be heated to reflux, the methanol solution that progressively adds L MALIC ACID, is cooled to room temperature, continues stirring and crystallizing 4-12h.
5. a crystalline polymorph as claimed in claim 1, is characterized in that using
radiation, 2 θ values of the characteristic peak in X-ray powder diffraction spectrogram are: 11.62, the error of 12.58,22.40,23.50,24.12 and 25.64,2 θ diffraction angle is 0.2.
6. according to the crystalline polymorph described in claim 5, it is characterized in that using
radiation, it has X-ray powder diffraction spectrogram substantially as shown in Figure 2.
7. according to the crystalline polymorph described in claim 5, it is characterized 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 absorption peak at place.
8. according to the crystalline polymorph described in claim 5, it is characterized in that infrared absorption pattern substantially as shown in Figure 3.
9. according to the crystalline polymorph described in claim 5, it is characterized in that DSC endothermic transition is at 170 ± 2 ℃.
10. a method of preparing the crystalline polymorph described in any one in claim 5-9, it is characterized in that: (Z)-N-[2-(diethylin) ethyl]-2-methyl-7-(1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-3-subunit)-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, L MALIC ACID add in the mixed solvent of anhydrous methanol, ethyl acetate, and heating, backflow, filtration, filtrate are cooled to room temperature, continue stirring and crystallizing 4-24h.
11. 1 kinds of pharmaceutical compositions, described pharmaceutical composition comprises the crystalline polymorph described in any one in claim 1-3, the 5-9 that treats significant quantity, and one or more pharmaceutically acceptable carrier or vehicle.
The purposes of crystalline polymorph in 12. claim 1-3,5-9 described in any one in the medicine of preparing overmedication proliferative disease or malignant tumour.
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| PCT/CN2013/083278 WO2014040528A1 (en) | 2012-09-12 | 2013-09-11 | Crystallized polymorph of carboxylamide compound l-malate |
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