CN106478615B - A kind of Itraconazole crystal-form compound and preparation method thereof - Google Patents
A kind of Itraconazole crystal-form compound and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of preparation methods of optical isomer 2R, 4S, 2 ' S- Itraconazole, which is characterized in that the X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurement is as shown in Figure 1.Crystal of the present invention is single, and purity is higher, and stability is more preferable, and solubility is higher, has good pharmaceutical activity and higher bioavailability.Stability of crystal form of the invention is high, even if being also able to maintain stabilization under harsher condition of storage, will not change in subsequent preparation preparation and storage.Preparation method of the invention is simple, and cost is relatively low, scale easy to accomplish, industrialized production.The optical isomer S- Itraconazole crystal form of 2R, 4S, 2 ', and the pharmaceutical composition containing the crystal form, it cannot be only used for anti-fungal infection or a kind of effective mTOR inhibitors, therefore can also be used in the treatment of various tumours (such as non-small cell lung cancer, prostate cancer).
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of optical isomer 2R, 4S, 2 ' S- Itraconazole crystal form and its system
Preparation Method.
Background technique
Itraconazole is that current curative effect is preferable, a kind of lesser triazole type broad-spectrum antifungal drug of side effect, external anti-
Bacterium spectrum is wider, and injection can reach pulmonary infection position, for treating lung's aspergillin infection.Its English name is
Itraconazole, Chinese chemical name: cis- 4- [4- [4- [4- [[- 2- (2,4- dichlorophenyl) -2- (1H-1,2,4- triazole -1-
Ylmethyl) -1,3- dioxolanes -4- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -2- [(2 ' S) -1- methyl-propyl] -1,
2,4- triazole -3- ketone.Its chemical structural formula is as follows:
Itraconazole has 3 asymmetric carbon atoms, shares 8 kinds of optical isomers, clinical use is dioxy penta in its structure
The mixture of 4 cis-isomers on alkane ring corresponds to the R- of 2R, 4S, 2 ' Itraconazole (A), the S- Itraconazole of 2R, 4S, 2 '
(B), the R- of 2S, 4R, 2 ' Itraconazole (C) and the S- of 2S, 4R, 2 ' Itraconazole (D), chemical structural formula is as follows:
The study found that there are larger differences for the bioactivity and toxic side effect of Itraconazole Isomers, such as
CN103263417A, which discloses itraconazole isomer composition, can be improved selectivity to fungi and endothelial cell, be also simultaneously
Drug candidate with treatment fungi and relevant diseases of angiogenesis potentiality, the optical voidness Itraconazole of single configuration can also be significant
Hepatotoxicity is reduced, can avoid side effect caused by Itraconazole.
Document ChemBiol, 2007 (2): 263-70 reports Itraconazole, and there is potential inhibition vascular endothelial cell to increase
Raw effect, and other antifungal drugs such as Fluconazole, ketoconazole etc. on vascular endothelial cell without influence；CN101711156 A
A kind of method that Itraconazole single chiral pure isomer prevents and treats relevant diseases of angiogenesis is disclosed, Itraconazole is different
Structure body can inhibit tumor neogenetic blood vessels, be antitumor candidate compound.
The serious adverse reaction of the Itraconazole of racemization clinically includes gastrointestinal discomfort, as anorexia, nausea, abdominal pain and
Constipation, rare side effect include headache, the raising of invertibity aminopherase, paramenia, dizziness and allergic reaction (such as scabies
Itch, erythema, wheal and angioedema), especially hepatotoxicity wind agitation, a general course for the treatment of are two weeks, very to the damage of liver
Obviously, liver failure, which can occur, for serious person leads to death, over the course for the treatment of usually not by as fiest-tire medication.Document DRUG
METABOLISM AND DISPOSITION.2006,34:583-590. reports the human body of four cis-isomers of Itraconazole
Intracellular metabolite result of study shows that the only R of 2R, 4S, 2 ' and the S of 2R, 4S, 2 ' can be metabolized to R 63373, ketone by CYP3A4
Base Itraconazole and N- take off alkyl Itraconazole, and 2S, 4R, 2 ' R and 2S, 4R, 2 ' S cannot be metabolized, thus have higher
Bioavilability, hepatotoxicity experiment test also indicate that Itraconazole isomers 2S, 4R, 2 ' S and the S of 2R, 4S, 2 ' have more
High safety.
Patent CN201510350844.3 discloses the optical isomer S- Itraconazole crystal form of 2S, 4R, 2 ', therefore, preparation
The stable crystalline of the individual isomer S- Itraconazole of 2R, 4S, 2 ', for further studying the physicochemical properties of the compound,
Its pharmaceutical composition and clinical application are studied, is had a very important significance.
Summary of the invention
To solve above-mentioned technical problem of the existing technology, the present invention provides a kind of new optical isomer 2R, 4S,
2 ' S- Itraconazole crystal forms have good stability, have preferable pharmaceutical activity.
To achieve the above object, the technical solution adopted by the present invention is that:
A kind of Itraconazole crystal-form compound, it is characterised in that: the compound be optical isomer 2R, 4S, 2 ' S- she
Triaconazole crystal-form compound, the X-ray powder diffraction collection indicated with the 2 θ ± 0.2 ° angles of diffraction 2.21 °, 3.37 °,
4.97°、5.38°、6.74°、8.21°、9.75°、11.07°、12.84°、13.86°、14.28°、15.05°、15.75°、
It is shown at 18.27 °, 20.86 °, 21.34 °, 24.72 °, 25.28 °, 25.85 °, 28.34 °, 28.72 °, 29.12 ° and 30.55 °
There is characteristic diffraction peak.
Preferably, the Itraconazole crystal-form compound, which is characterized in that obtained using Cu-K alpha ray measurement
X-ray powder diffraction spectrogram it is as shown in Figure 1.
The invention also discloses the preparation methods of the Itraconazole crystal-form compound, it is characterised in that including walking as follows
It is rapid:
A) the S- Itraconazole of 2R, 4S, 2 ' is dissolved in 40~60 DEG C of organic solvents, the organic solvent is acetic acid third
The volume ratio of the mixed solvent of ester and petroleum ether, petroleum ether and propyl acetate is 1:4~6；
B) side is stirred, and Bian Jiangwen is cooled to 10 DEG C~15 DEG C, precipitates crystal, continues to be cooled to -5 DEG C~0 DEG C, heat preservation is stirred
It is complete to crystallization to mix growing the grain；
C) it filters, collects crystal, a small amount of ethanol washing, vacuum drying obtains the crystallization of the S- Itraconazole of 2R, 4S, 2 '.
Preferably, the mass volume ratio of solute and solvent is 1:10~1:20 in step a).
Preferably, cooling extent is 1 DEG C per minute~5 DEG C in step b), growing the grain temperature is -5 DEG C~0 DEG C, growing the grain
Time is 0.5~10h.
Preferably, drying temperature is 40 DEG C~60 DEG C in step c).
The invention also discloses above-mentioned optical isomer 2R, 4S, 2 ' S- Itraconazole crystal forms to be used for antimycotic sense in preparation
Application in dye and tumor.
Compared with the existing technology, the present invention has the following beneficial effects:
1, optical isomer 2R, 4S, 2 ' S- Itraconazole crystal form crystal of the present invention is single, and purity is higher, stablizes
Property it is more preferable, solubility is higher, have good pharmaceutical activity and higher bioavailability.
2, stability of crystal form of the invention is high, even if stabilization is also able to maintain under harsher condition of storage, subsequent
Preparation preparation and storage in will not change.
3, preparation method of the invention is simple, and cost is relatively low, scale easy to accomplish, industrialized production.
4, optical isomer 2R, 4S, 2 ' S- Itraconazole crystal form of the present invention, and the medicine group containing the crystal form
Object is closed, cannot be only used for anti-fungal infection or a kind of effective mTOR inhibitors, therefore it is (such as non-to can also be used in various tumours
Small Cell Lung Cancer, prostate cancer etc.) treatment.
Detailed description of the invention
The present invention will be further described below with reference to the drawings.
Fig. 1 is X-ray powder diffraction (XRD) spectrogram of the optical isomer S- Itraconazole crystal form of 2R, 4S, 2 '.
Fig. 2 is the TG-DSC map of the optical isomer S- Itraconazole crystal form of 2R, 4S, 2 '.
Specific embodiment
Content in order to better understand the present invention is described further combined with specific embodiments below, but specific
Embodiment be not the limitation that the contents of the present invention are done.
Embodiment 1:
It takes the optical isomer S- Itraconazole of 2R, 4S, 2 ' 15g in reaction flask, 300ml petroleum ether and propyl acetate is added
Mixed solution (volume ratio 1:5), be heated to 40 DEG C, stir dissolved clarification, side stirring is precipitated solid while being cooled to 10 DEG C, continues
It is cooled to 0 DEG C of stirring 10h.Vacuum filtration, filter cake obtain 13.5g white needles, yield in 50 DEG C of vacuum drying 6h
90.3%.
Correlation analysis test:
1, X-ray powder diffraction is tested:
Instrument model: Bruker D8ADVANCE；Light source Cu-Ka 40kV 40mA；Graphite monochromator；Divergent slit
(DS): 1 °；LynxEye detector array, scanning mode: θ/θ, continuous scanning；Scanning range: 0 °~40 °.Experimental result: its
X-ray powder diffraction spectrogram is as shown in Figure 1, the X-ray powder diffraction spectrogram that the crystal form is indicated with the 2 θ ± 0.2 ° angles of diffraction
Spectrum 2.21 °, 3.37 °, 4.53 °, 4.97 °, 5.38 °, 6.74 °, 8.21 °, 9.75 °, 11.07 °, 12.84 °, 13.86 °,
14.28°、15.05°、15.75°、18.27°、20.86°、21.34°、24.72°、25.28°、25.85°、28.34°、28.72°、
Characteristic diffraction peak is shown at 29.12 ° and 30.55 °.It is disclosed with commercially available Itraconazole sample and patent CN201510350844.3
The X-ray powder diffraction of the optical isomer S- Itraconazole crystal form of 2S, 4R, 2 ' compose trace analysis, diffraction peak in map
Set entirely different with intensity, therefore it is a kind of new crystal form.
2, determination of moisture: measuring moisture in the substance with karr-Fei Xiushi method is 0.23%, be can be seen that by moisture result
The substance does not contain the crystallization water, is not hydrate, and moisture only adsorbs water.
3, differential thermal analysis and fusing point test:
Differential thermal and thermogravimetric analysis are carried out to the S- of 2R, 4S, 2 ' Itraconazole crystal prepared by the present invention, as a result such as 2 institute of attached drawing
Show；The result shows that this product before 150 DEG C without absorption peak, illustrate no crystal water or recrystallisation solvent in sample；This product is 157.5
There is exothermic peak at DEG C.This product is through fusing point test: 157~159 DEG C.The fusing point of Itraconazole known to the prior art is 165~169
DEG C, it is demonstrated from side as a kind of different crystal form.
Embodiment 2:
It takes the optical isomer S- Itraconazole of 2R, 4S, 2 ' 15g in reaction flask, 150ml petroleum ether and propyl acetate is added
Mixed solution (volume ratio 1:4), be heated to 60 DEG C, stir dissolved clarification, side stirring is precipitated solid while being cooled to 15 DEG C, continues
It is cooled to -5 DEG C of stirring 6h.Vacuum filtration, filter cake obtain 13.3g white needles, yield in 40 DEG C of vacuum drying 10h
88.5%.The X-ray powder diffraction spectrogram of obtained crystal obtained using Cu-K alpha ray measurement is similar to Example 1.
Embodiment 3:
It takes the optical isomer S- Itraconazole of 2R, 4S, 2 ' 15g in reaction flask, 225ml petroleum ether and propyl acetate is added
Mixed solution (volume ratio 1:5), be heated to 50 DEG C, stir dissolved clarification, side stirring is precipitated solid while being cooled to 15 DEG C, continues
It is cooled to -5 DEG C of stirring 4h.Vacuum filtration, filter cake obtain 13.8g white needles, yield in 60 DEG C of vacuum drying 4h
91.8%.The obtained S- Itraconazole crystal of 2R, 4S, 2 ' is composed using the X-ray powder diffraction that Cu-K alpha ray measurement obtains
Scheme similar to Example 1.
Embodiment 4: the illumination experiment of the optical isomer S- Itraconazole crystal form of 2R, 4S, 2 '
Optical isomer 2R, 4S, 2 ' S- Itraconazole crystal form provided by embodiment 3 is uniformly shared to open culture dish
In, thickness≤5mm, regulating illumination intensity is 4500 ± 500Lx, sample detection after 30 days, and being contrasted in 0 day result.
It the results are shown in Table 1.
The illumination experiment of the 1 optical isomer S- Itraconazole of 2R, 4S, 2 ' of table crystallization
The result shows that: significant changes do not occur, keep stablizing with this condition.
Embodiment 5: the high temperature experiment of the optical isomer S- Itraconazole crystal form of 2R, 4S, 2 '
Optical isomer 2R, 4S, 2 ' S- Itraconazole crystal form provided by the embodiment of the present invention 3 is placed in sealing aluminium foil
In bag, it is placed in 60 DEG C of thermostatic drying chambers, is detected after 30 days, and contrasted in 0 day result.It the results are shown in Table 2.
The 2 optical isomer S- Itraconazole of 2R, 4S, 2 ' of table crystallizes high temperature experiment
The result shows that: significant changes do not occur, keep stablizing with this condition.
Embodiment 6: the high humidity experiment of the optical isomer S- Itraconazole crystal form of 2R, 4S, 2 '
It is closed that the opening of optical isomer 2R, 4S, 2 ' S- Itraconazole crystal form provided by the embodiment of the present invention 3 is set into constant humidity
It in container, places ten days, was sampled in five, ten days, by stability high spot reviews under the conditions of 25 DEG C in relative humidity (90 ± 5) %
Project demand detection, while the weight of precise test front and back test sample, deliquesce performance to investigate the moisture absorption of test sample.As a result
It is shown in Table 3.
The 3 optical isomer S- Itraconazole crystal form of 2R, 4S, 2 ' of table crystallizes high humidity experiment
The result shows that: significant changes do not occur, keep stablizing with this condition, it is moist without drawing.
Embodiment 7: the Acceleration study of the optical isomer S- Itraconazole crystal form of 2R, 4S, 2 '
Experimental method: according to the Pharmacopoeia of the People's Republic of China two annex XIX C bulk pharmaceutical chemicals of version in 2010 and drug system
Method in agent stability test guideline carries out.By optical isomer 2R, 4S, 2 ' S- provided by the embodiment of the present invention 3
Itraconazole crystal is placed in aluminium foil bag, is placed in 40 ± 2 DEG C, in the thermostatic drying chamber that relative humidity is 75 ± 5%, January, 2
It is sampled detection respectively after the moon, March and June, to investigate its stability.It the results are shown in Table 4.
The 4 optical isomer S- Itraconazole of 2R, 4S, 2 ' of table crystallizes Acceleration study
The result shows that the S- of 2R, 4S, 2 ' Itraconazole provided by the embodiment of the present invention 3 was brilliant through 6 months accelerated tests
Type items quality index meets 2010 editions standard requirements of Chinese Pharmacopoeia, and related content of material is low, and each index has no significant change,
This product quality stability is good.
Itraconazole crystalline compounds of the present invention and the solubility pair of prior art crystal form in water at 8:25 DEG C of experimental example
Than
Trial target: sample prepared by 1-3 of the embodiment of the present invention；
Reference substance 1 is commercially available Itraconazole bulk pharmaceutical chemicals；
Reference substance 2 is the optical isomer S- of 2S, 4R, the 2 ' Yi Qu referring to the preparation of 201510350844.3 embodiment 2 of patent
Health azoles crystal form.
Measuring method: excessive trial target and reference substance are placed in 50ml conical flask, and 30ml distilled water, 25 DEG C of perseverances are added
Temperature stirring 72 hours, samples 5ml.Sample discards primary filtrate through 0.45 μm of filtering with microporous membrane, and 20 μ L of subsequent filtrate is taken to measure drug
Content is solubility in water (mg/ml).It the results are shown in Table 5:
The solubility of the crystal form of the present invention of table 5 and prior art crystal form in water compares
As can be seen from Table 5, at 25 DEG C, the dissolution of the S- of 2R, 4S, 2 ' Itraconazole crystal form provided by the present invention in water
Degree compared with prior art, is significantly increased.
Embodiment 9: the pharmaceutical activity test of the optical isomer S- Itraconazole crystal form of 2R, 4S, 2 '
Optical isomer 2R, 4S, 2 ' S- Itraconazole crystal form provided by the embodiment of the present invention 3 is compareed with Itraconazole
Product are incubated for HUVEC cell and human primary hepatocyte respectively, obtain two kinds of drugs to the inhibiting effect of cell activity, wherein
Trial target is sample prepared by the embodiment of the present invention 3；Reference substance 1 is commercially available Itraconazole bulk pharmaceutical chemicals；Reference substance 2 is referring to specially
The optical isomer S- Itraconazole crystal form of 2S, 4R, 2 ' of sharp 201510350844.3 embodiments 2 preparation.It the results are shown in Table shown in 6.
The pharmaceutical activity of the 6 optical isomer S- Itraconazole Itraconazole crystal form of 2R, 4S, 2 ' of table is tested
As result of study it is found that the S- of 2R, 4S, 2 ' Itraconazole crystal form is to human umbilical vein provided by the embodiment of the present invention 3
The inhibiting effect of endothelial cell (HUVEC) is better than raceme Itraconazole, and is lower than raceme to the inhibition of human primary hepatocyte
Itraconazole illustrates the S- Itraconazole crystal of 2R, 4S, 2 ' anti-tumor activity with higher and lower hepatotoxicity wind agitation.
Claims (7)
1. a kind of Itraconazole crystal-form compound, it is characterised in that: the compound is optical isomer 2R, 4S, 2 ' S- Yi Qu
Health azoles crystal-form compound, the X-ray powder diffraction collection indicated with the 2 θ ± 0.2 ° angles of diffraction 2.21 °, 3.37 °, 4.97 °,
5.38°、6.74°、8.21°、9.75°、11.07°、12.84°、13.86°、14.28°、15.05°、15.75°、18.27°、
Feature is shown at 20.86 °, 21.34 °, 24.72 °, 25.28 °, 25.85 °, 28.34 °, 28.72 °, 29.12 ° and 30.55 ° to spread out
Penetrate peak.
2. Itraconazole crystal-form compound as described in claim 1, which is characterized in that obtained using Cu-K alpha ray measurement
X-ray powder diffraction spectrogram is as shown in Figure 1.
3. the preparation method of Itraconazole crystal-form compound as claimed in claim 1 or 2, it is characterised in that including walking as follows
It is rapid:
A) the S- Itraconazole of 2R, 4S, 2 ' is dissolved in 40~60 DEG C of organic solvents, the organic solvent be propyl acetate and
The volume ratio of the mixed solvent of petroleum ether, petroleum ether and propyl acetate is 1:4~6；
B) side is stirred, and Bian Jiangwen is cooled to 10 DEG C~15 DEG C, precipitates crystal, and continues to be cooled to -5 DEG C~0 DEG C, insulated and stirred is supported
Crystalline substance is complete to crystallization；
C) it filters, collects crystal, a small amount of ethanol washing, vacuum drying obtains the crystallization of the S- Itraconazole of 2R, 4S, 2 '.
4. the preparation method of Itraconazole crystal-form compound as claimed in claim 3, it is characterised in that: in step a), solute
Mass volume ratio with solvent is 1:10~1:20.
5. the preparation method of Itraconazole crystal-form compound as claimed in claim 3, it is characterised in that: in step b), cooling
Amplitude is 1 DEG C per minute~5 DEG C, and growing the grain temperature is -5 DEG C~0 DEG C, and rearing crystal time is 0.5~10h.
6. the preparation method of Itraconazole crystal-form compound as claimed in claim 3, it is characterised in that: dry in step c)
Temperature is 40 DEG C~60 DEG C.
7. any optical isomer 2R, 4S, 2 ' the S- Itraconazole crystal form of claim 1-2 is used for antimycotic sense in preparation
Application in dye and tumor.
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