CN105061411A - Optical isomer 2S,4R,2'S-itraconazole crystal form, preparation method and applications thereof - Google Patents
Optical isomer 2S,4R,2'S-itraconazole crystal form, preparation method and applications thereof Download PDFInfo
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- CN105061411A CN105061411A CN201510350844.3A CN201510350844A CN105061411A CN 105061411 A CN105061411 A CN 105061411A CN 201510350844 A CN201510350844 A CN 201510350844A CN 105061411 A CN105061411 A CN 105061411A
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- 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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- C07B2200/07—Optical isomers
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Abstract
The present invention discloses an optical isomer 2S,4R,2'S-itraconazole crystal form, a preparation method and applications thereof. According to the present invention, the optical isomer 2S,4R,2'S-itraconazole crystal form has characteristics of high stability, high purity and good drug activity; the preparation method has characteristics of simpleness and low cost, and is easily subjected to large-scale and industrial production; and the optical isomer 2S,4R,2'S-itraconazole crystal form and the pharmaceutical composition containing the crystal form can be used for anti-fungal infection, and are the effective mTOR inhibitors so as to can be used for treatments of a variety of tumors (such as non-small-cell lung cancer, prostate cancer, and the like).
Description
Technical field
The present invention relates to optical isomer 2S, 4R, 2 ' S-itraconazole, especially relates to optical isomer 2S, 4R, 2 ' S-itraconazole crystal formation and preparation method and application.
Background technology
Itraconazole is a kind of triazole species broad-spectrum antifungal medicine, its English name is Itraconazole, the cis-4-of chinesization formal name used at school [4-[4-[4-[[-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl methyl)-DOX-4-base] methoxyl group] phenyl] piperazine-1-base] phenyl]-2-[(2 ' S)-1-methyl-propyl]-1,2,4-triazole-3-ketone.Itraconazole has 3 chiral carbon atoms, have 8 kinds of optical isomers, antimycotic Clinical practice be the mixture of 4 cis-isomerides on dioxolanes in its structure, correspond to 2S, 4R, 2 ' S-itraconazole, 2S, 4R, 2 ' R-itraconazole, 2R, 4S, 2 ' S-itraconazole and 2R, 4S, 2 ' R-itraconazole.
In the recent period, document ChemBiol, 2007 (2): 263-70 report itraconazole has potential suppression vascular endothelial proliferation effect, and other antifungal drugs as fluconazole, KETOKONAZOL etc. on vascular endothelial cell without impact; CN101711156A discloses a kind of method of itraconazole single chiral pure isomer prevention and therapy relevant diseases of angiogenesis, and itraconazole isomer can Tumor suppression new vessel, is antineoplastic candidate compound.
The itraconazole serious adverse reaction clinically of racemization comprises gastrointestinal discomfort, as apocleisis, feel sick, stomachache and constipation, rare side effect comprises headache, the rising of reversibility transaminase, menoxenia, dizziness and anaphylaxis (as itch, erythema, wheal and angioedema), especially liver toxicity, a general course for the treatment of is two weeks, to the damage of liver clearly, can be there is liver failure and cause death in severe patient, over the course for the treatment of usually not by as a line medication.Document DRUGMETABOLISMANDDISPOSITION.2006, human body metabolism's result of study that 34:583-590. reports itraconazole four cis-isomerides shows, only has 2R, 4S, 2 ' R and 2R, 4S, 2 ' S can be metabolized to R 63373 by CYP3A4, ketone group itraconazole and N-take off alkyl itraconazole, and 2S, 4R, 2 ' R and 2S, 4R, 2 ' S can not by metabolism, thus there is higher bioavailability, hepatotoxicity experiment test also shows, itraconazole isomer 2S, 4R, 2 ' S and 2R, 4S, 2 ' S has higher security, therefore, preparation individual isomer 2S, 4R, the stable crystalline of 2 ' S-itraconazole, for the physicochemical property studying this compound further, study its drug regimen and clinical application, tool is of great significance.
Summary of the invention
The object of the invention is the deficiency existed for prior art, provide a kind of new optical isomer 2S, 4R, 2 ' S-itraconazole crystal formation, has good stability, has good pharmaceutical activity.
For achieving the above object, the technical solution used in the present invention is:
A kind of optical isomer 2S, 4R, 2 ' S-itraconazole crystal formation, described optical isomer 2S, 4R, 2 ' S-itraconazole crystal form X diffraction data is as shown in the table:
Represent apart from d with crystal face,
with
there is diffraction peak at place.Optical isomer 2S, 4R, the X-ray diffractogram of 2 ' S-itraconazole crystal formation as shown in Figure 1.
Its DSC collection of illustrative plates, has endotherm(ic)peak at 162.3 DEG C.Optical isomer 2S, 4R, the DSC collection of illustrative plates of 2 ' S-itraconazole crystal formation as shown in Figure 2.
Its melting range is 162.5 DEG C ~ 162.9 DEG C.
Present invention also offers a kind of described optical isomer 2S, 4R, the preparation method of 2 ' S-itraconazole crystal formation, comprises the steps:
(1) by 2S, 4R, 2 ' S-itraconazole is dissolved in 40 ~ 100 DEG C of organic solvents, and described organic solvent is propyl carbinol, Virahol, ethyl acetate, methylene dichloride, toluene, acetonitrile, acetone, DMF, tetrahydrofuran (THF) or their mixed solvent;
(2) limit is stirred, and limit lowers the temperature, and be cooled to 35 ~ 55 DEG C, crystallize out, continue to be cooled to 0 ~ 25 DEG C, insulated and stirred growing the grain is complete to crystallization;
(3) vacuum filtration or centrifugation, collect crystal, air blast or vacuum-drying, obtain 2S, 4R, 2 ' S-itraconazole crystallization.
In step (1), the mass volume ratio of solute and solvent is 1:5 ~ 1:40.
In step (2), cooling extent is per minute 1 DEG C ~ 10 DEG C, and growing the grain temperature is 0 ~ 25 DEG C, and rearing crystal time is 0.5 ~ 10h.
In step (3), drying temperature is 30 DEG C ~ 90 DEG C.
Present invention also offers a kind of described optical isomer 2S, 4R, 2 ' S-itraconazole crystal formation is for the preparation of the application in anti-fungal infection and tumor.
Present invention also offers pharmaceutical composition, comprise described a kind of optical isomer 2S, 4R, 2 ' S-itraconazole crystal formation.
The present invention compared with prior art, has the following advantages:
Optical isomer 2S, 4R of the present invention, 2 ' S-itraconazole crystal formation crystal is single, and purity is higher, and stability is better, and solubleness is higher, has good pharmaceutical activity and higher bioavailability.Preparation method of the present invention is simple, and cost is lower, easily realizes mass-producing, suitability for industrialized production.Described optical isomer 2S, 4R, 2 ' S-itraconazole crystal formation, and the pharmaceutical composition containing this crystal formation, not only can be used for anti-fungal infection, or a kind of effective mTOR inhibitors, therefore also can be used for the treatment of various tumour (as nonsmall-cell lung cancer, prostate cancer etc.).
Accompanying drawing explanation
Fig. 1 is optical isomer 2S, 4R, the X-ray diffractogram of 2 ' S-itraconazole crystal formation.
Fig. 2 is optical isomer 2S, 4R, the DSC collection of illustrative plates of 2 ' S-itraconazole crystal formation.
Embodiment
Below in conjunction with the drawings and specific embodiments, illustrate the present invention further, these embodiments should be understood only be not used in for illustration of the present invention and limit the scope of the invention, after having read the present invention, the amendment of those skilled in the art to the various equivalent form of value of the present invention has all fallen within the application's claims limited range.
The invention discloses a kind of optical isomer 2S, 4R, 2 ' S-itraconazole crystal formation, has X-ray diffraction spectrogram as represented in figure 1.Those skilled in the art are to be understood that; optical isomer 2S of the present invention; 4R; 2 ' S-itraconazole crystal formation is not limited only to the diffraction peak occurred at above-mentioned 2 θ angle places; also should comprise due to be subject to impact as factors such as experimental errors and above-mentioned 2 θ angles ± 0.02 ° in the diffraction peak that occurs, should also in protection scope of the present invention.
As shown in Figure 1, a kind of optical isomer 2S, 4R, 2 ' S-itraconazole crystal formation, described optical isomer 2S, 4R, 2 ' S-itraconazole crystal form X diffraction data is as shown in the table:
Table 12S, 4R, the X diffraction data of 2 ' S-itraconazole crystallization
, represent apart from d with crystal face,
with
there is diffraction peak at place.Represent apart from d with crystal face, about
with
there is one or more characteristic diffraction peak at place.
As shown in Figure 2, optical isomer 2S, 4R, the DSC collection of illustrative plates of 2 ' S-itraconazole crystal formation, has endotherm(ic)peak at 162.3 DEG C, and its melting range is 162.5 DEG C ~ 162.9 DEG C.
Present invention also offers a kind of described optical isomer 2S, 4R, the preparation method of 2 ' S-itraconazole crystal formation, comprises the steps:
(1) by 2S, 4R, 2 ' S-itraconazole is dissolved in 40 ~ 100 DEG C of organic solvents, and described organic solvent is propyl carbinol, Virahol, ethyl acetate, methylene dichloride, toluene, acetonitrile, acetone, DMF, tetrahydrofuran (THF) or their mixed solvent;
(2) limit is stirred, and limit lowers the temperature, and be cooled to 35 ~ 55 DEG C, crystallize out, continue to be cooled to 0 ~ 25 DEG C, insulated and stirred growing the grain is complete to crystallization;
(3) vacuum filtration or centrifugation, collect crystal, air blast or vacuum-drying, obtain 2S, 4R, 2 ' S-itraconazole crystallization.
In step (1), the mass volume ratio of solute and solvent is 1:5 ~ 1:40.
In step (2), cooling extent is per minute 1 DEG C ~ 10 DEG C, and growing the grain temperature is 0 ~ 25 DEG C, and rearing crystal time is 0.5 ~ 10h.
In step (3), drying temperature is 30 DEG C ~ 90 DEG C.
Optical isomer 2S, 4R of the present invention, 2 ' S-itraconazole crystal formation is for the preparation of the active substance crystallization in medical composition, there is high purity and high stability, even if under harsher condition of storage, also can keep stable, can not change in preparation preparation subsequently and storage.
Embodiment 1: optical isomer 2S, 4R, the preparation of 2 ' S-itraconazole crystal formation
Get optical isomer 2S, 4R, 2 ' S-itraconazole 15g, in reaction flask, adds 600ml Virahol, reflux, stirs clearly molten, and limit is stirred, while be cooled to 0 DEG C, separates out solid, continues cooling and stirs 10h.Vacuum filtration, filter cake, in 90 DEG C of forced air drying 12h, obtains 12.8g white needles, yield 85.3%.
Embodiment 2: optical isomer 2S, 4R, the preparation of 2 ' S-itraconazole crystal formation
Get optical isomer 2S, 4R, 2 ' S-itraconazole 10g, in reaction flask, adds 50ml methylene dichloride, reflux, stirs clearly molten, be cooled to 0 DEG C, separates out solid, and continue insulated and stirred 5h, crystallization is complete.Suction filtration, filter cake, in 30 DEG C of vacuum-drying 12h, obtains 4.4g white needles, yield 44%.
Embodiment 3: optical isomer 2S, 4R, the preparation of 2 ' S-itraconazole crystal formation
Get 2S, 4R, 2 ' S-itraconazole 1kg, in reaction flask, adds 30L methylene dichloride, reflux, stirs clearly molten, be cooled to 25 DEG C, separates out solid, and continue insulated and stirred 0.5h, crystallization is complete.Centrifugation, obtains solid, and forced air drying 8h at 50 DEG C, obtains 870g white needles, yield 87%.
Embodiment 4: optical isomer 2S, 4R, the illumination experiment of 2 ' S-itraconazole crystal formation
Optical isomer 2S embodiment 3 provided, 4R, 2 ' S-itraconazole crystal formation is evenly shared in uncovered culture dish respectively, thickness≤5mm, and regulating illumination intensity is 4500 ± 500Lx, samples detection after 30 days, and contrasts in the result of 0 day.The results are shown in Table 2.
Table 22S, 4R, the illumination experiment of 2 ' S-itraconazole crystallization
Embodiment 5: optical isomer 2S, 4R, the high temperature experiment of 2 ' S-itraconazole crystal formation
The optical isomer 2S embodiment of the present invention 3 provided, 4R, 2 ' S-itraconazole crystal formation is positioned in sealing aluminium foil bag, is placed in 60 DEG C of thermostatic drying chambers, detects after 30 days, and contrast in the result of 0 day.The results are shown in Table 2.
Table 32S, 4R, 2 ' S-itraconazole crystallization high temperature experiment
Embodiment 6: optical isomer 2S, 4R, the Acceleration study of 2 ' S-itraconazole crystal formation
By the 2S provided of the embodiment of the present invention 3,4R, 2 ' S-itraconazole crystal is positioned in aluminium foil bag respectively, is placed in 40 ± 2 DEG C, and relative humidity is in the thermostatic drying chamber of 75 ± 5%, detects after 30 days, and contrasts in the result of 0 day.The results are shown in Table 4.
Table 42S, 4R, 2 ' S-itraconazole crystallization Acceleration study
Embodiment 7: optical isomer 2S, 4R, the pharmaceutical activity test of 2 ' S-itraconazole crystal formation
By the 2S provided of the embodiment of the present invention 3,4R, 2 ' S-itraconazole crystal formation and itraconazole are hatched with HUVEC cell and human primary hepatocyte respectively, obtain two kinds of medicines to the restraining effect of cytoactive.As shown in the table.
Table 52S, 4R, 2 ' S-itraconazole crystallization
From result of study, by the 2S provided of the embodiment of the present invention 3,4R, the restraining effect of 2 ' S-itraconazole crystal formation to Human umbilical vein endothelial cells (HUVEC) is better than raceme itraconazole, and to the suppression of human primary hepatocyte lower than raceme itraconazole, 2S is described, 4R, 2 ' S-itraconazole crystal has higher anti-tumor activity and lower liver toxicity.
Claims (10)
1. an optical isomer 2S, 4R, 2 ' S-itraconazole crystal formation, is characterized in that, described optical isomer 2S, 4R, and 2 ' S-itraconazole crystal form X diffraction data is as shown in the table:
2. optical isomer 2S, 4R according to claim 1,2 ' S-itraconazole crystal formation, is characterized in that: represent apart from d with crystal face,
with
there is diffraction peak at place.
3. optical isomer 2S, 4R according to claim 1,2 ' S-itraconazole crystal formation, is characterized in that: its DSC collection of illustrative plates, has endotherm(ic)peak at 162.3 DEG C.
4. optical isomer 2S, 4R according to claim 1,2 ' S-itraconazole crystal formation, is characterized in that: its melting range is 162.5 DEG C ~ 162.9 DEG C.
5. any one optical isomer 2S described in Claims 1-4,4R, the preparation method of 2 ' S-itraconazole crystal formation, is characterized in that, comprise the steps:
(1) by 2S, 4R, 2 ' S-itraconazole is dissolved in 40 ~ 100 DEG C of organic solvents, and described organic solvent is propyl carbinol, Virahol, ethyl acetate, methylene dichloride, toluene, acetonitrile, acetone, DMF, tetrahydrofuran (THF) or their mixed solvent;
(2) limit is stirred, and limit lowers the temperature, and be cooled to 35 ~ 55 DEG C, crystallize out, continue to be cooled to 0 ~ 25 DEG C, insulated and stirred growing the grain is complete to crystallization;
(3) vacuum filtration or centrifugation, collect crystal, air blast or vacuum-drying, obtain 2S, 4R, 2 ' S-itraconazole crystallization.
6. optical isomer 2S, 4R according to claim 5, the preparation method of 2 ' S-itraconazole crystal formation, is characterized in that: in step (1), and the mass volume ratio of solute and solvent is 1:5 ~ 1:40.
7. optical isomer 2S, 4R according to claim 5, the preparation method of 2 ' S-itraconazole crystal formation, is characterized in that: in step (2), and cooling extent is per minute 1 DEG C ~ 10 DEG C, and growing the grain temperature is 0 ~ 25 DEG C, and rearing crystal time is 0.5 ~ 10h.
8. optical isomer 2S, 4R according to claim 5, the preparation method of 2 ' S-itraconazole crystal formation, is characterized in that: in step (3), and drying temperature is 30 DEG C ~ 90 DEG C.
9. any one optical isomer 2S described in Claims 1-4,4R, 2 ' S-itraconazole crystal formation is for the preparation of the application in anti-fungal infection and tumor.
10. a pharmaceutical composition, is characterized in that: comprise any one optical isomer 2S described in Claims 1-4,4R, 2 ' S-itraconazole crystal formation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478615A (en) * | 2016-08-31 | 2017-03-08 | 山东罗欣药业集团股份有限公司 | A kind of Itraconazole crystal-form compound and preparation method thereof |
| CN111603470A (en) * | 2020-07-01 | 2020-09-01 | 江苏艾迪药业股份有限公司 | Application of itraconazole isomer in preparation of drugs for treating squamous non-small cell lung cancer |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993019061A1 (en) * | 1992-03-18 | 1993-09-30 | Janssen Pharmaceutica N.V. | Itraconazole and saperconazole stereoisomers |
| CN103191119A (en) * | 2013-04-03 | 2013-07-10 | 南京安赛莱医药科技有限公司 | Use of itraconazole in inhibiting of Akt kinase (protein kinase B) activity |
| CN104774195A (en) * | 2015-03-10 | 2015-07-15 | 扬州艾迪生物科技有限公司 | Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate |
| CN104788437A (en) * | 2015-04-14 | 2015-07-22 | 扬州艾迪生物科技有限公司 | Method for chiral resolution of itraconazole |
-
2015
- 2015-06-23 CN CN201510350844.3A patent/CN105061411A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993019061A1 (en) * | 1992-03-18 | 1993-09-30 | Janssen Pharmaceutica N.V. | Itraconazole and saperconazole stereoisomers |
| CN103191119A (en) * | 2013-04-03 | 2013-07-10 | 南京安赛莱医药科技有限公司 | Use of itraconazole in inhibiting of Akt kinase (protein kinase B) activity |
| CN104774195A (en) * | 2015-03-10 | 2015-07-15 | 扬州艾迪生物科技有限公司 | Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate |
| CN104788437A (en) * | 2015-04-14 | 2015-07-22 | 扬州艾迪生物科技有限公司 | Method for chiral resolution of itraconazole |
Non-Patent Citations (1)
| Title |
|---|
| WEI SHI，ET AL.: ""Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole"", 《ACS MED. CHEM. LETT.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478615A (en) * | 2016-08-31 | 2017-03-08 | 山东罗欣药业集团股份有限公司 | A kind of Itraconazole crystal-form compound and preparation method thereof |
| CN106478615B (en) * | 2016-08-31 | 2019-08-13 | 山东罗欣药业集团股份有限公司 | A kind of Itraconazole crystal-form compound and preparation method thereof |
| CN111603470A (en) * | 2020-07-01 | 2020-09-01 | 江苏艾迪药业股份有限公司 | Application of itraconazole isomer in preparation of drugs for treating squamous non-small cell lung cancer |
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