CN105646466A - B crystal form for heterocyclic ring aspartic protease inhibitor and preparing method thereof - Google Patents
B crystal form for heterocyclic ring aspartic protease inhibitor and preparing method thereof Download PDFInfo
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- CN105646466A CN105646466A CN201610055140.8A CN201610055140A CN105646466A CN 105646466 A CN105646466 A CN 105646466A CN 201610055140 A CN201610055140 A CN 201610055140A CN 105646466 A CN105646466 A CN 105646466A
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- heterocycle
- radix asparagi
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides a B crystal form for a heterocyclic ring aspartic protease inhibitor in the formula (I). Diffraction peaks exist on an XRPD pattern when 2 theta is equal to 8.70, 10.34, 13.96, 16.44, 16.76, 17.82, 18.12, 18.72, 19.38, 19.72, 20.70, 21.38, 21.80, 24.04, 24.56, 25.06, 26.30, 26.94, 27.52, 29.06 and 29.40, wherein the error range of the 2 theta value is +/-0.2. The B crystal form for the heterocyclic ring aspartic protease inhibitor has good high-temperature stability, high humidity stability and illumination stability.
Description
Technical field
The present invention relates to the polymorphic of a kind of Radix Asparagi amino protein enzyme inhibitor, in particular it relates to B crystal form of a kind of heterocycle Radix Asparagi amino protein enzyme inhibitor and preparation method thereof.
Background technology
Known multiple Radix Asparagi amino protein enzyme inhibitor, its regulating blood pressure, suppress such as alzheimer's disease neurodegenerative disease, reduce HIV (human immunodeficiency virus) and retrovirus retrovirus loading and kill plasmodium etc. in can play effect.
The heterocycle Radix Asparagi amino protein enzyme inhibitor of the present invention, chemical name (S)-2-imido grpup-3,6-dimethyl-6-(4-(5-(1-propinyl-1-base) pyridin-3-yl) thiophene-2-base) tetrahydropyrimidine-4 (1H)-one, as shown in formula (I)
It is a kind of Radix Asparagi amino protein inhibitor compound, can be used for treatment or the prevention cardiovascular disease to suppressing Radix Asparagi aminoprotease sensitive, cognitive illnesses and neurodegenerative disease and the disease caused by plasmodium etc. In Chinese invention patent publication number CN101484429A (WO2007/146225), disclose the preparation method and use of heterocycle Radix Asparagi amino protein enzyme inhibitor. The preparation method repeating above-mentioned patent, obtains compound powder, is detected as amorphous state. Although all having higher dissolubility and dissolution rate as it is known by the man skilled in the art, amorphous than crystal formation in most of occasions, but it being unstable, hygroscopicity is strong, it is easy to transfer stable crystal formation to. Therefore, the amorphous problem that there is processing stability and bin stability, and in process of production, the bulk density of amorphous particle is less, surface free energy is high, also easily cause a series of formulation problems such as cohesion, poor fluidity, elastic deformation be strong, have a strong impact on the clinical drug use value of amorphous heterocycle Radix Asparagi amino protein enzyme inhibitor.
It is known that same medicine, crystal formation is different, its bioavailability is likely to can exist difference, additionally its stability, mobility, compressibility are likely to meeting difference, and the application of medicine is produced certain impact by these physicochemical properties, thus affecting the curative effect of medicine. Accordingly, it would be desirable to have the crystal formation of the heterocycle Radix Asparagi amino protein enzyme inhibitor of superior physiochemical properties, it can advantageously use in medicine processing and pharmaceutical composition. The novel crystal forms of the heterocycle Radix Asparagi amino protein enzyme inhibitor that the present invention develops has no report.
Summary of the invention
Problem to be solved by this invention be existing heterocycle Radix Asparagi amino protein enzyme inhibitor unstability, hygroscopicity and easily transfer to the problems such as stable crystal formation be unfavorable for medicine processing and in pharmaceutical composition use, the novel crystal forms of heterocycle Radix Asparagi amino protein enzyme inhibitor, for the problem of the effectiveness study more qualitative, quantitative information of offer of solid drugs.
In order to solve above-mentioned technical problem, the invention provides the new crystal formation of a kind of heterocycle Radix Asparagi amino protein enzyme inhibitor (hereinafter referred to as " heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form "), as shown in formula (I).
Its XRPD collection of illustrative plates in 2 ��=8.70,10.34,13.96,16.44,16.76,17.82,18.12,18.72,19.38,19.72,20.70,21.38,21.80,24.04,24.56,25.06, there is diffraction maximum at 26.30,26.94,27.52,29.06,29.40 places, and wherein 2 �� value range of error are �� 0.2.
Heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form according to the present invention, has the XRPD collection of illustrative plates substantially the same with Figure of description Fig. 1.
Present invention also offers the method preparing above-mentioned heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form, comprise the following steps: in heterocycle Radix Asparagi amino protein enzyme inhibitor, be dissolved in organic solvent with the ratio of 1:2��1:10g/mL, solvent evaporated under room temperature, preserve at a temperature below the room temperature, by solid vacuum drying thus obtaining the B crystal form of heterocycle Radix Asparagi amino protein enzyme inhibitor.
In certain embodiments, described organic solvent is any one or the two or more mixed solvent with arbitrary proportion in organic solvent of ketone.
In some preferred embodiments, described organic solvent of ketone is acetone.
In certain embodiments, the described temperature lower than room temperature is 0 DEG C to 5 DEG C; It is particularly preferably 4 DEG C.
The consumption of the inventive method agents useful for same according to its knowledge and experience, can be adjusted by those of ordinary skill in the art, and including scaling up or reduce raw material dosage and adjusting solvent load, the scheme of these adjustment is also contained in the method for the present invention.
In above-mentioned steps, the ratio of heterocycle Radix Asparagi amino protein enzyme inhibitor and solvent is preferably 1:5g/mL.
In above-mentioned steps, the method for solvent evaporated can adopt any commonly employed experimental technique, it is preferred to use the method for rotary evaporation, and be particularly preferably, at 30 DEG C, solution rotating be evaporated to gel.
The compound with the heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form of the present invention is for treating or preventing suppressing the cardiovascular disease of Radix Asparagi aminoprotease sensitivity, cognitive illnesses and neurodegenerative disease and the disease caused by plasmodium etc. The compound of the present invention suppresses the protease of Radix Asparagi aminoprotease etc.
Therefore, the invention provides Radix Asparagi amino protein enzyme inhibitor B crystal form in preparation for suppressing the purposes in the medicine of Radix Asparagi aminoprotease; And in preparation for treating or preventing the purposes in the cardiovascular disease suppressing Radix Asparagi aminoprotease sensitive, cognitive illnesses and neurodegenerative disease and the medicine of disease that caused by plasmodium etc.
Present invention also offers pharmaceutical composition, it comprises the heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form according to the present invention and one or more pharmaceutically acceptable carriers, excipient or diluent.
In some embodiments of the invention, aforementioned pharmaceutical compositions comprises other therapeutic agent further, and described therapeutic agent is selected from chemotherapy or antiproliferative, antiinflammatory, immunomodulating or immunosuppressant, neurotrophic factor, anti-tumor agents or anticancer agent etc.
Heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form according to the present invention, there is outstanding high-temperature stability, high humility stability and light durability low, be conducive to medicine processing and use in pharmaceutical composition, can in treatment or prevention to suppressing application in the sensitive cardiovascular disease of Radix Asparagi aminoprotease, cognitive illnesses and neurodegenerative disease and the medicine of disease that caused by plasmodium etc., and there is good bioavailability, the qualitative, quantitative information simultaneously provided, has great importance to the curative effect studying this type of solid drugs further.
Accompanying drawing explanation
Fig. 1 is the XRPD collection of illustrative plates of heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form provided by the invention.
Fig. 2 is heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form high-temperature stability XRPD collection of illustrative plates provided by the invention; A:0 days, B:5 days, C:10 days.
Fig. 3 is heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form high humidity stability XRPD collection of illustrative plates provided by the invention; A:0 days, B:5 days, C:10 days.
Fig. 4 is heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form light durability XRPD collection of illustrative plates provided by the invention; A:0 days, B:5 days, C:10 days.
Fig. 5 is the existing heterocycle unbodied XRPD collection of illustrative plates of Radix Asparagi amino protein enzyme inhibitor.
Fig. 6 is the existing heterocycle amorphous high-temperature stability XRPD collection of illustrative plates of Radix Asparagi amino protein enzyme inhibitor; A:0 days, B:5 days, C:10 days.
Fig. 7 is the existing amorphous high humidity stability XRPD collection of illustrative plates of heterocycle Radix Asparagi amino protein enzyme inhibitor; A:0 days, B:5 days, C:10 days.
Fig. 8 is the existing amorphous light durability XRPD collection of illustrative plates of heterocycle Radix Asparagi amino protein enzyme inhibitor; A:0 days, B:5 days, C:10 days.
Detailed description of the invention
In from detailed description below, aforementioned aspect of the present invention and other aspects of the present invention will be apparent from.
The preparation of embodiment 1 heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form
Being dissolved in 1mL acetone by 200mg heterocycle Radix Asparagi aminoprotease inhibitor sample, at 30 DEG C, solution rotating is evaporated to gel, be placed on 48h at 4 DEG C, take out solid, ambient temperature in vacuum dries and obtains powder.
Embodiment 2. characterizes heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form by XRPD
The measurement of X-ray powder diffraction (XRPD) collection of illustrative plates, the multifunctional assembled X-ray diffractometer of RigakuUltimaIV model is used to carry out, concrete collection information is as follows: Cu anode (40kV, 40mA), scanning speed 20 ��/minute, sweep limits (2 �� scope) 5��45 ��, scanning step 0.02, slit width 0.01. Microscope slide is adopted directly in test board compacting, sample to be processed. Thereafter XRPD collection of illustrative plates all adopts similar measuring method.
The XRPD collection of illustrative plates of Radix Asparagi amino protein enzyme inhibitor B crystal form prepared by the method according to embodiment 1 of mensuration, in 2 ��=8.70,10.34,13.96,16.44,16.76,17.82,18.12,18.72,19.38,19.72,20.70,21.38,21.80,24.04,24.56,25.06,26.30,26.94,27.52,29.06, there is diffraction maximum at 29.40 places, as shown in Figure 1. Wherein 2 �� value range of error are �� 0.2. After testing, 2 �� value range of error can also be �� 0.15.
It will be understood by those skilled in the art that these diffraction maximums do not represent the detailed situation of diffraction maximum shown by heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form. 2 �� values of X-ray powder diffraction pattern be can along with machine and along with the change in sample preparation and batch between change and slightly change, cited value is not intended as absolute value. ?own ? hack badger neon lead a surname ? south the fervent flesh in Yun county support a kind of reed mentioned in ancient books beloved daughter �� cricket cold ? Ge of �� �� ? and suck the convulsion 19. intensity shown in demons and monsters ? ? Brain RPD trace and be illustrative of, be not used to definitely compare.
The high-temperature stability of embodiment 3. heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form is investigated
Heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form sample is placed in 60 DEG C of baking ovens, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 2), to investigate the sample stability of crystal form to temperature. It is shown that B crystal form sample is stable under hot conditions.
The high humidity study on the stability of embodiment 4. heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form
Heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form sample is placed under 92.5% damp condition, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 3), to investigate the sample stability of crystal form to humidity. It is shown that B crystal form sample is stable under super-humid conditions.
The light durability of embodiment 5 heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form is investigated
Heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form sample is placed under 4500lux intensity of illumination, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 4), to investigate the sample stability of crystal form to illumination. It is shown that B crystal form sample is stable under illumination condition.
The unbodied preparation of comparative example 1 heterocycle Radix Asparagi amino protein enzyme inhibitor
According to record method in Chinese invention patent application publication number CN101484429A, prepare free alkali (freebase) form of heterocycle Radix Asparagi amino protein enzyme inhibitor. The heterocycle Radix Asparagi amino protein enzyme inhibitor of synthesis obtains end product after flash column chromatography.
As it is shown in figure 5, measure through XRPD, the end product of gained is amorphous samples.
The unbodied high-temperature stability of comparative example 2. heterocycle Radix Asparagi amino protein enzyme inhibitor is investigated
Heterocycle Radix Asparagi amino protein enzyme inhibitor amorphous samples is placed in 60 DEG C of baking ovens, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 6), to investigate the sample stability of crystal form to temperature. It is shown that amorphous samples is stable under hot conditions.
The comparative example 3. heterocycle unbodied high humidity study on the stability of Radix Asparagi amino protein enzyme inhibitor
Heterocycle Radix Asparagi amino protein enzyme inhibitor amorphous samples is placed under 92.5% damp condition, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 7), to investigate the sample stability of crystal form to humidity. It is shown that amorphous samples is unstable under super-humid conditions.
And, by compare after lower 5 days of super-humid conditions and after 10 days the XRPD collection of illustrative plates of unbodied XRPD collection of illustrative plates and B crystal form it is found that amorphous other crystal formations that can be converted into the heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form being different from the present invention under light illumination of heterocycle Radix Asparagi amino protein enzyme inhibitor.
The unbodied light durability of comparative example 4 heterocycle Radix Asparagi amino protein enzyme inhibitor is investigated
Heterocycle Radix Asparagi amino protein enzyme inhibitor amorphous samples is placed under 4500lux intensity of illumination, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 8), to investigate the sample stability of crystal form to illumination. It is shown that amorphous samples is stable under illumination condition.
In sum, heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form can both remain stable under high temperature, high humidity and illumination condition, is better than amorphous products. As it is known to the person skilled in the art, the amorphous of instability can be changed into other crystal formations under certain condition, therefore stable crystal formation has advantage in the production process of pharmaceutical preparation. Due to the stability that heterocycle Radix Asparagi amino protein enzyme inhibitor B crystal form has, it can remain stable in the medicine course of processing of various solid dosages, can determine the crystal formation of active constituents of medicine in the medicine of final acquisition, it is able to ensure that known bioavailability, the drug effect difference brought because of crystal conversion will not occur.
Although those skilled in the art is it should be understood that for illustrative purposes, this document describes the specific embodiment of the present invention, but it can be carried out various amendment without departing from the spirit and scope of the present invention. Therefore, the specific embodiment of the present invention and embodiment should not be considered as limiting the scope of the invention. The present invention is limited only by the appended claims. The all documents quoted in the application are all intactly incorporated herein by reference.
Claims (6)
1. the B crystal form of the heterocycle Radix Asparagi amino protein enzyme inhibitor of a formula (I), it is characterised in that
Its XRPD collection of illustrative plates in 2 ��=8.70,10.34,13.96,16.44,16.76,17.82,18.12,18.72,19.38,19.72,20.70,21.38,21.80,24.04,24.56,25.06, there is diffraction maximum at 26.30,26.94,27.52,29.06,29.40 places, and wherein 2 �� value range of error are �� 0.2.
2. the B crystal form of heterocycle Radix Asparagi amino protein enzyme inhibitor as claimed in claim 1, it is characterised in that it has the XRPD collection of illustrative plates substantially the same with Figure of description Fig. 1.
3. the method preparing the B crystal form of heterocycle Radix Asparagi amino protein enzyme inhibitor as claimed in claim 1 or 2, it is characterized in that, comprise the following steps: in heterocycle Radix Asparagi amino protein enzyme inhibitor, be dissolved in organic solvent with the ratio of 1:2��1:10g/mL, solvent evaporated under room temperature, preserve at a temperature below the room temperature, by solid vacuum drying thus obtaining the B crystal form of heterocycle Radix Asparagi amino protein enzyme inhibitor.
4. method as claimed in claim 3, it is characterised in that described organic solvent is any one or the two or more mixed solvent with arbitrary proportion in organic solvent of ketone.
5. method as claimed in claim 4, it is characterised in that
Described organic solvent of ketone is acetone.
6. method as claimed in claim 3, it is characterised in that the described temperature lower than room temperature is 0 DEG C to 5 DEG C.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101484429A (en) * | 2006-06-12 | 2009-07-15 | 先灵公司 | Heterocyclic aspartyl protease inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484429A (en) * | 2006-06-12 | 2009-07-15 | 先灵公司 | Heterocyclic aspartyl protease inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| ANDREW W. STAMFORD，等: "Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction", 《ACS MEDICINAL CHEMISTRY LETTERS》 * |
| 吕扬，等: "《晶型药物》", 31 October 2009 * |
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Application publication date: 20160608 |