CN105524054A - Crystal form A of heterocyclic radix asparagi aminoprotease inhibitor and preparation method of crystal form A - Google Patents
Crystal form A of heterocyclic radix asparagi aminoprotease inhibitor and preparation method of crystal form A Download PDFInfo
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- CN105524054A CN105524054A CN201610055186.XA CN201610055186A CN105524054A CN 105524054 A CN105524054 A CN 105524054A CN 201610055186 A CN201610055186 A CN 201610055186A CN 105524054 A CN105524054 A CN 105524054A
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- C—CHEMISTRY; METALLURGY
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides a crystal form A of a heterocyclic radix asparagi aminoprotease inhibitor. The crystal form A of the heterocyclic radix asparagi aminoprotease inhibitor is shown in the formula (I) in the specification. Diffraction peaks of an XRPD (X-ray powder diffraction) pattern occur when 2 theta is equal to 8.72, 11.86, 14.86, 16.42, 16.76, 17.48, 17.84, 19.38, 20.60, 21.38, 22.18, 22.80, 23.84, 24.30, 24.54, 25.08, 26.32, 27.62, 28.42, 29.42, 31.04, 31.48 and 33.84, wherein the error of 2 theta fluctuates around 0.2. The crystal form A of the heterocyclic radix asparagi aminoprotease inhibitor has good high-temperature stability, high-humidity stability and illumination stability.
Description
Technical field
The present invention relates to a kind of polymorphic of asparagus fern amino protein enzyme inhibitors, particularly, relate to A crystal formation of a kind of heterocycle asparagus fern amino protein enzyme inhibitors and preparation method thereof.
Background technology
Known multiple asparagus fern amino protein enzyme inhibitors, its at adjustment blood pressure, suppress the neurodegenerative disorders of such as alzheimer's disease, reduce human immunodeficiency virus and retrovirus lifting capacity and kill in plasmodium etc. and can play effect.
Heterocycle asparagus fern amino protein enzyme inhibitors of the present invention, chemical name (S)-2-imido grpup-3,6-dimethyl-6-(4-(5-(1-proyl-1-base) pyridin-3-yl) thiophene-2-base) tetrahydropyrimidine-4 (1H)-one, shown in (I)
Be a kind of asparagus fern amino protein inhibitor compound, can be used for the disease for the treatment of or preventing the cardiovascular disorder to suppression asparagus fern aminoprotease sensitivity, cognitive illnesses and neurodegenerative disorders and being caused by plasmodium etc.In Chinese invention patent publication number CN101484429A (WO2007/146225), disclose the preparation method and use of heterocycle asparagus fern amino protein enzyme inhibitors.Repeating the preparation method of above-mentioned patent, obtain compound powder, is amorphous state after testing.As is known to the person skilled in the art, all have higher solubleness and dissolution rate than crystal formation although amorphous in most of occasion, it is unstable, and water absorbability is strong, easily transfers stable crystal formation to.Therefore, the amorphous problem that there is processing stability and package stability, and in process of production, the loose density of amorphous particle is less, surface free energy is high, a series of formulation problems such as also easily cause cohesion, poor fluidity, recoverable deformation strong, has a strong impact on the clinical drug use value of amorphous heterocycle asparagus fern amino protein enzyme inhibitors.
As everyone knows, same medicine, crystal formation is different, also difference may be there is in its bioavailability, its stability, mobility, compressibility also may be different in addition, and the application of these physico-chemical properties on medicine produces certain impact, thus affects the curative effect of medicine.Therefore, need the crystal formation of the heterocycle asparagus fern amino protein enzyme inhibitors with superior physiochemical properties, it can advantageously use in medicine processing and pharmaceutical composition.The new crystal of the heterocycle asparagus fern amino protein enzyme inhibitors of the present invention's development has no report.
Summary of the invention
Problem to be solved by this invention be existing heterocycle asparagus fern amino protein enzyme inhibitors unstable, water absorbability and easily transfer to the problems such as stable crystal formation be unfavorable for medicine processing and use in pharmaceutical composition, the new crystal of heterocycle asparagus fern amino protein enzyme inhibitors, the effectiveness study for solid pharmaceutical provides the problem of more qualitative, quantitative information.
In order to solve the problems of the technologies described above, the invention provides a kind of new crystal formation (hereinafter referred to as " heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation ") of heterocycle asparagus fern amino protein enzyme inhibitors, shown in (I).
Its XRPD collection of illustrative plates in 2 θ=8.72,11.86,14.86,16.42,16.76,17.48,17.84,19.38,20.60,21.38,22.18,22.80,23.84,24.30,24.54,25.08,26.32,27.62,28.42,29.42,31.04,31.48, there is diffraction peak at 33.84 places, and wherein 2 θ value limit of error are ± 0.2.
According to heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation of the present invention, there is 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 asparagus fern amino protein enzyme inhibitors A crystal formation, comprise the following steps: in heterocycle asparagus fern amino protein enzyme inhibitors, add organic solvent with the ratio of 1:50 ~ 1:150g/mL, at room temperature or the temperature low suspension higher than room temperature, then to filter, vacuum-drying thus obtain the A crystal formation of heterocycle asparagus fern amino protein enzyme inhibitors.
In certain embodiments, described organic solvent be any one solvent in alcohols, ethers, ester class, ketone, fat hydrocarbon, arene, nitrile or amides or two or more solvent with the mixed solvent of arbitrary proportion, or any one solvent described and water are with the mixed solvent of arbitrary proportion.
In some preferred embodiments, described alcohol organic solvent is Virahol or isopropylcarbinol; Described ether organic solvent is ether, isopropyl ether, methyl tertiary butyl ether or tetrahydrofuran (THF); Described based organic solvent is butylacetate or isopropyl acetate; Described organic solvent of ketone is acetone or butanone; Described fat hydrocarbon organic solvent is normal heptane, normal hexane or hexanaphthene; Described arene organic solvent is toluene or p-Xylol; Described nitrile organic solvent is acetonitrile; Described amides organic solvent is N, dinethylformamide.
In some preferred embodiments, described mixed solvent is the mixed solvent of acetone and butylacetate, acetone and water, acetone and isopropyl ether, acetone and normal hexane, butanone and isopropyl ether, butanone and p-Xylol, butanone and normal hexane, butanone and hexanaphthene, tetrahydrofuran (THF) and toluene, tetrahydrofuran (THF) and p-Xylol, tetrahydrofuran (THF) and normal hexane, acetonitrile and water, acetonitrile and isopropyl ether or N, dinethylformamide and water.
Those of ordinary skill in the art according to its knowledge and experience, can adjust the consumption of the inventive method agents useful for same, and comprise and scale up or reduce raw material dosage and adjustment solvent load, the scheme of these adjustment is also contained in method of the present invention.
In above-mentioned steps, the ratio of heterocycle asparagus fern amino protein enzyme inhibitors and solvent is preferably 1:100g/mL.
Present invention also offers the another kind of method preparing above-mentioned heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation, comprise the following steps: heterocycle asparagus fern amino protein enzyme inhibitors is dissolved in temperature higher than in Organic Solvent at Room Temperature, form saturated solution, naturally cool to room temperature, filter, vacuum-drying thus obtain the A crystal formation of heterocycle asparagus fern amino protein enzyme inhibitors.
In some preferred embodiments, described organic solvent n-propyl alcohol or Virahol.
In certain embodiments, the described temperature higher than room temperature is 50 DEG C to 80 DEG C, is particularly preferably 60 DEG C.
The compound with heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation of the present invention is the disease being used for the treatment of or preventing the cardiovascular disorder to suppression asparagus fern aminoprotease sensitivity, cognitive illnesses and neurodegenerative disorders and caused by plasmodium etc.Compound of the present invention suppresses the proteolytic enzyme of asparagus fern aminoprotease etc.
Therefore, the invention provides the purposes of asparagus fern amino protein enzyme inhibitors A crystal formation in the medicine for the preparation of suppression asparagus fern aminoprotease; And for the preparation for the treatment of or prevention to the purposes suppressed in the cardiovascular disorder of asparagus fern aminoprotease sensitivity, cognitive illnesses and neurodegenerative disorders and the medicine of disease that caused by plasmodium etc.
Present invention also offers pharmaceutical composition, it comprises according to heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation of the present invention and one or more pharmaceutically acceptable carrier, vehicle or thinner.
In some embodiments of the invention, aforementioned pharmaceutical compositions comprises other therapeutical agent further, and described therapeutical agent is selected from chemotherapy or antiproliferative, anti-inflammatory agent, immunomodulatory or immunosuppressor, neurotrophic factor, anti-tumor agents or anticancer agent etc.
According to heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation of the present invention, there is outstanding high-temperature stability, high humidity stability and light durability low, be conducive to medicine processing and use in pharmaceutical composition, can apply in the cardiovascular disorder of asparagus fern aminoprotease sensitivity, cognitive illnesses and neurodegenerative disorders and the medicine of disease that caused by plasmodium etc. suppressing in treatment or prevention, and there is good bioavailability, the qualitative, quantitative information simultaneously provided, has great importance to the curative effect studying this type of solid pharmaceutical further.
Accompanying drawing explanation
Fig. 1 is the XRPD collection of illustrative plates of heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation provided by the invention.
Fig. 2 is heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation 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 asparagus fern amino protein enzyme inhibitors A crystal formation 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 asparagus fern amino protein enzyme inhibitors A crystal formation light durability XRPD collection of illustrative plates provided by the invention; A:0 days, B:5 days, C:10 days.
Fig. 5 is the unbodied XRPD collection of illustrative plates of existing heterocycle asparagus fern amino protein enzyme inhibitors.
Fig. 6 is the amorphous high-temperature stability XRPD collection of illustrative plates of existing heterocycle asparagus fern amino protein enzyme inhibitors; A:0 days, B:5 days, C:10 days.
Fig. 7 is existing heterocycle asparagus fern amino protein enzyme inhibitors amorphous high humidity stability XRPD collection of illustrative plates; A:0 days, B:5 days, C:10 days.
Fig. 8 is existing heterocycle asparagus fern amino protein enzyme inhibitors amorphous light durability XRPD collection of illustrative plates; A:0 days, B:5 days, C:10 days.
Embodiment
From detailed description hereafter, above-mentioned aspect of the present invention and other aspects of the present invention will be obvious.
The preparation of embodiment 1 heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation
Take 20mg heterocycle asparagus fern amino protein enzyme inhibitors unformed in container, add 2mL Virahol, isopropylcarbinol, butylacetate, isopropyl acetate, ether, isopropyl ether, methyl tertiary butyl ether, normal heptane, normal hexane, hexanaphthene, toluene, one in p-Xylol, or butanone and isopropyl ether, p-Xylol, normal hexane, the mixed solvent of hexanaphthene, or acetone and butylacetate, water, isopropyl ether, the mixed solvent of normal hexane, or tetrahydrofuran (THF) and toluene, p-Xylol, the mixed solvent of normal hexane, or acetonitrile and water, the mixed solvent of isopropyl ether, or N, in the mixed solvent of dinethylformamide and water, 25 DEG C of condition low suspension 48h, filter to obtain solid, vacuum-drying obtains powder.
The preparation of embodiment 2 heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation
Take 20mg heterocycle asparagus fern amino protein enzyme inhibitors amorphous in container, add 2mL Virahol, isopropylcarbinol, butylacetate, isopropyl acetate, ether, isopropyl ether, methyl tertiary butyl ether, normal heptane, normal hexane, hexanaphthene, toluene, one in p-Xylol, or butanone and isopropyl ether, p-Xylol, normal hexane, the mixed solvent of hexanaphthene, or acetone and butylacetate, water, isopropyl ether, the mixed solvent of normal hexane, or tetrahydrofuran (THF) and toluene, p-Xylol, the mixed solvent of normal hexane, or acetonitrile and water, the mixed solvent of isopropyl ether, or N, in the mixed solvent of dinethylformamide and water, 50 DEG C of condition low suspension 24h, filter to obtain solid, vacuum-drying obtains powder.
The preparation of embodiment 3 heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation
To in Virahol or n-propyl alcohol, add the amorphous raw material of heterocycle asparagus fern amino protein enzyme inhibitors, be mixed with the saturated solution at 60 DEG C, naturally cool to room temperature, filter to obtain solid, vacuum-drying obtains powder.
Embodiment 4. characterizes heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation 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 Information Monitoring is as follows: Cu anode (40kV, 40mA), sweep velocity 20 °/minute, sweep limit (2 θ scope) 5 ~ 45 °, scanning step 0.02, slit width 0.01.Slide glass is adopted directly to process sample in test panel compacting.Thereafter XRPD collection of illustrative plates all adopts similar measuring method.
Measure the XRPD collection of illustrative plates of asparagus fern amino protein enzyme inhibitors A crystal formation prepared by method according to embodiment 1, in 2 θ=8.72,11.86,14.86,16.42,16.76,17.48,17.84,19.38,20.60,21.38,22.18,22.80,23.84,24.30,24.54,25.08,26.32,27.62,28.42,29.42,31.04,31.48, there is diffraction peak at 33.84 places, as shown in Figure 1.Wherein 2 θ value limit of error are ± 0.2.After testing, 2 θ value limit of error also can be ± 0.15.The heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation that according to embodiment 2-3 prepared by method, shown in its XRPD collection of illustrative plates with accompanying drawing 1, collection of illustrative plates is substantially identical.
It will be understood by those skilled in the art that these diffraction peaks do not represent the detailed situation of diffraction peak shown by heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation.2 θ 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 changing, the value quoted is not considered as absolute value.It will also be appreciated that the relative intensity at peak may become with orientation effect, the intensity shown in XRPD trace therefore contained by the present invention is exemplary, and is not used in and definitely compares.
The high-temperature stability of embodiment 5. heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation is investigated
Heterocycle asparagus fern amino protein enzyme inhibitors A crystal form 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 2), to investigate the stability of crystal form of sample to temperature.Result shows, under hot conditions, A crystal form samples is stablized.
The high humidity study on the stability of embodiment 6. heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation
Under heterocycle asparagus fern amino protein enzyme inhibitors A crystal form samples is placed in 92.5% humidity condition, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 3), to investigate the stability of crystal form of sample to humidity.Result shows, under super-humid conditions, A crystal form samples is stablized.
The light durability of embodiment 7 heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation is investigated
Under heterocycle asparagus fern amino protein enzyme inhibitors A crystal form samples is placed in 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 stability of crystal form of sample to illumination.Result shows, under illumination condition, A crystal form samples is stablized.
The unbodied preparation of comparative example 1 heterocycle asparagus fern amino protein enzyme inhibitors
According to record method in Chinese invention patent application publication number CN101484429A, prepare free alkali (freebase) form of heterocycle asparagus fern amino protein enzyme inhibitors.The heterocycle asparagus fern amino protein enzyme inhibitors of synthesis obtains final product after flash column chromatography.
As shown in Figure 5, measure through XRPD, the final product of gained is amorphous samples.
The unbodied high-temperature stability of comparative example 2. heterocycle asparagus fern amino protein enzyme inhibitors is investigated
Heterocycle asparagus fern amino protein enzyme inhibitors 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 stability of crystal form of sample to temperature.Result shows, under hot conditions, amorphous samples is stablized.
The unbodied high humidity study on the stability of comparative example 3. heterocycle asparagus fern amino protein enzyme inhibitors
Under heterocycle asparagus fern amino protein enzyme inhibitors amorphous samples is placed in 92.5% humidity condition, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 7), to investigate the stability of crystal form of sample to humidity.Result shows, under super-humid conditions, amorphous samples is unstable.
And, by compare super-humid conditions after lower 5 days and after 10 days the XRPD collection of illustrative plates of unbodied XRPD collection of illustrative plates and A crystal formation can find, heterocycle asparagus fern amino protein enzyme inhibitors is amorphous can be converted into heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation of the present invention under light illumination.
The unbodied light durability of comparative example 4 heterocycle asparagus fern amino protein enzyme inhibitors is investigated
Under heterocycle asparagus fern amino protein enzyme inhibitors amorphous samples is placed in 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 stability of crystal form of sample to illumination.Result shows, under illumination condition, amorphous samples is stablized.
In sum, heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation can both keep stable under high temperature, high humidity and illumination condition, is better than amorphous products.As is known to persons skilled in the art, the amorphous of instability can change other crystal formations under certain condition, and therefore stable crystal formation has advantage in the production process of pharmaceutical preparation.Due to the stability that heterocycle asparagus fern amino protein enzyme inhibitors A crystal formation has, it can keep stable in the medicine course of processing of various solid dosage, the crystal formation of the active constituents of medicine in the final medicine obtained can be determined, known bioavailability can be guaranteed, the drug effect difference brought because of crystal conversion can not occur.
Those skilled in the art should understand, although for illustrative purposes, this document describes the specific embodiment of the present invention, can carry out various amendment and without departing from the spirit and scope of the present invention to it.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 only by the restriction of claims.The all documents quoted in the application are all intactly incorporated to herein as a reference.
Claims (8)
1. an A crystal formation for the heterocycle asparagus fern amino protein enzyme inhibitors of formula (I), is characterized in that,
Its XRPD collection of illustrative plates in 2 θ=8.72,11.86,14.86,16.42,16.76,17.48,17.84,19.38,20.60,21.38,22.18,22.80,23.84,24.30,24.54,25.08,26.32,27.62,28.42,29.42,31.04,31.48, there is diffraction peak at 33.84 places, and wherein 2 θ value limit of error are ± 0.2.
2. the A crystal formation of heterocycle asparagus fern amino protein enzyme inhibitors as claimed in claim 1, it is characterized in that, it has the XRPD collection of illustrative plates substantially the same with Figure of description Fig. 1.
3. prepare the method for the A crystal formation of heterocycle asparagus fern amino protein enzyme inhibitors as claimed in claim 1 or 2, it is characterized in that, comprise the following steps: in heterocycle asparagus fern amino protein enzyme inhibitors, add organic solvent with the ratio of 1:50 ~ 1:150g/mL, at room temperature or the temperature low suspension higher than room temperature, then to filter, vacuum-drying thus obtain the A crystal formation of heterocycle asparagus fern amino protein enzyme inhibitors.
4. method as claimed in claim 3, it is characterized in that, described organic solvent be any one solvent in alcohols, ethers, ester class, ketone, fat hydrocarbon, arene, nitrile or amides or two or more solvent with the mixed solvent of arbitrary proportion, or any one solvent described and water are with the mixed solvent of arbitrary proportion.
5. method as claimed in claim 4, is characterized in that,
Described alcohol organic solvent is Virahol or isopropylcarbinol;
Described ether organic solvent is ether, isopropyl ether, methyl tertiary butyl ether or tetrahydrofuran (THF);
Described based organic solvent is butylacetate or isopropyl acetate;
Described organic solvent of ketone is acetone or butanone;
Described fat hydrocarbon organic solvent is normal heptane, normal hexane or hexanaphthene;
Described arene organic solvent is toluene or p-Xylol;
Described nitrile organic solvent is acetonitrile;
Described amides organic solvent is N, dinethylformamide.
6. method as claimed in claim 4, is characterized in that,
Described mixed solvent is the mixed solvent of acetone and butylacetate, acetone and water, acetone and isopropyl ether, acetone and normal hexane, butanone and isopropyl ether, butanone and p-Xylol, butanone and normal hexane, butanone and hexanaphthene, tetrahydrofuran (THF) and toluene, tetrahydrofuran (THF) and p-Xylol, tetrahydrofuran (THF) and normal hexane, acetonitrile and water, acetonitrile and isopropyl ether or N, dinethylformamide and water.
7. prepare the method for the A crystal formation of heterocycle asparagus fern amino protein enzyme inhibitors as claimed in claim 1 or 2, it is characterized in that, comprise the following steps: heterocycle asparagus fern amino protein enzyme inhibitors is dissolved in temperature higher than in Organic Solvent at Room Temperature, form saturated solution, naturally cool to room temperature, filter, vacuum-drying thus obtain the A crystal formation of heterocycle asparagus fern amino protein enzyme inhibitors.
8. method as claimed in claim 7, is characterized in that,
Described organic solvent is n-propyl alcohol or Virahol.
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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: 20160427 |