CN105461587A - AHU-377 hemicalcium salt crystal form, preparation method and application thereof - Google Patents
AHU-377 hemicalcium salt crystal form, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an AHU-377 hemicalcium salt crystal form, a preparation method and application thereof. The x-ray powder diffraction pattern of the AHU-377 hemicalcium salt crystal form includes peaks located at diffraction angles (2theta) of 12.70+/-0.2 degrees, 7.32+/-0.2 degrees, 15.90+/-0.2 degrees and 18.56+/-0.2 degrees, or the x-ray powder diffraction pattern includes peaks located at diffraction angles (2theta) of 4.02+/-0.2 degrees, 3.62+/-0.2 degrees and 17.82+/-0.2 degrees. AHU-377 is prepared into a calcium salt to change the physicochemical properties of AHU-377, improve the hygroscopicity of AHU-377 or its sodium salt and enhance the chemical stability, etc., and the AHU-377 hemicalcium salt crystal form is convenient to store and has broad application prospect.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of nep inhibitor AHU-377 half calcium salt crystal formation and its preparation method and application.
Background technology
Neutral endopeptidase (EC3.4.24.11; Enkephalinase; Must peptase; NEP) be a kind of can on the N-terminal of aromatic amino acid the metalloprotease comprising zinc of the various peptide substrates of cracking.The substrate of this enzyme comprises atrial natriuretic peptide (ANF is also referred to as ANP), brain natriuretic peptide (BNP), met and leu enkephalin, bradykinin, neurokinin A and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 without limitation.
ANF is gang's vasorelaxation, diuresis and antihypertensive peptide class, and a kind of form---ANF99-126 is the circulation peptide hormone discharged by heart in cardiac dilatation situation.The function of ANF is the homeostasis and the adjustment blood pressure that maintain salt and water.ANF is in the circulating cycle by least two process rapid inactivation: the removing of acceptor-mediation and the enzyme-deactivating carried out at NEP.Nep inhibitor enhance laboratory animal carry out pharmacology ANF injection after ypotension, diuresis, short natruresis and plasma ANF response.The enhancing of the ANF undertaken by two kinds of specific nep inhibitors, 1988, is disclosed in general manner in US Patent No. 4749688 and can strengthen ANF with NEP.In the same year, in US Patent No. 4740499, disclose the application that Thiorphan (thiorphan) and kelatorphan also may be used for strengthening atrial natriuretic peptide.In addition, nep inhibitor can reduce blood pressure and play the effect that the effect of ANF-sample is drained as the diuresis in the experimental hypertension of some forms and increase cyclic guanosine 3 ', 5 '-monophosphate (cGMP).Because the antibody of ANF is by offsetting the reduction of blood pressure, so the antihypertensive function of nep inhibitor is mediated by ANF.The hypertensive vascular disease carrying out controlling for a long time and not cause the most at last target organ after one's own heart with the various pathological changes of kidney.The hypertension continued also can cause the incidence of apoplexy to increase.Therefore, strongly need to assess effect of antihypertensive therapy, namely the benefit finding combination therapy is further checked to other cardiovascular endpoints event except blood pressure reduction.
1993, GaryKsander etc. disclose the 4-Aminobutanoicacid derivative of a class biaryl substituted in US Patent No. 5217996, this compounds is found to have obvious NEP inhibit activities, and wherein the representational compound of most is N-(3-carboxyl-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester via (also known as AHU-377).
In actual production preparation process, AHU-377 occurs with oily matter usually, is unfavorable for preserving and Subsequent pharmacological exploitation.AHU-377 crude product is through trimethyl carbinol esterification, the AHU-377 sodium salt obtained after sodium hydroxide basic hydrolysis state of aggregation after methylene dichloride/normal hexane recrystallization is failed to understand, and it is quite large to further investigate discovery AHU-377 sodium salt water absorbability through contriver, material is unstable and be unfavorable for storing, therefore, AHU-377 is as active constituents of medicine, its quality product, material stability, all there is very large problem in store or weighing etc., its sodium salt does not also solve the problem, although US Patent No. 5217996 also discloses AHU-377 can also be prepared into various salt type compound, such as an alkali metal salt, alkaline earth salt, amine salt, alkylamine salt, hydroxyalkyl amine salt etc., but, the main chemical structure deduction still containing a carboxyl from AHU-377 draws, unactually obtain various other salt type compound except sodium salt, AHU-377 poor product quality can not be solved, material is unstable, be difficult to the problems such as storage and weighing.
In addition, the application of this medicine is the patient having hypertension and heart failure class cardiovascular disorder, and the absorption of sodium also can increase cardiovascular burden, is therefore extremely necessary sodium salt to be replaced with other salt form, or other classes to cardiovascular harmless or useful salt as calcium salt etc.Calcium ion is extensively admitted cardiovascular beneficial effect, and the hypotensive effect of calcium ion may caused by following mechanism: 1, the membrane stabilizing action of calcium, and calcium is combined on cytolemma, can reduce permeability of cell membrane, improves excitation threshold, can make vascular smooth muscle relaxation; 2, calcium self calcium channel capable of blocking, makes extracellular calcium ion can not enter in cell; 3, the high row's potassium resisting caused by high natrium of blood calcium increases, and potassium ion plays an important role to stabilizing cell membrane.People maintains enough high calciums and takes in, and can resist the deleterious effect of high sodium; 4, have scholar to think, the elevation of blood pressure of 40% is relevant with parathyroid gland.Parathyroid gland can produce a kind of high heat-proof peptide material, and this causes hypertensive arch-criminal, is called as " the hypertension induced factor ".The generation of " the hypertension induced factor " stimulates by low calcium diet, and high calcium diet can suppress it to produce " the hypertension induced factor ".Modern study proves, the food that the elderly eats rich calcium more can harden by prevention of arterial, and hypertensive patient coordinates and replenishes the calcium while taking depressor, and too high blood pressure can also be made better to drop to normally.So for the people of calcium deficiency, supplement calcium in large quantities for a long time, makes blood calcium keep normal level, maintains the balance of smooth muscle cell intra-and extra-cellular calcium metabolism, avoid the spasm of vascular smooth muscle, thus the object reaching effective prevention of arterial arteriosclerosis, reduce blood pressure.Therefore, change the sodium salt of AHU377 into calcium salt, not only can reduce the side effect that sodium salt brings, the extra beneficial effect to cardiovascular disorder can also be brought.
Although WO2008031567 also discloses the synthetic route that AHU-377 free acid is prepared into calcium salt, as follows:
But, those skilled in the art can understand, above-mentioned common salify reflection technological line is the general technology route based on the compound containing carboxyl and calcium salt salify, but this technological line can not be applicable to all carboxylic compounds, also have no way of finding out about it and whether can be prepared the calcium salt of AHU377 by this reflection.This technological line is without embodiment support, so whether this technological line more unknowable can produce the calcium salt of crystal formation.In addition, this technological line is only set up under special conditions, especially second step in synthetic route, is the ion exchange reaction that AHU-377 sodium salt and CaCl2 occur, if can not create the special conditions that AHU-377 calcium salt or sodium-chlor are separated out from system, then said synthesis route is then false.Secondly, from the technological line that this is general, cannot infer the AHU-377 calcium salt whether can preparing solid form, whether gained calcium salt is crystal formation, is which kind of crystal formation.Therefore, this general technological line cannot obtain the AHU-337 crystals of calcium salts of AHU-377 calcium salt or crystallized form.
Summary of the invention
In order to solve prior art Problems existing, improve the physico-chemical property of AHU-377 or its sodium salt, contriver has prepared AHU-377 half calcium salt crystal formation on the basis of further investigation.By AHU-377 being prepared into the physico-chemical property that calcium salt changes AHU-377 or its sodium salt, such as crystallinity, solvability, water absorbability etc.
First aspect present invention provides a kind of AHU-377 half calcium salt crystal formation, its X-ray powder diffraction figure comprises and is positioned at 12.70 ± 0.2 °, 7.32 ± 0.2 °, the peak at diffraction angle (2 θ) place of 15.90 ± 0.2 ° and 18.56 ± 0.2 °, or its X-ray powder diffraction figure comprises and is positioned at 4.02 ± 0.2 °, the peak at diffraction angle (2 θ) place of 3.62 ± 0.2 ° and 17.82 ± 0.2 °.
Second aspect present invention provides a kind of AHU-377 half calcium salt trihydrate crystal formation (being appointed as crystal formation I), its X-ray powder diffraction figure comprises and is positioned at 12.70 ± 0.2 °, 7.32 ± 0.2 °, the peak at diffraction angle (2 θ) place of 15.90 ± 0.2 ° and 18.56 ± 0.2 °.
As further preferred scheme, preferably its X-ray powder diffraction figure also comprises and is positioned at 14.74 ± 0.2 °, 15.42 ± 0.2 °, 7.82 ± 0.2 °, 19.42 ± 0.2 °, the peak at diffraction angle (2 θ) place of 16.64 ± 0.2 ° and 17.54 ± 0.2 °.
As further preferred scheme, the peak at diffraction angle (2 θ) place most preferably shown in its X-ray powder diffraction figure and Fig. 1 is substantially the same, and its X-ray powder diffraction data are as shown in table 1:
Table 1
| 2θ(°) | Intensity % | 2θ(°) | Intensity % |
| 7.32 | 39 | 15.90 | 37.3 |
| 7.82 | 15.1 | 16.64 | 13.4 |
| 12.70 | 100 | 17.54 | 11.6 |
| 14.74 | 27.3 | 18.56 | 33.5 |
| 15.42 | 18.4 | 19.42 | 13.5 |
Third aspect present invention provides a kind of AHU-377 half calcium salt anhydrous crystal forms (being appointed as crystal form II), and its X-ray powder diffraction figure comprises and is positioned at 4.02 ± 0.2 °, the peak at diffraction angle (2 θ) place of 3.62 ± 0.2 ° and 17.82 ± 0.2 °.
As further preferred scheme, preferably its X-ray powder diffraction figure also comprises and is positioned at 20.48 ± 0.2 °, the peak at diffraction angle (2 θ) place of 14.50 ± 0.2 ° and 19.66 ± 0.2 °.
As further preferred scheme, the peak at diffraction angle (2 θ) place most preferably shown in its X-ray powder diffraction figure and Fig. 3 is substantially the same, and its X-ray powder diffraction data are as shown in table 2:
Table 2
| 2θ(°) | Intensity % | 2θ(°) | Intensity % |
| 3.62 | 58.2 | 17.82 | 36.8 |
| 4.02 | 100 | 19.66 | 13.8 |
| 14.50 | 25.8 | 20.48 | 29 |
Term about X-ray diffraction peak position used herein " substantially the same " means to consider typical peak position and intensity variable.Such as, it will be understood by those skilled in the art that peak position (2 θ) will be different due to XRPD instrument, and cause observed value to change to some extent, this change sometimes reaches sometimes nearly 0.2 °.In addition, it will be understood by those skilled in the art that XRPD sample method for making sample, XRPD instrument, sample crystallinity, the factors such as amount of samples and crystal preferred orientation will cause the change of relative peak intensities in sample XRPD diffractogram.
Fourth aspect present invention provides a kind of preparation method of AHU-377 half calcium salt trihydrate crystal formation, comprises,
1) by AHU-377 acid dissociable dissolution or suspendible in a suitable solvent, to equivalent or excessive dissolve in this system caustic alkali or weakly alkaline sodium salt or sylvite be mixed with mutually and generate the corresponding salt of AHU-377, preferably weakly alkaline sodium salt or sylvite are mixed mutually;
2) by above-mentioned AHU-377 salt system and water-soluble Ca salt water or containing the aqueous systems of organic solvent in mix mutually, produce AHU-377 calcium precipitation;
3) collect product in above-mentioned salt-forming reaction process and obtain AHU-377 half calcium salt trihydrate crystal formation.
As further preferred scheme, step 1) described suitable solvent is recrystallisation solvent, comprises water, water-soluble solvent or its mixture.
As further preferred scheme, described water-soluble solvent is selected from alcohols, ketone, cyclic ethers class, amides, sulfoxide type organic solvent or its mixture, preferably from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, acetonitrile, acetone, methylethylketone, tetrahydrofuran (THF), dioxane, DMF, dimethyl sulfoxide (DMSO) or its mixture;
As further preferred scheme, step 1) described caustic alkali is sodium hydroxide or potassium hydroxide.
As further preferred scheme, step 1) described weakly alkaline sodium salt is selected from sodium carbonate, sodium bicarbonate, sodium-acetate, sodium formiate, Sodium Propionate, sodium acrylate, Sodium Benzoate or its mixture; Preferred sodium bicarbonate, sodium-acetate or its mixture; Step 1) described weakly alkaline sylvite is selected from salt of wormwood, saleratus, Potassium ethanoate, potassium formiate, potassium propionate, potassium acrylate, potassium benzoate or its mixture; Potassium bicarbonate, Potassium ethanoate or its mixture;
As further preferred scheme, step 2) described water-soluble Ca salt is selected from calcium chloride, Calcium Bromide, calcium iodide, nitrocalcite, calcium chlorate, Losantin, calcium perchlorate, calcium lactate, calglucon or its mixture;
As further preferred scheme, step 2) described water-soluble Ca salt is selected from calcium chloride, calcium chlorate or its mixture.
As further preferred scheme, described dissolving refers to the operation that those of ordinary skill in the art is general, usually suitable heating can make AHU-377 free acid material dissolution or clearly molten, or the consumption strengthening solvent makes AHU-377 free acid material dissolution or clearly molten.
As further preferred scheme, positive for crystallization solvothermal to 30 ~ 80 DEG C are preferably made AHU-377 free acid material dissolution or clearly molten by described heating suitably.
As further preferred scheme, the add-on of the preferred recrystallisation solvent of consumption of described increasing solvent is 2-20 times of volume mass ratio of AHU-377 free acid, makes AHU-377 free acid material dissolution or clearly molten.
As further preferred scheme, step 3) described in collection above-mentioned salt-forming reaction process in the step of product can be specifically directly collect the solid product of separating out in above-mentioned one-tenth calcium salt reaction process or by solvent flashing or add anti-solvent or the crystallization or add crystal seed of directly lowering the temperature, obtain AHU-377 calcium salt polymorphic.
As further preferred scheme, described anti-solvent refers to the organic solvent that polarity is less, including but not limited to following solvent: normal heptane, normal hexane, octane-iso, pentane, hexanaphthene, pentamethylene, ether or its composition.The amount adding anti-solvent is recrystallisation solvent 1-10 times volume ratio.
As further preferred scheme, step 3 of the present invention) its x-ray diffractogram of powder of AHU-377 calcium salt crystal formation I of obtaining comprises and is positioned at 12.70 ± 0.2 °, 7.32 ± 0.2 °, the peak at diffraction angle (2 θ) place of 15.90 ± 0.2 ° and 18.56 ± 0.2 °.
Fifth aspect present invention provides a kind of preparation method of AHU-377 half calcium salt anhydrous crystal forms, and AHU-377 half calcium salt trihydrate is heated to more than 50 DEG C, makes it dewater to be transformed into anhydrous crystal forms to obtain AHU-377 half calcium salt anhydrous crystal forms.
As further preferred version, described heating is the operation that those of ordinary skill in the art is general, usually can heat up under nitrogen protection or under vacuum condition.
As further preferred version, described heating temperature range is at 50-100 DEG C.
As further preferred scheme, AHU-377 calcium salt anhydrous crystal forms (crystal form II) its X-ray powder diffraction figure that the present invention obtains comprises and is positioned at 4.02 ± 0.2 °, the peak at diffraction angle (2 θ) place of 3.62 ± 0.2 ° and 17.82 ± 0.2 °.
As further preferred scheme, preferably its X-ray powder diffraction figure also comprises and is positioned at 20.48 ± 0.2 °, the peak at diffraction angle (2 θ) place of 14.50 ± 0.2 ° and 19.66 ± 0.2 °.
Sixth aspect present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises aforementioned AHU-377 half calcium salt crystal formation, AHU-377 calcium salt crystal formation I or the crystal form II and pharmaceutically acceptable carrier or vehicle for the treatment of effective dose.
As further preferred scheme, described pharmaceutically acceptable carrier or vehicle are selected from thinner or weighting agent, disintegrating agent, tackiness agent, glidant, lubricant, tinting material or its combination.
As further preferred scheme, described thinner or weighting agent are selected from Icing Sugar, sompressible sugar, glucose, sucrose, lactose, dextrin, N.F,USP MANNITOL, Microcrystalline Cellulose, sorbyl alcohol, starch or its combination; The consumption of thinner or weighting agent is 4.0% ~ 60.0% of composition weight, preferably 10.0% ~ 40.0%.
As further preferred scheme, described disintegrating agent is selected from starch, clay, Mierocrystalline cellulose, alginate, natural gum, cross-linked polymer (such as cross-linked polyvinylpyrrolidone, croscarmellose sodium, cross-linked carboxymethyl cellulose calcium or its combination), soybean polysaccharide, guar gum or its combination; The consumption of disintegrating agent is 0% ~ 65.0% of composition weight, preferably 1.0% ~ 40.0%.
As further preferred scheme, described tackiness agent is selected from starch, cellulose and its derivates, sucrose, glucose, maize treacle, gelatin, polyvidone or its combination, and wherein cellulose and its derivates is selected from Microcrystalline Cellulose, hydroxypropylcellulose, Natvosol, Vltra tears or its combination; Preferred hydroxypropylcellulose; More preferably low-substituted hydroxypropyl cellulose; The consumption of tackiness agent is 1.0% ~ 60.0% of composition weight, preferably 5.0% ~ 40.0%, more preferably 10.0% ~ 30.0%.
As further preferred scheme, described glidant or lubricant are selected from colloidal silica, Magnesium Trisilicate, starch, talcum powder, tricalcium orthophosphate, Magnesium Stearate, aluminum stearate, calcium stearate, calcium carbonate, magnesium oxide, polyoxyethylene glycol, Solka-floc, Glyceryl Behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, sodium stearyl fumarate or its combination; The consumption of glidant or lubricant is 0% ~ 10.0% of composition weight, preferably 0.5% ~ 5.0%.
As further preferred scheme, described pharmaceutical composition comprises (IV) diuretic(s) further; Described diuretic(s) is selected from Furosemide, Ethacrynic Acid, bumetanide, torasemide, hydrochlorothiazide, chlorthalidone, Hydrex, cyclopenthiazide, polythiazide, metolazone, indapamide or its combination; The consumption of diuretic(s) is 0.1% ~ 10.0% of composition weight, preferably 0.5% ~ 5.0%.
As further preferred scheme, described pharmaceutical composition can be prepared into tablet, capsule, granule.
As further preferred scheme, described capsule component proportion is as follows:
| Component | Title | Weight percent |
| (ⅰ) | AHU-377 calcium salt crystal formation I | 5.0％～50.0％ |
| (ⅱ) | Thinner or weighting agent | 10.0％～40.0％ |
| (ⅲ) | Disintegrating agent | 1.0％～40.0％ |
| (ⅳ) | Tackiness agent | 10.0％～30.0％ |
| (ⅴ) | Glidant or lubricant | 0.5％～5.0％ |
As the scheme of optimum, described capsule component proportion is as follows:
| Component | Title | Weight percent |
| (ⅰ) | AHU-377 calcium salt crystal formation I | 20.0％～50.0％ |
| (ⅱ) | Thinner or weighting agent | 10.0％～30.0％ |
| (ⅲ) | Disintegrating agent | 5.0％～30.0％ |
| (ⅳ) | Tackiness agent | 10.0％～30.0％ |
| (ⅴ) | Glidant or lubricant | 1.0％～5.0％ |
| (ⅵ) | Diuretic(s) | 0.5％～5.0％ |
Seventh aspect present invention provides a kind of aforementioned AHU-377 half calcium salt crystal formation, AHU-377 calcium salt crystal formation I or crystal form II or comprises the purposes of pharmaceutical composition in the disease that preparation is treated or prevention is relevant with neutral endopeptidase, cardiovascular, antihypertensive medicine of the aforementioned AHU-377 half calcium salt crystal formation for the treatment of effective dose, AHU-377 calcium salt crystal formation I or crystal form II.
As further preferred scheme, described antihypertensive medicine refers to the medicine creating more effective antihypertensive therapy by improving effect and have higher corresponding rate, includes but not limited to anti-malignant hypertension, essential hypertension, renovascular hypertension, diabetic hypertension, isolated systolic hypertension or other secondary hypertension medicine.
Sixth aspect present invention provides a kind of aforementioned AHU-377 half calcium salt crystal formation, AHU-377 calcium salt crystal formation I or crystal form II, or comprise the aforementioned AHU-377 half calcium salt crystal formation for the treatment of effective dose, the pharmaceutical composition of AHU-377 calcium salt crystal formation I or crystal form II preparation treatment or prevention acute and chronic heart failure as, congestive heart failure, left ventricle dysfunction, hypertrophic neuropathy, diabetic cardiomyopathy, supraventricular and heart ventricle arrhythmia, atrial fibrillation, purposes in auricular flutter or harmful vascular remodeling medicine.
Eighth aspect present invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises the treatment aforementioned AHU-377 half calcium salt crystal formation of effective dose, AHU-377 calcium salt crystal formation I or crystal form II and angiotensinⅡ (AT1) receptor antagonist, and pharmaceutically acceptable carrier or vehicle.
As further preferred scheme, described angiotensinⅡantagonist is selected from that losartan, irbesartan, Olmesartan, telmisartan, valsartan, Azilsartan, Candesartan, Eprosartan, losartan, husky Puli's sand are smooth, Elisartan, Tasosartan, Ai Lishatan or its pharmacologically acceptable salt.
As further preferred scheme, described angiotensinⅡantagonist is selected from valsartan, Azilsartan or its pharmacologically acceptable salt.
Ninth aspect present invention provides a kind of foregoing pharmaceutical composition in preparation treatment or prevents myocardial infarction and sequela thereof, atherosclerosis, stenocardia, diabetic or non-diabetic renal insufficiency, secondary aldosteronism, primary or secondary pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, the proteinuria of Primary Nephrosis, renovascular hypertension, diabetic retinopathy, migraine, peripheral vascular disease, Raynaud disease, the hyperplasia in chamber, cognitive dysfunction, purposes in glaucoma or apoplexy medicine.
" pharmaceutical composition " represent containing on one or more compounds described herein or its physiology/mixture of pharmacy acceptable salt or prodrug and other chemical compositions, with or other components such as physiology/pharmaceutically acceptable carrier and vehicle.The object of pharmaceutical composition promotes the administration to organism, is beneficial to the absorption of activeconstituents and then plays biological activity.
Compared with prior art, the present invention has advantage:
1) the invention provides a kind of new AHU-377 calcium salt trihydrate, improve the water absorbability of AHU-377 or its sodium salt, improve chemical stability etc., be beneficial to storage.
2) AHU-377 calcium salt trihydrate of the present invention, purity is high, and steady quality is reliable.
3) crystallization method of the present invention is workable, technical maturity, is easy to control.
4) gained AHU-377 calcium salt crystal formation I of the present invention is beneficial to medicinal application, and prepared capsule can meet medical science or pharmacy needs, suitability for industrialized.
5) gained AHU-377 calcium salt of the present invention is compared with sodium salt, in hypertension and heart failure therapeutic process, can reduce the absorption of sodium, alleviates the cardiovascular burden of patient.And calcium, to the blood vessel effect of releiving, is conducive to the treatment of cardiovascular disorder.Therefore AHU-377 this be mainly used in hypertension and heart failure treatment medicine make calcium salt in security and validity comparatively sodium salt there is obvious advantage.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure (XRPD figure) of AHU-377 calcium salt trihydrate crystal formation;
Fig. 2 is the thermogravimetric analysis figure (TGA figure) of AHU-377 calcium salt trihydrate crystal formation;
Fig. 3 is the X-ray powder diffraction figure (XRPD figure) of AHU-377 calcium salt anhydrous crystal forms.
Embodiment
The specific embodiment below provided and preparation method's example will illustrate the particular aspects of embodiment of the present invention further.The scope that the scope of the following example will not limit the present invention in any way.
Method and material
AHU-377 calcium salt polymorphic is characterized by their X-ray powder diffraction figure.Therefore, there is use CuK α radiation
the BrukerD8DiscoverX ray powder diffractometer of GADDS (the general area diffraction detector system) CS of reflection mode operation to gather the X-ray powder diffraction figure of described salt.Tube voltage and the magnitude of current are set to 40kV and 40mA acquisition scans respectively.The 2 θ scope interscan samples period of 60 seconds of 3.0 ° to 40 °.For the peak position that 2 θ represent, use corundum standard product calibration diffractometer.All analyses are implemented under the normally room temperature of 20 DEG C-30 DEG C.Use the GADDS being used for 4.1.14T version WNT software, gather and integration data.The DiffracPlus software with 9.0.0.2 version Eva using issue for 2003, analyzes diffractogram.The preparation of XRPD sample, by being by sample as on monocrystalline silicon piece, by sheet glass or equivalent pressure sample powder to guarantee that the surface of sample is smooth and to have suitable height.Then sample holder is put into BrukerXRPD instrument, and use above-described instrument parameter to gather X-ray powder diffraction figure.The measurement difference relevant to this kind of X-ray powder diffraction analytical results is produced: the error in (a) sample preparation thing (such as height of specimen) by comprising following many factors, (b) instrumental error, (c) calibration difference, (d) personal error (being included in those errors occurred when measuring peak position), and the character of (e) material (such as preferred orientation error).Alignment error and sample height errors often cause the displacement of all peaks in equidirectional.In general, this calibration factor is by consistent for the peak position of the peak position with expection that make measurement and can in the scope of 2 θ value ± 0.2 of expecting °.
Raw material A HU-377 free acid of the present invention reports preparation method according to patent US5217996A and must be oily matter.Each polymorphous angle 2 θ (°) value of embodiment of the present invention gained and intensity level (% as peak-peak) have been listed in table 1-table 2.
Embodiment 1
Take 500mg (1.215mmol) AHU-377 free acid (oily) and be placed in 50.0mL round-bottomed flask, add 5.0mL acetone, stir clearly molten, add the sodium bicarbonate aqueous solution that 12.2mL concentration is 0.10mmol/mL, stirring reaction 12 hours, add the calcium chloride water that 0.65mL concentration is 1.0mmol/mL, and then add the water of 15mL, stir and make it fully react in 24 hours.Solid-liquid separation obtains AHU-377 calcium salt crystal formation I, and fusing point is: its X-ray powder diffraction figure (XRPD figure) as shown in Figure 1.
AHU-377 calcium salt crystal formation I thermal weight loss situation is measured with thermogravimetric analyzer (TGA, model TAQ500).Measuring condition is for be heated to 400 DEG C from room temperature, and temperature rise rate is 10 DEG C of per minutes, and heating is carried out in a nitrogen atmosphere, and nitrogen flow is 50mL per minute.The TGA figure of AHU-377 calcium salt crystal formation I as shown in Figure 2.Within 100 DEG C, weightlessness is 10%, therefore can judge that AHU-377 calcium salt crystal formation I is AHU377 half calcium three crystal compound with AHU377 half calcium salt trihydrate theoretical weightless approximate (theoretical weightlessness is 11%).
Embodiment 2
Take 50mg (0.12mmol) AHU-377 free acid (oily) and be placed in 10.0mL round-bottomed flask, add 1.0mL Virahol, stir clearly molten, add the sodium acetate aqueous solution that 0.25mL concentration is 0.50mmol/mL, stirring reaction 12 hours, add the solution of calcium bromide in water that 0.15mL concentration is 0.5mmol/mL, and then add the water of 5mL, stir and make it fully react in 24 hours.Solid-liquid separation obtains AHU-377 calcium salt crystal formation I, and its X-ray powder diffraction figure (XRPD figure) is basic with such as Fig. 1 is consistent.
Embodiment 3
Take 50mg (0.12mmol) AHU-377 free acid (oily) and be placed in 10.0mL round-bottomed flask, add 0.5mL tetrahydrofuran (THF), stir clearly molten, add the potassium bicarbonate aqueous solution that 1.0mL concentration is 0.10mmol/mL, stirring reaction 12 hours, add the calcium chloride water solution that 0.25mL concentration is 0.5mmol/mL, and then add the water of 5mL, stir and make it fully react in 24 hours.Solid-liquid separation obtains AHU-377 calcium salt crystal formation I, and its X-ray powder diffraction figure (XRPD figure) is basic with such as Fig. 1 is consistent.
Embodiment 4
Take 50mg (0.12mmol) AHU-377 free acid (oily) and be placed in 10.0mL round-bottomed flask, add 0.3mLN, dinethylformamide, stir clearly molten, add the potassium propionate aqueous solution that 0.65mL concentration is 0.20mmol/mL, stirring reaction 12 hours, add the calcium chloride water that 0.30mL concentration is 0.5mmol/mL, and then add the water of 5mL, stir and make it fully react in 24 hours.Solid-liquid separation obtains AHU-377 calcium salt crystal formation I, and its X-ray powder diffraction figure (XRPD figure) is basic with such as Fig. 1 is consistent.
Embodiment 5
Take 50mg (0.12mmol) AHU-377 free acid (oily) and be placed in 10.0mL round-bottomed flask, add 1.0mL ethanol, be heated to 60 DEG C of stirrings clearly molten, add the potassium bicarbonate aqueous solution that 1.4mL concentration is 0.10mmol/mL, stirring reaction 12 hours, add the calcium lactate aqueous solution that 0.15mL concentration is 0.5mmol/mL, and then add the water of 5mL, stir and make it fully react in 24 hours.Solid-liquid separation obtains AHU-377 calcium salt crystal formation I, and its X-ray powder diffraction figure (XRPD figure) is basic with such as Fig. 1 is consistent.
Embodiment 6
Take 50mg (0.12mmol) AHU-377 free acid (oily) and be placed in 10.0mL round-bottomed flask, add 1.0mL acetonitrile, be heated to 40 DEG C of stirrings clearly molten, add the Sodium Benzoate aqueous solution that 1.3mL concentration is 0.10mmol/mL, stirring reaction 12 hours, add the calcium lactate aqueous solution that 0.2mL concentration is 0.5mmol/mL, and then add the water of 5mL, stir and make it fully react in 24 hours.Solid-liquid separation obtains AHU-377 calcium salt crystal formation I, and its X-ray powder diffraction figure (XRPD figure) is basic with such as Fig. 1 is consistent.
Embodiment 7
Take 20mgAHU-377 calcium salt crystal formation I, in thermogravimetric analyzer, be heated to 90 DEG C, after Temperature fall, take out rapidly, detect crystal formation with XRPD, its X-ray powder diffraction figure (XRPD figure) is basic consistent with Fig. 3.
Embodiment 8
| Component | The composition (mg) of per unit | Composition (%) |
| AHU-377 calcium salt crystal formation I | 150 | 46.87 |
| Microcrystalline Cellulose | 32 | 10.0 |
| Polyvidone | 70 | 21.88 |
| Cross-linked polyvinylpyrrolidone | 21.6 | 6.75 |
| Colloidal silica | 3.2 | 1.0 |
| Magnesium Stearate | 3.2 | 1.0 |
| Gross weight | 320 | 100.0 |
First Magnesium Stearate, colloidal silica and Microcrystalline Cellulose are sieved by 30 mesh sieves.Then said mixture, active components A HU-377 calcium salt crystal formation I, cross-linked polyvinylpyrrolidone and polyvidone are mixed about 120 turns in hopper mixing machine.The pressure of roller press 30kN is used to suppress described mixture.After compacting, use shredder to grind described mixture and through 18 mesh sieve screenings, obtain final interior phase or particle.By granule filling in capsule, make capsule.
Embodiment 9
| Component | The composition (mg) of per unit | Composition (%) |
| AHU-377 calcium salt crystal formation I | 96 | 30.0 |
| Microcrystalline Cellulose | 96 | 30.0 |
| Low-substituted hydroxypropyl cellulose | 32 | 10.0 |
| Cross-linked polyvinylpyrrolidone | 89.6 | 28.0 |
| Colloidal silica | 3.2 | 1.0 |
| Magnesium Stearate | 3.2 | 1.0 |
| Gross weight | 320 | 100 |
First described active components A HU-377 calcium salt crystal formation I is sieved by 40 mesh sieves.In activeconstituents, add Microcrystalline Cellulose and cross-linked polyvinylpyrrolidone, sieve this mixture by 20 mesh sieves.Then this mixture is mixed in hopper mixing machine and rotate about 100 turns.Then low-substituted hydroxypropyl cellulose and colloidal silica are added in material bin mixing machine, then make it rotate 100 turns.Finally add Magnesium Stearate.Then by powder mixture compression in flakes.
The stability of preparation and stripping detect
Under the tablet of the capsule of embodiment 8 and embodiment 9 is put different condition respectively, investigate the stability of preparation, result is as shown in the table:
Finally should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted the present invention, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
Claims (21)
1. an AHU-377 half calcium salt crystal formation, its X-ray powder diffraction figure comprises and is positioned at 12.70 ± 0.2 °, 7.32 ± 0.2 °, the peak at diffraction angle (2 θ) place of 15.90 ± 0.2 ° and 18.56 ± 0.2 °, or its X-ray powder diffraction figure comprises and is positioned at 4.02 ± 0.2 °, the peak at diffraction angle (2 θ) place of 3.62 ± 0.2 ° and 17.82 ± 0.2 °.
2. an AHU-377 half calcium salt trihydrate crystal formation, its X-ray powder diffraction figure comprises and is positioned at 12.70 ± 0.2 °, 7.32 ± 0.2 °, the peak at diffraction angle (2 θ) place of 15.90 ± 0.2 ° and 18.56 ± 0.2 °; Preferably its X-ray powder diffraction figure also comprises and is positioned at 14.74 ± 0.2 °, 15.42 ± 0.2 °, 7.82 ± 0.2 °, 19.42 ± 0.2 °, the peak at diffraction angle (2 θ) place of 16.64 ± 0.2 ° and 17.54 ± 0.2 °; The peak at diffraction angle (2 θ) place more preferably shown in its X-ray powder diffraction figure and Fig. 1 is substantially the same.
3. an AHU-377 half calcium salt anhydrous crystal forms, its X-ray powder diffraction figure comprises and is positioned at 4.02 ± 0.2 °, the peak at diffraction angle (2 θ) place of 3.62 ± 0.2 ° and 17.82 ± 0.2 °; Preferably its X-ray powder diffraction figure also comprises and is positioned at 20.48 ± 0.2 °, the peak at diffraction angle (2 θ) place of 14.50 ± 0.2 ° and 19.66 ± 0.2 °; The peak at diffraction angle (2 θ) place more preferably shown in its X-ray powder diffraction figure and Fig. 3 is substantially the same.
4. a preparation method for AHU-377 half calcium salt trihydrate crystal formation, is characterized in that, comprise the steps,
1) by AHU-377 acid dissociable dissolution or suspendible in a suitable solvent, to equivalent or excessive dissolve in this system caustic alkali or weakly alkaline sodium salt or sylvite be mixed with mutually and generate the corresponding salt of AHU-377, preferably, mix mutually with equivalent or excessive weakly alkaline sodium salt or sylvite;
2) by above-mentioned AHU-377 salt system and water-soluble Ca salt water or containing the aqueous systems of machine solvent in mix mutually, produce AHU-377 calcium precipitation;
3) collect product in above-mentioned salt-forming reaction process and obtain AHU-377 half calcium salt trihydrate crystal formation;
Step 1) described suitable solvent is recrystallisation solvent, comprises water, water-soluble solvent or its mixture.
5. the preparation method of AHU-377 half calcium salt trihydrate crystal formation according to claim 4, it is characterized in that, described water-soluble solvent is selected from alcohols, ketone, cyclic ethers class, amides, sulfoxide type organic solvent or its mixture, preferably from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, acetonitrile, acetone, methylethylketone, tetrahydrofuran (THF), dioxane, DMF, dimethyl sulfoxide (DMSO) or its mixture.
6. the preparation method of AHU-377 half calcium salt trihydrate crystal formation according to claim 4, it is characterized in that, step 1) described caustic alkali is sodium hydroxide or potassium hydroxide, described weakly alkaline sodium salt is selected from sodium carbonate, sodium bicarbonate, sodium-acetate, sodium formiate, Sodium Propionate, sodium acrylate, Sodium Benzoate or its mixture, preferred sodium bicarbonate, sodium-acetate or its mixture, described weakly alkaline sylvite is selected from salt of wormwood, saleratus, Potassium ethanoate, potassium formiate, potassium propionate, potassium acrylate, potassium benzoate or its mixture, potassium bicarbonate, Potassium ethanoate or its mixture, step 2) described water-soluble Ca salt is selected from calcium chloride, Calcium Bromide, calcium iodide, nitrocalcite, calcium chlorate, Losantin, calcium perchlorate, calcium lactate, calglucon or its mixture, preferably from calcium chloride, calcium chlorate or its mixture.
7. the preparation method of AHU-377 half calcium salt trihydrate crystal formation according to claim 4, it is characterized in that, step 3) its x-ray diffractogram of powder of AHU-377 calcium salt crystal formation I of obtaining comprises and is positioned at 12.70 ± 0.2 °, 7.32 ± 0.2 °, the peak at diffraction angle (2 θ) place of 15.90 ± 0.2 ° and 18.56 ± 0.2 °, preferably its X-ray powder diffraction figure also comprises and is positioned at 14.74 ± 0.2 °, 15.42 ± 0.2 °, 7.82 ± 0.2 °, 19.42 ± 0.2 °, the peak at diffraction angle (2 θ) place of 16.64 ± 0.2 ° and 17.54 ± 0.2 °.
8. a preparation method for AHU-377 half calcium salt anhydrous crystal forms, is characterized in that, AHU-377 half calcium salt trihydrate is heated to more than 50 DEG C, makes it dewater and be transformed into anhydrous crystal forms; Preferred heating temperature range is at 50-100 DEG C.
9. the preparation method of AHU-377 half calcium salt anhydrous crystal forms according to claim 8, it is characterized in that, its X-ray powder diffraction of the AHU-377 half calcium salt anhydrous crystal forms figure obtained comprises and is positioned at 4.02 ± 0.2 °, the peak at diffraction angle (2 θ) place of 3.62 ± 0.2 ° and 17.82 ± 0.2 °; Preferably its X-ray powder diffraction figure also comprises and is positioned at 20.48 ± 0.2 °, the peak at diffraction angle (2 θ) place of 14.50 ± 0.2 ° and 19.66 ± 0.2 °.
10. a pharmaceutical composition, described pharmaceutical composition comprises AHU-377 according to claim 1 half calcium salt crystal formation, AHU-377 according to claim 2 half calcium salt trihydrate crystal formation or the AHU-377 according to claim 3 half calcium salt anhydrous crystal forms and pharmaceutically acceptable carrier or vehicle for the treatment of effective dose.
11. pharmaceutical compositions according to claim 10, is characterized in that, described pharmaceutically acceptable carrier or vehicle are selected from thinner or weighting agent, disintegrating agent, tackiness agent, glidant, lubricant, tinting material or its combination.
12. pharmaceutical compositions according to claim 11, it is characterized in that, described thinner or weighting agent are selected from Icing Sugar, sompressible sugar, glucose, sucrose, lactose, dextrin, N.F,USP MANNITOL, Microcrystalline Cellulose, sorbyl alcohol, starch or its combination, the consumption of thinner or weighting agent is 4.0% ~ 60.0% of composition weight, preferably 10.0% ~ 40.0%; Described disintegrating agent is selected from starch, clay, Mierocrystalline cellulose, alginate, natural gum, cross-linked polymer, soybean polysaccharide, guar gum or its combination, the preferred cross-linked polyvinyl pyrrolidone of described cross-linked polymer, croscarmellose sodium, cross-linked carboxymethyl cellulose calcium or its combination, the consumption of disintegrating agent is 0% ~ 65.0% of composition weight, preferably 1.0% ~ 40.0%; Described tackiness agent is selected from starch, cellulose and its derivates, sucrose, glucose, maize treacle, gelatin, polyvidone or its combination, and described cellulose and its derivates is preferably from Microcrystalline Cellulose, hydroxypropylcellulose, Natvosol, Vltra tears or its combination; More preferably hydroxypropylcellulose; Most preferably low-substituted hydroxypropyl cellulose, the consumption of tackiness agent is 1.0% ~ 60.0% of composition weight, preferably 5.0% ~ 40.0%, more preferably 10.0% ~ 30.0%; Described glidant or lubricant are selected from colloidal silica, Magnesium Trisilicate, starch, talcum powder, tricalcium orthophosphate, Magnesium Stearate, aluminum stearate, calcium stearate, calcium carbonate, magnesium oxide, polyoxyethylene glycol, Solka-floc, Glyceryl Behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, sodium stearyl fumarate or its combination, the consumption of glidant or lubricant is 0% ~ 10.0% of composition weight, preferably 0.5% ~ 5.0%.
13. pharmaceutical compositions according to claim 10, is characterized in that, described pharmaceutical composition comprises diuretic(s) further; Described diuretic(s) is selected from Furosemide, Ethacrynic Acid, bumetanide, torasemide, hydrochlorothiazide, chlorthalidone, Hydrex, cyclopenthiazide, polythiazide, metolazone, indapamide or its combination; The consumption of diuretic(s) is 0.1% ~ 10.0% of composition weight, preferably 0.5% ~ 5.0%.
14. pharmaceutical compositions according to any one of claim 10-13, it is characterized in that, described pharmaceutical composition can be prepared into tablet, capsule, granule.
15. pharmaceutical compositions according to claim 14, is characterized in that, described capsule component proportion is as follows:
16. pharmaceutical compositions according to claim 14, its spy is just, described capsule component proportion is as follows:
17. 1 kinds of AHU-377 half calcium salt crystal formations according to claim 1, AHU-377 half calcium salt trihydrate crystal formation according to claim 2 or AHU-377 according to claim 3 half calcium salt anhydrous crystal forms, or comprise the AHU-377 according to claim 1 half calcium salt crystal formation for the treatment of effective dose, the pharmaceutical composition of AHU-377 half calcium salt trihydrate crystal formation according to claim 2 or AHU-377 according to claim 3 half calcium salt anhydrous crystal forms is in preparation treatment or prevent the disease relevant with neutral endopeptidase, cardiovascular, purposes in antihypertensive medicine, described antihypertensive medicine is selected from anti-malignant hypertension, essential hypertension, renovascular hypertension, diabetic hypertension, isolated systolic hypertension or other secondary hypertension medicine.
18. 1 kinds of AHU-377 half calcium salt crystal formations according to claim 1, AHU-377 half calcium salt trihydrate crystal formation according to claim 2 or AHU-377 according to claim 3 half calcium salt anhydrous crystal forms, or comprise the AHU-377 according to claim 1 half calcium salt crystal formation for the treatment of effective dose, the purposes of pharmaceutical composition in preparation treatment or prevention acute and chronic heart failure or harmful vascular remodeling medicine of AHU-377 half calcium salt trihydrate crystal formation according to claim 2 or AHU-377 according to claim 3 half calcium salt anhydrous crystal forms, preferably, described acute and chronic heart failure is selected from congestive heart failure, left ventricle dysfunction, hypertrophic neuropathy, diabetic cardiomyopathy, supraventricular and heart ventricle arrhythmia, atrial fibrillation, auricular flutter.
19. pharmaceutical compositions according to claim 10, is characterized in that, described pharmaceutical composition also comprises Angiotensin Ⅱ receptor antagonist.
20. pharmaceutical compositions according to claim 19, it is characterized in that, described angiotensinⅡantagonist is selected from that losartan, irbesartan, Olmesartan, telmisartan, valsartan, Azilsartan, Candesartan, Eprosartan, losartan, husky Puli's sand are smooth, Elisartan, Tasosartan, Ai Lishatan or its pharmacologically acceptable salt; Preferably from valsartan, Azilsartan or its pharmacologically acceptable salt.
21. claims 10 or pharmaceutical composition according to claim 19 are in preparation treatment or prevent myocardial infarction and sequela thereof, atherosclerosis, stenocardia, diabetic or non-diabetic renal insufficiency, secondary aldosteronism, primary or secondary pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, the proteinuria of Primary Nephrosis, renovascular hypertension, diabetic retinopathy, migraine, peripheral vascular disease, Raynaud disease, the hyperplasia in chamber, cognitive dysfunction, purposes in glaucoma or apoplexy medicine.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410425633.7A CN105461587A (en) | 2014-08-27 | 2014-08-27 | AHU-377 hemicalcium salt crystal form, preparation method and application thereof |
| PCT/CN2015/087904 WO2016029828A1 (en) | 2014-08-27 | 2015-08-24 | Crystalline free acid, hemicalcium salt and α-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof |
| CN201580025325.8A CN106458857A (en) | 2014-08-27 | 2015-08-24 | Crystalline free acid, hemicalcium salt and alfa-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof |
| TW104128107A TWI718104B (en) | 2014-08-27 | 2015-08-27 | POLYMORPHIC FREE ACID, HEMI-CALCIUM SALT AND α-PHENETHYLAMINE SALT OF AHU-377 AND PREPARATION METHOD AND USE THEREOF |
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| CN201410425633.7A CN105461587A (en) | 2014-08-27 | 2014-08-27 | AHU-377 hemicalcium salt crystal form, preparation method and application thereof |
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| WO2017097275A1 (en) * | 2015-12-11 | 2017-06-15 | Zentiva, K.S. | Solid forms of (2r,4s)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2- -methylpentanoic acid ethyl ester, its salts and a preparation method |
| WO2017191620A1 (en) * | 2016-05-06 | 2017-11-09 | Sun Pharmaceutical Industries Limited | A crystalline form of a salt of sacubitril and a process of its preparation |
| WO2022111493A1 (en) * | 2020-11-25 | 2022-06-02 | 深圳信立泰药业股份有限公司 | Pharmaceutical use of complex of arb metabolite and nep inhibitor in prevention and/or treatment of nephropathy |
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| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017097275A1 (en) * | 2015-12-11 | 2017-06-15 | Zentiva, K.S. | Solid forms of (2r,4s)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2- -methylpentanoic acid ethyl ester, its salts and a preparation method |
| WO2017191620A1 (en) * | 2016-05-06 | 2017-11-09 | Sun Pharmaceutical Industries Limited | A crystalline form of a salt of sacubitril and a process of its preparation |
| WO2022111493A1 (en) * | 2020-11-25 | 2022-06-02 | 深圳信立泰药业股份有限公司 | Pharmaceutical use of complex of arb metabolite and nep inhibitor in prevention and/or treatment of nephropathy |
| CN115461052A (en) * | 2020-11-25 | 2022-12-09 | 深圳信立泰药业股份有限公司 | Pharmaceutical use of a complex of an ARB metabolite and a NEP inhibitor for the prevention and/or treatment of renal disease |
| CN115461052B (en) * | 2020-11-25 | 2023-12-22 | 深圳信立泰药业股份有限公司 | Pharmaceutical use of complexes of ARB metabolites with NEP inhibitors for the prevention and/or treatment of kidney disease |
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