CN105503760A - Crystalline ARB-NEPi dicationic compound and preparation method and application thereof - Google Patents
Crystalline ARB-NEPi dicationic compound and preparation method and application thereof Download PDFInfo
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- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Abstract
The present invention discloses a crystalline ARB-NEPi dicationic compound and a preparation method and application thereof. In particular, the present invention relates to the crystalline ARB-NEPi dicationic compound having the formula of NEPi.Nax.Ky.ARB.ZH2O. The present invention also relates to a pharmaceutical composition containing an effective amount of the crystalline dicationic compound and application of the pharmaceutical composition in the preparation of drugs for treatment or prevention of neutral-endopeptidase-related diseases, cardiovascular diseases, hypertension, acute and chronic heart failures, congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular arrhythmia and ventricular arrhythmia, atrial fibrillation, atrial flutter or detrimental vascular remodeling, and the like, and the pharmaceutical composition has broad application prospects.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of crystal type ARB-NEPi dication mixture with dual function 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).
Angiotensin II causes vasoconstrictive hormone, and vasoconstriction causes hypertension and heart strain.People have known that Angiotensin II can with the acceptor interaction on target cells.Identify two kinds of receptor subtypes of Angiotensin II at present, be called AT1 and AT2.Nearest for some time, people paid huge effort qualification can with the material of AT1 receptors bind.Know now, angiotensin receptor blocker (ARBs, angiotensin-ii antagonist) can by stoping Angiotensin II and its receptors bind on vessel wall, thus cause blood pressure to reduce.Due to AT1 acceptor can be suppressed, so this type of antagonist may be used for hypertension, or be used for the treatment of congestive heart failure and other indication.
2008, Chinese patent CN101098689 discloses the mixture (particularly supramolecular complex) of a kind of Angiotensin agent antagonist (ARB) and neutral endopeptidase inhibitor (NEPi) dual function, has described in following general formula: [ARB (NEPi)] Na
1-3xH
2o; wherein x is 0-3; preferably 2.5; concrete finger [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
32.5H
2o (LCZ696), simplified construction is as follows:
This patent also discloses crystallized form [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
32.5H
2the data of the crystal formation powdery diffractometry of O are:
The X-ray powder diffraction that ScintagXDS2000 powder diffractometer measures comprises interval, following lattice plane:
17.0 (w), 7.1 (s), 5.2 (w), 4.7 (w), 4.6 (w), 4.2 (w), 3.5 (w), 3.3 (w).
CN101098689 patent also discloses crystal type [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
32.5H
2fusing initial temperature (onsettemperature) and the maximum peak temperature (Peaktemperature) of O are respectively 139 DEG C and 145 DEG C.
The infrared absorption spectrum that this type of mixture also can obtain by adopting Fourier Transform Attenuated Total Reflect ion Infrared Spectroscopy (ATR-FTIR) spectrograph (NicoletMagna-IR560) is qualitative, adopts important wave band described below (with the inverse (cm of wavelength data
-1) represent) qualitative: 2956 (w), 1711 (st), 1637 (st), 1597 (st), 1488 (w), 1459 (m), 1401 (st), 1357 (w), 1295 (m), 1266 (m), 1176 (w), 1085 (m), 1010 (w), 1942 (w), 907 (w), 862 (w), 763 (st), 742 (m), 698 (m), 533 (st).The feature of complex compound is particularly in following peak: 1711 (st), 1637 (st), 1597 (st) and 1401 (st).The error of all absorption bandses of ATR-IR is ± 2cm
-1.The intensity of absorption bands is expressed as follows: (w)=and weak; (m)=in; (st)=strong.
This type of mixture also can by the Raman chromatographic qualitative measured by Raman chromatographic instrument, and this chromatographic instrument has 785nm laser-excitation source (KaiserOpticalSystems, Inc.), and following column weight wants wave band (with the inverse (cm of wavelength data
-1) represent: 3061 (m), 2930 (m, wide), 1612 (st), 1523 (m), 1461 (w), 1427 (w), 1287 (st), 1195 (w), 1108 (w), 11053 (w), 1041 (w), 1011 (w), 997 (m), 866 (w), 850 (w), 822 (w), 808 (w), 735 (w), 715 (w), 669 (w), 643 (w), 631 (w), 618 (w), 602 (w), 557 (w), 522 (w), 453 (w), 410 (w), 328 (w).Error ± the 2cm of all Raman bands
-1.The intensity of absorption bands is expressed as follows: (w)=and weak; (m)=in; (st)=strong.
Although CN101098689 patent also discloses other mode of connection of mixture, be only draw mixture salt form according to soda acid salify theoretical implications, cannot expect in practical study and whether can obtain above-mentioned mixture salt and crystallized form thereof.And in embodiment its preparation method is not disclosed.In fact; only obtain in this patent [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
32.5H
2the crystallization of O, and such sodium salt eutectic, the object applied after preparing patent medicine is the patient having hypertension and heart failure class cardiovascular disorder, and the absorption of sodium can increase cardiovascular burden greatly.According to " reducing the research of sodium salt and supplementary sylvite absorption and blood pressure relation " paper report (" Nanjing Medical University ", 2011, Yan Kunli) report, have ample evidence to show, the high intake of sodium salt (such as sodium-chlor) is the major reason of elevation of blood pressure.Potassium can cushion the effect of sodium salt raising blood pressure and suppress vascular smooth muscle hyperplasia, has independently provide protection to the cerebrovascular.Therefore, use sodium salt merely in the composite, the risk increasing cardiovascular burden can be brought.
Summary of the invention
In order to solve the defect that prior art exists, contriver is on the basis of further investigation, develop a kind of crystal type ARB-NEPi dication mixture with dual function newly, the negative impact of sodium ion to elevation of blood pressure can be corrected or offset to this new A RB-NEP sodium potassium mixture, by introducing potassium ion.This be compounded in preparation treatment or the prevention disease relevant with neutral endopeptidase, cardiovascular, hypertension, acute and chronic heart failure as, congestive heart failure, left ventricle dysfunction, hypertrophic neuropathy, diabetic cardiomyopathy, tool has been widely used in the medicine such as supraventricular and heart ventricle arrhythmia, atrial fibrillation, auricular flutter or harmful vascular remodeling, can effectively alleviating hypertension and heart failure class cardiovascular disorder patient because of the cardiovascular burden of the excessive generation of intake of sodium.
One aspect of the present invention provides a kind of crystal type ARB-NEPi dication mixture.
As further preferred scheme, the dication of described crystal type ARB-NEPi dication mixture is potassium and sodium respectively, and its molecular formula is as follows:
NEPi·Na
x·K
y·ARB·ZH
2O
Wherein, NEPi can be selected from following compound: SQ28603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-β-alanine), SQ29072 (7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl] amino] heptanoicacid), Thiorphan (±) N-(1-oxygen-2-thiopurine methyltransferase-3-hydrocinnamoyl) glycine, retro-thiorphan (the reversion thing of thiorphan amido linkage), phosphoramidon, N-[N-[1 (1S)-carboxyl-3-phenyl propyl]-(S)-phenylalanyl]-(S)-isoserine, N-[N-[((1S)-carboxyl-2-phenyl) ethyl]-(S)-phenylalanyl]-Beta-alanine, N-[2 (S)-mercapto methyl-3-(2-aminomethyl phenyl)-propionyl] methionine(Met), (cis-4-[[[1-[2-carboxyl-3-(2-methoxy ethoxy) propyl group]-cyclopentyl] carbonyl] is amino]-hexahydrobenzoic acid), N-(3-carboxyl-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester via, (S)-cis-4-[1-[2-(5-indanyl oxygen base carbonyl)-3-(2-methoxy ethoxy) propyl group]-1-cyclopentane formamide base]-1-hexahydrobenzoic acid, 3-(1-[in 6--hydroxymethyl dicyclo [2, 2, 1] heptane-2-outer-carbamyl] cyclopentyl)-2-(2-methoxy ethyl) propionic acid, N-(1-(3-(uncle N--butoxy carbonyl-(S)-prolylamino)-2 (S)-uncle-butoxy-carbonyl propyl group] amino] phenylformic acid, 3-[1-(cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1-carbamyl) cyclopentyl]-2S-(2-methoxvethoxvmethvl) propionic acid, N-((2S)-2-(4-diphenylmethyl)-4-carboxyl-5-phenoxy group pentanoyl) glycine, N-(1-(N-hydroxycarbamoyl methyl)-1-Cyclopentanecarbonyl) L-phenylalanine, (S)-(2-biphenyl-4-base)-1-(1H-TETRAZOLE-5-base) ethylamino) methyl-phosphorous acid, (S)-5-(N-(2-(phosphonomethyl amino group)-3-(4-xenyl) propionyl)-2-amino-ethyl) tetrazolium, Beta-alanine, 3-[1, 1 '-xenyl]-4-base-N-[two phenoxy group phosphinyls] methyl]-L-alanyl, N-(2-carboxyl-4-thienyl)-3-sulfydryl-2-benzyl propionic acid amide, 2-(2-mercapto methyl-3-phenylpropionyl is amino) thiazole-4-yl carboxylic acid, (L)-(1-((2, 2-dimethyl-1, 3-dioxolane-4-base)-methoxyl group) carbonyl)-2-phenylethyl)-L-phenylalanyl)-Beta-alanine, N-[N-(L)-[1-[(2, 2-dimethyl-1, 3-dioxolane-4-base)-methoxyl group] carbonyl]-2-phenylethyl]-L-phenylalanyl]-(R)-L-Ala, N-[N-[(L)-1-carboxyl-2-phenylethyl]-L-phenylalanyl]-(R)-L-Ala, N-[2-ethanoyl thiomethyl-3-(2-methylphenyl) propionyl]-methionine(Met) ethyl ester, N-[2-mercapto methyl-3-(2-aminomethyl phenyl) propionyl]-methionine(Met), N-[2 (S)-mercapto methyl-3-(2-aminomethyl phenyl) propionyl]-(S)-isoserine, N-(S)-[3-sulfydryl-2-(2-aminomethyl phenyl) propionyl]-(S)-2-methoxyl group-(R)-L-Ala, N-[1-[[1 (S)-benzyloxycarbonyl-3-phenyl propyl] is amino] cyclopentylcarbonyl]-(S)-isoserine, N-[1-[[1 (S)-carbonyl-3-phenyl propyl] is amino]-cyclopentylcarbonyl]-(S)-isoserine, 1, 1 '-[dithio two-[2 (S)-(2-methyl-benzyl)-1-oxo-3, 1-propane two base]]-two (S)-isoserine, 1, 1 '-[dithio two-[2 (S)-(2-methyl-benzyl)-1-oxo-3, 1-propane two base]]-two (S)-methionine(Met), N-(3-phenyl-2-(mercapto methyl)-propionyl)-(S)-4-(methyl mercapto) methionine(Met), N-[2-ethanoyl methylthio group-3-phenyl-propionyl]-3-benzaminic acid, N-[2-mercapto methyl-3-phenyl-propionyl]-3-benzaminic acid, N-[1-(2-carboxyl-4-phenyl butyl)-pentamethylene-carbonyl]-(S)-isoserine, N-[1-(ethanoyl thiomethyl) pentamethylene-carbonyl]-(S)-methionine(Met) ethyl ester, 3 (S)-[2-(ethanoyl thiomethyl)-3-phenyl-propionyl] amino-e-caprolactam, N-(2-ethanoyl thiomethyl-3-(2-aminomethyl phenyl) propionyl)-methionine(Met) ethyl ester, or its combination.
ARB is angiotensin II receptor antagonists, includes but not limited to following compounds: acetic acid Saralasin, candesartan Cilexetil, CGP-63170, EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-184698, Candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, Losartan Potassium, E-4177, EMD-73495, Eprosartan, HN-65021, Irb, L-159282, ME-3221, SL-91.0102, Tasosartan, telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, PD-123177, A-81988, BMS-180560, CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP-167, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, isoteoline, KRI-1177, L-158809, L-158978, L-159874, LRB087, LY-285434, LY-302289, LY-315995, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, husky Puli's sand is smooth, Saralasin, Sarmesin, WK-1360, X-6803, ZD-6888, ZD-7155, ZD-8731, BIBS39, CI-996, DMP-811, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-510, zolasartan and PD-123319, Azilsartan, Azilsartan, or its combination.
As further preferred scheme; in described crystal type ARB-NEPi dication mixture, NEPi is preferably from (2R; 4S)-5-biphenyl-4-base-5-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, ARB is preferably from valsartan.
As further preferred scheme; described crystal type ARB-NEPi dication mixture is crystal type [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
xk
yzH
2o, wherein, 0 < X < 3,0 < Y < 3 and 0 < Z < 9.
As further preferred scheme, in described crystal type ARB-NEPi dication mixture, X:Y is 1:10 ~ 17:1, and also namely the ratio of Na:K is 1:10 ~ 17:1.
As further preferred scheme, in described crystal type ARB-NEPi dication mixture, X:Y is 1:5 ~ 17:1.
As further preferred scheme, in described crystal type ARB-NEPi dication mixture, X:Y is 1:5,1:2,1:1,2:1,5:1,8:1 or 17:1.
As further preferred scheme, in described crystal type ARB-NEPi dication mixture, 2.0 < Z < 6.5.
As further preferred scheme, in described crystal type ARB-NEPi dication mixture, 2.5 < Z < 3.5.
As most preferred scheme, in described crystal type ARB-NEPi dication mixture, Z is 2.5,3.0 or 3.5.
As further preferred scheme; described [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
xk
yzH
2o is the skeleton symbol of super molecular compound; each asymmetric cell of this supramolecular structure is all containing 6 ARB, 6 NEPi, 0 ~ 18 sodium atom, 0 ~ 18 potassium atom and 0 ~ 54 water molecules; wherein said ARB is (S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid; described NEPi is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid.Each asymmetric cell can be expressed as [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
xk
yzH
2o}
6or [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid]
6na
6Xk
6y6ZH
2o
As further preferred scheme, each asymmetric cell of described supramolecular structure is all containing 6 ARB, 6 NEPi, 12-17 sodium atoms, a 1-6 potassium atom and 12-54 water moleculess.
As further preferred scheme; described crystal type ARB-NEPi dication mixture is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
xk
yzH
2o, its x-ray diffractogram of powder comprises and being positioned at: 4.2 ± 0.2 °, 12.6 ± 0.2 °, 17.0 ± 0.2 ° and 25.3 ± 0.2 °, the peak at diffraction angle (2 θ) place.
As most preferred scheme; described crystal type ARB-NEPi dication mixture is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
2k
13H
2o, its X-ray powder diffraction data are as shown in table 1:
Table 1
As most preferred scheme; described crystal type ARB-NEPi dication mixture is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
2.5k
0.53H
2o, its X-ray powder diffraction data table 2 as shown:
Table 2
As most preferred scheme; described crystal type ARB-NEPi dication mixture is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
0.5k
2.53H
2o, its X-ray powder diffraction data table 3 as shown:
Table 3
As most preferred scheme; described crystal type ARB-NEPi dication mixture is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
1.5k
1.52.5H
2o, its X-ray powder diffraction data table 4 as shown:
Table 4
As most preferred scheme; described crystal type ARB-NEPi dication mixture is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
2.67k
0.333H
2o, its X-ray powder diffraction data table 5 as shown:
Table 5
As most preferred scheme; described crystal type ARB-NEPi dication mixture is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
2.83k
0.172.5H
2o, its X-ray powder diffraction data table 6 as shown:
Table 6
The present invention also provides on the other hand a kind of crystal type [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
xk
yzH
2the preparation method of O, comprises the steps:
(1) by (S)-N-pentanoyl-N-{ [2 '-(1H-TETRAZOLE-5-base)-biphenyl-4-base]-methyl }-α-amino-isovaleric acid and (2R, 4S)-5-biphenyl-4-base-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester be dissolved in suitable organic solvent;
(2) mix mutually with the alkaline sodium of suitable proportion and potassium compound;
(3) naturally producing precipitation, adding crystal seed induction crystallization or producing solid sediment by creating supersaturated condition;
(4) solid-liquid separation;
(5) the humidity baking step (4) controlling dry environment is separated the solid obtained.
As further preferred scheme, the mode that step (2) and alkaline sodium and potassium compound mix mutually directly can add alkaline sodium and potassium compound or is dissolved in suitable solvent by alkaline sodium and potassium compound and then adds in step (1) system in step (1) system.
As further preferred scheme, described in step (1), organic solvent is including but not limited to following solvent: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, acetonitrile, acetone, methylethylketone, tetrahydrofuran (THF), dioxane, DMF, dimethyl sulfoxide (DMSO), Iso Butyl Acetate, ethyl acetate or its mixture.
As further preferred scheme, described in step (2), alkaline sodium compound is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, sodium-acetate, sodium methylate, sodium formiate, Sodium Propionate, sodium acrylate, Sodium Benzoate or its mixture; Preferred sodium hydroxide, sodium bicarbonate or its mixture.
As further preferred scheme, described in step (2), alkaline potassium compound is selected from potassium hydroxide, salt of wormwood, saleratus, dipotassium hydrogen phosphate, potassium primary phosphate, Potassium ethanoate, potassium methylate, potassium formiate, potassium propionate, potassium acrylate, potassium benzoate or its mixture; Preferred potassium hydroxide, saleratus or its mixture.
As further preferred scheme, the method for the creation supersaturated condition described in step (3) comprises cooling crystallization, evaporating solvent crystallization, add anti-solvent forces the mode such as crystalline substance or anti-solvent replacement.Anti-solvent refers to the solvent that target solids solubleness is lower.Anti-solvent substitute mode refers to, removes a part of original solvent, adds a part of anti-solvent, removes a part of original solvent again, until be substantially replaced by anti-solvent after balance.
As further preferred scheme, the furnace drying method described in step (5) can adopt vacuum-drying, evaporation, nitrogen drying etc.
As further preferred scheme, the humid control of the dry environment of step (5) is 45% ~ 70%.
As further preferred scheme, the humid control of the dry environment of step (5) is 50% ~ 65%.
As most preferred scheme, the humid control of the dry environment of step (5) is 55% ~ 65%.
As further preferred scheme, optional, carry out hydration under being fully exposed to specified moisture further after controlling moisture obtains corresponding hydrates in step (5) and obtain moisture higher hydrate.
Prepare [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
xk
yzH
2o mixture is complex compound, particularly supramolecular complex.In the present invention, term " supramolecular complex " refers to the interaction between Nepi and ARB, sodium and potassium ion and other material any (such as solvent, especially water), the complexing mutually by key between Non-covalent molecular between them.These complexing actions cause a component in supramolecule to be combined with each other by a certain percentage, and this complexing makes this complex compound of supramolecule be different from the physical mixture of these compositions.Supramolecular complex preferably with solid-state existence, but also can exist with liquid state.In the preferred embodiment of the invention, complex compound is xln.Preferably, the reticulated structure between any solvent (if present, preferably water) with non covalent bond (especially hydrogen bond) is also contained in preparation-obtained supramolecular complex.Positively charged ion is preferably combined with multiple oxygen aglucon, thus forms connection between these oxygen aglucons.Oxygen aglucon from the carbonyl of two kinds of active constituents of medicine and carboxylate salt/ester group, preferably also from any solvent, if solvent exists, preferably water.
The present invention provides a kind of pharmaceutical composition on the other hand; described pharmaceutical composition comprises aforementioned crystalline type [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } the is amino) butyric acid] Na for the treatment of effective dose
xk
yzH
2o and pharmaceutically acceptable carrier or vehicle.
Another aspect provides aforementioned [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
xk
yzH
2o or the purposes of its pharmaceutical composition aforementioned in the disease that preparation is treated or prevention is relevant with neutral endopeptidase, cardiovascular, antihypertensive medicine.
By improving effect and there is higher corresponding rate and creating more effective antihypertensive therapy, no matter be for malignant hypertension, essential hypertension, renovascular hypertension, diabetic hypertension, isolated systolic hypertension or be not always the case for other secondary hypertension.
Another aspect provides aforementioned crystalline type [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
xk
yzH
2o or its pharmaceutical composition aforementioned preparation treatment or prevention acute and chronic heart failure as, congestive heart failure, left ventricle dysfunction, hypertrophic neuropathy, diabetic cardiomyopathy, purposes in supraventricular and heart ventricle arrhythmia, atrial fibrillation, auricular flutter or harmful vascular remodeling medicine.
Of the present inventionly provide aforementioned crystalline type [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na on the one hand
xk
yzH
2o or its pharmaceutical composition aforementioned 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.
" 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.
Accompanying drawing explanation
Fig. 1 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 1
2k
13H
2o x-ray diffractogram of powder; Ordinate zou is intensity, and X-coordinate is 2 θ (°).
Fig. 2 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 1
2k
13H
2o powder thermogravimetric analysis (TGA) figure; Ordinate zou is changes in weight per-cent (%), and X-coordinate is temperature (DEG C).
Fig. 3 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 2
2.5k
0.53H
2o x-ray diffractogram of powder; Ordinate zou is intensity, and X-coordinate is 2 θ (°).
Fig. 4 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 2
2.5k
0.53H
2o powder thermogravimetric analysis (TGA) figure; Ordinate zou is changes in weight per-cent (%), and X-coordinate is temperature (DEG C).
Fig. 5 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 3
0.5k
2.53H
2o x-ray diffractogram of powder; Ordinate zou is intensity, and X-coordinate is 2 θ (°).
Fig. 6 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 3
0.5k
2.53H
2o powder thermogravimetric analysis (TGA) figure; Ordinate zou is changes in weight per-cent (%), and X-coordinate is temperature (DEG C).
Fig. 7 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 4
1.5k
1.52.5H
2o x-ray diffractogram of powder; Ordinate zou is intensity, and X-coordinate is 2 θ (°).
Fig. 8 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 4
1.5k
1.52.5H
2o powder thermogravimetric analysis (TGA) figure; Ordinate zou is changes in weight per-cent (%), and X-coordinate is temperature (DEG C).
Fig. 9 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 5
2.67k
0.333H
2o x-ray diffractogram of powder; Ordinate zou is intensity, and X-coordinate is 2 θ (°).
Figure 10 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 5
2.67k
0.333H
2o powder thermogravimetric analysis (TGA) figure; Ordinate zou is changes in weight per-cent (%), and X-coordinate is temperature (DEG C).
Figure 11 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 6
2.83k
0.172.5H
2o x-ray diffractogram of powder; Ordinate zou is intensity, and X-coordinate is 2 θ (°).
Figure 12 is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na in embodiment 6
2.83k
0.172.5H
2o powder thermogravimetric analysis (TGA) figure; Ordinate zou is changes in weight per-cent (%), and X-coordinate is temperature (DEG C).
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
Crystal type [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
xk
yzH
2o 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 diffractogram of powder.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 °.
Angle 2 θ (°) value of embodiment of the present invention gained crystal formation, intensity level (% as peak-peak) and spacing D value
list in table 1-4.
Obtained [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
xk
yzH
2o crystal formation differential scanning calorimeter (DSC) carries out thermal analyses, and DSC INSTRUMENT MODEL used is TAQ2000 (ThermoAnalysis).Dsc analysis method parameter is as follows: temperature range is room temperature to 300 degree Celsius, and scanning speed is 10 centigrade per minutes, and shielding gas is nitrogen (flow velocity 25 ml/min).
Obtained [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
xk
yzH
2o crystal formation thermogravimetric analyzer (TGA) carries out thermal analyses, and TGA INSTRUMENT MODEL used is TAQ500 (ThermoAnalysis).TGA analytical procedure parameter is as follows: temperature range is room temperature to 300 degree Celsius, and scanning speed is 10 centigrade per minutes, and shielding gas is nitrogen (flow velocity 25 ml/min).
Obtained [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
xk
yzH
2o crystal formation moisture content karl Fischer coulomb moisture analyser is analyzed, and Kinds of Moisture Monitors model used is C20 (plum Teller).Working method: first carry out pre-titration by starting to analyze starting in dialog box, waits that the drift value continuing to measure is reduced to below prescribed value, enters sample determination pattern.Click keys starts to test sample, takes out about 20-100mg sample fast, be placed in titration cup from sample.Press acknowledgement key, analyze and automatically start.The gross weight of sample comprises tare weight weighing in advance and obtains, and after again measuring application of sample, the quality of sample comprises tare weight.Weight after gross weight deducts application of sample is the actual add-on of moisture determination sample.Titration terminates rear display result dialog box, actual add-on is inputted, automatically obtains the result of water content.
Syrups by HPLC AHU377 and valsartan content: the solid product 10mg that precision weighing obtains is transferred in the volumetric flask of 20-mL, adds water and is settled to 20mL, is mixed with the solution of about 0.5mg/mL.With valsartan and AHU377 standard substance, analyze according to the chromatographic condition in following table, make typical curve.Measure solid product solution according to lower surface condition, calculate the content of AHU377 and valsartan in solid product according to typical curve, represent with mass/mass (w/w).
Measure sodium, potassium content: the content measuring sodium ion and potassium ion in solid product with inductive coupling plasma emission spectrograph (ICP).Working method is, precision takes product solid and is about 50mg, adds the nitric acid that 3mL top grade is pure, 80 DEG C of pyrolysis about 2 hours, then adds 0.5mL perchloric acid, is heated to 140 DEG C, and temperature control is to the white cigarette completely dissolve produced.Cool, be settled to 50mL.Carry out sodium according to following apparatus parameter, potassium content measure:
| INSTRUMENT MODEL | Agilent 725ES |
| Power | 110W |
| Plasma flow | 15L/min |
| Assisted gas flow | 1.5L/min |
| Atomization gas pressure | 200Kpa |
| Pump number | 15RPM |
| Observed altitude | 8CM |
Embodiment 1
Take 500mgAHU-377 free acid (oily) and 529mg valsartan is placed in 100-mL round-bottomed flask, then add 50mL acetone solution, stirring at room temperature.The potassium hydroxide of the sodium hydroxide and 68mg that separately take 97mg is dissolved in 0.4mL water and dissolves, then joins in the acetone soln of AHU377 and valsartan, stirred overnight at room temperature.Underpressure distillation is about the acetone of half, then adds 25mL Iso Butyl Acetate, and continue stirring 4 hours, the solvent volume of about half is fallen in underpressure distillation again, then adds 25mL Iso Butyl Acetate, stirs 4 hours.Filtered under nitrogen, and use Iso Butyl Acetate washing leaching cake, dry, obtain pulverulent solids.Its x-ray diffractogram of powder (XRPD) as shown in Figure 1.TGA analysis chart is shown in Fig. 2.In crystal powder, the content of each component is as shown in the table:
Products therefrom is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
2k
13H
2o, its X-ray powder diffraction data are as shown in table 1:
Table 1
Embodiment 2
Take 500mgAHU-377 free acid (oily) and 529mg valsartan is placed in 100-mL round-bottomed flask, then add 50mL acetone solution, stirring at room temperature.The potassium hydroxide of the sodium hydroxide and 34mg that separately take 121.5mg is dissolved in 0.4mL water and dissolves, then joins in the acetone soln of AHU377 and valsartan, stirred overnight at room temperature.Underpressure distillation is about the acetone of half, then adds 25mL Iso Butyl Acetate, and continue stirring 4 hours, the solvent volume of about half is fallen in underpressure distillation again, then adds 25mL Iso Butyl Acetate, stirs 4 hours.Filtered under nitrogen, and use Iso Butyl Acetate washing leaching cake, dry, obtain pulverulent solids.Its x-ray diffractogram of powder (XRPD) as shown in Figure 3.TGA analysis chart is shown in Fig. 4.In crystal powder, the content of each component is as shown in the table:
Products therefrom is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
2.5k
0.53H
2o, its X-ray powder diffraction data are as shown shown in table 2:
Table 2
Embodiment 3
Take 500mgAHU-377 free acid (oily) and 529mg valsartan is placed in 100-mL round-bottomed flask, then add 50mL acetone solution, stirring at room temperature.The potassium hydroxide of the sodium hydroxide and 170.1mg that separately take 24.3mg is dissolved in 0.4mL water and dissolves, then joins in the acetone soln of AHU377 and valsartan, stirred overnight at room temperature.Underpressure distillation is about the acetone of half, then adds 25mL Iso Butyl Acetate, and continue stirring 4 hours, about general solvent volume is fallen in underpressure distillation again, then adds 25mL Iso Butyl Acetate, stirs 4 hours.Filtered under nitrogen, and use Iso Butyl Acetate washing leaching cake, dry, obtain pulverulent solids.Its x-ray diffractogram of powder (XRPD) as shown in Figure 5.TGA analysis chart is shown in Fig. 6.In crystal powder, the content of each component is as shown in the table:
Products therefrom is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
0.5k
2.53H
2o, its X-ray powder diffraction data are as shown shown in table 3:
Table 3
Embodiment 4
Take 500mgAHU-377 free acid (oily) and 529mg valsartan is placed in 100-mL round-bottomed flask, then add 50mL acetone solution, stirring at room temperature.The potassium hydroxide of the sodium hydroxide and 102.1mg that separately take 72.9mg is dissolved in 0.4mL water and dissolves, then joins in the acetone soln of AHU377 and valsartan, stirred overnight at room temperature.Underpressure distillation is about the acetone of half, then adds 25mL Iso Butyl Acetate, and continue stirring 4 hours, about general solvent volume is fallen in underpressure distillation again, then adds 25mL Iso Butyl Acetate, stirs 4 hours.Filtered under nitrogen, and use Iso Butyl Acetate washing leaching cake, dry, obtain pulverulent solids.Its x-ray diffractogram of powder (XRPD) as shown in Figure 7.TGA analysis chart is shown in Fig. 8.In crystal powder, the content of each component is as shown in the table:
Products therefrom is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
1.5k
1.52.5H
2o, its X-ray powder diffraction data are as shown shown in table 4:
Table 4
Embodiment 5
Take 500mgAHU-377 free acid (oily) and 529mg valsartan is placed in 100-mL round-bottomed flask, then add 50mL acetone solution, stirring at room temperature.The potassium hydroxide of the sodium hydroxide and 17.8mg that separately take 200mg is dissolved in 0.4mL water and dissolves, then joins in the acetone soln of AHU377 and valsartan, stirred overnight at room temperature.Underpressure distillation is about the acetone of half, then adds 25mL Iso Butyl Acetate, and continue stirring 4 hours, about general solvent volume is fallen in underpressure distillation again, then adds 25mL Iso Butyl Acetate, stirs 4 hours.Filtered under nitrogen, and use Iso Butyl Acetate washing leaching cake, dry, obtain pulverulent solids.Its x-ray diffractogram of powder (XRPD) as shown in Figure 9.TGA analysis chart is shown in Figure 10.In crystal powder, the content of each component is as shown in the table:
Products therefrom is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
2.67k
0.333H
2o, its X-ray powder diffraction data are as shown shown in table 5:
Table 5
Embodiment 6
Take 500mgAHU-377 free acid (oily) and 529mg valsartan is placed in 100-mL round-bottomed flask, then add 50mL acetone solution, stirring at room temperature.The potassium hydroxide of the sodium hydroxide and 21mg that separately take 250mg is dissolved in 0.4mL water and dissolves, then joins in the acetone soln of AHU377 and valsartan, stirred overnight at room temperature.Underpressure distillation is about the acetone of half, then adds 25mL Iso Butyl Acetate, and continue stirring 4 hours, about general solvent volume is fallen in underpressure distillation again, then adds 25mL Iso Butyl Acetate, stirs 4 hours.Filtered under nitrogen, and use Iso Butyl Acetate washing leaching cake, dry, obtain pulverulent solids.Its x-ray diffractogram of powder (XRPD) as shown in figure 11.TGA analysis chart is shown in Figure 12.In crystal powder, the content of each component is as shown in the table:
Products therefrom is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
2.83k
0.172.5H
2o, its X-ray powder diffraction data are as shown shown in table 6:
Table 6
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 (28)
1. a crystal type ARB-NEPi dication mixture.
2. crystal type ARB-NEPi dication mixture according to claim 1, it is characterized in that, described dication is potassium and sodium respectively, and its molecular formula is as follows:
NEPi·Na
x·K
y·ARB·ZH
2O。
3. crystal type ARB-NEPi dication mixture according to claim 2, it is characterized in that, described NEPi is selected from following compound: SQ28603, SQ29072, Thiorphan, retro-thiorphan, phosphoramidon, N-[N-[1 (1S)-carboxyl-3-phenyl propyl]-(S)-phenylalanyl]-(S)-isoserine, N-[N-[((1S)-carboxyl-2-phenyl) ethyl]-(S)-phenylalanyl]-Beta-alanine, N-[2 (S)-mercapto methyl-3-(2-aminomethyl phenyl)-propionyl] methionine(Met), (cis-4-[[[1-[2-carboxyl-3-(2-methoxy ethoxy) propyl group]-cyclopentyl] carbonyl] is amino]-hexahydrobenzoic acid), N-(3-carboxyl-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester via, (S)-cis-4-[1-[2-(5-indanyl oxygen base carbonyl)-3-(2-methoxy ethoxy) propyl group]-1-cyclopentane formamide base]-1-hexahydrobenzoic acid, 3-(1-[in 6--hydroxymethyl dicyclo [2, 2, 1] heptane-2-outer-carbamyl] cyclopentyl)-2-(2-methoxy ethyl) propionic acid, N-(1-(3-(uncle N--butoxy carbonyl-(S)-prolylamino)-2 (S)-uncle-butoxy-carbonyl propyl group] amino] phenylformic acid, 3-[1-(cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1-carbamyl) cyclopentyl]-2S-(2-methoxvethoxvmethvl) propionic acid, N-((2S)-2-(4-diphenylmethyl)-4-carboxyl-5-phenoxy group pentanoyl) glycine, N-(1-(N-hydroxycarbamoyl methyl)-1-Cyclopentanecarbonyl) L-phenylalanine, (S)-(2-biphenyl-4-base)-1-(1H-TETRAZOLE-5-base) ethylamino) methyl-phosphorous acid, (S)-5-(N-(2-(phosphonomethyl amino group)-3-(4-xenyl) propionyl)-2-amino-ethyl) tetrazolium, Beta-alanine, 3-[1, 1 '-xenyl]-4-base-N-[two phenoxy group phosphinyls] methyl]-L-alanyl, N-(2-carboxyl-4-thienyl)-3-sulfydryl-2-benzyl propionic acid amide, 2-(2-mercapto methyl-3-phenylpropionyl is amino) thiazole-4-yl carboxylic acid, (L)-(1-((2, 2-dimethyl-1, 3-dioxolane-4-base)-methoxyl group) carbonyl)-2-phenylethyl)-L-phenylalanyl)-Beta-alanine, N-[N-(L)-[1-[(2, 2-dimethyl-1, 3-dioxolane-4-base)-methoxyl group] carbonyl]-2-phenylethyl]-L-phenylalanyl]-(R)-L-Ala, N-[N-[(L)-1-carboxyl-2-phenylethyl]-L-phenylalanyl]-(R)-L-Ala, N-[2-ethanoyl thiomethyl-3-(2-methylphenyl) propionyl]-methionine(Met) ethyl ester, N-[2-mercapto methyl-3-(2-aminomethyl phenyl) propionyl]-methionine(Met), N-[2 (S)-mercapto methyl-3-(2-aminomethyl phenyl) propionyl]-(S)-isoserine, N-(S)-[3-sulfydryl-2-(2-aminomethyl phenyl) propionyl]-(S)-2-methoxyl group-(R)-L-Ala, N-[1-[[1 (S)-benzyloxycarbonyl-3-phenyl propyl] is amino] cyclopentylcarbonyl]-(S)-isoserine, N-[1-[[1 (S)-carbonyl-3-phenyl propyl] is amino]-cyclopentylcarbonyl]-(S)-isoserine, 1, 1 '-[dithio two-[2 (S)-(2-methyl-benzyl)-1-oxo-3, 1-propane two base]]-two (S)-isoserine, 1, 1 '-[dithio two-[2 (S)-(2-methyl-benzyl)-1-oxo-3, 1-propane two base]]-two (S)-methionine(Met), N-(3-phenyl-2-(mercapto methyl)-propionyl)-(S)-4-(methyl mercapto) methionine(Met), N-[2-ethanoyl methylthio group-3-phenyl-propionyl]-3-benzaminic acid, N-[2-mercapto methyl-3-phenyl-propionyl]-3-benzaminic acid, N-[1-(2-carboxyl-4-phenyl butyl)-pentamethylene-carbonyl]-(S)-isoserine, N-[1-(ethanoyl thiomethyl) pentamethylene-carbonyl]-(S)-methionine(Met) ethyl ester, 3 (S)-[2-(ethanoyl thiomethyl)-3-phenyl-propionyl] amino-e-caprolactam, N-(2-ethanoyl thiomethyl-3-(2-aminomethyl phenyl) propionyl)-methionine(Met) ethyl ester or its combination.
4. crystal type ARB-NEPi dication mixture according to claim 2, it is characterized in that, described ARB is angiotensin II receptor antagonists, is selected from acetic acid Saralasin, candesartan Cilexetil, CGP-63170, EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-184698, Candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, Losartan Potassium, E-4177, EMD-73495, Eprosartan, HN-65021, Irb, L-159282, ME-3221, SL-91.0102, Tasosartan, telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, PD-123177, A-81988, BMS-180560, CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP-167, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, isoteoline, KRI-1177, L-158809, L-158978, L-159874, LRB087, LY-285434, LY-302289, LY-315995, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, husky Puli's sand is smooth, Saralasin, Sarmesin, WK-1360, X-6803, ZD-6888, ZD-7155, ZD-8731, BIBS39, CI-996, DMP-811, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-510, zolasartan and PD-123319, Azilsartan, Azilsartan or its combination.
5. crystal type ARB-NEPi dication mixture according to claim 2; it is characterized in that; described NEPi is selected from (2R, 4S)-5-biphenyl-4-base-5-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, and ARB is preferably from valsartan.
6. crystal type ARB-NEPi dication mixture according to claim 2; it is characterized in that; described crystal type ARB-NEPi dication mixture is crystal type [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } is amino) butyric acid] Na
xk
yzH
2o, wherein, 0 < X < 3,0 < Y < 3,0 < Z < 9.
7. crystal type ARB-NEPi dication mixture according to claim 6, is characterized in that, in described crystal type ARB-NEPi dication mixture, X:Y is 1:10 ~ 17:1; In preferred described crystal type ARB-NEPi dication mixture, X:Y is 1:5 ~ 17:1; More preferably in described crystal type ARB-NEPi dication mixture, X:Y is 1:5,1:2,1:1,2:1,5:1,8:1 or 17:1.
8. crystal type ARB-NEPi dication mixture according to claim 6, is characterized in that, in described crystal type ARB-NEPi dication mixture, and 2.0 < Z < 6.5; In preferred described crystal type ARB-NEPi dication mixture, 2.5 < Z < 3.5; More preferably, in described crystal type ARB-NEPi dication mixture, Z is 2.5,3.0 or 3.5.
9. the crystal type ARB-NEPi dication mixture according to any one of claim 6-8; it is characterized in that; described [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid-(S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid] Na
xk
yzH
2o is the skeleton symbol of super molecular compound; each asymmetric cell of this supramolecular structure is all containing 6 ARB, 6 NEPi, 0 ~ 18 sodium atom, 0 ~ 18 potassium atom and 0 ~ 54 water molecules; wherein said ARB is (S)-3 '-methyl-2 '-(pentanoyl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butyric acid; described NEPi is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propionic acid.
10. crystal type ARB-NEPi dication mixture according to claim 9, is characterized in that, each asymmetric cell of described supramolecular structure is all containing 6 ARB, 6 NEPi, 12-17 sodium atoms, a 1-6 potassium atom and 12-54 water moleculess.
11. crystal type ARB-NEPi dication mixtures according to any one of claim 6-10, it is characterized in that, described crystal type ARB-NEPi dication composite powder X-ray diffractogram comprises and being positioned at: 4.2 ± 0.2 °, 12.6 ± 0.2 °, 17.0 ± 0.2 ° and 25.3 ± 0.2 °, the peak at diffraction angle (2 θ) place.
12. crystal type ARB-NEPi dication mixtures according to claim 11, it is characterized in that, described crystal type ARB-NEPi dication composite powder X-ray diffractogram comprises and being positioned at: 4.2 ± 0.2 °, 5.0 ± 0.2 °, 5.4 ± 0.2 °, 8.4 ± 0.2 °, 9.8 ± 0.2 °, 12.6 ± 0.2 °, 17.0 ± 0.2 °, 18.2 ± 0.2 °, 19.6 ± 0.2 °, 21.4 ± 0.2 °, 22.8 ± 0.2 °, 23.1 ± 0.2 ° and 25.3 ± 0.2 °, the peak at diffraction angle (2 θ) place.
13. crystal type ARB-NEPi dication mixtures according to claim 11, it is characterized in that, described crystal type ARB-NEPi dication composite powder X-ray diffractogram comprises and being positioned at: 4.2 ± 0.2 °, 5.0 ± 0.2 °, 12.6 ± 0.2 °, 15.0 ± 0.2 °, 15.4 ± 0.2 °, 17.0 ± 0.2 °, 17.8 ± 0.2,18.2 ± 0.2 °, 19.5 ± 0.2 °, 19.8 ± 0.2 °, 22.7 ± 0.2 °, the peak at diffraction angle (2 θ) place of 23.1 ± 0.2 ° and 25.3 ± 0.2 °.
14. crystal type ARB-NEPi dication mixtures according to claim 11, it is characterized in that, described crystal type ARB-NEPi dication composite powder X-ray diffractogram comprises and being positioned at: 4.2 ± 0.2 °, 8.4 ± 0.2 °, 12.6 ± 0.2 °, 17.0 ± 0.2 °, 19.5 ± 0.2 °, 21.4 ± 0.2 °, the peak at diffraction angle (2 θ) place of 22.8 ± 0.2 ° and 25.3 ± 0.2 °.
15. crystal type ARB-NEPi dication mixtures according to claim 11, it is characterized in that, described crystal type ARB-NEPi dication composite powder X-ray diffractogram comprises and being positioned at: 4.2 ± 0.2 °, 5.1 ± 0.2 °, 5.6 ± 0.2 °, 8.4 ± 0.2 °, 12.6 ± 0.2 °, 17.0 ± 0.2 °, 18.3 ± 0.2 °, the peak at diffraction angle (2 θ) place of 20.1 ± 0.2 ° and 25.3 ± 0.2 °.
16. crystal type ARB-NEPi dication mixtures according to claim 11, is characterized in that, described crystal type ARB-NEPi dication composite powder X-ray diffractogram comprises and being positioned at: 4.2 ± 0.2 °, 4.9 ± 0.2 °, 8.2 ± 0.2 °, 12.6 ± 0.2 °, 14.8 ± 0.2 °, 17.0 ± 0.2 °, 18.8 ± 0.2 °, 20.0 ± 0.2 °, 25.4 ± 0.2 °, 22.5 ± 0.2 °, the peak at diffraction angle (2 θ) place of 25.3 ± 0.2 ° and 27.1 ± 0.2 °.
17. crystal type ARB-NEPi dication mixtures according to claim 11, is characterized in that, described crystal type ARB-NEPi dication composite powder X-ray diffractogram comprises and being positioned at: 4.2 ± 0.2 °, 5.0 ± 0.2 °, 8.2 ± 0.2 °, 12.6 ± 0.2 °, 14.8 ± 0.2 °, 17.0 ± 0.2 °, 17.9 ± 0.2 °, 18.7 ± 0.2 °, 19.9 ± 0.2 °, 22.5 ± 0.2 °, the peak at diffraction angle (2 θ) place of 25.1 ± 0.2 ° and 27.0 ± 0.2 °.
The preparation method of 18. crystal type ARB-NEPi dication mixtures according to any one of claim 6-17, comprises the steps:
1) by (S)-N-pentanoyl-N-{ [2 '-(1H-TETRAZOLE-5-base)-biphenyl-4-base]-methyl }-α-amino-isovaleric acid and (2R, 4S)-5-biphenyl-4-base-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester be dissolved in suitable organic solvent;
2) mix mutually with the alkaline sodium of suitable proportion and potassium compound;
3) naturally producing precipitation, adding crystal seed induction crystallization or producing solid sediment by creating supersaturated condition;
4) solid-liquid separation;
5) the humidity baking step 4 of dry environment is controlled) be separated the solid obtained.
19. preparation methods according to claim 18, it is characterized in that, step 2) mode that mixes mutually with alkaline sodium and potassium compound is in step 1) directly add alkaline sodium and potassium compound in system or alkaline sodium and potassium compound be dissolved in suitable solvent and then add step 1) in system.
20. preparation methods according to claim 18, it is characterized in that, step 1) described in organic solvent be selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, acetonitrile, acetone, methylethylketone, tetrahydrofuran (THF), dioxane, DMF, dimethyl sulfoxide (DMSO), Iso Butyl Acetate, ethyl acetate or its mixture.
21. preparation methods according to claim 18, it is characterized in that, step 2) described in alkaline sodium compound be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, sodium-acetate, sodium methylate, sodium formiate, Sodium Propionate, sodium acrylate, Sodium Benzoate or its mixture, preferred sodium hydroxide, sodium bicarbonate or its mixture; Step 2) described in alkaline potassium compound be selected from potassium hydroxide, salt of wormwood, saleratus, dipotassium hydrogen phosphate, potassium primary phosphate, Potassium ethanoate, potassium methylate, potassium formiate, potassium propionate, potassium acrylate, potassium benzoate or its mixture, preferred potassium hydroxide, saleratus or its mixture.
22. preparation methods according to claim 18, is characterized in that, step 5) the humid control of dry environment 45% ~ 70%; The humid control of preferred dry environment is 50% ~ 65%; More preferably the humid control of dry environment is 55% ~ 65%.
23. preparation methods according to claim 18, is characterized in that, in step 5) in controlling moisture obtain corresponding hydrates after be fully exposed to specified moisture further under carry out hydration and obtain moisture higher hydrate.
24. pharmaceutical compositions, is characterized in that, described pharmaceutical composition comprises the crystal type ARB-NEPi dication mixture according to any one of claim 6-17 and pharmaceutically acceptable carrier or vehicle for the treatment of effective dose.
25. crystal type ARB-NEPi dication mixtures according to any one of claim 6-17 or pharmaceutical composition according to claim 24 purposes in preparation treatment or the prevention disease relevant with neutral endopeptidase, cardiovascular, antihypertensive medicine.
26. purposes according to claim 25, is characterized in that, described antihypertensive drug is selected from anti-malignant hypertension, essential hypertension, renovascular hypertension, diabetic hypertension, isolated systolic hypertension or other secondary hypertension medicine.
27. crystal type ARB-NEPi dication mixtures according to any one of claim 6-17 or pharmaceutical composition according to claim 24 preparation treatment or prevention acute and chronic heart failure as, congestive heart failure, left ventricle dysfunction, hypertrophic neuropathy, diabetic cardiomyopathy, purposes in supraventricular and heart ventricle arrhythmia, atrial fibrillation, auricular flutter or harmful vascular remodeling medicine.
28. crystal type ARB-NEPi dication mixtures according to any one of claim 6-17 or pharmaceutical composition according to claim 24 are in preparation treatment or prevention 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.
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