CN110713465A - ARB-NEPi compound, crystal form, preparation method and application - Google Patents
ARB-NEPi compound, crystal form, preparation method and application Download PDFInfo
- Publication number
- CN110713465A CN110713465A CN201911009959.0A CN201911009959A CN110713465A CN 110713465 A CN110713465 A CN 110713465A CN 201911009959 A CN201911009959 A CN 201911009959A CN 110713465 A CN110713465 A CN 110713465A
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- CN
- China
- Prior art keywords
- ylmethyl
- biphenyl
- methyl
- butylcarbamoyl
- ethoxycarbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
The invention discloses an ARB-NEPi compound, a crystal form, a preparation method and application. The invention also provides [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Na3 .xH2The crystal form II of O and the new crystal form II have ideal physical and chemical properties, good stability and good drug forming property; the novel crystal form provided by the invention is simple in preparation method and low in cost, the prepared product is good in stability and high in purity, meets the requirements of raw material medicines, is more than 99.50% in HPLC purity and less than 0.1% in maximum single impurity, is green and environment-friendly, is suitable for industrial production, and has good market prospect.
Description
The application is a divisional application of an invention patent application with the application number of CN201710977389.9, the application date of 2017, 10 and 17, and the invention name of the invention is an ARB-NEPi compound, a crystal form, a preparation method and application.
Technical Field
The invention relates to an ARB-NEPi compound, a crystal form, a preparation method and application.
Background
Heart failure is a clinically significant and increasing problem, leading to significant morbidity and mortality. The increase in the life span of the population leads to an increase in cardiovascular risk factors and morbidity, and the number of patients with congestive heart failure increases with increasing survival rate after acute myocardial infarction, e.g., risk factors such as hypertension are a common predictor and common morbidity of chronic heart failure. At the same time, the number of concomitant admissions due to acute decompensated heart failure is also increasing.
Angiotensin II interacts with specific receptors on the surface of target cells. Inhibition of AT1 receptors by angiotensin II blockers may be useful in the treatment of conditions of hypertension and congestive heart failure.
Neutral Endopeptidase (NEP) is a matrix metalloprotease containing metallic zinc that cleaves a variety of peptide substrates at the amino terminus of aromatic amino acids, including, but not limited to, atrial natriuretic peptide, brain natriuretic peptide, met and Leu enkephalin, bradykinin, neurokinin a and P species.
Chronic and uncontrolled hypertensive vascular disease will eventually lead to pathological changes in target organs (e.g., heart and kidneys), and sustained hypertension can also lead to increased incidence of stroke. The nature of hypertensive vascular disease is multifactorial. Essential hypertension is a polygenic disease that cannot be completely controlled by a single treatment alone, and therefore, in some cases, drugs with different mechanisms of action may be used in combination, for example: angiotensin receptor blockers and neutral endopeptidase inhibitors can be used in combination to control hypertension.
The U.S. FDA approved a supramolecular complex, marketed under the trade name Entresto (r. development code "LCZ 696"), for the treatment of heart failure with a decreased ejection fraction, comprising valsartan (an ARB) and AHU-377 (sabotary, a neutral endopeptidase inhibitor).
Valsartan induces vasodilation and ECF volume reduction by blocking angiotensin II receptor 1(AT1), which is present in vascular smooth muscle cells and secretes aldosterone, acting in reaction to the distal tubule to promote sodium reabsorption, which in turn reduces extracellular fluid (ECF) volume.
Sakubiqu AHU-377 is a prodrug of Sackuqu (LBQ657), is activated to form Sackuqu through esterase deethylation, and AHU-377 can inhibit cerebropeptidase, improve the level of vasoactive peptides by relieving the hydrolysis of vasoactive peptides such as natriuretic peptide, bradykinin, adrenomedullin and the like, cause vasodilation and reduce ECF volume through sodium excretion, and further protect the cardiac neurohormone control system.
Entresto is a brand new innovative drug, is an angiotensin receptor and neutral endopeptidase inhibitor, has a unique action mechanism, can reduce the strain of a failing heart, resists heart failure by utilizing the natural defense of an organism, simultaneously plays a role in enhancing natriuresis and the level of other endogenous vasoactive peptides, and inhibits the renin-angiotensin-aldosterone system (RAAS). The drug was approved for FDA breakthrough therapy and EMEA priority approved. And received FDA and EMEA approval for marketing in the united states, respectively, on days 7/2015 and 19/11/2015.
Although US8877938B2 has reported that the supramolecular complex comprising valsartan and AHU-377 presents a crystalline form of the trisodium salt hemipentahydrate compound (referred to as the "patented crystalline form"). However, the search for new crystalline forms of supramolecular complexes comprising valsartan and AHU-377, in particular stable new crystalline forms which are pharmacologically active and suitable for pharmaceutical use, remains a problem which is currently urgently sought to be solved.
Disclosure of Invention
The invention aims to solve the technical problem of providing an ARB-NEPi compound, a crystal form, a preparation method and application which are completely different from the prior art. The two new crystal forms of the ARB-NEPi compound provided by the invention have ideal physicochemical properties, good stability and good drug forming property, the preparation method of the two new crystal forms provided by the invention is simple, the cost is low, the product prepared by the invention has good stability and high purity, meets the requirements of raw material medicines (the HPLC purity is more than 99.50%, and the maximum single impurity is less than 0.1%), is green and environment-friendly, is suitable for industrial production and has good market prospect.
The invention provides an ARB-NEPi complex which is [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown as a formula I]Na3·xH2O, wherein 3.0 < X.ltoreq.4.0 (excluding 3.0 but including 4.0);
the invention also provides the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form i of O having major diffraction peaks at diffraction angles 2 θ of 4.145, 12.492, 18.747, 27.096 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu — K α, with a 2 θ error range of ± 0.2 degrees.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form i of O having major diffraction peaks at diffraction angles 2 θ of 4.145, 5.013, 5.546, 7.319, 8.308, 8.984, 9.769, 10.183, 12.492, 13.319, 14.820, 15.254, 15.984, 16.894, 17.623, 18.018, 18.747, 19.339, 20.051, 20.683, 21.766, 23.464, 24.139, 25.179, 27.096, 29.148 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu — K α, with a 2 θ error range of ± 0.2 degrees.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form I of O having a powder X-ray diffraction spectrum using a radiation source of Cu-Ka as shown in FIG. 1.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2And the thermal analysis of differential scanning calorimetry shows that the crystal form I of O has endothermic peaks at 116 +/-2 ℃, 150.4 +/-2 ℃ and 222.0 +/-2 ℃.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxy group shown in the formula IAlkylcarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Na3·xH2And the peak area of the dissociation absorption heat corresponding to the endothermic peak of the crystal form I of O is 85.94J/g, and the peak areas of the melting absorption heat are 46.06J/g and 17.18J/g respectively, which are measured by the thermal analysis of differential scanning calorimetry.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form i of O, thermal analysis by differential scanning calorimetry is shown in figure 2.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form I of O has a DSC-TGA trace of 5.395% and 0.9719% in stages of thermogravimetric loss (total of about 6.37% of thermogravimetric loss) in the range of 25 ℃ to 200 ℃.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2The DSC-TGA trace of the crystal form I of O is shown as a figure 3.
The invention also provides the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2A process for preparing form i of O comprising the steps of: reacting [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Cooling and crystallizing a solution of trisodium salt and a solvent to obtain the (S) -3 ' methyl-2 ' - (pentanoyl {2 ' - (tetrazole-5-yl) propionic acid shown as the formula I (3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)Biphenyl-4' -ylmethyl } amino) butanoic acid]Na3·xH2Crystal form I is O; the cooling rate is 0.1-10 ℃/min; the solvent is a mixed solvent formed by an organic solvent A, an organic solvent B and water; the organic solvent A is an ether solvent; the organic solvent B is an aromatic hydrocarbon solvent.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form I of O, the ether solvent is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and cyclopentyl methyl ether. The aromatic hydrocarbon solvent is preferably benzene or C1-C4One or more of alkylbenzene, chlorobenzene, and nitrobenzene; said C1-C4The alkylbenzene of (a) is preferably one or more of toluene, xylene, ethylbenzene and cumene. The volume ratio of the organic solvent A to the organic solvent B is preferably 1:2 to 1:5, for example 1: 2.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form I of O, the volume ratio of the sum of the volumes of the organic solvent A and the organic solvent B to the volume of the water is preferably 50-300, more preferably 100-250, such as 100, 150 or 250.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form I of O, the organic solvent A and the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid]The volume mass ratio of the trisodium salt is preferably 0.5-30 mL/g, and more preferably 1-20 mL/gFor example, 2mL/g, 10mL/g, or 16.7 mL/g.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form I of O, the organic solvent B and the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid]The volume-to-mass ratio of the trisodium salt is preferably 2mL/g to 50mL/g, more preferably 3mL/g to 35mL/g, for example 4mL/g, 20mL/g or 33.3 mL/g.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the process for preparing form I of O, said water is admixed with said- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid]The volume/mass ratio of the trisodium salt is preferably 0.01mL/g to 0.5mL/g, more preferably 0.05mL/g to 0.4mL/g, for example 0.06mL/g, 0.2mL/g or 0.3 mL/g.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form I of O, the (S) -3 '-methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid of the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid is]The solution of the trisodium salt in a solvent "is preferably obtained by: reacting [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Heating the mixture of trisodium salt and solvent A to complete dissolution, and adding solvent B and water to obtain the compound"[ 3- ((1S,3R) -1-Biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2" - (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Solutions of trisodium salt in solvents ".
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form I of O, the (S) -3 '-methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid of the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid is]The temperature of the solution of the trisodium salt in the solvent "is preferably from 40 ℃ to 80 ℃, for example 40 ℃, 60 ℃ or 80 ℃.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form I of O, the temperature is preferably reduced to 5-55 ℃, more preferably 25-50 ℃, such as 25 ℃, 40 ℃, 45 ℃ or 50 ℃.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the process for preparing the crystal form I of O, the temperature of the "crystallization" is preferably 5 to 55 ℃, more preferably 25 to 50 ℃, for example, 25 ℃, 40 ℃, 45 ℃ or 50 ℃.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the process for preparing form I of O, the "crystallization" time is preferably 1 hour to 5 hours, more preferably 1.5 hours to 5 hours, for example 1.5 hours, 3 hours, 4.5 hours or 5 hours.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the process for preparing form i of O, the "crystallization" is preferably carried out under stirring at a rate of preferably 100 to 350 rpm, more preferably 100 to 250 rpm, for example at 100, 150, 200 or 250 rpm.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form I of O, the cooling rate is preferably 0.1-8 ℃/min, more preferably 0.1-5 ℃/min, such as 0.1 ℃/min, 0.5 ℃/min or 5 ℃/min.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2The preparation of form I of O preferably employs the following work-up steps: after the reaction is finished, filtering, washing and drying to obtain the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazole-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2And crystal form I of O.
The filtration, washing and drying may be carried out by methods conventional in the art for such procedures. The filtration is preferably carried out by medium-speed filter paper. The washing is preferably carried out by using an ester solvent, and the ester solvent is preferably isopropyl acetate. The number of washing is preferably 1 to 3, for example 1. The drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 30-45 ℃; the pressure of the vacuum drying is preferably-0.008 MPa to-0.001 MPa; the time for vacuum drying is preferably 12 hours to 24 hours, for example 24 hours.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2The preparation method of the crystal form I of O preferably adopts the following steps: reacting [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Mixing the trisodium salt with the organic solvent A, heating to dissolve, adding the organic solvent B and water to form a solution, cooling to 5-55 ℃ (preferably 25 ℃ -50 ℃, such as 25 ℃, 40 ℃, 45 ℃ or 50 ℃) at a speed of 0.1-10 ℃/min (preferably 0.1-8 ℃/min, further preferably 0.1-5 ℃/min, such as 0.1 ℃/min, 0.5 ℃/min or 5 ℃/min), keeping the temperature at 5-55 ℃ (preferably 25 ℃ -50 ℃, such as 25 ℃, 40 ℃, 45 ℃ or 50 ℃), crystallizing for 1 hour-5 hours (such as 1.5 hours, 3 hours, 4.5 hours or 5 hours), and obtaining the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - ((shown in the formula I) Pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]Na3·xH2And crystal form I is O.
The invention also provides the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I, prepared by the preparation method of the crystal form I of O]Na3·xH2Form I of O.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Crystal modification of OAnd II, which has main diffraction peaks at diffraction angles 2 theta of 4.104,5.210,6.279,8.248,9.592,11.463, 12.433,14.366,15.969,16.874,18.019,18.727,19.361,21.234,22.910,25.084,25.595,27.095 and 27.807 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu-Ka, wherein the error range of 2 theta is +/-0.2 degrees.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form II of O having a powder X-ray diffraction spectrum using a radiation source of Cu-Ka as shown in FIG. 4.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form II of O, having an endothermic peak at 128.5 ℃. + -. 2 ℃ as determined by differential scanning calorimetry thermal analysis.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2And the peak area of the melting absorption heat peak of the crystal form II of O is 161.8J/g by thermal analysis of differential scanning calorimetry.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form II of O, thermal analysis by differential scanning calorimetry is shown in figure 5.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form II of O has a DSC-TGA trace of 3.208% and 2.988% thermogravimetric weight (total of about 6.20% thermogravimetric weight) respectively over the range of 25 ℃ to 200 ℃ in stages.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form II of O having a DSC-TGA trace as shown in figure 6.
The invention also provides the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2A process for preparing form II of O comprising the steps of: reacting [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Mixing a solution of trisodium salt, an organic solvent C and water, and then mixing the solution with an organic solvent D, and crystallizing to obtain the (S) -3 'methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid of the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid shown as the formula I]Na3·xH2Crystal form II is O; the organic solvent C is N-methylpyrrolidone (NMP); the organic solvent D is an ether solvent and/or an ester solvent.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form II of O, the ether solvent is preferably one or more of diethyl ether, methyl tert-butyl ether, isopropyl ether and diphenyl ether; the ester solvent is preferably one or more of ethyl acetate, isopropyl acetate, methyl acetate and n-butyl acetate.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form II of O, the volumes of the organic solvent C and the organic solvent DThe ratio is preferably 1:2 to 1:4, for example 1: 2.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form II of O, the volume ratio of the sum of the volumes of the organic solvent C and the organic solvent D to the water is preferably 10-200, more preferably 30-150, such as 30, 60, 75 or 150.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form II of O, the organic solvent C and the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid]The volume-to-mass ratio of the trisodium salt is preferably 1mL/g to 30mL/g, more preferably 1mL/g to 20mL/g, for example 1mL/g, 2mL/g, 6.7mL/g, 10mL/g or 16.7 mL/g.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form II of O, the organic solvent D and the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid]The volume-to-mass ratio of the trisodium salt is preferably 1mL/g to 30mL/g, more preferably 2mL/g to 20mL/g, for example 2mL/g, 4mL/g, 13.3mL/g or 20 mL/g.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form II of O, the water and the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]The volume/mass ratio of the trisodium salt is preferably 0.01mL/g to 1mL/g, more preferably 0.02mL/g to 0.4mL/g, for example 0.02mL/g, 0.2mL/g, 0.3mL/g or 0.4 mL/g.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form II of O, the- (S) -3 'methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid of the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid is]The temperature of the solution of the trisodium salt and the solvent "is preferably 10 ℃ to 40 ℃, and more preferably 15 ℃ to 30 ℃.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form II of O, the temperature of the crystallization is preferably 10-40 ℃, and more preferably 15-30 ℃.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the process for producing form II of O, the "crystallization" time is preferably 1 hour to 5 hours, more preferably 2 hours to 4 hours, for example, 2 hours, 3 hours, 3.5 hours, or 4 hours.
In the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid represented by the formula I]Na3·xH2In the preparation method of the crystal form II of O, the time of crystallization is preferably carried out under the condition of stirring, and the stirring speed is preferably 100 rpm ∞350 rpm, more preferably 100 to 250 rpm, for example 100, 150, 200 or 250 rpm.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2The preparation method of the crystal form II of O preferably adopts the following post-treatment steps: after the reaction is finished, filtering, washing and drying to obtain the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazole-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Crystal form II of O.
The filtration, washing and drying may be carried out by methods conventional in the art for such procedures. The filtration is preferably carried out by medium-speed filter paper. The washing is preferably carried out by adopting an ester solvent and/or an ether solvent, and the ester solvent is preferably one or more of ethyl acetate, isopropyl acetate, methyl acetate and n-butyl acetate; further preferred is isopropyl acetate and/or ethyl acetate. The ether solvent is preferably one or more of diethyl ether, methyl tert-butyl ether, isopropyl ether and diphenyl ether; further preferred are isopropyl ether and/or methyl t-butyl ether. The number of washing is preferably 1 to 3, for example 1. The drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 30-45 ℃; the pressure of the vacuum drying is preferably-0.008 MPa to-0.001 MPa; the time for vacuum drying is preferably 12 hours to 24 hours, for example 24 hours.
The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2The preparation method of the crystal form II of O preferably adopts the following steps: to [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2"- (tetra)Oxazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]Adding an organic solvent D into a solution formed by the trisodium salt, an organic solvent C and water, and crystallizing to obtain the (S) -3 'methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid of the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid shown in the formula I]Na3·xH2And crystal form II is formed. The manner of addition is preferably dropwise addition, and the rate of dropwise addition is preferably 1 ml/min to 20 ml/min, more preferably 1 ml/min to 5 ml/min, for example 1 ml/min, 2 ml/min, 3 ml/min or 5 ml/min.
The invention also provides the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2The crystal form II of O is prepared by the preparation method of the crystal form II of O, and the crystal form II is shown in the formula I of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid]Na3·xH2Form II of O.
The invention also provides the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2O, [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid of the formula I]Na3·xH2Crystal form I of O and [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid, as shown in formula I]Na3·xH2Use of form II of O for the preparation of a medicament for the treatment and/or prevention of a disease or condition associated with the activity of Neutral Endopeptidase (NEP) and angiotensin receptor 1(AT 1).
The invention also provides a pharmaceutical composition comprising the same[3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid, as shown in formula I]Na3·xH2O, [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid of the formula I]Na3·xH2Crystal form I of O and [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid, as shown in formula I]Na3·xH2One or more of form II of O.
The pharmaceutical composition preferably further comprises pharmaceutically acceptable auxiliary materials. The pharmaceutically acceptable auxiliary materials are selected from one or more of diluents, fillers, disintegrants, glidants, lubricants, binders and coloring agents.
The invention also provides application of the pharmaceutical composition in preparing a medicament for treating and/or preventing diseases or symptoms related to the activities of Neutral Endopeptidase (NEP) and angiotensin receptor 1(AT 1).
The diseases or disorders associated with the activity of Neutral Endopeptidase (NEP) and angiotensin receptor 1(AT1) are selected from hypertension, heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular or ventricular arrhythmias, atrial fibrillation, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, arteriosclerosis, angina pectoris, atherosclerosis, renal insufficiency, diabetes and complications, glomerular sclerosis, renal insufficiency, primary nephrotic proteinuria, secondary hyperaldosteronism, glomerulonephritis, scleroderma, migraine, peripheral vascular disease, cognitive disorders, glaucoma and stroke.
The hypertension comprises primary and secondary pulmonary hypertension and/or renal vascular hypertension.
The heart failure comprises acute heart failure, chronic heart failure and congestive heart failure.
The angina pectoris comprises unstable angina pectoris and stable angina pectoris.
The diabetes and the complications comprise diabetes, diabetic renal insufficiency, diabetic retinopathy, diabetic nephropathy and diabetic cardiomyopathy.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the environment temperature of 10-35 ℃.
The positive progress effects of the invention are as follows: the two new crystal forms of the ARB-NEPi compound provided by the invention have ideal physicochemical properties, good stability and good drug forming property, the preparation method of the new crystal forms provided by the invention is simple, the cost is low, the product prepared by the invention has good stability and high purity, meets the requirements of raw material medicines (the HPLC purity is more than 99.50%, and the maximum single impurity is less than 0.1%), is green and environment-friendly, is suitable for industrial production and has good market prospect.
Drawings
FIG. 1 is a drawing of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid of formula I, prepared in example 1]Na3·xH2An XRPD pattern for form I of O;
FIG. 2 is a drawing of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid of formula I, prepared in example 1]Na3·xH2A DSC of form I of O;
FIG. 3 is a drawing of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid, formula I, prepared in example 1]Na3·xH2A DSC-TGA trace of form I of O;
FIG. 4 is a drawing of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid, formula I, prepared in example 5]Na3·xH2An XRPD pattern of form II of O;
FIG. 5 is a graph of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid, formula I, prepared in example 5]Na3·xH2A DSC profile for form II of O;
FIG. 6 is a drawing of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid, formula I, prepared in example 5]Na3·xH2TGA profile of form II of O.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
Weighing [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]Trisodium salt (1.0g) is put into a reaction flask, 10mL of tetrahydrofuran is added, the mixture is heated to 60 ℃ under stirring, the solid is completely dissolved, then 20mL of toluene is added and still completely dissolved, 0.2mL of water is added and still completely dissolved, no solid is separated out, then the mixture is cooled to 45 ℃ at the cooling rate of 0.1 ℃/min, the mixture is kept at 45 ℃ and stirred at the rate of 100 revolutions per minute for crystallization for 3 hours, and white solid is separated out. Filtering with medium-speed filter paper, leaching the filter cake with isopropyl acetate (0.5mL) once, and vacuum-drying at 30-45 ℃ for 24 hours (vacuum degree-0.008 MPa) to obtain 0.73g of (3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) ion-exchange resin shown in formula I3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Na3·xH2Form i of O, yield 73%, HPLC purity 99.65%, maximum single impurity 0.03%. The molar ratio of the Sacubitril to the valsartan and the sodium ions is 1:1:3, and the white powder is obtained by vacuum drying. The XRPD pattern is shown in figure 1; the DSC chart is shown in figure 2; the DSC-TGA trace is shown in FIG. 3.
FIG. 1 shows [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid according to formula I of the present invention]Na3·xH2Form i of O having a major diffraction peak at diffraction angles 2 θ of 4.145, 5.013, 5.546, 7.319, 8.308, 8.984, 9.769, 10.183, 12.492, 13.319, 14.820, 15.254, 15.984, 16.894, 17.623, 18.018, 18.747, 19.339, 20.051, 20.683, 21.766, 23.464, 24.139, 25.179, 27.096, 29.148 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu — K α, with a 2 θ error range of ± 0.2 degrees;
as can be seen in FIG. 2, the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid according to formula I of the present invention]Na3·xH2The crystal form I of O has dissociation absorption heat of 85.94J/g at 89.7-125.1 ℃ by thermogram spectrum (DSC) measured by differential scanning calorimetry; has a melting absorption heat peak of 46.06J/g at 144.3-156.0 ℃.
As can be seen in FIG. 3, [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid according to formula I of the present invention]Na3·xH2Form I of O having a DSC-TGA trace of about 6.37% weight loss at 25 ℃ to 200 ℃.
The solubility of the product obtained in example 1 was tested according to the method of the fourth general example of the pharmacopoeia of china 2015 edition and compared with the original ground product (Entresto of norwa). The experimental method is as follows: a test sample ground into fine powder is weighed, and is vigorously shaken in a solvent with a certain volume at 25 +/-2 ℃ for 30 seconds every five minutes, and the dissolution condition within 30 minutes is observed, and the results are shown in Table 1.
Table 1 saturated solubility test meter
The crystal form has good solubility in neutral medium, and can be well dissolved and absorbed in gastrointestinal tract.
Example 1 preparation of [3- ((1S,3R) -1-Biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid of formula I]Na3·xH2The crystal form I of O is kept stable for 12 months under the conditions that the temperature is 30 +/-2 ℃ and the relative humidity is 65% +/-5%. The crystal form of the invention is stable and is suitable for patent medicine.
Example 2
Weighing [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]Trisodium salt (1.5g) is put into a reaction flask, 25mL of 2-methyltetrahydrofuran is added, the mixture is heated to 60 ℃ under stirring, the solid is completely dissolved, 50mL of ethylbenzene is added and still completely dissolved, 0.3mL of water is added and still completely dissolved, no solid is separated out, the mixture is cooled to 40 ℃ at the cooling rate of 0.5 ℃/min, the mixture is kept at the temperature of 40 ℃ and stirred and crystallized at the speed of 150 r/min for 5 hours, and white solid is separated out. Filtering with medium-speed filter paper, leaching the filter cake with isopropyl acetate (3mL) once, and vacuum drying at 30-45 deg.C for 24 hr (vacuum degree-0.008 MPa) to obtain 1.08g of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in formula I]Na3·xH2Form O, yield 72.5%, HPLC purity 99.77%, maximum single impurity 0.02%. And (3) carrying out vacuum drying on the white powder, wherein the molar ratio of the Sacubitril to the valsartan to the sodium ions is 1:1: 3.
Example 3
Weighing [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]And putting trisodium salt (5g) into a reaction flask, adding 10mL of dioxane, heating to 80 ℃ under stirring until all solids are dissolved, then adding 20mL of xylene and still dissolving, adding 0.3mL of water and still dissolving until all solids are dissolved, then cooling to 50 ℃ at a cooling rate of 0.5 ℃/min, preserving heat at 50 ℃, stirring and crystallizing at a speed of 200 revolutions per minute for 1.5 hours, and separating out white solids. Filtering with medium-speed filter paper, leaching the filter cake with isopropyl acetate (3mL) once, and vacuum drying at 30-45 deg.C for 24 hr (vacuum degree-0.008 MPa) to obtain 3.9g of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in formula I]Na3·xH2Form O, yield 78%, HPLC purity 99.53%, maximum single impurity 0.04%. And (3) carrying out vacuum drying on the white powder, wherein the molar ratio of the Sacubitril to the valsartan to the sodium ions is 1:1: 3.
Example 4
Weighing [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]Trisodium salt (5g) is put into a reaction flask, 50mL of tetrahydrofuran is added, the mixture is heated to reflux (40 ℃) under stirring until all solids are dissolved, then 100mL of chlorobenzene is added and still all the solids are dissolved, 1.5mL of water is added and still all the solids are dissolved, no solid is separated out, then the mixture is cooled to 25 ℃ at the cooling rate of 5 ℃/min, and the mixture is kept at 25 ℃ and stirred for crystallization at the rate of 250 revolutions per minute for 4.5 hours, so that white solids are separated out. Filtering with medium-speed filter paper, leaching the filter cake with isopropyl acetate (5mL) once, and vacuum drying at 30-45 deg.C for 24 hr (vacuum degree-0.008 MPa) to obtain 3.3g of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in formula I]Na3·xH2Crystal form O, yieldThe yield was 66%, the HPLC purity was 99.87%, and the maximum single impurity was 0.02%. And (3) carrying out vacuum drying on the white powder, wherein the molar ratio of the Sacubitril to the valsartan to the sodium ions is 1:1: 3.
Example 5
Weighing [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]Placing trisodium salt (0.5g) into a reaction flask, adding 1mL of N-methylpyrrolidone, adding 0.1g of water, stirring to completely dissolve, slowly dropwise adding 2mL of isopropyl acetate (the dropwise adding rate is 1 mL/min) into the solution at room temperature (15-30 ℃), stirring at the speed of 100R/min for 2 hours until a large amount of white solid is separated out, filtering with medium-speed filter paper, leaching the filter cake with isopropyl acetate (0.5mL), and drying in vacuum at 30-45 ℃ for 24 hours (the vacuum degree is-0.008 MPa) to obtain 0.44g of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) shown in the formula I Butyric acid]Na3·xH2Form II of O, yield 88%, HPLC purity 99.64%, maximum single impurity 0.02%. And (3) carrying out vacuum drying on the white powder, wherein the molar ratio of the Sacubitril to the valsartan to the sodium ions is 1:1: 3. The XRPD pattern is shown in FIG. 4; the DSC chart is shown in figure 5; the DSC-TGA trace is shown in FIG. 6.
Fig. 4 shows that form II obtained according to example 5 has major diffraction peaks at diffraction angles 2 θ of 4.104,5.210,6.279,8.248,9.592,11.463, 12.433,14.366,15.969,16.874,18.019,18.727,19.361,21.234,22.910,25.084,25.595,27.095,27.807 degrees in the X-ray powder diffraction spectrum using a radiation source of Cu — K α, with an error range of ± 0.2 degrees 2 θ;
FIG. 5 shows the thermogram (DSC) of form II of the present invention measured by differential scanning calorimetry, which has a melting absorption heat peak of 161.8J/g at 117.4-135.7 deg.C (128.5 deg.C + -2 deg.C).
Fig. 6 shows that the DSC-TGA trace of form II of the present invention shows 3.208% and 2.988% of the thermogravimetric weight (total of about 6.20% of the thermogravimetric weight) in stages in the range of 25 ℃ to 200 ℃.
Example 5 preparationIs represented by formula I of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Na3·xH2And the crystal form II of the O keeps stable in 12 months under the conditions that the temperature is 30 +/-2 ℃ and the relative humidity is 65% +/-5%. The crystal form of the invention is stable and is suitable for patent medicine.
Example 6
Weighing [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]Placing trisodium salt (5g) in a reaction flask, adding 5mL of N-methylpyrrolidone, adding 0.1g of water, stirring to completely dissolve, slowly dropwise adding 10mL of methyl tert-butyl ether (the dropwise adding rate is 2 mL/min) into the solution at room temperature (15-30 ℃), stirring at the speed of 150 revolutions/min for 3.5 hours until a large amount of white solid is separated out, filtering with medium-speed filter paper, leaching the filter cake with methyl tert-butyl ether (1mL), and drying in vacuum at 30-45 ℃ for 24 hours (the vacuum degree is-0.008 MPa) to obtain 3.95g of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 '-methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } ammonia shown in the formula I Yl) butyric acid]Na3·xH2Form II of O, yield 79%, HPLC purity 99.55%, maximum single impurity 0.04%. And (3) carrying out vacuum drying on the white powder, wherein the molar ratio of the Sacubitril to the valsartan to the sodium ions is 1:1: 3.
Example 7
Weighing [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]Placing trisodium salt (1g) in a reaction flask, adding 10mL of N-methylpyrrolidone, adding 0.4g of water, stirring to completely dissolve, slowly dropwise adding 20mL of isopropyl ether (the dropwise adding rate is 3 mL/min) into the solution at room temperature (15-30 ℃), stirring at the speed of 200 r/min to crystallize for 4 hours until a large amount of white solid is separated out, filtering with medium-speed filter paper, leaching a filter cake once with isopropyl ether (1mL), and vacuum drying at the temperature of 30-45 ℃ for 24 hours (vacuum drying)Void-0.008 MPa), 0.73g of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid, as shown in formula I, was obtained]Na3·xH2Form II of O, yield 73%, HPLC purity 99.61%, maximum single impurity 0.02%. And (3) carrying out vacuum drying on the white powder, wherein the molar ratio of the Sacubitril to the valsartan to the sodium ions is 1:1: 3.
Example 8
Weighing [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butanoic acid]Placing trisodium salt (3g) in a reaction flask, adding 20mL of N-methylpyrrolidone, adding 1g of water, stirring to completely dissolve, slowly dropwise adding 40mL of ethyl acetate (the dropwise adding rate is 5 mL/min) into the solution at room temperature (15-30 ℃), stirring at the rate of 250 revolutions/min to crystallize for 3 hours until a large amount of white solid is separated out, filtering with medium-speed filter paper, leaching the filter cake with ethyl acetate (2mL), and drying in vacuum at 30-45 ℃ for 24 hours (the vacuum degree is-0.008 MPa) to obtain 2.25g of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) shown in the formula I Butyric acid]Na3·xH2Form II of O, yield 75%, HPLC purity 99.67%, maximum single impurity 0.02%. And (3) carrying out vacuum drying on the white powder, wherein the molar ratio of the Sacubitril to the valsartan to the sodium ions is 1:1: 3.
Claims (9)
1. [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown as formula I]Na3·xH2O, wherein X is more than 3.0 and less than or equal to 4.0, and the crystal form II is characterized in that: it has a main diffraction angle 2 theta of 4.104,5.210,6.279,8.248,9.592,11.463, 12.433,14.366,15.969,16.874,18.019,18.727,19.361,21.234,22.910,25.084,25.595,27.095 and 27.807 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu-KaDiffraction peak, 2 theta error range is plus or minus 0.2 degree;
2. the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid of the formula I as claimed in claim 1]Na3·xH2Form II of O, characterized by: the powder X-ray diffraction spectrum of Cu-K alpha used as a radiation source is shown in FIG. 4.
3. The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid of the formula I as claimed in claim 1]Na3·xH2Form II of O, characterized by: the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2The crystal form II of O has an endothermic peak at 128 +/-0.2 ℃ as measured by the thermal analysis of differential scanning calorimetry;
and/or the presence of a gas in the gas,
the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2The peak area of the melting absorption heat of the crystal form II of O is 161.8J/g as measured by the thermal analysis of differential scanning calorimetry;
and/or the presence of a gas in the gas,
the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form II of O having a DSC-TGA trace in the range of 25 ℃ to 200 ℃The staged weight loss on heating was 3.208% and 2.988%, respectively, for a total weight loss on heating of about 6.20%.
4. The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid of the formula I as claimed in claim 1]Na3·xH2Form II of O, characterized by: the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form II of O, thermal analysis by differential scanning calorimetry is shown in figure 5;
and/or the presence of a gas in the gas,
the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 'methyl-2' - (pentanoyl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid shown in the formula I]Na3·xH2Form II of O having a DSC-TGA trace as shown in figure 6.
5. The compound of any one of claims 1 to 4, wherein the compound is [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Na3·xH2A process for the preparation of form II of O, characterized in that it comprises the following steps: reacting [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Mixing a solution of trisodium salt, an organic solvent C and water, and then mixing the solution with an organic solvent D, and crystallizing to obtain the (S) -3 'methyl-2' - (valeryl {2 '- (tetrazol-5-yl) biphenyl-4' -ylmethyl } amino) butyric acid of the [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid shown as the formula I]Na3·xH2Crystal form II is O; the organic solvent C is N-methyl pyrrolidone; the organic solvent D is an ether solvent and/orAn ester solvent.
6. The compound of any one of claims 1 to 5, wherein the compound is [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Na3·xH2Use of form II of O for the preparation of a medicament for the treatment and/or prevention of a disease or condition associated with the activity of Neutral Endopeptidase (NEP) and angiotensin receptor 1(AT 1).
7. A pharmaceutical composition comprising [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3 ' methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid of the formula I as claimed in any one of claims 1 to 5]Na3·xH2Form II of O.
8. Use of a pharmaceutical composition according to claim 7 for the preparation of a medicament for the treatment and/or prevention of a disease or condition associated with the activity of neutral endopeptidase and angiotensin receptor 1.
9. The use of claim 8, wherein:
the diseases or disorders associated with the activity of neutral endopeptidase and angiotensin receptor 1 are selected from hypertension, heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular or ventricular arrhythmias, atrial fibrillation, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, arteriosclerosis, angina, atherosclerosis, renal insufficiency, diabetes and complications, glomerular sclerosis, renal insufficiency, primary nephrotic proteinuria, secondary hyperaldosteronism, glomerulonephritis, scleroderma, migraine, peripheral vascular disease, cognitive disorders, glaucoma and stroke.
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| WO2016037552A1 (en) * | 2014-09-09 | 2016-03-17 | 上海翰森生物医药科技有限公司 | Crystalline arb-nepi compound and preparation method therefor and application thereof |
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| CN105622452A (en) * | 2014-08-27 | 2016-06-01 | 上海翰森生物医药科技有限公司 | AHU-377 crystal-type free acid, preparation method and applications thereof |
| CN105461647B (en) * | 2014-09-28 | 2018-06-29 | 四川海思科制药有限公司 | Valsartan sand library is than solid-state form of bent trisodium salt composite and its preparation method and application |
| CN106032361A (en) * | 2015-03-11 | 2016-10-19 | 齐鲁制药有限公司 | LCZ-696 novel crystal form and preparation method thereof |
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| CN105622535B (en) * | 2015-12-28 | 2018-08-03 | 重庆两江药物研发中心有限公司 | A kind of preparation method of LCZ696 |
| CN106518709A (en) * | 2016-11-07 | 2017-03-22 | 济南益新医药技术有限公司 | Preparation method of amorphous sacubitri valsartan sodium salt composite |
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| CN105873586A (en) * | 2014-12-08 | 2016-08-17 | 美国晶云药物科技有限公司 | Crystalline forms of trisodium supramolecular complex comprising valsartan and AHU-377 and methods thereof |
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