CN107674038A - ARB NEPi compounds, crystal formation, preparation method and application - Google Patents
ARB NEPi compounds, crystal formation, preparation method and application Download PDFInfo
- Publication number
- CN107674038A CN107674038A CN201710977389.9A CN201710977389A CN107674038A CN 107674038 A CN107674038 A CN 107674038A CN 201710977389 A CN201710977389 A CN 201710977389A CN 107674038 A CN107674038 A CN 107674038A
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- CN
- China
- Prior art keywords
- biphenyl
- ylmethyl
- methyl
- bases
- valeryl
- 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.)
- Pending
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000692 natriuretic peptide Substances 0.000 description 1
- HPNRHPKXQZSDFX-OAQDCNSJSA-N nesiritide Chemical compound C([C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CO)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 HPNRHPKXQZSDFX-OAQDCNSJSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 201000008312 primary pulmonary hypertension Diseases 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 208000007278 renal glycosuria Diseases 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 208000037812 secondary pulmonary hypertension Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
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- C07D257/04—Five-membered rings
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Abstract
The invention discloses ARB NEPi compounds, crystal formation, preparation method and application.Present invention also offers [methyl 2 ' of 3 (butylcarbamoyl of 4 ylmethyl of (1S, 3R) 1 biphenyl, 3 ethoxy carbonyl 1) propionic acid (S) 3 ' (valeryl 2 " and (base of the tetrazolium 5) ylmethyl of biphenyl 4 ' } amino) butyric acid] Na3.xH2O crystal formation I and crystal formation II, two kinds of novel crystal forms is respectively provided with preferable physicochemical properties, and stability is good, has good druggability；Also, novel crystal forms preparation method provided by the present invention is simple, and cost is cheap, and product stability produced by the present invention is good, purity is high, meets the requirement of bulk drug, and HPLC purity is more than 99.50%, and maximum list is miscellaneous to be less than 0.1%, it is green, it is suitable for industrialized production, the marketization has good prospects.
Description
Technical field
The present invention relates to ARB-NEPi compounds, crystal formation, preparation method and application.
Background technology
Heart failure is clinically great and the problem of increasingly increases, and causes obvious morbidity and mortality.Population life
Extending causes the increase of cardiovascular risk factors and illness rate, with the increase of the survival rate after acute myocardial infarction, with filling
The patient populations of courageous and upright heart failure are also stepped up, for example, hypertension equivalent risk factor be the common omen of chronic heart failure and
Common fault.Meanwhile also it is continuously increased with the number being admitted to hospital due to acute decompensation heart failure occurred.
The special receptor of Angiotensin II and target cells interacts.Pass through Angiotensin II blocking agent pair
The inhibitory action of AT1 acceptors can be used for treating hypertension and the illness of congestive heart failure.
Neutral endopeptidase (enkephalinase, NEP) is a kind of various peptides can be cracked on the amino terminal of aromatic amino acid
The matrix metalloproteinase for including metallic zinc of substrate, the substrate of this enzyme are nonrestrictive including atrial natriuretic peptide, brain natriuretic peptide, met
With Leu enkephalins, bradykinin, neurokinin A and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2.
Long-term and uncontrolled hypertensive vascular disease most causes the pathology of target organ (such as heart and kidney) at last
Sexually revise, lasting hypertension also can result in the incidence of disease increase of apoplexy.The property of hypertensive vascular disease is multifactor.
Essential hypertension is multigenic disease, can not only be controlled completely by single treatment, and therefore, in some cases, difference is made
With the medicine of mechanism can with use in conjunction, such as：Angiotensin receptor blocker and neutral endopeptidase inhibitor can combine
For controlling hypertension.
The supramolecular complex that U.S. FDA have approved trade name Entresto (research and development code name " LCZ696 ") is used to penetrate blood
Fraction declines the treatment of heart failure, and it includes Valsartan (a kind of ARB) and AHU-377 (Sha Ku ratio songs, a kind of neutral endopeptidase suppression
Agent).
Valsartan is present in vascular smooth muscle cells and secretion aldosterone Angiotensin II receptor 1 by blocking
(AT1) reabsorption that distal renal tubular promotes sodium, is reacted on, and then reduces extracellular body fluid (ECF) volume, so as to cause blood
Pipe diastole and ECF volumes reduce.
Sha Ku takes off ethyl activation into husky storehouse Qula than the prodrug that bent AHU-377 is husky storehouse Qula (LBQ657), by esterase,
AHU-377 can suppress brain peptase, by alleviating the hydrolysis to vasoactive peptides such as natriuretic peptide, bradykinin, adrenomedulins,
The level of these vasoactive peptides is improved, causes vasodilation and ECF volumes, and then cardioprotection god is reduced by sodium excretion
Through hormone control system.
Entresto is brand-new new medicine, is a kind of angiotensin receptor and neutral endopeptidase inhibitor, is had only
Special mechanism of action, can reduce the strain of the heart of exhaustion, and heart failure, while the increasing that plays a role are resisted using the natural defence of body
It is strong to promote natruresis and the level of other endogenic vasoactive peptides, and suppress renin-angiotensin-aldosterone system
(RAAS).The medicine obtains FDA breakthrough sex therapy identifications and EMEA is preferentially examined.And first after on July 7th, 2015 and 2015
Obtained U.S. FDA and EMEA approval listings respectively on November 19.
Although it has been reported that there is one kind three in US8877938B2 comprising Valsartan and AHU-377 supramolecular complex
The crystal formation (being referred to as " patent crystal formation ") of five hydrates of sodium salt half.But find the supermolecule comprising Valsartan and AHU-377 and answer
The novel crystal forms of compound, it is still in the urgent need to address at present especially with pharmacological activity and suitable for the novel crystal forms of the stabilization of patent medicine
The problem of.
The content of the invention
The technical problems to be solved by the invention there is provided the ARB-NEPi compound entirely different with prior art, crystalline substance
Type, preparation method and application.Two kinds of novel crystal forms of ARB-NEPi compounds provided by the invention are respectively provided with preferable physical chemistry
Property, stability is good, has good druggability, also, two kinds of novel crystal forms preparation methods provided by the present invention are simple, cost
Cheap, product stability produced by the present invention is good, and purity is high, meets that (HPLC purity is more than 99.50%, most for the requirement of bulk drug
0.1%) big list is miscellaneous to be less than, green, is suitable for industrialized production, the marketization has good prospects.
The invention provides a kind of ARB-NEPi compounds, and it is [3- ((1S, 3R) -1- biphenyl -4- bases shown in formula I
Methyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) connection
Benzene -4 '-ylmethyl } amino) butyric acid] Na3·xH2O, wherein, 3.0 ＜ X≤4.0 are not (including 3.0, but including 4.0)；
Present invention also offers described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2O crystal formation I, it is in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, in the θ of the angle of diffraction 2
There is main diffraction peak at=4.145,12.492,18.747,27.096 degree, 2 θ error ranges are ± 0.2 degree.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation I, it is in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, in θ=4.145 of the angle of diffraction 2,
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,
There is main diffraction peak at 25.179,27.096,29.148 degree, 2 θ error ranges are ± 0.2 degree.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation I, it is as shown in Figure 1 using the powder x-ray diffraction spectrum that radiation source is Cu-K α.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation I, the heat analysis of differential scanning calorimetry are measured at 116 DEG C ± 2 DEG C, 150.4 DEG C ± 2 DEG C and 222.0 DEG C ± 2 DEG C
There is endothermic peak respectively.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation I, the heat analysis of differential scanning calorimetry measure the dissociation absorption thermal spike area corresponding with endothermic peak and are
85.94J/g, it is respectively 46.06J/g and 17.18J/g that fusing, which absorbs thermal spike area,.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation I, the heat analysis of differential scanning calorimetry are as shown in Figure 2.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation I, thermal weight loss is respectively 5.395% He to its DSC-TGA trace stage by stage in the range of 25 DEG C~200 DEG C
0.9719% (a total of about 6.37% thermal weight loss).
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation I, its DSC-TGA trace diagram are as shown in Figure 3.
Present invention also offers described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2The preparation method of O crystal formation I, it comprises the following steps：By [3- ((1S, 3R) -1- biphenyl -4- Ji Jia
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] solution that trisodium salt and solvent are formed, cooling, crystallization, obtain described [3- shown in formula I
((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl
Base 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formations I；The speed of described cooling
For 0.1 DEG C/min~10 DEG C/min；Described solvent is the mixed solvent that organic solvent A, organic solvent B and water are formed；It is described
Organic solvent A be ether solvent；Described organic solvent B is aromatic hydrocarbon solvent.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, the preferred tetrahydrofuran of described ether solvent, 2- methyltetrahydrofurans, dioxy six
One or more in ring and cyclopentyl-methyl ether.The preferred benzene of described aromatic hydrocarbon solvent, C1-C4Alkylbenzene, chlorobenzene and nitro
One or more in benzene；Described C1-C4The preferred toluene of alkylbenzene, dimethylbenzene, ethylbenzene and one kind or more in isopropylbenzene
Kind.The volume ratio preferably 1 of described organic solvent A and described organic solvent B:2~1:5, such as 1:2.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, the volume sum of described organic solvent A and organic solvent B and described water
Volume ratio preferably 50~300, further preferred 100~250, such as 100,150 or 250.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, described organic solvent A and described [3- ((1S, 3R) -1- biphenyl -4- Ji Jia
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] and trisodium salt volume mass ratio preferred 0.5mL/g~30mL/g, further preferred 1mL/g~
20mL/g, such as 2mL/g, 10mL/g or 16.7mL/g.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, described organic solvent B and described [3- ((1S, 3R) -1- biphenyl -4- Ji Jia
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] and trisodium salt volume mass ratio preferred 2mL/g~50mL/g, further preferred 3mL/g~
35mL/g, such as 4mL/g, 20mL/g or 33.3mL/g.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, described water and described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- second
Epoxide carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- the bases)-Ji Jia of biphenyl -4 '
Base } amino) butyric acid] and trisodium salt volume mass ratio preferred 0.01mL/g~0.5mL/g, further preferred 0.05mL/g~
0.4mL/g, such as 0.06mL/g, 0.2mL/g or 0.3mL/g.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, described " [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -
1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino)
Butyric acid] solution that is formed with solvent of trisodium salt " preferably obtained using following steps：By [3- ((1S, 3R) -1- biphenyl -4- Ji Jia
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] mixture of trisodium salt and solvent orange 2 A is heated to being completely dissolved, then adds solvent B and water obtains
Described " [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' first
Base -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] solution that is formed with solvent of trisodium salt ".
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, described " [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -
1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino)
Butyric acid] solution that is formed of trisodium salt and solvent " preferably 40 DEG C~80 DEG C of temperature, such as 40 DEG C, 60 DEG C or 80 DEG C.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, described " cooling " is preferably dropped to temperature as 5 DEG C~55 DEG C, further preferred 25
DEG C~50 DEG C, such as 25 DEG C, 40 DEG C, 45 DEG C or 50 DEG C.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, preferably 5 DEG C~55 DEG C of the temperature of described " crystallization ", further preferred 25 DEG C~
50 DEG C, such as 25 DEG C, 40 DEG C, 45 DEG C or 50 DEG C.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, preferably 1 hour~5 hours time of described " crystallization ", further preferred 1.5
Hour~5 hours, such as 1.5 hours, 3 hours, 4.5 hours or 5 hours.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, described " crystallization " is carried out preferably under conditions of stirring, the speed of described stirring
Preferably 100 revs/min~350 revs/min of rate, further preferred 100 revs/min~250 revs/min, such as with 100 revs/min
Clock, 150 revs/min, 200 revs/min or 250 revs/min.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In the preparation method of O crystal formation I, the speed preferably 0.1 DEG C/min~8 DEG C/min of described " cooling " is further excellent
Select 0.1 DEG C/min~5 DEG C/min, for example, 0.1 DEG C/min, 0.5 DEG C/min or 5 DEG C/min.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2The preparation method of O crystal formation I, it is preferred to use following post-processing step：After reaction terminates, filter, washing, be dried to obtain institute
State shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid -
(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation I
.
Described is filtered, washed and dried the conventional method that can use the generic operation in this area.Described filtering is excellent
Choosing is filtered using Medium speed filter paper.Described washing is preferably washed using esters solvent, the preferred acetic acid of described esters solvent
Isopropyl ester.The number of described washing preferably 1~3 time, such as 1 time.Described drying is preferably using vacuum drying；Described is true
Preferably 30 DEG C~45 DEG C of the temperature that sky is dried；Described vacuum drying pressure preferably -0.008MPa~-0.001MPa；It is described
Preferably 12 hours~24 hours vacuum drying time, such as 24 hours.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2The preparation method of O crystal formation I, it is preferred to use following steps：By [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyls
Carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl }
Amino) butyric acid] trisodium salt mixes with organic solvent A, is warming up to dissolving, and then add organic solvent B and water forms solution, then
Again with 0.1 DEG C~10 DEG C/min speed (preferably 0.1 DEG C/min~8 DEG C/min, further preferred 0.1 DEG C/min~5 DEG C/min,
Such as 0.1 DEG C/min, 0.5 DEG C/min or 5 DEG C/min) be cooled to 5~55 DEG C (preferably 25 DEG C~50 DEG C, for example, 25 DEG C, 40 DEG C,
45 DEG C or 50 DEG C), 5~55 DEG C of keeping temperature (preferably 25 DEG C~50 DEG C, such as 25 DEG C, 40 DEG C, 45 DEG C or 50 DEG C) crystallization 1 hour
~5 hours (such as 1.5 hours, 3 hours, 4.5 hours or 5 hours), obtain shown in formula I [3- ((1S, 3R) -1- biphenyl -
4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5-
Base) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formations I.
Present invention also offers described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2[3- ((1S, 3R) -1- biphenyl -4- Ji Jia made from the preparation method of O crystal formation I shown in formula I
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation I.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation II, it is in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, in θ=4.104 of the angle of diffraction 2,
5.210,6.279,8.248,9.592,11.463,12.433,14.366,15.969,16.874,18.019,18.727,
There is main diffraction peak at 19.361,21.234,22.910,25.084,25.595,27.095,27.807 degree, 2 θ error ranges are
± 0.2 degree.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation II, it is as shown in Figure 4 using the powder x-ray diffraction spectrum that radiation source is Cu-K α.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation II, the heat analysis of differential scanning calorimetry measures has endothermic peak at 128.5 DEG C ± 2 DEG C.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation II, it is 161.8J/g that the heat analysis of differential scanning calorimetry, which measures fusing to absorb thermal spike area,.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation II, the heat analysis of differential scanning calorimetry are as shown in Figure 5.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation II, thermal weight loss is respectively 3.208% He to its DSC-TGA trace stage by stage in the range of 25 DEG C~200 DEG C
2.988% (a total of about 6.20% thermal weight loss).
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation II, its DSC-TGA trace diagram are as shown in Figure 6.
Present invention also offers described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2O crystal formation II preparation method, it comprises the following steps：By [3- ((1S, 3R) -1- biphenyl -4- Ji Jia
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] solution that is formed of trisodium salt and organic solvent C and water, then mixed with organic solvent D, crystallization obtains
To described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) third shown in formula I
Acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formations
II；Described organic solvent C is 1-METHYLPYRROLIDONE (NMP)；Described organic solvent D is ether solvent and/or ester
Class solvent.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, the preferred ether of described ether solvent, methyl tertiary butyl ether(MTBE), isopropyl ether and hexichol
One or more in ether；In described esters solvent ethyl acetate, isopropyl acetate, methyl acetate and n-butyl acetate
One or more.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, described organic solvent C and described organic solvent D volume ratio preferably 1:2
~1:4, such as 1:2.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, described organic solvent C and organic solvent D volume sum and described water
Volume ratio preferably 10~200, further preferred 30~150, such as 30,60,75 or 150.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, described organic solvent C and described [3- ((1S, 3R) -1- biphenyl -4- Ji Jia
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] and trisodium salt volume mass ratio preferred 1mL/g~30mL/g, further preferred 1mL/g~
20mL/g, such as 1mL/g, 2mL/g, 6.7mL/g, 10mL/g or 16.7mL/g.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, described organic solvent D and described [3- ((1S, 3R) -1- biphenyl -4- Ji Jia
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] and trisodium salt volume mass ratio preferred 1mL/g~30mL/g, further preferred 2mL/g~
20mL/g, such as 2mL/g, 4mL/g, 13.3mL/g or 20mL/g.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, described water and described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- second
Epoxide carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- the bases)-Ji Jia of biphenyl -4 '
Base } amino) butyric acid] and trisodium salt volume mass ratio preferred 0.01mL/g~1mL/g, further preferred 0.02mL/g~
0.4mL/g, such as 0.02mL/g, 0.2mL/g, 0.3mL/g or 0.4mL/g.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, described " [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -
1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino)
Butyric acid] solution that is formed of trisodium salt and solvent " preferably 10 DEG C~40 DEG C, further preferred 15 DEG C~30 DEG C of temperature.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, preferably 10 DEG C~40 DEG C, further preferred 15 DEG C of the temperature of described " crystallization "
~30 DEG C.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, preferably 1 hour~5 hours time of described " crystallization ", further preferred 2 is small
When~4 hours, such as 2 hours, 3 hours, 3.5 hours or 4 hours.
In described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2In O crystal formation II preparation method, the time of described " crystallization " is carried out preferably under conditions of stirring, described
Preferably 100 revs/min~350 revs/min of the speed of stirring, further preferred 100 revs/min~250 revs/min, such as with
100 revs/min, 150 revs/min, 200 revs/min or 250 revs/min.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation II preparation method, it is preferred to use following post-processing step：After reaction terminates, filter, washing, be dried to obtain institute
State shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid -
(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation II
.
Described is filtered, washed and dried the conventional method that can use the generic operation in this area.Described filtering is excellent
Choosing is filtered using Medium speed filter paper.Described washing is preferably washed using esters solvent and/or ether solvent, described esters
The preferably described esters solvent ethyl acetate of solvent, isopropyl acetate, methyl acetate and one kind in n-butyl acetate or
It is a variety of；Further preferred isopropyl acetate and/or ethyl acetate.It is the preferred ether of described ether solvent, methyl tertiary butyl ether(MTBE), different
One or more in propyl ether and diphenyl ether；Further preferred isopropyl ether and/or methyl tertiary butyl ether(MTBE).The number of described washing
It is preferred that 1~3 time, such as 1 time.Described drying is preferably using vacuum drying；Preferably 30 DEG C of described vacuum drying temperature~
45℃；Described vacuum drying pressure preferably -0.008MPa~-0.001MPa；The described vacuum drying time preferably 12
Hour~24 hours, such as 24 hours.
Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia first shown in formula I
Acyl group) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·
xH2O crystal formation II preparation method, it is preferred to use following steps：To [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxies
Base carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- the bases)-Ji Jia of biphenyl -4 '
Base } amino) butyric acid] organic solvent D is added in the solution that is formed of trisodium salt and organic solvent C and water, crystallization, obtain such as Formulas I institute
Show [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -
2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formations II.Described adds
The mode entered is preferably added dropwise, speed preferred 1ml/ minutes~20ml/ minutes of described dropwise addition, and further preferred 1ml/ minutes~
5ml/ minutes, such as 1ml/ minutes, 2ml/ minutes, 3ml/ minutes or 5ml/ minutes.
Present invention also offers described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2[3- ((1S, 3R) -1- biphenyl -4- Ji Jia made from O crystal formation II preparation method shown in formula I
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation II.
Present invention also offers described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2O, [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2O crystal formation I and [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butyl ammonia shown in formula I
Formoxyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2O crystal formation II is preparing treatment and/or prevention and neutral endopeptidase (NEP) and angiotensin Ⅱ receptor type 1 (AT1)
Application in the medicine of the relevant disease of activity or illness.
Present invention also offers a kind of pharmaceutical composition, and it includes described [3- ((1S, 3R) -1- connection shown in formula I
Benzene -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -
5- yls) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O, [3- ((1S, 3R) -1- biphenyl -4- Ji Jia shown in formula I
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation I and shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyls -
3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -4 ' -
Ylmethyl } amino) butyric acid] Na3·xH2One or more in O crystal formation II.
Described pharmaceutical composition preferably further includes pharmaceutically acceptable auxiliary material.Described is pharmaceutically acceptable
One or more of the auxiliary material in diluent, filler, disintegrant, glidant, lubricant, adhesive and colouring agent.
Present invention also offers described pharmaceutical composition prepare treatment and/or prevention with neutral endopeptidase (NEP) and
Application in the medicine of the active relevant disease or illness of angiotensin Ⅱ receptor type 1 (AT1).
The described disease relevant with the activity of neutral endopeptidase (NEP) and angiotensin Ⅱ receptor type 1 (AT1) or illness choosing
From hypertension, the heart exhausts, left ventricular insufficiency, hypertrophic cardiomyopathy, diabetes cardiomyopathy, room mo(u)ld top half or the ventricle type rhythm of the heart lose
Often, atrial fibrillation, auricular flutter, harmful vascular remodeling, miocardial infarction and its sequelae, arteriosclerosis, angina pectoris, artery are athero-
Hardening, renal insufficiency, diabetes and complication, glomerulosclerosis, renal insufficiency, Primary Nephrosis albuminuria, Secondary cases
Hyperaldosteronism, glomerulonephritis, chorionitis, antimigraine, peripheral artery disease, cognitive disorder, glaucoma and apoplexy.
Described hypertension, including primary and secondary pulmonary hypertension, and/or renovascular hypertension.
Described heart failure, including acute heart failure, chronic heart failure and congestive heart failure.
Described angina pectoris, including unstable angina pectoris and stable angina cordis.
Described diabetes and complication, including diabetes, diabetic keratopathy renal insufficiency, diabetic retinopathy
Change, nephrosis and diabetes cardiomyopathy.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and it is each preferably to produce the present invention
Example.
Agents useful for same and raw material of the present invention are commercially available.
In the present invention, described room temperature refers to that environment temperature is 10 DEG C~35 DEG C.
The positive effect of the present invention is：Two kinds of novel crystal forms of ARB-NEPi compounds provided by the invention are respectively provided with
Preferable physicochemical properties, stability is good, has good druggability, also, novel crystal forms preparation side provided by the present invention
Method is simple, and cost is cheap, and product stability produced by the present invention is good, and purity is high, meets that (HPLC purity is more than for the requirement of bulk drug
99.50%, 0.1%) maximum list is miscellaneous to be less than, green, is suitable for industrialized production, the marketization has good prospects.
Brief description of the drawings
Fig. 1 is [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls made from embodiment 1 shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2The XRPD figures of O crystal formation I；
Fig. 2 is [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls made from embodiment 1 shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2The DSC figures of O crystal formation I；
Fig. 3 is [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls made from embodiment 1 shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2The DSC-TGA trajectory diagrams of O crystal formation I；
Fig. 4 is [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls made from embodiment 5 shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2O crystal formation II XRPD figures；
Fig. 5 is [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls made from embodiment 5 shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2O crystal formation II DSC figures；
Fig. 6 is [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls made from embodiment 5 shown in formula I
Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia
Base) butyric acid] Na3·xH2O crystal formation II TGA figures.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification selects.
Embodiment 1
Weigh [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -
3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] trisodium salt (1.0g) is put into reaction
In flask, 10mL tetrahydrofuran is added, under stirring, is heated to 60 DEG C, solid all dissolves, and it is still complete then to add 20mL toluene
Portion dissolves, and adds 0.2mL water, still all dissolvings, has no that solid separates out, is then cooled to 45 with 0.1 DEG C/min rate of temperature fall
DEG C, it is incubated at 45 DEG C with 100 revs/min of speed stirring and crystallizings 3 hours, separates out white solid.Filtered with Medium speed filter paper, filter cake
With isopropyl acetate (0.5mL) elution once, 30 DEG C~45 DEG C vacuum drying 24 hours (vacuum -0.008MPa), 0.73g is obtained
Shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -
3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation I, yield
73%, HPLC purity 99.65%, maximum single contaminant 0.03%.Sha Ku ratios are bent to be with Valsartan and sodium ion molar ratio
1:1:3, this white powder of vacuum drying gained.Its XRPD figure is shown in Fig. 1；Its DSC figure is shown in Fig. 2；Its DSC-TGA trajectory diagram is shown in Fig. 3.
Visible [3- ((1S, the 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -1- shown in formula I of the invention of Fig. 1
Butylcarbamoyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) fourth
Acid] Na3·xH2O crystal formation I, its using radiation source be Cu-K α powder x-ray diffraction spectrum in, the θ of the angle of diffraction 2=
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,
There is main diffraction peak at 25.179,27.096,29.148 degree, 2 θ error ranges are ± 0.2 degree；
Fig. 2 is visible, it is of the invention shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -
1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino)
Butyric acid] Na3·xH2O crystal formation I, the heat analysis collection of illustrative plates (DSC) that differential scanning calorimetry measures, there is solution at 89.7-125.1 DEG C
85.94J/g hot from absorption；There is fusing to absorb thermal spike 46.06J/g at 144.3-156.0 DEG C.
Fig. 3 is visible, it is of the invention shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -
1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino)
Butyric acid] Na3·xH2O crystal formation I, its DSC-TGA trace at 25 DEG C~200 DEG C about 6.37% weightlessness.
Method according to the 4th note on the use of Chinese Pharmacopoeia 2015 edition tests the solubility of product made from embodiment 1, and
And the contrast that original grinds product (Entresto of Novartis's production) is done.Experimental method is as follows：The test sample for being ground into fine powder is weighed, in 25
In the solvent of DEG C ± 2 DEG C of certain capacities, every strength shaking in five minutes 30 seconds, observation dissolved situation in 30 minutes, as a result such as
Shown in table 1.
The saturation solubility of table 1 tests table
Show that the crystal formation has good solubility in neutral medium, can be good at dissolving and absorbing in intestines and stomach.
[3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- fourths made from embodiment 1 shown in formula I
Base carbamyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2O crystal formation I is placed under conditions of relative humidity 65% ± 5% and keeps within 12 months crystal formation steady in 30 DEG C ± 2 DEG C of temperature
It is fixed.Illustrate the stable crystal form of the present invention, be adapted to patent medicine.
Embodiment 2
Weigh [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -
3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] trisodium salt (1.5g) is put into reaction
In flask, 25mL 2- methyltetrahydrofurans are added, under stirring, are heated to 60 DEG C, solid all dissolves, and then adds 50mL second
Benzene still all dissolves, and adds 0.3mL water, still all dissolvings, has no that solid separates out, is then dropped with 0.5 DEG C/min rate of temperature fall
Temperature is incubated with 150 revs/min of speed stirring and crystallizings 5 hours at 40 DEG C to 40 DEG C, separates out white solid.With Medium speed filter paper mistake
Filter, filter cake are eluted once with isopropyl acetate (3mL), 30 DEG C~45 DEG C vacuum drying 24 hours (vacuum -0.008MPa), are obtained
1.08g shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid -
(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation I, receive
Rate 72.5%, HPLC purity 99.77%, maximum single contaminant 0.02%.Sha Ku ratios are bent, Valsartan and sodium ion molar ratio are
1:1:3, this white powder of vacuum drying gained.
Embodiment 3
Weigh [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -
3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] trisodium salt (5g) is put into reaction and burns
In bottle, 10mL dioxane is added, under stirring, is heated to 80 DEG C, treated that solid all dissolves, then add 20mL dimethylbenzene still
All dissolvings, 0.3mL water is added, still all dissolvings, have no that solid separates out, be then cooled to 0.5 DEG C/min rate of temperature fall
50 DEG C, it is incubated at 50 DEG C with 200 revs/min of speed stirring and crystallizings 1.5 hours, separates out white solid.Filtered with Medium speed filter paper,
Filter cake is eluted once with isopropyl acetate (3mL), 30 DEG C~45 DEG C vacuum drying 24 hours (vacuum -0.008MPa), is obtained
3.9g shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid -
(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation I, receive
Rate 78%, HPLC purity 99.53%, maximum single contaminant 0.04%.Sha Ku is 1 than bent, Valsartan and sodium ion molar ratio:
1:3, this white powder of vacuum drying gained.
Embodiment 4
Weigh [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -
3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] trisodium salt (5g) is put into reaction and burns
In bottle, 50mL tetrahydrofuran is added, under stirring, is heated to flowing back (40 DEG C), treats that solid all dissolves, then add 100mL
Chlorobenzene still all dissolves, and adds 1.5mL water, still all dissolvings, has no that solid separates out, is then dropped with 5 DEG C/min rate of temperature fall
Temperature is incubated with 250 revs/min of speed stirring and crystallizings 4.5 hours at 25 DEG C to 25 DEG C, separates out white solid.Use Medium speed filter paper
Filtering, filter cake are eluted once with isopropyl acetate (5mL), 30 DEG C~45 DEG C vacuum drying 24 hours (vacuum -0.008MPa),
Obtain [the 3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) third of 3.3g shown in formula I
Acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formations
I, yield 66%, HPLC purity 99.87%, maximum single contaminant 0.02%.Sha Ku is than bent, Valsartan and sodium ion molar ratio
For 1:1:3, this white powder of vacuum drying gained.
Embodiment 5
Weigh [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -
3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] trisodium salt (0.5g) is placed in reaction
In flask, 1mL 1-METHYLPYRROLIDONE is added, 0.1g water is added, whole dissolved clarifications is stirred, to this under room temperature (15~30 DEG C)
2mL isopropyl acetate (drop rate is 1mL/ minutes) is slowly added dropwise in solution, 2 hours are stirred extremely with 100 revs/min of speed
There are a large amount of white solids to separate out, filtered with Medium speed filter paper, filter cake is eluted once with isopropyl acetate (0.5mL), 30 DEG C~45 DEG C
It is dried in vacuo 24 hours (vacuum -0.008MPa), obtains [3- ((1S, the 3R) -1- biphenyl -4- Ji Jia of 0.44g shown in formula I
Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -
4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation II, yield 88%, HPLC purity 99.64%, maximum single contaminant
0.02%.Sha Ku is 1 than bent, Valsartan and sodium ion molar ratio:1:3, this white powder of vacuum drying gained.Its XRPD schemes
See Fig. 4；Its DSC figure is shown in Fig. 5；Its DSC-TGA trajectory diagram is shown in Fig. 6.
Its powder x-ray diffraction in use radiation source for Cu-K α of the visible crystal formation II according to obtained by embodiment 5 of Fig. 4
In spectrum, in the θ=4.104 of the angle of diffraction 2,5.210,6.279,8.248,9.592,11.463,12.433,14.366,15.969,
There is master at 16.874,18.019,18.727,19.361,21.234,22.910,25.084,25.595,27.095,27.807 degree
Diffraction maximum is wanted, 2 θ error ranges are ± 0.2 degree；
The heat analysis collection of illustrative plates (DSC) that the visible crystal formation II differential scanning calorimetries of the invention of Fig. 5 measure, in 117.4-
135.7 DEG C of (128.5 DEG C ± 2 DEG C) places have fusing to absorb thermal spike 161.8J/g.
Visible its DSC-TGA trace of crystal formation II of the invention of Fig. 6 in the range of 25 DEG C~200 DEG C distinguish stage by stage by thermal weight loss
For 3.208% and 2.988% (a total of about 6.20% thermal weight loss).
[3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- fourths made from embodiment 5 shown in formula I
Base carbamyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid]
Na3·xH2O crystal formation II is placed under conditions of relative humidity 65% ± 5% and is kept within 12 months crystal formation steady in 30 DEG C ± 2 DEG C of temperature
It is fixed.Illustrate the stable crystal form of the present invention, be adapted to patent medicine.
Embodiment 6
Weigh [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -
3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] trisodium salt (5g) is placed in reaction and burns
In bottle, 5mL 1-METHYLPYRROLIDONE is added, 0.1g water is added, stirs whole dissolved clarifications, it is molten to this under room temperature (15~30 DEG C)
10mL methyl tertiary butyl ether(MTBE) (drop rate is 2ml/ minutes) is slowly added dropwise in liquid, it is small to stir 3.5 with 150 revs/min of speed
Up to there are a large amount of white solids to separate out, being filtered with Medium speed filter paper, filter cake is eluted once with methyl tertiary butyl ether(MTBE) (1mL), 30 DEG C~
45 DEG C of vacuum drying 24 hours (vacuum -0.008MPa), obtain [3- ((1S, the 3R) -1- biphenyl -4- bases of 3.95g shown in formula I
Methyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) connection
Benzene -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation II, yield 79%, HPLC purity 99.55%, maximum single contaminant
0.04%.Sha Ku is 1 than bent, Valsartan and sodium ion molar ratio:1:3, this white powder of vacuum drying gained.
Embodiment 7
Weigh [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -
3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] trisodium salt (1g) is placed in reaction and burns
In bottle, 10mL 1-METHYLPYRROLIDONE is added, 0.4g water is added, whole dissolved clarifications is stirred, to this under room temperature (15~30 DEG C)
20mL isopropyl ether (drop rate is 3ml/ minutes) is slowly added dropwise in solution, with 200 revs/min of speed stirring and crystallizings 4 hours
To there are a large amount of white solids to separate out, filtered with Medium speed filter paper, filter cake is eluted once with isopropyl ether (1mL), 30 DEG C~45 DEG C vacuum
Dry 24 hours (vacuum -0.008MPa), obtain [3- ((1S, the 3R) -1- biphenyl -4- ylmethyls -3- of 0.73g shown in formula I
Ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-base
Methyl } amino) butyric acid] Na3·xH2O crystal formation II, yield 73%, HPLC purity 99.61%, maximum single contaminant 0.02%.
Sha Ku is 1 than bent, Valsartan and sodium ion molar ratio:1:3, this white powder of vacuum drying gained.
Embodiment 8
Weigh [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -
3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] trisodium salt (3g) is placed in reaction and burns
In bottle, 20mL 1-METHYLPYRROLIDONE is added, 1g water is added, stirs whole dissolved clarifications, it is molten to this under room temperature (15~30 DEG C)
40mL ethyl acetate (drop rate is 5ml/ minutes) is slowly added dropwise in liquid, with 250 revs/min of speed stirring and crystallizings 3 hours
To there are a large amount of white solids to separate out, filtered with Medium speed filter paper, filter cake is eluted once with ethyl acetate (2mL), and 30 DEG C~45 DEG C true
Sky dry 24 hours (vacuum -0.008MPa), obtain 2.25g shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyls -
3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl -4 ' -
Ylmethyl } amino) butyric acid] Na3·xH2O crystal formation II, yield 75%, HPLC purity 99.67%, maximum single contaminant
0.02%.Sha Ku is 1 than bent, Valsartan and sodium ion molar ratio:1:3, this white powder of vacuum drying gained.
Claims (16)
- A kind of 1. ARB-NEPi compounds, it is characterised in that：It is [3- ((1S, 3R) -1- biphenyl -4- Ji Jia shown in formula I Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl - 4 '-ylmethyl } amino) butyric acid] Na3·xH2O, wherein, 3.0 ＜ X≤4.0；
- 2. [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -1- shown in formula I as claimed in claim 1 Butylcarbamoyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) fourth Acid] Na3·xH2O crystal formation I, it is characterised in that：It is spreading out in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α Firing angle 2 θ=4.145, there is main diffraction peak at 12.492,18.747,27.096 degree, 2 θ error ranges are ± 0.2 degree.
- 3. [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -1- shown in formula I as claimed in claim 2 Butylcarbamoyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) fourth Acid] Na3·xH2O crystal formation I, it is characterised in that：It is spreading out in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α Firing angle 2 θ=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, There is main diffraction peak at 23.464,24.139,25.179,27.096,29.148 degree, 2 θ error ranges are ± 0.2 degree.
- 4. [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -1- shown in formula I as claimed in claim 3 Butylcarbamoyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) fourth Acid] Na3·xH2O crystal formation I, it is characterised in that：It is in powder x-ray diffraction spectrum such as Fig. 1 institutes using radiation source for Cu-K α Show.
- 5. [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -1- shown in formula I as claimed in claim 2 Butylcarbamoyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) fourth Acid] Na3·xH2O crystal formation I, it is characterised in that：The heat analysis of its differential scanning calorimetry is measured at 116 DEG C ± 2 DEG C, 150.4 DEG C ± 2 DEG C and 222.0 DEG C ± 2 DEG C have endothermic peak respectively；And/orIt is 85.94J/g that the heat analysis of its differential scanning calorimetry, which measures the dissociation corresponding with endothermic peak to absorb thermal spike area, is melted It is respectively 46.06J/g and 17.18J/g to change absorption thermal spike area；And/orThermal weight loss is respectively 5.395% and 0.9719% to its DSC-TGA trace stage by stage in the range of 25 DEG C~200 DEG C, is amounted to About 6.37% thermal weight loss.
- 6. [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -1- shown in formula I as claimed in claim 2 Butylcarbamoyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) fourth Acid] Na3·xH2O crystal formation I, it is characterised in that：Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) shown in formula I Propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O's Crystal formation I, the heat analysis of differential scanning calorimetry are as shown in Figure 2；And/orDescribed [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) shown in formula I Propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O's Crystal formation I, its DSC-TGA trace diagram are as shown in Figure 3.
- 7. [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxies shown in formula I as described in any one of claim 1~6 Base carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- the bases)-Ji Jia of biphenyl -4 ' Base } amino) butyric acid] Na3·xH2The preparation method of O crystal formation I, it is characterised in that it comprises the following steps：Will [3- ((1S, 3R) -1- biphenyl -4- ylmethyls -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] solution that trisodium salt is formed with solvent, cooling, crystallization, obtain Described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) third shown in formula I Acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formations I ；The speed of described cooling is 0.1 DEG C/min~10 DEG C/min；Described solvent be organic solvent A, organic solvent B with The mixed solvent that water is formed；Described organic solvent A is ether solvent；Described organic solvent B is aromatic hydrocarbon solvent.
- 8. [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -1- shown in formula I as claimed in claim 1 Butylcarbamoyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) fourth Acid] Na3·xH2O crystal formation II, it is characterised in that：Its using radiation source be Cu-K α powder x-ray diffraction spectrum in, The angle of diffraction 2 θ=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 there is main diffraction at 27.807 degree Peak, 2 θ error ranges are ± 0.2 degree.
- 9. [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls -1- shown in formula I as claimed in claim 8 Butylcarbamoyl) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) fourth Acid] Na3·xH2O crystal formation II, it is characterised in that：It is using powder x-ray diffraction spectrum such as Fig. 4 that radiation source is Cu-K α It is shown.
- 10. as claimed in claim 8 shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls - 1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) Butyric acid] Na3·xH2O crystal formation II, it is characterised in that：Described [3- ((1S, 3R) -1- biphenyl -4- Ji Jia shown in formula I Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl - 4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation II, the heat analysis of differential scanning calorimetry are measured at 128 DEG C ± 0.2 DEG C There is endothermic peak；And/orDescribed [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) shown in formula I Propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O's Crystal formation II, it is 161.8J/g that the heat analysis of differential scanning calorimetry, which measures fusing to absorb thermal spike area,；And/orDescribed [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) shown in formula I Propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O's Crystal formation II, thermal weight loss is respectively 3.208% and 2.988% to its DSC-TGA trace stage by stage in the range of 25 DEG C~200 DEG C, always The thermal weight loss of meter about 6.20%.
- 11. as claimed in claim 10 shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls - 1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) Butyric acid] Na3·xH2O crystal formation II, it is characterised in that：Described [3- ((1S, 3R) -1- biphenyl -4- Ji Jia shown in formula I Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl - 4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation II, the heat analysis of differential scanning calorimetry are as shown in Figure 5；And/orDescribed [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) shown in formula I Propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O's Crystal formation II, its DSC-TGA trace diagram are as shown in Figure 6.
- 12. [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- second shown in formula I as described in any one of claim 8~11 Epoxide carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- the bases)-Ji Jia of biphenyl -4 ' Base } amino) butyric acid] Na3·xH2O crystal formation II preparation method, it is characterised in that it comprises the following steps：Will [3- ((1S, 3R) -1- biphenyl -4- ylmethyls -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] solution that is formed with organic solvent C and water of trisodium salt, then with Organic solvent D is mixed, and crystallization obtains described [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethyoxyl carbonyls shown in formula I Base -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } ammonia Base) butyric acid] Na3·xH2O crystal formations II；Described organic solvent C is 1-METHYLPYRROLIDONE；Described organic solvent D is Ether solvent and/or esters solvent.
- 13. as claimed in claim 1 shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyls - 1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) Butyric acid] Na3·xH2O, [3- ((1S, 3R) -1- biphenyl -4- Ji Jia shown in formula I as described in any one of claim 2~6 Base -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 "-(tetrazolium -5- bases) biphenyl - 4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation I and as described in any one of claim 8~11 shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 ' - (valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation II prepare treatment and/ Or prevent in the medicine of the disease relevant with the activity of neutral endopeptidase (NEP) and angiotensin Ⅱ receptor type 1 (AT1) or illness Using.
- 14. a kind of pharmaceutical composition, it includes [3- ((1S, 3R) -1- biphenyl -4- bases shown in formula I described in claim 1 Methyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl { 2 "-(tetrazolium -5- bases) connection Benzene -4 '-ylmethyl } amino) butyric acid] Na3·xH2O, as described in any one of claim 2~6 shown in formula I [3- ((1S, 3R) -1- biphenyl -4- ylmethyls -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystal formation I and such as claim 8~11 are any [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) third shown in formula I described in Acid-(S) -3 ' methyl -2 '-(valeryl 2 " and-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] Na3·xH2O crystalline substance One or more in type II.
- 15. pharmaceutical composition as claimed in claim 14 is preparing treatment and/or prevention and neutral endopeptidase and vasotonia Application in the medicine of the active relevant disease or illness of plain acceptor 1.
- 16. application as claimed in claim 15, it is characterised in that：The described disease relevant with the activity of neutral endopeptidase and angiotensin Ⅱ receptor type 1 or illness are selected from hypertension, the heart exhausts, Left ventricular insufficiency, hypertrophic cardiomyopathy, diabetes cardiomyopathy, room mo(u)ld top half or ventricle type arrhythmia cordis, atrial fibrillation, atrium are flutterred Dynamic, harmful vascular remodeling, miocardial infarction and its sequelae, arteriosclerosis, angina pectoris, atherosclerosis, renal function are not Entirely, diabetes and complication, glomerulosclerosis, renal insufficiency, Primary Nephrosis albuminuria, Secondary cases hyperaldosteronism, Glomerulonephritis, chorionitis, antimigraine, peripheral artery disease, cognitive disorder, glaucoma and apoplexy.
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| WO2020039394A1 (en) | 2018-08-24 | 2020-02-27 | Novartis Ag | New drug combinations |
| WO2020039386A1 (en) | 2018-08-23 | 2020-02-27 | Novartis Ag | New pharmaceutical use for the treatment of heart failure |
| US11642329B2 (en) | 2005-11-09 | 2023-05-09 | Novartis Pharmaceuticals Corporation | Amorphous solid form of compounds containing S—N-valeryl-N- {[2′-( 1 H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations |
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| CN106414416B (en) * | 2014-09-09 | 2020-03-27 | 上海翰森生物医药科技有限公司 | Crystalline ARB-NEPi compound and preparation method and application thereof |
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| 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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| CN102702119A (en) * | 2005-11-09 | 2012-10-03 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an NEP inhibitor |
| 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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| WO2020039386A1 (en) | 2018-08-23 | 2020-02-27 | Novartis Ag | New pharmaceutical use for the treatment of heart failure |
| WO2020039394A1 (en) | 2018-08-24 | 2020-02-27 | Novartis Ag | New drug combinations |
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