CN107074744B - Nep inhibitor crystal type free acid, calcium salt polymorphic and its preparation method and application - Google Patents
Nep inhibitor crystal type free acid, calcium salt polymorphic and its preparation method and application Download PDFInfo
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- CN107074744B CN107074744B CN201580049755.3A CN201580049755A CN107074744B CN 107074744 B CN107074744 B CN 107074744B CN 201580049755 A CN201580049755 A CN 201580049755A CN 107074744 B CN107074744 B CN 107074744B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Abstract
The invention discloses nep inhibitor crystal type free acids, calcium salt polymorphic and its preparation method and application.Its crystal type free acid for being related to compound shown in nep inhibitor formula 1 (also known as HAS-000129), calcium salt polymorphic and its preparation method and application, the x-ray diffractogram of powder of HAS-000129 crystal type free acid includes being located at 6.4 ± 0.2 °, peak at 15.9 ± 0.2 °, 20.8 ± 0.2 ° and 19.0 ± 0.2 ° of the angle of diffraction (2 θ).It further relates to the crystal type of HAS-000129 containing effective quantity free acid, calcium salt polymorphic and its pharmaceutical composition and treats or prevents the purposes in the drugs such as disease related with neutral endopeptidase, angiocarpy, anti-hypertension, acute and chronic heart failure, congestive heart failure, left ventricle dysfunction, hypertrophic cardiomyopathy, diabetes cardiomyopathy, supraventricular and heart ventricle arrhythmia, atrial fibrillation, auricular flutter or harmful vascular remodeling in preparation.HAS-000129 process operability of the present invention is strong, substance chemical stabilization, is conducive to preservation and pharmaceutical applications.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of nep inhibitor HAS-000129 crystal type free acid, calcium
Salt polymorphic and its preparation method and application.
Background technique
Neutral endopeptidase (EC 3.4.24.11；Enkephalinase；It must peptase；It NEP is) that one kind can be in aromatic amino acid
The metalloproteinases comprising zinc of various peptide substrates is cracked on amino terminal.The substrate of this enzyme includes atrial natriuretic peptide without limitation
(ANF, also referred to as ANP), brain natriuretic peptide (BNP), met and leu enkephalins, bradykinin, neurokinin A and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2.
ANF is family's vasodilation, diuresis and antihypertensive peptides, and a kind of form --- ANF 99-126 is in heart
The circulation peptide hormone discharged in dilatation by heart.The function of ANF is to maintain the homeostasis and adjusting blood pressure of salt and water.
ANF is in the circulating cycle by least two process rapid inactivations: receptor-mediation removing and the enzyme-deactivating carried out in NEP.NEP inhibits
Agent enhances the low blood pressure after experimental animal carries out pharmacology ANF injection, diuresis, promotees natruresis and plasma ANF response.Pass through
The enhancing for the ANF that two kinds of specific nep inhibitors carry out, 1988, generically disclosing in United States Patent (USP) US4749688 could
To enhance ANF with NEP.The same year discloses Thiorphan (thiorphan) and kelatorphan in United States Patent (USP) US4740499
It can be used for enhancing the application of atrial natriuretic peptide.In addition, nep inhibitor can reduce blood pressure and play the effect of ANF- sample such as in some forms
Experimental hypertension in diuresis and increase by 3 ', 5 '-monophosphate of cyclic guanosine (cGMP) excretion effect.Because of the antibody of ANF
The reduction of blood pressure will be offset, so the antihypertensive function of nep inhibitor is mediated by ANF.For a long time and without control
Hypertensive vascular disease finally will lead to the various pathological changes of the target organ such as heart and kidney.Lasting hypertension can result in
The incidence of apoplexy increases.Therefore, need to assess the effect of antihypertensive therapy strongly, i.e., in addition to blood pressure reduce with
Outer other cardiovascular endpoints events are checked the benefit to be further discovered that combination therapy.
The 4-Aminobutanoicacid that a kind of biaryl substituted is disclosed in Shanghai Han Sen house journal CN201410001940.2 spreads out
Biology, such compound are found to have apparent NEP inhibitory activity, wherein a most representative compound is 1 institute of formula
Show (9R, 11S) -11- ([1,1 '-biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8,13- trioxy- -3,5,7- trioxa -
12- azepine hexadecane -16- is sour (also known as HAS-000129).
HAS-000129 is grease in the prior art, it is difficult to be purified, dissolvent residual is difficult to up to standard, material stability, storage
It deposits, weigh in the presence of very big problem, and be difficult to that oral solid formulation is made, be unfavorable for pharmacy exploitation and industrial production.
Summary of the invention
It is of the existing technology in order to solve the problems, such as, improve HAS-000129 physicochemical property.There is an urgent need to by HAS-
000129 grease is transformed into solid state, especially crystalline state to meet pharmacy exploitation and industrial demand.Invention
People has extensively studied the different coherent condition of HAS-000129, and HAS-000129 crystal type is had developed in prior art basis
Free acid, calcium salt crystalline solids, so that the physicochemical properties such as the crystallinity of HAS-000129, dissolubility, hygroscopicity obtain thoroughly
Change, substance chemical stabilization, conducive to storage and oral solid formulation exploitation.By the way that HAS-000129 is changed into from oily
Crystalline solid can achieve and the residual of organic solvent is isolated and purified, removed to it, improves chemical stability, preparation admittedly
In terms of body preparation convenience, there is apparent progress.
One aspect of the present invention provides a kind of HAS-000129 crystal type free acid (being appointed as crystal form I), and X-ray powder spreads out
Penetrating figure includes the peak at 6.4 ± 0.2 °, 15.9 ± 0.2 °, 20.8 ± 0.2 ° and 19.0 ± 0.2 ° of the angle of diffraction (2 θ).
As further preferred scheme, x-ray diffractogram of powder further include be located at 20.4 ± 0.2 °, 19.2 ±
Peak at 0.2 °, 26.0 ± 0.2 °, 18.0 ± 0.2 ° and 7.9 ± 0.2 ° of the angle of diffraction (2 θ).
As scheme still more preferably, x-ray diffractogram of powder further include be located at 25.70 ± 0.2 °, 7.5 ±
Peak at 0.2 °, 24.7 ± 0.2 °, 20.2 ± 0.2 °, 10.2 ± 0.2 ° and 16.5 ± 0.2 ° of the angle of diffraction (2 θ).
As most preferred scheme, the peak at the angle of diffraction (2 θ) shown in x-ray diffractogram of powder and Fig. 1 is substantially
Identical, X-ray powder diffraction data are as shown in table 1:
Table 1
It is measured with differential calorimetric scan instrument, the fusing point of HAS-000129 crystal type free acid (crystal form I) is 131.5 DEG C or so
(onset point).
Another aspect of the present invention also provides a kind of HAS-000129 calcium salt polymorphic (being appointed as crystal form I), X-ray powder
Diffraction pattern includes the peak at 20.8 ± 0.2 °, 11.3 ± 0.2 °, 3.9 ± 0.2 ° and 19.2 ± 0.2 ° of the angle of diffraction (2 θ).
As further preferred scheme, x-ray diffractogram of powder further include be located at 11.7 ± 0.2 °, 14.8 ±
0.2 °, 20.3 ± 0.2 °, 5.6 ± 0.2 °, 19.9 ± 0.2 °
As scheme still more preferably, x-ray diffractogram of powder further include be located at 13.5 ± 0.2 °, 5.9 ±
Peak at 0.2 °, 12.7 ± 0.2 °, 24.8 ± 0.2 °, 14.6 ± 0.2 ° and 31.6 ± 0.2 ° of the angle of diffraction (2 θ).
As most preferred scheme, the peak at the angle of diffraction (2 θ) shown in x-ray diffractogram of powder and Fig. 4 is substantially
Identical, X-ray powder diffraction data are as shown in table 2:
Table 2
| 2θ(°) | Intensity % | 2θ(°) | Intensity % |
| 3.9 | 55.2 | 14.8 | 40.9 |
| 5.6 | 34.5 | 19.2 | 45 |
| 5.9 | 31.7 | 19.9 | 33.2 |
| 8.7 | 26.3 | 20.3 | 39.6 |
| 11.3 | 70.1 | 20.8 | 100 |
| 11.7 | 41.7 | 23.8 | 27.1 |
| 12.7 | 30.9 | 24.8 | 30.9 |
| 13.5 | 32.2 | 31.6 | 27.4 |
| 14.6 | 28.1 |
Term " substantially the same " used herein about X-ray diffraction peak position means to consider typical peak position
With intensity variable.For example, it will be understood by those skilled in the art that peak position (2 θ) will cause to survey due to XRPD instrument difference
Magnitude is varied, and this variation is up to up to 0.2 ° sometimes sometimes.Further, it will be understood by those skilled in the art that XRPD sample system
Quadrat method, XRPD instrument, sample crystallinity, the factors such as amount of samples and crystal preferred orientation will lead to sample XRPD diffraction pattern
The change of middle relative peak intensities.
Another aspect of the present invention additionally provides the preparation method of HAS-000129 crystal type free acid, including,
1) HAS-000129 free acid is dissolved in suitable organic solvent；
2) it is added with stirring appropriate anti-solvent to solution to occur muddy or a small amount of crystal seed is added, continues stirring and crystallizing；
3) it is separated by solid-liquid separation and obtains HAS-000129 crystal type free acid.
As further preferred scheme, the step 1) organic solvent is selected from alcohols, chloralkane, ketone, ethers, ring
Or mixtures thereof ethers, esters, alkanes, cycloalkane, benzene class, amides, sulfoxide type organic solvent；Including but not limited to
Following solvent: methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N,
Dinethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, methylene chloride, trichloroethanes, carbon tetrachloride, methyl
Tertbutyl ether, isopropyl ether, benzene,toluene,xylene or combinations thereof object；Ethyl acetate, isopropyl acetate, methylene chloride, first
Base tertbutyl ether, isopropyl ether or combinations thereof object.
The anti-solvent includes but is not limited to following solvent: normal heptane, n-hexane, isooctane, pentane, hexamethylene, ring
Pentane, ether, water or combinations thereof object；It is preferred that normal heptane, n-hexane, ether or combinations thereof object.
The dissolution refers to the general operation of those skilled in the art, and appropriate can usually heat makes raw material
Dissolution or dissolved clarification increase the dosage of solvent perhaps to make dissolution of raw material or dissolved clarification or its technical solution modify or wait
With replacement, should all cover within summary of the invention of the invention.
As further preferred scheme, concrete operations are as follows: 1) addition is suitable in HAS-000129 free acid has
Solvent dissolution, forms it into the solution that concentration is 1-200mg/mL, and the organic solvent is selected from ethyl acetate, isopropyl acetate
Ester, methylene chloride, methyl tertiary butyl ether(MTBE), isopropyl ether or combinations thereof object；2) appropriate anti-solvent normal heptane, just oneself are added with stirring
There is muddiness in alkane, ether or combinations thereof object to solution, and the amount of anti-solvent is 1-10 times of volume ratio of recrystallisation solvent, continue stirring analysis
It is brilliant；3) it is separated by solid-liquid separation and obtains HAS-000129 crystal type free acid.
As further preferred scheme, concrete operations are as follows: 1) addition is suitable in HAS-000129 free acid has
Solvent is heated to 30~80 DEG C and makes it dissolve, and forms it into the solution that concentration is 1-200mg/mL, and the organic solvent is selected from
Ethyl acetate, isopropyl acetate, methylene chloride, methyl tertiary butyl ether(MTBE), isopropyl ether or combinations thereof object；2) slow cooling is to 20~30
DEG C, the homology crystalline solid of mass ratio 0.1-10.0% is added with stirring as crystal seed, continues stirring and crystallizing；3) it is separated by solid-liquid separation and obtains
HAS-000129 crystal type free acid.
Another aspect of the present invention provides a kind of polymorphous preparation method of HAS-000129 calcium salt, including,
1) HAS-000129 free acid is dissolved or dispersed in water-miscible organic solvent or aqueous water-miscible organic solvent
In, preparation, which is mixed, with equivalent or excessive suitable alkali generates the corresponding salt of HAS-000129；
2) above-mentioned HAS-000129 salt system is mixed with calcium salt, continues to be stirred to react precipitation HAS-000129 calcium salt crystalline substance
Body；
3) it is separated by solid-liquid separation and obtains HAS-000129 calcium salt polymorphic.
Another aspect of the present invention also provides a kind of polymorphous preparation method of HAS-000129 calcium salt, including,
1) HAS-000129 free acid is dissolved in water-miscible organic solvent, is mixed with equivalent or excessive suitable alkali
Preparation generates the corresponding salt of HAS-000129；
2) above-mentioned HAS-000129 salt system is mixed with calcium salt, continues to be stirred to react, sediment is precipitated, is filtered to remove
Sediment；
3) above-mentioned mother liquor is collected, by solvent flashing or is concentrated to get HAS-000129 calcium salt polymorphic.
As further preferred scheme, the step 1) water-miscible organic solvent is selected from alcohols, ketone, amides, Asia
Or mixtures thereof sulfone class organic solvent；Including but not limited to following solvent: methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol,
Acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, n,N-Dimethylformamide, dimethyl sulfoxide or combinations thereof object.
As further preferred scheme, the suitable alkali be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate,
Sodium formate, sodium propionate, sodium acrylate, sodium benzoate, potassium hydroxide, potassium carbonate, saleratus, potassium acetate, potassium formate, propionic acid
Or mixtures thereof potassium, potassium acrylate, Potassium Benzoate；It is preferred that sodium bicarbonate, saleratus；The calcium salt is selected from calcium chloride, bromination
Calcium, calcium iodide, calcium nitrate, calcium chlorate, calcium hypochlorite, or mixtures thereof Calcium perchlorate, calcium lactate, calcium gluconate；It preferably is selected from
Calcium chloride.
The polymorphous method of above two preparation HAS-000129 calcium salt, step 2) continue stirring to precipitation sediment, institute
Stating sediment may be HAS-000129 calcium salt, it is also possible to the corresponding salt that alkali is added in step 1) be added, difference essentially consists in
Whether entire crystallizing system is aqueous, and crystallizing system is aqueous will to be precipitated HAS-000129 calcium salt.And the calcium salt being added can be added with solid
Enter, is also possible to be added after calcium salt is dissolved in water or calcium salt is dissolved in suitable organic solvent and is added.
Another aspect of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition is comprising before treatment effective dose
State HAS-000129 crystal type free acid, its calcium salt polymorphic and pharmaceutically acceptable carrier or excipient.
Another aspect provides aforementioned HAS-000129 crystal type free acid, its calcium salt polymorphic or its drugs
Purposes of the composition in preparation treatment or prevention disease related with neutral endopeptidase, angiocarpy, antihypertensive drug.
More effective antihypertensive therapy is produced and improve effect and there is higher response rate, whether for
Accelerated hypertension, essential hypertension, renovascular hypertension, diabetic hypertension, simple systolic hypertension or right
It is not always the case for other secondary hypertensions.
Another aspect provides aforementioned HAS-000129 crystal type free acid, its calcium salt polymorphic or its drugs
Composition preparation treat or prevent acute and chronic heart failure as, congestive heart failure, left ventricle dysfunction, hypertrophic cardiomyopathy, sugar
It urinates in characteristic of disease cardiomyopathy, supraventricular and heart ventricle arrhythmia, atrial fibrillation, auricular flutter or harmful vascular remodeling drug
Purposes.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically/it is pharmaceutically acceptable
Salt or pro-drug and other chemical constituents mixture or other components such as physiology/pharmaceutically acceptable load
Body or excipient.The purpose of pharmaceutical composition is the administration promoted to organism, plays life in turn conducive to the absorption of active constituent
Object activity.
Detailed description of the invention
Fig. 1 is the x-ray diffractogram of powder of HAS-000129 free acid crystal form in embodiment 1, and abscissa is 2 θ of angle
(°), ordinate are intensity；
Fig. 2 is the DSC figure of HAS-000129 free acid crystal form in embodiment 1, and abscissa is temperature (DEG C), ordinate position heat
It flows (W/g).
Fig. 3 is the TGA figure of HAS-000129 free acid crystal form in embodiment 1, and abscissa is temperature (DEG C), and ordinate is to lose
Weight ratio (%).
Fig. 4 is the x-ray diffractogram of powder of HAS-000129 calcium salt crystal form in embodiment 5, and abscissa is 2 θ (°) of angle,
Ordinate is intensity；
Fig. 5 is the TGA figure of HAS-000129 calcium salt crystal form in embodiment 5, and abscissa is temperature (DEG C), and ordinate is weightlessness
Ratio (%).
Fig. 6 is the dissolution curve of HAS-000129 calcium salt capsule in embodiment 8, and abscissa is time (minute), ordinate
For release (%).
Fig. 7 is the dissolution curve of crystal type HAS-000129 free acid capsule in embodiment 9, and abscissa is (to divide the time
Clock), ordinate is release (%).
Specific embodiment
The spy of embodiment of the present invention will be further illustrated in specific embodiment and preparation method example presented below
Fixed aspect.The range of the following example will not limit the scope of the invention in any way.
Method and material
HAS-000129 crystal type free acid and its calcium salt polymorphic are characterized by their X-ray powder diffraction figure.Therefore,
Cu K α radiation is used havingGADDS (the general area diffraction detector system) CS's operated in reflection
The X-ray powder diffraction figure of the salt is acquired on Bruker D8Discover x-ray powder diffraction instrument.Tube voltage and the magnitude of current
It is respectively set to 40kV and 40mA acquisition scans.In the period of scanning sample 60 seconds within the scope of 3.0 ° to 40 ° of 2 θ.For 2 θ tables
Diffractometer is calibrated using corundum standard product in the peak position shown.In usually 20 DEG C -30 DEG C of all analyses of implementation at room temperature.Make
With the GADDS for 4.1.14T editions WNT software, acquisition and integration data.There are 9.0.0.2 editions Eva using distribution in 2003
DiffracPlus software, analyze diffraction pattern.The preparation of XRPD sample, by the way that sample as on monocrystalline silicon piece, is used glass
Piece or equivalent press sample powder flat with the surface for ensuring sample and have height appropriate.Then sample holder is put into
Bruker XRPD instrument, and x-ray diffractogram of powder is acquired using above-described instrument parameter.By including below a variety of
Factor generates measurement difference relevant to this kind of X-ray powder diffraction analysis result: (a) sample preparation object (such as height of specimen)
In error, (b) instrument error, (c) calibrate difference, (d) personal error (be included in measurement peak position when occur those of
Error), and (e) property (such as preferred orientation error) of substance.Calibration error and sample height errors frequently result in all
Displacement of the peak in the same direction.In general, this calibration factor will keep the peak position of measurement consistent with expected peak position
And it can be in the range of value ± 0.2 ° expected 2 θ.
Each polymorphous 2 θ (°) value of angle and intensity value (% as peak-peak) obtained by the embodiment of the present invention have been included in
In table 1- table 2.
Raw materials used HAS-000129 free acid grease is according to Chinese patent in the embodiment of the present invention
What CN201410001940.2 embodiment 11 was prepared, other raw materials or city-level are commercial product.
Embodiment 1
It weighs 20mg HAS-000129 free acid (oily) to be placed in 4.0mL vial, the positive solvent of 0.5mL is then added
Methyl tertiary butyl ether(MTBE) stirs dissolved clarification, is slowly added to 2.0mL anti-solvent normal heptane, stirs 48 hours for (20-25 DEG C) at room temperature, Gu
The isolated HAS-000129 crystal type free acid of liquid, x-ray diffractogram of powder are as shown in Figure 1.
With the fusing point of differential calorimetric scan instrument (DSC, model Perkins Elmer 8500) measurement free acid crystal form.Measurement
Condition is that 160 degrees Celsius are heated to from room temperature, and heating rate is 10 centigrade per minutes, and heating carries out in a nitrogen atmosphere, nitrogen
Throughput is that 20mL is per minute.The DSC figure of free acid crystal form is as shown in Figure 2.The fusing point (onset point) of free acid crystal form are as follows:
131.5 degree Celsius.
With the thermal weight loss situation of thermogravimetric analyzer (TGA, model Netzsch F3) measurement free acid crystal form.Measuring condition is
350 degrees Celsius are heated to from room temperature, heating rate is 10 centigrade per minutes, and heating carries out in a nitrogen atmosphere, nitrogen flow
It is per minute for 50mL.The TGA figure of free acid crystal form is as shown in Figure 3.It is hardly weightless within 100 degrees Celsius, therefore can sentence
Determining compound free acid crystal form is anhydrous crystal forms.
Embodiment 2
It weighs 20mg HAS-000129 free acid (oily) to be placed in 4.0mL vial, the positive solvent of 0.3mL is then added
Isopropyl acetate is heated to 50 DEG C of stirring dissolved clarifications, is slowly added to 2.0mL anti-solvent n-hexane, is cooled to room temperature (20-25 DEG C),
Continue stirring 48 hours, separation of solid and liquid obtains HAS-000129 crystal type free acid, and x-ray diffractogram of powder is basic with Fig. 1
Unanimously.
Embodiment 3
It weighs 20mg HAS-000129 free acid (oily) to be placed in 4.0mL vial, 0.5mL acetic acid second is then added
Ester/n-hexane (20: 80, v/v) is heated to 60 DEG C of stirring dissolved clarifications, is cooled to room temperature (20-25 DEG C), is slowly added to 0.2mg implementation
1 crystal of example continues stirring 72 hours, and separation of solid and liquid obtains HAS-000129 crystal type free acid, x-ray diffractogram of powder with
Fig. 1 is almost the same.
Embodiment 4
It weighs 20mg HAS-000129 free acid (oily) to be placed in 4.0mL vial, 0.2mL dichloromethane is then added
Alkane is heated to 40 DEG C of stirring dissolved clarifications, is cooled to room temperature (20-25 DEG C), is slowly added to 1 crystal of 0.2mg embodiment, continues stirring 72
Hour, separation of solid and liquid obtains HAS-000129 crystal type free acid, and x-ray diffractogram of powder is almost the same with Fig. 1.
Embodiment 5
300mL acetone, stirring and dissolving are added in 30g (58.45mmol) HAS-000129 free acid (oily).It weighs
4.91g(58.45mmol)NaHCO3, the dissolution of 550mL water is added, is slowly dropped in above-mentioned acetone soln, is added dropwise, continues
It is stirred to react 1h, 40 DEG C of rotary evaporation solution to no fraction (remove acetone, collect fraction about 250mL).It is anhydrous to weigh 3.24g
CaCl2(29.3mmol), which is added in 450mL water, to be dissolved, and is slowly added dropwise into above-mentioned fraction, is added dropwise, continues to be stirred to react
For 24 hours, it filters, 40 DEG C of vacuum drying 20h obtain white solid 29.72g, and x-ray diffractogram of powder is as shown in Figure 4.
With the thermal weight loss situation of thermogravimetric analyzer (TGA, model TA Q500) measurement HAS-000129 calcium salt crystal form.Measurement
Condition is that 350 degrees Celsius are heated to from room temperature, and heating rate is 10 centigrade per minutes, and heating carries out in a nitrogen atmosphere, nitrogen
Throughput is that 50mL is per minute.The TGA figure of HAS-000129 calcium salt crystal form is as shown in the figure.Within 100 degrees Celsius it is weightless about
3.0%, it is that may determine that the crystal form is that (monohydrate is theoretical for HAS-000129 calcium salt monohydrate since dehydration causes
Dehydration is weightless 3.2%).
Embodiment 6
0.4mL methanol, stirring and dissolving are added in 20mg (0.039mmol) HAS-000129 free acid (oily).It weighs
2.4mg (0.043mmol) KOH is added the dissolution of 1.0mL methanol, is slowly dropped in above-mentioned HAS-000129 methanol solution, is added dropwise
It finishes, continues to be stirred to react 2h.Weigh 2.6mg (0.023mmol) anhydrous CaCl2It is added in 1.0mL methanol and dissolves, be slowly added dropwise
It in above-mentioned reaction system, is added dropwise, continues to be stirred to react for 24 hours, be filtered to remove solid, collect filtrate, be concentrated to dryness,
Then 40 DEG C of vacuum drying 20h obtain white solid 20.2mg, and x-ray diffractogram of powder is consistent with Fig. 4.
Embodiment 7
In order to compare the grease of HAS-000129 free acid, the chemical stability of crystal type and calcium salt, by HAS-
000129 free acid grease, crystal type HAS-000129 free acid (being prepared in this patent embodiment 1) and HAS-000129
Calcium salt (preparing in this patent embodiment 5) is placed in 80 degrees Celsius of insulating box, is placed after a week, is measured with high-efficient liquid phase technique pure
Degree, stability test result are as follows:
Test proves: the crystal type of HAS-000129 free acid and the chemical stability of calcium salt are remote after being tested by thermal acceleration
Better than HAS-000129 free acid grease.
Embodiment 8
(HAS-000129 calcium salt capsule)
| Component | Weight (mg) | Weight percent |
| HAS-000129 calcium salt monohydrate | 25 | 62.2% |
| Microcrystalline cellulose | 7 | 17.4% |
| Low-substituted hydroxypropyl cellulose (L-HPC) | 5 | 12.4% |
| Crospovidone (PVP) | 2 | 5.0% |
| Talcum powder (Talc) | 0.4 | 1.0% |
| Colloidal silicon dioxide | 0.2 | 0.5% |
| Magnesium stearate | 0.6 | 1.5% |
| It is total | 40.2 | 100% |
1, capsule preparation method thereof
Magnesium stearate, colloidal silicon dioxide and microcrystalline cellulose are sieved by 30 meshes first.It then will be above-mentioned
Mixture, active constituent HAS-000129 calcium salt, low-substituted hydroxypropyl cellulose (L-HPC) and povidone, talcum powder, colloidal state two
Silica mixes about 120 turns in hopper mixing machine.The mixture is suppressed using the roller press pressure of 30kN.After compacting,
The mixture is ground using grinder and is sieved through 18 meshes, and final interior phase or particle is obtained.By granule filling in capsule,
Capsule is made.
2, measuring method is dissolved out
The dissolution that gained capsule carries out is tested and is completed on ERWEKA DT827LH digestion instrument, specific dissolving-out method and item
Part are as follows: this product is taken, according to Chinese Pharmacopoeia (2010 editions, two) dissolution method (the second method of annex X C), with pH6.8 phosphate
Buffer 900ml is dissolution medium, and revolving speed is 100 turns per minute, is operated according to methods.It is sampled when 10,20,40,60 minutes
10ml, HPLC measure drug concentration, calculate release percentage.
3, process and result are tested
Weigh HAS-000129 calcium salt monohydrate 25g, and weigh auxiliary material by said ratio, by weighed drug and
Auxiliary material is mixed 24 hours with V-type powder mixer, loads capsule with capsule board.Capsule is gelatine capsule, model zero.Each capsule
Loading amount be 40.2mg ± 5%.Gained capsule takes 6 to do Dissolution Rate Testing, experimental condition are as follows: dissolution medium is 6.8 phosphoric acid of pH
Buffer, 37 degrees Celsius of temperature, basket method, samples when 10,20,40,60 minutes by 100 revs/min of revolving speed.HAS-
The capsule dissolution result of 000129 calcium salt is shown in Fig. 6.
Embodiment 9
(crystal type HAS-000129 free acid capsule)
1, capsule preparation method thereof
Magnesium stearate, colloidal silicon dioxide and microcrystalline cellulose are sieved by 30 meshes first.It then will be above-mentioned
Mixture, active constituent crystal type HAS-000129 free acid, low-substituted hydroxypropyl cellulose (L-HPC) and povidone, talcum
Powder, colloidal silicon dioxide mix about 120 turns in hopper mixing machine.The mixing is suppressed using the roller press pressure of 30kN
Object.After compacting, the mixture is ground using grinder and is sieved through 18 meshes, final interior phase or particle is obtained.By particle
It is filling in capsule, capsule is made.
2, measuring method is dissolved out
The dissolution that gained capsule carries out is tested and is completed on ERWEKA DT827LH digestion instrument, specific dissolving-out method and item
Part are as follows: this product is taken, according to Chinese Pharmacopoeia (2010 editions, two) dissolution method (the second method of annex X C), with pH6.8 phosphate
Buffer 900ml is dissolution medium, and revolving speed is 100 turns per minute, is operated according to methods.It is sampled when 10,20,40,60 minutes
10ml, HPLC measure drug concentration, calculate release percentage.
3, process and result are tested
Weigh crystal type HAS-000129 free acid 25g, and weigh auxiliary material by said ratio, by weighed drug and
Auxiliary material is mixed 24 hours with V-type powder mixer, loads capsule with capsule board.Capsule is gelatine capsule, model zero.Each capsule
Loading amount be 40.2mg ± 5%.Gained capsule takes 6 to do Dissolution Rate Testing, experimental condition are as follows: dissolution medium is 6.8 phosphoric acid of pH
Buffer, 37 degrees Celsius of temperature, basket method, samples when 10,20,40,60 minutes by 100 revs/min of revolving speed.Crystal type
HAS-000129 free acid capsule dissolution result is shown in Fig. 7.
Inventor has equally attempted oily HAS-000129 free acid being prepared into capsule, still, due to grease with it is upper
It states after auxiliary material mixes into lumps, can not be evenly dispersed at mobility powder, the filling of capsule can not be carried out.Therefore oily HAS-
Capsule can not be made in 000129 free acid.
Test proof, the HAS-000129 crystal type free acid and its calcium salt that the present invention is prepared, it may be convenient to make
It is standby to become oral solid formulation, and its grease can not then carry out oral solid formulation exploitation.
It is finally it should be noted that of the invention the above examples are only used to illustrate the technical scheme of the present invention and are not limiting,
Although being described the invention in detail referring to preferred embodiment, those skilled in the art should understand that, it can be right
The technical solution of invention is modified or replaced equivalently, without departing from the spirit and scope of the technical solution of the present invention, should all
Cover in scope of the presently claimed invention.
Claims (23)
1. (9R, 11S) -11- shown in a kind of formula 1 ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8,13- tri-
Oxo -3,5, the crystal type free acid of 7- trioxa -12- azepine hexadecane -16- acid,
Its x-ray diffractogram of powder includes spreading out positioned at 6.4 ± 0.2 °, 15.9 ± 0.2 °, 20.8 ± 0.2 ° and 19.0 ± 0.2 °
Peak at firing angle (2 θ).
2. crystal type free acid according to claim 1, which is characterized in that x-ray diffractogram of powder further includes being located at
Peak at 20.4 ± 0.2 °, 19.2 ± 0.2 °, 26.0 ± 0.2 °, 18.0 ± 0.2 ° and 7.9 ± 0.2 ° of 2 θ of the angle of diffraction.
3. crystal type free acid according to claim 2, which is characterized in that x-ray diffractogram of powder further comprises
Positioned at 25.70 ± 0.2 °, 7.5 ± 0.2 °, 24.7 ± 0.2 °, 20.2 ± 0.2 °, 10.2 ± 0.2 ° and 16.5 ± 0.2 ° of diffraction
Peak at 2 θ of angle.
4. crystal type free acid according to claim 3, which is characterized in that shown in x-ray diffractogram of powder and Fig. 1
Peak at the angle of diffraction (2 θ) is substantially the same.
5. (9R, 11S) -11- shown in a kind of formula 1 ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8,13- tri-
Oxo -3,5, the calcium salt monohydrate crystal form of 7- trioxa -12- azepine hexadecane -16- acid,
Its x-ray diffractogram of powder includes spreading out positioned at 20.8 ± 0.2 °, 11.3 ± 0.2 °, 3.9 ± 0.2 ° and 19.2 ± 0.2 °
Peak at 2 θ of firing angle.
6. calcium salt monohydrate crystal form according to claim 5, which is characterized in that x-ray diffractogram of powder further includes position
Peak at 11.7 ± 0.2 °, 14.8 ± 0.2 °, 20.3 ± 0.2 °, 5.6 ± 0.2 °, 19.9 ± 0.2 ° of 2 θ of the angle of diffraction.
7. calcium salt monohydrate crystal form according to claim 6, which is characterized in that x-ray diffractogram of powder is further gone back
Including positioned at 13.5 ± 0.2 °, 5.9 ± 0.2 °, 12.7 ± 0.2 °, 24.8 ± 0.2 °, 14.6 ± 0.2 ° and 31.6 ± 0.2 °
Peak at 2 θ of the angle of diffraction.
8. calcium salt monohydrate crystal form according to claim 7, which is characterized in that shown in x-ray diffractogram of powder and Fig. 4
The peak at 2 θ of the angle of diffraction shown is substantially the same.
9. (9R, 11S) -11- shown in formula 1 according to claim 1 ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- tri-
Methyl -4,8,13- trioxy- -3,5, the preparation method of the crystal type free acid of 7- trioxa -12- azepine hexadecane -16- acid,
Include:
1) by -2,6,9- trimethyl -4,8 of (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl), 13- trioxy- -3,5,7-
Trioxa -12- azepine hexadecane -16- acid free acid is dissolved in suitable organic solvent；
2) it is added with stirring appropriate anti-solvent to solution and muddiness occurs, or crystal seed is added, continue stirring and crystallizing；
3) it is separated by solid-liquid separation and obtains (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8, tri- oxygen of 13-
Generation -3,5,7- trioxa -12- azepine hexadecane -16- acid crystal type free acid；
Step 1) the organic solvent is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, four
Hydrogen furans, dioxane, n,N-Dimethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, methylene chloride, trichlorine
Ethane, carbon tetrachloride, methyl tertiary butyl ether(MTBE), isopropyl ether, benzene,toluene,xylene or combinations thereof object；
Step 2) the anti-solvent is selected from normal heptane, n-hexane, isooctane, pentane, hexamethylene, pentamethylene, ether, water or its group
Close object.
10. according to the method described in claim 9, it is characterized in that, the step 1) organic solvent is selected from ethyl acetate, acetic acid
Isopropyl ester, methylene chloride, methyl tertiary butyl ether(MTBE), isopropyl ether or combinations thereof object；Step 2) the anti-solvent is selected from normal heptane, just oneself
Alkane, ether or combinations thereof object.
11. preparation method according to claim 10, which is characterized in that including,
1) in (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8,13- trioxy- -3,5,7-
Suitable organic solvent dissolution is added in trioxa -12- azepine hexadecane -16- acid free acid, forming it into concentration is 1-
The solution of 200mg/mL, the organic solvent are selected from ethyl acetate, isopropyl acetate, methylene chloride, methyl tertiary butyl ether(MTBE), isopropyl
Ether or combinations thereof object；
2) be added with stirring appropriate anti-solvent to solution occur it is muddy, the anti-solvent be selected from normal heptane, n-hexane, ether or its
Composition, the volume of anti-solvent are 1-10 times of the step 1) organic solvent, continue stirring and crystallizing；
3) it is separated by solid-liquid separation and obtains (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8, tri- oxygen of 13-
Generation -3,5,7- trioxa -12- azepine hexadecane -16- acid crystal type free acid.
12. preparation method according to claim 10, which is characterized in that including,
1) in (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8,13- trioxy- -3,5,7-
Suitable organic solvent is added in trioxa -12- azepine hexadecane -16- acid free acid, is heated to 30~80 DEG C and makes it dissolve shape
The solution for being 1-200mg/mL at concentration, the organic solvent are selected from ethyl acetate, isopropyl acetate, methylene chloride, methyl- tert
Butyl ether, isopropyl ether or combinations thereof object；
2) slow cooling is to 20~30 DEG C, be added with stirring with (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,
The mass ratio of 9- trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid free acid is 0.1-
10.0% homology crystalline solid continues stirring and crystallizing as crystal seed；
3) it is separated by solid-liquid separation and obtains (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8, tri- oxygen of 13-
Generation -3,5,7- trioxa -12- azepine hexadecane -16- acid crystal type free acid.
13. (9R, 11S) -11- shown in formula 1 according to claim 5 ([1,1'- biphenyl] -4- ylmethyl) -2,6,9-
The preparation of the calcium salt monohydrate crystal form of trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid
Method, including,
1) by -2,6,9- trimethyl -4,8 of (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl), 13- trioxy- -3,5,7-
Trioxa -12- azepine hexadecane -16- acid free acid is dissolved or dispersed in water-miscible organic solvent or aqueous water solubility is organic
In solvent, mixes preparation with equivalent or excessive suitable alkali and generate (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -
The corresponding salt of 2,6,9- trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid；Wherein, work as institute
State water-miscible organic solvent it is not aqueous when, the solution of the alkali contains water；
2) by above-mentioned (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8, trioxy- -3 13-,
5,7- trioxa -12- azepine hexadecane -16- silicate systems are mixed with calcium salt, continue to be stirred to react precipitation (9R, 11S) -11-
([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -
16- acid calcium salt crystal；
3) it is separated by solid-liquid separation and obtains (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8, tri- oxygen of 13-
Generation -3,5,7- trioxa -12- azepine hexadecane -16- acid calcium salt monohydrate crystal form.
14. (9R, 11S) -11- shown in formula 1 according to claim 5 ([1,1'- biphenyl] -4- ylmethyl) -2,6,9-
The preparation of the calcium salt monohydrate crystal form of trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid
Method, including,
1) by -2,6,9- trimethyl -4,8 of (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl), 13- trioxy- -3,5,7-
Trioxa -12- azepine hexadecane -16- acid free acid is dissolved in water-miscible organic solvent, with equivalent or excessive suitable alkali phase
It is mixed with generation (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8, trioxy- -3 13-,
The corresponding salt of 5,7- trioxa -12- azepine hexadecane -16- acid；
2) by above-mentioned (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyls -4,8, trioxy- -3 13-,
5,7- trioxa -12- azepine hexadecane -16- silicate systems are mixed with calcium salt, continue to be stirred to react, and sediment, filtering is precipitated
Remove sediment；
3) above-mentioned mother liquor is collected, by solvent flashing or is concentrated to get (9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -
2,6,9- trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid calcium salt monohydrate crystal form.
15. preparation method described in 3 or 14 according to claim 1, which is characterized in that step 1) the water-miscible organic solvent choosing
From alcohols, ketone, amides, sulfoxide type organic solvent or combinations thereof object.
16. preparation method according to claim 15, which is characterized in that the step 1) water-miscible organic solvent is selected from first
Alcohol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N, N- dimethyl methyl
Amide, dimethyl sulfoxide or combinations thereof object.
17. preparation method described in any one of 3-14,16 according to claim 1, which is characterized in that the suitable alkali is selected from
Sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, sodium formate, sodium propionate, sodium acrylate, sodium benzoate, potassium hydroxide, carbonic acid
Or mixtures thereof potassium, saleratus, potassium acetate, potassium formate, potassium propionate, potassium acrylate, Potassium Benzoate；The calcium salt is selected from chlorination
Calcium, calcium bromide, calcium iodide, calcium nitrate, calcium chlorate, calcium hypochlorite, or mixtures thereof Calcium perchlorate, calcium lactate, calcium gluconate.
18. preparation method according to claim 17, which is characterized in that the suitable alkali is selected from sodium bicarbonate, carbonic acid
Hydrogen potassium；The calcium salt is selected from calcium chloride.
19. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition include treatment effective dose it is aforementioned (9R,
11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- nitrogen
Miscellaneous hexadecane -16- acid crystal type free acid, its calcium salt monohydrate crystal form and pharmaceutically acceptable carrier or excipient.
20. ([1,1'- the biphenyl] -4- Ji Jia of (9R, 11S) -11- shown in formula 1 according to claim 1-4
Base) -2,6,9- trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid crystal type it is free
(9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- shown in acid, the described in any item formulas 1 of claim 5-8
The calcium salt monohydrate crystal form of trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid, right
It is required that purposes of the pharmaceutical composition described in 19 in the drug that preparation treats or prevents disease related with neutral endopeptidase.
21. ([1,1'- the biphenyl] -4- Ji Jia of (9R, 11S) -11- shown in formula 1 according to claim 1-4
Base) -2,6,9- trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid crystal type it is free
(9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- shown in acid, the described in any item formulas 1 of claim 5-8
The calcium salt monohydrate crystal form of trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid, right
It is required that purposes of the pharmaceutical composition described in 19 in the drug that preparation treats or prevents hypertension.
22. ([1,1'- the biphenyl] -4- Ji Jia of (9R, 11S) -11- shown in formula 1 according to claim 1-4
Base) -2,6,9- trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid crystal type it is free
(9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- shown in acid, the described in any item formulas 1 of claim 5-8
The calcium salt monohydrate crystal form of trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid, right
It is required that pharmaceutical composition described in 19 preparation treat or prevent accelerated hypertension, essential hypertension, renovascular hypertension,
Diabetic hypertension, simple systolic hypertension drug in purposes.
23. ([1,1'- the biphenyl] -4- Ji Jia of (9R, 11S) -11- shown in formula 1 according to claim 1-4
Base) -2,6,9- trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid crystal type it is free
(9R, 11S) -11- ([1,1'- biphenyl] -4- ylmethyl) -2,6,9- shown in acid, the described in any item formulas 1 of claim 5-8
The calcium salt monohydrate crystal form of trimethyl -4,8,13- trioxy- -3,5,7- trioxa -12- azepine hexadecane -16- acid, right
It is required that pharmaceutical composition described in 19 treats or prevents acute and chronic heart failure, congestive heart failure, left ventricle dysfunction, fertilizer in preparation
Thickness cardiomyopathy, diabetes cardiomyopathy, supraventricular and heart ventricle arrhythmia, atrial fibrillation, auricular flutter or harmful
Purposes in vascular remodeling drug.
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| CN2014107254579 | 2014-12-03 | ||
| PCT/CN2015/095823 WO2016086798A1 (en) | 2014-12-03 | 2015-11-27 | Nep inhibitor crystalline free acid, calcium salt polymorph of same, preparation method for same, and applications thereof |
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| US20140045906A1 (en) * | 2012-08-08 | 2014-02-13 | Melissa Fleury | Neprilysin inhibitors |
| CN103906509A (en) * | 2011-11-02 | 2014-07-02 | 施万制药 | Neprilysin inhibitors |
| CN103896796A (en) * | 2009-05-28 | 2014-07-02 | 诺华股份有限公司 | Substituted Aminopropionic Derivatives as Neprilysin inhibitors |
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| MY151993A (en) * | 2007-01-12 | 2014-07-31 | Novartis Ag | Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid |
| AR076706A1 (en) * | 2009-05-28 | 2011-06-29 | Novartis Ag | AMINOBUTIRIC DERIVATIVES REPLACED AS NEPRILISINE INHIBITORS |
| CN104230865B (en) * | 2013-06-13 | 2018-01-09 | 上海翰森生物医药科技有限公司 | 4 amino butyric acid derivatives of biaryl substituted and its production and use |
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| CN103896796A (en) * | 2009-05-28 | 2014-07-02 | 诺华股份有限公司 | Substituted Aminopropionic Derivatives as Neprilysin inhibitors |
| CN103906509A (en) * | 2011-11-02 | 2014-07-02 | 施万制药 | Neprilysin inhibitors |
| US20140045906A1 (en) * | 2012-08-08 | 2014-02-13 | Melissa Fleury | Neprilysin inhibitors |
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