CN106032361A - LCZ-696 novel crystal form and preparation method thereof - Google Patents
LCZ-696 novel crystal form and preparation method thereof Download PDFInfo
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- CN106032361A CN106032361A CN201510106391.XA CN201510106391A CN106032361A CN 106032361 A CN106032361 A CN 106032361A CN 201510106391 A CN201510106391 A CN 201510106391A CN 106032361 A CN106032361 A CN 106032361A
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- deuterated
- hydrate
- valsartan
- ahu
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000013078 crystal Substances 0.000 title abstract description 9
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 title abstract description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims abstract description 14
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 claims abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 19
- 229960004699 valsartan Drugs 0.000 claims description 19
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 10
- 229940011051 isopropyl acetate Drugs 0.000 claims description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000005855 radiation Effects 0.000 claims description 5
- 206010019280 Heart failures Diseases 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 claims 1
- 229910052805 deuterium Inorganic materials 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 2
- 238000004566 IR spectroscopy Methods 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000002411 thermogravimetry Methods 0.000 description 5
- 108050000824 Angiotensin II receptor Proteins 0.000 description 4
- 102000008873 Angiotensin II receptor Human genes 0.000 description 4
- 206010007558 Cardiac failure chronic Diseases 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 102000005862 Angiotensin II Human genes 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 101150059573 AGTR1 gene Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100021202 Desmocollin-1 Human genes 0.000 description 2
- 108010061435 Enalapril Proteins 0.000 description 2
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 2
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 2
- 102000003729 Neprilysin Human genes 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 2
- 229960000873 enalapril Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of medicinal chemistry, and specifically relates to an LCZ-696 novel crystal form and a preparation method thereof. The novel crystal is deuterated hydrate of [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethyoxylcarbonyl-1-butylcarbamoyl)propionic acid-(S)-3'-methyl-2'-(valeryl{2''-(tetrazole-5-yl)biphenyl-4'-ylmethyl}amino)butyric acid] trisodium. The provided crystal form has a good chemical stability and crystal form stability, can be better dissolved in ethanol and water, and has a good pharmaceutical application prospect.
Description
Technical field
The invention belongs to technical field of medical chemistry, a kind of novel crystal forms being specifically related to LCZ-696 and preparation method thereof.
Background technology
Angiotensin II is most important ingredient in angiotensin, and it can be mutual with the receptor on target cells
Effect.The two kinds of receptor subtypes being currently known Angiotensin II are respectively AT1 and AT2.Research finds, angiotensin
Receptor blocking agent (ARBs, angiotensin-ii antagonist) can be by stoping Angiotensin II with it in blood vessel wall
Receptor combines, thus causes blood pressure to reduce.Owing to AT1 receptor can be suppressed, so this type of antagonist may be used for anti-high blood
Pressure, or be used for treating congestive heart failure and other indication.
LCZ-696, chemical name is [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) third
Acid-(S)-3 '-methyl-2 '-(valeryl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butanoic acid] trisodium 2.5 hydrate, have
Chemical constitution shown in Formulas I, by valsartan (Valsartan) and nep inhibitor prodrug AHU-377 according to mol ratio
(1:1) constitute, be first II type angiotensin receptor (AT2) developed of Novartis (Novartis) and enkephalinase (neprilysin)
Double inhibitor, is currently used primarily in the treatment of chronic heart failure and hypertension.
Existing clinical testing data shows, LCZ-696 has the binding mode of uniqueness, shows and surmounts conventional medicine more
High security, is believed to reduce the strain of failure heart；Compared with clinical criteria medicine enalapril (enalapril),
LCZ-696 can significantly reduce cardiovascular disease mortality rate and significantly improve patients ' life quality.
At present, CN101098689A and CN102702119A individually discloses [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-
Ethoxy carbonyl-1-butylcarbamoyl) propanoic acid-(S)-3 '-methyl-2 '-(valeryl 2 " and-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } ammonia
Base) butanoic acid] trisodium 2.5 hydrate and 0.5 hydrate and preparation method thereof.But current existing document is also not disclosed [3-((1S, 3R)-1-
Biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propanoic acid-(S)-3 '-methyl-2 '-(valeryl 2 "-(tetrazolium-5-base)
Biphenyl-4 '-ylmethyl } amino) butanoic acid] the deuterated hydrate of trisodium, the present invention completes based on this.
Summary of the invention:
First aspect present invention provides a kind of [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl)
Propanoic acid-(S)-3 '-methyl-2 '-(valeryl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butanoic acid] the deuterated hydrate of trisodium；
Wherein, containing deuterated water (D in every mole of described deuterated hydrate2O) molal quantity is 2.1～2.9, preferably 2.2～2.7, optimum
Select 2.5.
Specifically, described deuterated hydrate is crystal form, it is characterised in that use Cu-Ka radiation, with 2 θ angle tables
The X-ray powder diffraction shown, at 4.2 ± 0.2 °, 5.2 ± 0.2 °, has diffraction maximum at 12.5 ± 0.2 °；
More specifically, described deuterated hydrate, it is characterised in that use Cu-Ka radiation, the X-represented with 2 θ angles
Ray powder diffraction, at 4.2 ± 0.2 °, 5.2 ± 0.2 °, 8.3 ± 0.2 °, 12.5 ± 0.2 °, 17.0 ± 0.2 °, has diffraction maximum at 25.1 ± 0.2 °；
In one embodiment of the invention, described deuterated hydrate has X-ray powder diagram as shown in Figure 1.
Measure through differential scanning calorimetric analysis (DSC), deuterated hydrate described in first aspect present invention, its DSC collection of illustrative plates
In the range of 80～162 DEG C, 230～255, endothermic peak occurs respectively；Preferably, the peak value of the endothermic peak of its DSC collection of illustrative plates divides
Do not occur in 130 ± 10 DEG C, at 230 ± 10 DEG C；In a preferred embodiment of the invention, described deuterated hydrate
DSC collection of illustrative plates is as shown in Figure 2.
Deuterated hydrate described in first aspect present invention understands through thermogravimetric analysis (TGA), and it goes out in the range of 30～200 DEG C
Existing weight loss, the mass fraction of weight loss is 4.5%～6.0%, preferably 4.7%～5.5%, most preferably 5.2%；At this
In a bright embodiment, thermogravimetric analysis (TGA) collection of illustrative plates of described deuterated hydrate is as shown in Figure 2.
Deuterated hydrate described in first aspect present invention is analyzed through INFRARED ABSORPTION (IR), and it has infrared suction as described in Figure 3
Receive spectrum.
Second aspect present invention provides the preparation method of deuterated hydrate described in first aspect present invention, and the method includes following step
Rapid:
(1) valsartan and AHU-377 are dissolved in acetone, 20～40 DEG C of deuterated water (D adding alkali compounds2O)
Solution, stirring and crystallizing 1～10 hours；
(2) sucking filtration, is dried, obtains deuterated hydrate described in first aspect present invention；
Wherein, one or more in sodium hydroxide, sodium carbonate, sodium bicarbonate of described alkali compounds；
Valsartan is 1:0.9～1.1, preferably 1:1 with the molar ratio of AHU-377；
The mass fraction of the deuterated aqueous solution of alkali compounds is 10%～95%, preferably 50%～80%, more preferably 60%～70%；
The gross mass (g) of valsartan and AHU-377 is 1:10～20 with the rate of charge (units/ml/g) of acetone (ml),
Preferably 1:13～18；
The molal quantity of valsartan and AHU-377 and the mole ratio of alkali compounds are 1:2～4, preferably 1:3；
Described being dried of step (2) is preferably vacuum dried, and baking temperature is 30～50 DEG C, preferably 35～45 DEG C.
Alternatively, after step (1) adds the deuterated aqueous solution of alkali compounds, isopropyl acetate is added；Stirring analysis
Brilliant；Isopropyl acetate is 1:0.8～1.5, preferably 1:1 with the volume ratio that feeds intake of acetone；
More specifically, the preparation method described in second aspect present invention comprises the following steps:
(1) under room temperature, 1g AHU-377,1g valsartan is put into 30ml acetone, stir 20～30 minutes；Add
The deuterated aqueous solution of 0.4ml of 0.7g sodium hydroxide, reacts 1～3 hour, adds 30ml isopropyl acetate, at 20～25 DEG C
Crystallize 1～2 hours,
(2) sucking filtration, 35～40 DEG C are vacuum dried to obtain white solid.
Third aspect present invention provides a kind of pharmaceutical composition, and it comprises the deuterated hydrate described in first aspect present invention, with
And at least one pharmaceutically acceptable excipient.
Those skilled in the art according to disclosed technical data it is contemplated that the deuterated hydration that provides of first aspect present invention
The pharmaceutical composition that thing and third aspect present invention provide may be used for treating chronic heart failure and hypertension drug.
Fourth aspect present invention provides deuterated hydrate described in first aspect present invention to be used for treating chronic heart failure and height in preparation
The purposes of blood pressure medicine.
Fifth aspect present invention provides pharmaceutical composition described in third aspect present invention to be used for treating chronic heart failure and height in preparation
The purposes of blood pressure medicine.
It should be noted that AHU-377 of the present invention refers to compound 4-(((2S, 4R)-1-([1,1'-biphenyl]-4-base)-5-
Ethyoxyl-4-methyl-5-oxo-pentane-2-base) amino)-4-ketobutyric acid, its No. CAS is 149709-62-6, can be according to existing
There is document to prepare or be commercially available (such as Yi Jie bio tech ltd, Shanghai)；Valsartan refers to compound N-(1-
Valeryl)-N-[4-[2-(1H-tetrazole-5-base) phenyl] benzyl]-Valine, can be by being commercially available, as above hypo
With your Chemical Co., Ltd..It will be apparent to those skilled in the art that if not otherwise specified, the operation that the present invention is carried out is this skill
Carry out under the room temperature condition in art field；Described room temperature has art-recognized meanings well known in the art, specifically refers to 15～40 DEG C, excellent
Select 20～35 DEG C, more preferably 20～30 DEG C.
[3-((1S, the 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propanoic acid that the present invention prepares
-(S)-3 '-methyl-2 '-(valeryl { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butanoic acid] the deuterated hydrate of trisodium has
Higher purity and stability, HPLC purity is higher than 99.9%, and in ethanol, water has good dissolubility,
Can be used in preparation treatment heart failure and the medicine of hypertension, and its preparation technology favorable reproducibility, it is more beneficial for industrialized production.
Accompanying drawing explanation
The X-RPD collection of illustrative plates of the deuterated hydrate of Fig. 1 embodiment 1 gained；
The DSC-TGA collection of illustrative plates of the deuterated hydrate of Fig. 2 embodiment 1 gained；
The infrared absorption pattern of the deuterated hydrate of Fig. 3 embodiment 1 gained；
Detailed description of the invention
Below by way of specific embodiment, the foregoing of the present invention is described in further detail, but should be by
This is interpreted as any limitation of the invention.All technical schemes realized based on the present invention belong to the scope of the present invention.
The present invention to test used in material and test method carry out generality and/or concrete description.
Instrument of the present invention and method:
(1) X-ray powder diffractometer
INSTRUMENT MODEL: PANalytical x-ray powder diffraction instrument
Method of testing: fill out in glass plate groove by the sample (100mg) after finely ground, hangs its plane with glass surface with microscope slide
After flushing, sample is placed in PANalytical x-ray powder diffraction instrument, uses the copper X-ray source of 40kV, 40mA,
Sweep limits is 3～45 ° (2 θ), scanning speed 8 °/minute, and scanning error is usually ± 0.2 degree (2 θ)；
(2) TGA/DSC1 synchronous solving
INSTRUMENT MODEL: METTLER TGA/DSC1
Method of testing: be placed in the sealed aluminum pan with little pin hole by the sample of weight 10mg, keeps balance, so at 30 DEG C
After be heated to 250 DEG C with the sweep speed of 10 DEG C/min, drying nitrogen be used as purge gas；
(3) infrared spectrometer
INSTRUMENT MODEL: Bruker TENSOR 27
Method of testing: weigh sample 1-2mg, adds the KBr powder 200mg of 200 mesh, under infrared lamp in agate mortar
Grind uniformly, after tabletting (thickness about 1mm), carry out infrared scan mensuration.
Embodiment 1
At 25 DEG C, 1g AHU-377,1g valsartan and 30ml acetone are put into, stirs 20～30 minutes；Add 0.7g
The deuterated aqueous solution of 0.4ml of sodium hydroxide, reacts 2.5 hours, adds 30ml isopropyl acetate, 20～25 DEG C of stirring and crystallizing
1.5 hours, sucking filtration, obtain white solid 1.8g, purity 99.9%；After measured, its X-RPD collection of illustrative plates as it is shown in figure 1, its
As described in Figure 2, its infrared absorption spectroscopy is as shown in Figure 3 for synchronization DS C-TGA collection of illustrative plates.
Embodiment 2
At 20 DEG C, 1g AHU-377,1g valsartan and 20ml acetone are put into, stirs 20～30 minutes；Add 0.7g
The deuterated aqueous solution of 0.5ml of sodium hydroxide, reacts 3 hours, adds 35ml isopropyl acetate；Stirring and crystallizing 1 hour, takes out
Filter, obtains white solid 1.9g, purity 99.8%；After measured, its X-RPD collection of illustrative plates is basically identical with Fig. 1, its synchronization DS C-TGA
Collection of illustrative plates is basically identical with Fig. 2, and its infrared absorption spectroscopy is basically identical with Fig. 3.
Embodiment 3
At 25～30 DEG C, 1g AHU-377,1g valsartan and 25ml acetone are put into, stirs 15 minutes；Add 0.7g
The deuterated aqueous solution of 0.6ml of sodium hydroxide, reacts 2 hours, addition 50ml isopropyl acetate, crystallize 3 hours, sucking filtration,
Obtain white solid 1.9g, purity 99.6%；After measured, its X-RPD collection of illustrative plates is basically identical with Fig. 1, its synchronization DS C-TGA
Collection of illustrative plates is basically identical with Fig. 2, and its infrared absorption spectroscopy is basically identical with Fig. 3.
Embodiment 4
At 25 DEG C, 1g AHU-377,1g valsartan and 30ml acetone are put into, stirs 20～30 minutes；Add 0.7g
The deuterated aqueous solution of 0.5ml of sodium hydroxide, reacts 2.5 hours, addition 60ml isopropyl acetate, stirring and crystallizing 3 hours,
Sucking filtration, obtains white solid 1.8g, purity 99.7%；After measured, its X-RPD collection of illustrative plates is basically identical with Fig. 1, and it synchronizes
DSC-TGA collection of illustrative plates is basically identical with Fig. 2, and its infrared absorption spectroscopy is basically identical with Fig. 3.
Embodiment 5
At 25 DEG C, 1gAHU-377,1g valsartan and 30ml acetone are put into, stirs 20～30 minutes；Add 0.7g
The deuterated aqueous solution of 0.45ml of sodium hydroxide, stirring and crystallizing 4 hours, sucking filtration, 35 DEG C of vacuum drying, obtain white solid 1.7g,
Purity 99.7%；After measured, its X-RPD collection of illustrative plates is basically identical with Fig. 1, and its synchronization DS C-TGA collection of illustrative plates is basic with Fig. 2
Unanimously, its infrared absorption spectroscopy is basically identical with Fig. 3.
Embodiment 6
At 25 DEG C, 1g AHU-377,1g valsartan and 25ml acetone are put into, stirs 10 minutes；Add 0.7g hydrogen
The deuterated aqueous solution of 0.7ml of sodium oxide, stirring and crystallizing 4 hours, sucking filtration, 35 DEG C of vacuum drying, obtain white solid 1.6g,
Purity 99.8%；After measured, its X-RPD collection of illustrative plates is basically identical with Fig. 1, and its synchronization DS C-TGA collection of illustrative plates is basic with Fig. 2
Unanimously, its infrared absorption spectroscopy is basically identical with Fig. 3.
Stability test
Sample that Example 1, embodiment 5 prepare each 1 part be individually positioned in 40 DEG C under conditions of, investigate 10d,
The stability of 20d, 30d, the results are shown in Table 1.
The method of concrete study on the stability is referred to the method for 2010 editions second annex XIX C of Chinese Pharmacopoeia；Purity
HPLC method is used in detection, the method being referred to 2010 editions second annex V D of Chinese Pharmacopoeia.
The stability test result of table 1. inventive samples
By above-mentioned experiment it can be seen that the deuterated hydrate that the present invention prepares has good chemical stability；Further
Detect the X-ray powder diffraction spectrum through stability test sample on the 30th, do not change, illustrate that the present invention provides
Deuterated hydrate there is good stability of crystal form.
Claims (10)
1. [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxy carbonyl-1-butylcarbamoyl) propanoic acid-(S)-3 '-methyl-2 '-(penta
Acyl group { 2 "-(tetrazolium-5-base) biphenyl-4 '-ylmethyl } amino) butanoic acid] the deuterated hydrate of trisodium.
Deuterated hydrate the most according to claim 1, it is characterised in that every mole of described deuterated hydrate is containing deuterated
Water (D2O) molal quantity is 2.1～2.9, preferably 2.2～2.7, most preferably 2.5.
The most deuterated hydrate, it is characterised in that use Cu-Ka radiation, represent with 2 θ angles
X-ray powder diffraction at 4.2 ± 0.2 °, 5.2 ± 0.2 °, at 12.5 ± 0.2 °, have diffraction maximum；Preferably, described deuterated hydrate,
It is characterized in that, use Cu-Ka radiation, the X-ray powder diffraction represented with 2 θ angles at 4.2 ± 0.2 °, 5.2 ± 0.2 °,
8.3 ± 0.2 °, 12.5 ± 0.2 °, 17.0 ± 0.2 °, at 25.1 ± 0.2 °, there is diffraction maximum；It is highly preferred that described deuterated hydrate, it is special
Levy and be, use Cu-Ka radiation, with the X-ray powder diffraction that 2 θ angles represent, there is collection of illustrative plates as shown in Figure 1.
The most deuterated hydrate, it is characterised in that its DSC collection of illustrative plates respectively 80～162 DEG C,
In the range of 230～255, endothermic peak occurs；Preferably, the peak value of the endothermic peak of its DSC collection of illustrative plates respectively appears in 130 ± 10
DEG C, at 230 ± 10 DEG C；In a preferred embodiment of the invention, described deuterated hydrate has as described in Figure 2
DSC-TGA collection of illustrative plates.
5. preparing a method for deuterated hydrate described in claim 1, the method comprises the following steps:
(1) valsartan and AHU-377 are dissolved in acetone, 20～40 DEG C of deuterated water (D adding alkali compounds2O)
Solution, stirring and crystallizing 1～10 hours；
(2) sucking filtration, is dried, obtains deuterated hydrate described in first aspect present invention.
Method the most according to claim 5, it is characterised in that described alkali compounds is selected from sodium hydroxide, carbonic acid
One or more in sodium, sodium bicarbonate；
Valsartan is 1:0.9～1.1, preferably 1:1 with the molar ratio of AHU-377；
The mass fraction of the deuterated aqueous solution of alkali compounds is 10%～95%, preferably 50%～80%, more preferably 60%～70%；
The gross mass (g) of valsartan and AHU-377 is 1:10～20 with the rate of charge (units/ml/g) of acetone (ml),
Preferably 1:13～18；
The molal quantity of valsartan and AHU-377 and the mole ratio of alkali compounds are 1:2～4, preferably 1:3；
Described being dried of step (2) is preferably vacuum dried, and baking temperature is 30～50 DEG C, preferably 35～45 DEG C.
7. according to the method described in claim 5 or 6, it is characterised in that step (1) adds the deuterium of alkali compounds
After aqueous solution, add isopropyl acetate；Stirring and crystallizing；Isopropyl acetate and the volume ratio 1:0.8～1.5 that feeds intake of acetone,
Preferably 1:1.
8. a preparation method for deuterated hydrate described in claim 1, the method comprises the following steps:
(1) under room temperature, 1g AHU-377,1g valsartan is put into 30ml acetone, stir 20～30 minutes；Add
The deuterated aqueous solution of 0.4ml of 0.7g sodium hydroxide, reacts 1～3 hour, adds 30ml isopropyl acetate, at 20～25 DEG C
Crystallize 1～2 hours,
(2) sucking filtration, 35～40 DEG C are vacuum dried to obtain white solid.
9. a pharmaceutical composition, it comprises the deuterated hydrate described in claim 1, and at least one pharmaceutically may be used
The excipient accepted.
10. pharmaceutical composition described in deuterated hydrate described in claim 1 and claim 9 is used for treating chronic in preparation
Heart failure and the purposes of hypertension drug.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776441A (en) * | 2018-05-24 | 2019-05-21 | 合肥合源药业有限公司 | Unformed Valsartan Sha Kuba song sodium compound |
| 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 |
| CN111592500A (en) * | 2017-01-03 | 2020-08-28 | 上海博志研新药物技术有限公司 | ARB-NEPi compound, crystal form, preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098689A (en) * | 2005-11-09 | 2008-01-02 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
| WO2015030711A1 (en) * | 2013-08-26 | 2015-03-05 | Novartis Ag | New use |
-
2015
- 2015-03-11 CN CN201510106391.XA patent/CN106032361A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098689A (en) * | 2005-11-09 | 2008-01-02 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
| 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 |
| WO2015030711A1 (en) * | 2013-08-26 | 2015-03-05 | Novartis Ag | New use |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111592500A (en) * | 2017-01-03 | 2020-08-28 | 上海博志研新药物技术有限公司 | ARB-NEPi compound, crystal form, preparation method and application |
| CN109776441A (en) * | 2018-05-24 | 2019-05-21 | 合肥合源药业有限公司 | Unformed Valsartan Sha Kuba song sodium compound |
| CN109776441B (en) * | 2018-05-24 | 2022-08-19 | 合肥合源药业有限公司 | Amorphous valsartan-sabotargol sodium compound |
| 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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