WO2020222393A1 - 신규한 테노포비어 알라펜아미드 염 및 이의 제조방법 - Google Patents
신규한 테노포비어 알라펜아미드 염 및 이의 제조방법 Download PDFInfo
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- WO2020222393A1 WO2020222393A1 PCT/KR2019/018435 KR2019018435W WO2020222393A1 WO 2020222393 A1 WO2020222393 A1 WO 2020222393A1 KR 2019018435 W KR2019018435 W KR 2019018435W WO 2020222393 A1 WO2020222393 A1 WO 2020222393A1
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- Prior art keywords
- tenofovir alafenamide
- heminapadacylate
- present
- crystalline
- ray diffraction
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- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical class O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title 1
- 229960004946 tenofovir alafenamide Drugs 0.000 claims abstract description 55
- 208000000419 Chronic Hepatitis B Diseases 0.000 claims abstract 2
- 208000031886 HIV Infections Diseases 0.000 claims abstract 2
- 208000002672 hepatitis B Diseases 0.000 claims abstract 2
- 230000001225 therapeutic effect Effects 0.000 claims abstract 2
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 9
- 238000004458 analytical method Methods 0.000 claims description 6
- 108700024845 Hepatitis B virus P Proteins 0.000 claims description 2
- 102100034343 Integrase Human genes 0.000 claims description 2
- 229940123066 Polymerase inhibitor Drugs 0.000 claims description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 229940043274 prophylactic drug Drugs 0.000 claims 1
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 17
- 150000003839 salts Chemical group 0.000 abstract description 12
- 238000010521 absorption reaction Methods 0.000 abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 230000002708 enhancing effect Effects 0.000 abstract description 2
- 230000003449 preventive effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 239000012458 free base Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000007707 calorimetry Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 208000016350 chronic hepatitis B virus infection Diseases 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
- C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
- C07C309/35—Naphthalene sulfonic acids
Definitions
- the present invention relates to tenofovir alafenamide heminapadacylate, a novel salt form of tenofovir alafenamide, and a method for preparing the same.
- Tenofovir alafenamide hemifumarate is a nucleotide analog reverse transcriptase and HBV polymerase inhibitor that was developed by Gilead Sciences and sold under the brand name vemlidy. It is a useful drug for the treatment of chronic hepatitis B infection.
- Tenofovir alafenamide hemifumarate is described in Korean Patent Publication No. 10-0767432, Korean Patent Publication No. 10-0749160, and Korean Registered Patent Publication No. 10-1612642, and chemical name 9-[(R) It is represented by the hemifumarate of -2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosfinyl]methoxy]propyl]adenine, and the following structural formula ( It is represented by formula 1).
- Tenofovir alafenamide hemifumarate has a water-friendly structure, but it has a water solubility of only 0.236 mg/mL, so it is reported that the oral absorption rate for the drug is only 1%.
- the present inventors intend to disclose a novel salt of tenofovir alafenamide, tenofovir alafenamide heminapadacylate, a method for preparing the same, and results of aqueous solubility.
- the present inventors have repeatedly studied a novel salt form capable of enhancing the pharmacological effect by overcoming the problems of low water solubility and oral absorption of only 1% of the currently available tenofovir alafenamide hemifumarate.
- Tenofovir alafenamide heminapadacylate which has a water solubility of 240 times higher than that of nofovir alafenamide hemifumaric acid, was developed.
- the present invention in powder X-ray diffraction (PXRD) analysis, has 2 ⁇ diffraction angles of 7.004 ⁇ 0.2, 7.484 ⁇ 0.2, 8.338 ⁇ 0.2, 8.631 ⁇ 0.2, 8.907 ⁇ 0.2, 9.875 ⁇ 0.2, 10.573 ⁇ 0.2 , 10.866 ⁇ 0.2, 11.172 ⁇ 0.2, 11.833 ⁇ 0.2, 12.142 ⁇ 0.2, 12.573 ⁇ 0.2, 13.037 ⁇ 0.2, 14.044 ⁇ 0.2, 14.98 ⁇ 0.2, 15.471 ⁇ 0.2, 15.793 ⁇ 0.2, 16.03 ⁇ 0.2, 16.831 ⁇ 0.2, 17.205 ⁇ 0.2, 17.769 ⁇ 0.2, 18.489 ⁇ 0.2, 19.045 ⁇ 0.2, 19.899 ⁇ 0.2, 20.188 ⁇ 0.2, 21.049 ⁇ 0.2, 21.714 ⁇ 0.2, 22.307 ⁇ 0.2, 22.875 ⁇ 0.2, 23.364 ⁇ 0.2, 23.673 ⁇ 0.2, 24.444 ⁇ 0.2 , 24.719 ⁇ 0.2, 25.095 ⁇ 0.2, 26.036 ⁇ 0.2, 26.411 ⁇ 0.2, 26.869
- the intensity and peak position of the powder X-ray diffraction of one embodiment of tenofovir alafenamide heminapadasylate according to the present invention may be as shown in Table 1 below.
- the present invention provides tenofovir alafenamide heminapadacylate showing an endothermic peak of 177.20°C ⁇ 3°C and an endothermic temperature of 180.69°C ⁇ 3°C in a temperature differential scanning calorimetry (DSC) analysis using a sealed fan. do.
- DSC temperature differential scanning calorimetry
- the present inventors In order to overcome the oral absorption rate of only 1% due to the low solubility of the conventional tenofovir alafenamide hemifumarate, the present inventors have a high water solubility, and are a novel salt that can improve the oral absorption rate. It was intended to obtain nofovir alafenamide heminapadasylate.
- the present inventors have developed a method and conditions for producing tenofovir alafenamide heminapadasilate having the above-described advantages, and tenofovir alafenamide heminapadacylate prepared in this way is 240 It was found that the oral absorption rate can be increased by the double increased water solubility, so that it is suitable for use as an active ingredient in pharmaceuticals.
- the crystalline tenofovir alafenamide heminapadacylate of the present invention represented by Chemical Formula 2 in FIGS. 1 and 2 exhibits a different X-ray diffraction pattern from tenofovir alafenamide hemifumarate.
- Tenofovir alafenamide heminapadacylate of the present invention represented by Chemical Formula 2 in FIGS. 3 and 4 shows a calorific value of tenofovir alepanamide hemifumarate and different temperature differential calorimetry analysis.
- the crystalline tenofovir alafenamide heminapadacylate of the present invention has an X-ray diffraction pattern shown in FIG. 1.
- the crystalline tenofovir alafenamide heminapadacylate of the present invention has a calorific value curve of the temperature differential scanning (DSC) calorimetry of FIG. 3.
- the present invention overcomes the problem of the absorption rate in the body due to the low water solubility of the currently available tenofovir alafenamide hemifumarate, and is used as a new salt form of tenofovir alafenamide that is more thermodynamically stable and used as a pharmaceutical active ingredient. It is suitable to
- the present invention provides a method for preparing a novel salt form of tenofovir alafenamide heminapadacylate comprising the following steps:
- step (b) mixing the solution of step (a) and stirring at 100 rpm-500 rpm, preferably 200 rpm-300 rpm or more preferably 200 rpm.
- step (c) filtering the crystals precipitated in step (b).
- step (d) vacuum drying the crystals obtained in step (c) at 45 degrees for 16 hours.
- tenofovir alafenamide free base is prepared as follows.
- step (b) adding magnesium sulfate (MgSO 4 ) or sodium sulfate (Na 2 SO 4 ) as a desiccant to the resultant of step (a) and stirring;
- step (c) filtering the resultant of step (b) and then concentrating and drying under reduced pressure;
- step (d) Acetone, isopropanol, ethyl acetate, or a mixed solvent of ethyl acetate was added to the result of step (c), and through vigorous stirring and selective seeding, the crystalline tenofovir alafenamide free base To obtain.
- Tenofovir alafenamide heminapadacylate according to the present invention has a 240-fold increase in water solubility compared to tenofovir alafenamide hemifumarate, thereby increasing oral absorption, and thus can be used as a useful active ingredient in pharmaceutical compositions. .
- tenofovir alafenamide heminapadacylate according to the present invention can increase the absorption rate in the body compared to tenofovir alafenamide hemifumarate salt, and thus can be used as a useful active ingredient in pharmaceutical compositions.
- FIG. 1 shows a powder X-ray diffraction pattern of tenofovir alafenamide heminapadacylate prepared according to an embodiment of the present invention.
- FIG. 2 shows a powder X-ray diffraction pattern of tenofovir alafenamide hemifumarate in Republic of Korea Patent Publication No. 10-1612642.
- DSC temperature differential scanning calorimeter
- FIG 4 shows a temperature differential scanning calorimeter (DSC) of tenofovir alafenamide hemifumarate in Korean Patent Publication No. 10-1612642.
- FIG. 5 shows a result of a hydrogen nuclear magnetic resonance spectroscopy (H-NMR) of tenofovir alafenamide heminapadacylate prepared according to an embodiment of the present invention.
- H-NMR hydrogen nuclear magnetic resonance spectroscopy
- C-NMR carbon nuclear magnetic resonance spectroscopy
- FIG. 7 shows the results of the water solubility of tenofovir alafenamide free base and tenofovir alafenamide hemifumarate prepared according to an embodiment of the present invention.
- PXRD analysis (see Figs. 1,2) was performed on an X-ray powder diffractometer (D8 Advance) using Cu K ⁇ radiation.
- the instrument was equipped with tube power, and the amount of current was set at 45 kV and 40 mA.
- the divergence and scattering slits were set to 1°, and the light receiving slits were set to 0.2 mm.
- DSC Q20 obtained from TA company, DSC measurements (see Figs. 3 and 4) were performed in a closed pan at a scan rate of 10°C/min from 30°C to 300°C under nitrogen purification.
- tenofovir alafenamide heminapadacylate of the present invention exhibited a water solubility that is about 240 times higher than that of tenofovir alafenamide hemifumarate.
- tenofovir alafenamide heminapadacylate and tenofovir alafenamide hemifumarate of the present invention were each 60 mg/mL and it was confirmed that they are dissolved in water.
- tenofovir alafenamide hemifumarate was not dissolved, and that the tenofovir alafenamide heminapadasylate of the present invention was well soluble.
- tenofovir alafenamide heminapadacylate of the present invention can increase absorption in the body, which is a problem of tenofovir alafenamide hemifumarate, thereby improving pharmacological effects.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Tropical Medicine & Parasitology (AREA)
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Abstract
Description
Claims (4)
- 제 1 항에 있어서, 결정형 테노포비어 알라펜아미드 헤미나파다실레이트는 도1에 표시된 분말 X선 회절패턴을 갖는 것을 특징으로 하는 결정형 테노포비어 알라펜아미드 헤미나파다실레이트.
- 제 1 항에 있어서, 결정형 테노포비어 알라펜아미드 헤미나파다실레이트는 도3에 표시된 온도시차주사 열량분석을 특징으로 하는 결정형 테노포비어 알라펜아미드 헤미나파다실레이트.
- 제 1 항에 따른 테노포비어 알라펜아미드 헤미나파다실레이트 결정형을 주성분으로 하는 클레오타이드 아날로그 역전사효소 및 HBV 폴리머라아제 억제제로서 HIV-1 감염 및 만성 B형 간염의 치료에 유용한 치료 또는 예방용 약제학적 조성물.
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KR10-2019-0051037 | 2019-04-30 |
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KR102054104B1 (ko) * | 2019-04-30 | 2019-12-09 | 유니셀랩 주식회사 | 신규한 테노포비어 알라펜아미드 염 및 이의 제조방법 |
KR20220141457A (ko) | 2021-04-13 | 2022-10-20 | 경동제약 주식회사 | 신규 결정형의 테노포비어 알라펜아미드 말레산염 및 이를 포함하는 약제학적 조성물 |
WO2023282698A1 (ko) * | 2021-07-08 | 2023-01-12 | 동아에스티 주식회사 | 제제 안정성이 향상된 테노포비르 알라펜아미드 함유 속방성 제제 |
Citations (5)
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KR20140054068A (ko) * | 2011-08-16 | 2014-05-08 | 길리애드 사이언시즈, 인코포레이티드 | 테노포비어 알라펜아미드 헤미푸마레이트 |
CN105085571A (zh) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | 替诺福韦艾拉酚胺复合物及其制备方法和用途 |
US20180179208A1 (en) * | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | Antiviral aliphatic ester prodrugs of tenofovir |
US20180265530A1 (en) * | 2017-01-31 | 2018-09-20 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
KR102054104B1 (ko) * | 2019-04-30 | 2019-12-09 | 유니셀랩 주식회사 | 신규한 테노포비어 알라펜아미드 염 및 이의 제조방법 |
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2019
- 2019-04-30 KR KR1020190051037A patent/KR102054104B1/ko active IP Right Grant
- 2019-12-24 WO PCT/KR2019/018435 patent/WO2020222393A1/ko active Application Filing
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KR20140054068A (ko) * | 2011-08-16 | 2014-05-08 | 길리애드 사이언시즈, 인코포레이티드 | 테노포비어 알라펜아미드 헤미푸마레이트 |
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KR102054104B1 (ko) * | 2019-04-30 | 2019-12-09 | 유니셀랩 주식회사 | 신규한 테노포비어 알라펜아미드 염 및 이의 제조방법 |
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