JP2023520826A - エンテカビルモノホスフェートアラニンアミドフェノールエステル及びその医薬用途 - Google Patents
エンテカビルモノホスフェートアラニンアミドフェノールエステル及びその医薬用途 Download PDFInfo
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- entecavir
- monophosphate
- phenol ester
- alanine amide
- pharmaceutically acceptable
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- 229960000980 entecavir Drugs 0.000 title claims abstract description 47
- -1 Entecavir monophosphate alanine amide phenol ester Chemical class 0.000 title claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 21
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 21
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 229940124405 anti-hepatitis b virus drug Drugs 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 6
- 208000002672 hepatitis B Diseases 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 9
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 8
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 229940017219 methyl propionate Drugs 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- QYXBNPBZWXNBGN-DFWYDOINSA-N (2s)-2-(methylamino)propanoic acid;hydrochloride Chemical compound Cl.CN[C@@H](C)C(O)=O QYXBNPBZWXNBGN-DFWYDOINSA-N 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- ZTWBIZVVFNIRSF-HAFWLYHUSA-N [(1s,3s,5s)-3-(2-amino-6-oxo-3h-purin-9-yl)-5-hydroxy-2-methylidenecyclopentyl] [hydroxy(phosphonooxy)phosphoryl] hydrogen phosphate Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](OP(O)(=O)OP(O)(=O)OP(O)(O)=O)C1=C ZTWBIZVVFNIRSF-HAFWLYHUSA-N 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
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- 238000005259 measurement Methods 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 3
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 238000010828 elution Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
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- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UNGBCEGLHJGXFL-DKWTVANSSA-N (2s)-2-aminopropanoic acid;chloromethane Chemical compound ClC.C[C@H](N)C(O)=O UNGBCEGLHJGXFL-DKWTVANSSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- 206010059193 Acute hepatitis B Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- IJMWOMHMDSDKGK-UHFFFAOYSA-N Isopropyl propionate Chemical compound CCC(=O)OC(C)C IJMWOMHMDSDKGK-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 208000037628 acute hepatitis B virus infection Diseases 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
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- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- AOQKTXNIXJZEJT-UHFFFAOYSA-N formic acid;methanol;hydrate Chemical compound O.OC.OC=O AOQKTXNIXJZEJT-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- UKZCGMDMXDLAGZ-UHFFFAOYSA-M magnesium;2-methylpropane;bromide Chemical compound [Mg+2].[Br-].C[C-](C)C UKZCGMDMXDLAGZ-UHFFFAOYSA-M 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
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- 235000009566 rice Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
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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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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- A—HUMAN NECESSITIES
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A61K9/20—Pills, tablets, discs, rods
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- 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
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
Description
本発明は、医薬技術分野に属し、具体的には、新規なエンテカビルモノホスフェートアラニンアミドフェノールエステル誘導体及びその薬学的に許容される非有毒な塩、並びにその抗B型肝炎ウイルス薬の製造における使用に関する。
式IIにおいて、XはH、ハロゲン、R又は-ORであり、RはC1-3アルキル基又は置換されたC1-3アルキル基である。
文献(Ross BS, et al. Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates. J Org Chem, 2011, 76: 8311-8319.)により報道される方法を参照して、L-アラニンメチル塩酸塩6.6 g(0.047 mol)を無水ジクロロメタン50 mLに溶解し、-70 ℃に冷却し、トリエチルアミン13.8 mLを滴下した。その後、更にジクロロりん酸フェニル10 gを無水ジクロロメタン40 mLに溶解して、得られた溶液を反応系に滴下した。反応系を2時間以内で0 ℃に昇温し、引き続き1時間攪拌した。ペンタフルオロフェノール8.7 gとトリエチルアミン7.3 mLを無水ジクロロメタン30 mLに溶解して、得られた溶液を20分間以内で反応混合物に加えた。反応混合物を0 ℃で引き続き4時間攪拌し、白色固体を濾過により除去して、濾過ケーキをジクロロメタン20 mLでリンスした。濾液を減圧下で蒸発乾燥し、残量物をn-ヘキサンと酢酸エチル(4:1)の混合溶媒で2回再結晶し、iii-1の白色固体3.8 gを得て、de値は98.6%であった。プロトン核磁気共鳴δ (ppm, DMSO-d6, 400 MHz):1.28(3H, d), 3.61(3H, s), 3.96-4.06(1H, m), 6.91-6.97(1H, m), 7.23-7.28(3H, m), 7.40-7.45(2H, m)。
参考実施例の方法を参照して、(S)-2-[-(S)-(2,3,4,5,6-ペンタフルオロフェノキシ)-フェノキシ-ホスファミド]-プロピオン酸イソプロピル(iii-0)の代わりに、iii-1を無水エンテカビルと反応し、反応生成物をシリカゲルカラムクロマトグラフィーで分離し、化合物II-1を得て、収率は15%であった。プロトン核磁気共鳴δ (ppm, DMSO-d6, 400 MHz):1.24(3H, d), 2.04-2.09(1H, m), 2.26-2.33(1H, m), 2.75(1H, s, br), 3.61(3H, s), 3.85-3.91(1H, m), 4.07-4.11(1H, m), 4.21-4.27(2H, m), 4.61(1H, s, br), 5.03(1H, d), 5.16(1H, s, br), 5.36(1H, m), 6.01-6.07(1H, m), 6.39(2H, s, br), 7.16-7.24(3H, m), 7.36-7.40(2H, m), 7.66(1H, s), 10.55(1H, s)。
実施例7.1 ヒト血漿安定性の評価
5 mM MgCl2を含むヒト血漿1 mLに、50 mM測定待ち化合物のDMSO溶液2 μLを加えて、37 ℃で保温した。異なる時点で100 μLサンプリングし、メタノール200 μLを加えて、4 ℃、14000 rpmで30 min遠心分離した。上澄100 μLを取り、メタノール100 μLを加え、-20 ℃で冷凍して、使用に備えた。
5 mM MgCl2と50 mM K2HPO4(pH 7.4)を含む緩衝液1 mLに、50 mM測定待ち化合物のDMSO溶液2 μLを加えてから、4 mg/mLとなるようにヒト肝臓S9成分を加えて、37 ℃で保温した。異なる時点で100 μLサンプリングし、メタノール300 μLを加えて、4 ℃、14000 rpmで30 min遠心分離した。上澄100 μLを取り、メタノール100 μLを加え、-20 ℃で冷凍して、使用に備えた。
SDラットは、体重が180~220 gであり、1群あたりに6匹であり、雌と雄が半々であり、投与前に12時間絶食させた。測定待ち化合物を0.5%カルボキシメチルセルロースナトリウム溶液に加え、均一に混合して、胃内投与した(投与量100 μmol/kg)。投与前及び投与後の0.25 h、0.5 h、1 h、2 h、3 h、4 h、5 h、6 h、8 h、10 h、12 h、24 hに、0.3 mL/回で頸静脈から採血し、ヘパリンナトリウムで凝固を阻止し、血漿を遠心分離し、-80 ℃で保存して、測定に備えた。
雄ビーグル(7~8月齢、体重7~10 kg)をランダムに群分けして、1群あたりに2匹で体重を量った。投与前に12時間絶食させた。所定濃度の測定待ちサンプルを研磨して、0.5%カルボキシメチルセルロースナトリウム溶液に懸濁し、II-1(5 mg/kg)、II-6(5.13 mg/kg)又はI-5-B(5.27 mg/kg)を胃内投与した。投与前及び投与後の0.5 h、1 h、2 h、4 h、6 h、8 h、10 h、24 hに、0.5 mL/回で前足の橈側皮静脈から採血し、ヘパリンナトリウムで凝固を阻止し、血漿を遠心分離し、-80 ℃で保存して、測定に備えた。
雄ビーグル(7~8月齢、体重7~10 kg)をランダムに群分けして、1群あたりに4匹で体重を量った。所定濃度の測定待ちサンプルを研磨して、0.5%カルボキシメチルセルロースナトリウム溶液に懸濁し、II-1(用量:5 mg/kg)又はI-5-B(用量:5.27 mg/kg)のカルボキシメチルセルロースナトリウム懸濁液を、1日1回で連続4日胃内投与した。最終回の投与後に、水を制限せずに4時間絶食させ、ペントバルビタールで動物を麻酔し、臓器を取り出して、食塩氷水で洗浄してから、液体窒素で冷凍し、使用に備えた。
Claims (10)
- 前記置換されたC1-3アルキル基は、ヒドロキシ基又はハロゲンで置換されたC1-3アルキル基である、請求項1に記載のエンテカビルモノホスフェートアラニンアミドフェノールエステル誘導体又はその薬学的に許容される非有毒な塩。
- ハロゲンはF、Cl、Br又はIであり、好ましくはF、Cl又はBrである、請求項1又は2に記載のエンテカビルモノホスフェートアラニンアミドフェノールエステル誘導体又はその薬学的に許容される非有毒な塩。
- Rはメチル基、エチル基又はプロピル基である、請求項1~3の何れか1項に記載のエンテカビルモノホスフェートアラニンアミドフェノールエステル誘導体又はその薬学的に許容される非有毒な塩。
- XはH、F、Cl、Br、メチル基又はメトキシ基である、請求項1~4の何れか1項に記載のエンテカビルモノホスフェートアラニンアミドフェノールエステル誘導体又はその薬学的に許容される非有毒な塩。
- Xはパラ位炭素原子にある、請求項1~5の何れか1項に記載のエンテカビルモノホスフェートアラニンアミドフェノールエステル誘導体又はその薬学的に許容される非有毒な塩。
- 請求項1~7の何れか1項に記載のエンテカビルモノホスフェートアラニンアミドフェノールエステル誘導体又はその薬学的に許容される非有毒な塩を活性成分として含む、医薬組成物。
- カプセル剤、錠剤、顆粒剤、散剤、懸濁剤、液剤又は外用錠剤である、請求項8に記載の医薬組成物。
- 請求項1~9の何れか1項に記載のエンテカビルモノホスフェートアラニンアミドフェノールエステル誘導体又はその薬学的に許容される非有毒な塩、或いは請求項8~9の何れか1項に記載の医薬組成物の、抗B型肝炎ウイルス薬の製造における使用。
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