JP2016520070A - リン酸/ホスホン酸誘導体及びその医薬用途 - Google Patents
リン酸/ホスホン酸誘導体及びその医薬用途 Download PDFInfo
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- JP2016520070A JP2016520070A JP2016513204A JP2016513204A JP2016520070A JP 2016520070 A JP2016520070 A JP 2016520070A JP 2016513204 A JP2016513204 A JP 2016513204A JP 2016513204 A JP2016513204 A JP 2016513204A JP 2016520070 A JP2016520070 A JP 2016520070A
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- Prior art keywords
- phosphonic acid
- group
- phosphate
- formula
- pharmacologically active
- Prior art date
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229910000147 aluminium phosphate Inorganic materials 0.000 title claims abstract description 16
- 150000003007 phosphonic acid derivatives Chemical class 0.000 title claims abstract description 15
- 229940042400 direct acting antivirals phosphonic acid derivative Drugs 0.000 title description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 20
- 239000010452 phosphate Substances 0.000 claims abstract description 20
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 150000002148 esters Chemical class 0.000 claims abstract description 5
- 125000004437 phosphorous atom Chemical group 0.000 claims abstract description 5
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical group C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000008575 L-amino acids Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 52
- 238000004519 manufacturing process Methods 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 27
- 229940079593 drug Drugs 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 17
- 231100000252 nontoxic Toxicity 0.000 claims description 16
- 230000003000 nontoxic effect Effects 0.000 claims description 16
- 239000012453 solvate Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 206010019799 Hepatitis viral Diseases 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 201000001862 viral hepatitis Diseases 0.000 claims description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000006454 hepatitis Diseases 0.000 claims description 3
- 231100000283 hepatitis Toxicity 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 230000010224 hepatic metabolism Effects 0.000 claims description 2
- 201000001421 hyperglycemia Diseases 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 4
- 125000001424 substituent group Chemical group 0.000 claims 3
- AFINAILKDBCXMX-PBHICJAKSA-N (2s,3r)-2-amino-3-hydroxy-n-(4-octylphenyl)butanamide Chemical compound CCCCCCCCC1=CC=C(NC(=O)[C@@H](N)[C@@H](C)O)C=C1 AFINAILKDBCXMX-PBHICJAKSA-N 0.000 claims 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 110
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- -1 Nucleoside phosphate Chemical class 0.000 description 85
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- 238000000034 method Methods 0.000 description 53
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000706 filtrate Substances 0.000 description 30
- 238000003756 stirring Methods 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 23
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 22
- LUSZGTFNYDARNI-UHFFFAOYSA-N Sesamol Chemical compound OC1=CC=C2OCOC2=C1 LUSZGTFNYDARNI-UHFFFAOYSA-N 0.000 description 20
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 229960004150 aciclovir Drugs 0.000 description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 229960000643 adenine Drugs 0.000 description 14
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 13
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 13
- 229960003767 alanine Drugs 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 229940002612 prodrug Drugs 0.000 description 12
- 239000000651 prodrug Substances 0.000 description 12
- XRSKRSVTUVLURN-UHFFFAOYSA-N 1,3-benzodioxol-4-ol Chemical compound OC1=CC=CC2=C1OCO2 XRSKRSVTUVLURN-UHFFFAOYSA-N 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 210000004185 liver Anatomy 0.000 description 10
- 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 10
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 9
- 238000004237 preparative chromatography Methods 0.000 description 9
- 229960001627 lamivudine Drugs 0.000 description 8
- 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 8
- 239000012046 mixed solvent Substances 0.000 description 8
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 7
- 0 CCC(C(OC1CCCCC1)=O)N[P@](OCC(CC1C)OC1N(C=CC(N1)=*)C1=O)(Oc(cc1)cc2c1OCO2)=O Chemical compound CCC(C(OC1CCCCC1)=O)N[P@](OCC(CC1C)OC1N(C=CC(N1)=*)C1=O)(Oc(cc1)cc2c1OCO2)=O 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical group COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960000980 entecavir Drugs 0.000 description 6
- 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 6
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- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- VDBGPMJFHCJMOL-UHFFFAOYSA-N 9-[2-[bis(2,2,2-trifluoroethoxy)phosphorylmethoxy]ethyl]-6-(4-methoxyphenyl)sulfanylpurin-2-amine Chemical compound C1=CC(OC)=CC=C1SC1=NC(N)=NC2=C1N=CN2CCOCP(=O)(OCC(F)(F)F)OCC(F)(F)F VDBGPMJFHCJMOL-UHFFFAOYSA-N 0.000 description 4
- 229930024421 Adenine Natural products 0.000 description 4
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- 239000012230 colorless oil Substances 0.000 description 4
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 4
- 235000019799 monosodium phosphate Nutrition 0.000 description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 4
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 4
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 4
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- 239000000126 substance Substances 0.000 description 4
- MDFHMUJOSKTPIX-UHFFFAOYSA-N 2-[2-amino-6-(4-methoxyphenyl)sulfanylpurin-9-yl]ethoxymethylphosphonic acid Chemical compound C1=CC(OC)=CC=C1SC1=NC(N)=NC2=C1N=CN2CCOCP(O)(O)=O MDFHMUJOSKTPIX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- XJMYIJPPDSZOPN-UHFFFAOYSA-N [5-[2-amino-5-(2-methylpropyl)-1,3-thiazol-4-yl]furan-2-yl]phosphonic acid Chemical compound S1C(N)=NC(C=2OC(=CC=2)P(O)(O)=O)=C1CC(C)C XJMYIJPPDSZOPN-UHFFFAOYSA-N 0.000 description 3
- JLKJXDOWBVVABZ-UHFFFAOYSA-N [[1-[(2-aminopurin-9-yl)methyl]cyclopropyl]oxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound C1=NC2=CN=C(N)N=C2N1CC1(OCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)CC1 JLKJXDOWBVVABZ-UHFFFAOYSA-N 0.000 description 3
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- YHPMDBWWRCBXNU-POYBYMJQSA-N [(2s,5r)-5-(2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl dihydrogen phosphate Chemical compound O1[C@H](COP(O)(=O)O)CC[C@@H]1N1C(=O)NC(=O)C=C1 YHPMDBWWRCBXNU-POYBYMJQSA-N 0.000 description 2
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Abstract
Description
Q1はL−アミノ酸のエステル誘導体を表示し、R3は炭素数1−6のアルキル基又はシクロアルキル基であり、R4はH又は炭素数1−6のアルキル基であり、Q2はヒドロキシ基で置換されるベンゾジオキサン誘導体を表示し、Q3はヒドロキシ基で置換されるベンゾジオキソール誘導体を表示し、R1又はR2は同一又は異なり、少なくとも一つがQ2又はQ3であり、Dはリン酸/ホスホン酸基を含む薬理学的活性分子の残基を表示し、即ち、
);2.11(d,2H);1.43(m,1H);0.97(d,6H)。
Hep G 2.2.15細胞を96ウェルプレートに接種し、細胞数3.5×104個であり、培養し、CO2インキュベーターに置いて、細胞密度が80%となるまでインキュベーションし、培養液を捨て、濃度の異なる被検薬が含まれる新しい培養液を加えて、3つの平行ウェルを設定し、2日間おきに培養液を変更した。投与後の10日目に、100μlの上清を取り出し、定量PCR方法により、HBV DNAの含有量を測定し、IC50値を計算した。結果は表1に示される。
Hep G 2.2.15細胞を96ウェルプレートに接種し、細胞数5.5×104個であり、3日間培養し続け、濃度の異なる薬物が含まれる新しい培養液を加えて、3つの平行ウェルを設定し、投与後の3日目に、MTTを7.5mg/mlとなるまで加えて、2時間培養し続け、上清を捨て、10%ツイーンX−100含有イソプロパノールを120ml/ウェル加えて、更に、0.4ml/ウェル加えて、マイクロプレートリーダーを用いて540nmにおける吸収を測定し、50%CC50値を計算した。結果は表2に示される。
高速液体クロマトグラフィー−タンデム質量分析法(HPLC−MS/MS)を用いて、目的化合物をマウスに強制経口投与した後の様々な時点における血液と肝組織中の活性薬物(遊離ホスホン酸又は遊離リン酸)の濃度/含有量を測定し、肝臓薬物濃度/血中薬物濃度の比率を計算し、肝臓標的性を比較した。
16h断食した雄性Balb/Cマウスを、各グループが3匹となるように3つのグループにランダムに分けて、それぞれホスホマイシン(200mg/kg)又は等モル用量の目的化合物のカルボキシメチルセルロースナトリウム懸濁液を強制経口投与し、それぞれ投与後の1時間と6時間に採血し、遠心分離させて血清を取り出し、同時に肝組織を取り出してホモジェネートを製造し、遠心分離させて上清を取り出し、血液と肝組織中の活性薬物(遊離ホスホン酸又は遊離リン酸)の濃度/含有量を測定し、肝臓薬物濃度/血中薬物濃度の比率を計算した。結果は表3に示される。
昆明マウス(20g)をグループ(各グループ8匹)にランダムに分けた。0.2mmolの被験化合物を経口投与し、投与1h後、0.1%CCl4のピーナッツ油溶液(10mL/kg)を皮下注射し、肝損傷モデルを製造し、生理的食塩水を正常な対照群として注射した。モデル製造後の12時間後、再び0.2mmolの被験化合物を経口投与した。二回目投与後の24時間に、採血して血清試料を取り出し、ALT、ASTを測定した。結果は表4に示される。
昆明マウス(20g)をグループ(各グループ8匹)にランダムに分けた。0.2mmolの被験化合物を経口投与し、投与2h後に、750mg/kgの用量でD−ガラクトサミンを腹腔内注射投与し、肝損傷モデルを製造し、生理的食塩水を正常な対照群として皮下注射した。モデル製造後の12h後、再び0.2mmolの被験化合物を経口投与した。二回目投与後の24時間に、採血して血清試料を取り出し、ALT、ASTを測定した。結果は表5に示される。
垂直伝播で感染し、DHBV DNA検出が陽性となったツクシガモをグループ(各グループ5匹)にランダムに分けた。それぞれ水、及び用量の異なる被験化合物を強制経口投与し、毎日一回、14日間投与した。それぞれ投与前、投与後の14日目、及び投与中止後の7日目に静脈採血し、外部標準TaqManリアルタイム蛍光PCR法により、血清のDHBV DNA含有量を測定し、溶媒群と比較し、抑制率を計算した。結果は表6に示される。
Claims (10)
- 式I:
ただし、R1又はR2は、
Q1はL−アミノ酸のエステル誘導体を表示し、R3は炭素数1−6のアルキル基又はシクロアルキル基であり、R4はH又は炭素数1−6のアルキル基であり、Q2はヒドロキシ基で置換されるベンゾジオキサン誘導体を表示し、Q3はヒドロキシ基で置換されるベンゾジオキソール誘導体を表示し、R1又はR2は同一又は異なり、少なくとも一つがQ2又はQ3であり、Dはリン酸/ホスホン酸基を含む薬理学的活性分子の残基を表示し、即ち、
- 活性成分としての請求項1−6に記載の式Iで示される化合物又はその薬学的に許容される塩又はその溶媒和物、及び一種又は複数種の薬学的な担体又は賦形剤を含む、薬物組成物。
- 肝炎を治療する薬物を製造するための請求項1−6に記載の式Iで示されるリン酸/ホスホン酸誘導体及びその非毒性薬学的に許容される塩及びその溶媒和物の用途。
- ウイルス性肝炎を治療する薬物を製造するための請求項1−6に記載の式Iで示されるリン酸/ホスホン酸誘導体及びその非毒性薬学的に許容される塩及びその溶媒和物の用途。
- 高脂血症や高血糖症等の、肝臓代謝障害による疾患を治療する薬物を製造するための請求項1−6に記載の式Iで示されるリン酸/ホスホン酸誘導体及びその非毒性薬学的に許容される塩及びその溶媒和物の用途。
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CN103665043B (zh) | 2012-08-30 | 2017-11-10 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药及其在医药上的应用 |
CN104761604A (zh) * | 2014-01-02 | 2015-07-08 | 江苏豪森药业股份有限公司 | 尿嘧啶核苷酸类似物及其制备方法和应用 |
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CN110156838A (zh) | 2019-08-23 |
CN104151360A (zh) | 2014-11-19 |
WO2014183462A1 (zh) | 2014-11-20 |
US20160115186A1 (en) | 2016-04-28 |
AU2014268040B2 (en) | 2017-02-02 |
CN104151360B (zh) | 2019-02-22 |
AU2014268040A1 (en) | 2016-01-07 |
EP2998307A1 (en) | 2016-03-23 |
EP2998307A4 (en) | 2017-02-15 |
EP2998307B1 (en) | 2018-10-31 |
KR20160007651A (ko) | 2016-01-20 |
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