CN108129514A - 磷酸/膦酸衍生物的单一异构体及其医药用途 - Google Patents
磷酸/膦酸衍生物的单一异构体及其医药用途 Download PDFInfo
- Publication number
- CN108129514A CN108129514A CN201611086405.7A CN201611086405A CN108129514A CN 108129514 A CN108129514 A CN 108129514A CN 201611086405 A CN201611086405 A CN 201611086405A CN 108129514 A CN108129514 A CN 108129514A
- Authority
- CN
- China
- Prior art keywords
- phosphoric acid
- formulas
- pharmaceutically acceptable
- acceptable salt
- represent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000003016 phosphoric acids Chemical class 0.000 title claims abstract description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 36
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 23
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 21
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 18
- 230000000144 pharmacologic effect Effects 0.000 claims abstract description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 150000002790 naphthalenes Chemical class 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 12
- 239000003814 drug Substances 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000470 constituent Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 208000019423 liver disease Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 230000000694 effects Effects 0.000 description 19
- 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 15
- 210000001519 tissue Anatomy 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 14
- 239000000651 prodrug Substances 0.000 description 14
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 13
- -1 tenofovir pyrrole furan ester Chemical class 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 210000004185 liver Anatomy 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002207 metabolite Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound 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 description 9
- 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 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- TTZHDVOVKQGIBA-YBSJRAAASA-N propan-2-yl (2s)-2-[[[(2r,3r,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-YBSJRAAASA-N 0.000 description 8
- 229960004556 tenofovir Drugs 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000002777 nucleoside Substances 0.000 description 7
- 229960004946 tenofovir alafenamide Drugs 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- IJMWOMHMDSDKGK-UHFFFAOYSA-N Isopropyl propionate Chemical compound CCC(=O)OC(C)C IJMWOMHMDSDKGK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 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 6
- 238000001727 in vivo Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229960002063 sofosbuvir Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 206010013786 Dry skin Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-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
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 210000001541 thymus gland Anatomy 0.000 description 4
- 210000001835 viscera Anatomy 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 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 0 C[C@@](C(O*)=O)N[P@@](*)(O[Al])=O Chemical compound C[C@@](C(O*)=O)N[P@@](*)(O[Al])=O 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- IPHULAIUXUVCHH-VPCXQMTMSA-N [[(2r,3r,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound C[C@@]1(F)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 IPHULAIUXUVCHH-VPCXQMTMSA-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
- 229960003205 adefovir dipivoxil Drugs 0.000 description 3
- 238000010241 blood sampling Methods 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 244000144993 groups of animals Species 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 229940126701 oral medication Drugs 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000003009 phosphonic acids Chemical class 0.000 description 3
- KVCZQFHLXRMEIB-LZEIJKKFSA-N propan-2-yl (2s)-2-[[[(2r,3r,4r,5r)-5-(2-amino-6-methoxypurin-9-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate Chemical compound O([P@](=O)(N[C@@H](C)C(=O)OC(C)C)OC[C@H]1O[C@H]([C@]([C@@H]1O)(C)F)N1C=2N=C(N)N=C(C=2N=C1)OC)C1=CC=CC=C1 KVCZQFHLXRMEIB-LZEIJKKFSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QBALDQHTPWRRLH-UHFFFAOYSA-N (2,3-dichlorophenyl) dihydrogen phosphate Chemical class OP(O)(=O)OC1=CC=CC(Cl)=C1Cl QBALDQHTPWRRLH-UHFFFAOYSA-N 0.000 description 2
- JXQUAHHUSMJUFV-HZPZRMRQSA-N 9-[2-[[(2r,4s)-4-(3-chlorophenyl)-2-oxo-1,3,2$l^{5}-dioxaphosphinan-2-yl]methoxy]ethyl]purin-6-amine;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1([C@@H]2CCO[P@](O2)(=O)COCCN2C=3N=CN=C(C=3N=C2)N)=CC=CC(Cl)=C1 JXQUAHHUSMJUFV-HZPZRMRQSA-N 0.000 description 2
- 235000010894 Artemisia argyi Nutrition 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 244000030166 artemisia Species 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- AOQKTXNIXJZEJT-UHFFFAOYSA-N formic acid;methanol;hydrate Chemical compound O.OC.OC=O AOQKTXNIXJZEJT-UHFFFAOYSA-N 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 229950010765 pivalate Drugs 0.000 description 2
- 229950001452 pradefovir Drugs 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 description 2
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 108091006084 receptor activators Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- OCJRRXHWPBXZSU-BNCZGPJRSA-N rovafovir etalafenamide Chemical compound O([P@@](=O)(CO[C@@H]1C=C(F)[C@@H](O1)N1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OCC)C1=CC=CC=C1 OCJRRXHWPBXZSU-BNCZGPJRSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 231100000456 subacute toxicity Toxicity 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 2
- 229960001355 tenofovir disoproxil Drugs 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- 229940048102 triphosphoric acid Drugs 0.000 description 2
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- BOFRXDMCQRTGII-UHFFFAOYSA-N 619-08-9 Chemical class OC1=CC=C([N+]([O-])=O)C=C1Cl BOFRXDMCQRTGII-UHFFFAOYSA-N 0.000 description 1
- 208000005676 Adrenogenital syndrome Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010004173 Basophilia Diseases 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N C[C@H](C[n]1c2ncnc(N)c2nc1)OCP(O)(O)=O Chemical compound C[C@H](C[n]1c2ncnc(N)c2nc1)OCP(O)(O)=O SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- KIOOPXXIFXEVLQ-UHFFFAOYSA-N Cl[P]Cl Chemical compound Cl[P]Cl KIOOPXXIFXEVLQ-UHFFFAOYSA-N 0.000 description 1
- 208000008448 Congenital adrenal hyperplasia Diseases 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000020564 Eye injury Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical class CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical compound NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 description 1
- SUPKOOSCJHTBAH-UHFFFAOYSA-N Nc1c2nc[n](CCOCP(O)(O)=O)c2ncn1 Chemical compound Nc1c2nc[n](CCOCP(O)(O)=O)c2ncn1 SUPKOOSCJHTBAH-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- MPSGQQOHTJUJKB-QUBYGPBYSA-N [(2r,5r)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethylphosphonic acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](OCP(O)(O)=O)C=C1F MPSGQQOHTJUJKB-QUBYGPBYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229940059260 amidate Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- 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 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007948 fast release tablet Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 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 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 210000002231 macronucleus Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical class O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical class [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000003007 phosphonic acid derivatives Chemical class 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002213 purine nucleotide Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical class ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000001745 uvea Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及式Ia所示的磷酸/膦酸衍生物及其非毒性药学上可接受的盐；其中，式Ib所示的非对映异构体的含量小于2％：结构式Ia和Ib中，Ar代表取代或未取代的苯环或萘环，R1代表H或碳原子数1‑6的烷基；R2代表碳原子数1‑6的烷基或环烷基；D代表含磷酸/膦酸基的药理活性分子的残基，即
Description
技术领域
本发明涉及含有磷酸或膦酸基的药理活性分子的新的肝靶向前药衍生物的单一异构体及其非毒性的药学上可接受的盐。
背景技术
肝脏是病毒性肝炎、肝硬化、肝癌的靶器官。针对这些疾病的治疗药物的研究，在近十年中取得了重要进展，但是远不能满足临床的需求。
结构如下所示的分子中含有磷酸基或膦酸基的化合物是肝病治疗中重要的药理活性分子：
如阿德福韦(PMEA)、替诺福韦(PMPA)和PMPDAP是具有抗HIV和HBV活性的无环核苷膦酸类似物：
拉米夫定、恩替卡韦、阿昔洛韦等核苷类似物均是通过磷酸化形成具有药理活性的核苷酸类似物，发挥抗病毒作用：
MB05032是具有降糖作用的膦酸类果糖1，6-二磷酸酶抑制剂，MB07344是具有降脂作用的膦酸类甲状腺受体激动剂：
但是，由于磷酸或膦酸基的强极性，含有磷酸或膦酸基的药理活性分子难以透过细胞膜，因此其口服给药的生物利用度低，难以达到有效治疗浓度。因此，研究开发安全有效的含有磷酸或膦酸基的药理活性分子的前药是该类药物研发的关键。
将含膦酸基的药物分子制成羧酸酯或碳酸酯前药，可以显著提高膦酸类药物的口服生物利用度。阿德福韦酯和LB-80380是特戊酸活泼酯前药，替诺福韦酯是碳酸异丙酯的前药。阿德福韦酯和替诺福韦酯是临床应用最广泛的抗病毒药物。
但是，阿德福韦特戊酸酯、LB-80380及替诺福韦吡呋酯化学稳定性差，其原料药及制剂对温度湿度较敏感，易分解形成人体不能吸收的单酯；而且由于其在胃肠道不稳定，易水解生成强酸性的膦酸化合物，对胃肠道有刺激性。另外，阿德福韦特戊酸酯和LB-80380进入体内，水解生成的特戊酸，不易代谢排泄，有一定的副作用。
MCC-478是具有抗乙肝病毒作用的无环核苷酸的三氟乙醇酯，具有较好的化学稳定性。MCC-478进入体内后水解释放出游离酸(602076)发挥抗病毒作用；但是I期临床的药代动力学研究结果表明，MCC-478在人体内的主要代谢产物为核苷酸单酯(602074)，游离酸602076的血药浓度只有单酯602074的1/10。
Pradefovir、MB07811和MB07133分别为抗乙肝药物PMEA、甲状腺受体激动剂MB07344及抗肿瘤药物阿糖胞苷的苯取代环状膦酸酯的前药；该类前药具有较好的化学稳定性，在胃肠道和血液中保持稳定，而在肝脏中能够被细胞色素P450酶选择性活化，在肝脏释放活性药物PMEA、MB07344或阿糖胞苷，发挥药理作用：
但是，Pradefovir、MB07811和MB07133进入体内后，会产生高度致癌作用的代谢中间体，具有致癌作用。
结构式如下所示的磷酸/膦酸衍生物前药具有较好的口服生物利用度，其进入体内能够活化为磷酸/膦酸的活性形式：
结构式I中，Ar代表取代或未取代的苯环或萘环，R1代表H或碳原子数1-6的烷基；R2代表碳原子数1-6的烷基或环烷基；D代表含磷酸/膦酸基的药理活性分子的残基，即代表含磷酸/膦酸基的药理活性分子。
由于磷原子的手性，结构式I所示的分子中含有由结构式Ia和Ib所示的两种异构体，两种异构体在体内能够转化为相同的活性膦酸/磷酸衍生物：
由于代谢酶的立体选择性，式Ia和Ib所示的两种异构体在不同组织中代谢转化速率有所不同，因此表现出不同的药理活性。
PSI-7977为具有抗HCV活性的核苷酸的磷酰胺酚酯的单一异构体：
PSI-7977和异构体PSI-7976在体内均能转化为相同的三磷酸核苷酸类似物PSI-7409，发挥抗HCV作用；但是PSI-7977体外抗HCV活性为PSI-7976的11倍(Michael J.Sofia，et al.Discovery of aβ-D-2’-Deoxy-2’-α-fluoro-2’-β-C-methyluridine NucleotideProdrug(PSI-7977)for the Treatment of Hepatitis C Virus.J Med Chem 2010；53：7202-7218.)。PSI-7977(通用名：Sofosbuvir，索非布韦)已经获准上市，成为治疗HCV的首选药物。但是，在临床应用中发现，索非布韦和其它抗病毒药物联合使用能够引起症状性心动过缓。
GS-7340为具有抗HIV活性的膦酸衍生物的单一异构体：
GS-7339和GS-7340在体内均能转化为相同的替诺福韦二磷酸衍生物，发挥抗HIV作用，但是GS-7340的体外抗HIV活性为GS-7339的6倍。(Darius Babusis，et al.Mechanismfor Effective Lymphoid Cell and Tissue Loading Following Oral Administrationof Nucleotide Prodrug GS-7340.Mol.Pharmaceutics 2013；10：459-466)。GS-7340(商品名：Tenofovir Alafenamide，替诺福韦艾拉酚胺，TAF)已经获准上市，成为治疗HIV的有效药物。但是，对于HBV的治疗，希望具有更高肝脏选择性的替诺福韦前药，以减少其在淋巴系统或其它组织的分布，进一步降低副作用。
类似的，PSI-353661为抗HCV活性更强的核苷单磷酸类似物的磷酰胺单酯的单一异构体Wonsuk Chang，et al.Discovery of PSI-353661，a Novel Purine NucleotideProdrug for the Treatment of HCV Infection.|ACS Med.Chem.Lett.2011，2，130-135)；GS-9131为PSI-353661为抗HIV活性更强的核苷单膦酸类似物的膦酰胺单酯的单一异构体(Richard L.Mackman Discovery of GS-9131：Design，synthesis and optimizationof amidate prodrugs of the novel nucleoside phosphonate HIV reversetranscriptase(RT)inhibitor GS-9148.Bioorganic&Medicinal Chemistry18(2010)3606-3617.)
我们意外地发现，口服给药后，结构式Ib所示的磷酸/膦酸衍生物异构体在肝脏中的活性代谢物的含量与异构体Ib相当；但是Ib口服给药后，在其它组织中的活性代谢物的含量显著低于Ib；而且，Ib的副作用显著低于Ib：
发明内容
因此，本发明提供式Ia所示的磷酸/膦酸衍生物及其非毒性药学上可接受的盐；其中，式Ib所示的非对映异构体的含量小于10％：
结构式Ia和Ib中，Ar代表取代或未取代的苯环或萘环，R1代表H或碳原子数1-6的烷基；R2代表碳原子数1-6的烷基或环烷基；D代表含磷酸/膦酸基的药理活性分子的残基，即代表含磷酸/膦酸基的药理活性分子。
进一步地，本发明提供式Ia所示的磷酸/膦酸衍生物及其非毒性药学上可接受的盐，其中，式Ib所示的非对映异构体的含量小于5％。
更进一步地，本发明提供式Ia所示的磷酸/膦酸衍生物及其非毒性药学上可接受的盐，其中，式Ib所示的非对映异构体的含量小于2％。
进一步地，本发明提供式Ia-1所示的膦酸衍生物及其非毒性药学上可接受的盐；其中，式Ib-1所示的非对映异构体的含量小于2％：
结构式Ia-1和Ib-1中，R1代表H或碳原子数1-6的烷基；R2代表碳原子数1-6的烷基或环烷基。
本发明还提供式Ia-2所示的磷酸衍生物及其非毒性药学上可接受的盐；
结构式Ia-2和Ib-2中，R1代表H或碳原子数1-6的烷基；R2代表碳原子数1-6的烷基或环烷基。
本发明另一方面提供含式Ia所示的磷酸/膦酸衍生物及其非毒性药学上可接受的盐作为活性成分及药用赋形剂的药物组合物；这些药物组合物可以是片剂，如速释片、缓释片、控释片、薄膜衣片、糖衣片、口含片等；胶囊剂如硬胶囊剂、软胶囊剂等。
以PMPA的膦酸类衍生物Ia-1的制备为例，化合物Ia可以按照如下合成路线制备：
以PMPA为原料，在DCC作用下与苯酚缩合，得到PMPA的苯酚单酯(i)；然后与氯化亚砜反应，得到膦酰氯中间体(ii)，后者与氨基酸酯(iii)反应，得到PMPA单酰胺酚酯的异构体混合物(iv)；最后参考文献(H.Chapman，et al.PRACTICAL SYNTHESIS，SEPARATION，ANDSTEREOCHEMICAL ASSIGNMENT OF THE PMPA PRO-DRUG GS-7340.NUCLEOSIDES，NUCLEOTIDES&NUCLEIC ACIDS，2001；20：621-628)报道的方法，利用手性制备色谱分离制备单一异构体Ia-1。
以Ia-2-1的合成为例，磷酸类衍生物Ia-2可以按照如下合成路线制备：
参考文献(Ross BS，et al.Synthesis of Diastereomerically PureNucleotide Phosphoramidates.J Org Chem，2011，76：8311-8319.)报道的方法，以二氯磷酸苯酯为原料，丙氨酸异丙酯反应(iii-1)，得到单磷酰胺中间体(v)；v与2-氯-4-硝基-苯酚缩合，制备关键手性中间体(S)-2-[(R)-(2-氯-4-硝基-苯氧基)-苯氧基-磷酰基氨基]丙酸异丙酯(vi-1)。β-D-2’-脱氧-2’-a-氟-2’-β-C-甲基尿苷(vii)与vi-1反应，制得目标化合物Ia-2-1。
具体实施方式
下述实施例用于具体地解释本发明，然而本发明的范围并不限于下述实施例。
实施例1 9-[(R)-2-[[(R)-[[(S)-1-(异丙氧基羰基)-乙基]-胺基]-苯氧基膦酰基]-甲氧基]-丙基]-腺嘌呤(Ia-1-1)的制备
在50ml N-甲基吡咯烷酮中加入14.6g 9-[(R)-2-(膦酸基甲氧基)-丙基]-腺嘌呤(PMPA)，9.6g苯酚，加热至85℃，加入6.3ml三乙胺。搅拌下缓慢加入13.4g DCC，于100℃加热搅拌过夜，冷却后加入30ml水。放置，滤去固体，合并洗滤液，减压蒸干，加入30ml水，用25％的氢氧化钠调节pH至11，滤去固体，合并洗滤液，用30ml乙酸乙酯萃取。将水溶液用37％盐酸调节pH至3.1，放置析出固体。滤取固体，加入50ml甲醇搅拌洗涤，过滤，真空干燥，得7.2g PMPA的苯酚单酯衍生物i。
将7.1gi加于30ml乙腈中，搅拌下滴加6.2g氯化亚砜，保持温度50℃以下。将反应混合物于75℃加热至固体溶解，然后加热至80℃，蒸干。冷却至25℃，加入40ml二氯甲烷，冷却至-30℃；在30min内，滴加6.5g L-丙氨酸异丙酯(iii-1)于35ml二氯甲烷的溶液，保持温度-18℃。然后在15min内，滴加7ml三乙胺，保持温度-18℃至-11℃。室温搅拌2h，用10％的磷酸二氢钠溶液洗(3X15ml)。将有机层用无水硫酸钠干燥，过滤后将滤液减压蒸干，将残留物用硅胶柱层析分离，用丙酮洗脱，收集所需组分，减压蒸干，得3.6g PMPA单酰胺酚酯的异构体混合物(iv)。用手性制备色谱(Diacel’s Chiralpak AS)分离，用含30％甲醇的乙腈洗脱，收集第1个主峰，减压蒸干，得1.5g Ia-1-1。HPLC分析结果表明，产品纯度99.298％(保留时间15.171分钟)，异构体含量0.702％(保留时间19.354分钟)；附图1为TAF的HPLC色谱图，附图2为Ia-1-1的HPLC色谱图。H NMR(ppm，DMSO-d6)：8.07(s，1H)；8.05(s，1H)；7.3-7.0(m，5H)；6.56(s，2H)；5.5-5.40(m，1H)；4.77-4.74(m，1H)；4.2-3.7(m，6H)；1.07-1.06(m，12H).31P NMR(ppm，CH3OD)：25.03。
实施例2 5’-[(S)-[[(S)-1-(异丙氧基羰基)-乙基]-胺基]-苯氧基磷酰基]-β-D-2’-脱氧-2’-a-氟-2’-β-C-甲基尿苷(Ia-2-1)的制备
2.1(S)-2-[(R)-(2-氯-4-硝基-苯氧基)-苯氧基-磷酰基氨基]丙酸异丙酯(vi-b)的小量制备
将10克(47.3mmol)二氯磷酸苯酯溶于50mL干燥的二氯甲烷中，冷却至0℃；加入7.94克(47.3mmol)L-丙氨酸异丙酯盐酸盐(iii-1)固体，冷却至-78℃。搅拌下滴加13.8ml三乙胺(94.6mmol)溶于50mL干燥二氯甲烷的溶液，控制滴加速度以保持反应温度-78℃。加完后搅拌30分钟，然后升温至0℃；在5-10分钟内，搅拌下滴加8.2克(47.3mmol)2-氯-4-硝基-苯酚和6.6ml(47.3mmol)三乙胺溶于20mL干燥二氯甲烷的溶液；保持0℃，继续搅拌24小时。过滤，以20ml二氯甲烷洗涤，合并洗滤液，减压蒸干，得vi-a和vi-b两种异构体的油状物。加入特丁基甲醚50ml，研磨，搅拌10分钟；滤去固体，滤饼用少许特丁基甲醚洗涤，合并洗滤液，减压蒸干。将残留物用硅胶柱层析分离，用二氯甲烷洗脱，收集所需组分，用乙酸乙酯/正己烷(2∶3)的混合溶剂重结晶，得到5.2g vi-a(产率25％，de＞98％)，[α]25 D(c 1.00，CHCl3)-16.1；mp 70-72℃；以乙酸乙酯/正己烷(2∶3)的混合溶剂重结晶，得到vi-a的精制品1.8g(de＞99％)，[α]25 D(c 1.00，CHCl3)+26.6；mp 70-72℃。
将母液冷却至-5℃，析出白色固体，过滤得到2.3g vi-b(产率7.5％，de＞95％)；以乙酸乙酯/正己烷(2∶3)的混合溶剂重结晶，得到vi-b的精制品0.58g(de＞99％)，[α]25 D(c 1.00，CHCl3)+26.6；mp 77-80℃。核磁共振氢谱δ(ppm，CDCl3)：8.33-8.32(m，1H)；8.13-8.10(m，1H)；7.75-7.72(m，1H)；7.39-7.20(m，5H)；5.04(m，1H)；4.22-4.13(m，1H)；4.03-3.97(m，1H)；1.42(d，3H)；1.27-1.24(m，6H).
2.2(S)-2-[(R)-(2-氯-4-硝基-苯氧基)-苯氧基-磷酰基氨基]丙酸异丙酯(vi-b)的放大量制备
将200克二氯磷酸苯酯溶于1000mL干燥的二氯甲烷中，冷却至0℃；加入158.8克L-丙氨酸异丙酯盐酸盐(iii-1)固体，冷却至-78℃。搅拌下滴加276ml三乙胺溶于800mL干燥二氯甲烷的溶液，控制滴加速度以保持反应温度-78℃。加完后搅拌30分钟，然后升温至0℃；在20分钟内，搅拌下滴加164克2-氯-4-硝基-苯酚和132ml三乙胺溶于300mL干燥二氯甲烷的溶液；保持0℃，继续搅拌24小时。过滤，以300ml二氯甲烷洗涤，合并洗滤液，减压蒸干。将残留物用硅胶柱层析分离，用二氯甲烷洗脱，收集所需组分，加压蒸干；将残留物用乙酸乙酯/正己烷(2∶3)的混合溶剂重结晶，加入vi-a精制品作为晶种，室温放置过夜，过滤，干燥得到147g vi-a；将母液冷却至-5℃，加入vi-b精制品作为晶种，析出白色固体，过滤得到135g vi-b(de＞99％)[α]25 D(c 1.00，CHCl3)+26.6；mp 77-80℃。
2.3 5’-[(S)-[[(S)-1-(异丙氧基羰基)-乙基]-胺基]-苯氧基磷酰基]-β-D-2’-脱氧-2’-a-氟-2’-β-C-甲基尿苷(Ia-2-1)的制备
将1gβ-D-2’-脱氧-2’-a-氟-2’-β-C-甲基尿苷(vii)50℃真空干燥10小时，然后溶于20ml干燥的THF中，冷却至-5℃，缓慢滴加1.7M的特丁基氯化镁的THF溶液5ml；保持-5℃，搅拌30分钟，然后室温再搅拌30分钟。将反应混合物冷却至5℃，缓慢滴加2.5克vi-b溶于10ml THF的溶液。冰浴下，继续搅拌12小时；然后将反应混合物冷却至-5℃，滴加2N盐酸5ml，减压蒸去THF，加入二氯甲烷50ml萃取；分出有机层，依次用2N盐酸5ml、水5ml、5％的碳酸钠5ml、水5ml洗涤，然后用无水硫酸钠干燥；过滤除去干燥剂，将滤液减压蒸干，用硅胶柱层析分离，用二氯甲烷∶石油醚(2∶8)洗脱，收集所需组分，蒸干；将残留物用异丙醇和正庚烷的混合溶剂重结晶，得Ia-2-10.92克。mp 136.5-138.0℃。HPLC分析结果表明，产品纯度99.472％(保留时间12.384分钟)，异构体含量0.528％(保留时间10.448分钟)。附图3为索非布韦和Ia-2-1混合物的HPLC色谱图，附图4为Ia-2-1的HPLC色谱图。核磁共振氢谱δ(ppm，DMSO-d6)：11.55(s，1H)；7.58(d，1H)；7.41-7.38(m，2H)；7.22-7.17(m，3H)；6.15-6.09(m，1H)；5.93(d，1H)；5.59(dd，1H)；4.87(m，1H)；4.45-4.25(m，2H)；4.07(m，1H)；3.80-3.72(m，2H)；1.26(d，3H)；1.22(d，3H)；1.17(dd，6H).
实施例3替诺福韦艾拉酚胺(TAF)和Ia-1-1比格犬连续给药的亚急性毒性评价和组织分布评价
取雄性比格犬(7-8月龄，体重7-10kg)随机分组，4只一组，称重。灌胃给予含有30mg/kg TAF(购自上海瀚香生物科技有限公司，HPLC含量98％)或Ia-1-1的羧甲基纤维素钠悬浮液，每天1次，连续14天。末次给药后，禁食不禁水4小时，静脉取血，制备血清，供血液生化指标测定。然后，处死，取脏器组织，分成两部分。取一部分组织，称重，于匀浆器中加纯净水制成10％的匀浆，采用高效液相色谱-串联质谱法(HPLC-MS/MS)测定各组织中的活性形式替诺福韦二磷酸的含量，评价肝靶向性。另一部分组织经充分固定后，逐级乙醇脱水，二甲苯透明，石蜡，制备4μm切片，HE染色，光学显微镜检查。
组织中活性代谢产物的测定方法如下：仪器：美国Finnigan公司TSQ Quantum型液相色谱-质谱联用仪(LC/MS/MS)，由Finnigan Surveyor LC泵、Surveyor AS自动进样器、电喷雾离子化电离源(ESI)及三级串联质谱组成。控制软件为Xcalibur 1.4，质谱数据分析采用Lcquan 2.0数据处理系统。色谱柱为Discovery ODS柱(250mm×4.6mm，5μm)，C18保护柱(4mm×3.0mm)，流动相为甲醇-水-甲酸(10-30：90-70：0.5，V/V/V)，流速0.7ml/min；进样量20μL；柱温为室温。
测定结果表明，Ia-1-1和TAF给药后，肝脏中活性代谢物的含量相当，但是TAF给药组动物肾脏、胸腺、淋巴结、脾脏及肺等组织中活性代谢物替诺福韦二磷酸(TFV-DP)的含量显著高于Ia-1-1组。具体结果见表1：
表1 Ia-1-1和TAF给药后，肝脏中TFV-DP的含量(ng/g)
血液学测定结果表明，两组动物单核细胞计数、网织红细胞比、红细胞分布体积等略有升高，两组之间无显著差异；生化指标测定结果表明，AST，ALP，总胆红素及肌酐激酶有所升高，两组之间无显著差异。
组织病理学检测结果表明，TAF组动物多见以肾小管巨核化和嗜碱性粒细胞增多为特征的肾损伤、胸腺萎缩、以葡萄膜单核细胞侵润为特征的眼损伤、以及以巨噬细胞侵润为特征的肺损伤和脾损伤。具体结果见表2：
表2 Ia-1-1和TAF给药病理主要病变发生率
实施例4索非布韦和Ia-2-1比格犬连续给药的组织分布评价
取雄性比格犬(7-8月龄，体重7-10kg)随机分组，4只一组，称重。将一定浓度的待测样品研磨悬浮于0.5％的羧甲基纤维素钠溶液中，灌胃给予含有50mg/kg索非布韦(购自湖北鑫鸣泰化学有限公司，HPLC含量99％)或Ia-2-1的羧甲基纤维素钠悬浮液，每天1次，连续4天。末次给药后，禁食不禁水4小时，末次给药后，禁食不禁水4小时，静脉取血，制备血清，供血液生化指标测定。然后，处死，取脏器组织，制备匀浆。采用高效液相色谱-串联质谱法(HPLC-MS/MS)测定各组织中的三磷酸活性代谢物PSI-7409的含量。仪器：美国Finnigan公司TSQ Quantum型液相色谱-质谱联用仪(LC/MS/MS)，由Finnigan Surveyor LC泵、Surveyor AS自动进样器、电喷雾离子化电离源(ESI)及三级串联质谱组成。控制软件为Xcalibur 1.4，质谱数据分析采用Lcquan 2.0数据处理系统。色谱柱为Discovery ODS柱(250mm×4.6mm，5μm)，C18保护柱(4mm×3.0mm)，流动相为甲醇-水-甲酸(10-30：90-70：0.5，V/V/V)，流速0.7ml/min；进样量20μL；柱温为室温。
测定结果表明，索非布韦和Ia-2-1给药后，肝脏中三磷酸活性代谢物PSI-7409的含量相当，但是索非布韦给药组动物胸腺、淋巴结、脾脏及心脏等组织中活性代谢物的含量显著高于Ia-2-1组。具体结果见表3：
表3 索非布韦和Ia-2-1给药后各脏器中PSI-7409的含量(ng/g)
实施例5索非布韦和Ia-2-1比格犬连续给药的亚急性毒性评价
取雄性比格犬(7-8月龄，体重7-10kg)随机分组，4只一组，称重。将一定浓度的待测样品研磨悬浮于0.5％的羧甲基纤维素钠溶液中，灌胃给予含有1000mg/kg索非布韦或Ia-2-1的羧甲基纤维素钠悬浮液，每天1次，连续14天。于第13天给药后不同时间，测定QTc，结果见表4；于第14天给药后，禁食不禁水4小时，静脉取血，制备血清，供血液生化指标测定。然后处死，取脏器组织经充分固定后，逐级乙醇脱水，二甲苯透明，石蜡，制备4μm切片，HE染色，光学显微镜检查。
QTc测定结果表明，给药两组动物的QTc为202毫秒；给药后索非布韦组动物的QTc显著高于Ia-1-1组。具体结果见表4：
表4 索非布韦和Ia-2-1第13天给药后不同时间(min)的QTc(毫秒)
血液学测定结果表明，两组动物均无显著异常；生化指标测定结果表明，AST，ALP，总胆红素有所升高，两组之间无显著差异。
组织病理学检测结果表明，两给药组均见肝脏增生；但是索非布韦组多见胸腺萎缩、肾上腺皮质增生及胆囊单核细胞侵润。具体结果见表5：
表5 索非布韦和Ia-2-1给药后病理主要病变发生率
Claims (16)
1.式Ia所示的磷酸/膦酸衍生物及其非毒性药学上可接受的盐：
其中，式Ib所示的非对映异构体的含量小于10％，
结构式Ia和Ib中，Ar代表取代或未取代的苯环或萘环，R1代表H或碳原子数1-6的烷基；R2代表碳原子数1-6的烷基或环烷基；D代表含磷酸/膦酸基的药理活性分子的残基，即代表含磷酸/膦酸基的药理活性分子。
2.根据权利要求1，式Ia所示的磷酸/膦酸衍生物及其非毒性药学上可接受的盐：
其中，式Ib所示的非对映异构体的含量小于5％，
结构式Ia和Ib中，Ar代表取代或未取代的苯环或萘环，R1代表H或碳原子数1-6的烷基；R2代表碳原子数1-6的烷基或环烷基；D代表含磷酸/膦酸基的药理活性分子的残基，即代表含磷酸/膦酸基的药理活性分子。
3.根据权利要求1，式Ia所示的磷酸/膦酸衍生物及其非毒性药学上可接受的盐：
其中，式Ib所示的非对映异构体的含量小于2％，
结构式Ia和Ib中，Ar代表取代或未取代的苯环或萘环，R1代表H或碳原子数1-6的烷基；R2代表碳原子数1-6的烷基或环烷基；D代表含磷酸/膦酸基的药理活性分子的残基，即代表含磷酸/膦酸基的药理活性分子。
4.根据权利要求3，式Ia-1所示的膦酸衍生物及其非毒性药学上可接受的盐：
其中，式Ib-1所示的非对映异构体的含量小于2％，
结构式Ia-1和Ib-1中，R1代表H或碳原子数1-6的烷基；R2代表碳原子数1-6的烷基或环烷基。
5.根据权利要求4，式Ia-1-1所示的膦酸衍生物及其非毒性药学上可接受的盐：
其中，Ib-1-1的含量小于2％，
6.根据权利要求5，式Ia-1-1所示的膦酸衍生物及其非毒性药学上可接受的盐：
其中，Ib-1-1的含量小于1％，
7.根据权利要求3，式Ia-2所示的磷酸衍生物及其非毒性药学上可接受的盐：
其中，式Ib-2所示的非对映异构体的含量小于2％，
结构式Ia-2和Ib-2中，R1代表H或碳原子数1-6的烷基；R2代表碳原子数1-6的烷基或环烷基。
8.根据权利要求7，式Ia-2-1所示的磷酸衍生物及其非毒性药学上可接受的盐：
其中，式Ib-2-1所示的非对映异构体的含量小于2％，
9.根据权利要求8，式Ia-2-1所示的磷酸衍生物及其非毒性药学上可接受的盐：
其中，式Ib-2-1所示的非对映异构体的含量小于1％，
10.权利要求1-9中所述的磷酸/膦酸衍生物及其非毒性药学上可接受的盐在制备治疗肝病的药物中的用途。
11.权利要求4-6中所述的膦酸衍生物及其非毒性药学上可接受的盐在制备治疗HBV的药物中的用途。
12.权利要求7-9中所述的磷酸衍生物及其非毒性药学上可接受的盐在制备治疗HCV的药物中的用途。
13.含有20-50mg的权利要求5或6中所述的膦酸衍生物及其非毒性药学上可接受的盐作为活性成分，以及一种或多种药用载体或赋形剂的药物组合物。
14.含有200-600mg的权利要求8或9中所述的磷酸衍生物及其非毒性药学上可接受的盐作为活性成分，以及一种或多种药用载体或赋形剂的药物组合物。
15.含有20-50mg的权利要求5或6中所述的膦酸衍生物及其非毒性药学上可接受的盐作为活性成分，以及一种或多种药用载体或赋形剂的药物组合物，在制备治疗HBV药物中的用途。
16.含有200-600mg的权利要求8或9中所述的磷酸衍生物及其非毒性药学上可接受的盐作为活性成分，以及一种或多种药用载体或赋形剂的药物组合物。在制备治疗HCV药物中的用途。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611086405.7A CN108129514A (zh) | 2016-12-01 | 2016-12-01 | 磷酸/膦酸衍生物的单一异构体及其医药用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611086405.7A CN108129514A (zh) | 2016-12-01 | 2016-12-01 | 磷酸/膦酸衍生物的单一异构体及其医药用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108129514A true CN108129514A (zh) | 2018-06-08 |
Family
ID=62387390
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611086405.7A Withdrawn CN108129514A (zh) | 2016-12-01 | 2016-12-01 | 磷酸/膦酸衍生物的单一异构体及其医药用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108129514A (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590844A (zh) * | 2019-09-21 | 2019-12-20 | 江西农业大学 | 一种两步法合成替诺福韦艾拉酚胺的制备方法 |
| CN111393494A (zh) * | 2020-04-17 | 2020-07-10 | 广东帕派恩生物科技有限公司 | 基于核苷酸结构的化合物、制备方法、用途 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443189A (zh) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | 核苷酸膦酸酯类似物前药及其筛选和制备方法 |
| CN102459299A (zh) * | 2009-05-20 | 2012-05-16 | 法莫赛特股份有限公司 | N-[(2′r)-2′-脱氧-2′-氟-2′-甲基-p-苯基-5′-尿苷酰基]-l-丙氨酸1-甲基乙基酯及其制备方法 |
| WO2013025788A1 (en) * | 2011-08-16 | 2013-02-21 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
-
2016
- 2016-12-01 CN CN201611086405.7A patent/CN108129514A/zh not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443189A (zh) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | 核苷酸膦酸酯类似物前药及其筛选和制备方法 |
| CN102459299A (zh) * | 2009-05-20 | 2012-05-16 | 法莫赛特股份有限公司 | N-[(2′r)-2′-脱氧-2′-氟-2′-甲基-p-苯基-5′-尿苷酰基]-l-丙氨酸1-甲基乙基酯及其制备方法 |
| WO2013025788A1 (en) * | 2011-08-16 | 2013-02-21 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590844A (zh) * | 2019-09-21 | 2019-12-20 | 江西农业大学 | 一种两步法合成替诺福韦艾拉酚胺的制备方法 |
| CN111393494A (zh) * | 2020-04-17 | 2020-07-10 | 广东帕派恩生物科技有限公司 | 基于核苷酸结构的化合物、制备方法、用途 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104640444B (zh) | 双肝脏靶向氨基磷酸酯和氨基膦酸酯前药 | |
| EP2998307B1 (en) | Phosphoric acid/phosphonic acid derivatives and medicinal uses thereof | |
| CN103980318B (zh) | 含有取代苄基的核苷磷酸酯前药及其制备方法和用途 | |
| AU2013307899B2 (en) | Tenofovir prodrug and pharmaceutical uses thereof | |
| EP0820461B1 (en) | Aryl-ester phosphoramidate derivatives of 2',3'-didehydronucleosides | |
| US9156874B2 (en) | Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs | |
| CA2915187C (en) | N-[(2'r)-2'-deoxy-2'-fluoro-2'-methyl-p-phenyl-5'-uridylyl]-l-alanine 1-methylethyl ester and process for its production | |
| CN106188192B (zh) | 含d-氨基酸酯的核苷氨基磷酸/膦酸酯衍生物及其医药用途 | |
| PT1628685E (pt) | Análogos de fosfonatos antivirais | |
| CN107286190A (zh) | 核苷之烃氧基苄基氨基磷酸/膦酸酯衍生物的制备及其医药用途 | |
| NZ535246A (en) | 3'-prodrugs of 2'-deoxy-beta-L-nucleosides | |
| PT2552930E (pt) | 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihidropirimidin- 1-(2h)-il)-4-fluoro-3-hidroxi-4-metiltetrahidrofuran-2- il)metoxi) (fenoxi)fosforil)amino)propanoato de (s)- isopropilo cristalino | |
| CA2890676A1 (en) | Phosphonucleosides useful in the treatment of viral disorders | |
| Roman et al. | Diastereoselective synthesis of aryloxy phosphoramidate prodrugs of 3′-deoxy-2′, 3′-didehydrothymidine monophosphate | |
| CN104119385B (zh) | 核苷类似物的磷酸酯前药及其应用 | |
| WO2015101183A1 (zh) | 尿嘧啶核苷酸类似物及其制备方法和应用 | |
| CN106661075A (zh) | 二磷酸和三磷酸前体药物 | |
| CN108129514A (zh) | 磷酸/膦酸衍生物的单一异构体及其医药用途 | |
| CN107820499A (zh) | 新的抗病毒化合物、其制备工艺、以及其用于治疗病毒感染的用途 | |
| WO2011113173A1 (zh) | 阿糖胞苷衍生物及其在抗癌抗肿瘤中的用途 | |
| KR101231925B1 (ko) | 젬시타빈의 전구약물 및 이의 제조방법 | |
| KR20210038562A (ko) | 젬시타빈의 인-함유 프로드러그 | |
| CN109134568B (zh) | 核苷磷酸酯/酰胺衍生物及其医药用途 | |
| CA2849694C (en) | Nucleoside phosphoramidates | |
| CN101085785A (zh) | 用于治疗乙型肝炎的嘌呤类化合物及其制备方法和用途，以及包括该化合物的组合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180608 |
|
| WW01 | Invention patent application withdrawn after publication |