CN112979705A - 核苷酸类似物化合物及其盐、制备方法及其药物用途 - Google Patents
核苷酸类似物化合物及其盐、制备方法及其药物用途 Download PDFInfo
- Publication number
- CN112979705A CN112979705A CN201911315301.2A CN201911315301A CN112979705A CN 112979705 A CN112979705 A CN 112979705A CN 201911315301 A CN201911315301 A CN 201911315301A CN 112979705 A CN112979705 A CN 112979705A
- Authority
- CN
- China
- Prior art keywords
- amino
- cyclopropylethoxy
- purin
- isopropyl
- methyl
- 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.)
- Granted
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- -1 Nucleotide analogue compound Chemical class 0.000 title claims description 60
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 125000003729 nucleotide group Chemical group 0.000 claims abstract description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 15
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 15
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 14
- 239000001530 fumaric acid Substances 0.000 claims description 14
- 239000003112 inhibitor Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- 230000003612 virological effect Effects 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 4
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000002777 nucleoside Substances 0.000 claims description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 3
- 239000006186 oral dosage form Substances 0.000 claims description 3
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 claims description 2
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims description 2
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims description 2
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims description 2
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 claims description 2
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 2
- 108010002459 HIV Integrase Proteins 0.000 claims description 2
- 108010010369 HIV Protease Proteins 0.000 claims description 2
- 229940099797 HIV integrase inhibitor Drugs 0.000 claims description 2
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 claims description 2
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- 229960005261 aspartic acid Drugs 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- 210000000234 capsid Anatomy 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 229940124784 gp41 inhibitor Drugs 0.000 claims description 2
- 230000002443 hepatoprotective effect Effects 0.000 claims description 2
- 239000003084 hiv integrase inhibitor Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 229930014626 natural product Natural products 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 claims description 2
- 229940100243 oleanolic acid Drugs 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229940116315 oxalic acid Drugs 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 claims description 2
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 150000003460 sulfonic acids Chemical class 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 22
- 229940079593 drug Drugs 0.000 abstract description 21
- 241000713772 Human immunodeficiency virus 1 Species 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 208000002672 hepatitis B Diseases 0.000 abstract description 11
- 238000012360 testing method Methods 0.000 abstract description 11
- 229960004946 tenofovir alafenamide Drugs 0.000 abstract 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 abstract description 9
- 230000029812 viral genome replication Effects 0.000 abstract description 9
- 238000002474 experimental method Methods 0.000 abstract description 7
- 150000002632 lipids Chemical class 0.000 abstract description 7
- 241000700721 Hepatitis B virus Species 0.000 abstract description 6
- 208000030507 AIDS Diseases 0.000 abstract description 4
- 238000011282 treatment Methods 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 description 31
- 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 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 21
- 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 21
- 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 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 241000700605 Viruses Species 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 229960004556 tenofovir Drugs 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- 239000000523 sample Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229960001997 adefovir Drugs 0.000 description 9
- 229960003205 adefovir dipivoxil Drugs 0.000 description 9
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 229960001355 tenofovir disoproxil Drugs 0.000 description 9
- 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 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 238000012258 culturing Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 101710205625 Capsid protein p24 Proteins 0.000 description 4
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 4
- 101710142246 External core antigen Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 101710177166 Phosphoprotein Proteins 0.000 description 4
- 101710149279 Small delta antigen Proteins 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000011221 initial treatment Methods 0.000 description 4
- 230000003907 kidney function Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 206010067484 Adverse reaction Diseases 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 230000006838 adverse reaction Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- ILUWUBMXUOXRFY-YFKPBYRVSA-N (2R)-2-cyclopropyloxirane Chemical compound C1CC1[C@@H]1CO1 ILUWUBMXUOXRFY-YFKPBYRVSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- 241001112090 Pseudovirus Species 0.000 description 2
- IACQCQDWSIQSRP-ZCFIWIBFSA-N [(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-[hydroxy(phosphonooxy)phosphoryl]oxyphosphinic acid Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(=O)OP(O)(=O)OP(O)(O)=O)C=NC2=C1N IACQCQDWSIQSRP-ZCFIWIBFSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 239000008101 lactose Substances 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
- 210000004185 liver Anatomy 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GXBYFVGCMPJVJX-SCSAIBSYSA-N (2r)-2-ethenyloxirane Chemical compound C=C[C@@H]1CO1 GXBYFVGCMPJVJX-SCSAIBSYSA-N 0.000 description 1
- HBZBAMXERPYTFS-SECBINFHSA-N (4S)-2-(6,7-dihydro-5H-pyrrolo[3,2-f][1,3]benzothiazol-2-yl)-4,5-dihydro-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)[C@H]1CSC(=N1)c1nc2cc3CCNc3cc2s1 HBZBAMXERPYTFS-SECBINFHSA-N 0.000 description 1
- KTVKQTNGWVJHFL-UHFFFAOYSA-N 2-ethylchromen-4-one Chemical compound C1=CC=C2OC(CC)=CC(=O)C2=C1 KTVKQTNGWVJHFL-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 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
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 108091036055 CccDNA Proteins 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- GXBYFVGCMPJVJX-UHFFFAOYSA-N Epoxybutene Chemical compound C=CC1CO1 GXBYFVGCMPJVJX-UHFFFAOYSA-N 0.000 description 1
- 208000026019 Fanconi renotubular syndrome Diseases 0.000 description 1
- 201000006328 Fanconi syndrome Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 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
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 229940124405 anti-hepatitis b virus drug Drugs 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 208000019804 backache Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- UOEFFQWLRUBDME-UHFFFAOYSA-N diethoxyphosphorylmethyl 4-methylbenzenesulfonate Chemical compound CCOP(=O)(OCC)COS(=O)(=O)C1=CC=C(C)C=C1 UOEFFQWLRUBDME-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000006443 lactic acidosis Diseases 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003589 nefrotoxic effect Effects 0.000 description 1
- 231100000381 nephrotoxic Toxicity 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 238000012257 pre-denaturation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 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 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation 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
-
- 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
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一组核苷酸类似物化合物、其盐、其非对映异构体及其盐,还公开了制备方法以及含有该组化合物的药物组合物。试验证明本发明化合物具有抑制HBV病毒复制的活性,同时所述化合物具有比目前治疗艾滋病药物替诺福韦艾拉酚胺(TAF)脂溶性高、生物利用度高、活性高、毒性低等优点。实验还证明本发明化合物还具有抑制HIV‑1病毒复制的活性,可用于治疗艾滋病药物或乙型肝炎药物的开发。
Description
技术领域
本发明涉及一组核苷酸类似物化合物及其盐,尤其涉及一组具有抑制HIV-1/HBV病毒复制活性的核苷酸类似物化合物及其盐、制备方法及其药物用途。
本发明涉及对药物分子进行化学修饰以改善现有药物的不足,具体来说是替诺福韦艾拉酚胺(TAF)中的替诺福韦的甲基修饰为环丙基所制成的化合物及其盐,还涉及它们的制备方法和在抗病毒方面的应用。
背景技术
阿德福韦和泰诺福韦是结构相近的核苷类似物,具有广谱的抗病毒活性,其结构式为:
其中A可选择H或CH3,当A代表H时,即为阿德福韦;当A代表CH3时,即为泰诺福韦。
临床试验发现阿德福韦和泰诺福韦都具有较好的抗艾滋病病毒(HIV)、乙肝病毒(HBV)活性。实验证实阿德福韦和泰诺福韦对体外培养的鸭肝细胞、人肝癌细胞系中乙型肝炎病毒的复制和表达具有显著的抑制作用。动物试验研究表明,阿德福韦和泰诺福韦对于体内的肝炎病毒的复制和表达也具有显著的抑制作用。在长期应用核苷类似物如拉咪夫定等治疗过程中,容易发生病毒基因的突变,从而发生抗药性。研究表明,阿德福韦和泰诺福韦不仅对于野生株具有显著的抑制作用,而且对于拉咪夫定等的耐药病毒株也具有显著的抑制作用。
但在生理pH情况下,分子中直接暴露的膦酸根限制了阿德福韦和泰诺福韦对肠道的穿透力,使得它们在动物和人体中的生物利用度降低,限制了其对疾病的治疗作用。通过对阿德福韦上膦酸官能团的修饰,已经合成出阿德福韦酯(Adefovir dipivoxil)和泰诺福韦酯(tenofovir disoproxil),结构式如下:
阿德福韦酯和替泰诺福韦酯的抗病毒部分分别是PMEA和PMPA,进入体内完全转化为PMEA和PMPA而发挥作用。作为阿德福韦和泰诺福韦的前体药物,阿德福韦酯和泰诺福韦酯中膦酸盐上的电荷得到了屏蔽,增加了母体的脂溶性,提高了对肠道细胞膜的穿透力,其口服生物利用度也得到相应的增加。
但是,阿得福韦酯在人体内主要集中分布在肾、肝和肺,临床研究发现阿得福韦酯具有较大的肾毒性,因此只能采用10mg/天的非优化的治疗剂量,这在一定程度上限制了其对疾病的治疗效果。泰诺福韦酯的肾毒性比阿得福韦酯小,但口服剂量需要150-300mg,生物利用度较低,因此,目前仍在寻找更好的前体药物。
近年来随着治疗慢性乙肝的抗病毒药物研发的进行,一种名为替诺福韦艾拉酚胺富马酸盐(Tenofovir Alafenamide Fumarate,简称TAF)的新药逐渐进入大众视野。该药是已上市的口服抗病毒药物替诺福韦酯(Tenofovir Disoprox,简称TDF)的升级版。
在临床试验中,替诺福韦艾拉酚胺富马酸盐已被证明在服用量仅为替诺福韦酯的十分之一剂量时,就具有非常高的抗病毒疗效,耐药率和替诺福韦酯一样都非常低,同时该药相比替诺福韦酯具有更好的安全性,对肾功能和骨骼的副作用更小。
替诺福韦艾拉酚胺富马酸盐是一种逆转录酶抑制剂,进入肝细胞后,药物可水解成替诺福韦。替诺福韦随后被细胞内的激酶磷酸化,成为具有药理活性的替诺福韦二磷酸盐。替诺福韦二磷酸盐由HBV逆转录酶整合进入病毒的DNA,从而导致DNA链合成的中断,达到抑制病毒复制的目的。
该药主要适用于乙肝病毒复制活动活跃,转氨酶持续升高或者肝脏组织学显示为活动性肝病的成年慢性乙型肝炎患者。
根据国外的研究报道,在一项编号为NCT01940341的临床实验中,让425名慢性乙肝患者按计算机生成码分配顺序,随机接受TAF和TDF治疗48周。并对这两组患者进行对照研究,其中服用TAF的剂量为每日一次,每次25mg;服用TDF的剂量为每日一次,每次300mg,结果TAF的HBV DNA转阴率,ALT复常率均优于TDF。
HBeAg阳性患者初始治疗每日服用25mgTAF经48周治疗:HBVDNA转阴率为68%;ALT复常率为72%;HBeAg阴性患者初始治疗每日服用25mgTAF经48周治疗:HBVDNA转阴率为94%;ALT复常率为83%;HBeAg阳性患者初始治疗每日服用300mgTDF经48周治疗:HBVDNA转阴率为76%;ALT复常率为68%;HBeAg阴性患者初始治疗每日服用300mgTDF经48周治疗:HBVDNA转阴率为93%;ALT复常率为76%;
遗憾的是48周治疗后,替诺福韦艾拉酚胺富马酸盐的HBsAg阴转率为0。因此,替诺福韦艾拉酚胺富马酸还是改变不了慢性乙型肝炎患者长期用药的现状。
替诺福韦艾拉酚胺富马酸盐虽然是替诺福韦酯的升级版,但还是未能完全治愈乙肝。和其他口服抗乙肝病毒药物一样,替诺福韦艾拉酚胺富马酸盐对cccDNA没有清除作用,因此也不能完全清除体内的乙肝病毒。所以治疗中间不能随意停药,随意停药有可能出现病毒反弹,也有可能出现明显的生物化学反弹,甚至出现致命性的反弹。
在服用该药也会出现一些不良反应,主要包括头痛、上呼吸道感染、咽炎、咳嗽等。其中据临床研究试验数据显示TAF治疗期间发生头痛、腹痛、疲乏、咳嗽、恶心、背痛的比例分别为9%、7%、6%、6%、5%、5%。在服用该药期间还需要关注乳酸酸中毒、脂肪变性的表现。
另一方面,替诺福韦艾拉酚胺富马酸盐还会引发肾功能的不良发应,建议患者在服用替诺福韦艾拉酚胺富马酸前和服用期间都要进行肾功能、血清磷等监测,进而降低患者发生肾功能损害和出现范可尼综合征的发生率。
综上所述,虽然目前全球的抗HIV-1/HBV药物,吉利德公司的TDF、TAF复方制剂几乎独占市场,但是我们的基于TNF的治疗艾滋病药物研究仍然意义巨大。充分提高其脂溶性,进一步改善其人体的生物利用度而充分发挥治疗乙肝和艾滋病的药效仍然具有重要的价值。
发明内容
本发明的目的是针对现有技术的不足,对替诺福韦艾拉酚胺(TAF)的结构进行更进一步的改造,得到具有更高的生物利用度、更高抑制病毒活性和更低毒性的新的核苷酸类似物
本发明的另一个目的是提供对替诺福韦艾拉酚胺(TAF)进行化学修饰的方法。
本发明的再一个目的是提供上述替诺福韦艾拉酚胺(TAF)类似的药物在抗病毒领域、特别是抗乙肝病毒领域的应用。
本发明所述的对替诺福韦艾拉酚胺(TAF)的结构修饰的化合物,具有如下通式:
其中,A为环丙基,R1为H、CH3、CH2F、CHF2、CF3或OH,R2为苯基,R3为-CH(CH3)-C(O)-O-CH(CH3)2。
本发明还提供了所述的化合物及其非对映异构体,所优选的化合物结构式为下列结构式:
本发明还提供了所述的化合物及其非对映异构体的盐,其中酸为无机酸,有机磺酸,有机羧酸或含有酸性基团的且具有保护肝脏作用的有机化合物或天然产物,酸和如权利要求1所述的化合物及其非对映异构体的摩尔比的范围为0.5至1。
本发明还提供了所述的盐,其中有机磺酸为C6-16芳基磺酸、C6-16杂芳基磺酸或C1-16烷基磺酸。
本发明还提供了所述的盐,其中有机羧酸为C1-16烷基羧酸、C6-16芳基羧酸、C4-16杂芳基羧酸或氨基酸。
本发明还提供了所述的盐,其中酸为富马酸、草酸、水杨酸、齐墩果酸或天冬氨酸。
本发明公开了所述的盐,其为如下结构式的富马酸盐:
本发明公开了所述的化合物及其对非对映异构体、经及其药学上可接受的盐的合成路线:
本发明还提供了一种药物组合物,其特征在于,所述药物组合物含有治疗有效量的权利要求1-5中任一项所述的核苷酸类似物化合物或其药学上可接受的盐和一种或多种药学上可接受的载体或赋形剂。
本发明还公开了所述的药物组合物,其特征在于:所述药物组合物还包含治疗有效量的额外的治疗剂,其中所述额外的治疗剂是抑制HIV蛋白酶的化合物,逆转录酶的HIV非核苷抑制剂,逆转录酶的HIV核苷抑制剂,逆转录酶的HIV核苷酸抑制剂,HIV整合酶抑制剂,gp41抑制剂,CXCR4抑制剂,gp120抑制剂,CCR5抑制剂,病毒壳体聚合抑制剂,或非催化部位HIV整合酶部位抑制剂和其组合。
本发明化开了所述的组合物,其特征在于口服剂型为片剂,胶囊剂、颗粒剂或口服液;注射剂是注射液、注射用无菌粉针和注射用浓溶液。
本发明还公开了所提供的药物组合物在制备用于预防或治疗病毒疾病药物中的应用。
本发明还公开了所提供的药物组合物在制备用于预防或治疗病毒疾病药物中的应用中病毒疾病为HIV-1或HBV感染或HIV-1与HBV同时感染。
总之,本发明化合物集高活性、低毒性、高生物利用度等各种良好属性于一体,有着成为新一代治疗艾滋病或治疗乙型肝炎的药物的前景。
具体实施方式:
以下实施例可以使本专业技术人员更全面地理解本发明,但不以任何方式限制本发明。
实施例1(R)-2-环丙基环氧乙烷的制备
将35g(0.5mol)的(R)-2-乙烯基环氧乙烷加入到100ml的乙醚中,冷却至0-5℃,加入适量Pd(acac)2,加入52.55g(1.25mol)重氮甲烷,加毕继续反应3小时,即得(R)-2-环丙基环氧乙烷(收率72%)。
实施例2(S)-2-环丙基环氧乙烷的制备
实施例 | 2-乙烯基环氧乙烷 | 产物 |
2 | (S)-2-乙烯基环氧乙烷 | (S)-2-环丙基环氧乙烷 |
制备方法参照实施例1。
实施例3(R)-2-(6-氨基嘌呤-9-基)-1-环丙基乙醇的制备
向腺嘌呤(40g,0.296mol)的DMF(42ml)的悬浮液中加入(R)-2-环丙基环氧乙烷(28.4g,0.338mol)和氢氧化钠(0.48g,0.012mol),升温至130℃反应5小时,反应毕,冷却至0-5℃,析晶,纯化分离,得类白色(R)2-(6-氨基嘌呤-9-基)-1-环丙基乙醇33.9g(收率70%)。
实施例4(S)2-(6-氨基嘌呤-9-基)-1-环丙基-乙醇的制备
制备方法参照实施例3。
实施例5FHCP181的制备
步骤一:(S)-(2-(6-氨基-6H-嘌呤-9-基)-1-环丙基乙氧基)甲基膦酸(I)的制备
将(R)-2-(6-氨基嘌呤-9-基)-1-环丙基乙醇(22.8g,0.104mol)加入DMF(50ml)中,并加热至65℃。分次加入叔丁醇镁(14.2g,0.083mol),加毕,保持温度为78℃,的2小时内加入对甲苯磺酰基氧基甲基膦酸二乙酯(66.0g,0.205mol)。75℃搅拌反应4小时。冷却反应液低于50℃后,加入三甲基溴硅烷(73.9g,0.478mol),并在75℃加热反应3小时,减压回收溶剂,将残留物溶于50℃水中,乙酸乙酯(100ml)萃取。水层用氢氧化钠调节pH值至2.0,低温冷藏过夜,过滤,分离出固体,用水(50ml)洗涤,50℃真空干燥,得21.2g(65%)类白色固体粗产物(S)-(2-(6-氨基-6H-嘌呤-9-基)-1-环丙基乙氧基)甲基膦酸(I)。
将(S)-(2-(6-氨基-6H-嘌呤-9-基)-1-环丙基乙氧基)甲基膦酸粗产物加入水(250ml)中,加热回流至全部溶解,加入少量活性炭脱色15分钟,过滤,滤液自然冷却至室温,后冷至5℃低温析晶3小时,过滤分离出固体,用少量水和丙酮洗涤,50℃真空干燥,得到15.9g(75%)白色固体(S)-(2-(6-氨基-6H-嘌呤-9-基)-1-环丙基乙氧基)甲基膦酸(I)。
步骤二:苯基氢((S)-2-(6-氨基-9H-嘌呤-9-基)-1-环丙基乙氧基)甲基膦酸酯(II)的制备
将无水(S)-(2-(6-氨基-6H-嘌呤-9-基)-1-环丙基乙氧基)甲基膦酸(159.1g,0.508mol)、苯酚(96g,1.02mol)和1-甲基-2-吡咯烷酮(390g)加入到三口烧瓶中。加热至80℃并加入三乙胺(63g,0.623mol)。升温至100℃缓慢滴加1,3-二环己基碳化二亚胺(171g,0.829mol)的1-甲基-2-吡咯烷酮(16g)溶液。保温反应至完全,冷却反应液温度至25℃,过滤,弃去固体物,滤液减压浓缩至干,加水(250g),用氢氧化钠溶液调节pH至11。通过硅藻土过滤,除去细小沉淀,用水洗涤,用乙酸乙酯萃取合并的滤液和冲洗液,用盐酸调节pH值至3.5。过滤分离固体,并用适量甲醇打桨洗涤,过滤,减压干燥得93.5g白色固体苯基氢((S)-2-(6-氨基-9H-嘌呤-9-基)-1-环丙基乙氧基)甲基膦酸酯(II)。
步骤三:(S)-异丙基-2-((((R)-2-(6-氨基-9H-嘌呤-9-基)-1-环丙基乙氧基)甲基)(苯氧基)磷酰基氨基)丙酸(III)的制备
将固体物II(93.4g,0.240mol)和乙腈(300ml)加入到三口烧瓶中,在低于50℃的条件下加入亚硫酰氯(657g,0.567mol)。在75℃加热反应至混合物溶解。减压蒸馏反应液至干,冷却至25℃,加入二氯甲烷(400g),并冷却至-25℃。保持-18℃,加入(L)-丙氨酸异丙酯(71.1g,0.544mol)的二氯甲烷溶液。然后在-18℃--11℃之间中入三乙胺(766.6g,0.757mol)。加毕,加热升温至25℃,用10%磷酸二氢钠溶液洗涤3次,无水硫酸钠干燥有机溶剂,过滤,用二氯甲烷洗涤,减压浓缩得油状物,向得到的油状物中入丙酮(190g)使溶解。硅胶柱层析提纯,减压浓缩含纯产物的馏份,得60.7g黑色油状物(S)-异丙基-2-((((R)-2-(6-氨基-9H-嘌呤-9-基)-1-环丙基乙氧基)甲基)(苯氧基)磷酰基氨基)丙酸(III)。
步骤四:非对映异构体拆分
将中间体化合物(III)20g溶解在30ml乙腈溶液,并加入HCP018-1的晶体作为晶种。混合搅拌18小时,2-8℃冷却3小时,过滤分离出固体,50℃减压干燥,得到3.0g白色固体(S)-异丙基2-((R)-(((R)-2-(6-氨基-9H-嘌呤-9-基)-1-环丙基乙氧基)甲基)(苯氧基)磷酰基氨基)丙酸酯(HCP181),非对映异构体纯度为98%。
步骤五:(S)-异丙基2-((R)-(((R)-2-(6-氨基-9H-嘌呤-9-基)-1-环丙基乙氧基)甲基)(苯氧基)磷酰基氨基)丙酸酯,富马酸(2∶1)的制备
将HCP181(IV)(2.01g,0.004mol)、富马酸(0.24g,0.002mol)和乙腈(50ml)加入到烧瓶中,加热至回流使全部溶解,趁热过滤,滤液缓慢冷却至0-5℃并静置过夜,过滤,用适量冷乙腈洗涤,真空干燥得到白色粉末状固体,即目标化合物(HCP018-1F)(1.99g),收率89.9%。样品的质量分数为99.6%,光学异构体质量分数为0.14%(HPLC面积归一化法,检测条件:色谱柱为Agilent ODS-BP C18(4.6*150mm,5μm);流动相为V(乙腈)-V(醋酸铵)10mmol/L,pH6.0)(30:70);流速为1.0ml/min;检测波长为260nm;进样量为10μl;柱温为30℃。HPLC光学异构体检测条件:色谱柱为CHIRALPAK AD-H C18(4.6*250mm,5μm);流动相为V(正己烷)-V(异丙醇)(80:20);流速为1.0ml/min;检测波长为260nm;进样量为10μl;柱温为30℃)。
实施例6-8用实施例1、实施例2、实施例4、实施例5描述的方法,合成了一系列类似化合物,并通过拆分得到目标化合物,所使用的原料及产物列表如下:
实施例9-12用实施例2、实施例3、实施例4、实施例5描述的方法,合成了一系列类似化合物,并通过拆分得到目标化合物,所使用的原料及产物列表如下:
实施例13 HCP181单富马酸盐的制备
将HCP181(IV)(2.01g,0.004mol)、富马酸(0.48g,0.004mol)和乙腈(50ml)加入到烧瓶中,加热至回流使全部溶解,趁热过滤,滤液缓慢冷却至0-5℃并静置过夜,过滤,用适量冷乙腈洗涤,真空干燥得到白色粉末状固体,即得到FHCP181半富马酸盐(1.85g),收率89.9%。样品的质量分数为98.5%,光学异构体质量分数为0.25%(HPLC面积归一化法,检测条件:色谱柱为Agilent ZorBax SB-C18(4.6*150mm,5μm);流动相为V(乙腈)-V(醋酸铵)10mmol/L,pH6.0)(30∶70);流速为1.0ml/min;检测波长为260nm;进样量为10μl;柱温为30℃。HPLC光学异构体检测条件:色谱柱为CHIRALPAK AD-H C18(4.6*250mm,5μm);流动相为V(正己烷)-V(异丙醇)(80∶20);流速为1.0ml/min;检测波长为260nm;进样量为10μl;柱温为30℃)。
实施例14 HCP181半富马酸盐与HCP181单马酸盐化学稳定性
比较HCP181的半富马酸盐形式与单富马酸盐形式的化学稳定性。如下表中所示,在相同条件下,HCP181的半富马酸盐形式比单富马酸盐形式在化学上更稳定,并且展现更好的长期储存稳定性,并且降解(%总降解产物)明显更少。评估条件包括温度、相对湿度(RH)和容器封盖的打开或关闭状态。
实施例15本发明化合物抗HIV-1病毒活性的测定
1.实验材料
1.1供试品:化合物HCP0181、HCP0182
1.2对照品:阳性对照品替诺福韦艾拉酚胺(TAF)由检测单位提供。
1.3细胞株
1.4病毒株
1.5培养基
1.6实验用介质
二甲基亚砜(DMSO)美国Sigma。
1.7主要仪器及试剂
BS124S电子天平:德国Sartorius公司
离心机:美国Beckman公司;
CO2细胞培养箱:美国ShelIAB公司;
Sirius化学发光检测仪:德国Berthold公司;
胰蛋白酶:美国Invitrogen公司;
青链霉素:美国Invitrogen公司;
胎牛血清:美国Gibco公司;
细胞裂解液及荧光素酶检测试剂盒:美国Promega公司
2.实验
2.1供试品、对照品配制
受试样品:称重化合物并溶解于DMSO中,贮液浓度为10mmol/L;
对照品:称重TDF溶解于DMSO,贮液浓度为10mmol/L。
2.2实验步骤
2.2.1野生型HIV-1重组假病毒的制备:
转染前一天,按2.2×106个细胞的密度接种293T细胞到100mm培养皿中,用改良的磷酸钙沉淀法共转染3μgVSV-G质粒和8μg野生型HIV-1核心基因,转染后16小时,用PBS冲洗细胞并换新鲜的培养基继续培养32小时,收集上清并经0.45m的滤膜过滤,生成野生型HlV-1重组病毒颗粒VSVG/HIV-WT。
2.2.2HIV-1重组假病毒的p24抗原测定:
倍比稀释病毒原液野生型后各取450μl,用50μl的裂解液进行裂解,按照p24抗原ELISA试剂盒说明书(ZeptoMetrix,Cat:1908015),测定并计算重组病毒原液的p24抗原浓度。
2.2.3药物对HIV-1抑制性检测:
感染前一天,将293T细胞按每孔6×104的密度接种到24孔板上,用DMSO溶解待测化合物,于感染前15分钟加入细胞培养液中,DMSO溶剂作空白对照,再加入0.5ml病毒液(根据p24浓度将病毒原液稀释至0.1-0.5ngp24/ml)。感染后48小时,去除上清,每孔中加入50I细胞裂解液(Promega)裂解细胞,再将20I细胞裂解产物加入至30I荧光素酶底物中(Promega),用FB15荧光检测器(Sirius)仪器测定细胞荧光素酶的相对活性,以DMSO作对照,计算化合物对野生型HIV-1复制的半数抑制浓度,检测数据见药理筛选结果表1。
化合物 | 药理模型 | 细胞 | IC50(nM) |
HCP181 | VSVG/HIV-1uc | 293T细胞 | 1.6 |
HCP182 | VSVG/HIV-1uc | 293T细胞 | 3.5 |
TAF | VSVG/HIV-1uc | 293T细胞 | 10.9 |
2.2.4应用MTS法检测化合物对细胞存活的影响
将对数生长期的293T细胞按8000~10000个/孔的细胞密度接种至96孔板中,每孔100ul,37℃,5%CO2培养箱中培养24h后,加入待测化合物,并以DMSO为空白对照(终浓度为0.1%),37℃,5%CO2培养箱中继续培养44小时。向每孔中加入20μl MTS/PMS现配的混合液,37℃,5%CO2培养箱中继续培养4h后显色。在酶联检测仪上,波长490nm和650nm(本底)处检测各孔的光吸收值(OD),并计算细胞的存活率。
4、实验结论
化合物HCP181、HCP182可有效抑制野生型HIV-1的复制,其半抑制浓度IC50分别为:HCP181(1.6nmol/L);HCP182(3.5nmol/L);在相同条件下平行测定的阳性对照TAF半抑制效浓度为10.9nM。
所有化合物在终浓度10μmol/L时均无细胞毒性。
上述对本发明化合物抗HIV活性与细胞毒性的测定表明:
本发明化合物HCP181、HCP182的体外活性比TAF高出了3-7倍,达到了纳摩级(10-9)水平。其中化合物HCP181抑制病毒复制活性的IC50值为1.5±0.15nM,这说明本发明化合物HCP181抑制病毒复制的活性高出TDF7倍。
这种活性级别在药物研发筛选中是非常罕见的,而且本发明化合物HCP181、HCP182的细胞毒性也是很低的。这些检测数据充分证明本发明化合物HCP181、HCP182不仅具有很高的抑制HIV-1/HBV病毒复制活性的优点,而且具有很低的毒性,有望成为治疗HIV-1/HBV的药物的前景。
实施例16本发明化合物抗HBV病毒活性的体外测定
1.体外细胞模型:HepG22.215细胞
2.试验过程
2.1药液配制
药物先用DMSO溶解为40mg/mL的母液,临用前用细胞培养液将母液稀释为200、100、50、25和12.5μg/mL五个工作浓度。
2.2药物的细胞毒性检测
HepG22.2.15细胞在48孔细胞培养板中培养48小时后,加入上述所配不同浓度含药培养液,继续培养9天(每3天换液一次),观察药物对HepG22.2.15细胞的毒性。
2.3药物对HBV病毒抗原和DNA抑制作用检测
HepG22.2.15细胞在24孔细胞培养板中培养48小时后,加入所配不同浓度含药培养液,继续培养9天(每3天换液一次),收集上清液,用ELISA方法检测样品对HBV s抗原和e抗原的抑制,用荧光探针法进行实时定量PCR检测HBV引物HBV上游引物:
5′-TgT CCT ggT TAT CgC Tgg-3′
HBV下游引物:
5′-CAA ACg ggC AAC ATA CCT T-3′
HBV荧光探针序列:
5′(FAM)-TgT gTC TgC ggC gTT TTA TCA T-(TAMRA)3′
PCR:
95℃预变性5min;95℃变性10s,60℃退火和延伸共30s,40个循环
3.结果:见下表-体外抗乙肝病毒活性筛选表
4.实验结论:
化合物拆分之后,两个异构体活性数据差距还是较大的,EC50:HCP181-2是HCP181-1的1.51倍,HCP182-2是HCP182-1的1.51倍,是HCP181-1、HCP182-1可有效抑制HBV的复制,其SI(CC50/EC50)分别为13333、5714,而在相同条件下平行测定的阳性对照TAF的SI是5181,尤其是HCP181-1,其SI是3TC的2.57倍。
这充分表明:本发明化合物比目前抗乙肝药物TAF抑制病毒复制的活性高出很多,有望成为治疗HBV感染的药物。
实施例17化合物HCP181与TAF脂溶性大小的测定
比较两种物质脂溶性大小的原理:
物质的脂溶性与物质的极性大小相关,物质的极性越大,则该物质的脂溶性越小,物质的极性越小,则该物质的脂溶性越大。
各种物质的脂溶性大小的比较,通常通过测定不同物质在一定的条件下,在反向液相色谱图上,保留时间的长短来表征。物质的脂溶性越高,则表现为该物质在反向液相色谱图上,保留时间越长。
本发明化合物HCP181与TAF脂溶性大小的比较就是根据上述的原理来进行的。
色谱条件:色谱柱,Agilent ZorBax SB-C18(250×4.6mm,5μm);流动相,甲醇∶水=(80∶20,v/v);检测波长:260nm;流速:1.0ml/min;柱温:30℃下,TAF的保留时间为4.361分钟,化合物HCP181的保留时间为5.025分钟。化合物HCP181的保留时间比TAF的保留时间延长了0.664分钟。
根据上述检测,本发明化合物HCP181的脂溶性比TAF的脂溶性脂溶性高出了许多。这也就是说本发明化合物HCP181的膜透过性比TAF膜透过性的高出了许多,从而提高了药物的治疗疾病的效果。
实施例18FHCP181半富马酸盐片剂的制备
在该制剂中,微晶纤维素用作压片时的粘合剂和崩解剂。内加交联羧甲基纤维素钠,有助于片剂的崩解和溶解。乳糖用作稀释剂来便于制备以及有助于片剂溶解。硬脂酸镁用作润滑剂有助于片剂从压片机中排出。
含有FHCP181的片剂制备如下:把微晶纤维素、交联羧甲基纤维素钠和乳糖在混合器中混合,加入水直至形成合适的湿颗粒。研磨该湿颗粒,在流化床中干燥直至含湿量不高于3%,干燥后的颗粒进行研磨,然后将该研磨后的颗粒与颗粒外辅料交联羧甲基纤维素钠,在混合器中混合得到粉末混合物。该粉末混合物然后与硬脂酸镁混合,再压成片剂。把片剂装入高密度聚乙烯瓶或玻璃瓶中,并应用聚酯包装材料和任选的硅胶干燥剂。
Claims (12)
2.如权利要求1所述的化合物及其非对映异构体,所优选的化合物结构式为下列结构式:
3.如权利要求1所述的化合物及其非对映异构体的盐,其中酸为无机酸,有机磺酸,有机羧酸或含有酸性基团的且具有保护肝脏作用的有机化合物或天然产物,酸和如权利要求1所述的化合物及其非对映异构体的摩尔比的范围为0.5至1。
4. 如权利要求3所述的盐,其中有机磺酸为C6-16芳基磺酸、C6-16杂芳基磺酸或C1-16 烷基磺酸。
5. 如权利要求3所述的盐,其中有机羧酸为C1-16 烷基羧酸、C6-16芳基羧酸、C4-16 杂芳基羧酸或氨基酸。
6.如权利要求3所述的盐,其中酸为富马酸、草酸、水杨酸、齐墩果酸或天冬氨酸。
7.如权利要求6所述的盐,其为如下结构式的富马酸盐:
9.一种药物组合物,其特征在于,所述药物组合物含有治疗有效量的权利要求1-7中任一项所述的核苷酸类似物化合物或其药学上可接受的盐和一种或多种药学上可接受的载体或赋形剂。
10.如权利要求1-7所述的药物组合物,其特征在于:所述药物组合物还包含治疗有效量的额外的治疗剂,其中所述额外的治疗剂是抑制HIV蛋白酶的化合物,逆转录酶的HIV非核苷抑制剂,逆转录酶的HIV核苷抑制剂,逆转录酶的HIV核苷酸抑制剂,HIV整合酶抑制剂,gp41抑制剂,CXCR4抑制剂,gp120抑制剂,CCR5抑制剂,病毒壳体聚合抑制剂,或非催化部位HIV整合酶部位抑制剂和其组合。
11.如权利要求6-7所述的组合物,为口服剂型或注射剂型。
12.如权利要求11所述的组合物,其特征在于口服剂型为片剂,胶囊剂、颗粒剂或口服液;注射剂是注射液、注射用无菌粉针和注射用浓溶液。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911315301.2A CN112979705B (zh) | 2019-12-18 | 2019-12-18 | 核苷酸类似物化合物及其盐、制备方法及其药物用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911315301.2A CN112979705B (zh) | 2019-12-18 | 2019-12-18 | 核苷酸类似物化合物及其盐、制备方法及其药物用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112979705A true CN112979705A (zh) | 2021-06-18 |
CN112979705B CN112979705B (zh) | 2024-01-26 |
Family
ID=76344123
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911315301.2A Active CN112979705B (zh) | 2019-12-18 | 2019-12-18 | 核苷酸类似物化合物及其盐、制备方法及其药物用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112979705B (zh) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1523028A (zh) * | 2003-02-18 | 2004-08-25 | 田镇华 | 一种新型的膦酸酯-核苷酸化合物 |
-
2019
- 2019-12-18 CN CN201911315301.2A patent/CN112979705B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1523028A (zh) * | 2003-02-18 | 2004-08-25 | 田镇华 | 一种新型的膦酸酯-核苷酸化合物 |
Non-Patent Citations (1)
Title |
---|
HANA DVOŘÁKOVÁ 等: "Synthesis of Some 2\'-C-Alkyl Derivatives of 9-(2-Phosphonomethoxyethyl)adenine and Related Compounds", COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, vol. 59, no. 9, pages 2069 - 2094 * |
Also Published As
Publication number | Publication date |
---|---|
CN112979705B (zh) | 2024-01-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102786549B (zh) | 一组具有抑制hiv-1病毒复制活性的替诺福韦双酯化合物、制备方法及其药物用途 | |
KR102057751B1 (ko) | 테노포비르 전구약물 및 그의 약학적 용도 | |
TWI641609B (zh) | 一種jak激酶抑制劑的硫酸氫鹽及其製備方法 | |
CN101031306B (zh) | 作为抗hiv剂的核苷膦酸酯缀合物 | |
CN103232490B (zh) | 具有抑制hiv-1/hbv病毒复制活性的核苷类化合物、制备方法及抗病毒方面的应用 | |
PT1628685E (pt) | Análogos de fosfonatos antivirais | |
CN102240297A (zh) | 泰诺福韦的晶体 | |
IL238217A (en) | Phosphonate ester derivatives and their synthesis methods | |
WO2017219915A1 (zh) | 一种腺嘌呤衍生物的膦酸酯前药及其在医药上的应用 | |
WO2015197006A1 (zh) | 一种取代的氨基酸硫酯类化合物、其组合物及应用 | |
WO2006082821A1 (ja) | ヘルペスウイルスが関与する疾患の予防若しくは治療剤 | |
CA2954395C (en) | New polycrystalline form of tenofovir prodrug, and preparation method and application therefor | |
CN111909204B (zh) | 一种替诺福韦双苯丙酸酯基氨基磷酸酯化合物及其药物组合物和用途 | |
CN112979705B (zh) | 核苷酸类似物化合物及其盐、制备方法及其药物用途 | |
CN109400647A (zh) | 一组替诺福韦双酯化合物及其盐、制备方法及其药物用途 | |
JP4482883B2 (ja) | 抗ウイルス作用を有する化合物およびその配合剤 | |
JP5993088B2 (ja) | ゲルマニウムの錯化合物、その生産方法、及び薬物 | |
RU2666727C1 (ru) | Ингибитор вируса гепатита В (ВГВ) | |
CN111909205B (zh) | 一种替诺福韦双丙酸酯基氨基磷酸酯化合物及其药物组合物和用途 | |
CN108690080A (zh) | 一组核苷酸类似物化合物及其盐、制备方法及其药物用途 | |
EP2841162A1 (en) | A method of mitigating virus associated end-organ damage | |
KR20100087241A (ko) | 아데포비어 디피복실 오로트산 염 및 이의 제조방법 | |
RU2665037C2 (ru) | Изопропил N-[{ [(1R)-2-(6-амино-9H-пурин-9-ил)-1-метилэтокси]метил} (1,3-бензотиазол-6-ил-окси)фосфорил]-L-аланинат фумарат в качестве противовирусного препарата - пролекарства Тенофовира | |
CN107849074A (zh) | 一种核苷类似物的烷氧烷基酯前药及其应用 | |
CN111018915A (zh) | 一种替诺福韦苯丙酸酯基氨基磷酸酯化合物及其药物组合物和应用 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |