CN106543227B - A kind of phosphonate prodrugs of adenine derivative and its application in medicine - Google Patents
A kind of phosphonate prodrugs of adenine derivative and its application in medicine Download PDFInfo
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- CN106543227B CN106543227B CN201610994945.9A CN201610994945A CN106543227B CN 106543227 B CN106543227 B CN 106543227B CN 201610994945 A CN201610994945 A CN 201610994945A CN 106543227 B CN106543227 B CN 106543227B
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- compound
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- officinal salt
- medicine
- optical isomer
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- 239000003814 drug Substances 0.000 title claims abstract description 21
- 229940002612 prodrug Drugs 0.000 title abstract description 12
- 239000000651 prodrug Substances 0.000 title abstract description 12
- FCZOVUJWOBSMSS-UHFFFAOYSA-N 5-[(6-aminopurin-9-yl)methyl]-5-methyl-3-methylideneoxolan-2-one Chemical compound C1=NC2=C(N)N=CN=C2N1CC1(C)CC(=C)C(=O)O1 FCZOVUJWOBSMSS-UHFFFAOYSA-N 0.000 title abstract description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 230000003287 optical effect Effects 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 208000036142 Viral infection Diseases 0.000 claims abstract description 8
- 230000009385 viral infection Effects 0.000 claims abstract description 8
- -1 normal-butyl Chemical group 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004437 phosphorous atom Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000031886 HIV Infections Diseases 0.000 claims description 3
- 208000037357 HIV infectious disease Diseases 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- 239000012453 solvate Substances 0.000 abstract description 2
- 208000030507 AIDS Diseases 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 27
- 229960004556 tenofovir Drugs 0.000 description 23
- 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 238000010189 synthetic method Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 14
- 238000011017 operating method Methods 0.000 description 14
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 14
- 210000002381 plasma Anatomy 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000000523 sample Substances 0.000 description 12
- 235000004400 serine Nutrition 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 210000004051 gastric juice Anatomy 0.000 description 10
- 229930024421 Adenine Natural products 0.000 description 8
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 8
- 229960000643 adenine Drugs 0.000 description 8
- 230000000977 initiatory effect Effects 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 210000004907 gland Anatomy 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000004679 31P NMR spectroscopy Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 229910006124 SOCl2 Inorganic materials 0.000 description 5
- 239000012228 culture supernatant Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- CQMGHTAETMKMBZ-LURJTMIESA-N propan-2-yl (2S)-2-amino-3-methoxypropanoate Chemical compound C(C)(C)OC([C@@H](N)COC)=O CQMGHTAETMKMBZ-LURJTMIESA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UJGRWVTWIDHCGO-VIFPVBQESA-N C(C)(C)OC([C@@H](NCCC)CCO)=O Chemical compound C(C)(C)OC([C@@H](NCCC)CCO)=O UJGRWVTWIDHCGO-VIFPVBQESA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000165940 Houjia Species 0.000 description 2
- KNTFCRCCPLEUQZ-VKHMYHEASA-N O-methylserine Chemical compound COC[C@H](N)C(O)=O KNTFCRCCPLEUQZ-VKHMYHEASA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BAYGVMXZJBFEMB-UHFFFAOYSA-N 4-(trifluoromethyl)phenol Chemical class OC1=CC=C(C(F)(F)F)C=C1 BAYGVMXZJBFEMB-UHFFFAOYSA-N 0.000 description 1
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical class OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101710142246 External core antigen Proteins 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 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
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229940005654 nitrite ion Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 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
- 239000002777 nucleoside Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- OTCVAHKKMMUFAY-UHFFFAOYSA-N oxosilver Chemical class [Ag]=O OTCVAHKKMMUFAY-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 150000003355 serines Chemical class 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 239000003643 water by type Substances 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Application the present invention relates to a kind of phosphonate prodrugs of adenine derivative and its in medicine.Specifically, the present invention relates to a kind of compound or its optical isomer, officinal salt, hydrate or solvate as led to shown in formula (I), and they are preparing treatment disease of viral infection, application particularly in hepatitis B (HBV) and AIDS (HIV) medicine, each substituent in its formula of (I) it is defined as the description.
Description
Technical field
The present invention relates to a kind of phosphonate prodrugs of adenine derivative or its isomers, officinal salt, hydrate or molten
Agent compound, and its application in medicine.
Background technology
Shown according to statistics in 2015, China hepatitis type B virus（HBV）Carrier is up to 90,000,000, hepatitis B patient two
Over thousands of ten thousand, therefore hepatitis B is still the current severe infection disease for endangering the health of our people.B-mode liver is clinically used at present
Scorching medicine is based on nucleoside compound, including Lamivudine, Aldoforwe ester, tenofovir dipivoxil etc..Its
Middle tenofovir dipivoxil（Tenofovir disoproxil fumarate, TDF）It is the mouth of Gilead Sciences Inc's research and development
Prodrugs of phosphonate nucleotide analogues is taken, for treating HBV and inhibition of HIV infection.And recently, promise good fortune is replaced in the said firm's invention
Wei Aila phenol amine hemifumarates（TAF）During 1/10 dosage less than TDF, just there is very high antiviral effect, its blood plasma
Stability is more preferable than TDF.But TAF still has a certain degree of degraded in blood plasma, 1-2% tenofovir is can detect,
A certain degree of kidney and bone toxic action can be caused, certain potential safety hazard be present.Therefore, further research and development low toxicity is high
The tenofovir prodrug of effect has important clinical treatment meaning.The invention provides a kind of new tenofovir prodrug, one
Aspect further increases the stability in blood plasma compared with TAF, is hardly degraded in blood plasma；On the other hand, with TAF
Compare, in PMBC（PBMCs the concentration of active metabolite tenofovir dramatically increases in), has more preferable liver target
Tropism.
The content of the invention
Inventor draws phenol amine fumarate structure to optimize by being ended to tenofovir, it was found that a series of brand news
Compound, with tenofovir end draw phenol amine fumarate（TAF）Compare, in IC50In the case of, toxic side effect substantially drops
It is low, therefore the compound in the present invention, its therapeutic index is substantially better than TAF, and has superior pharmacokinetic properties, in blood
More stable in slurry, its metabolite-tenofovir can't detect completely in blood plasma, and its concentration in PBMCs substantially carries
Height, there is more preferable hepatic targeting, such result is advantageously in the treatment of the viral infectious diseases such as hepatitis B.
The present invention relates to a kind of such as formula（I）Shown compound or optical isomer, officinal salt, hydrate or solvent
Compound,
Wherein：
R1Selected from hydrogen, halogen, C1-6Alkyl, C1-6Alkoxy, trifluoromethoxy, trifluoromethyl；
R2Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, trifluoromethyl, difluoromethyl etc.；
Halogen represents fluorine, chlorine, bromine or iodine；
Optical isomer refers to formula（I）The configuration of phosphorus atoms in compound and mark * carbon atom change and
The isomers of formation.
The formula（I）Phosphorus atoms have chirality in shown compound, and its configuration is S- or R- configurations, or S- structures
The mixture of type and R- configurations.
The formula（I）In shown compound, the carbon atom for identifying * has chirality, and its configuration is S- or R- configurations, or
Person is the mixture of S- configurations and R- configurations.
The compound with following structure is disclosed in the preferred embodiment of the present invention, but the present invention
Compound as shown in formula is not limited only to following structure：
。
The compound with following structure, but this are further disclosed in the preferred embodiment of the present invention
The compound as shown in formula of invention is not limited only to following structure：
。
The compound with following structure is further disclosed in the preferred embodiment of the present invention, but
The compound as shown in formula of the present invention is not limited only to following structure：
。
The compound with following structure is further disclosed in the preferred embodiment of the present invention, but
The compound as shown in formula of the present invention is not limited only to following structure：
The present invention such as formula（I）Shown compound can be prepared through following method：
Present invention also offers a kind of pharmaceutical composition, it contains compound as shown in formula or its isomers, can medicine
With salt, hydrate or solvate and pharmaceutically acceptable carrier, wherein pharmaceutically acceptable carrier can be selected from water for injection,
Freeze dried powder auxiliary material or oral formulations auxiliary material.
Another aspect of the present invention further relates to the compound or its isomers, officinal salt, hydrate or molten as shown in formula
The purposes of agent compound or foregoing pharmaceutical composition in the medicine for preparing treatment disease of viral infection, preferably preparing treatment
Purposes in the medicine of disease caused by hepatitis B or hepatitis B.
Embodiment
The present invention is explained in detail below with reference to specific embodiment so that this is more fully understood in those skilled in the art
Patent, specific embodiment are merely to illustrate technical scheme, do not limit the present invention in any way.
Embodiment 1：The preparation of O- methyl-serine isopropyl ester
Step 1：
5.00g serines are added in 50mL isopropanols, 11.32g SOCl are added dropwise2.It is directly dense after reaction backflow overnight
Contracting, obtains 8.47g white serine isopropyl ester hydrochlorides, yield 96.9%.
Step 2：
Take in the 6.00g serine isopropyl ester hydrochlorides DCM obtained in the step 1 of above-described embodiment 1, be then added dropwise
8.25g Et3N.8.64g Boc are added under ice bath2O, then room temperature reaction are stayed overnight.Add water, liquid separation, the washing of organic layer salt, do
It is dry, cross post and obtain 7.41g white solids（N- tertbutyloxycarbonyls-serine isopropyl ester）, yield 91.7%.
Step 3：
The 7.36g N- tertbutyloxycarbonyls-serine isopropyl ester obtained in the step 2 of above-described embodiment 1 is taken to add 147mL
In DCM, 35.46g silver oxides and 43.43g MeI are added, illumination is prevented with masking foil parcel, reacts at room temperature 48h.Filtering, Gu
The a small amount of DCM of body is washed, and post is crossed after mother liquor concentrations and obtains 4.70g white solids（N- tertbutyloxycarbonyls-O- methyl-serine isopropyl ester）,
Yield 60.4%.
Step 4：
The 4.70g N- tertbutyloxycarbonyls-O- methyl-serine isopropyl ester obtained in the step 3 of above-described embodiment 1 is taken to add
Enter into 70mL DCM, add 20.52g TFA, room temperature reaction is overnight.Add saturation Na after concentration2CO3The aqueous solution is adjusted to alkalescence,
DCM is extracted, anhydrous sodium sulfate drying organic phase, and post is crossed after concentration and obtains 1.70g white solids（O- methyl-serine isopropyl ester）,
Yield 58.6%.
Embodiment 2：The preparation of 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] adenine
By 1.01g tenofovirs（PMPA）Add at room temperature in 14mL pyridines, at room temperature by 3.24g phosphorous triphenyl phosphates
Ester is added in reaction solution, is heated to 115 DEG C of reflux temperature and is reacted 8 hours, and solution first becomes clarification, then separates out substantial amounts of white admittedly
Body, is cooled to -5 DEG C~5 DEG C or so, adds 14mL acetone, stirs 1.5 hours, filtering, filter cake washed with 1mL acetone after 60
DEG C~70 DEG C of dryings 5 hours, gained white solid is gained target product, and 1.12g white solids 9- [(R) -2- are always obtained
(phenyl phosphonic ylmethoxy) propyl group] adenine.
Embodiment 3：Compound Ia-1 synthesis
0.67g 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] adenine obtained in Example 2 adds 5mL
SOCl2In, back flow reaction 2 hours is stand-by after concentration.The 1.30g O- methyl-serine obtained in the step 4 of Example 1
Isopropyl ester and 0.36g triethylamines are added in 10mL DCM, are cooled to -10 DEG C, are then added above-mentioned stand-by concentrate.Add, -10
DEG C reaction about 2h, then move to and about 1h be stirred at room temperature.Post is crossed after concentration and obtains 0.75g compound Ia-1, yield 80.6%.
Embodiment 4：Compound Ia-2 synthesis
Step 1：
Using synthetic method of the Serine as initiation material according to the step 1-4 of embodiment 1,2.2g O- methyl-L- silks are synthesized
Propylhomoserin isopropyl ester.
Step 2：
It is fast according to the synthetic method of embodiment 2, synthesis 1.12g 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] gland
Purine.
Step 3：
1.00g 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] adenine obtained in the step 2 of Example 4
Add 7mL SOCl2In, back flow reaction 2 hours is stand-by after concentration.The 1.94g O- first obtained in the step 1 of Example 4
Base-Serine isopropyl ester and 0.55g triethylamines are added in 15mL DCM, are cooled to -10 DEG C, are then added above-mentioned stand-by concentration
Thing.Add, -10 DEG C of reaction about 2h, then move to and about 1h is stirred at room temperature.Post is crossed after concentration and obtains 1.22g compound Ia-2, yield
87.8%。
Embodiment 5：Compound Ia-3 synthesis
The 800mg Ia-2 obtained in Example 4 are through HPLC preparative separations（Prepare post：CHIRALPAK AS-H, flowing
Phase：A:N-hexane；B:Ethanol）After obtain 305mg compounds Ia-3, MS (m/z)：506.5.
Embodiment 6：Compound Ib-3 synthesis
Step 1：
Using synthetic method of the Serine as initiation material according to the step 1-4 of embodiment 1, synthesis 2.43g O- methyl-L-
Serine isopropyl ester.
Step 2：
（1）5.00g parachlorophenols are added in 65mL acetonitriles, 1.78g PCl are added dropwise3.After reaction backflow overnight directly
Concentration, it is directly used in and reacts in next step；
（2）According to the synthetic method of embodiment 2,1.37g 9- [(R) -2- (4- chlorphenyls phosphonium mesitoyl methoxy) have been synthesized
Propyl group] adenine.
Step 3：
According to the synthetic method of embodiment 3,0.97g compounds Ib-2 has been synthesized.
Step 4：
According to the operating method of embodiment 5, take 0.97g Ib-2 that 312mg compounds Ib-3, MS (m/z) has been prepared：
540.3。
Embodiment 7：Compound Ic-3 synthesis
Step 1：
Using synthetic method of the Serine as initiation material according to the step 1-4 of embodiment 1, synthesized 2.23g O- methyl-
Serine isopropyl ester.
Step 2：
（1）5.00g p-fluorophenols are added in 75 mL acetonitriles, 2.06g PCl are added dropwise3.After reaction backflow overnight directly
Concentration, it is directly used in and reacts in next step.
（2）According to the synthetic method of embodiment 2,1.48g 9- [(R) -2- (4- fluorophenyls phosphonium mesitoyl methoxy) have been synthesized
Propyl group] adenine.
Step 3：
According to the synthetic method of embodiment 3,975mg compounds Ic-2 has been synthesized.
Step 4：
According to the operating method of embodiment 5, take 975mg Ic-2 that 365mg compounds Ic-3, MS (m/z) has been prepared：
524.4。
Embodiment 8：Compound Id-3 synthesis
Step 1：
Using synthetic method of the Serine as initiation material according to the step 1-4 of embodiment 1, synthesized 2.51g O- methyl-
Serine isopropyl ester.
Step 2：
（1）5.00g p-trifluoromethyl-phenols are added in 50 mL acetonitriles, 1.37g PCl are added dropwise3.Reaction backflow is overnight
Directly concentrate afterwards, be directly used in and react in next step.
（2）According to the synthetic method of embodiment 2,1.01g 9- [(R) -2- (4- trifluoromethyl phosphono first has been synthesized
Epoxide) propyl group] adenine.
Step 3：
According to the synthetic method of embodiment 3,900mg compounds Id-2 has been synthesized.
Step 4：
According to the operating method of embodiment 5, take 900mg Id-2 that 358mg compounds Id-3, MS (m/z) has been prepared：
574.4。
Embodiment 9：Compound Ie-3 synthesis
Step 1：
Using synthetic method of the Serine as initiation material according to the step 1-4 of embodiment 1,2.8g O- methyl-L- has been synthesized
Serine isopropyl ester.
Step 2：
（1）5.00g p methoxy phenols are added in 65 mL acetonitriles, 1.83g PCl are added dropwise3.After reaction backflow overnight
Directly concentrate, be directly used in and react in next step.
（2）According to the synthetic method of embodiment 2,1.27g 9- [(R) -2- (4- methoxyphenyl phosphonyl methoxyls have been synthesized
Base) propyl group] adenine.
Step 3：
According to the synthetic method of embodiment 3,880mg compounds Ie-2 has been synthesized.
Step 4：
According to the operating method of embodiment 5, take 880mg Ie-2 that 310mg compounds Ie-3, MS (m/z) has been prepared：
536.5。
Embodiment 10：Compound If-3 synthesis
Step 1：
（1）Using synthetic method of the Serine as initiation material according to the step 1-2 of embodiment 1,10.52g uncles N- have been synthesized
Butoxy carbonyl-Serine isopropyl ester.
（2）The step 1 of Example 10（1）In 9.64g N- tertbutyloxycarbonyls-Serine isopropyl ester be added to 150
In mL DCM, 0 DEG C is down to, 20%KOH solution is added dropwise, 15.84g TMSCF are then added dropwise2Br.Reaction 0.5 hour, add 300mL
Water, extracted 2 times with DCM, each 300mL, organic phase is dried with anhydrous magnesium sulfate, is then concentrated, and residue column chromatography obtains
6.57 grease, yield 56.7%.
（3）Take the step 1 of above-described embodiment 10（2）In obtained 6.57g N- tertbutyloxycarbonyl-O- difluoromethyls-L-
Serine isopropyl ester is added in 100mL DCM, adds 25.08g TFA, room temperature reaction is overnight.Add saturation Na after concentration2CO3Water
Solution is adjusted to alkalescence, DCM extractions, anhydrous sodium sulfate drying organic phase, post is crossed after concentration and obtains 3.05g white solids, yield
70.0%。
Step 2：
According to the synthetic method of embodiment 2,1.02g 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] gland has been synthesized
Purine.
Step 3：
Take 1.02g 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] gland obtained in the step 2 of above-described embodiment 10
Purine adds 5mL SOCl2In, back flow reaction 2 hours is stand-by after concentration.By what is obtained in the step 1 of above-described embodiment 10
2.44g O- difluoromethyls-Serine isopropyl ester and 0.57g triethylamines are added in 10mL DCM, are cooled to -10 DEG C, Ran Houjia
Enter above-mentioned stand-by concentrate.Add, -10 DEG C of reaction about 2h, then move to and about 1h is stirred at room temperature.It is white to obtain 1.15g for mistake post after concentration
Color solid If-2, yield 77.2%.
Step 4：
According to the operating method of embodiment 5, take above-mentioned If-2 that 290mg compounds If-3, MS (m/z) has been prepared：
542.4。
Embodiment 11：The synthesis of Compound Ig per -3
Step 1：
（1）Using synthetic method of the Serine as initiation material according to the step 1-2 of embodiment 1,13.02g uncles N- have been synthesized
Butoxy carbonyl-Serine isopropyl ester.
（2）Under nitrogen protection, by 39.31g AgOTf, 27.10g selection fluorine, 11.85g KF and the step 1 of embodiment 11
（1）In 12.61g N- tertbutyloxycarbonyls-serine isopropyl ester sequentially add in reaction bulb, add 14.85g 2- fluorine pyrroles
Pyridine, 500mL ethyl acetate, 21.75g TMSCF3.Reaction 12 hours, directly concentrate, cross post and obtain 7.25g white solids, receive
Rate 45.1%.
（3）Take the step 1 of above-described embodiment 11（2）In obtained 7.25g N- tertbutyloxycarbonyl-O- trifluoromethyl-L- silks
Propylhomoserin isopropyl ester is added in 100mL DCM, adds 26.22g TFA, room temperature reaction is overnight.Add saturation Na after concentration2CO3It is water-soluble
Liquid is adjusted to alkalescence, DCM extractions, anhydrous sodium sulfate drying organic phase, post is crossed after concentration and obtains 3.21g white solids, yield 64.8%.
Step 2：
According to the synthetic method of embodiment 2,1.52g 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] gland has been synthesized
Purine.
Step 3：
Take 1.00g 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] gland obtained in the step 2 of above-described embodiment 11
Purine adds 5mL SOCl2In, back flow reaction 2 hours is stand-by after concentration.By what is obtained in the step 1 of above-described embodiment 11
2.71g O- trifluoromethyls-Serine isopropyl ester and 0.57g triethylamines are added in 15mL DCM, are cooled to -10 DEG C, Ran Houjia
Enter above-mentioned stand-by concentrate.Add, -10 DEG C of reaction about 2h, then move to and about 1h is stirred at room temperature.Post is crossed after concentration and obtains 0.82gization
Compound Ig-2, yield 53.2%.
Step 4：
According to the operating method of embodiment 5, take above-mentioned Ig -2 that 266mg Compound Ig pers -3, MS (m/z) have been prepared：
560.4。
Embodiment 12：Compound Ih-3 synthesis
Step 1：
（1）Using synthetic method of the Serine as initiation material according to the step 1-2 of embodiment 1,25.1g uncles N- have been synthesized
Butoxy carbonyl-Serine isopropyl ester.
（2）0.32g sodium hydrogen is stirred in 50mlDMF, is down to 0 DEG C, successively by the step 1 of embodiment 12（1）In
21.76g N- tertbutyloxycarbonyls-Serine isopropyl ester and the bromoacetonitriles of 11.63g mono- add, and react at room temperature 12 hours, after reaction
It is diluted with water, is directly concentrated after ethyl acetate extraction, crosses post and obtain 10.30g grease, yield 40.9%.
（3）Take the step 1 of above-described embodiment 12（2）In obtained 10.30g N- tertbutyloxycarbonyl-O- acetonitrile-bases-L-
Serine isopropyl ester is added in 150mL DCM, adds 41.05g TFA, room temperature reaction is overnight.Add saturation Na after concentration2CO3Water
Solution is adjusted to alkalescence, DCM extractions, anhydrous sodium sulfate drying organic phase, post is crossed after concentration and obtains 3.01g white solids, yield
44.9%。
Step 2：
According to the synthetic method of embodiment 2,1.01g 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] gland has been synthesized
Purine.
Step 3：
Take 1.01g 9- [(R) -2- (phenyl phosphonic ylmethoxy) propyl group] gland obtained in the step 2 of above-described embodiment 12
Purine adds 5mL SOCl2In, back flow reaction 2 hours is stand-by after concentration.By what is obtained in the step 1 of above-described embodiment 12
2.35g O- acetonitrile-bases-Serine isopropyl ester and 0.57g triethylamines are added in 15mL DCM, are cooled to -10 DEG C, are then added
Above-mentioned stand-by concentrate.Add, -10 DEG C of reaction about 2h, then move to and about 1h is stirred at room temperature.Post is crossed after concentration and obtains 0.87g chemical combination
Thing Ih-2, yield 58.8%.
Step 4：
According to the operating method of embodiment 5, take above-mentioned Ih-2 that 255mg compounds Ih-3, MS (m/z) has been prepared：
531.4。
Embodiment 13：Compound Ia-4 preparation
At room temperature, 0.217g Ia-3,0.047g fumaric acid in 50ml single port bottles, adds 5mL acetonitriles in Example 5,
It is placed in 80 DEG C of water-baths, stirring insulated and stirred 1 hour, then naturally cools to room temperature, filtered until solid all dissolvings,
Filtration cakes torrefaction obtains 0.173g white solids Ia-4.
1H NMR（500MHz, DMSO-d6）：δ 8.149 (s, 1H), 8.117 (s, 1H), 7.308~7.276 (t, 2H),
7.227 (s, 2H), 7.151~7.121 (t, 1H), 7.071~7.054 (d, 2H), 6.634 (s, 2H), 5.573~5.527
(dd, 1H), 4.884~4.834 (m, 1H), 4.302~4.266 (dd, 1H), 4.188~4.146 (dd, 1H), 4.011~
3.945 (m, 2H), 3.907~3.863 (dd, 1H), 3.820~3.775 (dd, 1H), 3.445~3.415 (dd, 1H), 3.384
~3.354 (dd, 1H), 3.192 (s, 3H), 1.148~1.133 (dd, 6H), 1.087~1.075 (d, 3H)；31P NMR
（202MHz, DMSO-d6）：27.763.MS(m/z)：506.2.
Embodiment 14：Compound Ib-4 preparation
According to the operating method of embodiment 13, take above-mentioned Ib-3 that 0.231g white solids Ib-4 is prepared.
1H NMR（500MHz, DMSO-d6）：δ 8.136~8.104 (m, 2H), 7.357~7.339 (m, 2H),
7.207~7.166 (s, 1H), 7.083~7.063 (m, 1H), 6.772~6.754 (m, 2H), 6.614 (s, 3H),
5.753 (s, 3H), 5.627~5.581 (m, 1H), 5.013~4.963 (m, 1H), 4.864~4.814 (m, 1H),
4.289~4.253 (m, 2H), 4.178~4.131 (m, 2H), 3.189 (s, 2H), 1.239~1.205 (m, 5H),
1.132~1.120 (d,J=6 Hz, 5H), 0.989~0.976 (d,J= 6.5 Hz,2H)；31P NMR（202MHz,
DMSO-d6）：23.789.MS(m/z)：540.2.
Embodiment 15：Compound Ic-4 preparation
According to the operating method of embodiment 13, take above-mentioned Ic-3 that 0.134g white solids Ic-4 is prepared.
1H NMR（500MHz, DMSO-d6）：δ 8.122 (s, 1H), 8.092 (s, 1H), 7.183~7.159 (m,
2H), 7.125~7.090 (m, 2H), 7.067~7.041 (m, 2H), 6.972~6.937 (m, 1H), 6.731~
6.704 (m, 1H), 6.601 (s, 2H), 5.565 (t,J=11.5Hz, 1H), 4.856~4.806 (m, 1H),
4.277~4.241 (m, 1H), 4.166~4.124 (m, 1H), 3.979~3.915 (m, 2H), 3.889~3.845 (m,
1H), 3.796~3.751 (m, 1H), 3.371~3.341 (m, 1H), 3.178 (s, 2H), 1.122 (d,J =
6.0Hz, 5H), 1.054 (t,J=7.0Hz,6H)；31P NMR（202MHz, DMSO-d6）：23.614.MS(m/z)：524.2.
Embodiment 16：Compound Id-4 preparation
According to the operating method of embodiment 13, take above-mentioned Id-3 that 0.222g white solids Id-4 is prepared. MS(m/z)：
574.2。
Embodiment 17：Compound Ie-4 preparation
According to the operating method of embodiment 13, take above-mentioned Ie-3 that 0.234g white solids Ie-4 is prepared.
1H NMR（500MHz, DMSO-d6）：δ 8.131 (s, 1H), 8.099 (s, 1H), 7.182 (s, 2H),
7.033~7.012 (m, 2H), 6.877~6.859 (m, 2H), 6.624 (s, 3H), 5.752 (s, 3H), 5.448~
5.403 (m, 1H), 4.887~4.837 (m, 1H), 4.300~4.169 (m, 2H), 3.993~3.936 (m, 2H),
3.868(d, J=8.5Hz, 2H), 3.717 (s, 3H), 3.446~3.411 (m, 3H), 3.143 (s, 3H), 1.152
~1.133 (m, 6H), 1.068~1.041 (m, 4H)；31P NMR（202MHz, DMSO-d6）：23.445.MS(m/z)：
536.2。
Embodiment 18：Compound If-4 preparation
According to the operating method of embodiment 13, take above-mentioned If-3 that 0.342g white solids If-4 is prepared.
1H NMR（500MHz, DMSO-d6）：δ 8.669 (s, 1H), 8.133 (s, 1H), 7.378 (t,J =8.0Hz,
2H), 7.195~7.102 (m, 2H), 6.888 (t,J=8.5Hz, 1H), 6.700 (s, 1H), 6.620 (s,
3H), 5.750 (s, 2H), 4.970~4.907 (m, 2H), 4.673~4.657 (m, 1H), 4.484~4.460 (m,
1H), 4.201~4.126 (m, 3H), 3.460~3.418 (m, 3H), 1.214~1.172 (m, 10H), 1.117~
1.101 (m, 3H)；31P NMR（202MHz, DMSO-d6）：23.641.MS(m/z)：542.2.
Embodiment 19：The preparation of Compound Ig per -4
According to the operating method of embodiment 13, take above-mentioned Ig-3 that 0.321g white solids Ig-4 is prepared.MS(m/z)：
560.2。
Embodiment 20：Compound Ih-4 preparation
According to the operating method of embodiment 13, take above-mentioned Ic-3 that 0.233g white solids Ih-4 is prepared.MS(m/z)：
531.2。
Embodiment 21：Antiviral breeding
1st, external anti-hepatitis B virus activity research
Using HepG2.2.15 cells as hepatitis B poisonous carrier, measure compound suppresses hepatitis type B virus and carries out DNA
The ability of duplication.
2nd, method of testing：
The collection of culture supernatant：HepG2.2.15 cells are inoculated in 96 orifice plates, and next day adds example pharmaceuticals, and the 4th day more
Nutrient solution and example pharmaceuticals are changed, it is to be measured to collect culture supernatant with the 8th day.
HBV-DNA purifying in supernatant：Purified using Qiaphony nucleic acid purifiers.
Quantitative real-time PCR surveys the content of HBV-DNA in culture supernatant：2 microlitres of supernatants are taken to be expanded for PCR, together
When HBV-DNA standard samples 4 are set, do standard curve.According to corresponding HBV-DNA copies in the culture supernatant of detection gained
Number, calculates the inhibiting rate that sample replicates to HBV-DNA, then carries out the calculating of example pharmaceuticals half inhibiting rate again, obtains it
IC50。
ELISA method surveys HBsAg and HBeAg
Sample is added into the stripe board for be coated with corresponding antibodies（Each sample does duplicate hole）, and add the enzyme of equivalent
Mark conjugate, 37 DEG C reaction 30 minutes after board-washing, be repeated 5 times, successively add nitrite ion A and B, terminating reaction after 15 minutes, survey
Determine OD450/630, and the half inhibiting rate that sample secretes to HBV antigens is calculated according to OD values（IC50）
The compound of table 1 secretes into culture supernatant the influence of HBV-DNA contents levels to HepG2.2.15
Note：IC50It is suppression of the sample to DNA copy up to concentration when 50%；
CC50For the influence of growth of the example pharmaceuticals to HepG2.2.15 cells, 50% lethasl concentration；
SI is that sample bioactivity selects coefficient, and SI values ＞ 2 is effective, and is the bigger the better.
3. experiment conclusion
Experimental result shows compound Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4 and Ih-4 to hepatitis B
Viral dna replication has strong inhibitory action, is in the same order of magnitude with positive control drug TAF, and bioactivity selects
Coefficient S I is significantly better than that positive compound TAF, it is thus possible to has in diseases such as clinical treatment hepatitis B, HIV potential
Superiority.
Based on above-mentioned experimental result, we choose Ia-4, and Ib-4, Ic-4 carry out further extracorporeal biology evaluation.
Embodiment 22：Stability test in acid medium and simulate the gastric juice
1st, reagent and raw material and source
2nd, reagent
Hydrochloric acid solution（pH2.0）Simulate the gastric juice（pH2.0）
The preparation of 2.1 sample solutions
2.1.1 TAF hydrochloric acid solutions
Precision is weighed in 5.0mg TAF to 5mL volumetric flasks, and first plus 2.5mL isopropanols are into volumetric flask, shaking dissolving, so
Afterwards plus hydrochloric acid solution（pH2.0）To scale.Vibration shakes up, and filtering is standby.
2.1.2 TAF simulate the gastric juice solution
Precision is weighed in 5.0mg TAF to 5mL volumetric flasks, and first plus 2.5mL isopropanols are into volumetric flask, shaking dissolving, so
Afterwards plus simulate the gastric juice is to scale.Vibration shakes up, and filtering is standby.
2.1.3 Ia-4, Ib-4, Ic-4 hydrochloric acid solution
Precision weighs 5.0mg samples into 5mL volumetric flasks, and first plus 2.5mL isopropanols are into volumetric flask, shaking dissolving, so
Afterwards plus hydrochloric acid solution（pH2.0）To scale.Vibration shakes up, and filtering is standby.
2.1.4 Ia-4, Ib-4, Ic-4 simulate the gastric juice solution
Precision weighs 5.0mg samples into 5mL measuring bottles, and first plus 2.5mL isopropanols are into volumetric flask, shaking dissolving, then
Add simulate the gastric juice to scale.Vibration shakes up, and filtering is standby.
The sampling of 2.2 sample solutions
Horse back sample introduction after the sample loading sample introduction bottle prepared, as initial sample.At the same time remaining sample
Product, which are immediately placed into, have been reached and in stablizing in 37 degree of insulating box, has been sampled after 6.0 hours into efficient liquid phase.
The stability result of compound Ia-4, Ib-4, Ic-4 and TAF in acid medium and simulate the gastric juice is shown in Table 2.
The stability result of table 2 compound Ia-4, Ib-4, Ic-4 and TAF in acid medium and simulate the gastric juice
3rd, experiment conclusion
Test result indicates that compared with TAF, Ia-4, Ib-4, stability of the Ic-4 in acid medium and simulate the gastric juice have
Increased, prompt these three compounds after oral administration, can keep stable the long period in gastric juice, it is more steady than TAF
It is qualitative more preferable.
Embodiment 23：Metabolic stability of the tenofovir prodrug in human whole blood and the distribution in PBMCs cells
Experiment
1st, material
Compound：Compound Ia-4, Ib-4, Ic-4 and TAF
2nd, test method
Under the conditions of 37 °C, different tenofovir prodrugs and human whole blood are incubated jointly, respectively in incubation 1 hour, 2
Separated plasma and PBMC cells after hour（Ficoll density-gradient centrifugation methods）, determine medicine original shape in blood plasma and PBMCs cells
And the concentration of metabolin tenofovir, cell counter calculates PBMCs cells, and is calculated carefully by 200fL of each PBMC cells
Intracellular drug concentration.
3rd, blood plasma/PBMC sample treatments
20 μ L inner mark solutions are separately added into 100 μ L plasma samples or PBMC samples（400ng/mL SN-38 solution）,
5.0 μ L methanol-waters（50:50, v/v）With 200 μ L acetonitriles, vortex mixes 1min, centrifuges 5min（14000rpm）.Take 20 μ L of supernatant
Liquid and 180 μ l mobile phases mix, and are vortexed 1min, take 10 μ L to carry out LC/MS/MS analyses.
Metabolic stability of the tenofovir prodrug in human whole blood and distribution results are shown in Table 3 in PBMCs cells.
Metabolic stability of the tenofovir prodrug of table 3 in human whole blood and the distribution results in PBMCs cells
Note：PMPA is active metabolite-tenofovir of prodrug
4th, experiment conclusion
As can be seen from Table 3：
1）Positive control TAF detects a certain amount of active generation after being incubated jointly with fresh mouse whole blood in blood plasma
Thank to product-tenofovir, and with the extension of incubation time, the active metabolite-tenofovir discharged in blood plasma
Be doubled and redoubled, and Ia-4, Ib-4, Ic-4 with fresh mouse whole blood jointly be incubated after, do not detect completely active metabolite-
Tenofovir, even if with the extension of incubation time, also it is not detected by active metabolite-tenofovir all the time in blood plasma,
Illustrate Ia-4, the stability of Ib-4, Ic-4 in blood plasma is significantly better than positive control TAF, and therefore, it is being reduced because of blood plasma
There is significant superiority in terms of toxic side effect caused by middle metabolism production tenofovir.
2）With the extension of incubation time, Ia-4, Ib-4, Ic-4 is in PMBC（PBMCs）In active generation
The concentration for thanking to product-tenofovir significantly increases, and TAF is in PMBC（PBMCs）In active metabolite-
The concentration of tenofovir does not increase substantially with the extension of incubation time.After 2 hours are incubated, in PMBC
（PBMCs）In the concentration of active metabolite-tenofovir be about 2-4 times of positive control TAF.Therefore, Ia-4,
Ib-4, Ic-4 also have significant superiority in terms of curative effect than TAF.
Claims (13)
1. a kind of compound or its optical isomer, officinal salt as led to shown in formula (I),
Wherein：
R1Selected from hydrogen, halogen, C1-6Alkyl, C1-6Alkoxy, trifluoromethoxy, trifluoromethyl；
R2Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, trifluoromethyl, difluoromethyl；
Halogen represents fluorine, chlorine, bromine or iodine；
Optical isomer refers to that the configuration of the carbon atom of the phosphorus atoms and mark * in logical formula (I) compound changes and formed
Isomers.
2. the compound or its optical isomer, officinal salt according to claim 1 as led to shown in formula (I), its feature
It is, phosphorus atoms have chirality in the compound shown in the logical formula (I), and its configuration is S- or R- configurations.
3. the compound or its optical isomer, officinal salt according to claim 1 as led to shown in formula (I), its feature
It is, the carbon atom that * is identified in the compound shown in the logical formula (I) has chirality, and its configuration is S- or R- configurations.
4. the compound or its optical isomer, officinal salt according to claim 1 as led to shown in formula (I), it is selected from：
5. the compound or its optical isomer, officinal salt according to claim 1 as led to shown in formula (I), it enters one
Step is selected from：
6. the compound or its optical isomer, officinal salt according to claim 1 as led to shown in formula (I), it more enters
One step is selected from：
7. the compound or its optical isomer, officinal salt according to claim 1 as led to shown in formula (I), it more enters
One step is selected from：
8. according to a kind of compound as shown in formula (Ia-3, Ib-3, Ic-3) of described in claim 1, officinal salt,
9. a kind of pharmaceutical composition, its containing the compound any one of with good grounds claim 1-8 or its isomers, can medicine
With salt and pharmaceutically acceptable carrier, wherein, pharmaceutically acceptable carrier is selected from water for injection, freeze dried powder auxiliary material or oral
Pharmaceutical adjunct.
10. the compound, officinal salt according to any one of claim 1-8 are preparing treatment disease of viral infection
Purposes in medicine.
11. compound according to claim 10, officinal salt are in the medicine for preparing treatment disease of viral infection
Purposes, it is characterised in that described disease of viral infection is HIV infection, hepatitis B or disease caused by hepatitis B
Disease.
12. purposes of the pharmaceutical composition according to claim 9 in the medicine for preparing treatment disease of viral infection.
13. purposes of the pharmaceutical composition according to claim 12 in the medicine for preparing treatment disease of viral infection,
Characterized in that, described disease of viral infection is HIV infection, hepatitis B or disease caused by hepatitis B.
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| CN109942633B (en) * | 2017-12-20 | 2021-08-31 | 上海新礼泰药业有限公司 | Preparation method of tenofovir alafenamide intermediate |
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| CN108101943B (en) * | 2018-02-28 | 2020-11-24 | 顾世海 | Tenofovir prodrug or pharmaceutically acceptable salt and application thereof in medicine |
| CN108299500A (en) * | 2018-04-04 | 2018-07-20 | 安徽安科恒益药业有限公司 | A kind of fumaric acid tenofovir Chinese mugwort draws phenol amine bulk pharmaceutical chemicals and its production technology |
| CN108467410B (en) * | 2018-04-09 | 2021-04-09 | 重庆三圣实业股份有限公司 | Preparation method, product and application of TAF intermediate |
| CN110105392A (en) * | 2019-06-04 | 2019-08-09 | 石家庄凯赛医药科技有限公司 | What a kind of tenofovir Chinese mugwort drew phenol amine efficiently synthesizes technique |
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