CN108101943A - A kind of tenofovir prodrug or officinal salt and its application in medicine - Google Patents
A kind of tenofovir prodrug or officinal salt and its application in medicine Download PDFInfo
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- CN108101943A CN108101943A CN201810169314.2A CN201810169314A CN108101943A CN 108101943 A CN108101943 A CN 108101943A CN 201810169314 A CN201810169314 A CN 201810169314A CN 108101943 A CN108101943 A CN 108101943A
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- 239000003814 drug Substances 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 title claims abstract description 16
- 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 title abstract description 16
- 229960004556 tenofovir Drugs 0.000 title abstract description 12
- 229940002612 prodrug Drugs 0.000 title abstract description 5
- 239000000651 prodrug Substances 0.000 title abstract description 5
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 208000036142 Viral infection Diseases 0.000 claims abstract description 4
- 230000009385 viral infection Effects 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 208000031886 HIV Infections Diseases 0.000 claims description 4
- 208000037357 HIV infectious disease Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 208000006454 hepatitis Diseases 0.000 claims description 4
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 4
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 231100000283 hepatitis Toxicity 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000004437 phosphorous atom Chemical group 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 abstract description 3
- 208000030507 AIDS Diseases 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- -1 Amine fumarate Chemical class 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 235000010894 Artemisia argyi Nutrition 0.000 description 3
- 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 244000030166 artemisia Species 0.000 description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 206010056522 Hepatic infection Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 208000034189 Sclerosis 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000005292 vacuum distillation 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Application the present invention relates to a kind of tenofovir prodrug and its in medicine.Specifically, the present invention relates to a kind of such as general formula (I) or general formula (II) compound represented or its isomers, officinal salt, and their applications in the treatment disease of viral infection particularly drug of disease caused by AIDS (HIV) infection, hepatitis B and hepatitis B is prepared, formula of (I) or each substituent group in general formula (II) it is defined as the description.
Description
Technical field
Application the present invention relates to a kind of tenofovir prodrug or officinal salt and its in medicine.
Background technology
Hepatitis type B virus (hepatitis B virus) refers to cause the DNA of acute human hepatitis and chronic hepatitis sick
Poison, abbreviation HBV.According to the statistics of the World Health Organization, the whole world has 2,000,000,000 people to infect hepatitis B, and more than 3.5 hundred million people is with slow
Property（For a long time）Hepatic infection disease, wherein the hepatitis B patient of China accounts for 1/3, China takes at present for the total for the treatment of hepatitis B every year
With more than 100,000,000,000, it has also become the maximum hepatitis B medicine market in the whole world.Chronic Hepatitis B develops into hepatic sclerosis or hepatocellular carcinoma
Probability for 15%-40%, the whole world have every year 1000000 people die of chronic hepatitis B and hepatitis B be presently considered can't be by
It thoroughly cures, therefore antiviral is considered as wherein most basic, most important treatment means.
Tenofovir is the parent nucleus of anti-hepatitis B virus, is published in the Czech patents of 1985 earliest.But the drug
It is under physiological ph conditions diphosphonic acid, it is oral not absorb substantially, limit its Clinical practice.Lucky Leadd B.V carries out the drug
In-depth study, finds can greatly to improve the oral absorption of the drug after making prodrug and improve life the drug into ester
Object availability.Lucky moral has developed tenofovir disoproxil fumarate on this basis（TDF）It ends with tenofovir and draws phenol
Amine fumarate (TAF), for treating HIV infection and hepatitis B.A large amount of clinical tests show：TAF is chronic for treating
HBV infection adult patient, only needs TDF（300 mg•d-1）1/10 dosage（25 mg•d-1）, can obtain similar disease-resistant
Toxic effect is used.The targeting of TAF, security, plasma stability are better than TDF, and remain to keep after entering the cell of HBV infection
Maximum integrality, therefore TAF has good market prospects.
。
But TAF, because technical barrier, patent limits, the reasons such as price factor, it is also very long that the country will introduce the drug
A period of time.At present, modified in the structure that company ends drawing phenol amine in tenofovir, make it to reach and even better than replace promise
The therapeutic effect of Fu Weiaila phenol amine.Since medicines structure and tenofovir Chinese mugwort draw phenol amine inconsistent, original public affairs can be effectively avoided
The intellectual property protection of department is the treatment of hepatitis B patient, provides a kind of new effective selection.
The content of the invention
It is modified in the structure that inventor ends drawing phenol amine in tenofovir, makes it to reach even better than tenofovir Chinese mugwort
Draw the therapeutic effect of phenol amine.Since medicines structure and tenofovir Chinese mugwort draw phenol amine inconsistent, knowing for original company can be effectively avoided
Know property right protection, be the treatment of hepatitis B patient, a kind of new effective selection is provided.
The present invention relates to a kind of such as general formula (I) or general formula (II) compound represented or its officinal salt.
Wherein：
（1）R1It is hydrogen or C1-6Alkyl, substituted or non-substituted C6-10Aryl or 6 ~ 10 unit's heteroaryls；
（2）R2It is hydrogen or C1-6Alkyl, cyano；
（3）Ar is substituted or non-substituted C6-10Aryl；；
（4）X is independently selected from O, N, S, P；
（5）Y is substituted or non-substituted C1-6Alkyl；
（6）Alkyl refers to the aliphatic hydrocarbon groups of saturation, includes the linear chain or branch chain group of 1 to 6 carbon atom；
（7）When substituted, substituent group is one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy,
Alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkanes oxygen
Base, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group；
（8）Phosphorus atoms have chirality in compound, and configuration is the mixing of S- or R- configurations or S- configurations and R- configurations
Object.
It is described such as general formula (I) or general formula (II) compound represented or its officinal salt, be selected from but be not limited only to
Lower structure：
。
The present invention preferred embodiment in further disclose with as lower structure compound or its can
Pharmaceutical salts.
。
The present invention also provides a kind of pharmaceutical composition, contain compound as described in general formula (I) or general formula (II) or
Its officinal salt and pharmaceutically acceptable carrier.
Pharmaceutical composition provided by the invention, wherein the pharmaceutically acceptable carrier is selected from water for injection, freeze-dried powder
Agent auxiliary material or oral formulations auxiliary material.
Another aspect of the present invention further relates to compound as described in general formula (I) or general formula (II), its officinal salt or foregoing
Pharmaceutical composition prepare treatment disease of viral infection drug in purposes preferably prepare treatment HIV infection, second
Purposes in the drug of disease caused by type hepatitis or hepatitis B.
Unless stated to the contrary, the term in the present invention has following meaning.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 6 carbon atom.Nonrestrictive reality
Example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, sec-butyl, n-pentyl, 1,1- dimethyl
Propyl, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl,
1- Ethyl-2-Methyls propyl, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- bis-
Methyl butyl, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- bis-
Methyl butyl etc..
" alkyl " can be substituted or unsubstituted, and when substituted, substituent group can be in any workable connection
Be substituted on point, be preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group,
Alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkane
Oxygroup, cycloalkylthio, heterocycle alkylthio group, oxo.
" aryl " refers to that 6 to 10 yuan of full carbon are monocyclic or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, tool
There are polycyclic (i.e. it carries the ring of the phase adjacency pair carbon atom) group of the pi-electron system of conjugation, such as phenyl and naphthalene.Aryl can
To be substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkane
Base, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, cycloalkyl, heterocycle alkane
Base, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" heteroaryl " refers to comprising 1,2,3 or 4 hetero atom, the preferably heteroaromatic system of 6 to 10 annular atoms, 5 to 6
Annular atom, wherein hetero atom include oxygen, sulphur and nitrogen；Such as pyridyl group, pyrimidine radicals etc.." heteroaryl " can be optionally substitute or
Unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl,
Alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl,
Cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
Specific 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
Step 1:
。
By tenofovir（70.5 g）, triethylamine, DMAP, triphenyl phosphite and acetonitrile mixture it is small in 80 DEG C of reflux 48
When after stop heating, revolving remove acetonitrile, respectively with water, ethyl acetate, acetonitrile extraction liquid separation.Water is mutually in low temperature（≤25℃）Under
Concentrated hydrochloric acid is added dropwise（30%）It is 3 to pH, continues to stir, there is solid precipitation.Continue that concentrated hydrochloric acid is added dropwise to pH less than 2.Filtering is done
It is dry, obtain 73.1 g of white powdery solids IIA, yield 81.57%.MS(m/z):364.1(M+H)+。
Step 2:
。
By thionyl chloride（336mg）Add in IIA（513m g）Acetonitrile mixture in, stir 5 h in 80 DEG C, be precipitated solid
Body, vacuum distillation remove acetonitrile, and solid is spin-dried for after adding toluene.Then solid with dichloromethane is dissolved, is added dropwise at -30 DEG C
IIIA（337mg）With the mixed solution of dichloromethane.It drips and finishes, it is 6 ~ 7 that stirring, which continues that triethylamine is added dropwise to pH after five minutes, is dripped
Finish, the reaction was continued 1 it is small when.- 5 DEG C are warming up to, successively with sodium dihydrogen phosphate dihydrate solution, sodium bicarbonate solution, saturated salt washing
After washing, anhydrous sodium sulfate drying is spin-dried for, pale yellow oil 537mg, yield 75.3% is obtained after column chromatography.
1H-NMR (400MHz, CDCl3) δ 8 .34 (s, 1H), 7.93 (m, 1H), 7 .30~7.43 (m, 1H), 7 .21~
7.35 (m, 1H), 7 .0~7.21 (m, 2H), 6.80~6.99 (m, 1H), 5.50~5.65 (m, 2H), 4.58~4.92 (m,
4H), the .50 (m, 9H) of 4.38~4.48 (m, 1H), 4.01~4.20 (m, 4H), 3.60~3.74 (m, 2H), 1 .28~1.
MS(m/z):505.1(M+H)+。
The preparation of chipal compounds A1 and A2:
。
Sterling A（100 mg）Through HPLC preparative separations（Prepare column：Waters Symmetry C18, mobile phase A:0.02%
Trifluoroacetic acid aqueous solution；B:Methanol）After obtain 38.5 mg MS (m/z) of compound A1 31.5 mg and A2:505.1(M+H
)+。
Embodiment 2
。
By thionyl chloride（336mg）Add in IIA（513m g）Acetonitrile mixture in, stir 5 h in 80 DEG C, be precipitated solid
Body, vacuum distillation remove acetonitrile, and solid is spin-dried for after adding toluene.Then solid with dichloromethane is dissolved, is added dropwise at -30 DEG C
IIIA（337mg）With the mixed solution of dichloromethane.It drips and finishes, it is 6 ~ 7 that stirring, which continues that triethylamine is added dropwise to pH after five minutes, is dripped
Finish, the reaction was continued 1 it is small when.- 5 DEG C are warming up to, successively with sodium dihydrogen phosphate dihydrate solution, sodium bicarbonate solution, saturated salt washing
After washing, anhydrous sodium sulfate drying is spin-dried for, pale yellow oil 482mg, yield 71.5% is obtained after column chromatography.
1H-NMR (400MHz, CDCl3) δ 8 .35 (s, 1H), 7.94 (m, 1H), 7 .30~7.43 (m, 1H), 7 .21~
7.35 (m, 1H), 7 .0~7.21 (m, 2H), 6.80~6.99 (m, 1H), 5.50~5.65 (m, 2H), 4.58~4.92 (m,
4H), the .31 (m, 6H) of 4.38~4.48 (m, 1H), 4.01~4.20 (m, 3H), 3.60~3.74 (m, 2H), 1 .28~1.
Sterling C（150 mg）Through HPLC preparative separations（Prepare column：Waters Symmetry C18, mobile phase A:0.02%
Trifluoroacetic acid aqueous solution；B:Methanol）After obtain 50.0 mg of compound C1.MS(m/z): 477.2(M+H)+。
。
Embodiment 3：By the synthesis compound C methods similar with C1, compound D and D1 have been synthesized.
。
D: 1H-NMR (400MHz, CDCl3) δ 8 .34 (s, 1H), 7.93 (m, 1H), 7 .00~7.21 (m, 2H), 6.80
~6.99 (m, 2H), 5.50~5.65 (m, 2H), 4.58~4.92 (m, 4H), 4.38~4.48 (m, 1H), 4.01~4.20 (m,
4H), the .50 (m, 9H) of 3.60~3.74 (m, 2H), 1 .28~1.
D1: MS(m/z):523.2(M+H)+。
Embodiment 4：By the synthesis compound C methods similar with C1, compound I and I1 have been synthesized.
。
I: 1H-NMR (400MHz, CDCl3) δ 8 .34 (s, 1H), 8.01 (m, 1H), 7 .30~7.43 (m, 1H), 7 .21
~7.35 (m, 1H), 7 .0~7.21 (m, 2H), 6.80~6.99 (m, 1H), 5.50~5.65 (m, 2H), 4.38~4.48 (m,
1H), the .70 (m, 12H) of 4.01~4.20 (m, 4H), 3.60~3.74 (m, 2H), 1 .28~1.
I1:MS(m/z):502.2(M+H)+。
Embodiment 5：The preparation of fumarate.
。
Under room temperature, compound A1 (504mg), fumaric acid (116mg) and acetonitrile are sequentially added into single-necked flask, is warming up to
70 ~ 75 DEG C, and at this temperature stirring 1 it is small when.Cool down crystallization overnight, filters, obtains white solid A1 fumarates 502mg.
1H-NMR (400MHz, CDCl3) δ 8.10 (m, 2H), 7.28 (m, 2H), 7.18 (s, 2H), 7.10 (m, 1H), 7.05
(m, 2H), 6.59 (S, 2H), 4.84~4.98 (m, 3H), 4 .5 (d, 2H), 4.29 (m, 1H), 4.17 (m, 1H), 3.94 (m,
1H), 3.70~3.91 (m, 3H), 1.12~1.23 (m, 9H).
Embodiment 6：Antiviral breeding.
External anti-hepatitis B virus activity research.
Using 2 .2 .15 cells of HepG as hepatitis B poisonous carrier, measure compound and inhibit hepatitis type B virus progress
The ability that DNA is replicated.
Test method：2 .2 .15 cells kinds of HepG, 96 well culture plate, 24 it is small when after by different dilution factors be separately added into sample
Product and positive control drug, while set cell control well, when dosing 72 is small after replace the culture containing different diluted concentration samples respectively
Liquid collects cell conditioned medium and 2.2.15 cells in the 6th day after dosing, measures cells and supernatant and intracellular HBV respectively
DNA content, three wells, which is averaged, carries out evaluation hbv replication and release conditions, calculates IC50(the results are shown in Table 1).
Cell toxicity test.
Test method：2 .2 .15 cells kinds of HepG, 96 well culture plate, sample and the positive are separately added by different dilution factors
Comparison medicine per 3 hole of concentration, changes same concentration liquid in every 4 days, if blank control group, cultivates 8 d.Micro- Microscopic observation cell
Lesion is destroyed completely as 4；75% destroys as 3；50% destroys as 2；25% destroys as 1；It is disease-free to become 0.It calculates every
Concentration liquid average cell lesion degree and inhibiting rate.Half toxic concentration CC is calculated by Reed ＆ Muench methods50 (result
It is shown in Table 1).
The HBV inhibiting rates and cytotoxicity result of table 1, each compound
| Compound | IC50（nM） | CC50（nM） |
| Positive control TAF free alkalis | 18 | More than 20000 |
| A (mixture) | 31 | More than 20000 |
| A1 (chirality) | 13 | More than 20000 |
| A2 (chirality) | 121 | More than 20000 |
| C (mixture) | 71 | More than 20000 |
| D (mixture) | 36 | More than 20000 |
| E (mixture) | 182 | More than 20000 |
| F (mixture) | 96 | More than 20000 |
| H (mixture) | 225 | More than 20000 |
| I (mixture) | 45 | More than 20000 |
| I1 (chirality) | 22 | More than 20000 |
| I2 (chirality) | 210 | More than 20000 |
Claims (9)
1. a kind of such as general formula (I) or general formula (II) compound represented or its officinal salt,
Wherein：
（1）R1It is hydrogen or C1-6Alkyl, substituted or non-substituted C6-10Aryl or 6 ~ 10 unit's heteroaryls；
（2）R2It is hydrogen or C1-6Alkyl, cyano；
（3）Ar is substituted or non-substituted C6-10Aryl；
（4）X is independently selected from O, N, S, P；
（5）Y is substituted or non-substituted C1-6Alkyl；
（6）Alkyl refers to the aliphatic hydrocarbon groups of saturation, includes the linear chain or branch chain group of 1 to 6 carbon atom；
（7）When substituted, substituent group is one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy,
Alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkanes oxygen
Base, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group；
（8）Phosphorus atoms have chirality in compound, and configuration is the mixing of S- or R- configurations or S- configurations and R- configurations
Object.
2. such as general formula (I) or general formula (II) compound represented or its officinal salt according to claim 1, are selected from：
。
3. one kind is such as formula（A1）Or（I1）Compound represented or its officinal salt,
。
4. a kind of pharmaceutical composition, containing compound or pharmaceutically acceptable salt thereof according to any one of claim 1-3 with
Pharmaceutically acceptable carrier.
5. pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable carrier is selected from water for injection, freezes
Pulvis auxiliary material or oral formulations auxiliary material.
6. compound or pharmaceutically acceptable salt thereof according to any one of claim 1-3 is preparing treatment disease of viral infection
Drug in purposes.
7. compound or pharmaceutically acceptable salt thereof according to any one of claim 1-3 is preparing treatment HIV infection, second
Purposes in the drug of disease caused by type hepatitis or hepatitis B.
8. purposes of the pharmaceutical composition according to claim 4 or 5 in the drug for preparing treatment disease of viral infection.
9. pharmaceutical composition according to claim 4 or 5 is preparing treatment HIV infection, hepatitis B or hepatitis B
Purposes in the drug of caused disease.
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