CN100584828C - New 5-hydroxy indole-3- carboxylic esters derivative - Google Patents
New 5-hydroxy indole-3- carboxylic esters derivative Download PDFInfo
- Publication number
- CN100584828C CN100584828C CN200510005454A CN200510005454A CN100584828C CN 100584828 C CN100584828 C CN 100584828C CN 200510005454 A CN200510005454 A CN 200510005454A CN 200510005454 A CN200510005454 A CN 200510005454A CN 100584828 C CN100584828 C CN 100584828C
- Authority
- CN
- China
- Prior art keywords
- methyl
- hydroxy
- indole
- carboxylic acid
- ethyl ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- RVWZUOPFHTYIEO-UHFFFAOYSA-N 5-hydroxy-1h-indole-3-carboxylic acid Chemical class C1=C(O)C=C2C(C(=O)O)=CNC2=C1 RVWZUOPFHTYIEO-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 208000001528 Coronaviridae Infections Diseases 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 5
- -1 C2-C6Alkenyl radical Chemical class 0.000 claims description 76
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 229920006395 saturated elastomer Polymers 0.000 claims description 22
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 10
- 241000315672 SARS coronavirus Species 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 239000001301 oxygen Chemical group 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 229910052717 sulfur Chemical group 0.000 claims description 9
- 239000011593 sulfur Chemical group 0.000 claims description 9
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 8
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000003367 polycyclic group Chemical group 0.000 claims description 7
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 125000006766 (C2-C6) alkynyloxy group Chemical group 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 47
- 238000000034 method Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 abstract description 5
- 238000009472 formulation Methods 0.000 abstract description 3
- 239000000890 drug combination Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 241000711573 Coronaviridae Species 0.000 description 9
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 4
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- RLFROUSCJIREJR-UHFFFAOYSA-N ethyl 3-(methylamino)but-3-enoate Chemical compound CCOC(=O)CC(=C)NC RLFROUSCJIREJR-UHFFFAOYSA-N 0.000 description 4
- AEWNSBCPMQKSLN-UHFFFAOYSA-N ethyl 5-acetyloxy-1,2-dimethylindole-3-carboxylate Chemical compound C1=C(OC(C)=O)C=C2C(C(=O)OCC)=C(C)N(C)C2=C1 AEWNSBCPMQKSLN-UHFFFAOYSA-N 0.000 description 4
- YTBNTDMBGXAOCG-UHFFFAOYSA-N ethyl 5-hydroxy-1,2-dimethylindole-3-carboxylate Chemical compound C1=C(O)C=C2C(C(=O)OCC)=C(C)N(C)C2=C1 YTBNTDMBGXAOCG-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 206010003757 Atypical pneumonia Diseases 0.000 description 2
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 238000006683 Mannich reaction Methods 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XPUMMHFHRMSMBA-UHFFFAOYSA-N o-ethyl 3-oxo-4-phenylbutanethioate Chemical compound CCOC(=S)CC(=O)CC1=CC=CC=C1 XPUMMHFHRMSMBA-UHFFFAOYSA-N 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UCTNTYHJFWMUBD-UHFFFAOYSA-N 4-chloro-3-oxobutanoic acid Chemical class OC(=O)CC(=O)CCl UCTNTYHJFWMUBD-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 241001292005 Nidovirales Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010062106 Respiratory tract infection viral 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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 208000015606 cardiovascular system disease Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- XPXTWCDGHDBLKF-UHFFFAOYSA-N ethyl 3-(methylamino)-4-phenylsulfanylbut-2-enoate Chemical compound CCOC(=O)C=C(NC)CSC1=CC=CC=C1 XPXTWCDGHDBLKF-UHFFFAOYSA-N 0.000 description 1
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 1
- RTIBLQQLUBXQDX-UHFFFAOYSA-N ethyl 5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)indole-3-carboxylate Chemical compound CN1C2=CC=C(O)C=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 RTIBLQQLUBXQDX-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 description 1
- 229960004626 umifenovir Drugs 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The present invention is a new 5-hydroxy indole-3-carboxylic esters ramification which includes an acceptable salt pharmaceutically and a drug combination which takes this compounds as its activity components,also includes the application of preparing the coronavirus infection drug used to treat and/or prevent SARS,among which,R[1],R[2],R[3],R[4] and X is multi substituent.This ramification can be made by the common method of pharmacy field and the combination of this invention can be made into various formulation including the common excipient of pharmacy field.
Description
The technical field is as follows:
the invention relates to the technical field of medicines, in particular to a novel 5-hydroxyindole-3-carboxylic ester derivative, which comprises a racemate or an optical isomer or a pharmaceutically acceptable salt and/or hydrate thereof, and a pharmaceutical composition taking the compound as an active ingredient, and application of the derivative in preparing medicines for treating and/or preventing SARS coronavirus infection.
Background art:
severe Acute Respiratory Syndrome (SARS), also known as "infectious atypical pneumonia", first appeared in local areas of guangdong province in our country since 2002 in 11 th of the month, and then rapidly spread to 33 countries and regions in five continents including hong kong, taiwan, vietnam, singapore, and germany, local spread occurred in at least 6 countries, and accumulated over 8200 patients and over 700 patients died of illness. The disease has high propagation speed and high death rate, thereby causing great attention to the international society. Based on the global influenza surveillance network of WHO, SARS working groups of 13 laboratories in 10 countries are participated in a multi-center research plan, and a pathogenic virus of SARS, namely a new coronavirus, is found. The WHO formally announced that the pathogen of SARS is this new Coronavirus at 16.4.2003 and was named SARS Coronavirus (SARS Coronavir, SARS-Cov).
Coronavirus (Coronavir) belongs to the order Nidovirales, family Coronaviridae, genus Coronaviridae. Coronavirus can infect birds and mammals and cause respiratory, intestinal, cardiovascular and nervous system diseases. The SARS coronavirus causing SARS epidemic is different from coronavirus found before, and is a new coronavirus, which is probably originated from an ancient ancestor of coronavirus and is formed after repeated passage of animals. SARS is characterized by acute onset, fast course, strong infectivity and high fatality rate, and is a serious infectious disease seriously harming human life and health. Clinically, there is a lack of antiviral drugs against SARS-Cov. Research and development of antiviral medicine with SARS-Cov inhibiting effect and capable of preventing and treating SARS is significant.
The research of 5-hydroxyindole-3-carboxylic ester derivatives as novel anti-influenza virus medicaments starts in the early eighties of the twentieth century. Grinev a.h., et al, khim-Farm Zh, 1987, 21(1), 52; parshevae.k.et al. khim Farm Zh, 1988, 22(5), 565; mezentseva m.v.et al.khim FarmZh, 1990, 24(10), 52; otova s.a., et al, khim Farm Zh, 1992, 26(1), 52; the synthesis and pharmacological activity research of some 5-hydroxyindole-3-carboxylate compounds are reported in ZotovoAs.A.et al, Khim Farm Zh, 1995, 29(1), 51 and other documents, and experiments show that some of the compounds have the activity of resisting influenza viruses, and have the pharmacological effects of inducing the production of interferon and enhancing the immunity of human bodies.
In 1993, the structural derivative, 1-methyl-4- (dimethylamino) methyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride (Arbidol, pct appl.wo 9008135(RUSS), 1990-6-26), developed by the former soviet company VNIKhFI, was marketed in russia for the treatment and prevention of influenza a, b and acute viral respiratory infections, and it also has interferon-inducing and immunomodulating effects.
The inventor conducts extensive research on 5-hydroxyindole-3-carboxylic ester compounds, modifies and reforms a plurality of structural sites to synthesize a series of new derivatives, and in vitro antiviral activity tests show that the compounds have good antiviral effect. The inventor applies Chinese patent application No. 03110803.2 to the compound.
The inventor adopts the established model of the pathological effect of African green monkey kidney cells (VERO-E6) caused by SARS-Cov to carry out in vitro screening on the synthesized 5-oxindole-3-carboxylic ester derivatives, so as to obtain the compound with strong inhibition effect on SARS-Cov from the derivatives, and develop the compound into the clinical medicine for preventing and treating SARS.
The invention content is as follows:
the invention aims to provide a new application of 5-hydroxy indole-3-carboxylic ester derivatives including racemates or optical isomers or pharmaceutically acceptable salts and/or hydrates thereof in preparing medicaments for treating and/or preventing SARS coronavirus infection.
Wherein,
R1is C1~C8Alkyl radical, C3-C8A cycloalkyl group;
R2is C1~C8Alkyl radical, C3-C8A cycloalkyl group;
x represents H, halogen;
z is CH2SR5,CH2NR6R7;
R3、R4Independently selected from H, amino, C1-C10Alkyl radical, C3~C8Cycloalkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, which may be substituted by 1 to 3R8Optionally substituted;
or R3、R4And N together form a guanidino group, or a 4-to 10-membered monocyclic or polycyclic saturated ring or a 5-to 10-membered heteroaromatic ring, wherein said saturated ring and heteroaromatic ring optionally include 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, except R3And R4The saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds in addition to the nitrogen atom to which it is attached, and the saturated ring and the heteroaromatic ring may be substituted with 1 to 3R8Optionally substituted;
R5is unsubstituted or substituted by 1 to 3R8Optionally substituted phenyl;
or R5Is a 4-to 10-membered monocyclic or polycyclic saturated ring or a 5-to 10-membered heteroaromatic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the saturated ring and the heteroaromatic ring may be substituted with 1 to 3R8Optionally substituted;
R6、R7independently selected from H, amino, C1-C10Alkyl radical, C3~C8Cycloalkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, which may be substituted by 1 to 3R8Optionally substituted
Or R6、R7And N together form a 4-to 10-membered monocyclic or polycyclic saturated ring or a 5-to 10-membered heteroaromatic ring, wherein the saturated ring and heteroaromatic ring optionally include 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur, except R3And R4The saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds in addition to the nitrogen atom to which it is attached, and the saturated ring and the heteroaromatic ring may be substituted with 1 to 3R8Optionally substituted;
R8is represented by C1-C6Alkyl radical, C3~C8Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy, C1-C6Alkoxy radical, C2-C6Alkenyloxy radical, C2-C6Alkynyloxy, mercapto, C1-C6Alkylthio radical, C2-C6Alkenylthio, phenyl, benzyl, free, salified, esterified and amidated carboxyl, halogen, trifluoromethyl, C1-C6Alkanoyl, nitro, cyano, amino, C1-C6Alkylamido, or mono-or di (C)1-C6Alkyl) substituted amino;
according to the invention, in the definition of the substituents:
preferred R1Is methyl, ethyl, propyl, isopropyl, cyclopropyl;
preferred Z is CH2SR5;
Preferred R5Is unsubstituted or substituted by 1 to 3 groups selected from C1-C4Straight or branched alkyl, C1-C4Alkoxy and halogenPhenyl substituted with an aryl group.
Preferred R6、R7And N together is a 5-or 6-membered monocyclic or polycyclic saturated ring, wherein said saturated ring optionally comprises 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
Preferred R3And R4Independently selected from C1~C8Alkyl radical, C3~C8A cycloalkyl group.
Preferred R3、R4And N together are 1-pyrrolidinyl, 1-piperidinyl, 4-carboxylic acid-1-piperidinyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-morpholinyl.
Preferred X is H, a bromine atom.
Particularly preferred 5-hydroxyindole-3-carboxylic acid ester derivatives of formula I above according to the present invention include:
1-methyl-4- (1-piperidinyl) methyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (N-methyl-N-butyl-amino) methyl-2- (3-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (N-methyl-N-octylamino) methyl-2- (3-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (N-methyl-N-cyclopropylamino) methyl-2- (4-methoxyphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (3, 4-difluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (3-methoxyphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (2-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
4- (1-pyrrolidinyl) methyl-1-cyclopropyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (4-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (3-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (2-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (1-pyrrolidinyl) methyl-1-cyclopropyl-2- (4-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
1-ethyl-4- (diethylamino) methyl-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (4-morpholinyl) methyl-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (diethylamino) methyl-2- (4-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (2, 6-dichlorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (dimethylamino) methyl-2- (2, 6-dichlorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (4-morpholinyl) methyl-1-isopropyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (dimethylamino) methyl-1-cyclopropyl-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (dimethylamino) methyl-2- (1-piperidinyl) methyl-1-cyclopropyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (dimethylamino) methyl-2- (4-morpholinyl) methyl-1-cyclopropyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (dimethylamino) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (1-pyrrolidinyl) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (N-methyl-N-cyclopropylamino) methyl-1-cyclopropyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester oxalate;
4- (N-methyl-N-isobutylamino) methyl-1-cyclopropyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (4-carboxylic acid-1-piperidinyl) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (2-methyl-1H-1-imidazolyl) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester;
furthermore, the 5-hydroxy-3-carboxylate indole derivatives of formula I of the present invention may be formed into pharmaceutically acceptable salts with acids according to conventional methods in the art. The acid may include inorganic or organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
The term "alkyl" as used above refers to a straight or branched chain alkyl group, "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl group, "alkenyl" refers to a straight or branched chain alkenyl group, and "alkynyl" refers to a substituted or unsubstituted alkynyl group.
The 5-hydroxy indole-3-carboxylic ester compound of the above formula I according to the present invention has the activity of inhibiting SARS-Cov and protecting infected cells, so that it can be clinically used for preparing anti-SARS-Cov virus agent and medicine for treating and/or preventing SARS-Cov infection.
The compounds according to the invention can be used as active ingredients for the preparation of medicaments for the treatment or prophylaxis of SARS-Cov infection, and the invention also provides methods for the treatment or prophylaxis of the abovementioned diseases, which comprise administering a therapeutically effective amount of a compound according to the invention to a patient suffering from or susceptible to such a disease.
The invention comprises a pharmaceutical composition, which contains the 5-oxindole-3-carboxylic ester compound shown in the formula I or pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The compounds of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field; for example, oral formulations (e.g., tablets, capsules, lozenges, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are immediately ready for use by addition of water for injection prior to injection); topical formulations (e.g. ointments or solutions).
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art and include: binders, lubricants, disintegrants, solubilizing agents, diluents, stabilizers, suspending agents, non-coloring agents, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers and the like for injectable preparations; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
Furthermore, the clinical dosage of the 5-hydroxyindole-3-carboxylate compounds of formula I above for a patient may be based on: the therapeutic efficacy and bioavailability of the active ingredients in vivo, their metabolic and excretory rates and the age, sex, disease stage of the patient are suitably adjusted, although the daily dose for an adult should generally be 10 to 500mg, preferably 50 to 300 mg. Therefore, when the pharmaceutical composition of the present invention is formulated into a unit dosage form, each unit dosage form should contain 10 to 500mg of the 5-hydroxy-3-carboxylate indole compound of the above formula I, preferably 50 to 300mg, in view of the above effective dose. These formulations may be administered in several doses (preferably one to six times) at regular intervals, according to the guidance of a doctor or pharmacist.
The following synthetic schemes A-C describe the preparation of the compounds of formula I of the present invention, all starting materials prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these diagrams are as defined below or in the claims.
Compounds of formula I according to the invention, in scheme A, Z is CH2SR5Or CH2NR6R7Substituent R1、R2、R5、R6And R7As defined above, wherein R3、R4Independently selected from H, amino, C1~C10Alkyl radical, C3~C8Cycloalkyl radical, C2~C10Alkenyl radical, C2~C10Alkynyl, which may be substituted by 1 to 3R8Optionally substituted; or R3、R4And N together form a 4-to 10-membered monocyclic or polycyclic saturated ring, wherein the saturated ring optionally includes 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur, except that R3And R4The saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds other than the nitrogen atom to which it is attached, and may be substituted with 1 to 3R8Optionally substituted;
route A
R is to be1Adding substituted amine into acetoacetic ester, heating to react to generate a compound 3-substituted amino-2-butenoic ester (A-1), refluxing the compound A-1 and p-benzoquinone in 1, 2-dichloroethane to obtain a compound 1-alkyl substituted-2-methyl-5-hydroxyindole-3-carboxylate (A-2), acylating with acetic anhydride or acetyl chloride to obtain 1-alkyl substituted-2-methyl-5-acetoxy indole-3-carboxylate (A-3), heating and refluxing the A-3 and liquid bromine in carbon tetrachloride under the catalysis of benzoyl peroxide to obtain 1-substituted-5-acetoxy-6-bromo-2-bromomethyl-1H-indole-3-carboxylate (A-4), under alkaline conditions, with suitable HSR5Or HNR6R7Substitution reaction is carried out to obtain a compound A-5, and then the compound A-5, formaldehyde and R are added3R4The NH undergoes a Mannich reaction to produce compound A-6 of formula I.
Compounds of formula I according to the invention have in scheme B the substituents X as hydrogen, fluorine or chlorine atoms, the other substituents being as defined for the substituents of the compounds of scheme A.
Route B
Chloroacetoacetates are commercially available as a commercial product, which is reacted with HSR5Or HNR6R7Reacting (substituted thiophenol or amine) at room temperature under an alkaline condition to obtain a compound B-1, then performing reflux reaction on the compound B-1 and substituted amine in 1, hot 2-dichloroethane for 12-24 h to obtain a compound B-2, performing reflux reaction on the compound B-2 and p-benzoquinone in 1, 2-dichloroethane for 6-12 h, cooling to separate out a compound B-3, and performing Mannich reaction to obtain a compound B-4 in a formula I.
Route C
Compounds of formula I according to the invention, in scheme C, Z is as defined for compounds of formula I, R3、R4And N together is a guanidino group or a 5-to 10-membered heteroaromatic ring, wherein the heteroaromatic ring optionally includes 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and may be substituted with 1 to 3R8Optionally substituted; other substituents are as defined for compounds of formula I.
Preparation of Compound C-1 As described in scheme A or B above, Compound C-1 is reacted with a compound of formula HNR3R4Of compounds of (2) wherein NR3R4As defined above, the organic solvent used in the reaction is C1~C4And (3) heating and refluxing the linear chain or branched chain alcohol and acetonitrile and other polar organic solvents at the reaction temperature for 4-6 h to obtain the compound C-2 shown in the formula I.
The invention has the advantages that: provides a new 5-hydroxy indole-3-carboxylic ester derivative which can be prepared into a medicine for treating or preventing SARS virus, and provides a new medicine for treating infectious atypical pneumonia patients.
The specific implementation mode is as follows:
the compounds of the present invention and their preparation will be better understood in connection with the following examples, which are intended to illustrate, but not to limit, the scope of the invention.
Example 1:
1-methyl-4- (1-piperidinyl) methyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride
Step A: preparation of 3-methylamino-3-butenoic acid ethyl ester (1)
Under stirring and slight heating, 274mL (1.4mol) of methylamine solution is dropped into 300mL of 50% sodium hydroxide solution, generated methylamine gas is introduced into 169mL (1.3mol) of ethyl acetoacetate, the reaction is released heat, stirring is carried out, the reaction solution is cooled in a water bath, the reaction temperature is maintained at 35-40 ℃ until the reaction solution is turbid, light green turbid solution is obtained, the ventilation is stopped, and the reaction solution is stirred at room temperature overnight. The next day, stirring and pumping for 2h, adding 300mL of ether for layering, washing the organic layer with water until the pH value is 8, drying the organic layer with anhydrous sodium sulfate, and concentrating the organic layer under reduced pressure to obtain 180.6g of transparent liquid, wherein the yield is as follows: 97.1%, the concentrate obtained was used directly in the next reaction.
And B: preparation of 1, 2-dimethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester (2)
Dissolving 117.5g (1.05mol) of p-benzoquinone in 1200mL of 1, 2-dichloroethane, dropwise adding the compound (1) under stirring, controlling the reaction temperature to be 40-45 ℃, reacting for 1h, naturally cooling to room temperature, standing overnight, separating out a solid, performing suction filtration, washing with cold acetone, drying, and recrystallizing with acetone to obtain 165.0g of the compound (2), wherein the yield is as follows: 57.8 percent and mp 207-208 ℃.
And C: preparation of 1, 2-dimethyl-5-acetoxy-1H-indole-3-carboxylic acid ethyl ester (3)
Adding 82.7g (0.355mol) of the compound (2) into 500mL of acetone, adding 98.6mL (0.71mol) of triethylamine, stirring until the mixture is completely dissolved, dropwise adding 52mL (0.71mol) of acetyl chloride, controlling the reaction temperature to be 20-25 ℃, stirring at room temperature for reacting for 4 hours, pouring the reaction liquid into ice water while stirring, separating out a solid, filtering, washing with water, drying, and recrystallizing 1, 4-dioxane to obtain 87.4g of a white solid compound (3), wherein the yield is 89.6%.
Step D: preparation of 1-methyl-2- (bromomethyl) -5-acetoxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester (4)
82.5g (0.30mol) of the compound (3) is added into 400mL of carbon tetrachloride, 3 pieces of benzoyl peroxide are added, 43mL (0.84mol) of bromine is added dropwise, the mixture is refluxed for 4 hours after the dropwise addition, and after the reaction, the mixture is kept stand, cooled, filtered, and recrystallized by ethyl acetate to obtain 109g of the compound (4), wherein the yield is 84%.
Step E: preparation of 1-methyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester (5)
Adding 11.5g (0.29mol) of sodium hydroxide and 30.4g (0.24mol) of thiophenol into 400mL of methanol, stirring for 2h at room temperature, adding 94.0g (0.24mol) of the compound (4) in portions, stirring for 6h at room temperature, neutralizing the reaction solution with dilute acetic acid to be neutral, precipitating a large amount of solid, carrying out suction filtration, washing with water, drying, and recrystallizing with ethyl acetate to obtain 92.7g of the compound (5), wherein the yield is as follows: 92.0 percent.
Step F: preparation of 1-methyl-4- (1-piperidinyl) methyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride
Sequentially adding 8.3mL (0.029mol) of piperidine, 3.8mL (0.024mol) of 37% formaldehyde solution and 10g (0.024mol) of compound (5) into 40mL of ethanol, adding a proper amount of glacial acetic acid to adjust the pH value to 4-5, reacting at 40-45 ℃ for 6h, evaporating part of ethanol under reduced pressure, pouring the concentrated solution into 20mL of water, adding 50% sodium hydroxide solution to adjust the pH value to 10-12, extracting diethyl ether, drying an organic layer with anhydrous magnesium sulfate, evaporating to dryness, dissolving the obtained oily substance into 30mL of acetone, dropwise adding hydrochloric ether solution under reflux until the pH value of the reaction solution is 2-3, continuously refluxing for 0.5h, naturally cooling, standing for crystallization, and recrystallizing acetone-ethanol to obtain 9.8g of a solid with the yield of 74%.
1H-NMR(CDCl3):δppm:1.35(t,3H),1.38(m,1H),1.75(m,2H),1.87(m,1H),2.27(m,2H),2.91(m,2H),3.32(m,2H),3.58(s,3H),4.21(q,2H),4.54(s,2H),5.20(s,2H),7.22~7.32(m,5H),7.63(s,1H),10.25(br s,2H)
The preparation of the compounds of examples 2 to 24 is the same as in example 1.
Example 2
1-methyl-4- (N-methyl-N-butylamino) methyl-2- (3-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:0.98(t,3H),1.35(t,3H),1.41(m,2H),1.96(m,2H),2.27(s,3H),2.64(d,2H),3.14(m,2H),3.59(s,3H),4.20(q,2H),4.48(d,1H),4.60(d,2H),5.01(m,1H),5.48(m,1H),7.05~7.16(m,4H),7.63(s,1H),10.48(s,1H)
example 3
1-methyl-4- (N-methyl-N-octylamino) methyl-2- (3-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:0.88(t,3H),1.27(m,13H),1.96(m,2H),2.26(s,3H),2.63(d,3H),3.13(m,2H),3.58(s,3H),4.19(q,2H),4.47(d,1H),4.59(d,1H),4.98(m,1H),5.47(m,1H),7.05~7.16(m,4H),8.29(s,1H),10.50(br s,1H)
example 4
1-methyl-4- (N-methyl-N-octylamino) methyl-2- (4-methoxyphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:0.88(t,3H),1.27~1.33(m,10H),1.38(t,3H),1.96(m,2H),2.63(d,3H),3.16(m,2H),3.50(s,3H),3.7(s,3H),4.20(q,2H),4.17(d,2H),4.22(d,2H),4.54(m,1H),5.47(m,1H),6.75(d,2H),7.16(d,2H),7.60(s,1H),8.26(brs,1H),10.29(br s,1H)
example 5
1-methyl-4- (N-methyl-N-cyclopropylamino) methyl-2- (4-methoxyphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:0.81(t,3H),3.19(s,1H),3.21(m,1H),3.53(d,3H),3.78(s,3H),3.89(m,2H),4.22(q,2H),4.29(m,2H),4.45(s,2H),5.28(d,2H),6.74(d,2H),7.17(d,2H),7.63(s,1H),11.18(br s,1H)
example 6
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (3, 4-difluorophenyl) thiomethyl-6-bromo-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
1H-NMR(DMSO):δppm:1.06(m,2H),1.26~1.28(m,5H),2.79(d,3H),3.17(m,1H),3.57(m,4H),3.93(m,4H),4.23(q,2H),4.79(s,2H),5.0(br s,2H),7.22(m,1H),7.13(q,1H),7.53(m,1H),7.95(s,1H),9.88(br s,2H),11.95(br s,1H)
example 7
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (3-methoxyphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
1H-NMR(CDCl3):δppm:1.11(m,2H),1.22(m,2H),1.35(t,3H),2.87(s,3H),2.95(m,1H),3.46(m,2H),3.64(m,2H),3.70(s,3H),4.16(m,2H),4.32(m,5H),4.78(s,2H),5.387(s,2H),6.82(m,2H),6.91(d,1H),7.19(m,1H),7.90(s,1H),11.66(br s,1H),13.61(br s,1H)
example 8
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (2-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
1H-NMR(DMSO):δppm:1.07(m,2H),1.26(m,5H),2.77(s,3H),3.14(m,3H),3.56(m,2H),3.74(m,4H),4.21(q,2H),4.76(s,2H),5.00(br s,2H),7.20(m,1H),7.27(m,1H),7.39~7.46(m,2H),7.93(s,1H),9.95(br s,2H),12.00(br s,1H)
example 9
4- (1-pyrrolidinyl) methyl-1-cyclopropyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.08(m,2H),1.24(m,2H),1.35(t,3H),2.07(m,2H),2.15(m,2H),2.91(m,1H),3.13(m,2H),3.53(m,2H),4.21(q,2H),4.73(s,2H),5.21(d,2H),7.21~7.26(m,5H),7.89(s,1H),10.78(br s,1H)
example 10
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (4-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.34(t,3H),1.38(t,3H),2.08(m,2H),2.15(m,2H),2.32(s,3H),3.17(m,2H),3.54(m,2H),4.09(q,2H),4.18(,2H),5.24(d,2H),5.26(s,2H),7.05(d,2H),7.17(d,2H),8.10(s,1H),8.10(br s,1H),10.76(br s,1H)
example 11
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (3-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
H-NMR(CDCl3):δppm:1.36(t,3H),2.09(m,2H),2.16(m,2H),2.28(s,3H),3.15(m,2H),3.52(m,2H),4.11(q,2H),4.21(q,2H),4.53(s,2H),5.26(d,2H),7.05~7.17(m,4H),7.63(s,1H),10.77(br s,1H)
example 12
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (2-fluorophenyl) thiomethyl-6-bromo-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.37(t,3H),1.45(t,3H),2.07(m,2H),2.18(m,2H),3.13(m,2H),3.52(m,2H),4.17~4.26(m,4H),4.56(s,2H),5.22(d,2H),6.98~7.11(m,2H),7.22~7.33(m,2H),7.64(s,1H),10.74(s,1H)
example 13
1-ethyl-4- (1-pyrrolidinyl) methyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.33(t,3H),1.40(t,3H),2.07(m,2H),2.16(m,2H),3.14(m,2H),3.53(m,2H),4.10(q,2H),4.18(q,2H),4.54(s,2H),5.25(d,2H),7.22~7.26(m,5H),7.63(s,1H),10.79(br s,1H)
example 14
4- (1-pyrrolidinyl) methyl-1-cyclopropyl-2- (4-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.07(m,2H),1.21(m,2H),1.35(t,3H),2.08(m,2H),2.16(m,2H),2.32(s,3H),2.87(m,1H),3.14(m,2H),3.53(m,2H),4.21(q,2H),4.68(s,2H),5.22(d,2H),7.04(d,2H),7.16(d,2H),8.00(s,1H),8.01(br s,1H),10.80(br s,1H)
example 15
1-ethyl-4- (4-methyl-1-piperazinyl) methyl-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
1H-NMR(DMSO):δppm:1.22(t,3H),1.25(t,3H),2.77(d,3H),3.30~3.48(m,8H),4.18(q,2H),4.24(q,2H),4.65(s,2H),5.02(br s,2H),7.18(m,2H),7.39(m,2H)8.00(s,1H),9.69(br s,1H),11.70(br s,1H)
example 16
1-ethyl-4- (diethylamino) methyl-bromo-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.33(t,3H),1.41(t,6H),1.44(t,3H),3.10~3.15(m,4H),4.10(q,2H),4.17(q,2H),4.48(s,2H),5.23(d,2H),6.94(m,2H),7.23(m,2H),7.66(s,1H),10.04(br s,1H)
example 17
1-ethyl-4- (4-morpholinyl) methyl-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.36(t,3H),1.41(t,3H),3.18~3.21(m,4H),3.87~3.91(m,2H),4.11(q,2H),4.21(q,2H),4.27~4.36(m,2H),4.50(s,2H),5.27(d,2H),6.94(m,2H),7.23(m,2H),7.67(s,1H),9.46(br s,1H),11.20(br s,1H)
example 18
1-methyl-4- (diethylamino) methyl-2- (4-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.35(t,3H),1.43(t,6H),2.33(s,3H),3.14(m,4H),3.54(s,3H),4.19(q,2H),4.49(s,2H),5.26(d,2H),7.06(d,2H),7.17(d,2H),7.61(s1H),9.98(br s,1H)
example 19
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (2, 6-dichlorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.35(t,3H),1.46(t,3H),2.05(m,2H),2.17(m,2H),3.12(m,2H),3.49(m,2H),4.15(q,2H),4.24(q,2H),4.54(s,2H),5.14(d,2H),7.18~7.33(m,3H),7.63(s,1H),10.80(br s,1H)
example 20
1-ethyl-4- (dimethylamino) methyl-2- (2, 6-dichlorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.36(t,3H),1.46(t,3H),2.80(d,6H),4.16(q,2H),4.24(q,2H),4.55(s,2H),5.11(d,2H),7.20~7.33(m,3H),7.65(s,1H),10.71(br s,1H)
example 21
4- (4-morpholinyl) methyl-1-isopropyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.31(t,3H),1.67(d,2H),3.18(br s,4h),3.87(m,2H),4.19(q,2H),432(m,2H),4.59(s,2H),4.81(m,1H),5.19(d,2H),7.26(m,5H),7.91(s,1H),11.18(br s,1H)
example 22
4- (dimethylamino) methyl-1-cyclopropyl-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(CDCl3):δppm:1.07(m,2H),1.24(m,2H),1.33(t,3H),2.79(d,6H),2.91(m,1H),4.20(q,2H),4.67(s,2H),5.16(d,2H),6.92(t,2H),7.21(t,2H),7.89(s,1H),10.81(s,1H)
example 23
4- (dimethylamino) methyl-2- (1-piperidinyl) methyl-1-cyclopropyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(DMSO):δppm:1.05(m,2H),1.41(m,5H),1.65~1.78(m,3H),1.91~2.01(m,3H),2.72(s,6H),3.20(m,2H),3.46(m,2H),3.73(s,1H),4.41(q,2H),4.87(s,2H),4.99(s,2H),8.07(s,1H),9.21(br s,1H),9.61(s,1H),9.93(br s,1H)
example 24
4- (dimethylamino) methyl-2- (4-morpholinyl) methyl-1-cyclopropyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(DMSO):δppm:1.05(m,2H),1.41(m,5H),2.75(s,6H),3.77(s,1H),4.42(q,2H),4.90(br s,2H),4.98(s,2H),8.08(s,1H),9.16(br s,1H),9.62(b rs,1H),10.85(br s,1H)
example 25:
1-methyl-4- (dimethylamino) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride
Step A: preparation of ethyl phenylthioacetacetate:
dissolving 4.7g (0.12mol) of sodium hydroxide in 80mL of absolute ethanol, dropwise adding 12g (0.11mol) of thiophenol, stirring at room temperature for 1h, dropwise adding 16.4g (0.1mol) of ethyl chloroacetoacetate, reacting at room temperature for 6h, concentrating the reaction solution after the reaction is finished, extracting with diethyl ether, washing with 10% sodium carbonate solution, drying, and evaporating to dryness to obtain 20g of ethyl phenylthioacetoacetate, wherein the yield is 67%.
And B: preparation of 3-methylamino-4-thiophenyl-2-butenoic acid ethyl ester
Introducing methylamine gas (about 0.14mol) into 150mL of 1, 2-dichloroethane solution containing 16.7g (0.07mol) of ethyl phenylthioacetoacetate, reacting at 50-60 ℃ for 18h, washing with water, drying, and evaporating to dryness to obtain 15g of ethyl 4-phenylthio-3-methylamino-2-butenoate with the yield of 86%.
And C: preparation of 1-methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester
Dripping 100mL of 1, 2-dichloroethane solution containing 25g (0.1mol) of 4-thiophenyl-3-methylamino-2-butenoic acid ethyl ester into 60mL of 1, 2-dichloroethane solution containing 11.9g (0.11mol) of p-benzoquinone, keeping the solution slightly boiling in the dripping process, carrying out reflux reaction for 8H after finishing the dripping, cooling for crystallization, carrying out suction filtration and drying after the reaction is finished, thus obtaining 20.1g of 5-hydroxy-1-methyl-2- (phenylthio) methyl-1H-indole-3-carboxylic acid ethyl ester, wherein the yield is 59%.
Step D: preparation of 1-methyl-4- (dimethylamino) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride
According to the procedure of step E of example 1, the compound ethyl 1-methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylate was reacted with dimethylamine and formaldehyde to give ethyl 1-methyl-4- (dimethylamino) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylate, which was then reacted with ethyl hydrochloride to give hydrochloride.
1H-NMR(DMSO):1.25(t,3H),2.76(d,6H),3.69(s,3H),4.20(m,2H),4.73(s,2H),4.75(s,2H),7.04(d,1H),7.29~7.41(m,5H),7.56(d,1H),8.69(s,1H)
The preparation of the compounds of examples 26 to 29 is carried out in the same manner as in example 24.
Example 26
4- (N-methyl-N-cyclopropylamino) methyl-1-cyclopropyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester oxalate;
1H-NMR(DMSO):δppm:0.72(m,2H),0.85(m,2H),1.09(m,2H),1.23(m,2H),1.30(t,2H),2.61(s,3H),2.74(m,1H),3.12(m,1H),4.24(q,2H),4.77(s,2H),4.84(d,2H),7.00(d,2H),7.32~7.43(m,5H),7.65(d,1H),8.50(br s,2H).
example 27
4- (N-methyl-N-isobutylamino) methyl-1-cyclopropyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(DMSO):δppm:0.97(s,3H),0.99(s,3H),1.04(m,2H),1.22~1.27(m,5H),2.13(m,1H),2.63(s,3H),3.10(m,3H),4.20(m,2H),4.61(m,2H),4.81(s,2H),7.02(d,1H),7.31~7.41(m,5H),7.67(d,1H),10.08(s,1H)
example 28
1-methyl-4- (4-carboxylic acid-1-piperidinyl) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1H-NMR(DMSO):δppm:1.24(t,3H),1.77(m,2H),2.06(m,2H),3.15(m,3H),3.70(s,3H),4.19(q,2H),4.77(m,4H),7.02(d,1H),7.30~7.42(m,4H),7.56(d,1H),8.46(br s,1H),8.65(br s,1H),10.02(d,1H),12.46(br s,1H)
example 29
1-methyl-4- (1-pyrrolidinyl) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride
1H-NMR(DMSO):1.24(t,3H),1.89(m,2H),2.03(s,2H),3.25(m,2H),3.39(m,4H),3.69(s,3H),4.20(m,2H),4.76(s,2H),4.83(d,2H)7.04(d,1H),7.30~7.42(m,5H),7.54(d,1H),9.07(s,1H)
Example 30
1-methyl-6-bromo-4- (1H-1-imidazolyl) methyl-2- (4-chlorophenyl) thiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride
Ethyl 1-methyl-4- (dimethylamino) methyl-2- (4-chlorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylate prepared according to the procedure of example 1, 10.2g (0.02mol) of this compound was added to 80mL of ethanol, stirred to dissolve it, 3.4g (0.05mol) of imidazole was added thereto, and the mixture was refluxed for 4 hours, concentrated under reduced pressure to give an oily substance, reacted with ethyl ether hydrochloride to give a solid, and recrystallized to give 9.7g of the objective compound, with a yield: 91 percent.
1H-NMR(DMSO):1.14(t,3H),3.72(s,3H),4.08(q,2),4.65(s,2H),5.73(s,2H),7.28~7.39(m,5H),7.89(s,1H),9.05(s,1H)
Example 31
1-methyl-4- (2-methyl-1H-1-imidazolyl) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester
Prepared according to the method of example 30.
1H-NMR(DMSO):1.07(t,3H),2.33(s,3H),3.71(s,3H),3.99(q,2H),4.65(s,2H),5.52(s,2H),6.27(s,1H),6.52(s,1H),7.29(m,5H),7.88(s,1H),8.95(br s,1H)
Pharmacological study of the products of the invention
Next, the anti-SARS-Cov activity of the 5-hydroxyindole-3-carboxylic acid ester derivative of the above formula I according to the present invention was evaluated in vitro. The Vero-E6 is used as virus host cell, the test sample resists the effect of virus infection cell, the test index is cell denaturation reaction (CPE) and the protection rate of infected cell, the virus strain adopts BJ-01.
The experimental method comprises the following steps:
the samples were dissolved in culture medium or DMSO to make up the appropriate initial concentration, 5-fold dilution, 3 dilutions. Vero-E6 cells are inoculated on a 96-well culture plate, cultured at 37 ℃ under 5% CO, and after SARS virus infects cells, samples with different dilution concentrations are respectively added, and virus control, cell control and sample control are set. The results were observed daily under the mirror, CPE recorded and OD values determined by neutral red staining, and the effect of the samples against SARS virus was calculated and evaluated with reference to the control.
The results of the assay of the partial compounds of the invention are as follows:
protection rate of infected cells: calculating the protective activity of the sample on virus-infected cells by comparing the OD values of the virus control, the cell control and the sample control, wherein the protective rate is more than EC20It was preliminarily thought that the sample had some protective effect on cells infected with the virus and had antiviral activity.
*Sample cytotoxicity: if the sample has a cytotoxicity to cell control ratio of greater than 50 (> CC)50) CPE evaluation and protection ratio calculation were not given.
Claims (7)
1. The application of 5-hydroxy indole-3-carboxylic ester derivative or racemate or optical isomer or pharmaceutically acceptable salt or hydrate thereof in the preparation of drugs for treating or preventing SARS coronavirus infection,
wherein,
R1is C1-C3Alkyl, cyclopropyl;
R2Is ethyl;
x represents H, halogen;
z is CH2SR5,CH2NR6R7;
R3、R4And N together form a guanidino group, or form a 5-or 6-membered saturated or heteroaromatic ring, wherein said saturated or heteroaromatic ring is other than R3And R4Optionally 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the nitrogen atom to which it is attached, said saturated and heteroaromatic rings being substituted with 1 to 3R8Substitution;
R5is unsubstituted or substituted by 1 to 3R8Optionally substituted phenyl;
or R5Is a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaromatic ring having 1-4 heteroatoms selected from nitrogen, oxygen, sulfur, wherein said saturated ring and heteroaromatic ring may be substituted with 1-3R8Optionally substituted;
R6、R7and N together is a 5-or 6-membered monocyclic or polycyclic saturated ring, wherein said saturated ring optionally contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;
R8is represented by C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy, C1-C6Alkoxy radical, C2-C6Alkenyloxy radical, C2-C6Alkynyloxy, mercapto, C1-C6Alkylthio radical, C2-C6Alkenylthio, phenyl, benzyl, free, salified, esterified or amidated carboxyl, halogen, trifluoromethyl, C1-C6Alkanoyl, nitro, cyano, amino, C1-C6Alkylamido, or mono-or di (C)1-C6Alkyl) substituted amino.
2. The use as claimed in claim 1, wherein Z is CH2SR5。
3. The use of claim 2, wherein R5Is unsubstituted or substituted by 1 to 3 substituents selected from C1-C4Alkyl radical, C1-C4Alkoxy and halo groups substituted phenyl.
4. The use of claim 1, wherein R3、R4And N together are 1-pyrrolidinyl, 1-piperidinyl, 4-carboxylic acid-1-piperidinyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-morpholinyl.
5. The use according to claim 1, wherein X is H, a bromine atom.
6. The use according to claim 1, wherein the derivative of formula I is:
1-methyl-4- (1-piperidinyl) methyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (3, 4-difluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (3-methoxyphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (2-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
4- (1-pyrrolidinyl) methyl-1-cyclopropyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (4-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (3-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (2-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (1-pyrrolidinyl) methyl-1-cyclopropyl-2- (4-methylphenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (4-methyl-1-piperazinyl) methyl-1-cyclopropyl-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester dihydrochloride;
1-ethyl-4- (4-morpholinyl) methyl-2- (4-fluorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-ethyl-4- (1-pyrrolidinyl) methyl-2- (2, 6-dichlorophenyl) thiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
4- (4-morpholinyl) methyl-1-isopropyl-2-phenylthiomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (1-pyrrolidinyl) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (4-carboxylic acid-1-piperidinyl) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester hydrochloride;
1-methyl-4- (2-methyl-1H-1-imidazolyl) methyl-2-phenylthiomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester.
7. Use of a pharmaceutical composition comprising a derivative of formula I according to claim 1 and pharmaceutically acceptable salts thereof as active ingredient in combination with pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment or prevention of SARS coronavirus infection.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200510005454A CN100584828C (en) | 2004-01-07 | 2005-01-01 | New 5-hydroxy indole-3- carboxylic esters derivative |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200410021013 | 2004-01-07 | ||
CN200410021013.3 | 2004-01-07 | ||
CN200510005454A CN100584828C (en) | 2004-01-07 | 2005-01-01 | New 5-hydroxy indole-3- carboxylic esters derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1660807A CN1660807A (en) | 2005-08-31 |
CN100584828C true CN100584828C (en) | 2010-01-27 |
Family
ID=35010407
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200510005454A Expired - Fee Related CN100584828C (en) | 2004-01-07 | 2005-01-01 | New 5-hydroxy indole-3- carboxylic esters derivative |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN100584828C (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2330018C2 (en) * | 2006-04-18 | 2008-07-27 | Общество с ограниченной ответственностью "МБФ" | Derivative 4-aminomethyl-6-bromine-5-hydroxyindole-3-carboxylate, methods of their obtaining (versions) and their application |
EP2036889A4 (en) * | 2006-05-23 | 2009-11-04 | Alla Chem Llc | Substituted indoles and a method for the production and use thereof |
CN102786463B (en) * | 2012-07-02 | 2013-12-18 | 浙江金伯士药业有限公司 | Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester |
-
2005
- 2005-01-01 CN CN200510005454A patent/CN100584828C/en not_active Expired - Fee Related
Non-Patent Citations (8)
Title |
---|
"Synthesis and biological activity of indole and benzofuransulfides". Zotova, S. A., et al.Khim-Farm. Zh,,Vol.29 No.1. 1995 |
"Synthesis and antimicrobial activity of some new4-isogramines, 4-arylthiomethyl and 4-arylazo derivatives of5-hydroxyindoles",. Raghavendra G. Joshi, et al.J. Indian Chem. Soc.,,Vol.71 . 1994 |
"Synthesis and antimicrobial activity of some new4-isogramines, 4-arylthiomethyl and 4-arylazo derivatives of5-hydroxyindoles",. Raghavendra G. Joshi,et al.J.Indian Chem.Soc,Vol.71. 1994 * |
"Synthesis and biological activity of indole and benzofuransulfides". Zotova,S.A.,et al.Khim-Farm. Zh,Vol.29 No.1. 1995 * |
"Synthesis and biological ofsubstituted 5-hydroxy-6-bromoindole",. Panisheve, E. K., et al.Khim-Farm. Zh,,Vol.22 No.5. 1988 |
"Use of enzyme immunoindication or virus-specific antigensin the study of the new antiinfluenza drug arbiol",. Leneva, I. A. et al.Khim-Farm. Zh,,Vol.28 No.9. 1994 |
Synthesis and antiviral activity of2-alkylaminomethylderivatives of 5-hydroxyindoles. Mezentseva, M. V. Et al.Khim-Farm. Zh,,Vol.21 No.1. 1987 |
Synthesis and some pharmacological properties ofindoleandbenzofuran derivatives containinganimidazolepharmacophore.. Zotova, S. A., et al.Khim-Farm. Zh,,Vol.28 No.2. 1994 |
Also Published As
Publication number | Publication date |
---|---|
CN1660807A (en) | 2005-08-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4792025B2 (en) | 5-hydroxyindole-3-carboxylic acid ester derivatives and uses thereof | |
BR112017002370B1 (en) | INDOLE COMPOUNDS, PHARMACEUTICAL COMPOSITION COMPRISING THEM AND THEIR USE IN INHIBITING THE REPLICATION OF THE FLU VIRUS | |
PT2627334E (en) | Compositions for use in the treatment of viral infections | |
CN100361975C (en) | Novel 5-hydroxy-3-carboxylate indoles derivant and method for preparing the same | |
CN102924443B (en) | 5-hydroxy indole derivative contain heterocyclic ring and applications thereof | |
WO2014168522A1 (en) | Glutarimide derivatives, use thereof, pharmaceutical composition based thereon and methods for producing glutarimide derivatives | |
WO2018174442A1 (en) | Compound for treating diseases caused by coronavirus infection | |
JP2006515004A5 (en) | ||
EA021989B1 (en) | Substituted indoles, antiviral active component, method for producing and using same | |
CN107459496B (en) | Use of thiazole derivatives for treating viral infections | |
BR112020024807A2 (en) | ascorbic acid and quinone compounds in combination with an antiparasitic agent to treat a parasitic disease | |
CN100584828C (en) | New 5-hydroxy indole-3- carboxylic esters derivative | |
PT1636185E (en) | Novel crystalline forms of perindopril erbumine | |
CN105367558B (en) | Andrographolidume derivative and its preparation method and application | |
CN100519523C (en) | 5-hydroxyindole-3-carboxylate derivative and its use | |
CN111670189A (en) | Cycloalkyl-substituted pyrazolopyrimidines having activity on RSV | |
WO2020151296A1 (en) | Dinucleotide precursor for drug and preparation method therefor | |
CN110386893A (en) | Isoindole derivatives | |
AU2021260048B2 (en) | Antiviral 1,3-di-oxo-indene compounds | |
WO2023185763A1 (en) | Peptidomimetic compound, and preparation method, pharmaceutical composition and use therefor | |
JP2005511787A (en) | Method for preparing sodium-hydrogen exchange type 1 inhibitor | |
CN117586330A (en) | Novel nucleoside derivative, pharmaceutical composition and application thereof | |
JPH04208223A (en) | Therapeutic agent for hepatopathy | |
CN112724130A (en) | Anti-influenza virus compound and preparation method and application thereof | |
JP2022104747A (en) | Antiviral agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100127 Termination date: 20140101 |