CN102924443B - 5-hydroxy indole derivative contain heterocyclic ring and applications thereof - Google Patents
5-hydroxy indole derivative contain heterocyclic ring and applications thereof Download PDFInfo
- Publication number
- CN102924443B CN102924443B CN201210459223.5A CN201210459223A CN102924443B CN 102924443 B CN102924443 B CN 102924443B CN 201210459223 A CN201210459223 A CN 201210459223A CN 102924443 B CN102924443 B CN 102924443B
- Authority
- CN
- China
- Prior art keywords
- methyl
- hydroxy
- indole
- bromo
- carboxylic acid
- 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.)
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- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 24
- LMIQERWZRIFWNZ-UHFFFAOYSA-N 5-hydroxyindole Chemical class OC1=CC=C2NC=CC2=C1 LMIQERWZRIFWNZ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 15
- 230000003287 optical effect Effects 0.000 claims abstract description 12
- -1 cyano, carboxy Chemical group 0.000 claims description 105
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 18
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 14
- 229910052736 halogen Chemical group 0.000 claims description 14
- 150000002367 halogens Chemical group 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 10
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 9
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 9
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 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 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 6
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- 125000005257 alkyl acyl group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000011737 fluorine Chemical group 0.000 claims description 3
- 229910052731 fluorine Chemical group 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- SUMAHXUOAXQMMP-UHFFFAOYSA-N C(C)OC(=O)C1=C(N(C2=CC(=C(C(=C12)CN1C=NC=C1)O)Br)C1CC1)CS(=O)C=1SC=C(N1)C Chemical compound C(C)OC(=O)C1=C(N(C2=CC(=C(C(=C12)CN1C=NC=C1)O)Br)C1CC1)CS(=O)C=1SC=C(N1)C SUMAHXUOAXQMMP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- WOAAEJJAILFDCB-UHFFFAOYSA-N ethyl 6-bromo-1-cyclopropyl-4-[(dimethylamino)methyl]-5-hydroxy-2-[(4-phenyl-1,3-thiazol-2-yl)sulfanylmethyl]indole-3-carboxylate Chemical compound C1CC1N1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC(SC=1)=NC=1C1=CC=CC=C1 WOAAEJJAILFDCB-UHFFFAOYSA-N 0.000 claims 1
- FBHBWPQNRKEEEM-UHFFFAOYSA-N ethyl 6-bromo-1-cyclopropyl-5-hydroxy-4-(imidazol-1-ylmethyl)-2-(1,3-thiazol-2-ylsulfanylmethyl)indole-3-carboxylate Chemical compound C1CC1N1C2=CC(Br)=C(O)C(CN3C=NC=C3)=C2C(C(=O)OCC)=C1CSC1=NC=CS1 FBHBWPQNRKEEEM-UHFFFAOYSA-N 0.000 claims 1
- OYAAOEMLPFYPEA-UHFFFAOYSA-N ethyl 6-bromo-1-cyclopropyl-5-hydroxy-4-(imidazol-1-ylmethyl)-2-(1,3-thiazol-2-ylsulfonylmethyl)indole-3-carboxylate Chemical compound C1CC1N1C2=CC(Br)=C(O)C(CN3C=NC=C3)=C2C(C(=O)OCC)=C1CS(=O)(=O)C1=NC=CS1 OYAAOEMLPFYPEA-UHFFFAOYSA-N 0.000 claims 1
- UWWGPSJGXQUUSF-UHFFFAOYSA-N ethyl 6-bromo-5-hydroxy-4-(imidazol-1-ylmethyl)-1-methyl-2-[(4-methyl-1,3-thiazol-2-yl)sulfinylmethyl]indole-3-carboxylate Chemical compound C(C)OC(=O)C1=C(N(C2=CC(=C(C(=C12)CN1C=NC=C1)O)Br)C)CS(=O)C=1SC=C(N=1)C UWWGPSJGXQUUSF-UHFFFAOYSA-N 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 241000700605 Viruses Species 0.000 abstract description 18
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- 206010022000 influenza Diseases 0.000 abstract description 8
- 230000009385 viral infection Effects 0.000 abstract description 7
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- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 abstract description 4
- 208000036142 Viral infection Diseases 0.000 abstract description 4
- 150000004677 hydrates Chemical class 0.000 abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 44
- 238000002360 preparation method Methods 0.000 description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 22
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000002431 hydrogen Chemical group 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 description 8
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- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 6
- 0 C*C1=**C(C)*1=C Chemical compound C*C1=**C(C)*1=C 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 101710142246 External core antigen Proteins 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 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 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- YNNGZCVDIREDDK-UHFFFAOYSA-N aminocarbamodithioic acid Chemical compound NNC(S)=S YNNGZCVDIREDDK-UHFFFAOYSA-N 0.000 description 4
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Health & Medical Sciences (AREA)
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Abstract
本发明涉及通式Ⅰ所示的含有杂环的5-羟基吲哚类衍生物，包括其消旋体、旋光异构体及其药学上可接受的盐和/或水合物，其中取代基R1、R2、X、Y、Z具有在说明书中给出的含义。式Ⅰ的化合物可用于制备治疗和/或预防病毒性感染药物，尤其是用于制备抗乙肝病毒药物和抗流感病毒药物。<CNIPR:IMG <CNIPR:IMG wi="57.94" he="41.28" file="2012104592235100004dest_path_image002.GIF" img-format="jpg"The present invention relates to heterocycle-containing 5-oxindole derivatives represented by general formula I, including their racemates, optical isomers and pharmaceutically acceptable salts and/or hydrates thereof, wherein the substituent R 1 , R 2 , X, Y, and Z have the meanings given in the specification. The compound of formula I can be used for preparing medicines for treating and/or preventing viral infections, especially for preparing anti-hepatitis B virus medicines and anti-influenza virus medicines. <CNIPR:IMG <CNIPR:IMG wi="57.94"he="41.28"file="2012104592235100004dest_path_image002.GIF"img-format="jpg"
Description
技术领域 technical field
本发明涉及一系列含有杂环的5-羟基吲哚类衍生物及其用途，以及以该化合物为活性成分的药物组合物，以及其在制备用于治疗和/或预防病毒性感染特别是乙型肝炎病毒、流感病毒感染药物中的用途。 The present invention relates to a series of heterocycle-containing 5-oxindole derivatives and uses thereof, as well as a pharmaceutical composition containing the compound as an active ingredient, and its preparation for treating and/or preventing viral infections, especially B Use in medicines for hepatitis virus and influenza virus infection.
背景技术 Background technique
病毒感染可引起多种疾病，严重危害人类的健康和生命。迄今全世界已发现的病毒超过3000种，而且新的病毒仍不断被发现。据统计，60-65%的流行性传染病由病毒感染引起。由于病毒与宿主相互作用的复杂性，因此大多数抗病毒药物在发挥治疗作用时，对人体产生毒性或抗病毒的作用较低。这也是抗病毒药物发展较慢的原因。就目前的抗病毒药物品种结构而言，可供临床使用的药物仍十分匮乏，远远不能满足预防和治疗病毒性疾病的需要。研究具有新型抗病毒机制、抗病毒活性强且毒性低的抗病毒药物具有重要意义。 Virus infection can cause a variety of diseases and seriously endanger human health and life. So far, more than 3,000 viruses have been discovered in the world, and new viruses are still being discovered. According to statistics, 60-65% of epidemic infectious diseases are caused by virus infection. Due to the complexity of the interaction between the virus and the host, most antiviral drugs have low toxicity to the human body or low antiviral effects when exerting therapeutic effects. This is also the reason for the slow development of antiviral drugs. As far as the current structure of antiviral drugs is concerned, the drugs available for clinical use are still very scarce, far from meeting the needs of preventing and treating viral diseases. It is of great significance to study antiviral drugs with novel antiviral mechanism, strong antiviral activity and low toxicity.
5-羟基吲哚-3-羧酸酯类衍生物起始是作为新型抗流感病毒药物进行研究的。Grinev A.H., et al. Khim-Farm Zh, 1987, 21(1), 52；Parisheva E.K. et al. Khim Farm Zh, 1988, 22(5), 565；Mezentseva M.V. et al. Khim Farm Zh, 1990, 24(10), 52；Otova S.A., et al. Khim Farm Zh, 1992, 26(1), 52；Zotova S.A. et al. Khim Farm Zh, 1995, 29(1), 51等文献报道了一些5-羟基吲哚-3-羧酸酯类化合物的合成及其药理活性研究，实验表明其中一些化合物具有抗流感病毒活性，并且具有诱导干扰素产生，增强人体免疫力的药理作用。 5-Hydroxyindole-3-carboxylate derivatives were initially studied as new anti-influenza drugs. Grinev AH, et al . Khim-Farm Zh, 1987, 21(1), 52; Parisheva EK et al . Khim Farm Zh, 1988, 22(5), 565; Mezentseva MV et al . Khim Farm Zh, 1990, 24 (10), 52; Otova SA, et al . Khim Farm Zh, 1992, 26(1), 52; Zotova SA et al . Khim Farm Zh, 1995, 29(1), 51 and other literatures reported some 5-hydroxy Synthesis of indole-3-carboxylate compounds and research on their pharmacological activity. Experiments show that some of these compounds have anti-influenza virus activity, and have the pharmacological effect of inducing interferon production and enhancing human immunity.
1993年，由前苏联VNIKhFI公司开发的该类结构衍生物—1-甲基-4-[(二甲氨基)甲基]-2-（苯基硫甲基）-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯盐酸盐(Arbidol，PCT Int Appl. WO 9008135 (RUSS)，1990-6-26)在俄罗斯上市，用于治疗和预防甲、乙型流感和急性病毒性呼吸道感染。 In 1993, this type of structural derivative developed by the former Soviet Union VNIKhFI company—1-methyl-4-[(dimethylamino)methyl]-2-(phenylthiomethyl)-5-hydroxyl-6-bromo -1 H -indole-3-carboxylic acid ethyl ester hydrochloride (Arbidol, PCT Int Appl. WO 9008135 (RUSS), 1990-6-26) is listed in Russia for the treatment and prevention of influenza A, B and Acute viral respiratory infection.
本课题组，以阿比朵尔为先导化合物，对其结构进行进一步改造和优化，先后得到了一系列结构新颖的5-羟基吲哚-3-羧酸酯类衍生物，并先后对其申请了相关专利。 Our research group, using Arbidol as the lead compound, further modified and optimized its structure, obtained a series of novel 5-hydroxyindole-3-carboxylate derivatives, and applied for related patents.
2003年，CN1482118公开了新颖的5-羟基-3-羧酸酯吲哚类衍生物及其制备方法，描述了5-羟基-3-羧酸酯吲哚类化合物或其药学上所接受的盐，对流感病毒和呼吸道病毒具有显著的抑制作用，提供了一种新型高效的抗流感病毒药物。 In 2003, CN1482118 disclosed novel 5-hydroxyl-3-carboxylate indole derivatives and their preparation methods, describing 5-hydroxyl-3-carboxylate indole compounds or their pharmaceutically acceptable salts , has significant inhibitory effect on influenza virus and respiratory virus, and provides a new type of highly effective anti-influenza virus drug.
2004年，CN1706827公开了5-羟基吲哚-3-羧酸酯类衍生物及其用途，描述了另外一种结构的5-羟基吲哚-3-羧酸酯类衍生物或其药学上所接受的盐，可用于制备治疗和/或预防病毒性感染药物，尤其是用于制备抗乙肝病毒和抗人免疫缺陷病毒药物。 In 2004, CN1706827 disclosed 5-hydroxyindole-3-carboxylate derivatives and their uses, and described another structure of 5-hydroxyindole-3-carboxylate derivatives or their pharmaceutically The accepted salt can be used for the preparation of medicines for treating and/or preventing viral infections, especially for the preparation of anti-hepatitis B virus and anti-human immunodeficiency virus medicines.
在HBV的病毒学指标中，HBeAg是HBV复制明显和传染性强的重要标志。在HBV感染过程中，HBeAg可与人白细胞抗原协同调节宿主的免疫应答，抑制宿主T细胞的细胞毒活性，形成对HBV感染的免疫耐受性，使HBV逃避免疫清除，得以在无症状携带者群体中长期贮存。在抗病毒治疗后所出现的HBeAg血清学转换与HBV-DNA水平降低相比则具有更重要的意义：患者可获得持续应答，预后改善，对HBV的免疫力提高；表明HBV复制被持续控制。 Among the virological indexes of HBV, HBeAg is an important symbol of obvious replication and strong infectivity of HBV. During HBV infection, HBeAg can cooperate with human leukocyte antigens to regulate the host's immune response, inhibit the cytotoxic activity of host T cells, form immune tolerance to HBV infection, and enable HBV to escape immune clearance and be able to spread in asymptomatic carriers. Long-term storage in groups. The HBeAg seroconversion after antiviral treatment is more important than the reduction of HBV-DNA level : patients can obtain sustained response, improved prognosis, and improved immunity to HBV; indicating that HBV replication is continuously controlled.
在前期基础上，对5-羟基吲哚类化合物继续进行深入研究，发现在吲哚环的2位上引入含硫杂环如噻二唑基、噻唑基、噻唑烷酮基团，可以大幅度提高化合物对乙肝病毒HBeAg分泌的活性。 On the previous basis, the in-depth research on 5-oxindole compounds continued, and it was found that the introduction of sulfur-containing heterocycles such as thiadiazolyl, thiazolyl, and thiazolidinone groups at the 2-position of the indole ring can greatly Improve the activity of the compound on HBeAg secretion of hepatitis B virus.
发明内容 Contents of the invention
本发明涉及通式I含有杂环的5-羟基吲哚类衍生物，或其消旋体或旋光异构体，或其药学上可接受的盐和/或水合物， The present invention relates to 5-oxindole derivatives of general formula I containing heterocycles, or racemates or optical isomers thereof, or pharmaceutically acceptable salts and/or hydrates thereof,
其中 in
R1为 (C1-C6)烷基、(C3-C6)环烷基； R 1 is (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl;
R2为(C1-C6)烷基； R 2 is (C 1 -C 6 ) alkyl;
X为氢、卤代； X is hydrogen, halogenated;
Y为-NR3R4； Y is -NR 3 R 4 ;
R3和R4相同或不同，分别独立地选自(C1-C6)烷基、(C3-C6)环烷基，任选被1-3个相同或不同的R8任选取代； R 3 and R 4 are the same or different, each independently selected from (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, optionally optionally 1-3 same or different R 8 replace;
或R3和R4与和它们所连接的氮原子一起形成胍基、5-10元杂环基或5-10元杂芳基，所述杂环基和杂芳基除了与R3和R4连接的氮原子外，任选1-4个选自N、O和S的杂原子，所述杂环基和杂芳基任选1~3个相同或不同的R8取代； Or R 3 and R 4 form a guanidino group, a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group together with the nitrogen atom to which they are attached, and the heterocyclic group and the heteroaryl group are not combined with R 3 and R In addition to the nitrogen atoms connected to 4 , optionally 1-4 heteroatoms selected from N, O and S, and the heterocyclic group and heteroaryl group are optionally substituted by 1 to 3 identical or different R 8 ;
R8代表(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、酯基、硝基； R 8 represents (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo, hydroxyl, cyano, carboxyl, ester, nitro;
Z为； Z is ;
m为0、1、2； m is 0, 1, 2;
n为0-4之间的整数； n is an integer between 0-4;
Q为、、； Q is , , ;
R5为氢、(C1-C4)烷基、C1-C4烷氧基、羟基、任选被羟基、氨基或卤代的(C1-C4)烷基或(C1-C4)烷氧基、(C1-C4)烷硫基、游离的、成盐的、酯化的和酰胺化的羧基、卤代、(C1-C4)烷基酰基、硝基、氰基、氨基、(C1-C4)烷基酰氨基或被单或二[(C1-C6)烷基)]取代的氨基； R 5 is hydrogen, (C 1 -C 4 ) alkyl, C 1 -C 4 alkoxy, hydroxyl, (C 1 -C 4 ) alkyl optionally substituted by hydroxyl, amino or halogen, or (C 1 - C 4 )alkoxy, (C 1 -C 4 )alkylthio, free, salified, esterified and amidated carboxyl, halo, (C 1 -C 4 )alkylacyl, nitro , cyano, amino, (C 1 -C 4 ) alkyl amido or amino substituted by mono or di [(C 1 -C 6 ) alkyl)];
或者R5为(C6-C10)芳基或5-10元杂芳基，它们任选被1-3个相同或不同的R9取代，其中，所述杂芳基和杂环基任选含有1-3个选自N、O或S的杂原子； Or R 5 is (C 6 -C 10 )aryl or 5-10 membered heteroaryl, which are optionally substituted by 1-3 identical or different R 9 , wherein the heteroaryl and heterocyclyl are any Optionally contain 1-3 heteroatoms selected from N, O or S;
R9为(C1-C4)烷基、(C1-C4)烷氧基、羟基、卤素、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、巯基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷硫基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、烯丙基、(2-甲基)烯丙基、(3-甲基)烯丙基、(2-甲基)-2-烯丁基、(C1-C4)烷基酰氨基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N, N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N, N-二(C1-C4)烷基氨基磺酰基和(C1-C3)亚烷基二氧基。 R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano, mercapto , (C 1 -C 4 ) alkenyl, (C 1 -C 4 ) alkynyl, (C 1 -C 4 ) alkylthio, hydroxy (C 1 -C 4 ) alkyl, amino (C 1 -C 4 )alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl, (2-methyl)-2-enylbutyl, (C 1 -C 4 )alkyl Amino, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxymethyl, (C 1 -C 4 )alkyl Acyl, carbamoyl, N -(C 1 -C 4 )alkylcarbamoyl, N, N -di(C 1 -C 4 )alkylcarbamoyl, aminosulfonyl, N -(C 1 -C 4 ) Alkylaminosulfonyl, N,N -di(C 1 -C 4 )alkylaminosulfonyl and (C 1 -C 3 )alkylenedioxy.
本发明优选还涉及定义如下的通式Ⅰ化合物，或其消旋体或旋光异构体，或其药学上可接受的盐和/或水合物， The present invention preferably also relates to a compound of general formula I as defined below, or its racemate or optical isomer, or a pharmaceutically acceptable salt and/or hydrate thereof,
其中 in
R1为 (C1-C6)烷基、(C3-C6)环烷基； R 1 is (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl;
R2为(C1-C6)烷基； R 2 is (C 1 -C 6 ) alkyl;
X为氢、卤代； X is hydrogen, halogenated;
Y为-NR3R4； Y is -NR 3 R 4 ;
R3和R4相同或不同，分别独立地选自(C1-C6)烷基、(C3-C6)环烷基，任选被1-3个相同或不同的R8任选取代； R 3 and R 4 are the same or different, each independently selected from (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, optionally optionally 1-3 same or different R 8 replace;
或R3和R4与和它们所连接的氮原子一起形成胍基、5-10元杂环基或5-10元杂芳基，所述杂环基和杂芳基除了与R3和R4连接的氮原子外，任选1-4个选自N、O和S的杂原子，所述杂环基和杂芳基任选1~3个相同或不同的R8取代； Or R 3 and R 4 form a guanidino group, a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group together with the nitrogen atom to which they are attached, and the heterocyclic group and the heteroaryl group are except for R 3 and R In addition to the nitrogen atoms connected to 4 , optionally 1-4 heteroatoms selected from N, O and S, and the heterocyclic group and heteroaryl group are optionally substituted by 1 to 3 identical or different R 8 ;
R8代表(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、酯基、硝基； R 8 represents (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo, hydroxyl, cyano, carboxyl, ester, nitro;
Z为； Z is ;
m为0、1、2； m is 0, 1, 2;
n为0-4之间的整数； n is an integer between 0-4;
Q为、、； Q is , , ;
R5为氢、(C1-C4)烷基、(C1-C4)烷氧基、羟基、任选被(羟基、氨基或卤素)取代的(C1-C4)烷基或(C1-C4)烷氧基、(C1-C4)烷硫基、(游离的、成盐的、酯化的或酰胺化的)羧基、卤代、(C1-C4)烷基酰基、硝基、氰基、氨基、(C1-C4)烷基酰胺基或被单或二(C1-C6)烷基取代的氨基； R 5 is hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy, (C 1 -C 4 )alkyl optionally substituted by (hydroxyl, amino or halogen), or (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (free, salified, esterified or amidated) carboxyl, halo, (C 1 -C 4 ) Alkylacyl, nitro, cyano, amino, (C 1 -C 4 )alkylamido or amino substituted by mono- or di-(C 1 -C 6 )alkyl;
或者R5为苯基或5-6元杂芳基，其中，所述杂芳基任选含有1-3个选自N、O或S的杂原子，并且R5任选被1-3个相同或不同的R9取代； Or R is phenyl or 5-6 membered heteroaryl, wherein, the heteroaryl optionally contains 1-3 heteroatoms selected from N, O or S, and R is optionally replaced by 1-3 Same or different R 9 substitutions;
R9为(C1-C4)烷基、(C1-C4)烷氧基、羟基、卤素、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、巯基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷硫基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、烯丙基、(2-甲基)烯丙基、(3-甲基)烯丙基、(2-甲基)-2-烯丁基、(C1-C4)烷基酰氨基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N, N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N, N-二(C1-C4)烷基氨基磺酰基和(C1-C3)亚烷基二氧基。 R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano, mercapto , (C 1 -C 4 ) alkenyl, (C 1 -C 4 ) alkynyl, (C 1 -C 4 ) alkylthio, hydroxy (C 1 -C 4 ) alkyl, amino (C 1 -C 4 )alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl, (2-methyl)-2-enylbutyl, (C 1 -C 4 )alkyl Amino, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxymethyl, (C 1 -C 4 )alkyl Acyl, carbamoyl, N -(C 1 -C 4 )alkylcarbamoyl, N, N -di(C 1 -C 4 )alkylcarbamoyl, aminosulfonyl, N -(C 1 -C 4 ) Alkylaminosulfonyl, N,N -di(C 1 -C 4 )alkylaminosulfonyl and (C 1 -C 3 )alkylenedioxy.
本发明还涉及定义如下的通式I化合物，或其消旋体或旋光异构体，或其药学上可接受的盐和/或水合物， The present invention also relates to a compound of general formula I as defined below, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,
其中， in,
R1为 (C1-C6)烷基、(C3-C6)环烷基； R 1 is (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl;
R2为(C1-C6)烷基； R 2 is (C 1 -C 6 ) alkyl;
X为氢、卤代； X is hydrogen, halogenated;
Y为-NR3R4； Y is -NR 3 R 4 ;
R3和R4相同或不同，分别独立地选自(C1-C6)烷基、(C3-C6)环烷基，任选被1-3个相同或不同的R8任选取代； R 3 and R 4 are the same or different, each independently selected from (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, optionally optionally 1-3 same or different R 8 replace;
或R3和R4与和它们所连接的氮原子一起形成胍基、5-10元杂环基或5-10元杂芳基，所述杂环基和杂芳基除了与R3和R4连接的氮原子外，任选1-4个选自N、O和S的杂原子，所述杂环基和杂芳基任选1~3个相同或不同的R8取代； Or R 3 and R 4 form a guanidino group, a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group together with the nitrogen atom to which they are attached, and the heterocyclic group and the heteroaryl group are not combined with R 3 and R In addition to the nitrogen atoms connected to 4 , optionally 1-4 heteroatoms selected from N, O and S, and the heterocyclic group and heteroaryl group are optionally substituted by 1 to 3 identical or different R 8 ;
R8代表(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、酯基、硝基； R 8 represents (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo, hydroxyl, cyano, carboxyl, ester, nitro;
Z为； Z is ;
m为0、1、2； m is 0, 1, 2;
n为0-4之间的整数； n is an integer between 0-4;
Q为； Q is ;
R5为苯基或5-6元杂芳基，其中，所述杂芳基任选含有1-3个选自N、O或S的杂原子，并且R5任选被1-3个相同或不同的R9取代； R 5 is phenyl or 5-6 membered heteroaryl, wherein, said heteroaryl optionally contains 1-3 heteroatoms selected from N, O or S, and R 5 is optionally replaced by 1-3 identical or different R 9 substitutions;
R9为(C1-C4)烷基、(C1-C4)烷氧基、羟基、卤素、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、巯基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷硫基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、烯丙基、(2-甲基)烯丙基、(3-甲基)烯丙基、(2-甲基)-2-烯丁基、(C1-C4)烷基酰氨基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N, N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N, N-二(C1-C4)烷基氨基磺酰基和(C1-C3)亚烷基二氧基。 R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano, mercapto , (C 1 -C 4 ) alkenyl, (C 1 -C 4 ) alkynyl, (C 1 -C 4 ) alkylthio, hydroxy (C 1 -C 4 ) alkyl, amino (C 1 -C 4 )alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl, (2-methyl)-2-enylbutyl, (C 1 -C 4 )alkyl Amino, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxymethyl, (C 1 -C 4 )alkyl Acyl, carbamoyl, N -(C 1 -C 4 )alkylcarbamoyl, N, N -di(C 1 -C 4 )alkylcarbamoyl, aminosulfonyl, N -(C 1 -C 4 ) Alkylaminosulfonyl, N,N -di(C 1 -C 4 )alkylaminosulfonyl and (C 1 -C 3 )alkylenedioxy.
本发明优选还涉及定义如下的通式Ⅰ化合物，或其消旋体或旋光异构体，或其药学上可接受的盐和/或水合物， The present invention preferably also relates to a compound of general formula I as defined below, or its racemate or optical isomer, or a pharmaceutically acceptable salt and/or hydrate thereof,
其中 in
R1为甲基、乙基、丙基、异丙基、环丙基； R is methyl, ethyl, propyl, isopropyl, cyclopropyl;
R2为(C1-C6)烷基； R 2 is (C 1 -C 6 ) alkyl;
X为氢、溴、氟； X is hydrogen, bromine, fluorine;
Y为-NR3R4； Y is -NR 3 R 4 ;
R3和R4相同或不同，分别选自(C1-C4)烷基、环丙基； R 3 and R 4 are the same or different, respectively selected from (C 1 -C 4 ) alkyl, cyclopropyl;
或R3和R4与和它们所连接的氮原子一起形成胍基、4-吗啉基、4-甲基-1-哌嗪基、1-哌啶基、1-吡咯烷基、1H-1, 2, 4-三氮唑-1-基、1-咪唑基、2-甲基-1-咪唑基和1H-四氮唑-1-基； Or R 3 and R 4 form guanidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1 H together with the nitrogen atoms they are attached to -1, 2, 4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1 H -tetrazol-1-yl;
R8代表(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、酯基、硝基； R 8 represents (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo, hydroxyl, cyano, carboxyl, ester, nitro;
Z为； Z is ;
m为0、1、2； m is 0, 1, 2;
n为0-4之间的整数； n is an integer between 0-4;
Q为、； Q is , ;
R5为氢、(C1-C4)烷基、(C1-C4)烷氧基、羟基、任选被(羟基、氨基或卤素)取代的(C1-C4)烷基或(C1-C4)烷氧基、(C1-C4)烷硫基、(游离的、成盐的、酯化的和酰胺化的)羧基、卤代、(C1-C4)烷基酰基、硝基、氰基、氨基、(C1-C4)烷基酰胺基或被单或二(C1-C6)烷基取代的氨基； R 5 is hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy, (C 1 -C 4 )alkyl optionally substituted by (hydroxyl, amino or halogen), or (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (free, salified, esterified and amidated) carboxyl, halo, (C 1 -C 4 ) Alkylacyl, nitro, cyano, amino, (C 1 -C 4 )alkylamido or amino substituted by mono- or di-(C 1 -C 6 )alkyl;
或者R5为苯基或5-6元杂芳基，其中，所述杂芳基任选含有1-3个选自N、O或S的杂原子，并且R5任选被1-3个相同或不同的R9取代； Or R is phenyl or 5-6 membered heteroaryl, wherein, the heteroaryl optionally contains 1-3 heteroatoms selected from N, O or S, and R is optionally replaced by 1-3 Same or different R 9 substitutions;
R9为(C1-C4)烷基、(C1-C4)烷氧基、羟基、卤素、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、巯基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷硫基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、烯丙基、(2-甲基)烯丙基、(3-甲基)烯丙基、(2-甲基)-2-烯丁基、(C1-C4)烷基酰氨基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N, N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N, N-二(C1-C4)烷基氨基磺酰基和(C1-C3)亚烷基二氧基。 R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano, mercapto , (C 1 -C 4 ) alkenyl, (C 1 -C 4 ) alkynyl, (C 1 -C 4 ) alkylthio, hydroxy (C 1 -C 4 ) alkyl, amino (C 1 -C 4 )alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl, (2-methyl)-2-enylbutyl, (C 1 -C 4 )alkyl Amino, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxymethyl, (C 1 -C 4 )alkyl Acyl, carbamoyl, N -(C 1 -C 4 )alkylcarbamoyl, N, N -di(C 1 -C 4 )alkylcarbamoyl, aminosulfonyl, N -(C 1 -C 4 ) Alkylaminosulfonyl, N,N -di(C 1 -C 4 )alkylaminosulfonyl and (C 1 -C 3 )alkylenedioxy.
本发明特别优选涉及定义如下的通式Ⅰ化合物，或其消旋体或旋光异构体，或其药学上可接受的盐和/或水合物， The present invention particularly preferably relates to a compound of general formula I as defined below, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,
其中 in
R1为甲基、乙基、丙基、异丙基、环丙基； R is methyl, ethyl, propyl, isopropyl, cyclopropyl;
R2为(C1-C6)烷基； R 2 is (C 1 -C 6 ) alkyl;
X为氢、溴、氟； X is hydrogen, bromine, fluorine;
Y为-NR3R4； Y is -NR 3 R 4 ;
R3和R4相同或不同，分别选自(C1-C4)烷基、环丙基； R 3 and R 4 are the same or different, respectively selected from (C 1 -C 4 ) alkyl, cyclopropyl;
或R3和R4与和它们所连接的氮原子一起形成胍基、4-吗啉基、4-甲基-1-哌嗪基、1-哌啶基、1-吡咯烷基、1H-1, 2, 4-三氮唑-1-基、1-咪唑基、2-甲基-1-咪唑基和1H-四氮唑-1-基； Or R 3 and R 4 form guanidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1 H together with the nitrogen atoms they are attached to -1, 2, 4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1 H -tetrazol-1-yl;
R8代表(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、酯基、硝基； R 8 represents (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo, hydroxyl, cyano, carboxyl, ester, nitro;
Z为； Z is ;
m为0、1、2； m is 0, 1, 2;
n为0-4之间的整数； n is an integer between 0-4;
Q为、； Q is , ;
R5为氢、(C1-C4)烷基、被1-3个相同或不同的R9任选取代的苯基； R 5 is hydrogen, (C 1 -C 4 ) alkyl, phenyl optionally substituted by 1-3 identical or different R 9 ;
R9为(C1-C4)烷基、(C1-C4)烷氧基、羟基、卤素、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、巯基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷硫基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、烯丙基、(2-甲基)烯丙基、(3-甲基)烯丙基、(2-甲基)-2-烯丁基、(C1-C4)烷基酰氨基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N, N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N, N-二(C1-C4)烷基氨基磺酰基和(C1-C3)亚烷基二氧基。 R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano, mercapto , (C 1 -C 4 ) alkenyl, (C 1 -C 4 ) alkynyl, (C 1 -C 4 ) alkylthio, hydroxy (C 1 -C 4 ) alkyl, amino (C 1 -C 4 )alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl, (2-methyl)-2-enylbutyl, (C 1 -C 4 )alkyl Amino, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxymethyl, (C 1 -C 4 )alkyl Acyl, carbamoyl, N -(C 1 -C 4 )alkylcarbamoyl, N, N -di(C 1 -C 4 )alkylcarbamoyl, aminosulfonyl, N -(C 1 -C 4 ) Alkylaminosulfonyl, N,N -di(C 1 -C 4 )alkylaminosulfonyl and (C 1 -C 3 )alkylenedioxy.
本发明优选还涉及定义如下的通式Ⅰ化合物，或其消旋体或旋光异构体，或其药学上可接受的盐和/或水合物， The present invention preferably also relates to a compound of general formula I as defined below, or its racemate or optical isomer, or a pharmaceutically acceptable salt and/or hydrate thereof,
其中， in,
R1为甲基、乙基、丙基、异丙基、环丙基； R is methyl, ethyl, propyl, isopropyl, cyclopropyl;
R2为(C1-C6)烷基； R 2 is (C 1 -C 6 ) alkyl;
X为氢、溴； X is hydrogen, bromine;
Y为-NR3R4； Y is -NR 3 R 4 ;
R3和R4相同或不同，分别选自(C1-C4)烷基、环丙基； R 3 and R 4 are the same or different, respectively selected from (C 1 -C 4 ) alkyl, cyclopropyl;
或R3和R4与和它们所连接的氮原子一起形成胍基、4-吗啉基、4-甲基-1-哌嗪基、1-哌啶基、1-吡咯烷基、1H-1, 2, 4-三氮唑-1-基、1-咪唑基、2-甲基-1-咪唑基和1H-四氮唑-1-基； Or R 3 and R 4 form guanidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1 H together with the nitrogen atoms they are attached to -1, 2, 4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1 H -tetrazol-1-yl;
R8代表(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、酯基、硝基； R 8 represents (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo, hydroxyl, cyano, carboxyl, ester, nitro;
Z为； Z is ;
m为0、1、2； m is 0, 1, 2;
n为0-4之间的整数； n is an integer between 0-4;
Q为； Q is ;
R5为苯基或5-6元杂芳基，其中，所述杂芳基任选含有1-3个选自N、O或S的杂原子，并且R5任选被1-3个相同或不同的R9取代； R 5 is phenyl or 5-6 membered heteroaryl, wherein, said heteroaryl optionally contains 1-3 heteroatoms selected from N, O or S, and R 5 is optionally replaced by 1-3 identical or different R 9 substitutions;
R9为(C1-C4)烷基、(C1-C4)烷氧基、羟基、卤素、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、巯基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷硫基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、烯丙基、(2-甲基)烯丙基、(3-甲基)烯丙基、(2-甲基)-2-烯丁基、(C1-C4)烷基酰氨基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N, N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N, N-二(C1-C4)烷基氨基磺酰基和(C1-C3)亚烷基二氧基。 R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano, mercapto , (C 1 -C 4 ) alkenyl, (C 1 -C 4 ) alkynyl, (C 1 -C 4 ) alkylthio, hydroxy (C 1 -C 4 ) alkyl, amino (C 1 -C 4 )alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl, (2-methyl)-2-enylbutyl, (C 1 -C 4 )alkyl Amino, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxymethyl, (C 1 -C 4 )alkyl Acyl, carbamoyl, N -(C 1 -C 4 )alkylcarbamoyl, N, N -di(C 1 -C 4 )alkylcarbamoyl, aminosulfonyl, N -(C 1 -C 4 ) Alkylaminosulfonyl, N,N -di(C 1 -C 4 )alkylaminosulfonyl and (C 1 -C 3 )alkylenedioxy.
本发明优选还涉及定义如下的通式Ⅰ化合物，或其消旋体或旋光异构体，或其药学上可接受的盐和/或水合物， The present invention preferably also relates to a compound of general formula I as defined below, or its racemate or optical isomer, or a pharmaceutically acceptable salt and/or hydrate thereof,
其中， in,
R1为甲基、乙基、丙基、异丙基、环丙基； R is methyl, ethyl, propyl, isopropyl, cyclopropyl;
R2为(C1-C6)烷基； R 2 is (C 1 -C 6 ) alkyl;
X为氢、溴； X is hydrogen, bromine;
R3和R4相同或不同，分别选自(C1-C4)烷基、环丙基； R 3 and R 4 are the same or different, respectively selected from (C 1 -C 4 ) alkyl, cyclopropyl;
或R3和R4与和它们所连接的氮原子一起形成胍基、4-吗啉基、4-甲基-1-哌嗪基、1-哌啶基、1-吡咯烷基、1H-1, 2, 4-三氮唑-1-基、1-咪唑基、2-甲基-1-咪唑基和1H-四氮唑-1-基； Or R 3 and R 4 form guanidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1 H together with the nitrogen atoms they are attached to -1, 2, 4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1 H -tetrazol-1-yl;
R8代表(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、酯基、硝基； R 8 represents (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo, hydroxyl, cyano, carboxyl, ester, nitro;
Z为； Z is ;
m为0、1、2； m is 0, 1, 2;
n为0-4之间的整数； n is an integer between 0-4;
Q为； Q is ;
R5为苯基、呋喃基、吡咯基、噻吩基、吡啶基，并且R5被1-3个相同或不同的R9任选取代； R 5 is phenyl, furyl, pyrrolyl, thienyl, pyridyl, and R 5 is optionally substituted by 1-3 identical or different R 9 ;
R9为(C1-C4)烷基、(C1-C4)烷氧基、羟基、卤素、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、巯基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷硫基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、烯丙基、(2-甲基)烯丙基、(3-甲基)烯丙基、(2-甲基)-2-烯丁基、(C1-C4)烷基酰氨基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N, N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N, N-二(C1-C4)烷基氨基磺酰基和(C1-C3)亚烷基二氧基。 R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano, mercapto , (C 1 -C 4 ) alkenyl, (C 1 -C 4 ) alkynyl, (C 1 -C 4 ) alkylthio, hydroxy (C 1 -C 4 ) alkyl, amino (C 1 -C 4 )alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl, (2-methyl)-2-enylbutyl, (C 1 -C 4 )alkyl Amino, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxymethyl, (C 1 -C 4 )alkyl Acyl, carbamoyl, N -(C 1 -C 4 )alkylcarbamoyl, N, N -di(C 1 -C 4 )alkylcarbamoyl, aminosulfonyl, N -(C 1 -C 4 ) Alkylaminosulfonyl, N,N -di(C 1 -C 4 )alkylaminosulfonyl and (C 1 -C 3 )alkylenedioxy.
本发明优选还涉及定义如下的通式Ⅰ化合物，或其消旋体或旋光异构体，或其药学上可接受的盐和/或水合物， The present invention preferably also relates to a compound of general formula I as defined below, or its racemate or optical isomer, or a pharmaceutically acceptable salt and/or hydrate thereof,
其中， in,
R1为甲基、乙基、丙基、异丙基、环丙基； R is methyl, ethyl, propyl, isopropyl, cyclopropyl;
R2为(C1-C6)烷基； R 2 is (C 1 -C 6 ) alkyl;
X为氢、溴； X is hydrogen, bromine;
R3和R4相同或不同，分别选自(C1-C4)烷基、环丙基； R 3 and R 4 are the same or different, respectively selected from (C 1 -C 4 ) alkyl, cyclopropyl;
或R3和R4与和它们所连接的氮原子一起形成胍基、4-吗啉基、4-甲基-1-哌嗪基、1-哌啶基、1-吡咯烷基、1H-1, 2, 4-三氮唑-1-基、1-咪唑基、2-甲基-1-咪唑基和1H-四氮唑-1-基； Or R 3 and R 4 form guanidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1 H together with the nitrogen atoms they are attached to -1, 2, 4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1 H -tetrazol-1-yl;
R8代表(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、酯基、硝基； R 8 represents (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo, hydroxyl, cyano, carboxyl, ester, nitro;
Z为； Z is ;
m为0、1、2； m is 0, 1, 2;
n为0-4之间的整数； n is an integer between 0-4;
Q为； Q is ;
R5为呋喃-2-基、吡啶-2-基、噻吩-2-基； R 5 is furan-2-yl, pyridin-2-yl, thiophen-2-yl;
R9为(C1-C4)烷基、(C1-C4)烷氧基、羟基、卤素、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、巯基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷硫基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、烯丙基、(2-甲基)烯丙基、(3-甲基)烯丙基、(2-甲基)-2-烯丁基、(C1-C4)烷基酰氨基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N, N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N, N-二(C1-C4)烷基氨基磺酰基和(C1-C3)亚烷基二氧基。 R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano, mercapto , (C 1 -C 4 ) alkenyl, (C 1 -C 4 ) alkynyl, (C 1 -C 4 ) alkylthio, hydroxy (C 1 -C 4 ) alkyl, amino (C 1 -C 4 )alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl, (2-methyl)-2-enylbutyl, (C 1 -C 4 )alkyl Amino, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxymethyl, (C 1 -C 4 )alkyl Acyl, carbamoyl, N -(C 1 -C 4 )alkylcarbamoyl, N, N -di(C 1 -C 4 )alkylcarbamoyl, aminosulfonyl, N -(C 1 -C 4 ) Alkylaminosulfonyl, N,N -di(C 1 -C 4 )alkylaminosulfonyl and (C 1 -C 3 )alkylenedioxy.
本发明非常特别优选的下列通式Ⅰ衍生物，包括其消旋体或旋光异构体，及其药学上可接受的盐和/或水合物： Very particularly preferred derivatives of the following general formula I of the present invention, including their racemates or optical isomers, and pharmaceutically acceptable salts and/or hydrates thereof:
1-环丙基-4-[(二甲氨基)甲基]-2-[(4-苯基噻唑-2-基)硫甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(dimethylamino)methyl]-2-[(4-phenylthiazol-2-yl)thiomethyl]-5-hydroxy-6-bromo-1 H -indole - ethyl 3-carboxylate;
1-环丙基-4-[(吗啉-4-基)甲基]-2-[(4-苯基噻唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(morpholin-4-yl)methyl]-2-[(4-phenylthiazol-2-yl)sulfinylmethyl]-5-hydroxyl-6-bromo- 1 H -Indole-3-carboxylic acid ethyl ester;
1-环丙基-4-[(二甲氨基)甲基]-2-[(4-苯基噻唑-2-基)磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(dimethylamino)methyl]-2-[(4-phenylthiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1 H -ind Indole-3-carboxylic acid ethyl ester;
1-环丙基-4-[(二甲氨基)甲基]-2-[(5-甲基-1,3,4-噻二唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(dimethylamino)methyl]-2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfinylmethyl]-5- Ethyl hydroxy-6-bromo- 1H -indole-3-carboxylate;
1-环丙基-4-[(四氢吡咯-1-基)甲基]-2-[(5-甲基-1,3,4-噻二唑-2-基)磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(tetrahydropyrrol-1-yl)methyl]-2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfonylmethyl] - ethyl 5-hydroxy-6-bromo-1 H -indole-3-carboxylate;
1-环丙基-4-[(咪唑-1-基)甲基]-2-[(4-苯基噻唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(4-phenylthiazol-2-yl)sulfinylmethyl]-5-hydroxyl-6-bromo-1 H -Indole-3-carboxylic acid ethyl ester;
1-环丙基-4-[(咪唑-1-基)甲基]-2-[(4-苯基噻唑-2-基)磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(4-phenylthiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1 H - ethyl indole-3-carboxylate;
1-环丙基-4-[(咪唑-1-基)甲基]-2-[(噻唑-2-基)硫甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-Cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(thiazol-2-yl)thiomethyl]-5-hydroxy-6-bromo-1 H -indole-3 - ethyl carboxylate;
1-环丙基-4-[(2-甲基咪唑-1-基)甲基]-2-[(噻唑-2-基)硫甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(2-methylimidazol-1-yl)methyl]-2-[(thiazol-2-yl)thiomethyl]-5-hydroxy-6-bromo-1 H - Ethyl indole-3-carboxylate;
1-甲基-4-[(咪唑-1-基)甲基]-2-[(4-甲基噻唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-Methyl-4-[(imidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfinylmethyl]-5-hydroxy-6-bromo-1 H - ethyl indole-3-carboxylate;
1-甲基-4-[(2-甲基咪唑-1-基)甲基]-2-[(4-甲基噻唑-2-基)磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-Methyl-4-[(2-methylimidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfonylmethyl]-5-hydroxyl-6-bromo -1 H -indole-3-carboxylic acid ethyl ester;
1-环丙基-4-[(咪唑-1-基)甲基]-2-[(噻唑-2-基)磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(thiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1 H -indole- 3-Ethyl carboxylate;
1-环丙基-4-[(2-甲基咪唑-1-基)甲基]-2-[(噻唑-2-基)磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(2-methylimidazol-1-yl)methyl]-2-[(thiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1 H - ethyl indole-3-carboxylate;
1-甲基-4-[(二甲氨基)甲基]-2-[(4-甲基噻唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-methyl-4-[(dimethylamino)methyl]-2-[(4-methylthiazol-2-yl)sulfinylmethyl]-5-hydroxy-6-bromo-1 H -ind Indole-3-carboxylic acid ethyl ester;
1-甲基-4-[(2-甲基咪唑-1-基)甲基]-2-[噻唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-methyl-4-[(2-methylimidazol-1-yl)methyl]-2-[thiazol-2-yl)sulfinylmethyl]-5-hydroxy-6-bromo-1 H - Ethyl indole-3-carboxylate;
1-环丙基-4-[(2-甲基咪唑-1-基)甲基]-2-[(4-甲基噻唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(2-methylimidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfinylmethyl]-5-hydroxyl-6 - ethyl bromo- 1H -indole-3-carboxylate;
1-环丙基-4-[(咪唑-1-基)甲基]-2-[(4-甲基噻唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfinylmethyl]-5-hydroxyl-6-bromo-1 H -Indole-3-carboxylic acid ethyl ester;
1-环丙基-4-[(咪唑-1-基)甲基]-2-[(4-甲基噻唑-2-基)磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1 H - ethyl indole-3-carboxylate;
1-环丙基-4-[(咪唑-1-基)甲基]-2-[(5-甲基-1,3,4-噻二唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfinylmethyl]- Ethyl 5-hydroxy-6-bromo- 1H -indole-3-carboxylate;
1-甲基-4-[(2-甲基咪唑-1-基)甲基]-2-[(5-甲基-1,3,4-噻二唑-2-基)亚磺酰甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯。 1-methyl-4-[(2-methylimidazol-1-yl)methyl]-2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfinylform base]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester.
1-甲基-4-[(四氢吡咯-1-基)甲基]-2-[[2-(2-苯基-4-氧代噻唑啉-3-基)乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-Methyl-4-[(tetrahydropyrrol-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio]methyl ]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester;
1-甲基-4-[(吗啉-4-基)甲基]-2-[[2-(2-苯基-4-氧代噻唑啉-3-基)乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-Methyl-4-[(morpholin-4-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio]methyl] - ethyl 5-hydroxy-6-bromo-1 H -indole-3-carboxylate;
1-甲基-4-[(二甲氨基)甲基]-2-[[2-(2-苯基-4-氧代噻唑啉-3-基)乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-methyl-4-[(dimethylamino)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio]methyl]-5- Ethyl hydroxy-6-bromo- 1H -indole-3-carboxylate;
1-甲基-4-[(4-甲基哌嗪-1-基)甲基]-2-[[2-(2-苯基-4-氧代噻唑啉-3-基)乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-methyl-4-[(4-methylpiperazin-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio ]methyl]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester;
1-甲基-4-[(4-甲基哌嗪-1-基)甲基]-2-[[2-[2-(3-三氟甲基苯基)-4-氧代噻唑啉-3-基]乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-Methyl-4-[(4-methylpiperazin-1-yl)methyl]-2-[[2-[2-(3-trifluoromethylphenyl)-4-oxothiazoline -3-yl]ethylthio]methyl]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester;
1-甲基-4-[(二乙氨基)甲基]-2-[[2-[2-(4-甲氧基苯基)-4-氧代噻唑啉-3-基]乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-methyl-4-[(diethylamino)methyl]-2-[[2-[2-(4-methoxyphenyl)-4-oxothiazolin-3-yl]ethylthio ]methyl]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester;
1-甲基-4-[(二甲氨基)甲基]-2-[[2-(2-苯基-4-氧代噻唑啉-3-基)乙基亚磺酰基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-methyl-4-[(dimethylamino)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylsulfinyl]methyl]- Ethyl 5-hydroxy-6-bromo- 1H -indole-3-carboxylate;
1-环丙基-4-[(吗啉-4-基)甲基]-2-[[2-(2-苯基-4-氧代噻唑啉-3-基)乙基亚磺酰基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(morpholin-4-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylsulfinyl] Methyl]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester;
1-环丙基-4-[(二甲氨基)甲基]-2-[[2-[2-(吡啶-4-基)-4-氧代噻唑啉-3-基]乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-cyclopropyl-4-[(dimethylamino)methyl]-2-[[2-[2-(pyridin-4-yl)-4-oxothiazolin-3-yl]ethylthio] Methyl]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester;
1-甲基-4-[(咪唑-1-基)甲基]-2-[[2-(2-苯基-4-氧代噻唑啉-3-基)乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-methyl-4-[(imidazol-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio]methyl]- Ethyl 5-hydroxy-6-bromo- 1H -indole-3-carboxylate;
1-甲基-4-[(2-甲基咪唑-1-基)甲基]-2-[[2-(2-苯基-4-氧代噻唑啉-3-基)乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-methyl-4-[(2-methylimidazol-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio] Methyl]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester;
1-甲基-4-[(咪唑-1-基)甲基]-2-[[2-[2-(3-三氟甲基苯基)-4-氧代噻唑啉-3-基]乙硫基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯； 1-methyl-4-[(imidazol-1-yl)methyl]-2-[[2-[2-(3-trifluoromethylphenyl)-4-oxothiazolin-3-yl] Ethylthio]methyl]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester;
1-环丙基-4-[(2-甲基咪唑-1-基)甲基]-2-[[2-(2-苯基-4-氧代噻唑啉-3-基)乙基亚磺酰基]甲基]-5-羟基-6-溴-1H-吲哚-3-羧酸乙酯。 1-cyclopropyl-4-[(2-methylimidazol-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylidene Sulfonyl]methyl]-5-hydroxy-6-bromo- 1H -indole-3-carboxylic acid ethyl ester.
而且，按照本发明所属领域的一些通常方法，本发明的通式Ⅰ的含有杂环的5-羟基吲哚类衍生物可以与酸生成它的药学上可接受的盐。酸可以包括无机酸或有机酸，与下列酸形成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、洒石酸、苯磺酸、苯甲酸或对甲苯磺酸等。 Moreover, the heterocycle-containing 5-oxindole derivatives of the general formula I of the present invention can form their pharmaceutically acceptable salts with acids according to some common methods in the field of the present invention. The acids may include inorganic or organic acids, the salts with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid , acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid or p-toluenesulfonic acid, etc.
本发明化合物可以以立体异构体形式存在，这些立体异构形式可以是对映体或非对映体。本发明既涉及对映体或非对映体，也涉及它们各自的混合物，象非对映体一样，可按照自身已知的方法将外消旋形式分离成为立体异构的单一组分。 The compounds of the present invention may exist in stereoisomeric forms which may be enantiomers or diastereomers. The present invention relates both to the enantiomers or diastereomers, and also to their individual mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomeric individual components by methods known per se.
此外，本发明还包括本发明化合物的前药。依据本发明，前药是通式Ⅰ化合物的衍生物，它们自身可能具有较弱的活性或甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。 Furthermore, the present invention also includes prodrugs of the compounds of the present invention. According to the invention, prodrugs are derivatives of the compounds of general formula I, which themselves may have weak activity or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) is converted into the corresponding biologically active form.
除非另外指出，本发明所用的术语“卤代”是指氟代、氯代、溴代或碘代；“烷基”是指直链或支链的烷基；“环烷基”是指取代或未取代的环烷基；“烯基”是指直链或支链的烯基；“炔基”是指直链或支链的炔基；“芳基”是指除去芳烃中的一个氢原子而得的有机基团，如苯基、萘基；5-10元杂芳基包括含有一个或多个选自N、O和S的杂原子，其中每个杂芳基的环状体系可以是单环或多环的，环状体系是芳香性的，一共含有5-10个原子，可以举出例如咪唑基、吡啶基、嘧啶基、吡唑基、(1, 2, 3)-和(1, 2, 4)-三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噁唑基、吡唑基、吡咯基、噻唑基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并噻唑基、吲哚基、喹啉基等；5-10元杂环基包括含有一个或多个选自N、O和S的杂原子，其中每个杂芳基的环状体系可以是单环或多环的，但是是非芳香性的，环状体系一共含有5-10个原子，可以任选包括1或2个碳碳双键或碳碳叁键，可以举出例如吡咯烷基、吗啉基、哌嗪基、哌啶基、噻唑啉基等。 Unless otherwise indicated, the term "halo" used in the present invention refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to substituted or unsubstituted cycloalkyl; "alkenyl" refers to straight-chain or branched alkenyl; "alkynyl" refers to straight-chain or branched alkynyl; "aryl" refers to the removal of one hydrogen in aromatic Atom-derived organic groups, such as phenyl, naphthyl; 5-10 membered heteroaryls include one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl can be It is monocyclic or polycyclic, and the ring system is aromatic, containing 5-10 atoms in total, such as imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1, 2, 3)- and (1, 2, 4)-triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, Benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolinyl, etc.; 5-10 membered heterocyclic groups include one or more heteroatoms selected from N, O and S, wherein each The ring system of each heteroaryl group can be monocyclic or polycyclic, but is non-aromatic, and the ring system contains 5-10 atoms in total, and can optionally include 1 or 2 carbon-carbon double bonds or carbon-carbon triple bonds. Bonds include, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.
本发明的特定化合物可具有不对称的中心，因此以不同的对映体和非对映体的形式存在。本发明涉及本发明化合物的所有旋光异构体、消旋体及其混合物。“消旋体”是指含有等量的一对对映异构体的混合物。 Certain compounds of the invention may possess asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers, racemates and mixtures thereof of the compounds of the present invention. "Racemate" means a mixture containing equal amounts of a pair of enantiomers.
由于按照本发明的上式通Ⅰ的5-羟基吲哚类化合物具有抗病毒作用，特别是抗HBV和抗流感病毒的活性，因此，它可以用作制备治疗和/或预防病毒性感染的药物，特别是由下述病毒如HBV、甲型流感病毒、乙型流感病毒、呼吸道合胞病毒、副流感病毒、鼻病毒和腺病毒等引起的感染。 Since the 5-hydroxyindole compounds of the above formula I according to the present invention have antiviral effects, especially anti-HBV and anti-influenza virus activity, therefore, it can be used as a medicament for the preparation of treatment and/or prevention of viral infections , especially infections caused by viruses such as HBV, influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, rhinovirus, and adenovirus.
根据本发明的化合物可作为活性成分用于制备治疗和/或预防乙型肝炎、流感、急性病毒性呼吸道感染和流感，本发明也提供治疗或预防上述疾病的方法，包括给予患有或易患有此病的病人治疗有效量的根据本发明的化合物。 The compounds according to the present invention can be used as active ingredients for the preparation of treatment and/or prevention of hepatitis B, influenza, acute viral respiratory infections and influenza, and the present invention also provides methods for the treatment or prevention of the above diseases, including administering A therapeutically effective amount of a compound according to the invention is administered to a patient suffering from this disease.
本发明包括药物组合物，该组合物含有通式Ⅰ的5-羟基吲哚类化合物或其药学上可接受的盐作为活性成分，以及药学上可接受的赋型剂。所述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的化合物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应。 The present invention includes a pharmaceutical composition, which contains the 5-oxindole compound of the general formula I or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The compounds according to the invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.
本发明的药物组合物可配制成若干种剂型，其中含有药学领域中常用的一些赋形剂；例如，口服制剂(如片剂，胶囊剂，溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末，在注射前加入注射用水可立即使用)；局部制剂(例如软膏或溶液)。 The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some excipients commonly used in the pharmaceutical field; for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as Injectable solution or suspension, or injectable dry powder, add water for injection immediately before injection); topical preparations (eg ointment or solution).
用于本发明药物组合物的载体是药学领域中可得到的常见类型，包括：口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂等；可注射制剂用的防腐剂、加溶剂、稳定剂等；局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可将其配制成肠衣片剂。 The carrier used for the pharmaceutical composition of the present invention is a common type available in the field of pharmacy, including: adhesives for oral preparations, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, pigment-free , flavoring agents, etc.; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. Pharmaceutical preparations can be administered orally or parenterally (eg intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are unstable under gastric conditions, they can be formulated as enteric-coated tablets.
而且，通式Ⅰ的5-羟基吲哚类化合物用于患者的临床剂量可以根据：活性成分在体内的治疗功效和生物利用度、它们的代谢和排泄速率和患者的年龄、性别、疾病期来进行适当调整，不过成人的每日剂量一般应当为10-500mg，优选为50-300mg。因此，当本发明的药物组合物被制成单位剂型时，考虑到上述有效剂量，每单位制剂应当含有10-500mg上式通Ⅰ的5-羟基吲哚类化合物，优选为50-300mg。按照医生或药师的指导，这些制剂可以以一定间隔分若干次给药(优选为一至六次)。 Moreover, the clinical dose of the 5-oxindole compounds of general formula I for patients can be determined according to: the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolism and excretion rate, and the patient's age, sex, and disease stage. Suitably adjusted, however, the daily dosage for an adult should generally be 10-500 mg, preferably 50-300 mg. Therefore, when the pharmaceutical composition of the present invention is made into a unit dosage form, each unit preparation should contain 10-500 mg of the 5-oxindole compound of the above formula I, preferably 50-300 mg, in consideration of the above-mentioned effective dosage. According to the doctor's or pharmacist's instruction, these preparations can be administered several times (preferably one to six times) at certain intervals.
下面合成路线A-C描述了本发明的通式Ⅰ化合物的制备，所有的原料都是通过这些示意图中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些示意图中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些示意图中应用的全部可变因数如下文的定义或如权利要求中的定义。 The following Synthetic Schemes A-C describe the preparation of compounds of general formula I of the present invention. All starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All final compounds of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which methods are well known to those of ordinary skill in the art of organic chemistry. All variables used in these diagrams are as defined below or as defined in the claims.
按照本发明的式Ⅰ或式Ⅱ化合物，在路线A中， Y为-NR3R4，其中，R3、R4相同或不同，分别选自氢、氨基、C1-C10烷基、C3-C7环烷基，C2-C10烯基和C2-C10炔基，它们可以被1-3个R8任选取代；或者R3、R4与和它们所连接的氮原子一起形成5-10元杂环基，所述杂环基除了与R3和R4连接的氮原子外，可以含有1-4个选自N、O和S的杂原子，除了R3和R4所连接的氮原子外，所述杂环基任选包括1或2个碳碳双键或叁键，所述杂环基可以被1-3个R8任选取代；Q为、；取代基R1、R2和R5如发明内容部分所定义。 According to the compound of formula I or formula II of the present invention, in route A, Y is -NR 3 R 4 , wherein R 3 and R 4 are the same or different, and are respectively selected from hydrogen, amino, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 10 alkenyl and C 2 -C 10 alkynyl, which may be optionally substituted by 1-3 R 8 ; or R 3 , R 4 and their connected The nitrogen atoms together form a 5-10 membered heterocyclic group, which may contain 1-4 heteroatoms selected from N, O and S, except for the nitrogen atom connected to R3 and R4 , except for R3 In addition to the nitrogen atom connected to R 4 , the heterocyclic group optionally includes 1 or 2 carbon-carbon double bonds or triple bonds, and the heterocyclic group can be optionally substituted by 1-3 R 8 ; Q is , ; Substituents R 1 , R 2 and R 5 are as defined in the Summary of the Invention.
路线A Route A
按照本发明的通式Ⅰ化合物，在路线B中，取代基X、R1、R2如权利要求中所定义；Q、R3和R4如路线A中化合物取代基所定义。 According to the compound of general formula I of the present invention, in route B, the substituents X, R 1 , R 2 are as defined in the claims; Q, R 3 and R 4 are as defined in the substituents of the compound in route A.
路线B Route B
化合物B-1可按照路线A所提供的合成方法制得，化合物B-1在冰乙酸中以过硼酸钠(NaBO3)为氧化剂，40℃~60℃反应，通过改变氧化剂的配比和反应时间，可得到单氧化物B-2和双氧化物B-3，再进行Mannich反应即制得式Ⅰ或式Ⅱ的化合物B-4和B-5。 Compound B-1 can be prepared according to the synthetic method provided in route A. Compound B-1 uses sodium perborate (NaBO 3 ) as an oxidant in glacial acetic acid, and reacts at 40°C to 60°C. By changing the ratio of the oxidant and the reaction time, single oxide B-2 and double oxide B-3 can be obtained, and then Mannich reaction is carried out to obtain compounds B-4 and B-5 of formula I or formula II.
按照本发明的式Ⅰ或式Ⅱ化合物，在路线C中，Y为-NR3R4，-S(CH2)rR8，r为1-4之间的整数，R1、R2和Z如权利要求中式Ⅱ化合物所定义，R3、R4和与和它们所连接的氮原子一起形成胍基或5-10元杂芳基，所述杂芳基除了与R3和R4连接的氮原子外，可以含有1-4个选自N、O和S的杂原子，所述杂芳基可以被1-3个相同或不同的R8任选取代；其他取代基如权利要求式Ⅱ化合物所定义。 According to the compound of formula I or formula II of the present invention, in route C, Y is -NR 3 R 4 , -S(CH 2 ) r R 8 , r is an integer between 1-4, R 1 , R 2 and Z is as defined in the formula II compound in the claim, R 3 , R 4 and together with the nitrogen atom connected to them form a guanidino group or a 5-10 membered heteroaryl group, the heteroaryl group is not connected to R 3 and R 4 In addition to the nitrogen atom, it can contain 1-4 heteroatoms selected from N, O and S, and the heteroaryl group can be optionally substituted by 1-3 identical or different R 8 ; other substituents are as claimed in the formula II compound defined.
路线C Route C
化合物C-1可按照路线A和B所提供的合成方法制得，将化合物C-1与化合物HNR3R4或HS(CH2)mR8反应，反应使用的有机溶剂为乙醇-水(1：1)溶剂，反应温度为60-80℃，反应时间为4-12 h，反应毕，浓缩反应液，二氯甲烷提取，合并，干燥，蒸干，以乙醇或甲醇重结晶或经柱层析，得到式Ⅰ或式Ⅱ的化合物C-2。 Compound C-1 can be prepared according to the synthetic methods provided by Routes A and B. Compound C-1 is reacted with compound HNR 3 R 4 or HS(CH 2 )mR 8. The organic solvent used in the reaction is ethanol-water (1 : 1) solvent, the reaction temperature is 60-80°C, the reaction time is 4-12 h, after the reaction is completed, the reaction solution is concentrated, extracted with dichloromethane, combined, dried, evaporated to dryness, recrystallized with ethanol or methanol or passed through column layer Analysis, to obtain the compound C-2 of formula I or formula II.
具体实施方式 Detailed ways
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用Bruker ARX-300测定，质谱用Agilent 1100 LC/MSD测定；所用试剂均为分析纯或化学纯。 The examples are intended to illustrate, not limit, the scope of the invention. The proton nuclear magnetic resonance spectrum of the compound was determined by Bruker ARX-300, and the mass spectrum was determined by Agilent 1100 LC/MSD; the reagents used were analytical or chemically pure.
硫醇或硫酚中间体的制备 Preparation of thiol or thiophenol intermediates
部分硫醇或硫酚可在市场上购得；其他硫醇或硫酚的制备方法如下： Some mercaptans or thiophenols are commercially available; other mercaptans or thiophenols are prepared as follows:
方法1：的制备 method 1: preparation of
将二硫化碳100 mL（1.6 mole）加入三颈瓶中，降温至-5℃，滴加15%的氨气-乙醇溶液300 mL，滴毕，继续于-5℃搅拌4 h。抽滤，乙醚洗，干燥，得黄色晶体二硫代氨基甲酸铵152 g，收率86%。 Add 100 mL (1.6 mole) of carbon disulfide into the three-neck flask, cool down to -5°C, add 300 mL of 15% ammonia-ethanol solution dropwise, and continue stirring at -5°C for 4 h. Suction filtration, washing with ether, and drying gave 152 g of ammonium dithiocarbamate as yellow crystals, with a yield of 86%.
将苯乙酮100 mL（0.85 mol）加入150 mL乙醇中，保持温度不高于-5℃分批加入三溴化苯基三甲基铵（phenyl trimethylammonium tribromide, PTT）320 g （0.85 mol），加毕，继续搅拌30 min，抽滤，滤液减压浓缩，得无色液体α-溴代苯乙酮164g，含量95%，收率92%。 Add 100 mL (0.85 mol) of acetophenone into 150 mL ethanol, keep the temperature not higher than -5°C and add 320 g (0.85 mol) of phenyl trimethylammonium tribromide (PTT) in batches, After the addition, continue to stir for 30 min, filter with suction, and concentrate the filtrate under reduced pressure to obtain 164 g of α-bromoacetophenone as a colorless liquid, with a content of 95% and a yield of 92%.
将40%氯乙醛100 mL（0.61 mol）加入100 mL水中，控制温度低于5℃，分批加入二硫代氨基甲酸铵67 g（0.61 mol），加毕，升至室温继续搅拌2 h，析出白色固体，抽滤，分别用少量乙醇和水洗涤滤饼，干燥，得白色固体噻唑-2-硫醇66.2 g，收率93%。 Add 100 mL (0.61 mol) of 40% chloroacetaldehyde into 100 mL of water, control the temperature below 5°C, add 67 g (0.61 mol) of ammonium dithiocarbamate in batches, after the addition is complete, raise it to room temperature and continue stirring for 2 h , precipitated a white solid, filtered it with suction, washed the filter cake with a small amount of ethanol and water, and dried to obtain 66.2 g of thiazole-2-thiol as a white solid, with a yield of 93%.
按照噻唑-2-硫醇的制备方法，以氯丙酮和二硫代氨基甲酸铵为原料，以乙醇为溶剂，制得白色固体4-甲基噻唑-2-硫醇，收率87%。 According to the preparation method of thiazole-2-thiol, chloroacetone and ammonium dithiocarbamate were used as raw materials, and ethanol was used as solvent to prepare white solid 4-methylthiazole-2-thiol with a yield of 87%.
按照4-甲基噻唑-2-硫醇的制备方法，以α-溴代苯乙酮和二硫代氨基甲酸铵为原料，制得白色固体4-苯基噻唑-2-硫醇，收率91%。 According to the preparation method of 4-methylthiazole-2-thiol, using α-bromoacetophenone and ammonium dithiocarbamate as raw materials, a white solid 4-phenylthiazole-2-thiol was obtained with a yield of 91%.
制备通法1(路线A)： Preparation General Method 1 (Route A):
步骤A：3-烃基胺基-2-丁烯酸酯(A-1)的制备 Step A: Preparation of 3-hydrocarbylamino-2-butenoic acid ester (A-1)
安装气体发生装置，在三颈瓶中加入50%氢氧化钠溶液300 mL，在搅拌微热下，滴加甲胺溶液或乙胺水溶液(1.4 mol)，将发生的甲胺或乙胺气体导入乙酰乙酸酯(1.3 mol)中，反应放热，搅拌，水浴冷却反应液，反应温度维持在35-40 ℃，通气完毕后，室温搅拌17 h。向反应液中加入乙醚300 mL，分出有机层，有机层水洗至pH为8，无水硫酸钠干燥，减压蒸干，得3-甲胺基(乙胺基)-2-丁烯酸酯，收率70~90%，所得浓缩液直接用于下步反应。 Install a gas generating device, add 300 mL of 50% sodium hydroxide solution into the three-necked bottle, add methylamine solution or ethylamine aqueous solution (1.4 mol) dropwise under stirring with slight heat, and introduce the generated methylamine or ethylamine gas In acetoacetate (1.3 mol), the reaction was exothermic, stirred, and the reaction solution was cooled in a water bath. The reaction temperature was maintained at 35-40 °C. After the aeration was completed, it was stirred at room temperature for 17 h. Add 300 mL of ether to the reaction solution, separate the organic layer, wash the organic layer with water until the pH is 8, dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure to obtain 3-methylamino (ethylamino)-2-butenoic acid Esters, yield 70 ~ 90%, the resulting concentrated solution is directly used for the next step reaction.
对于烃基为C3~C6烷基、C3-C7环烷基及取代的烷基、环烷基的3-烃基胺基-2-丁烯酸酯，不需气体发生装置，可直接将烃基取代的胺滴入乙酰乙酸酯中，按照上法制备。 For 3-hydrocarbylamino-2-butenoic acid esters whose hydrocarbon group is C 3 ~C 6 alkyl, C 3 -C 7 cycloalkyl and substituted alkyl, cycloalkyl, no gas generating device is needed, and it can be directly The hydrocarbyl-substituted amine was dropped into the acetoacetate and prepared as above.
步骤B：1-烃基-2-甲基-5-羟基-1H-吲哚-3-羧酸酯(A-2)的制备 Step B: Preparation of 1-hydrocarbyl-2-methyl-5-hydroxy- 1H -indole-3-carboxylate (A-2)
将对苯醌(0.096 mol)溶于1, 2-二氯乙烷100 mL中，加热至60℃，搅拌至溶解完全，滴加化合物A-1，滴毕，回流反应8 h，将反应液自然冷却至室温，放置过夜，析出固体，抽滤，冷丙酮洗，干燥，丙酮重结晶得化合物A-2，收率：40~60 %。 Dissolve p-benzoquinone (0.096 mol) in 100 mL of 1,2-dichloroethane, heat to 60°C, stir until completely dissolved, add compound A-1 dropwise, after the drop is complete, reflux for 8 h, and dissolve the reaction solution Naturally cooled to room temperature, left overnight, precipitated solid, suction filtered, washed with cold acetone, dried, recrystallized from acetone to obtain compound A-2, yield: 40~60%.
步骤C：1-烃基-2-甲基-5-乙酰氧基-1H-吲哚-3-羧酸酯(A-3) Step C: 1-Alkyl-2-methyl-5-acetoxy-1 H -indole-3-carboxylate (A-3)
将化合物A-2 (0.05 mol) 加入到丙酮80 mL中，加入吡啶10 mL (0.1 mol)，搅拌至全溶，滴加乙酰氯5.5 mL (0.075 mol)，控制反应温度低于30℃，滴毕，室温搅拌反应4 h，搅拌下将反应液倾入冰水中，放置过夜，析出固体，抽滤，水洗，干燥，得化合物A-3，收率75-90%。 Add compound A-2 (0.05 mol) to 80 mL of acetone, add 10 mL (0.1 mol) of pyridine, stir until completely dissolved, add dropwise 5.5 mL (0.075 mol) of acetyl chloride, control the reaction temperature below 30°C, drop After completion, the reaction was stirred at room temperature for 4 h, and the reaction solution was poured into ice water under stirring, and left overnight, and a solid was precipitated, filtered with suction, washed with water, and dried to obtain compound A-3 with a yield of 75-90%.
步骤D：1-烃基-2-溴甲基-5-乙酰氧基-6-溴-1H-吲哚-3-羧酸酯(A-4)的制备 Step D: Preparation of 1-alkyl-2-bromomethyl-5-acetoxy-6-bromo- 1H -indole-3-carboxylate (A-4)
将化合物A-3 (0.04 mol) 加入到四氯化碳50 mL中，加热回流至固体全溶。加入催化量的过氧化苯甲酰，加热回流下向反应液滴加干燥的溴5.1 mL (0.1 mol)，滴毕，回流5 h，反应毕，静置，冷却，抽滤，水洗，甲醇洗，得化合物Ⅴ，收率为65%-85%。 Compound A-3 (0.04 mol) was added to 50 mL of carbon tetrachloride, heated to reflux until the solids were completely dissolved. Add a catalytic amount of benzoyl peroxide, add 5.1 mL (0.1 mol) of dry bromine dropwise to the reaction solution under heating and reflux, after the drop is complete, reflux for 5 h, after the reaction is complete, let stand, cool, filter with suction, wash with water, and wash with methanol , to obtain compound V with a yield of 65%-85%.
步骤E：1-烃基-2-(取代的硫甲基)-5-羟基-6-溴-1H-吲哚-3-羧酸酯(A-5)的制备 Step E: Preparation of 1-hydrocarbyl-2-(substituted thiomethyl)-5-hydroxy-6-bromo-1 H -indole-3-carboxylate (A-5)
在甲醇40mL中，加入氢氧化钾5 g (0.09 mol) 和取代的硫酚或硫醇 (0.03 mol)，室温搅拌2 h后，分次加入化合物A-4(0.03 mol)，室温搅拌6-8 h，稀盐酸中和反应液至中性，析出大量固体，抽滤，水洗，甲醇洗，乙酸乙酯洗，乙醇重结晶，得白色固体，干燥得化合物A-5，收率：60%-90%。 In methanol 40mL, add potassium hydroxide 5 g (0.09 mol) and substituted thiophenol or thiol (0.03 mol), after stirring at room temperature for 2 h, add compound A-4 (0.03 mol) in portions, and stir at room temperature for 6- 8 h, dilute hydrochloric acid to neutralize the reaction solution to neutral, a large amount of solid precipitated, suction filtered, washed with water, washed with methanol, washed with ethyl acetate, recrystallized with ethanol to obtain a white solid, dried to obtain compound A-5, yield: 60% -90%.
步骤H：1-烃基-4-[(脂肪胺基)甲基]-2-(取代的硫甲基)-5-羟基-6-溴-1H-吲哚-3-羧酸酯(A-6)的制备 Step H: 1-Alkyl-4-[(aliphatic amino)methyl]-2-(substituted thiomethyl)-5-hydroxy-6-bromo- 1H -indole-3-carboxylate (A -6) Preparation
将脂肪胺 (0.032 mol)、37%甲醛溶液1.1 mL (0.014 mol) 和化合物A-5 (0.013 mol) 依次加入冰醋酸50 mL中，于50-55℃反应6~8 h，减压蒸除醋酸，将浓缩液倒入水20 mL中，加入20%氢氧化钠溶液调pH至10，二氯甲烷提取水层，合并有机层，无水硫酸镁干燥，蒸干，得油状物。 Add aliphatic amine (0.032 mol), 1.1 mL (0.014 mol) of 37% formaldehyde solution and compound A-5 (0.013 mol) to 50 mL of glacial acetic acid in sequence, react at 50-55°C for 6-8 h, evaporate under reduced pressure Acetic acid, pour the concentrated solution into 20 mL of water, add 20% sodium hydroxide solution to adjust the pH to 10, extract the aqueous layer with dichloromethane, combine the organic layers, dry over anhydrous magnesium sulfate, and evaporate to dryness to obtain an oily substance.
将所得油状物溶于丙酮30 mL中，滴加适量乙醚，静置析晶，过滤，以少量丙酮洗、乙醚洗，得A-6，收率为40~70%； Dissolve the obtained oil in 30 mL of acetone, add an appropriate amount of diethyl ether dropwise, stand for crystallization, filter, wash with a small amount of acetone and diethyl ether to obtain A-6 with a yield of 40-70%;
或将油状物溶于丙酮30 mL中，滴加盐酸乙醇溶液至pH 1-2，滴加少量乙醚至混浊，静置，过夜，析晶得A-6盐酸盐，收率为40~70%。 Or dissolve the oil in 30 mL of acetone, add hydrochloric acid ethanol solution dropwise to pH 1-2, add a small amount of ether until cloudy, let it stand overnight, and crystallize to obtain A-6 hydrochloride with a yield of 40-70 %.
按照制备通法1，分别制得实施例1-27化合物(见表一)。 According to Preparation General Method 1, the compounds of Examples 1-27 were respectively prepared (see Table 1).
表一： Table I:
制备通法2 Preparation method 2
步骤A：1-烃基-2-取代的硫甲基-5-羟基-6-取代(氢)-1H-吲哚-3-羧酸乙酯(B-1)的制备 Step A: Preparation of 1-hydrocarbyl-2-substituted thiomethyl-5-hydroxy-6-substituted (hydrogen)-1 H -indole-3-carboxylic acid ethyl ester (B-1)
化合物B-1的制备可按照制备通法1和2的合成方法制备得到。 Compound B-1 can be prepared according to the synthetic methods of Preparation 1 and 2.
步骤B：1-烃基-2-取代的亚磺酰甲基-5-羟基-6-取代(氢)-1H-吲哚-3-羧酸乙酯(B-2)的制备 Step B: Preparation of 1-hydrocarbyl-2-substituted sulfinylmethyl-5-hydroxy-6-substituted (hydrogen)-1 H -indole-3-carboxylic acid ethyl ester (B-2)
在冰乙酸50 mL中，加入化合物B-1(0.01 mol)和过硼酸钠四水合物(NaBO3.4H2O)1.85g(0.012 mol)，搅拌，将反应液升温至40-60℃，反应1-2 h，薄层色谱监测反应时间。反应毕，蒸干，加入水25 mL，用NaOH(10%)溶液调pH值至10，二氯甲烷提取，合并提取液，水洗，无水硫酸钠干燥，过滤，蒸干，加入乙醚，析出固体，以乙醚/丙酮重结晶，得化合物B-2，收率60-80 %。 In 50 mL of glacial acetic acid, add compound B-1 (0.01 mol) and sodium perborate tetrahydrate (NaBO 3 .4H 2 O) 1.85 g (0.012 mol), stir, and raise the temperature of the reaction solution to 40-60°C, React for 1-2 h, and monitor the reaction time by TLC. After the reaction is complete, evaporate to dryness, add 25 mL of water, adjust the pH value to 10 with NaOH (10%) solution, extract with dichloromethane, combine the extracts, wash with water, dry over anhydrous sodium sulfate, filter, evaporate to dryness, add ether, and precipitate The solid was recrystallized from ether/acetone to obtain compound B-2 with a yield of 60-80%.
步骤C：1-烃基-2-取代的磺酰甲基-5-羟基-6-取代(氢)-1H-吲哚-3-羧酸乙酯(B-3)的制备 Step C: Preparation of 1-hydrocarbyl-2-substituted sulfonylmethyl-5-hydroxy-6-substituted (hydrogen)-1 H -indole-3-carboxylic acid ethyl ester (B-3)
在冰乙酸50 mL中，加入化合物B-1(0.01 mol)和过硼酸钠四水合物(NaBO3.4H2O)3.85 g(0.025 mol)，搅拌，将反应液升温至40-60℃，反应24-36 h，薄层色谱监测反应时间。反应毕，蒸干，加入水25 mL，用NaOH(10%)溶液调pH值至10，二氯甲烷提取，合并提取液，饱和氯化钠水溶液洗，水洗，无水硫酸钠干燥。过滤，蒸干，甲醇重结晶，得化合物B-3，收率50-80 %。 In 50 mL of glacial acetic acid, add compound B-1 (0.01 mol) and sodium perborate tetrahydrate (NaBO 3 .4H 2 O) 3.85 g (0.025 mol), stir, and raise the temperature of the reaction solution to 40-60°C, The reaction was 24-36 h, and the reaction time was monitored by TLC. After the reaction was completed, evaporate to dryness, add 25 mL of water, adjust the pH value to 10 with NaOH (10%) solution, extract with dichloromethane, combine the extracts, wash with saturated aqueous sodium chloride solution, wash with water, and dry over anhydrous sodium sulfate. Filter, evaporate to dryness, and recrystallize from methanol to obtain compound B-3 with a yield of 50-80%.
步骤D：1-烃基-4-取代的胺甲基-2-取代的亚磺酰甲基(取代的磺酰甲基)-5-羟基-6-取代(氢)-1H-吲哚-3-羧酸乙酯(B4或B-5)的制备 Step D: 1-Alkyl-4-substituted aminomethyl-2-substituted sulfinylmethyl(substituted sulfonylmethyl)-5-hydroxy-6-substituted(hydrogen) -1H -indole- Preparation of ethyl 3-carboxylate (B4 or B-5)
按照制备通法1步骤H操作，化合物B-2或B-3与适合的脂肪胺、37%甲醛溶液反应制备得到目标产物B-4或B-5。 According to Step H of Preparation Method 1, compound B-2 or B-3 was reacted with a suitable aliphatic amine and 37% formaldehyde solution to obtain the target product B-4 or B-5.
按照制备通法2，分别制得实施例29-34化合物(见表二)。 According to Preparation Method 2, the compounds of Examples 29-34 were prepared respectively (see Table 2).
表二：Table II:
制备通法3： Preparation method 3:
化合物C-1的制备： Preparation of compound C-1:
化合物C-1可按照制备通法1或2制得。 Compound C-1 can be prepared according to Preparation 1 or 2.
化合物C-2的制备 Preparation of Compound C-2
将化合物C-1(0.02 mol)加至乙醇：水(1：1)80mL中，加入HNR3R4(胍、芳香胺或含氮芳杂环)或HS(CH2)rR8(0.05 mol)，将反应液升温至80℃，反应6-8 h，减压浓缩，二氯甲烷提取，合并，干燥，蒸干，以适合溶剂重结晶，或者以硅胶柱层析分离，得到化合物C-2，收率：50-80%。 Add compound C-1 (0.02 mol) to ethanol: water (1:1) 80mL, add HNR 3 R 4 (guanidine, aromatic amine or nitrogen-containing aromatic heterocycle) or HS(CH 2 ) r R 8 (0.05 mol), the reaction solution was heated to 80°C, reacted for 6-8 h, concentrated under reduced pressure, extracted with dichloromethane, combined, dried, evaporated to dryness, recrystallized with a suitable solvent, or separated by silica gel column chromatography to obtain compound C -2, Yield: 50-80%.
按照制备通法3，分别制得实施例35~65化合物(见表三)。 According to Preparation General Method 3, the compounds of Examples 35-65 were respectively prepared (see Table 3).
表三：Table three:
本发明产物的药理研究 Pharmacological research on the product of the present invention
下面，对按照本发明的上式Ⅰ或式Ⅱ的噻唑-5-羟基吲哚类衍生物进行了体外抗乙型肝炎病毒活性筛选和抗HIV-1蛋白酶活性筛选。 Next, in vitro anti-hepatitis B virus activity screening and anti-HIV-1 protease activity screening were performed on the thiazole-5-oxindole derivatives of the above formula I or formula II according to the present invention.
一、体外抗乙型肝炎病毒活性筛选 1. In vitro anti-HBV activity screening
以2.2.15细胞为乙型肝炎病毒载体，测定样品抑制乙型肝炎病毒进行DNA复制和产生HBsAg、HBeAg的能力。 Using 2.2.15 cells as the hepatitis B virus carrier, the ability of the sample to inhibit the DNA replication of the hepatitis B virus and the production of HBsAg and HBeAg was determined.
测试材料和方法： Test materials and methods:
1、细胞株：2.2.15细胞； 1. Cell line: 2.2.15 cells;
2、样品处理：将样品溶于DMSO配成适当浓度，各样品用培养液作3倍稀释，共8个稀释度。 2. Sample treatment: Dissolve the sample in DMSO to make an appropriate concentration, and make a 3-fold dilution of each sample with culture medium, a total of 8 dilutions.
3、阳性对照药：拉米夫定(3TC)，由葛兰素威康公司生产。 3. Positive control drug: lamivudine (3TC), produced by Glaxo Wellcome.
4、主要试剂：乙肝病毒e抗原及s抗原放免检测试剂盒，北京北方生物技术研究所提供；α32PdCTP，中国福瑞生物工程有限公司提供。 4. Main reagents: Hepatitis B virus e antigen and s antigen radioimmunoassay kit, provided by Beijing North Institute of Biotechnology; α 32 PdCTP, provided by China Furui Bioengineering Co., Ltd.
5、测试方法：2.2.15细胞种96孔培养板，36小时后按以上稀释度分别加入样品及阳性对照药，同时设细胞对照孔，96小时后分别更换含不同稀释浓度的样品培养液，于种板第8天分别收集细胞上清及2.2.15细胞，采用RIA法检测细胞上清中HBsAg、HBeAg的分泌量，点杂交方法检测细胞中HBV DNA复制程度，分别计算IC50及SI。 5. Test method: 2.2.15 Cell species 96-well culture plate, after 36 hours, add samples and positive control drugs according to the above dilution respectively, and set cell control wells at the same time, replace the sample culture solution containing different dilution concentrations after 96 hours, The cell supernatant and 2.2.15 cells were collected on the 8th day of the seeding plate, and the secretion of HBsAg and HBeAg in the cell supernatant was detected by RIA method, and the degree of HBV DNA replication in the cells was detected by dot hybridization, and IC 50 and SI were calculated respectively.
测试结果如表四。 The test results are shown in Table 4.
表四 化合物体外抗乙型肝炎病毒活性筛选结果 Table 4 Compound in vitro anti-hepatitis B virus activity screening results
“/”表示未测活性 "/" indicates untested activity
二、抗流感病毒活性筛选2. Anti-influenza virus activity screening
以MDCK(地鼠肾)细胞为病毒宿主，测定样品抑制流感病毒甲型引起MDCK细胞病变程度。 Using MDCK (hamster kidney) cells as virus hosts, the extent to which the samples inhibit influenza virus A from causing MDCK cell lesions was determined.
测试材料和方法： Test materials and methods:
1、病毒株：甲3型病毒90-15株。 1. Virus strain: Type A 3 virus 90-15 strain.
2、样品处理：样品临用前溶于DMSO配成适当浓度，检测时用培养液作2倍稀释，共8个稀释度。 2. Sample treatment: Dissolve the sample in DMSO to make an appropriate concentration before use, and make a 2-fold dilution with the culture medium for detection, a total of 8 dilutions.
3、阳性对照药：利巴韦林(RBV)，由湖北科益制药厂生产。 3. Positive control drug: ribavirin (RBV), produced by Hubei Keyi Pharmaceutical Factory.
4、测试方法：MDCK细胞种96孔培养板，24小时后感染A/济防/90-15株10-3，吸附3小时，弃病毒液，按以上稀释度加入样品及阳性对照药，同时设细胞对照孔和病毒对照孔，30小时观察细胞病变程度(CPE)，用Reed-Muench法分别计算样品对流感病毒甲型的半数抑制浓度(IC50)。 4. Test method: MDCK cell species 96-well culture plate, infect A/Jifang/90-15 strain 10 -3 after 24 hours, absorb for 3 hours, discard the virus solution, add the sample and positive control drug according to the above dilution, and at the same time Cell control wells and virus control wells were set up, and the degree of cytopathic changes (CPE) was observed for 30 hours, and the half inhibitory concentration (IC 50 ) of the samples against influenza virus A was calculated by the Reed-Muench method.
测定结果见表五。 The measurement results are shown in Table 5.
表五化合物体外抗流感病毒活性筛选结果Table 5 compound in vitro anti-influenza virus activity screening results
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