CN108276323A - N (O, S)-miscellaneous indene derivative of a kind of 3- function dough and its application in anti respiratory syncytial virus - Google Patents
N (O, S)-miscellaneous indene derivative of a kind of 3- function dough and its application in anti respiratory syncytial virus Download PDFInfo
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- CN108276323A CN108276323A CN201810109813.2A CN201810109813A CN108276323A CN 108276323 A CN108276323 A CN 108276323A CN 201810109813 A CN201810109813 A CN 201810109813A CN 108276323 A CN108276323 A CN 108276323A
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- 241000725643 Respiratory syncytial virus Species 0.000 title claims abstract description 25
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 23
- 229910052717 sulfur Inorganic materials 0.000 title claims abstract description 19
- 230000003097 anti-respiratory effect Effects 0.000 title claims abstract description 13
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 title abstract 2
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 22
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- -1 nitro, amino Chemical group 0.000 claims abstract description 14
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 10
- 125000003375 sulfoxide group Chemical group 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 150000002469 indenes Chemical class 0.000 claims description 18
- 238000006467 substitution reaction Methods 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
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- 239000000651 prodrug Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 11
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract 3
- 239000003443 antiviral agent Substances 0.000 abstract 1
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- 238000002360 preparation method Methods 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 23
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
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- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 13
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- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 description 7
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
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- 229910052708 sodium Inorganic materials 0.000 description 6
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- 206010061603 Respiratory syncytial virus infection Diseases 0.000 description 5
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000005864 Sulphur Substances 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 5
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- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
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- 238000000034 method Methods 0.000 description 4
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- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 1
- 229930192474 thiophene Natural products 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
- 238000000844 transformation Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/64—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the miscellaneous indene derivatives of N (O, S) of a kind of 3 function dough and its applications in anti respiratory syncytial virus.Its structure is：Wherein：N is 0 or 1；X indicates carbon atom or nitrogen-atoms；Y indicates NH, NMe, oxygen atom or sulphur atom；Z indicates NH, oxygen atom, sulphur atom, sulfoxide group or sulfuryl；When Z is sulphur atom, sulfoxide group or sulfuryl：R1Indicate C1 C6 alkyl, C1 C6 alkoxies, halogen, nitro, amino or hydroxyl；R2Indicate H, C1 C6 alkyl, C1 C6 alkoxies, halogen, nitro, amino or hydroxyl；R1With R2It is identical or different；The R1And R2Respectively 1 or 2；When Z is NH or oxygen atom：R1、R2Indicate H, C1 C6 alkyl, C1 C6 alkoxies, halogen, nitro, amino or hydroxyl；R1With R2It is identical or different；The R1And R2Respectively 1 or 2.Present invention research finds that the analog derivative has stronger anti respiratory syncytial virus activity, is expected to be developed into clinical effective antiviral drugs.
Description
Technical field
The present invention relates to medical synthesis technical fields, and in particular to N (O, S)-miscellaneous indene of a kind of 3- function dough is spread out
Biology and its application in anti respiratory syncytial virus.
Background technology
Respiratory Syncytial Virus(RSV) (Human Respiratory Syncytial Virus, RSV) belong to Paramyxoviridae,
Pneumovirus is sub-thread strand RNA enveloped virus.Respiratory Syncytial Virus(RSV) is cause infant's lower respiratory tract infection most important
Virus causing disease, more than infecting Respiratory Syncytial Virus(RSV) in 70% infant after birth 1 year.5 years old global or less children,
(the Acute lower respiratory tract of the acute lower respiratory infection caused by Respiratory Syncytial Virus(RSV) every year
Infection, ALRIs) number about 3,380,000, account for the 22% of all 5 years old or less children's ALRIs numbers, death toll about 6.6 ten thousand
To 19.9 ten thousand.Caused by respiratory syncytial virus infection in infant's acute lower respiratory infection of China, 23.6%-25.0%
's.The elderly and there are the crowds of immune deficiency to be also subject to severe infections caused by Respiratory Syncytial Virus(RSV), and have infection history
The Pulmonary Diseases such as abnormal pulmonary function, bronchial asthma easily occur for person.In the U.S., annual respiratory syncytial virus infection can cause about
17.7 ten thousand the elderlys are hospitalized, and there are about 1.1 ten thousand people death.It is estimated that annual hospitalization cost is more than 1,000,000,000 dollars.
Up to the present, U.S. Food and Drug Administration only ratifies pa profit pearl (Palivizumab) and Ribavirin
(Ribavirin) two kinds of drugs are prevented for respiratory syncytial virus infection.Pa profit pearl is mainly used for preventing to suffer from chrome lung
The high risk childs such as disease and congenital heart disease and the respiratory syncytial virus infection of premature can not be used for respiratory tract conjunction
It is treated after cellular virus infection, and somewhat expensive.Ribavirin can be used for the treatment of Respiratory Syncytial Virus(RSV) severe infections, but exist
The problems such as curative effect is general and side effect is big, paediatrics association of the U.S. (American Academy of Pediatrics) is not recommended
Ribavirin is used for the treatment of respiratory syncytial virus infection infant.Although based on to Respiratory Syncytial Virus(RSV) life cycle
Understand, and to the understanding of Respiratory Syncytial Virus(RSV) and host cell interaction, devises a variety of anti respiratory syncytial virus
Drug, but there has been no the appearances of safe and efficient anti respiratory syncytial virus curative drug so far.Thus, it finds safe efficient
Anti respiratory syncytial virus curative drug, have important researching value.
Invention content
Based on background above technology, present invention application anti respiratory syncytial virus medicament high flux screening technology platform is right
52800 kinds of compounds in national new drug compound library (001C-120C) carry out primary dcreening operation and secondary screening, and obtaining 48 has anti-breathing
The active compound of road syncytial virus.By synthesis difficulty, druggability, stability and the toxicity etc. of analysis of compounds, determining pair
6092B-E5 (2- ((1H- indol-3-yls) sulfenyl)-N- (3,4- dichlorophenyl) acetamide) further structural modification and transformations,
And further activity rating is carried out to its derivative, it is found that N (O, S)-miscellaneous indene derivative of 3- function dough of one kind has
Good anti respiratory syncytial virus effect.
The present invention is using scheme in detail below：
N (O, S)-miscellaneous indene derivative of a kind of 3- function dough, structure are as shown in Equation 1：
Wherein：N is 0 or 1；
X indicates carbon atom or nitrogen-atoms；
Y indicates NH, NMe, oxygen atom or sulphur atom；
Z indicates NH, oxygen atom, sulphur atom, sulfoxide group or sulfuryl；
When Z is sulphur atom, sulfoxide group or sulfuryl：
R1Indicate C1-C6 alkyl, C1-C6 alkoxies, halogen, nitro, amino or hydroxyl；R2Indicate H, C1-C6 alkyl, C1-
C6 alkoxies, halogen, nitro, amino or hydroxyl；R1With R2It is identical or different；
The R1And R2Respectively 1 or 2；
When Z is NH or oxygen atom：
R1、R2Indicate H, C1-C6 alkyl, C1-C6 alkoxies, halogen, nitro, amino or hydroxyl；R1With R2It is identical or not
Together；The R1And R2Respectively 1 or 2.
Preferably, the C1-C6 alkyl includes C1-C6 straight chained alkyls, C3-C6 branched alkyls, C3-C6 naphthenic base；It is described
C1-C6 alkoxies include C1-C6 unbranched alkoxies, C3-C6 branched alkoxies, the miscellaneous oxygen naphthenic base of C3-C6；
The halogen is fluorine, chlorine, bromine or iodine；
The R1The position of substitution be 4-, 5-, 6- or 7-, R2The position of substitution be ortho position, meta or para position；
R1And R2The position of substitution is independent mutually.
The R1The position of substitution be marked in formula 2：
Further, N (O, S)-miscellaneous indene derivative of 3- function dough of one kind of the present invention includes them
The mixture of stereoisomer or stereoisomer.
Another aspect of the present invention also provides a kind of pharmaceutical composition and its application in anti respiratory syncytial virus.It is described
Pharmaceutical composition includes N (O, the S)-miscellaneous indene derivative or its pharmaceutically acceptable salt of a kind of 3- above-mentioned function dough
Or pro-drug.The compound of the present invention can be with the pharmaceutically acceptable salt derived from inorganic acid, organic acid or inorganic base
Form uses.The acid that can be used to form pharmaceutically acceptable acid-addition salts includes inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphorus
Acid and organic acid such as oxalic acid, maleic acid, succinic acid and citric acid.Base addition salts can by make the compounds of this invention contain phenol
Hydroxylic moiety is reacted with suitable alkali, is prepared in situ in the final separation of the compounds of this invention and purification process, the alkali
Such as hydroxide, carbonate and the bicarbonate of pharmaceutically acceptable metal cation, cation include but not limited to be based on
Cationic such as lithium, sodium, potassium, calcium, magnesium and the aluminium salt of alkali or alkaline earth metal.
N (O, S)-miscellaneous indene derivative that further aspect of the present invention also provides 3- function dough of one kind is closed in preventing respiratory
The structure of application in cellular virus, N (O, S)-miscellaneous indene derivative of the 3- function dough is as shown in Equation 3：
Wherein：N is 0 or 1；
X indicates carbon atom or nitrogen-atoms；
Y indicates NH, NMe, oxygen atom or sulphur atom；
W indicates NH, oxygen atom, sulphur atom, sulfoxide group or sulfuryl；
R1、R2Indicate H, C1-C6 alkyl, C1-C6 alkoxies, halogen, nitro, amino or hydroxyl；R1With R2It is identical or not
Together；The R1And R2Respectively 1 or 2.
Preferably, the C1-C6 alkyl includes C1-C6 straight chained alkyls, C3-C6 branched alkyls, C3-C6 naphthenic base；It is described
C1-C6 alkoxies include C1-C6 unbranched alkoxies, C3-C6 branched alkoxies, the miscellaneous oxygen naphthenic base of C3-C6；
The halogen is fluorine, chlorine, bromine or iodine；
The R1The position of substitution be 4-, 5-, 6- or 7-, R2The position of substitution be ortho position, meta or para position；
R1And R2The position of substitution is independent mutually.
It is further preferred that N (O, S)-miscellaneous indene derivative of the 3- function dough include its stereoisomer or
The mixture of stereoisomer.
Beneficial effects of the present invention
It is defined present invention demonstrates that N (O, S)-miscellaneous indene derivative of the 3- function dough of one kind as shown in formula I has
Anti respiratory syncytial virus effect, there is apparent inhibitory activity to the duplication of Respiratory Syncytial Virus(RSV)；Preliminary toxicity is studied
It is shown with good druggability, shows that the analog derivative has applications well foreground as antituberculotic.
Description of the drawings
Fig. 1 is the building-up process of the miscellaneous indene derivatives of S- of 3- sulphur atoms of the present invention substitution.
Fig. 2 is the building-up process of N (O)-miscellaneous indene derivative of 3- nitrogen of the present invention/oxygen atom substitution.
Specific implementation mode
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that the present embodiment is served only for pair
The present invention is further described, and should not be understood as limiting the scope of the invention, and the person skilled in the art in the field can
To make some nonessential modifications and adaptations according to the content invented above.In the absence of conflict, the reality in the present invention
The feature applied in example and embodiment can be combined with each other.
As depicted in figs. 1 and 2, the building-up process of N (O, S)-miscellaneous indene derivative of 3- function dough of the present invention is summarized
It is as follows：It is that starting material obtains intermediate 3 through acylation reaction with aniline (or benzylamine) 1 and bromoacetyl bromide 2, is sent out with sodium thiosulfate
Raw substitution obtains intermediate 4, and target product 5 is obtained through step c, then is aoxidized with metachloroperbenzoic acid to obtain 6 He of target product
7.In addition, intermediate 3 obtains target product 9 through step e.
Reagent and reaction condition：A. triethylamine, dichloromethane, room temperature.B. sodium thiosulfate, methanol/water (3:1), 65 DEG C.
C. iodine, dimethyl sulfoxide, 80 DEG C.D. metachloroperbenzoic acid, dichloromethane, 0 DEG C.E. potassium carbonate (or sodium hydride), N, N- diformazans
Base formamide.
Embodiment 1
The preparation of 2- ((1H- indol-3-yls) sulfenyl)-N- (o-tolyl) acetamide
1) preparation of the bromo- N- of 2- (o-tolyl) acetamide (intermediate 3)
2-aminotoluene (10.7g, 100mmol) is dissolved in 200mL dichloromethane, addition triethylamine (21mL,
150mmol), it is cooled to 0 DEG C, is slowly added dropwise into bromoacetyl bromide (10mL, 110mmol), reacts at room temperature 30 minutes.TLC monitorings are former
Whether material reaction is completely rear to be added ethyl acetate 500ml, uses 1N hydrochloric acid and saturated common salt water washing, the anhydrous sulphur of organic phase successively
Sour sodium drying, recycles organic solvent, obtains light red solid 21.0g, be directly used in next step without being further purified.ESI-MS,
m/z：225.9[M-H]-。
2) preparation of sulphur-(2- oxos -2- (o-tolylamino) ethyl) sodium thiosulfate (intermediate 4)
2- bromo- N- (o-tolyl) acetamide (intermediate 3) (2.84g, 12.5mmol) is added in 100mL reaction bulbs to add
Enter methanol 21mL and water 7mL dissolvings, sodium thiosulfate pentahydrate (3.72g, 15.0mmol) is added, 65 DEG C are reacted 2 hours,
HPLC-MS detects raw material, and the reaction was complete, is evaporated reaction dissolvent, and 100mL methanol is then added and stirs 30 minutes, filters and retains filter
Liquid is concentrated to give yellow solid 3.39g, is directly used in next step without being further purified.
ESI-MS, m/z：260.2[M-H]-。
3) preparation of 2- ((1H- indol-3-yls) sulfenyl)-N- (o-tolyl) acetamide
Indoles (1.0g, 8.55mmol), sulphur-(2- oxos -2- (o-tolylamino) ethyl) sodium thiosulfate is (intermediate
Body 4) (3.54g, 12.5mmol) be dissolved in the dimethyl sulfoxide of 30mL, 70 DEG C of reactions of elemental iodine (0.42g, 1.67mmol) are added
1h, HPLC-MS detect raw material, and the reaction was complete.Be added 100ml ethyl acetate, successively use saturated aqueous sodium thiosulfate, water and
Saturated salt solution 100ml washings, organic phase are dried with anhydrous sodium sulfate.Concentration silica gel column chromatography obtains colorless solid 1.58g, yield
64.0%.
1H NMR(600MHz,CDCl3)′:8.45 (s, 1H), 8.34 (s, 1H), 7.74 (d, J=7.8Hz, 1H), 7.66
(d, J=7.8Hz, 1H), 7.27 (m, 1H) 7.16-7.07 (m, 4H), 6.99-6.97 (m, 1H), 3.55 (s, 2H), 2.09 (s,
3H)；13C NMR(150MHz,CDCl3)′166.14,135.26,134.46,129.46,127.64,127.60,127.14,
125.81,124.14,122.12,121.23,119.85,117.76,110.84,103.03,40.15,16.59.ESI-MS, m/
z：295.1[M-H]-。
Embodiment 2
The preparation of 2- ((1- Methyl-1H-indole -3- bases) sulfinyl)-N- (2- chlorphenyls) acetamide
1) preparation of the bromo- N- of 2- (2- chlorphenyls) acetamides (intermediate 3)
By the 2-aminotoluene in the preparation of the bromo- N- of 2- (o-tolyl) acetamide (intermediate 3) in embodiment 1
It is constant that (10.7g, 100mmol) replaces with 2- chloroanilines (12.8g, 100mmol) other operations, obtains 2- bromo- N- (2- chlorobenzenes
Base) acetamide (intermediate 3).
ESI-MS, m/z：245.9[M-H]-。
2) preparation of sulphur-(2- oxos -2- (2- chlorphenylaminos) ethyl) sodium thiosulfate (intermediate 4)
By the 2) system of sulphur-(2- oxos -2- (o-tolylamino) ethyl) sodium thiosulfate (intermediate 4) in embodiment 1
2- bromo- N- (o-tolyl) acetamide (intermediate 3) (2.84g, 12.5mmol) in standby replaces with the bromo- N- of 2- (2- chlorphenyls)
Other operations of acetamide (intermediate 3) (3.11g, 12.5mmol) are constant, obtain sulphur-(2- oxos -2- (2- chlorphenylaminos) second
Base) sodium thiosulfate (intermediate 4).
ESI-MS, m/z：279.8[M-H]-。
3) preparation of 2- ((1- Methyl-1H-indole -3- bases) sulfenyl)-N- (2- chlorphenyls) acetamides (intermediate 5)
By indoles (1.0g, 8.55mmol), sulphur-(2- oxos -2- (o-tolylamino) ethyl) thio sulphur in embodiment 1
Sour sodium (intermediate 4) (3.54g, 12.5mmol) replaces with N- methyl indols (1.12g, 8.55mmol), sulphur-(2- oxos-respectively
2- (2- chlorphenylaminos) ethyl) other operations of sodium thiosulfate (intermediate 4) (3.80g, 12.5mmol) are constant, obtain 2-
((1- Methyl-1H-indole -3- bases) sulfinyl)-N- (2- chlorphenyls) acetamide.Colorless solid 1.97g, yield 69.9%.
1H NMR (600MHz, Chloroform-d) ' 9.23 (s, 1H), 8.39 (dd, J=8.3,1.5Hz, 1H), 7.75
(dt, J=7.9,0.9Hz, 1H), 7.38 (dd, J=8.1,1.5Hz, 1H), 7.31 (dt, J=8.2,0.9Hz, 1H), 7.20
(ddd, J=8.0,7.0,1.1Hz, 1H), 7.04 (ddd, J=8.0,7.4,1.6Hz, 1H), 3.73 (s, 3H), 3.59 (s,
2H).13C NMR(151MHz,CDCl3)′167.30,137.33,134.56,133.84,129.06,128.95,127.77,
124.65,122.75,122.70,121.02,120.53,118.97,109.86,101.65,41.93,33.06.ESI-MS, m/
z：329.1[M-H]-。
4) preparation of 2- ((1- Methyl-1H-indole -3- bases) sulfinyl)-N- (2- chlorphenyls) acetamide
By 2- ((1- Methyl-1H-indole -3- bases) sulfenyl)-N- (2- chlorphenyls) acetamide (intermediate 5) (60mg,
It 0.18mmol) is dissolved in 1mL dichloromethane, is cooled to 0 DEG C, metachloroperbenzoic acid (50mg, 0.289mmol), ice bath is added
Reaction 2 hours reacts at room temperature 12 hours.10ml ethyl acetate is added, is washed with disodium phosphate soln.Solvent is evaporated off in concentration,
Silica gel column chromatography, methylene chloride/methanol (100:1) it elutes, obtains colorless solid 49mg, yield 78.2%.
1H NMR (600MHz, Chloroform-d) ' 9.41 (s, 1H), 8.26 (dd, J=8.2,1.5Hz, 1H), 7.82
(dt, J=8.0,1.0Hz, 1H), 7.56 (s, 1H), 7.41-7.30 (m, 3H), 7.23-7.28 (m, 2H), 7.09-7.02 (m,
1H), 4.05 (d, J=5.5Hz, 2H), 3.81 (s, 3H)13C NMR(151MHz,CDCl3)′163.05,137.72,134.69,
130.51,129.31,127.45,125.11,124.29,123.67,123.65,122.26,121.81,119.09,110.58,
57.95,33.60.ESI-MS, m/z：345.2[M-H]-。
Embodiment 3
The preparation of 2- ((1H- indol-3-yls) sulfonyl)-N- (2- chlorphenyls) acetamide
1) preparation of the bromo- N- of 2- (2- chlorphenyls) acetamides (intermediate 3)
By the 2-aminotoluene in the preparation of the bromo- N- of 2- (o-tolyl) acetamide (intermediate 3) in embodiment 1
It is constant that (10.7g, 100mmol) replaces with 2- chloroanilines (12.8g, 100mmol) other operations, obtains 2- bromo- N- (2- chlorobenzenes
Base) acetamide (intermediate 3).
ESI-MS, m/z：245.9[M-H]-.
2) preparation of sulphur-(2- oxos -2- (2- chlorphenylaminos) ethyl) sodium thiosulfate (intermediate 4)
By the 2) system of sulphur-(2- oxos -2- (o-tolylamino) ethyl) sodium thiosulfate (intermediate 4) in embodiment 1
2- bromo- N- (o-tolyl) acetamide (intermediate 3) (2.84g, 12.5mmol) in standby replaces with the bromo- N- of 2- (2- chlorphenyls)
Other operations of acetamide (intermediate 3) (3.11g, 12.5mmol) are constant, obtain sulphur-(2- oxos -2- (2- chlorphenylaminos) second
Base) sodium thiosulfate (intermediate 4).
ESI-MS, m/z：279.8[M-H]-。
3) preparation of 2- ((1H- indol-3-yls) sulfenyl)-N- (2- chlorphenyls) acetamides (intermediate 5)
By sulphur-in embodiment 1 (2- oxos -2- (o-tolylamino) ethyl) sodium thiosulfate (intermediate 4) (3.54g,
12.5mmol) replace with sulphur-(2- oxos -2- (2- chlorphenylaminos) ethyl) sodium thiosulfate (intermediate 4) (3.80g,
12.5mmol) other operations are constant, obtain 2- ((1H- indol-3-yls) sulfinyl)-N- (2- chlorphenyls) acetamide.It is colourless
Solid 1.92g, yield 70.9%.
1H NMR (400MHz, Chloroform-d) ' 9.28 (s, 1H), 8.37 (dd, J=8.2,1.6Hz, 2H), 7.77
(ddd, J=7.5,1.8,0.8Hz, 1H), 7.44-7.34 (m, 3H), 7.26-7.18 (m, 3H), 7.05 (ddd, J=8.0,
7.5,1.6Hz,1H),3.62(s,2H).13C NMR(101MHz,CDCl3)′167.40,136.42,134.60,129.60,
129.23,128.39,127.93,124.89,123.30,122.96,121.18,121.07,118.98,111.90,103.85,
41.67.ESI-MS m/z：315.0[M-H]-.
4) preparation of 2- ((1- Methyl-1H-indole -3- bases) sulfonyl)-N- (2- chlorphenyls) acetamide
2- ((1H- indol-3-yls) sulfenyl)-N- (2- chlorphenyls) acetamide (intermediate 5) (57mg, 0.18mmol) is molten
In 1mL dichloromethane, it is cooled to 0 DEG C, metachloroperbenzoic acid (62mg, 0.36mmol) is added, ice bath reacts 2 hours, room
Temperature reaction 12 hours.10ml ethyl acetate is added, is washed with disodium phosphate soln.It concentrates and solvent is evaporated off, silica gel column chromatography, two
Chloromethanes/methanol (100:1) it elutes, obtains colorless solid 49mg, yield 78.0%.
1H NMR (600MHz, DMSO-d6) ' 12.23 (d, J=3.0Hz, 1H), 9.71 (s, 1H), 8.02 (d, J=
3.1Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.61 (dd, J=8.1,1.6Hz, 1H), 7.53 (dt, J=8.1,1.0Hz,
1H), 7.46 (dd, J=8.0,1.5Hz, 1H), 7.27 (tdd, J=8.2,5.0,1.4Hz, 1H), 7.24-7.14 (m, 1H),
2.50 (d, J=3.7Hz, 2H)；13C NMR(151MHz,DMSO)′161.01,136.62,134.68,133.07,129.95,
127.86,126.91,126.02,125.56,124.28,123.49,122.05,119.53,113.28,113.16,63.20；
ESI-MS, m/z：347.0[M-H].
Embodiment 4
The preparation of 2- ((1H- pyrrolo-es [2,3-b] pyridin-3-yl) sulfenyl)-N- (o-tolyl) acetamide
1) preparation of the bromo- N- of 2- (2- ethoxyl phenenyls) acetamides (intermediate 3)
2- phenetidines (13.7g, 100mmol) are dissolved in 200mL dichloromethane, addition triethylamine (21mL,
150mmol), it is cooled to 0 DEG C, is slowly added dropwise into bromoacetyl bromide (10mL, 110mmol), reacts at room temperature 30 minutes.TLC monitorings are former
Ethyl acetate 500ml is added after the reaction was complete in material, uses 1N hydrochloric acid and saturated common salt water washing, organic phase anhydrous sodium sulfate successively
It is dry, organic solvent is recycled, light red solid 22.0g is obtained, is directly used in next step without being further purified.
ESI-MS, m/z：255.7[M-H]-。
2) preparation of sulphur-(2- oxos -2- (2- ethoxyl phenenyls) ethyl) sodium thiosulfate (intermediate 4)
In 100mL reaction bulbs be added 2- bromo- N- (2- ethoxyl phenenyls) acetamide (intermediate 3) (3.21g,
Methanol 21mL 12.5mmol) is added and water 7mL dissolves, addition sodium thiosulfate pentahydrate (3.72g, 15.0mmol), 65 DEG C
Reaction 2 hours, HPLC-MS detects raw material, and the reaction was complete, is evaporated reaction dissolvent, and 100mL methanol is then added and stirs 30 minutes, takes out
Filter retains filtrate, is concentrated to give yellow solid 3.62g, is directly used in next step without being further purified.
ESI-MS, m/z：290.2[M-H]-。
3) preparation of 2- ((1H- pyrrolo-es [2,3-b] pyridin-3-yl) sulfenyl)-N- (2- ethoxyl phenenyls) acetamide
By 7- azaindoles 1.0g, 8.55mmol), sulphur-(2- oxos -2- (2- ethoxyl phenenyls) ethyl) sodium thiosulfate
(intermediate 4) (3.64g, 12.5mmol) is dissolved in the dimethyl sulfoxide of 30mL, and 70 DEG C of elemental iodine (0.42g, 1.67mmol) is added
1h is reacted, HPLC-MS detects raw material, and the reaction was complete.Be added 100ml ethyl acetate, successively use saturated aqueous sodium thiosulfate,
Water and saturated salt solution 100ml washings, organic phase are dried with anhydrous sodium sulfate.Concentration silica gel column chromatography obtains colorless solid 1.98g,
Yield 70.8%.
1H NMR(600MHz,DMSO-d6) ' 11.99 (s, 1H), 9.15 (s, 1H), 8.25 (dd, J=4.7,1.7Hz,
1H), 8.04-7.99 (m, 1H), 7.98-7.93 (m, 1H), 7.66 (d, J=2.5Hz, 1H), 7.10 (dd, J=7.9,4.6Hz,
1H), 7.05-6.99 (m, 2H), 6.88 (ddd, J=8.6,6.6,2.2Hz, 1H), 4.06 (q, J=7.0Hz, 2H), 3.64 (s,
2H), 1.32 (t, J=7.0Hz, 3H)13C NMR(151MHz,DMSO)′167.76,148.97,148.58,143.83,
131.82,127.76,127.29,124.68,121.49,121.12,120.75,116.59,112.60,101.89,64.44,
41.41,40.41,40.27,40.13,40.00,39.86,39.72,39.58,15.02.ESI-MS, m/z：326.2[M-H]-。
Embodiment 5
The preparation of 2- ((6- methoxyl group -1H- indol-3-yls) sulfenyl)-N- (2- ethoxyl phenenyls) acetamide
1) preparation of the bromo- N- of 2- (3,4- dichlorophenyls) acetamides (intermediate 3)
3,4-DCA (16.2g, 100mmol) is dissolved in 200mL dichloromethane, addition triethylamine (21mL,
150mmol), it is cooled to 0 DEG C, is slowly added dropwise into bromoacetyl bromide (10mL, 110mmol), reacts at room temperature 30 minutes.TLC monitorings are former
Whether material reaction is completely rear to be added ethyl acetate 500ml, uses 1N hydrochloric acid and saturated common salt water washing, the anhydrous sulphur of organic phase successively
Sour sodium drying, recycles organic solvent, obtains light red solid 23.0g, be directly used in next step without being further purified.
ESI-MS, m/z：278.7[M-H]-。
2) preparation of sulphur-(2- oxos -2- (3,4- dichlorophenyls) ethyl) sodium thiosulfate (intermediate 4)
In 100mL reaction bulbs be added 2- bromo- N- (3,4- dichlorophenyl) acetamide (intermediate 3) (3.48g,
Methanol 21mL 12.5mmol) is added and water 7mL dissolves, addition sodium thiosulfate pentahydrate (3.72g, 15.0mmol), 65 DEG C
Reaction 2 hours, HPLC-MS detects raw material, and the reaction was complete, is evaporated reaction dissolvent, and 100mL methanol is then added and stirs 30 minutes, takes out
Filter retains filtrate, is concentrated to give yellow solid 3.62g, is directly used in next step without being further purified.ESI-MS, m/z：313.6
[M-H]-。
3) preparation of 2- ((6- methoxyl group -1H- indol-3-yls) sulfenyl)-N- (3,4- dichlorophenyls) acetamide
By 6- methoxy-Indoles (1.5g, 8.55mmol), sulphur-(2- oxos -2- (3,4- dichlorophenyl) ethyl) thio sulphur
Sour sodium (intermediate 4) (3.94g, 12.5mmol) is dissolved in the dimethyl sulfoxide of 30mL, and elemental iodine (0.42g, 1.67mmol) is added
70 DEG C of reaction 1h, HPLC-MS detects raw material, and the reaction was complete.100ml ethyl acetate is added, uses saturated sodium thiosulfate water-soluble successively
Liquid, water and saturated salt solution 100ml washings, organic phase are dried with anhydrous sodium sulfate.Concentration silica gel column chromatography obtains colorless solid
2.27g, yield 69.6%.
1H NMR(600MHz,DMSO-d6)′11.18(s,1H),9.23(s,1H),7.90(s,1H),7.55-7.62(m,
2H), 7.49 (d, J=8.6Hz, 1H), 7.37 (d, J=2.5Hz, 1H), 6.89 (d, J=3.1Hz, 1H), 6.71 (dd, J=
8.6,2.3Hz, 1H), 3.75 (s, 3H) 3.59 (s, 2H) .ESI-MS, m/z：379.2[M-H]-。
Embodiment 6
The preparation of 2- ((1H- indol-3-yls) amino)-N- (2- ethoxyl phenenyls) acetamide
1) preparation of the bromo- N- of 2- (2- ethoxyl phenenyls) acetamides (intermediate 3)
2- phenetidines (13.7g, 100mmol) are dissolved in 200mL dichloromethane, addition triethylamine (21mL,
150mmol), it is cooled to 0 DEG C, is slowly added dropwise into bromoacetyl bromide (10mL, 110mmol), reacts at room temperature 30 minutes.TLC monitorings are former
Whether material reaction is completely rear to be added ethyl acetate 500ml, uses 1N hydrochloric acid and saturated common salt water washing, the anhydrous sulphur of organic phase successively
Sour sodium drying, recycles organic solvent, obtains light red solid 22.0g, be directly used in next step without being further purified.ESI-MS,
m/z：255.7[M-H]-。
2) preparation of 2- ((1H- indol-3-yls) amino)-N- (2- ethoxyl phenenyls) acetamide
By 3- amino indoles (1.32g, 10mmol) and the bromo- N- of 2- (2- ethoxyl phenenyls) acetamide (intermediate 3)
(3.1g, 12mmol), which is dissolved in 10mL n,N-Dimethylformamide, is added potassium carbonate (2.76g, 20mmol), is vigorously stirred reflux
5h.Ethyl acetate 100mL is added, massive laundering is washed, saturated common salt water washing, the drying of organic phase anhydrous sodium sulfate, concentration.Silica gel
Column chromatography, methylene chloride/methanol (100:1) it elutes, obtains white solid 2.24g, yield 72.6%.
1H NMR (400MHz, Chloroform-d) ' 9.48 (s, 1H), 8.49 (s, 1H), 8.35 (dd, J=8.0,
1.7Hz, 1H), 7.77 (dd, J=7.5,1.4Hz, 1H), 7.36 (d, J=2.6Hz, 1H), 7.35-7.31 (m, 1H), 7.19
(pd, J=7.1,1.4Hz, 2H), 7.04 (td, J=7.8,1.7Hz, 1H), 6.97-6.88 (m, 2H), 4.14 (q, J=
7.0Hz, 2H), 3.57 (s, 2H), 1.48 (t, J=7.0Hz, 3H)13CNMR(101MHz,CDCl3)′167.05,147.67,
136.34,129.68,128.55,127.68,124.04,123.07,121.18,120.87,119.60,118.98,111.81,
111.20,77.48,77.16,76.84,64.50,42.00,38.78,15.09.ESI-MS, m/z：308.3[M-H]-。
Embodiment 7
The preparation of 2- (benzo [b] thiene-3-yl oxygroup)-N- (4- nitrobenzophenones) acetamide
1) preparation of the bromo- N- of 2- (4- nitrobenzophenones) acetamides (intermediate 3)
By 1 in embodiment 6) 2- ethyoxyls in the preparations of the bromo- N- of 2- (2- ethoxyl phenenyls) acetamides (intermediate 3)
Aniline (13.7g, 100mmol) replaces with 4- nitroanilines (13.8g, 100mmol), other operations constant just obtain the bromo- N- of 2-
(4- nitrobenzophenones) acetamide (intermediate 3).ESI-MS, m/z：257.0[M-H]-。
2) preparation of 2- (benzo [b] thiene-3-yl oxygroup)-N- (4- nitrobenzophenones) acetamide
By inciting somebody to action in the preparation of 2- in embodiment 6 ((1H- indol-3-yls) amino)-N- (2- ethoxyl phenenyls) acetamide
3- amino indoles (1.32g, 10mmol) and the bromo- N- of 2- (2- ethoxyl phenenyls) acetamide (intermediate 3) (3.1g, 12mmol) point
3- hydroxy benzos thiophene (1.50g, 10mmol) and the bromo- N- of 2- (4- nitrobenzophenones) acetamide (intermediate 3) are not replaced with
(3.1g, 12mmol), other operations are constant, just obtain 2- (benzo [b] thiene-3-yl oxygroup)-N- (4- nitrobenzophenones) acetyl
Amine, yield 63.2%.ESI-MS, m/z：327.3[M-H]-。
Embodiment 8
The preparation of N- (4- aminophenyls) -2- (benzo [b] thiene-3-yl oxygroup) acetamide
2- (benzo [b] thiene-3-yl oxygroup)-N- (4- nitrobenzophenones) acetamides (0.33g, 1mmol) are dissolved in 10ml
In methanol, iron powder (0.17g, 3mmol) is added, hydrochloric acid 0.5mmol, flow back 8h.Solvent is evaporated off in suction filtration, obtains white solid, yield
74.9%.ESI-MS, m/z：297.2[M-H]-。
Embodiment 9
2- ((1H- indol-3-yls) sulfenyl)-N- (3,4- dichloro benzyls) acetamide
By the 2-aminotoluene (10.7g, 100mmol) in embodiment 1 replace with 3,4- dichloro-benzylamines (17.5g,
100mmol), other operations are constant, just obtain 2- ((1H- indol-3-yls) sulfenyl)-N- (3,4- dichloro benzyl) acetamide, in vain
Color solid.1H NMR (500MHz, Chloroform-d) ' 9.20 (s, 1H), 7.60 (d, J=7.8Hz, 1H), 7.27 (d, J=
8.1Hz, 1H), 7.17 (dd, J=19.9,8.0Hz, 2H), 7.13-7.05 (m, 3H), 7.01 (t, J=6.0Hz, 1H), 6.76
(dd, J=8.2,2.0Hz, 1H), 4.16 (d, J=
6.0Hz,2H),3.35(s,2H).13C NMR(126MHz,CDCl3)′169.90,138.18,136.37,
132.44,131.31,130.48,129.81,129.31,128.48,126.90,122.90,120.69,118.60,
112.16,103.39,42.59,40.48.ESI-MS, m/z：363.2[M-H]-。
Embodiment 10
The evaluation of the compounds of this invention Anti-viral activity in vitro
It is virus host that antiviral activity to the compound of the present invention, which is by HEp-2 (human laryngeal cancer epithelial cell), is surveyed
Determine Respiratory Syncytial Virus(RSV) and causes HEp-2 cytopathy degree.
HEp-2 cells are spread into 96 orifice plates, by 0.5 × 104Cells/well inoculating cell；Compound is serially diluted by 10 times,
5 gradients are diluted, each gradient sets 3 multiple holes, and 100 holes μ l/ are added in 96 orifice plates；After infection 48h with MTS methods to cell activity
It is detected.In microplate reader at Detection wavelength 490nm each hole absorbance value (OD).Calculate cell activity, cell activity
(%)=experimental group absorbance value-blank control group light absorption value/control group absorbance value-cell blank control group absorbance value ×
100%.Control group (only cell, no drug-treated), experimental group (existing cell adds drug-treated again), cell blank control group
(neither refinement born of the same parents, and be not added with drug-treated)
HEp-2 cells are spread into 96 orifice plates, by 1.5 × 104Cells/well inoculating cell；By compound respiratory tract containing 50pfu
The virus liquid in syncytial virus/hole is diluted by multiple, dilutes 5 gradients, and each gradient sets 3 multiple holes, 96 are added to by 100 holes μ l/
In orifice plate；37 DEG C of culture 1h；By compound cell maintenance medium 1:10 dilutions, then with 1% methylcellulose maintaining liquid 1:10 is dilute
It releases, vortex mixing.37 DEG C of culture 3-4d；Measure titre, inhibiting rate=(virus-infected controls group-experimental group)/(virus infection pair
According to group-cell negative control group) × 100%.Virus-infected controls group (virus infection, no drug-treated), experimental group (were both felt
Catch an illness poison, and add compound), cell negative control group (neither plus virus infection, and being not added with drug-treated) calculate IC50And CC50
Value.IC50And CC50Value is calculated by Graphpad Prism softwares.
Partial derivatives are listed in the formula 1 of the present invention in table 1 to the half-inhibition concentration IC of Respiratory Syncytial Virus(RSV)50With
Half cytotoxic concentration CC50。
The Anti-viral activity in vitro and cytotoxicity of 1 partial derivatives of table
SI=CC50/IC50
The experimental results showed that all test compounds significantly inhibit effect to Respiratory Syncytial Virus(RSV) in table 1, it is most
Activity is better than positive control medicine, the IC of majority of compounds to compound on a cellular level50Value is at 10 μM hereinafter, wherein chemical combination
The IC50 of object 13,15,19 and 20 is respectively 3.93,1.10,4.11 and 0.51 μM and is substantially better than positive control drug Ribavirin
(IC50=17.56 μM).In addition cytotoxicity test has higher safety the result shows that the toxicity of majority of compounds is relatively low
Index SI (general compound SI thinks acellular poison more than 10).
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on this
Embodiment in invention, every other reality obtained by those of ordinary skill in the art without making creative efforts
Example is applied, the scope of the present invention is belonged to.
Claims (8)
1. N (O, S)-miscellaneous indene derivative of 3- function dough of one kind, which is characterized in that structure is as shown in Equation 1：
Wherein：N is 0 or 1；
X indicates carbon atom or nitrogen-atoms；
Y indicates NH, NMe, oxygen atom or sulphur atom；
Z indicates NH, oxygen atom, sulphur atom, sulfoxide group or sulfuryl；
When Z is sulphur atom, sulfoxide group or sulfuryl：
R1Indicate C1-C6 alkyl, C1-C6 alkoxies, halogen, nitro, amino or hydroxyl；R2Indicate H, C1-C6 alkyl, C1-C6 alkane
Oxygroup, halogen, nitro, amino or hydroxyl；R1With R2It is identical or different；
The R1And R2Respectively 1 or 2；
When Z is NH or oxygen atom：
R1、R2Indicate H, C1-C6 alkyl, C1-C6 alkoxies, halogen, nitro, amino or hydroxyl；R1With R2It is identical or different；It is described
R1And R2Respectively 1 or 2.
2. N (O, S)-miscellaneous indene derivative of 3- function dough according to claim 1, which is characterized in that the C1-
C6 alkyl includes C1-C6 straight chained alkyls, C3-C6 branched alkyls, C3-C6 naphthenic base；The C1-C6 alkoxies include C1-C6 straight
The miscellaneous oxygen naphthenic base of chain alkoxy, C3-C6 branched alkoxies, C3-C6；
The halogen is fluorine, chlorine, bromine or iodine；
The R1The position of substitution be 4-, 5-, 6- or 7-, R2The position of substitution be ortho position, meta or para position；R1And R2
The position of substitution is independent mutually.
3. N (O, S)-miscellaneous indene derivative of 3- function dough according to claim 1 or 2, which is characterized in that described
Derivative includes the mixture of its stereoisomer or stereoisomer.
4. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes any positions the 3- officials of claim 1-3
Can dough N (O, S)-miscellaneous indene derivative or its salt or pro-drug pharmaceutically.
5. application of the pharmaceutical composition described in claim 4 in anti respiratory syncytial virus.
6. the N (O, S) of 3- function dough of one kind-application of the miscellaneous indene derivative in anti respiratory syncytial virus, feature
It is, the structure of N (O, S)-miscellaneous indene derivative of the 3- function dough is as shown in Equation 3：
Wherein：N is 0 or 1；
X indicates carbon atom or nitrogen-atoms；
Y indicates NH, NMe, oxygen atom or sulphur atom；
W indicates NH, oxygen atom, sulphur atom, sulfoxide group or sulfuryl；
R1、R2Indicate H, C1-C6 alkyl, C1-C6 alkoxies, halogen, nitro, amino or hydroxyl；R1With R2It is identical or different；It is described
R1And R2Respectively 1 or 2.
7. application according to claim 6, which is characterized in that the C1-C6 alkyl includes C1-C6 straight chained alkyls, C3-C6
Branched alkyl, C3-C6 naphthenic base；The C1-C6 alkoxies include C1-C6 unbranched alkoxies, C3-C6 branched alkoxies, C3-C6
Miscellaneous oxygen naphthenic base；
The halogen is fluorine, chlorine, bromine or iodine；
The R1The position of substitution be 4-, 5-, 6- or 7-, R2The position of substitution be ortho position, meta or para position；R1And R2
The position of substitution is independent mutually.
8. the application described according to claim 6 or 7, which is characterized in that N (O, S)-miscellaneous indene of the 3- function dough is spread out
Biology includes the mixture of its stereoisomer or stereoisomer.
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| CN1482118A (en) * | 2003-01-04 | 2004-03-17 | 沈阳药科大学 | Novel 5-hydroxy-3-carboxylate indoles derivant and method for preparing the same |
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| CN1482118A (en) * | 2003-01-04 | 2004-03-17 | 沈阳药科大学 | Novel 5-hydroxy-3-carboxylate indoles derivant and method for preparing the same |
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| CN110960526A (en) * | 2019-12-30 | 2020-04-07 | 中国医学科学院医药生物技术研究所 | Application of 3-position functionalized N (O, S) -heteroandene derivative in preparation of anti-Zika virus drugs and pharmaceutical composition |
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