CN104193669A - Arbidol analogues or salts and preparation method and application thereof - Google Patents

Arbidol analogues or salts and preparation method and application thereof Download PDF

Info

Publication number
CN104193669A
CN104193669A CN201410377499.8A CN201410377499A CN104193669A CN 104193669 A CN104193669 A CN 104193669A CN 201410377499 A CN201410377499 A CN 201410377499A CN 104193669 A CN104193669 A CN 104193669A
Authority
CN
China
Prior art keywords
arh
compound
salt
arbidol
general formula
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.)
Granted
Application number
CN201410377499.8A
Other languages
Chinese (zh)
Other versions
CN104193669B (en
Inventor
刘建辉
匡露
潘景喜
刘洋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dalian University of Technology
Original Assignee
Dalian University of Technology
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dalian University of Technology filed Critical Dalian University of Technology
Priority to CN201410377499.8A priority Critical patent/CN104193669B/en
Publication of CN104193669A publication Critical patent/CN104193669A/en
Application granted granted Critical
Publication of CN104193669B publication Critical patent/CN104193669B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The invention relates to arbidol analogues or salts and a preparation method and application thereof, and belongs to the field of organic synthesis. The analogues are compounds having a structure shown in the general formula I described in the specification; in the general formula I, R1, R2 and R3 are C1-4 alkyl; R4 is H or C1-4 acyl; X is Cl, Br or I; Y is C, N, O or S; and Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl. The synthesized arbidol analogues show a good viral inhibition effect, thereby providing a new potential drug for treatment of influenza.

Description

One class Arbidol analogue or its salt, its preparation method and application
Technical field
The present invention relates to a class Arbidol analogue or its salt, its preparation method and application, belong to organic synthesis field.
Background technology
Arbidol HCl, have another name called the bromo-4-dimethylamino methyl-5-of 6-hydroxyl-1-methyl-2-(benzene thiomethyl)-1H-Indole-3-Carboxylic Acid carbethoxy hydrochloride, its precursor structure is 5-hydroxyl-1H-indoles, it is a kind of non-nucleoside antiviral being developed by USSR (Union of Soviet Socialist Republics) VNIKHFI company, got permission listing in 1993 in Russia, for prevention and the treatment of A, Type B influenza, be applicable to each age group crowd, and there is the advantages such as convenient oral, security are good, no cytotoxicity.
The structure that the synthetic committed step of Arbidol is indole ring, it is generally by Nenitzescu annulation, i.e. the cyclic condensation with 3-hydroxylamine base-2-butylene acid esters by para benzoquinone (or replacing para benzoquinone).On this basis, react by acylation reaction, bromination reaction, deprotection reaction, the nucleophilic substitution with thiophenol, Mannich amination, salify seven steps, finally obtain arbidol HCl.Other synthetic route is all to have carried out on this basis change to a certain degree.
Arbidol has interferon-induced effect and immunoregulation effect, and its disease-resistant spectrum is wide in addition, toxic side effect is little, Guang Shou various countries scholar's concern, and since Arbidol exploitation, the research of Arbidol and derivative thereof never stops.USSR (Union of Soviet Socialist Republics) chemist has synthesized polytype Arbidol derivative in the eighties in last century, and has analyzed the activity of their resisiting influenza virus, for the structure activity study of this compounds is laid a good foundation.
Because the variability of influenza virus is strong especially, develop that new resistance is better, suitability Arbidol derivative wider, that toxicity is less has very important meaning.The research of Arbidol series compound, since the eighties in last century, is comprised to the transformation of 1-6 position, wherein in the transformation of 2 of Arbidols, be included in and on phenyl ring, introduce different substituents or replace S with N, O.Research shows, in the time being connected with electron-donating group on phenyl ring, antiviral activity strengthens; In the time being connected with electron-withdrawing group, active decline; When being fluorine atom when monosubstituted, cytotoxicity reduces, but along with the number of fluorine atom increases, this compound increases the toxicity of cell; Replace thiophenyl with nitrogenous cycloaliphatic ring, the antiviral selectivity of compound decreases.We notice, in Ah 's flower structure of modification process, though 2-bit substituent has done a large amount of research, but only limit on phenyl ring substituent conversion or phenyl ring by the replacement of heterocycle, and do not make a search for carbochain length.
Summary of the invention
The present invention, by the structural modification of 2 of Arbidols, prepares 2-benzyl Arbidol, finds Arbidol antiviral analogs more efficiently.
The invention provides a class Arbidol analogue or its salt, described analogue is the compound with formula I structure:
Wherein in formula I:
R 1, R 2and R 3be selected from independently of one another C 1-4alkyl;
R 4for H or C 1-4acyl group;
X is Cl, Br or I;
Y is C, N, O or S;
Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl.
The salt with formula I structural compounds of the present invention is preferably hydrochloride, vitriol, tosilate or tartrate.
R of the present invention 1be preferably C 1-4straight chained alkyl, more preferably methyl or ethyl.
R of the present invention 2be preferably C 1-4straight chained alkyl, more preferably C 1-3straight chained alkyl, most preferably be methyl or ethyl.
R of the present invention 3be preferably C 1-4straight chained alkyl, more preferably C 1-3straight chained alkyl, most preferably be methyl or ethyl.
R of the present invention 4be preferably H or C 1-2acyl group, most preferably be H or ethanoyl.
Aryl of the present invention is preferably phenyl or naphthyl.
The substituting group of substituted aryl of the present invention is preferably the C that optional position replaces 1-4alkyl, C 1-4alkoxyl group, halogen, amino, nitro or C 1-4acyl group, more preferably adjacent,, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, F, Cl, Br or the I of contraposition.
Heteroaryl of the present invention is preferably and contains 1～3 heteroatomic heteroaryl that is selected from N, O or S, more preferably, containing 5 yuan or the 6 yuan of heteroaryls of 1～2 N, most preferably is pyrryl or pyridyl.
Another object of the present invention is to provide the preparation method of above-mentioned Arbidol analogue or its salt, and described method comprises the steps:
1. the compound that the compound of the compound of general formula I and general formula II is obtained to general formula III through Suzuki linked reaction, described R4 ' is C 1-4acyl group;
2. the compound of general formula III is obtained to the compound of general formula IV through phenolic hydroxyl group deprotection;
3. the compound of general formula III or general formula IV is reacted to the compound that obtains formula I through Mannich.
The salt of Arbidol analogue of the present invention can obtain by the idic acid of formula I is changed into salt.
Another object of the present invention is to provide above-mentioned Arbidol analogue or the application of its salt in preparation Tamiflu.
Beneficial effect of the present invention is the class Arbidol analogue that the present invention synthesizes, and demonstrates good viral inhibition, for the treatment of influenza provides new potential drug.
Brief description of the drawings
Accompanying drawing 1 width of the present invention,
Fig. 1 is inhibiting rate average table;
Wherein, 6, Arbidol, 7, Arbidol hydrochloride.
Embodiment
Following non-limiting example can make the present invention of those of ordinary skill in the art's comprehend, but does not limit the present invention in any way.
Embodiment 1
Synthesizing of 6-bromo-5-acetoxyl group-2-benzyl-1-Methyl-1H-indole-3-carboxylic acid, ethyl ester (2a)
At N 2under protection; in bis-mouthfuls of bottles of 50mL, add successively 1.0mmol formula 1,1.1mmol phenylo boric acid, 2.0mmol anhydrous sodium carbonate and mixed solvent 10mL; described mixed solvent is, the volume ratio of ethanol and water is 1:1:2, adds 0.01mmol Pd (PPh after stirring 3) 435 DEG C of reaction 3h, solution filter after reacting, dichloromethane extraction 3 times, organic layer is water, saturated common salt water washing successively, anhydrous sodium sulfate drying, except desolventizing, post separates (sherwood oil: ethyl acetate=6:1) and obtains 0.328g white solid (2a), mp:100 DEG C, productive rate 76.3%.
1H?NMR(400MHz,CDCl 3)δ:1.40(t,J＝16Hz,3H,CH 3),2.40(s,3H,CH 3),3.53(s,3H,CH 3),4.36-4.41(m,2H,CH 2),4.68(s,2H,CH 2),7.10-7.28(m,5H,ArH),7.51(s,1H,ArH),7.93(s,1H,ArH)； 13C?NMR(400MHz,CDCl 3)δ:9.41,15.76,25.11,26.15,54.66,100.14,105.16,108.35,110.75,121.18,121.43,122.95,123.60,130.10,131.82,137.85,142.68,160.04,164.39.m/z:429.0584[M+H] +.
Embodiment 2
Synthesizing of 6-bromo-5-acetoxyl group-2-(4-methyl-benzyl)-1-Methyl-1H-indole-3-carboxylic acid, ethyl ester (2b)
With the difference of embodiment 1 be: phenylo boric acid is replaced with to 4-methylphenylboronic acid, obtain 0.350g white solid (2b), mp:196 DEG C, productive rate 78.8%.
1H?NMR(400MHz,CDCl 3)δ:1.40(t,J＝16Hz,3H,CH 3),2.29(s,3H,CH 3),2.40(s,3H,CH 3)，3.52(s,3H,CH 3),4.36-4.41(m,2H,CH 2),4.62(s,2H,CH 2),7.00(d,J＝8Hz,2H,ArH),7.07(d,J＝16Hz,2H,ArH),7.50(s,1H,ArH),7.93(s,1H,ArH)； 13C?NMR(400MHz,CDCl 3)δ:14.58,20.91,21.00,30.28,30.95,59.78,105.28,110.28,113.48,115.94,126.43,128.00,129.45,133.90,135.32,136.16,143.03,148.11,165.21,169.53.m/z:443.0723[M+H] +.
Embodiment 3
Synthesizing of the bromo-2-of 1-methyl-5-acetoxyl group-6-(4-methoxy-benzyl)-benzyl-1H-Indole-3-Carboxylic Acid ethyl ester (2c)
With the difference of embodiment 1 be: phenylo boric acid is replaced with to 4-methoxyphenylboronic acid, obtain 0.373g white solid (2c), mp:202 DEG C, productive rate 81.2%.
1H?NMR(400MHz,CDCl 3)δ:1.33(t,J＝16Hz,3H,CH 3),2.32(s,3H,CH 3),3.46(s,3H,CH 3),3.68(s,3H,CH 3),4.29-4.34(m,2H,CH 2),4.52(s,2H,CH 2),6.72(d,J＝8Hz,2H,ArH),6.96(d,J＝8Hz,2H,ArH),7.43(s,1H,ArH),7.84(s,1H,ArH)； 13C?NMR(400MHz,CDCl 3)δ:14.58,20.91,30.25,30.48,55.26,59.80,105.16,110.28,113.48,114.17,115.93,126.39,128.95,129.13,135.30,143.02,148.30,158.27,165.23,169.56.MS,m/z:459.0687[M+H] +.
Embodiment 4
Synthesizing of the bromo-2-of 1-methyl-5-acetoxyl group-6-(4-chlorobenzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (2d)
With the difference of embodiment 1 be: phenylo boric acid is replaced with to 4-chlorobenzene boric acid, obtain 0.340g white solid (2d), mp:193 DEG C, productive rate 73.2%.
1H?NMR(400MHz,CDCl 3)δ:1.29-1.33(t,J＝16Hz,3H,CH 3),2.32(s,3H,CH 3),3.38(s,3H,CH 3),4.27-4.32(m,2H,CH 2),4.50(s,2H,CH 2),6.95(d,J＝8Hz,2H,ArH),7.13(d,J＝8Hz,2H,ArH),7.40(s,1H,ArH),7.83(s,1H,ArH)； 13C?NMR(400MHz,CDCl 3)δ:14.57,20.92,30.22,30.64,59.86,105.35,110.55,113.53,115.92,126.21,129.41,129.46,132.39,135.20,135.47,143.09,147.14,165.05,169.49.MS,m/z:463.0184[M+H] +.
Embodiment 5
Synthesizing of the bromo-2-of 1-methyl-5-acetoxyl group-6-(4-luorobenzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (2e)
With the difference of embodiment 1 be: phenylo boric acid is replaced with to 4-fluorobenzoic boric acid, obtain 0.259g white solid (2e), mp:162 DEG C, productive rate 57.9%.
1H?NMR(400MHz,CDCl 3)δ:1.33(t,J＝16Hz,3H,CH 3),2.33(s,3H,CH 3),3.47(s,3H,CH 3),4.29-4.34(m,2H,CH 2),4.56(s,2H,CH 2),6.87(d,J＝8Hz,2H,ArH),7.02(d,J＝8Hz,2H,ArH),7.45(s,1H,ArH),7.84(s,1H,ArH)； 13C?NMR(400MHz,CDCl 3)δ:14.57,20.91,30.20,30.47,59.88,105.27,110.48,113.55,115.49,115.70,115.96,126.25,129.56,132.65,135.25,143.11,147.63,165.15,169.55.MS,m/z:447.0477[M+H] +.
Embodiment 6
Synthesizing of the bromo-2-of 1-methyl-5-acetoxyl group-6-(1-naphthyl methyl)-1H-Indole-3-Carboxylic Acid ethyl ester (2f)
With the difference of embodiment 1 be: phenylo boric acid is replaced with to 2-naphthalene boronic acids, obtain 0.323g white solid (2f), mp:247 DEG C, productive rate 67.4%.
1H?NMR(400MHz,CDCl 3)δ:1.20(t,J＝16Hz,3H,CH 3),2.33(s,3H,CH 3),3.37(s,3H,CH 3),4.20-4.25(m,2H,CH 2),4.99(s,2H,CH 2),6.56(d,J＝8Hz,1H,ArH),7.17(t,J＝16Hz,1H,ArH),7.46(t,J＝16Hz,1H,ArH),7.48(s,1H,ArH),7.53(t,J＝16Hz,1H,ArH),7.64(d,J＝8Hz,1H,ArH),7.81(d,J＝8Hz,1H,ArH),7.90(s,1H,ArH),8.11(d,J＝8Hz,1H,ArH)； 13C?NMR(400MHz,CDCl 3)δ:14.45,20.92,28.33,30.25,59.78,106.18,110.47,113.64,115.96,122.94,124.45,125.63,125.90,126.44,126.52,127.32,128.92,131.61,132.99,133.78,135.46,143.17,147.48,165.09,169.54.MS,m/z:479.0736[M+H] +.
Embodiment 7
Synthesizing of the bromo-2-of 1-methyl-5-acetoxyl group-6-(2-methoxy-benzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (2g)
With the difference of embodiment 1 be: phenylo boric acid is replaced with to 2-methoxyphenylboronic acid, obtain 0.290g white solid (2g), mp:196 DEG C, productive rate 63.3%.
1H?NMR(400MHz,CDCl 3)δ:1.19(t,J＝12Hz,3H,CH 3),2.32(s,3H,CH 3),3.44(s,3H,CH 3),3.84(s,3H,CH 3),4.01-4.06(m,2H,CH 2),4.56(s,2H,CH 2),6.61-6.63(m,1H,ArH),6.68-6.72(m,1H,ArH),6.82(d,J＝8Hz,1H,ArH),7.08-7.13(m,1H,ArH),7.45(s,1H,ArH),7.85(s,1H,ArH)； 13C?NMR(400MHz,CDCl 3)δ:14.51,20.90,24.79,30.02,55.46,59.69,105.68,110.13,110.19,113.49,115.83,120.82,125.40,126.55,127.68,128.71,135.35,142.99,148.46,156.58,165.18,169.53.MS,m/z:459.0675[M+H] +.
Embodiment 8
Synthesizing of the bromo-2-of 1-methyl-5-acetoxyl group-6-(2-luorobenzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (2h)
With the difference of embodiment 1 be: phenylo boric acid is replaced with to 2-fluorobenzoic boric acid, obtain 0.209g white solid (2h), productive rate 46.8%.
1H?NMR(400MHz,CDCl 3)δ:1.30(t,J＝12Hz,3H,CH 3),2.31(s,3H,CH 3),3.43(s,3H,CH 3),4.27-4.32(m,2H,CH 2),4.58(s,2H,CH 2),6.76-6.79(m,1H,ArH),6.86-6.90(m,1H,ArH),6.96-7.00(m,1H,ArH),7.07-7.12(m,1H,ArH),7.42(s,1H,ArH),7.83(s,1H,ArH)； 13C?NMR(400MHz,CDCl 3)δ:14.52,20.90,23.76,30.03,59.88,105.76,110.51,113.64,115.16,115.38,115.89,123.92,124.51,126.28,128.40,129.81,135.27,143.11,146.75,165.10,169.52.MS,m/z:447.0487[M+H] +.
Embodiment 9
Synthesizing of 1-methyl-6-bromo-5-hydroxyl-2-benzyl-1H-Indole-3-Carboxylic Acid's ethyl ester (3a)
In 25mL single port bottle, add 2mL anhydrous methanol and 1.8mmol sodium hydroxide, after dissolving, add 0.6mmol compound 2a, room temperature reaction 0.5h, pours solution after reaction in 20mL water into, with dilute hydrochloric acid tune, pH is extremely acid, separate out light yellow solid, filter filter cake water, methanol wash, dry, obtain 0.225g white solid (3a), mp:186 DEG C, productive rate 94.2%.
1H?NMR(400MHz,DMSO)δ:1.33(t,J＝16Hz,3H,CH 3),3.57(s,3H,CH 3),4.25-4.30(m,2H,CH 2),4.61(s,2H,CH 2),7.14-7.29(m,5H,ArH),7.66(s,1H,ArH),7.69(s,1H,ArH),9.84(s,1H,OH)； 13C?NMR(400MHz,DMSO)δ:19.79,35.53,35.78,64.47,107.97,111.08,111.82,119.51,131.71,133.17,133.48,133.99,134.87,143.06,152.63,154.60,170.17.MS,m/z:388.0546[M+H] +.
Embodiment 10
Synthesizing of the bromo-5-hydroxyl-2-of 1-methyl-6-(4-methyl-benzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (3b)
With the difference of embodiment 9 be: compound 2a is replaced with to compound 2b, obtain 0.230g white solid (3b), mp:191 DEG C, productive rate 95.3%.
1H?NMR(400MHz,DMSO)δ:1.33(t,J＝16Hz,3H,CH 3),2.22(s,3H,CH 3),3.55(s,3H,CH 3),4.24-4.29(m,2H,CH 2),4.55(s,2H,CH 2),7.02-7.08(m,4H,ArH),7.66(d,J＝8Hz,2H,ArH),9.82(s,1H,OH)； 13C?NMR(400MHz,DMSO)δ:14.42,20.59,29.99,30.12,59.07,102.48,105.63,106.44,114.08,126.30,127.99,129.17,131.30,135.33,147.50,149.18,164.79.MS,m/z:402.0704[M+H] +.
Embodiment 11
Synthesizing of the bromo-5-hydroxyl-2-of 1-methyl-6-(4-methoxy-benzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (3c)
With the difference of embodiment 9 be: compound 2a is replaced with to compound 2c, obtain 0.234g white solid (3c), mp:194 DEG C, productive rate 933%.
1H?NMR(400MHz,DMSO)δ:1.34(t,J＝16Hz,3H,CH 3),3.56(s,3H,CH 3),3.68(s,3H,CH 3),4.27-4.29(m,2H,CH 2),4.52(s,2H,CH 2),6.82(d,J＝12Hz,2H,ArH),7.08(d,J＝8Hz,2H,ArH),7.66(d,J＝8Hz,2H,ArH),9.82(s,1H,OH)； 13C?NMR(400MHz,DMSO)δ:14.43,29.52,30.11,54.98,59.08,102.38,105.63,106.47,114.01,126.32,129.15,129.44,131.31,147.75,149.19,157.75,164.81.MS,m/z:418.0656[M+H] +.
Embodiment 12
Synthesizing of the bromo-5-hydroxyl-2-of 1-methyl-6-(4-chlorobenzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (3d)
With the difference of embodiment 9 be: compound 2a is replaced with to compound 2d, obtain 0.239g white solid (3d), mp:208 DEG C, productive rate 94.1%.
1HNMR(400MHz,DMSO)δ:1.33(t,J＝16Hz,3H,CH 3),3.58(s,3H,CH 3),4.25-4.30(m,2H,CH 2),4.60(s,2H,CH 2),7.18(d,J＝8Hz,2H,ArH),7.33(d,J＝8Hz,2H,ArH),7.65(s,1H,ArH),7.70(s,1H,ArH),9.82(s,1H,OH)； 13C?NMR(400MHz,DMSO)δ:14.36,29.72,30.12,59.09,102.64,105.80,106.39,114.17,126.19,128.52,129.91,130.95,131.30,136.69,146.63,149.23,164.68.MS,m/z:422.0157[M+H] +.
Embodiment 13
Synthesizing of the bromo-5-hydroxyl-2-of 1-methyl-6-(4-luorobenzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (3e)
With the difference of embodiment 9 be: compound 2a is replaced with to compound 2e, obtain 0.228g white solid (3e), mp:165 DEG C, productive rate 93.6%.
1HNMR(400MHz，DMSO)δ:1.36(t,J＝12Hz,3H,CH 3),3.45(s,3H,CH 3),4.29-4.34(m,2H,CH 2),4.55(s,2H,CH 2),5.41(s,1H,OH),6.86(d,J＝8Hz,2H,ArH),7.03(d,J＝8Hz,2H,ArH),7.33(s,1H,ArH),7.74(s,1H,ArH)； 13C?NMR(400MHz,DMSO)δ:14.37,29.73,30.13,59.10,102.65,105.82,106.41,114.19,126.21,128.53,129.92,130.96,131.31,136.70,146.65,149.25,164.70.MS,m/z:406.0451[M+H] +.
Embodiment 14
Synthesizing of 1-methyl-6-bromo-5-hydroxyl-4-dimethylamine methyl-2-benzyl-1H-Indole-3-Carboxylic Acid's ethyl ester (4a)
In reaction flask, add successively 6mL THF, 0.3mL Glacial acetic acid, 33% dimethylamine of 1.32mmol and 37% formaldehyde of 0.6mmol, after stirring at room temperature is even, add 0.5mmol compound 3a, back flow reaction 3h, solution after reaction is poured in 20mL water, with dilute NaOH solution tune pH to 10-12, dichloromethane extraction 3 times, merge organic layer, anhydrous sodium sulfate drying, filter, underpressure distillation is except desolventizing, obtain yellow oil, post separates (sherwood oil: ethyl acetate: triethylamine=50:20:1) and obtains 0.173g yellow solid (3a), mp:119 DEG C, productive rate 77.7%.
1H?NMR(400MHz,CDCl 3)δ:1.19(t,J＝24Hz,3H,CH 3),2.23(s,6H,N(CH 3) 2),3.39(s,3H,CH 3),4.15(s,2H,CH 2),4.21-4.26(m,2H,CH 2),4.36(s,2H,CH 2),7.03-7.19(m,5H,ArH),7.32(s,1H,ArH),10.34(s,1H,OH)； 13C?NMR(400MHz,CDCl 3)δ:14.53,30.33,32.01,44.19,59.86,60.35,112.48,114.22,124.31,126.63,128.13,128.85,129.13,131.75,137.59,144.75,151.44,158.31,166.31.MS,m/z:445.1112[M+H] +.
Embodiment 15
Synthesizing of the bromo-5-hydroxyl-4-of 1-methyl-6-dimethylamine methyl-2-(4-methyl-benzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (4b)
With the difference of embodiment 14 be: compound 3a is replaced with to compound 3b, obtain 0.185g yellow solid (4b), mp:152 DEG C, productive rate 80.6%.
1H?NMR(400MHz,CDCl 3)δ:1.30(t,J＝12Hz,3H,CH 3),2.29(s,3H,CH 3),2.40(s,6H,N(CH 3) 2),3.46(s,3H,CH 3),4.23(s,2H,CH 2),4.29-4.34(m,2H,CH 2),4.39(s,2H,CH 2),7.00(d,J＝8Hz,2H,ArH),7.07(d,J＝8Hz,2H,ArH),7.39(s,1H,ArH),11.13(s,1H,OH)； 13C?NMR(400MHz,CDCl 3)δ:14.53,21.09,30.28,31.56,44.18,59.88,60.29,105.90,107.70,112.40,113.01,124.31,127.99,129.48,131.73,134.47,136.13,145.01,151.37,166.31.MS,m/z:459.1269[M+H] +.
Embodiment 16
Synthesizing of the bromo-5-hydroxyl-4-of 1-methyl-6-dimethylamine methyl-2-(4-methoxy-benzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (4c)
With the difference of embodiment 14 be: compound 3a is replaced with to compound 3c, obtain yellow solid (4c).
1H?NMR(400MHz,CDCl 3)δ:1.31(t,J＝12Hz,3H,CH 3),2.41(s,6H,N(CH 3) 2),3.48(s,3H,CH 3),3.76(s,3H,CH 3),4.23(s,2H,CH 2),4.32-4.33(m,2H,CH 2),4.36(s,2H,CH 2),6.80(d,J＝12Hz,2H,ArH),7.05(d,J＝12Hz,2H,ArH),7.40(s,1H,ArH),11.36(s,1H,OH)； 13C?NMR(400MHz,CDCl 3)δ:14.57,30.29,31.15,44.19,55.38,59.83,60.35,105.84,107.80,112.47,113.01,114.22,124.32,129.13,129.54,131.76,145.18,151.18,158.31,166.35.MS,m/z:475.1219[M+H] +.
Embodiment 17
Synthesizing of the bromo-5-hydroxyl-4-of 1-methyl-6-dimethylamine methyl-2-(4-chlorobenzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (4d)
With the difference of embodiment 14 be: compound 3a is replaced with to compound 3d, obtain 0.165g yellow solid (4d), mp:147 DEG C, productive rate 71.2%.
1H?NMR(400MHz,CDCl 3)δ:1.15-1.24(m,3H,CH 3),2.32(s,6H,N(CH 3) 2),3.38(s,3H,CH 3),4.13(s,2H,CH 2),4.21-4.25(m,2H,CH 2),4.33(s,2H,CH 2),6.98(d,J＝16Hz,2H,ArH),7.16(d,J＝12Hz,2H,ArH),7.32(s,1H,ArH),8.75(s,1H,OH)； 13C?NMR(400MHz,CDCl 3)δ:14.43,30.20,31.29,44.07,59.74,60.30,106.01,107.96,112.46,112.91,124.09,128.85,129.37,131.60,132.34,135.98,144.01,151.42,166.06.MS,m/z:479.0687[M+H] +.
Embodiment 18
Synthesizing of the bromo-5-hydroxyl-4-of 1-methyl-6-dimethylamine methyl-2-(4-luorobenzyl)-1H-Indole-3-Carboxylic Acid ethyl ester (4e)
With the difference of embodiment 14 be: compound 3a is replaced with to compound 3e, obtain 0.174g yellow solid (4e), mp:135 DEG C, productive rate 72.5%.
1H?NMR(400MHz,CDCl 3)δ:1.29(t,J＝12Hz,3H,CH 3),2.42(s,6H,N(CH 3) 2),3.48(s,3H,CH 3),4.25(s,2H,CH 2),4.29-4.35(m,2H,CH 2),4.40(s,2H,CH 2),6.97(d,J＝8Hz,2H,ArH),7.10(d,J＝8Hz,2H,ArH),7.41(s,1H,ArH),10.96(s,1H,OH)； 13C?NMR(400MHz,CDCl 3)δ:14.38,30.22,30.80,43.92,60.15,60.27,105.93,107.91,112.45,112.91,115.44,115.65,124.13,129.43,131.62,133.09,144.39,151.37,166.11.MS,m/z:463.1000[M+H] +.
Embodiment 19
Synthesizing of 6-bromo-5-hydroxyl-4-dimethylamine methyl-2-benzyl-1-Methyl-1H-indole-3-carboxylic acid, ethyl ester hydrochloride (5a)
0.45mmol compound 4a is added to acetone to just dissolving, drip HCl-diethyl ether solution and adjust pH to 2-4, separate out white solid, filter, ether washing 2 times for filter cake, dry 0.205g white solid (5a), mp:112 DEG C, the productive rate 95.2% of obtaining.
1H?NMR(400MHz,DMSO)δ:1.19(t,J＝16Hz,3H,CH 3),2.79(s,3H,CH 3),3.35(s,6H,N(CH 3) 2),4.24-4.28(m,2H,CH 2),4.60(s,2H,CH 2),4.89(s,2H,CH 2),6.85-7.30(m,5H,ArH),8.01(s,1H,ArH),9.34(s,1H,OH).
Embodiment 20
Synthesizing of 6-bromo-5-hydroxyl-4-dimethylamine methyl-2-(4-methyl-benzyl)-1-Methyl-1H-indole-3-carboxylic acid, ethyl ester hydrochloride (5b)
With the difference of embodiment 19 be: compound 4a is replaced with to compound 4b, obtain 0.221g white solid (5b), mp:196 DEG C, productive rate 97.3%.
1H?NMR(400MHz,DMSO)δ:1.20(t,J＝16Hz,3H,CH 3),2.25(s,3H,CH 3),2.51(s,3H,CH 3),2.75(s,6H,N(CH 3) 2),3.64(s,2H,CH 2),4.23-4.26(m,2H,CH 2),4.52(s,2H,CH 2),7.03(d,J＝8Hz,2H,ArH),7.10(d,J＝8Hz,2H,ArH),7.82(s,1H,ArH),9.33(s,1H,OH).
Embodiment 21
Synthesizing of the bromo-5-hydroxyl-4-of 1-methyl-6-dimethylamine methyl-2-(4-methoxy-benzyl)-1H-Indole-3-Carboxylic Acid carbethoxy hydrochloride (5c)
With the difference of embodiment 19 be: compound 4a is replaced with to compound 4c, obtain 0.218g white solid (5c), mp:200 DEG C, productive rate 95.3%.
1H?NMR(400MHz,DMSO)δ:1.21(t,J＝12Hz,3H,CH 3),2.73(s,6H,N(CH 3) 2),3.64(s,3H,CH 3),3.70(s,3H,CH 3),4.24-4.28(m,2H,CH 2),4.49(s,2H,CH 2),4.79(s,2H,CH 2),6.86(d,J＝8Hz,2H,ArH),7.08(d,J＝8Hz,2H,ArH),7.95(s,1H,ArH),9.28(s,1H,OH).
Embodiment 22
Synthesizing of the bromo-5-hydroxyl-4-of 1-methyl-6-dimethylamine methyl-2-(4-chlorobenzyl)-1H-Indole-3-Carboxylic Acid carbethoxy hydrochloride (5d)
With the difference of embodiment 19 be: compound 4a is replaced with to compound 4d, obtain 0.206g white solid (5d), m:146 DEG C of productive rate 925%
1H?NMR(400MHz,DMSO)δ:1.16(t,J＝12Hz,3H,CH 3),2.78(s,6H,N(CH 3) 2),3.66(s,3H,CH 3),4.23-4.25(m,2H,CH 2),4.58(s,2H,CH 2),4.94(s,2H,CH 2),7.18(d,J＝8Hz,2H,ArH),7.36(d,J＝8Hz,2H,ArH),8.01(s,1H,ArH),9.38(s,1H,OH).
Embodiment 23
Synthesizing of the bromo-5-hydroxyl-4-of 1-methyl-6-dimethylamine methyl-2-(4-luorobenzyl)-1H-Indole-3-Carboxylic Acid carbethoxy hydrochloride (5e)
With the difference of embodiment 19 be: compound 4a is replaced with to compound 4e, obtain 0.210g white solid (5e), mp:194 DEG C, productive rate 91.4%.
1H?NMR(400MHz,DMSO)δ:1.18(t,J＝12Hz,3H,CH 3),2.78(s,6H,N(CH 3) 2),3.67(s,3H,CH 3),4.23-4.28(m,2H,CH 2),4.57(s,2H,CH 2),4.92(s,2H,CH 2),7.11-7.19(m,4H,ArH),8.01(s,1H,ArH),9.37(s,1H,OH).
Application examples 1
1. embodiment 1,2,3.......15,17.......21,22,23 synthetic compound, Arbidol and Arbidol hydrochlorides are dissolved in respectively to DMSO and are mixed with the solution that concentration is 2mM;
2. 293T-Gluc cell is inoculated in 96 orifice plates to every hole 7 × 10 5individual, 100 μ L systems, after inoculation, cell is placed in 37 DEG C, 5%CO 2in incubator, hatch;
3. after cell inoculation 24h, the solution that 1. step is prepared joins respectively in cell and is mixed with the solution that concentration is 20 μ M, and 3 multiple holes are set.Add after the solution 2h that 1. step prepare, influenza virus A/WSN/33 is diluted in the DMEM of serum-free, with MOI=0.05 cells infected, infectosome is 10 μ L, and infection system includes TPCK-trypsin, and its concentration in final system is 1 μ g/mL;
4. infect after 24h, draw cell conditioned medium liquid 10 μ L, measure Gluc activity;
5. every group of experiment all arranges positive controls (uninfecting virus, without drug treating) and negative control group (infection virus, without drug treating), inhibiting rate=(negative control group-sample sets)/(negative control group-positive controls) × 100%;
6. the IC of medicine 50calculate and completed by software GraphPad.
Experimental result is shown in Fig. 1.

Claims (10)

1. a class Arbidol analogue or its salt, described analogue is the compound with formula I structure:
Wherein in formula I:
R 1, R 2and R 3be selected from independently of one another C 1-4alkyl;
R 4for H or C 1-4acyl group;
X is Cl, Br or I;
Y is C, N, O or S;
Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl.
2. analogue according to claim 1 or its salt, is characterized in that: described in there is formula I structural compounds salt be hydrochloride, vitriol, tosilate or tartrate.
3. analogue according to claim 1 or its salt, is characterized in that: described R 1for C 1-4straight chained alkyl.
4. analogue according to claim 1 or its salt, is characterized in that: described R 2for C 1-4straight chained alkyl.
5. analogue according to claim 1 or its salt, is characterized in that: described R 3for C 1-4straight chained alkyl.
6. analogue according to claim 1 or its salt, is characterized in that: described aryl is phenyl, naphthyl.
7. analogue according to claim 1 or its salt, is characterized in that: the substituting group of described substituted aryl is the C that optional position replaces 1-4alkyl, C 1-4alkoxyl group, halogen, amino, nitro or C 1-4acyl group.
8. analogue according to claim 1 or its salt, is characterized in that: described heteroaryl is to contain 1～3 heteroatomic heteroaryl that is selected from N, O or S.
9. the Arbidol analogue described in claim 1,2,3,4,5,6,7 or 8 or the preparation method of its salt, is characterized in that: described method comprises the steps:
1. the compound that the compound of the compound of general formula I and general formula II is obtained to general formula III through Suzuki linked reaction, described R4 ' is C 1-4acyl group;
2. the compound of general formula III is obtained to the compound of general formula IV through phenolic hydroxyl group deprotection;
3. the compound of general formula III or general formula IV is reacted to the compound that obtains formula I through Mannich.
10. the Arbidol analogue described in claim 1,2,3,4,5,6,7 or 8 or its salt application in preparation Tamiflu.
CN201410377499.8A 2014-08-01 2014-08-01 One class Abiduoer analog or its salt, its preparation method and application Expired - Fee Related CN104193669B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410377499.8A CN104193669B (en) 2014-08-01 2014-08-01 One class Abiduoer analog or its salt, its preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410377499.8A CN104193669B (en) 2014-08-01 2014-08-01 One class Abiduoer analog or its salt, its preparation method and application

Publications (2)

Publication Number Publication Date
CN104193669A true CN104193669A (en) 2014-12-10
CN104193669B CN104193669B (en) 2016-12-07

Family

ID=52079080

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410377499.8A Expired - Fee Related CN104193669B (en) 2014-08-01 2014-08-01 One class Abiduoer analog or its salt, its preparation method and application

Country Status (1)

Country Link
CN (1) CN104193669B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106366029A (en) * 2016-08-19 2017-02-01 江苏吴中医药集团有限公司苏州制药厂 Arbidol mesylate monohydrate crystal C and its preparation method and use
CN115232055A (en) * 2022-08-10 2022-10-25 湖州恒远生物化学技术有限公司 Synthesis method of arbidol hydrochloride

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990008135A1 (en) * 1989-01-12 1990-07-26 Vsesojuzny Nauchno-Issledovatelsky Khimiko-Farmatsevtichesky Institut Imeni S.Ordzhonikidze (Vnikhfi) Ethyl ester 6-bromine-5-hydroxy-4-dimethyl-aminomethyl-1-methyl-2-phenylthiomethyl indole-3-carboxylic acid hydrochloride monohydrate, method of obtaining it and a pharmaceutical preparation of antiviral, interferon inducing and immunomodulating action based on it
CN1344270A (en) * 1999-01-13 2002-04-10 千年药品公司 Functionalized heterocycles as chemokine receptor modulators
WO2005087729A1 (en) * 2004-03-12 2005-09-22 Shenyang Pharmaceutical University 5-hydroxyindole-3-carboxylates derivatives and their use
WO2007136302A2 (en) * 2006-05-23 2007-11-29 Alla Chem, Llc Active substances, pharmaceutical composition and a method for the production and use thereof
US20110160197A1 (en) * 2006-03-23 2011-06-30 Alla Chem, Llc Substituted Indoles and a Method for the Production and Use Thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990008135A1 (en) * 1989-01-12 1990-07-26 Vsesojuzny Nauchno-Issledovatelsky Khimiko-Farmatsevtichesky Institut Imeni S.Ordzhonikidze (Vnikhfi) Ethyl ester 6-bromine-5-hydroxy-4-dimethyl-aminomethyl-1-methyl-2-phenylthiomethyl indole-3-carboxylic acid hydrochloride monohydrate, method of obtaining it and a pharmaceutical preparation of antiviral, interferon inducing and immunomodulating action based on it
CN1344270A (en) * 1999-01-13 2002-04-10 千年药品公司 Functionalized heterocycles as chemokine receptor modulators
WO2005087729A1 (en) * 2004-03-12 2005-09-22 Shenyang Pharmaceutical University 5-hydroxyindole-3-carboxylates derivatives and their use
US20110160197A1 (en) * 2006-03-23 2011-06-30 Alla Chem, Llc Substituted Indoles and a Method for the Production and Use Thereof
WO2007136302A2 (en) * 2006-05-23 2007-11-29 Alla Chem, Llc Active substances, pharmaceutical composition and a method for the production and use thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106366029A (en) * 2016-08-19 2017-02-01 江苏吴中医药集团有限公司苏州制药厂 Arbidol mesylate monohydrate crystal C and its preparation method and use
CN115232055A (en) * 2022-08-10 2022-10-25 湖州恒远生物化学技术有限公司 Synthesis method of arbidol hydrochloride
CN115232055B (en) * 2022-08-10 2023-12-01 湖州恒远生物化学技术有限公司 Synthesis method of arbidol hydrochloride

Also Published As

Publication number Publication date
CN104193669B (en) 2016-12-07

Similar Documents

Publication Publication Date Title
CN101781269B (en) 4-tertiary butyl-2-(nitrobenzyl imino) thiazole derivative as well as preparation method and application thereof
CN102344351B (en) Aryl-substituted chalcones compound, its preparation method and its application
CN102438995A (en) Process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof
CN102584841B (en) Quinoline coumarin derivate and preparation method and application thereof
CN101190899B (en) Method for synthesizing 1.2-dihydroquinazolin-4(3H)-one compound
CN106831550A (en) A kind of optical activity two（It is miscellaneous）Aryl methyl alcohol and its method of asymmetric synthesis
CN104193669A (en) Arbidol analogues or salts and preparation method and application thereof
CN103467426B (en) Quercetin hydrocarbylation derivative and preparation method thereof and application
CN104945332A (en) Preparation method of erlotinib
CN102001979B (en) Preparation method of 2-(2', 2'-difluoroethoxyl)-6-trifluoromethyl phenyl propyl sulfide
CN102093343B (en) N-aryl axially chiral carbene-oxazoline compound and application thereof
CN105399644A (en) Molecular tweezer compounds with (1S,2S)-1,2-cyclohexanediamine as spacer group and isosteviol as chiral arm, and preparation method and application thereof
CN101372477B (en) Method for synthesizing diaza-onium salt
CN105481781A (en) Compound, preparation method therefor and application of compound
CN105111161A (en) Method for efficiently synthesizing 2-phenylbenzoxazole and derivatives of 2-phenylbenzoxazole through coupling and series connection
CN104447228A (en) Method for synthesizing trans-stilbene compound under assistance of microwave
CN103601676B (en) High enantioselectivity N-ethanoyl-2-replaces the synthetic method of-2,3-two hydrogen-4-quinolinones compound
CN104230689A (en) 6,7-dihydro-5H-diphenyl[a,c]cyclohepta-5-ketone compound and preparation method thereof
CN100556886C (en) Produce the method for 2-O-Benzoylglycolaldehyde derivative
CN104119319A (en) Pyrimidine derivative containing 1,2,3-triazole and urea structure unit as well as preparation method and application thereof
CN104016959B (en) A kind of protosappanin A and its derivatives chemical total synthesis method
CN104086342B (en) A kind of synthetic method of medicine intermediate aryl substituted carbinol compound
CN110759860B (en) Preparation method of 3-methyl formate-4-methoxy-5-cyanopyridine
CN103339124A (en) Method for producing di(arylamino)aryl compound, and synthetic intermediate therefor
CN109721630A (en) A kind of synthetic method of Ugi ' s amine and its derivative

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20161207

Termination date: 20190801