CN104193669B - One class Abiduoer analog or its salt, its preparation method and application - Google Patents
One class Abiduoer analog or its salt, its preparation method and application Download PDFInfo
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- CN104193669B CN104193669B CN201410377499.8A CN201410377499A CN104193669B CN 104193669 B CN104193669 B CN 104193669B CN 201410377499 A CN201410377499 A CN 201410377499A CN 104193669 B CN104193669 B CN 104193669B
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- analog
- salt
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- 150000003839 salts Chemical class 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 4
- -1 substituted-phenyl Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 238000006683 Mannich reaction Methods 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
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- 229940061367 tamiflu Drugs 0.000 claims description 2
- 229950004288 tosilate Drugs 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
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- 125000001072 heteroaryl group Chemical group 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 3
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- 125000003107 substituted aryl group Chemical group 0.000 abstract description 3
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- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 66
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- 201000010099 disease Diseases 0.000 description 2
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- OMZHXQXQJGCSKN-UHFFFAOYSA-N ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)-1h-indol-1-ium-3-carboxylate;chloride Chemical compound Cl.CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 OMZHXQXQJGCSKN-UHFFFAOYSA-N 0.000 description 2
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- ROEQGIFOWRQYHD-UHFFFAOYSA-N (2-methoxyphenyl)boronic acid Chemical group COC1=CC=CC=C1B(O)O ROEQGIFOWRQYHD-UHFFFAOYSA-N 0.000 description 1
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical group CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical group OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
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- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical group C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 1
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical group C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 1
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- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical group N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- LMIQERWZRIFWNZ-UHFFFAOYSA-N 5-hydroxyindole Chemical group OC1=CC=C2NC=CC2=C1 LMIQERWZRIFWNZ-UHFFFAOYSA-N 0.000 description 1
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- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical group ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- 229940126559 Compound 4e Drugs 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
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- 108010050904 Interferons Proteins 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
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- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical group C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
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- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical group CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 230000002588 toxic effect Effects 0.000 description 1
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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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to class Abiduoer analog or its salt, its preparation method and an application, belong to organic synthesis field, described analog is the compound with formula I structure, wherein in formula I: R1、R2、R3For C1‑4Alkyl；R4For H or C1‑4Acyl group；X is Cl, Br or I；Y is C, N, O or S；Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the present invention has the beneficial effect that a class Abiduoer analog of synthesis, demonstrates good viral inhibition, and the treatment for influenza provides new potential drug.
Description
Technical field
The present invention relates to class Abiduoer analog or its salt, its preparation method and an application, belong to organic synthesis field.
Background technology
Arbidol HCl, has another name called 6-bromo-4-dimethylamino methyl-5-hydroxyl-1-methyl-2-(benzene sulfidomethyl)-1H-Yin
Diindyl-3-carboxylate hydrochloride, its precursor structure is 5-hydroxyl-1H-indole, is to be developed by VNIKHFI company of the former Soviet Union
A kind of non-nucleoside antiviral drugs out, was approved listing in 1993 in Russia, for A, the prevention of Type B influenza with control
Treat, it is adaptable to each age group crowd, and there is the advantage such as convenient oral, good, the no cytotoxicity of safety.
The structure that committed step is indole ring of Abiduoer synthesis, it is generally by Nenitzescu annulation,
I.e. by the cyclic condensation of 1,4-benzoquinone (or replacing 1,4-benzoquinone) with 3-hydroxylamine base-2-butylene acid esters.On this basis, by acylated anti-
, nucleophilic displacement of fluorine, the Mannich amination of bromination reaction, deprotection reaction and phenylmercaptan., salt seven step should be become to react, finally give salt
Acid Abiduoer.Other synthetic route is all to have carried out a certain degree of change on this basis.
Abiduoer has interferon-induced effect and an immunoregulation effect, in addition its disease-resistant spectrum is wide, toxic and side effects is little, extensively
Being paid close attention to by scholars, since Abiduoer is developed, the research of Abiduoer and derivant thereof never stops.The former Soviet Union
Scholar has synthesized polytype Abiduoer derivant in the eighties in last century, and analyzes the work of their resisiting influenza virus
Property, the structure activity study for this compounds is laid a good foundation.
Owing to the variability of influenza virus is strong especially, develop the Ah that new Drug resistance is more preferable, the suitability is wider, toxicity is less
Very important meaning is had than Duo Er derivant.Research to Abiduoer series compound is opened from the eighties in last century
Begin, including the transformation of 1-6 position, wherein in the transformation to Abiduoer 2, be included on phenyl ring introducing different substituents or with N,
O replaces S.Research shows, when being connected with electron-donating group on phenyl ring, antiviral activity strengthens；When being connected with electron withdraw group, live
Property decline；When for fluorine atom monosubstituted time, cytotoxicity reduces, but along with the number of fluorine atom increases, this compound on intracellular
Toxicity increase；Replacing thiophenyl with nitrogenous cycloaliphatic ring, the antiviral selectivity of compound decreases.It was noticed that Ah
Ratio, during flower structure of modification, though 2-bit substituent has done substantial amounts of research, but is only limitted to the change of benzene ring substituents
Change or phenyl ring is by the replacement of heterocycle, and carbochain length is not made a search.
Summary of the invention
The present invention structural modification by Abiduoer 2, i.e. prepares 2-benzyl Abiduoer, finds more efficient
Abiduoer antiviral analogs.
The invention provides class Abiduoer analog or its salt, described analog is the chemical combination with formula I structure
Thing:
Wherein in formula I:
R1、R2And R3It is each independently selected from C1-4Alkyl；
R4For H or C1-4Acyl 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 hydrochlorate, sulfate, tosilate or wine
Stone hydrochlorate.
R of the present invention1It is preferably C1-4Straight chained alkyl, more preferably methyl or ethyl.
R of the present invention2It is preferably C1-4Straight chained alkyl, more preferably C1-3Straight chained alkyl, most preferably first
Base or ethyl.
R of the present invention3It is preferably C1-4Straight chained alkyl, more preferably C1-3Straight chained alkyl, most preferably first
Base or ethyl.
R of the present invention4It is preferably H or C1-2Acyl group, most preferably H or acetyl group.
Aryl of the present invention is preferably phenyl or naphthyl.
The substituent group of substituted aryl of the present invention is preferably the substituted C in optional position1-4Alkyl, C1-4Alkoxyl,
Halogen, amino, nitro or C1-4Acyl group, the most o-, m-, the methyl of para-position, ethyl, n-pro-pyl, isopropyl, first
Epoxide, ethyoxyl, positive propoxy, isopropoxy, F, Cl, Br or I.
Heteroaryl of the present invention is preferably containing 1～3 heteroatomic heteroaryl selected from N, O or S, more preferably
Containing 1～2 N 5 yuan or 6 yuan of heteroaryls, most preferably pyrrole radicals or pyridine radicals.
It is a further object of the present invention to provide the preparation method of above-mentioned Abiduoer analog or its salt, described method includes
Following steps:
1. the compound of the compound of formula and formula is obtained through Suzuki coupling reaction the chemical combination of formula
Thing, described R4 ' is C1-4Acyl group；
2. the compound of formula is obtained through phenolic hydroxyl group deprotection the compound of formula；
3. the compound of formula or formula is obtained through Mannich reaction the compound of formula I.
The salt of Abiduoer analog of the present invention is the most available by the idic acid of formula I is melted into salt.
It is yet another object of the invention to provide above-mentioned Abiduoer analog or its salt answering in preparation Tamiflu
With.
The present invention has the beneficial effect that the class Abiduoer analog that the present invention synthesizes, and demonstrates that good HIV suppression is made
With, the treatment for influenza provides new potential drug.
Accompanying drawing explanation
Accompanying drawing 1 width of the present invention,
Fig. 1 is suppression ratio average table；
Wherein, 6, Abiduoer, 7, Arbidol hydrochloride.
Detailed description of the invention
Following non-limiting example can make those of ordinary skill in the art that the present invention be more fully understood, but not with
Any mode limits the present invention.
Embodiment 1
The synthesis of 6-bromo-5-acetoxyl group-2-benzyl-1-Methyl-1H-indole-3-carboxylic acid, ethyl ester (2a)
At N2Under protection, bis-mouthfuls of bottles of 50mL are sequentially added into 1.0mmol formula 1,1.1mmol phenylboric acid, 2.0mmol anhydrous
Sodium carbonate and mixed solvent 10mL, described mixed solvent is, ethanol is 1:1:2 with the volume ratio of water, is stirring evenly and then adding into
0.01mmol Pd(PPh3)4, 35 DEG C reaction 3h, will reaction after solution filter, dichloromethane extract 3 times, organic layer successively with water,
Saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and removes solvent, and post separates (petroleum ether: ethyl acetate=6:1) and obtains 0.328g
White solid (2a), mp:100 DEG C, productivity 76.3%.
1H NMR(400MHz,CDCl3) δ: 1.40 (t, J=16Hz, 3H, CH3),2.40(s,3H,CH3),3.53(s,3H,
CH3),4.36-4.41(m,2H,CH2),4.68(s,2H,CH2),7.10-7.28(m,5H,ArH),7.51(s,1H,ArH),
7.93(s,1H,ArH)；13C NMR(400MHz,CDCl3)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
The synthesis of 6-bromo-5-acetoxyl group-2-(4-methyl-benzyl)-1-Methyl-1H-indole-3-carboxylic acid, ethyl ester (2b)
With being distinguished as of embodiment 1: phenylboric acid to be replaced with 4-methylphenylboronic acid, obtain 0.350g white solid (2b),
Mp:196 DEG C, productivity 78.8%.
1H NMR(400MHz,CDCl3) δ: 1.40 (t, J=16Hz, 3H, CH3),2.29(s,3H,CH3),2.40(s,3H,
CH3), 3.52 (s, 3H, CH3),4.36-4.41(m,2H,CH2),4.62(s,2H,CH2), 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,CDCl3)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
1-methyl-5-bromo-the 2-of acetoxyl group-6-(4-methoxy-benzyl)-benzyl-1H-indole-3-carboxylic acid's ethyl ester (2c)
Synthesis
With being distinguished as of embodiment 1: phenylboric acid to be replaced with 4-methoxyphenylboronic acid, obtain 0.373g white solid
(2c), mp:202 DEG C, productivity 81.2%.
1H NMR(400MHz,CDCl3) δ: 1.33 (t, J=16Hz, 3H, CH3),2.32(s,3H,CH3),3.46(s,3H,
CH3),3.68(s,3H,CH3),4.29-4.34(m,2H,CH2),4.52(s,2H,CH2), 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,CDCl3)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
The synthesis of the 1-methyl-5-bromo-2-of acetoxyl group-6-(4-chlorobenzyl)-1H-indole-3-carboxylic acid's ethyl ester (2d)
With being distinguished as of embodiment 1: phenylboric acid to be replaced with 4-chlorophenylboronic acid, obtain 0.340g white solid (2d), mp:
193 DEG C, productivity 73.2%.
1H NMR(400MHz,CDCl3) δ: 1.29-1.33 (t, J=16Hz, 3H, CH3),2.32(s,3H,CH3),3.38
(s,3H,CH3),4.27-4.32(m,2H,CH2),4.50(s,2H,CH2), 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,CDCl3)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
The synthesis of the 1-methyl-5-bromo-2-of acetoxyl group-6-(4-luorobenzyl)-1H-indole-3-carboxylic acid's ethyl ester (2e)
With being distinguished as of embodiment 1: phenylboric acid to be replaced with 4-fluorobenzoic boric acid, obtain 0.259g white solid (2e), mp:
162 DEG C, productivity 57.9%.
1H NMR(400MHz,CDCl3) δ: 1.33 (t, J=16Hz, 3H, CH3),2.33(s,3H,CH3),3.47(s,3H,
CH3),4.29-4.34(m,2H,CH2),4.56(s,2H,CH2), 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,CDCl3)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
The synthesis of the 1-methyl-5-bromo-2-of acetoxyl group-6-(1-naphthyl methyl)-1H-indole-3-carboxylic acid's ethyl ester (2f)
With being distinguished as of embodiment 1: phenylboric acid to be replaced with 2-naphthalene boronic acids, obtain 0.323g white solid (2f), mp:
247 DEG C, productivity 67.4%.
1H NMR(400MHz,CDCl3) δ: 1.20 (t, J=16Hz, 3H, CH3),2.33(s,3H,CH3),3.37(s,3H,
CH3),4.20-4.25(m,2H,CH2),4.99(s,2H,CH2), 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,CDCl3)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
The synthesis of the 1-methyl-5-bromo-2-of acetoxyl group-6-(2-methoxy-benzyl)-1H-indole-3-carboxylic acid's ethyl ester (2g)
With being distinguished as of embodiment 1: phenylboric acid to be replaced with 2-methoxyphenylboronic acid, obtain 0.290g white solid
(2g), mp:196 DEG C, productivity 63.3%.
1H NMR(400MHz,CDCl3) δ: 1.19 (t, J=12Hz, 3H, CH3),2.32(s,3H,CH3),3.44(s,3H,
CH3),3.84(s,3H,CH3),4.01-4.06(m,2H,CH2),4.56(s,2H,CH2),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,CDCl3)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
The synthesis of the 1-methyl-5-bromo-2-of acetoxyl group-6-(2-luorobenzyl)-1H-indole-3-carboxylic acid's ethyl ester (2h)
With being distinguished as of embodiment 1: phenylboric acid to be replaced with 2-fluorobenzoic boric acid, obtain 0.209g white solid (2h), produce
Rate 46.8%.
1H NMR(400MHz,CDCl3) δ: 1.30 (t, J=12Hz, 3H, CH3),2.31(s,3H,CH3),3.43(s,3H,
CH3),4.27-4.32(m,2H,CH2),4.58(s,2H,CH2),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,CDCl3)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
The synthesis 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 absolute methanol and 1.8mmol sodium hydroxide, after dissolving, add 0.6mmol chemical combination
Thing 2a, room temperature reaction 0.5h, pour into solution after reaction in 20mL water, adjusts pH to acid with dilute hydrochloric acid, separates out light yellow solid,
Filtering, filter cake use water, methanol wash, and are dried, obtain 0.225g white solid (3a), mp:186 DEG C, productivity 94.2%.
1H NMR (400MHz, DMSO) δ: 1.33 (t, J=16Hz, 3H, CH3),3.57(s,3H,CH3),4.25-4.30
(m,2H,CH2),4.61(s,2H,CH2),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
The synthesis of 1-methyl-6-bromo-5-hydroxyl-2-(4-methyl-benzyl)-1H-indole-3-carboxylic acid's ethyl ester (3b)
With being distinguished as of embodiment 9: compound 2a is replaced with compound 2b, obtain 0.230g white solid (3b), mp:
191 DEG C, productivity 95.3%.
1H NMR (400MHz, DMSO) δ: 1.33 (t, J=16Hz, 3H, CH3),2.22(s,3H,CH3),3.55(s,3H,
CH3),4.24-4.29(m,2H,CH2),4.55(s,2H,CH2), 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
The synthesis of 1-methyl-6-bromo-5-hydroxyl-2-(4-methoxy-benzyl)-1H-indole-3-carboxylic acid's ethyl ester (3c)
With being distinguished as of embodiment 9: compound 2a is replaced with compound 2c, obtain 0.234g white solid (3c), mp:
194 DEG C, productivity 933%.
1H NMR (400MHz, DMSO) δ: 1.34 (t, J=16Hz, 3H, CH3),3.56(s,3H,CH3),3.68(s,3H,
CH3),4.27-4.29(m,2H,CH2),4.52(s,2H,CH2), 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
The synthesis of 1-methyl-6-bromo-5-hydroxyl-2-(4-chlorobenzyl)-1H-indole-3-carboxylic acid's ethyl ester (3d)
With being distinguished as of embodiment 9: compound 2a is replaced with compound 2d, obtain 0.239g white solid (3d), mp:
208 DEG C, productivity 94.1%.
1HNMR (400MHz, DMSO) δ: 1.33 (t, J=16Hz, 3H, CH3),3.58(s,3H,CH3),4.25-4.30(m,
2H,CH2),4.60(s,2H,CH2), 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
The synthesis of 1-methyl-6-bromo-5-hydroxyl-2-(4-luorobenzyl)-1H-indole-3-carboxylic acid's ethyl ester (3e)
With being distinguished as of embodiment 9: compound 2a is replaced with compound 2e, obtain 0.228g white solid (3e), mp:
165 DEG C, productivity 93.6%.
1HNMR (400MHz, DMSO) δ: 1.36 (t, J=12Hz, 3H, CH3),3.45(s,3H,CH3),4.29-4.34(m,
2H,CH2),4.55(s,2H,CH2), 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
The synthesis of 1-methyl-6-bromo-5-hydroxyl-4-dimethylamine methyl-2-benzyl-1H-indole-3-carboxylic acid's ethyl ester (4a)
6mL THF, 0.3mL glacial acetic acid, 33% dimethylamine of 1.32mmol and 0.6mmol it is sequentially added in reaction bulb
37% formaldehyde, adds 0.5mmol compound 3a, back flow reaction 3h, pours solution after reaction into 20mL water after being stirred at room temperature uniformly
In, adjust pH to 10-12 with dilute NaOH solution, dichloromethane extracts 3 times, merges organic layer, and anhydrous sodium sulfate is dried, and filters, subtracts
Pressure is distilled off solvent, obtains yellow oil, and post separates (petroleum ether: ethyl acetate: triethylamine=50:20:1) and obtains
0.173g yellow solid (3a), mp:119 DEG C, productivity 77.7%.
1H NMR(400MHz,CDCl3) δ: 1.19 (t, J=24Hz, 3H, CH3),2.23(s,6H,N(CH3)2),3.39(s,
3H,CH3),4.15(s,2H,CH2),4.21-4.26(m,2H,CH2),4.36(s,2H,CH2),7.03-7.19(m,5H,ArH),
7.32(s,1H,ArH),10.34(s,1H,OH)；13C NMR(400MHz,CDCl3)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
1-methyl-6-bromo-5-hydroxyl-4-dimethylamine methyl-2-(4-methyl-benzyl)-1H-indole-3-carboxylic acid's ethyl ester (4b)
Synthesis
With being distinguished as of embodiment 14: compound 3a is replaced with compound 3b, obtain 0.185g yellow solid (4b),
Mp:152 DEG C, productivity 80.6%.
1H NMR(400MHz,CDCl3) δ: 1.30 (t, J=12Hz, 3H, CH3),2.29(s,3H,CH3),2.40(s,6H,
N(CH3)2),3.46(s,3H,CH3),4.23(s,2H,CH2),4.29-4.34(m,2H,CH2),4.39(s,2H,CH2),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,CDCl3)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
1-methyl-6-bromo-5-hydroxyl-4-dimethylamine methyl-2-(4-methoxy-benzyl)-1H-indole-3-carboxylic acid's ethyl ester
(4c) synthesis
With being distinguished as of embodiment 14: compound 3a is replaced with compound 3c, obtain yellow solid (4c).
1H NMR(400MHz,CDCl3) δ: 1.31 (t, J=12Hz, 3H, CH3),2.41(s,6H,N(CH3)2),3.48(s,
3H,CH3),3.76(s,3H,CH3),4.23(s,2H,CH2),4.32-4.33(m,2H,CH2),4.36(s,2H,CH2),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,CDCl3)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
1-methyl-6-'s bromo-5-hydroxyl-4-dimethylamine methyl-2-(4-chlorobenzyl)-1H-indole-3-carboxylic acid's ethyl ester (4d)
Synthesis
With being distinguished as of embodiment 14: compound 3a is replaced with compound 3d, obtain 0.165g yellow solid (4d),
Mp:147 DEG C, productivity 71.2%.
1H NMR(400MHz,CDCl3)δ:1.15-1.24(m,3H,CH3),2.32(s,6H,N(CH3)2),3.38(s,3H,
CH3),4.13(s,2H,CH2),4.21-4.25(m,2H,CH2),4.33(s,2H,CH2), 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,CDCl3)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
1-methyl-6-'s bromo-5-hydroxyl-4-dimethylamine methyl-2-(4-luorobenzyl)-1H-indole-3-carboxylic acid's ethyl ester (4e)
Synthesis
With being distinguished as of embodiment 14: compound 3a is replaced with compound 3e, obtain 0.174g yellow solid (4e),
Mp:135 DEG C, productivity 72.5%.
1H NMR(400MHz,CDCl3) δ: 1.29 (t, J=12Hz, 3H, CH3),2.42(s,6H,N(CH3)2),3.48(s,
3H,CH3),4.25(s,2H,CH2),4.29-4.35(m,2H,CH2),4.40(s,2H,CH2), 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,CDCl3)
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
6-'s bromo-5-hydroxyl-4-dimethylamine methyl-2-benzyl-1-Methyl-1H-indole-3-carboxylate hydrochloride (5a)
Synthesis
0.45mmol compound 4a adds acetone adjust pH to 2-4 to dissolving just, dropping HCl-diethyl ether solution, separate out white
Solid, filters, and filter cake ether washs 2 times, is dried to obtain 0.205g white solid (5a), mp:112 DEG C, productivity 95.2%.
1H NMR (400MHz, DMSO) δ: 1.19 (t, J=16Hz, 3H, CH3),2.79(s,3H,CH3),3.35(s,6H,N
(CH3)2),4.24-4.28(m,2H,CH2),4.60(s,2H,CH2),4.89(s,2H,CH2),6.85-7.30(m,5H,ArH),
8.01(s,1H,ArH),9.34(s,1H,OH).
Embodiment 20
6-bromo-5-hydroxyl-4-dimethylamine methyl-2-(4-methyl-benzyl)-1-Methyl-1H-indole-3-carboxylic acid, ethyl ester hydrochloric acid
The synthesis of salt (5b)
With being distinguished as of embodiment 19: compound 4a is replaced with compound 4b, obtain 0.221g white solid (5b),
Mp:196 DEG C, productivity 97.3%.
1H NMR (400MHz, DMSO) δ: 1.20 (t, J=16Hz, 3H, CH3),2.25(s,3H,CH3),2.51(s,3H,
CH3),2.75(s,6H,N(CH3)2),3.64(s,2H,CH2),4.23-4.26(m,2H,CH2),4.52(s,2H,CH2),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
1-methyl-6-bromo-5-hydroxyl-4-dimethylamine methyl-2-(4-methoxy-benzyl)-1H-indole-3-carboxylic acid's ethyl ester salt
The synthesis of hydrochlorate (5c)
With being distinguished as of embodiment 19: compound 4a is replaced with compound 4c, obtain 0.218g white solid (5c),
Mp:200 DEG C, productivity 95.3%.
1H NMR (400MHz, DMSO) δ: 1.21 (t, J=12Hz, 3H, CH3),2.73(s,6H,N(CH3)2),3.64(s,
3H,CH3),3.70(s,3H,CH3),4.24-4.28(m,2H,CH2),4.49(s,2H,CH2),4.79(s,2H,CH2),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
1-methyl-6-bromo-5-hydroxyl-4-dimethylamine methyl-2-(4-chlorobenzyl)-1H-indole-3-carboxylic acid's carbethoxy hydrochloride
(5d) synthesis
With being distinguished as of embodiment 19: compound 4a is replaced with compound 4d, obtain 0.206g white solid (5d), m:
146 DEG C of productivity 925%
1H NMR (400MHz, DMSO) δ: 1.16 (t, J=12Hz, 3H, CH3),2.78(s,6H,N(CH3)2),3.66(s,
3H,CH3),4.23-4.25(m,2H,CH2),4.58(s,2H,CH2),4.94(s,2H,CH2), 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
1-methyl-6-bromo-5-hydroxyl-4-dimethylamine methyl-2-(4-luorobenzyl)-1H-indole-3-carboxylic acid's carbethoxy hydrochloride
(5e) synthesis
With being distinguished as of embodiment 19: compound 4a is replaced with compound 4e, obtain 0.210g white solid (5e),
Mp:194 DEG C, productivity 91.4%.
1H NMR (400MHz, DMSO) δ: 1.18 (t, J=12Hz, 3H, CH3),2.78(s,6H,N(CH3)2),3.67(s,
3H,CH3),4.23-4.28(m,2H,CH2),4.57(s,2H,CH2),4.92(s,2H,CH2),7.11-7.19(m,4H,ArH),
8.01(s,1H,ArH),9.37(s,1H,OH).
Application examples 1
1. by embodiment 1,2,3.......15, compound, Abiduoer and the Ah ratio of 17.......21,22,23 synthesis
Duo Er hydrochlorate is dissolved in DMSO respectively and is configured to the solution that concentration is 2mM；
2. 293T-Gluc cell is inoculated in 96 orifice plates, every hole 7 × 105Individual, 100 μ L systems, after inoculation, cell is placed in
37 DEG C, 5%CO2Incubator is hatched；
3., after cell inoculation 24h, it is 20 μMs that solution step 1. prepared is added separately in cell be configured to concentration
Solution, arranges 3 multiple holes.After adding the solution 2h that 1. step prepares, influenza virus A/WSN/33 is diluted in serum-free
In DMEM, with MOI=0.05 infection cell, infection system is 10 μ L, and infection system includes TPCK-trypsin, and it is at final body
In system, concentration is 1 μ g/mL；
4. after infecting 24h, draw cell supernatant 10 μ L, measure Gluc activity；
The most often group experiment all arranges positive controls (uninfecting virus, without drug treating) and negative control group (infects disease
Poison, without drug treating), suppression ratio=(negative control group-sample sets)/(negative control group-positive controls) × 100%；
6. the IC of medicine50Calculate and completed by software GraphPad.
Experimental result is shown in Fig. 1.
Claims (7)
1. class Abiduoer analog or its salt, described analog is the compound with formula I structure:
Wherein in formula I:
R1、R2And R3It is each independently selected from C1-4Alkyl；
R4For H or C1-4Acyl group；
X is Cl, Br or I；
Y is CH2；
Ar is phenyl, naphthyl, substituted-phenyl；
The substituent group of described substituted-phenyl is the substituted C in optional position1-4Alkyl, C1-4Alkoxyl, halogen.
Analog the most according to claim 1 or its salt, it is characterised in that there is described in: the salt of formula I structural compounds
For hydrochlorate, sulfate, tosilate or tartrate.
Analog the most according to claim 1 or its salt, it is characterised in that: described R1For C1-4Straight chained alkyl.
Analog the most according to claim 1 or its salt, it is characterised in that: described R2For C1-4Straight chained alkyl.
Analog the most according to claim 1 or its salt, it is characterised in that: described R3For C1-4Straight chained alkyl.
6. the Abiduoer analog described in claim 1,2,3,4 or 5 or the preparation method of its salt, it is characterised in that: described
Method comprises the steps:
1. the compound of the compound of formula and formula is obtained through Suzuki coupling reaction the compound of formula, institute
State R4 ' for C1-4Acyl group；
2. the compound of formula is obtained through phenolic hydroxyl group deprotection the compound of formula；
3. the compound of formula or formula is obtained through Mannich reaction the compound of formula I；
7. the Abiduoer analog described in claim 1,2,3,4 or 5 or the application in preparation Tamiflu of its salt.
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