CN101066957A - 4-hydroxy pyranone compound with substituting aryloxy methyl or arylthio methyl radical in 6-th place and its prepn and use - Google Patents
4-hydroxy pyranone compound with substituting aryloxy methyl or arylthio methyl radical in 6-th place and its prepn and use Download PDFInfo
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Abstract
The present invention is 4-hydroxy pyranone compound with substituting aryloxy methyl or arylthio methyl radical in 6-position and its preparation process and use. The present invention has the structure of the compound shown.
Description
The present invention relates to 6 4-hydroxy pyranone new compound and 6 4-hydroxy pyranone new compounds that the fragrant thiomethyl of quilt replaces that replaced by aryloxy methyl; The present invention also relates to the preparation method and the production method of these new compounds; The invention still further relates to these new compounds in the purposes of making on the antiviral.
Acquired immune deficiency syndrome (AIDS) is the global epidemic disease that is caused by human immunodeficiency virus (HIV), along with aspects such as HIV virusology and molecular biology are discovered that HIV-1 proteolytic enzyme is one of HIV genome key enzyme in reproduction process.HIV-1 proteolytic enzyme is that aspartic acid belongs to proteolytic ferment, by the homodimer that two peptide chains are formed, has the C2 symmetry axis.Its active centre is made up of two β hairpin structure and two aspartic acid-Threonine-glycine fragments that are rich in glycine between two peptide chains.HIV-1 proteolytic enzyme is given HIV-1 infection activity by cutting apart precursor protein, and has suppressed the HIV-1 protease activities or the activity of this enzyme is reduced to extremely low level, and the progeny virus of generation is not just had an infectivity, thereby has stoped the further infection of virus.Therefore design the focus that anti-AIDS drug becomes research recent years at HIV-1 proteolytic enzyme.
6 substituted 4-hydroxy pyranone compounds are the relatively more popular a category of HIV proteinase inhibitor of research recently.Wherein Tipranavir (PNU-140690) has efficiently owing to it, the characteristic of low toxicity and high bioavailability, promise to be the anti-AIDS drug (Turner of a new generation, S.R., et al, J.Med.Chem1998,41,3467), also be in blank in 6 4-hydroxy pyranone compound researchs at home and abroad that replaced by aryloxy methyl or fragrant thiomethyl.
Therefore, we serve as that foundation has designed and synthesized a series of compounds with 6 4-hydroxy pyranone micromolecular compounds that replaced by aryloxy methyl or fragrant thiomethyl and the interactional molecular recognition of HIV-1 proteolytic enzyme and with the molecular docking of AutoDock3.0, and estimate with regard to its restraining effect to the HIV virus replication, the result shows that this compounds has the effect of more tangible anti-HIV replication in vitro.
The present invention more properly relates to the compound of formula (I):
Formula (I)
Wherein:
A is O atom or S atom.
R
1Represent aryl.
R
2Represent hydrogen atom, straight or branched (C
1-C
6) alkyl, cycloalkyl, heterocycle, aryl, aryl-(C
1-C
6) alkyl, the latter's moieties can be a straight or branched.
R
a, R
bRepresent hydrogen atom, straight or branched (C
1-C
6) alkyl, alkoxyl group, halogen, R
a, R
bThe group of representative can be the same or different.
R
cRepresent hydrogen atom, hydroxyl, hydroxyl (C
1-C
6) alkyl, amino, amino (C
1-C
6) alkyl, alkoxyl group, the moieties of each group can be a straight or branched.
This patent comprises the compound of above representative.
---" aryl " is understood that phenyl, naphthyl, tetralyl, dihydro naphthyl, indenyl or 2,3-dihydro indenyl, randomly replaced by one or more identical or different groups separately, substituting group is selected from halogen, hydroxyl, cyano group, nitro, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, amino, straight or branched amino (C
1-C
6) alkyl;--wherein each alkoxyl group part can be a straight or branched--, straight or branched (C
1-C
6) acyl group, straight or branched (C
1-C
6) alkoxy carbonyl, straight or branched (C
1-C
6) alkyl amino-carbonyl and oxo.
---" heterocycle " is understood that saturated or undersaturated list-or two-cyclic group, have aromatics and non-aromatic character, have 5 to 12 annular atomses, contain one, heteroatoms that two or three are identical or different, heteroatoms is selected from oxygen, nitrogen and sulphur, what heterocycle was understood that to choose wantonly is replaced by one or more identical or different substituting groups, and substituting group is selected from halogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, nitro, oxo and amino is (arbitrarily by one or two straight or branched (C
1-C
6) the alkyl replacement).
In heterocycle, can be symbolic and do not add any pyridyl, thienyl, furyl, imidazolyl, 4-H-pyrans-4-ketone, pyrazinyl, pyrimidyl, isoxazolyl, tetrazyl, pyrryl, pyrazolyl, quinolyl, isoquinolyl, quinazolyl, pyrrolidyl, piperidyl, piperazinyl, 1 restrictedly mentioned, 2, the 3-thiadiazolyl group.
According to a kind of favourable change example, preferably formula of the present invention (I) compound is, wherein, and A represention oxygen atom, sulphur atom, R
1, R
2Represent aryl, R
cRepresent hydrogen atom, R
a, R
bRepresent hydrogen atom, straight or branched (C
1-C
6) alkyl, alkoxyl group, halogen, especially advantageously R
1Representative [1] naphthyl or [2] naphthyl or phenyl, R
2Represent phenyl, R
cRepresent hydrogen atom, R
a, R
bRepresent hydrogen atom or chlorine atom or methyl or ethyl or oxyethyl group.
According to the present invention, preferred compound is:
5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-thiophenyl-pyran-2-one
5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2-methylbenzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2-ethylbenzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2-chlorobenzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2,5-dimethyl benzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2,5-diethoxy thiophenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-thiophenyl-pyran-2-one
5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2-methylbenzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2-ethylbenzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2-chlorobenzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2,5-dimethyl benzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2,5-diethoxy thiophenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-thiophenyl-pyran-2-one
5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2-methylbenzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2-ethylbenzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2-chlorobenzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2,5-dimethyl benzene sulfenyl)-pyran-2-one
5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2,5-diethoxy thiophenyl)-pyran-2-one
Preferred compound constitutes the part of complete content of the present invention.
The invention still further relates to the preparation method of formula (I) compound, it is characterized in that use formula (II) compound and formula (III) compound are as raw material:
Formula (II)
Formula (III)
R wherein
1, R
2, A is as defined above.
Under the normal temperature, be solvent with the dehydrated alcohol, in the presence of salt of wormwood, formula (II) compound and formula (III) compound react, and obtain formula (IV) compound:
Formula (IV)
R wherein
1, R
2, A is as defined above.
Under the lucifuge condition, be solvent with the anhydrous tertiary butanol, formula (IV) compound and NBS reaction obtain the formula V compound:
Formula V
R wherein
1, R
2, A is as defined above.
Under the normal temperature, be solvent with the methylene dichloride, in the presence of hexahydropyridine, the reaction of formula V compound and formula (VI) compound:
Formula (VI)
R wherein
a, R
b, R
cBe as defined above.
Obtain formula (I) compound:
The invention still further relates to pharmaceutical composition, comprise at least a formula (I) compound, independent or pharmaceutically acceptable, inert, nontoxic vehicle or carrier in conjunction with one or more as activeconstituents.
In according to pharmaceutical composition of the present invention, can mention especially and be applicable to oral, parenteral (intravenously, muscle or subcutaneous), through skin or transdermal, intranasal, rectum, through those of tongue, particularly tablet or drageeing, capsule, lozenge, suppository, skin gel, injectable formulation etc.
The compounds of this invention has tangible anti-HIV-1 activity.Contain therefore at least a formula (I) compound can be used for anti-HIV-1 virus as the drug regimen of active compound component treatment.
Part of compounds is through the test of vitro inhibition HIV-1 virus replication screening active ingredients, and the result shows that compound has the activity of certain inhibition HIV-1 virus replication.
The following example is used for further specifying the present invention rather than is used for limiting the present invention.
Raw materials used and (or) reagent is known product, or according to the product of known operation preparation.
The structure of compound described in embodiment and the synthesis step is that the spectroscopic techniques (infrared, UV, NMR, MS) according to routine is measured.
Embodiment 15,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-thiophenyl-pyran-2-one
Steps A: phenyl benzene thiomethyl ketone
5.6 gram 2-bromo-, 1 methyl phenyl ketone is dissolved in the 50ml dehydrated alcohol, add salt of wormwood 4.2 grams, stir normal temperature dropping thiophenol 3.1ml down, dropwise back normal-temperature reaction 2h, filtering salt of wormwood, extract with 2 * 30ml saturated nacl aqueous solution after adding the 50ml chloroform in the filtrate, discard water layer, the organic layer anhydrous sodium sulfate drying removes by filter sodium sulfate, the filtrate decompression evaporate to dryness, residue obtains expecting product through purification by silica gel column chromatography.
Step B:5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-pyran-2-one
In the four-hole boiling flask of nitrogen protection; add 1.4g NaH and disperse thing (contain is 60%) in oily matter; the anhydrous THF of 50ml; under 0 ℃, slowly splash into the 3.4ml methyl acetoacetate; after dripping off; continue reaction 15 minutes down at 0 ℃; under 0 ℃, slowly splash into the butyllithium of 15ml 2.4mol/l again; after dripping off, continue reaction 15 minutes down, form the pairs of anion of methyl acetoacetate at 0 ℃; the phenyl benzene thiomethyl ketone that adds the preparation of 3.42g steps A; continue down to react half an hour at 0 ℃, remove ice-water bath, stirred overnight at room temperature.Add 50ml water to reaction solution, stirring at room 3 hours adds the extraction of 50ml anhydrous diethyl ether, use 2 * 30ml anhydrous diethyl ether wash water layer again, discard ether layer, water layer is cooled to 0 ℃, hydrochloric acid with 6mol/l is neutralized to PH2-3, add the 50ml ethyl acetate extraction, use 2 * 30ml ethyl acetate wash water layer again, the combined ethyl acetate layer, use anhydrous sodium sulfate drying, remove by filter sodium sulfate, the filtrate decompression evaporate to dryness obtains expecting product.
Step C:5,6-dihydro-3-bromo-6-phenyl-6-benzene thiomethyl-4-hydroxyl-pyran-2-one
Add product and 2.4gNBS that 3.2g step B obtains in the 50ml anhydrous tertiary butanol, under the lucifuge condition, refluxed 2 hours, evaporated under reduced pressure is removed and is desolvated, and adds 15ml water and 15ml methylene dichloride, extraction, use 2 * 30ml methylene dichloride wash water layer again, the combined dichloromethane layer is used anhydrous sodium sulfate drying, removes by filter sodium sulfate, the filtrate decompression evaporate to dryness obtains expecting product.
Step D:5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-thiophenyl-pyran-2-one
Add the product that 400mg step C obtains in the 20ml methylene dichloride, the 115mg thiophenol is cooled to 0 ℃, slowly drip the 0.10ml hexahydropyridine, remove ice-water bath, room temperature reaction 2 hours, add 20ml water, extraction is used 2 * 15ml methylene dichloride wash water layer, the combined dichloromethane layer again, use anhydrous sodium sulfate drying, remove by filter sodium sulfate, the filtrate decompression evaporate to dryness, residue obtains expecting product through purification by silica gel column chromatography.
White solid
Fusing point: 173-175 ℃
EI-MS：420
1H?NMR(CDCl
3)δ3.38(d，1H)，3.42(d，1H)，3.58(d，1H)，3.62(d，1H)，6.55(d，2H)，6.90(m，3H)，7.17-7.33(m，5H)，7.35-7.50(m，5H)
Embodiment 2:5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2-methylbenzene sulfenyl)-pyran-2-one
Operation uses 2-methylbenzene thiophenol as reactant in step D with embodiment 1.
White crystal
Fusing point: 162-163 ℃
EI-MS：434
1H?NMR(CDCl
3)δ1.25(s，3H)，3.36(d，1H)，3.43(d，1H)，3.57(d，1H)，3.62(d，1H)，6.68(d，2H)，7.05(dd，2H)，7.15-7.30(m，5H).7.32-7.48(m，5H)
Embodiment 3:5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2-ethylbenzene sulfenyl)-pyran-2-one
Operation uses the 2-ethyl thiophenol as reactant in step D with embodiment 1.
White solid
Fusing point: 105-107 ℃
EI-MS：448
1H?NMR(CDCl
3)1.22(t，3H)，2.72(q，2H)，3.38(d，1H)，3.44(d，1H)，3.60(d，1H)，3.65(d，1H)，5.78(d，1H)，6.58(t，1H)，6.98(t，1H)，7.05(d，1H)7.17-7.31(m，5H)，7.33-7.47(m，5H)
Embodiment 4:5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2-chlorobenzene sulfenyl)-pyran-2-one
Operation uses the 2-chlorothio-phenol as reactant in step D with embodiment 1.
White solid
Fusing point: 83-85 ℃
EI-MS：454
1H?NMR(CDCl
3)δ3.36(d，1H)，3.42(d，1H)，3.59(d，1H)，3.62(d，1H)，6.55(d，2H)，6.90(t，2H)，7.10-7.28(m，5H)，7.30-7.45(m，5H)
Embodiment 5:5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2,5-dimethyl benzene sulfenyl)-pyran-2-one
Operation uses 2 with embodiment 1 in step D, the 5-thiophenol dimethyl benzene is as reactant.
White crystal
Fusing point: 156-158 ℃
EI-MS：448
1H?NMR(CDCl
3)δ1.92(s，3H)，2.28(s，3H)，3.37(d，1H)，3.42(d，1H)，3.58d，1H)，3.64(d，1H)，6.78(s，1H)，6.96(d，2H)，7.15-7.30(m，5H)，7.32-7.48(m，5H)
Embodiment 6:5,6-dihydro-6-phenyl-6-benzene thiomethyl-4-hydroxyl-3-(2,5-diethoxy thiophenyl)-pyran-2-one
Operation uses 2 with embodiment 1 in step D, 5-diethoxy thiophenol is as reactant.
White oily matter
EI-MS：508
1H?NMR(CDCl
3)δ1.33(t，6H)，3.38(d，1H)，3.44(d，1H)，3.59(d，1H)，3.62(d，1H)，3.98(t，4H)，6.83(s，1H)，6.90(d，2H)，7.14-7.29(m，5H)，7.33-7.49(m，5H)
Embodiment 7:5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-thiophenyl-pyran-2-one
Steps A: [1] naphthalene oxygen acetophenone
5.6 gram 2-bromo-, 1 methyl phenyl ketone is dissolved in the 50ml dehydrated alcohol, add salt of wormwood 4.2 grams, [1] naphthols 4.4g, stirring at normal temperature 1h, reflux 2h adds 100ml saturated ammonium chloride solution cancellation reaction, extract with 3 * 50ml anhydrous diethyl ether, organic layer is used anhydrous sodium sulfate drying after successively using 3 * 50ml sodium hydroxide solution and 3 * 50ml washing, removes by filter sodium sulfate, the filtrate decompression evaporate to dryness, residue obtains expecting product through purification by silica gel column chromatography.
Step B:5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-pyran-2-one
In the four-hole boiling flask of nitrogen protection; add 1.4g NaH and disperse thing (contain is 60%) in oily matter; the anhydrous THF of 50ml; under 0 ℃, slowly splash into the 3.4ml methyl acetoacetate; after dripping off; continue reaction 15 minutes down at 0 ℃; under 0 ℃, slowly splash into the butyllithium of 15ml 2.4mol/l again; after dripping off, continue reaction 15 minutes down, form the pairs of anion of methyl acetoacetate at 0 ℃; [1] the naphthalene oxygen acetophenone that adds the preparation of 3.93g steps A; continue down to react half an hour at 0 ℃, remove ice-water bath, stirred overnight at room temperature.Add 50ml water to reaction solution, stirring at room 3 hours adds the extraction of 50ml anhydrous diethyl ether, use 2 * 30ml anhydrous diethyl ether wash water layer again, discard ether layer, water layer is cooled to 0 ℃, hydrochloric acid with 6mol/l is neutralized to PH2-3, add the 50ml ethyl acetate extraction, use 2 * 30ml ethyl acetate wash water layer again, the combined ethyl acetate layer, use anhydrous sodium sulfate drying, remove by filter sodium sulfate, the filtrate decompression evaporate to dryness obtains expecting product.
Step C:5,6-dihydro-3-bromo-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-pyran-2-one
Add product and 2.4gNBS that 4.5g step B obtains in the 50ml anhydrous tertiary butanol, under the lucifuge condition, refluxed 2 hours, evaporated under reduced pressure is removed and is desolvated, and adds 15ml water and 15ml methylene dichloride, extraction, use 2 * 30ml methylene dichloride wash water layer again, the combined dichloromethane layer is used anhydrous sodium sulfate drying, removes by filter sodium sulfate, the filtrate decompression evaporate to dryness obtains expecting product.
Step D:5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-thiophenyl-pyran-2-one
Add the product that 430mg step C obtains in the 20ml methylene dichloride, the 115mg thiophenol is cooled to 0 ℃, slowly drip the 0.10ml hexahydropyridine, remove ice-water bath, room temperature reaction 2 hours, add 20ml water, extraction is used 2 * 15ml methylene dichloride wash water layer, the combined dichloromethane layer again, use anhydrous sodium sulfate drying, remove by filter sodium sulfate, the filtrate decompression evaporate to dryness, residue obtains expecting product through purification by silica gel column chromatography.
White solid
Fusing point: 164-166 ℃
EI-MS：454
1H?NMR(CDCl
3)δ3.59(d，1H)，3.90(d，1H)，4.28(d，1H)，4.56(d，1H)，6.60(t，1H)，6.78(d，1H)，7.00(t，2H)，7.35(t，1H)，7.40-7.60(m，10H)，7.63(t，1H)，7.80(d，1H)
Embodiment 8:5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2-methylbenzene sulfenyl)-pyran-2-one
Operation uses 2-methylbenzene thiophenol as reactant in step D with embodiment 7.
White solid
Fusing point: 151-153 ℃
EI-MS：468
1H?NMR(CDCl
3)δ2.38(s，3H)，3.60(d，1H)，3.92(d，1H)，4.28(d，1H)，4.57(d，1H)，6.60(t，1H)，6.78(d，1H)，6.96(t，1H)，7.06(d，1H)，7.38(t，1H)，7.41-7.59(m，7H)，7.65(m，3H)，7.80(d，1H)
Embodiment 9:5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2-ethylbenzene sulfenyl)-pyran-2-one
Operation uses the 2-ethyl thiophenol as reactant in step D with embodiment 7.
White crystal
Fusing point: 102-104 ℃
EI-MS：482
1H?NMR(CDCl
3)δ1.27(t，3H)，2.78(q，2H)，3.62(d，1H)，3.92(d，1H)，4.30(d，1H)，4.58(d，1H)，6.59(t，1H)，6.79(d，1H)，6.98(t，1H)，7.05(d，1H)，7.38(t，1H)，7.39-7.48(m，6H)，7.63(m，3H)，7.82(d，1H)
Embodiment 10:5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2-chlorobenzene sulfenyl) pyran-2-one
Operation uses the 2-chlorothio-phenol as reactant in step D with embodiment 7.
White crystal
Fusing point: 173-175 ℃
EI-MS：488
1H?NMR(CDCl
3)δ3.12(d，1H)，3.46(d，1H)，4.26(d，1H)，4.56(d，1H)，6.61(t，1H)，6.76(d，1H)，7.03(t，2H)，7.34(t，1H)，7.40-7.60(m，10H)，7.65(t，1H)，
Embodiment 11:5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2,5-dimethyl benzene sulfenyl)-pyran-2-one
Operation uses 2 with embodiment 7 in step D, the 5-thiophenol dimethyl benzene is as reactant.
White solid
Fusing point: 176-178 ℃
EI-MS：482
1H?NMR(CDCl
3)δ1.90(s，3H)，2.31(s，3H)，3.60(d，1H)，3.92(d，1H)，4.26(d，1H)，4.53(d，1H)，6.79(t，2H)，6.89(d，1H)，7.31(t，1H)，7.39-7.49(m，6H)，7.65(d，2H)，7.78(t，1H)，8.20(s，1H)
Embodiment 12:5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-(2,5-diethoxy thiophenyl)-pyran-2-one
Operation uses 2 with embodiment 7 in step D, 5-diethoxy thiophenol is as reactant.
White solid
Fusing point: 142-144 ℃
EI-MS：542
1H?NMR(CDCl
3)δ1.40(dt，6H)，3.38(d，1H)，3.76(d，1H)，3.98(q，4H)，4.20(d，1H)，4.40(d，1H)，6.65-6.82(m，3H)，7.08(d，1H)，7.30(t，2H)，7.40-7.58(m，6H)，7.80(t，1H)，8.18(t，1H)，8.96(s，1H)
Embodiment 13:5,6-dihydro-6-phenyl-6-[1] naphthalene oxygen methyl-4-hydroxyl-3-thiophenyl-pyran-2-one
Steps A: [2] naphthalene oxygen acetophenone
5.6 gram 2-bromo-, 1 methyl phenyl ketone is dissolved in 50ml acetone, add salt of wormwood 4.2 grams, [2] naphthols 4.4g, normal temperature 1h, reflux 2h adds 100ml saturated ammonium chloride solution cancellation reaction, extract with 3 * 50ml anhydrous diethyl ether, organic layer is used anhydrous sodium sulfate drying after successively using 3 * 50ml sodium hydroxide solution and 3 * 50ml washing, removes by filter sodium sulfate, the filtrate decompression evaporate to dryness, residue obtains expecting product through purification by silica gel column chromatography.
Step B:5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-pyran-2-one
In the four-hole boiling flask of nitrogen protection; add 1.4g NaH and disperse thing (contain is 60%) in oily matter; the anhydrous THF of 50ml; under 0 ℃, slowly splash into the 3.4ml methyl acetoacetate; after dripping off; continue reaction 15 minutes down at 0 ℃; under 0 ℃, slowly splash into the butyllithium of 15ml 2.4mol/l again; after dripping off, continue reaction 15 minutes down, form the pairs of anion of methyl acetoacetate at 0 ℃; [2] the naphthalene oxygen acetophenone that adds the preparation of 3.93g steps A; continue down to react half an hour at 0 ℃, remove ice-water bath, stirred overnight at room temperature.Add 50ml water to reaction solution, stirring at room 3 hours adds the extraction of 50ml anhydrous diethyl ether, use 2 * 30ml anhydrous diethyl ether wash water layer again, discard ether layer, water layer is cooled to 0 ℃, hydrochloric acid with 6mol/l is neutralized to PH2-3, add the 50ml ethyl acetate extraction, use 2 * 30ml ethyl acetate wash water layer again, the combined ethyl acetate layer, use anhydrous sodium sulfate drying, remove by filter sodium sulfate, the filtrate decompression evaporate to dryness obtains expecting product.
Step C:5,6-dihydro-3-bromo-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-pyran-2-one
Add product and 2.4gNBS that 4.5g step B obtains in the 50ml anhydrous tertiary butanol, under the lucifuge condition, refluxed 2 hours, evaporated under reduced pressure is removed and is desolvated, and adds 15ml water and 15ml methylene dichloride, extraction, use 2 * 30ml methylene dichloride wash water layer again, the combined dichloromethane layer is used anhydrous sodium sulfate drying, removes by filter sodium sulfate, the filtrate decompression evaporate to dryness obtains expecting product.
Step D:5,6-dihydro-6-phenyl-6-[2] add the product that 430mg step C obtains in naphthalene oxygen methyl-4-hydroxyl-3-thiophenyl-pyran-2-one 20ml methylene dichloride, the 115mg thiophenol, be cooled to 0 ℃, slowly drip the 0.10ml hexahydropyridine, remove ice-water bath, room temperature reaction 2 hours adds 20ml water, extraction, use 2 * 15ml methylene dichloride wash water layer again, the combined dichloromethane layer is used anhydrous sodium sulfate drying, removes by filter sodium sulfate, the filtrate decompression evaporate to dryness, residue obtains expecting product through purification by silica gel column chromatography.
White solid
Fusing point: 182-184 ℃
EI-MS：454
1H?NMR(CDCl
3)δ3.48(d，1H)，3.90(d，1H)，4.18(d，1H)，4.44(d，1H)，6.60(d，1H)，6.88(t，1H)，7.01(t，2H)，7.34(t，1H)，7.42-7.58(m，10H)，7.60(t，1H)，7.80(d，1H)
Embodiment 14:5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2-methylbenzene sulfenyl)-pyran-2-one
Operation uses 2-methylbenzene thiophenol as reactant in step D with embodiment 13.
White crystal
Fusing point: 92-94 ℃
EI-MS：468
1H?NMR(CDCl
3)δ2.38(s，3H)，3.50(d，1H)，3.90(d，1H)，4.20(d，1H)，4.48(d，1H)，6.60(t，1H)，6.96(t，1H)，7.06(t，2H)，7.20(d，1H)，7.30-7.54(m，5H)，7.60-7.74(m，4H)，7.72-7.82(m，2H)
Embodiment 15:5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2-ethylbenzene sulfenyl)-pyran-2-one
Operation uses the 2-ethyl thiophenol as reactant in step D with embodiment 13.
White crystal
Fusing point: 150-152 ℃
EI-MS：482
1H?NMR(CDCl
3)δ1.24(t，3H)，2.75(q，2H)，3.50(d，1H)，3.90(d，1H)，4.18(d，1H)，4.44(d，1H)，6.59(t，1H)，6.78(d，1H)，6.96(t，1H)，7.05(d，1H)，7.36(t，1H)，7.39-7.48(m，6H)，7.65(m，3H)，7.81(d，1H)
Embodiment 16:5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2-chlorobenzene sulfenyl) pyran-2-one
Operation uses the 2-chlorothio-phenol as reactant in step D with embodiment 13.
White crystal
Fusing point: 65-67 ℃
EI-MS：488
1H?NMR(CDCl
3)δ3.48(d，1H)，3.88(d，1H)，4.20(d，1H)，4.46(d，1H)，6.65(t，1H)，6.78d，1H)，7.05(t，2H)，7.32(t，1H)，7.43-7.61(m，10H)，7.66(t，1H)，
Embodiment 17:5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2,5-dimethyl benzene sulfenyl)-pyran-2-one
Operation uses 2 with embodiment 13 in step D, the 5-thiophenol dimethyl benzene is as reactant.
White solid
Fusing point: 73-75 ℃
EI-MS：482
1H?NMR(CDCl
3)δ1.95(s，3H)，2.34(s，3H)，3.48(d，1H)，3.95(d，1H)，4.18(d，1H)，4.45(d，1H)，6.79(d，1H)，6.99(d，1H)，7.10(s，1H)，7.20(d，1H)，7.39-7.53(m，5H)，7.60-7.81(m，5H)
Embodiment 18:5,6-dihydro-6-phenyl-6-[2] naphthalene oxygen methyl-4-hydroxyl-3-(2,5-diethoxy thiophenyl)-pyran-2-one
Operation uses 2 with embodiment 13 in step D, 5-diethoxy thiophenol is as reactant.
White solid
Fusing point: 135-137 ℃
EI-MS：542
1H?NMR(CDCl
3)δ1.40(dt，6H)，3.25(d，1H)，3.75(d，1H)，3.98(q，4H)，4.10(d，1H)，4.38(d，1H)，6.78(m，2H)，7.10(m，3H)，7.23-7.58(m，5H)，7.60-7.81(m，3H)，8.98(s，1H)
The pharmacological research of The compounds of this invention.
Embodiment 19: suppress HIV-1 and duplicate experiment in vitro.
The MT that growth conditions is good
4It is 40 * 10 that cell is made into concentration
5The cell suspension of individual/milliliter, every hole 100 microlitres add 96 orifice plates.Medicine filtration sterilization to be measured is carried out serial dilution (1.0 μ M, 0.5 μ M, 0.25 μ M, 0.125 μ M, 0.0625 μ M, 0.03125 μ M) with the RPMI1640 nutrient solution, and every hole 50 μ L add in 96 orifice plates.Adding titre again is respectively 100TCID
50And 1000TCID
50The HIV-150 μ L of (tissue cultured infectiondose), 4 multiple holes are done in every kind of drug level and virus titer combination.If positive control (AZT+MT
4Cell+HIV-1), negative control (water+MT
4Cell+HIV-1), drug toxicity contrast (medicine+MT
4Cell) and blank (MT
4Cell+HIV-1).At 37 ℃, 5%CO
2Cultivated 7 days under the condition.Every day is the observation of cell growing state regularly, cultivates the 3rd day every hole and adds 50 μ L fresh cultures, the 6th day observation of cell pathology (CPE).
All experiment is carried out in 3 grades of (BSL-3) laboratories of Biosafety according to working specification, repeats twice.Calculate inhibiting rate and IC
50
Claims (9)
1. the compound of formula (I) expression:
Wherein:
A is O atom or S atom.
R
1Represent aryl.
R
2Represent hydrogen atom, straight or branched (C
1-C
6) alkyl, cycloalkyl, heterocycle, aryl, aryl-(C
1-C
6) alkyl, the latter's moieties can be a straight or branched.
R
a, R
bRepresent hydrogen atom, straight or branched (C
1-C
6) alkyl, alkoxyl group, halogen, R
a, R
bThe group of representative can be the same or different.
R
cRepresent hydrogen atom, hydroxyl, hydroxyl (C
1-C
6) alkyl, amino, amino (C
1-C
6) alkyl, alkoxyl group, the moieties of each group can be a straight or branched.
This patent comprises the compound of above representative.
---" aryl " is understood that phenyl, naphthyl, tetralyl, dihydro naphthyl, indenyl or 2,3-dihydro indenyl, randomly replaced by one or more identical or different groups separately, substituting group is selected from halogen, hydroxyl, cyano group, nitro, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, amino, straight or branched amino (C
1-C
6) alkyl;--wherein each alkoxyl group part can be a straight or branched--, straight or branched (C
1-C
6) acyl group, straight or branched (C
1-C
6) alkoxy carbonyl, straight or branched (C
1-C
6) alkyl amino-carbonyl and oxo.
---" heterocycle " is understood that saturated or undersaturated list-or two-cyclic group, have aromatics and non-aromatic character, have 5 to 12 annular atomses, contain one, heteroatoms that two or three are identical or different, heteroatoms is selected from oxygen, nitrogen and sulphur, what heterocycle was understood that to choose wantonly is replaced by one or more identical or different substituting groups, and substituting group is selected from halogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, nitro, oxo and amino is (arbitrarily by one or two straight or branched (C
1-C
6) the alkyl replacement).
In heterocycle, can be symbolic and do not add any pyridyl, thienyl, furyl, imidazolyl, 4-H-pyrans-4-ketone, pyrazinyl, pyrimidyl, isoxazolyl, tetrazyl, pyrryl, pyrazolyl, quinolyl, isoquinolyl, quinazolyl, pyrrolidyl, piperidyl, piperazinyl, 1 restrictedly mentioned, 2, the 3-thiadiazolyl group.
2 formulas according to claim 1 (I) compound is characterized in that A is a Sauerstoffatom, R
1, R
2Represent aryl, R
1, R
2Can be identical or different.
3 formulas according to claim 1 (I) compound is characterized in that A is a sulphur atom, R
1, R
2Represent aryl, R
1, R
2Can be identical or different.
4 formulas according to claim 1 (I) compound is characterized in that R
aRepresent hydrogen atom, chlorine atom, methyl, ethyl, oxyethyl group, R
bRepresent hydrogen atom, methyl, oxyethyl group, R
cRepresent hydrogen atom.
5 formulas according to claim 2 (I) compound is characterized in that R
1Representative [1] naphthyl, [2] naphthyl, R
2Represent phenyl.
6 formulas according to claim 3 (I) compound is characterized in that R
1Represent phenyl, R
2Represent phenyl.
The preparation method of 7 formulas (I) compound is characterized in that use formula (II) compound and formula (III) compound are as raw material:
R wherein
1, R
2, A is as defined above.
Such compound comprises following process:
Under the normal temperature, be solvent with the dehydrated alcohol, in the presence of salt of wormwood, formula (II) compound and formula (III) compound react, and obtain formula (IV) compound:
R wherein
1, R
2, A is as defined above.
Under the lucifuge condition, be solvent with the anhydrous tertiary butanol, formula (IV) compound and NBS reaction obtain the formula V compound:
R wherein
1, R
2, A is as defined above.
Under the normal temperature, be solvent with the methylene dichloride, in the presence of hexahydropyridine, the reaction of formula V compound and formula (VI) compound:
R wherein
a, R
b, R
cBe as defined above.
Obtain formula (I) compound:
8 pharmaceutical compositions comprise at least a formula any according to claim 1 to 6 (I) compound as activeconstituents, independent or pharmaceutically acceptable in conjunction with one or more, inert, nontoxic vehicle or carrier.
9 according to Claim 8 pharmaceutical compositions comprise at least a activeconstituents any according to claim 1 to 6, are used for antiviral therapy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710086628 CN101066957A (en) | 2007-03-27 | 2007-03-27 | 4-hydroxy pyranone compound with substituting aryloxy methyl or arylthio methyl radical in 6-th place and its prepn and use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710086628 CN101066957A (en) | 2007-03-27 | 2007-03-27 | 4-hydroxy pyranone compound with substituting aryloxy methyl or arylthio methyl radical in 6-th place and its prepn and use |
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|---|---|
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Family
ID=38879675
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|---|---|---|---|
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|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333092A (en) * | 2013-06-17 | 2013-10-02 | 温州大学 | Synthesis method of 1-thiophenyl-2-isonaphthol compound |
| CN103333093A (en) * | 2013-06-17 | 2013-10-02 | 温州大学 | Synthesis method of 1-arylsulfenylnaphthalene compound |
| WO2019170050A1 (en) * | 2018-03-06 | 2019-09-12 | 云南大学 | 2-thiomethylpyrazolopyrimidinone compound, preparation method thereof, pharmaceutical composition and application thereof |
-
2007
- 2007-03-27 CN CN 200710086628 patent/CN101066957A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333092A (en) * | 2013-06-17 | 2013-10-02 | 温州大学 | Synthesis method of 1-thiophenyl-2-isonaphthol compound |
| CN103333093A (en) * | 2013-06-17 | 2013-10-02 | 温州大学 | Synthesis method of 1-arylsulfenylnaphthalene compound |
| WO2019170050A1 (en) * | 2018-03-06 | 2019-09-12 | 云南大学 | 2-thiomethylpyrazolopyrimidinone compound, preparation method thereof, pharmaceutical composition and application thereof |
| US11447470B2 (en) | 2018-03-06 | 2022-09-20 | Yunnan University | Pyrimidinone-containing compound, preparation method thereof, pharmaceutical composition and application thereof |
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