CN101062909A - HIV-1prolease peptide mimic new inhibitor having biological activity, preparation method and usage - Google Patents
HIV-1prolease peptide mimic new inhibitor having biological activity, preparation method and usage Download PDFInfo
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- CN101062909A CN101062909A CN 200610076169 CN200610076169A CN101062909A CN 101062909 A CN101062909 A CN 101062909A CN 200610076169 CN200610076169 CN 200610076169 CN 200610076169 A CN200610076169 A CN 200610076169A CN 101062909 A CN101062909 A CN 101062909A
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Abstract
The invention discloses a formula (I) compound, which is characterized by the following: setting n as 0, 1, or 2; expressing R1 as phthalimide group, 2-naphthoxy, 3-naphthoxy, phenoxy, 2-metyl group phenoxy, 2-methoxy phenoxy, 3-methoxy phenoxy, 4-methoxy phenoxy, 2, 6-dimethyl phenoxy, 3-nitro group phenoxy, 3-amido phenoxy, 4-nitro group phenoxy, 4-amido phenoxy, 2-nitro group phenoxy, 2-amido phenoxy, indole-3-methylene, tetrazoline group, triazine azoles group, benzosulphimide group and 2-benzoxazoles ketone; expressing R2 as hydrogen atom, C1-C4 alkyl group and -CH2OH; expressing R3 as tert-butyl group, isobutyl group, benzyl group and cyclopropyl metyl group; expressing R4 as -NHCOCH3, methoxy, amido, nitro group, fluorine atom, chlorine atom and bromine atom.
Description
The present invention relates to the HIV-1 prolease peptide mimic new inhibitor.Such inhibitor mainly acts on HIV-1 proteolytic enzyme, can suppress the HIV-1 protease activities, and HIV will produce the not infective virion of tool in infected cells, causes the noninductive malicious particulate of catching an illness to be piled up, thereby reaches antiviral effect.Suppress the ripe experiment in vitro result of HIV-1 and show, do not showing under the toxic dosage, such compound exhibits good antiviral activity.
The homodimer that HIV-1 proteolytic enzyme is made up of two identical peptide chains, each monomer is made up of 99 amino acid, 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 chains.HIV encode in reproduction process two kinds of polyprotein p55 and p160, these two kinds of amyloid protein precursors are cracked into the enzyme with the active and virus-specific of structural protein respectively under the effect of HIV-1pol gene coded protein enzyme.The activity that has suppressed hiv protease, though its progeny virus can produce, but immature and do not have communicablely, can stop the further infection of viral pair cell.Therefore, the specificity lytic activity of hiv protease is most important to this virus replication cycle normal operation and viral virion maturation.The hydrolytic activity that has suppressed HIV-1 proteolytic enzyme, will produce does not have the active virion of infection, reaches antiviral effect.
In the efficient combined strategy of treatment HIV, need one or both proteinase inhibitor and reverse transcriptase inhibitors drug combination.And up to the present, only 7 kinds in the hiv protease inhibitor of drugs approved by FDA, and because virus variation itself and genetic heterogeneity have produced resistance.Therefore, the research of novel protein enzyme inhibitors is hot subject in recent years always.Researching and developing out the novel proteinase inhibitor with anti-drug resistance can increase the scheme of drug combination for highly active antiretroviral therapy, reaches more effective treatment AIDS patient's purpose.At present, the domestic proteinase inhibitor that does not also have independent intellectual property right of China becomes marketed drug, and therefore research and development have the strong needs that the novel protein enzyme inhibitors of independent intellectual property right is the domestic AIDS patient of treatment.
A large amount of proteinase inhibitor has been described in the document.Have antiviral activity, anti-tumor activity has good anti-HIV-1, the activity of HIV-2.
Except The compounds of this invention was novel, they also were proved to be the material of anti-HIV-1 effect effectively.Therefore they can be used for treating AIDS
The present invention more properly relates to (I) compound.
Wherein:
R
1The group of representative is selected from:
Phthalimide-based, 2-naphthyloxy, 3-naphthyloxy, phenoxy group, 2-methylphenoxy, 3-methylphenoxy, 4-methylphenoxy, 2-methoxyl group phenoxy group, 3-methoxyl group phenoxy group, 4-methoxyl group phenoxy group, 2,6-dimethyl phenoxy, 3-nitro-phenoxy, 3-amino-benzene oxygen, 4-nitrophenoxy, 4-amino-benzene oxygen, 2-nitro-phenoxy, 2-amino-benzene oxygen, indoles-3-methylene radical, tetrazole base, triazol radical, benzoic sulfimide base, 2-benzoxazoles ketone group;
R
2The group of representative is selected from:
Hydrogen, straight or branched (C
1-C
4) alkyl ,-CH
2OH ,=CH
2
R
3The group of representative is selected from:
Isobutyl-, the tertiary butyl, ring third methylene radical, benzyl, to methoxy-benzyl;
R
4The group of representative is selected from:
Hydrogen, straight or branched (C
1-C
4) alkyl, methoxyl group ,-NHCOCH
3,-COCH
3, fluorine, chlorine, bromine, nitro, amino;
Letter n represents any one integer among the 0-3;
All compounds and at pharmaceutically acceptable acid or the formed additive salt of alkali,
Undoubtedly:
In pharmaceutically acceptable acid, can not add any hydrochloric acid, cyanogen bromic acid, sulfuric acid, phosphonic acids, acetate, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, dextrocamphoric acid restrictedly mentioned.
According to a kind of favourable change example, preferred substituted R
1Be phthalimide-based, 2,6-dimethyl phenoxy, preferred substituted R
2Be methyl, ethyl, sec.-propyl, isobutyl-, preferred substituted R
3Be isobutyl-, ring third methyl, benzyl, preferred substituted R
4Be amino, methoxyl group ,-NHCOCH
3
According to the present invention, preferred compound is:
(S)-N-((2S, 3R)-4-(4-acetylaminohydroxyphenylarsonic acid N-isobutyl-benzene sulfoamido)-3-hydroxyl-1-benzene butyl-2-)-2-(1, the propionic acid amide of 3-dioxo dihydro-iso indolyl-2-)
N-((2S, 3R)-4-(4-acetylaminohydroxyphenylarsonic acid N-isobutyl-benzene sulfonamido)-3-hydroxyl-1-benzene butyl-2-)-2-(2,6-dimethoxy phenoxy group) ethanamide
N-((2S, 3R)-4-(4-amino-N-encircles the third Methyl benzenesulfonyl amino)-3-hydroxyl-1-benzene butyl-2-)-2-(2,6-dimethoxy phenoxy group) propionic acid amide
Preferred compound and they and pharmaceutically acceptable acid or the formed additive salt of alkali constitute 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 using (II) compound as raw material:
Epoxy alkalescence ring-opening reaction condition according to the routine in the organic synthesis makes this formula (II) compound and (III) compound reaction:
R
2NH
2 (III)
Wherein, R
3Define suc as formula (I).
Obtain formula (IV) compound:
R wherein
3Be as defined above.
According to conventional sulfonylation condition in the organic synthesis, react with (V) compound:
Wherein, R
4Define suc as formula (I).
Obtain formula (VI) compound.
R wherein
3And R
4Be as defined above.
According to the conventional condition that removes carbobenzoxy-(Cbz) in the organic synthesis, reaction obtains formula (VII)
R wherein
3And R
4Be as defined above.
According to the reaction conditions of synthetic peptide bond conventional in the organic synthesis, make this formula (VII) and the reaction of formula (VIII) compound:
R wherein
1And R
2Be as defined above.
Obtain the compound of formula (I).
R wherein
1, R
2, R
3And R
4Be as defined above.
Formula (II), (III), (VIII) compound are the compounds that the currently known methods according to organic synthesis obtains.
The invention still further relates to pharmaceutical composition, comprise at least a formula (I) compound or with pharmaceutically acceptable acid or the formed additive salt of alkali as activeconstituents, independent or pharmaceutically acceptable, inert, nontoxic vehicle or carrier in conjunction with one or more.
In according to drug regimen of the present invention, can mention especially and be applicable to oral, parenteral (intravenously, muscle or subcutaneous), through skin or transdermal, intranasal, rectum, through tongue, through those of eye or respiratory administration, especially tablet or drageeing, Sublingual tablet, cachet, capsule, lozenge, suppository, creme, ointment, skin gel, can be injected into drinkable preparation, aerosol, eye drops or nasal drop etc.
The compounds of this invention has the anti-HIV-1 activity.Therefore the drug regimen that contains at least a formula (I) compound can be used for the treatment of HIV-1.
As medicine, useful dosage is different because of patient age and body weight, route of administration, disease character and seriousness and any other treatment of being accepted.
The following example is set forth and is limited the present invention absolutely not:
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 spectroscopic techniques (NMR, the FAB-mass spectrum according to routine ...) measure.
Embodiment 1 (S)-N-((2S, 3R)-4-(4-acetylaminohydroxyphenylarsonic acid N-isobutyl-benzene sulfoamido)-3-hydroxyl-1-benzene butyl-2-)-2-(1, the propionic acid amide of the different dihydro-iso indolyl of 3-dioxo-2-)
Steps A:
(2S, 3R)-3-hydroxyl-(4-isobutyl amine)-1-benzene butyl-2-amino-carbon acid benzyl ester
Adding (S)-1-in round-bottomed flask ((S)-oxo-2-)-2-styroyl amino-carbon acid benzyl ester 1g (3.36mmol), add Virahol 30ml and isobutylamine 1.7ml under the room temperature, the stirring reaction system, being heated to 68 ℃ reacted 3 hours down, TLC detects (sherwood oil: ethyl acetate=3: 1, v/v), reaction finishes.Be evaporated to Rotary Evaporators dried, column chromatography for separation, with dichloromethane rinse agent wash-out, white solid 1.18g, productive rate is 95%.
Step B:
(2S, 3R)-4-(4-acetylaminohydroxyphenylarsonic acid N-isobutyl-benzene sulfoamido)-3-hydroxyl-1-benzene butyl-2-carbon acid benzyl ester
In round-bottomed flask, add (2S, 3R)-3-hydroxyl-(4-isobutyl amine)-1-benzene butyl-2-amino-carbon acid benzyl ester 1g (2.70mmol), add methylene dichloride 30ml dissolving again, add saturated sodium bicarbonate solution 5ml, stirring at room 16 hours, TLC (methylene dichloride: methyl alcohol=30: 1, v/v) detect, show that reaction finishes separatory, leave standstill, with dichloromethane extraction twice, merge organic layer, drying, be evaporated to dried, column chromatography for separation, use methylene dichloride: methyl alcohol (30: 1, v/v) wash-out, get white solid 1.2g, productive rate is 80%.
Step C:
N-(4-(N-((2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl)-N-isobutyl-sulfoamido) phenyl) ethanamide
With (2S, 3R)-4-(4-acetylaminohydroxyphenylarsonic acid N-isobutyl-benzene sulfoamido)-3-hydroxyl-1-benzene butyl-2-carbon acid benzyl ester 1g (1.76mmol) is dissolved in the 100ml round-bottomed flask that fills 20ml methyl alcohol, the Pd/C and the ammonium formiate 0.4g (7.0mmol) that add 200mg under the room temperature, 40 ℃ of following stirring reactions 30 minutes, TLC (methylene dichloride: methyl alcohol=20: 1) detect, show that reaction finishes, be evaporated to driedly, residue is with the dissolving of ethyl acetate/saturated sodium carbonate solution, and separatory leaves standstill, collected organic layer, drying, be concentrated into dried, column chromatography for separation, get white solid 0.61g, productive rate is 80%.
Step D:
(S)-and 2-(1, the propionic acid of 3-dioxy xylylenimine-2-)
In the 100ml round-bottomed flask, add the 20ml glacial acetic acid, reach (S)-2-alanine 1.78g (20mmol) to wherein adding Tetra hydro Phthalic anhydride 3.05g (20mmol), the backflow reaction system is 2 hours under stirring, stop heating, be cooled to room temperature, be evaporated to dried, column chromatography for separation, use sherwood oil: ethyl acetate=3: 1 wash-outs, get white crystal 3.1g, productive rate is 71%.
Step e:
(S)-N-((2S, 3R)-4-(4-acetylaminohydroxyphenylarsonic acid N-isobutyl-benzene sulfoamido)-3-hydroxyl-1-benzene butyl-2-)-2-(1, the propionic acid amide of 3-dioxo dihydro-iso indolyl-2-)
In filling the 100ml round-bottomed flask of 10ml anhydrous tetrahydro furan, add (S)-2-(1, the propionic acid 77mg (0.35mmol) of 3-dioxy xylylenimine-2-), ice bath is cooled to 0 ℃, in bottle, add HOBT (39mg, 0.35mmol) the following 80mg DCC (0.385mmol) that in batches adds of stirring, make temperature remain on 0 ℃, continue to stir 30 minutes, slow Dropwise 5 ml N-(4-(N-((2R in system again, 3S)-3-amino-2-hydroxyl-4-benzene butyl)-N-isobutyl-sulfoamido) phenyl) ethanamide (0.15g, 0.35mmol) tetrahydrofuran solution, after dropwising, be raised to room temperature reaction 8 hours naturally, TLC detects, show the basic end of reaction, stopped reaction.Suction filtration, filtrate decompression is concentrated into dried, residue with 1N HCl washed twice, is used saturated sodium bicarbonate solution, saturated aqueous common salt washed twice with ethyl acetate/water dissolution then successively, the organic layer anhydrous sodium sulfate drying, be evaporated to driedly, column chromatography for separation is used sherwood oil: ethyl acetate=1: 1 wash-out, get white solid 0.17g, productive rate is 80%.
FAB-MS：635.3(M+H)
+
1H-NMR：(CDCl
3)δ(0.83，0.86，dd，6H，J＝6.84Hz)，1.22(d，3H，J＝7.2Hz)，1.84(m，1H)，2.18(s，3H)，2.80-2.96(m，6H)，3.86(m，1H)，4.10-4.15(m，1H)，6.02(d，1H，J＝8.0Hz)，7.20-7.25(m，5H)，7.53-7.74(m，3H)，7.77-7.84(m，5H).
Embodiment 2 N-((2S, 3R)-4-(4-acetylaminohydroxyphenylarsonic acid N-isobutyl-benzene sulfonamido)-3-hydroxyl-1-benzene butyl-2-)-2-(2,6-dimethoxy phenoxy group) ethanamide
Operation uses 2 with embodiment 1 in step e, 6-dimethyl benzene fluoroacetic acid is a reactant.Productive rate 85%, fusing point is:
FAB-MS：596.3(M+H)
+
1H-NMR：(CDCl
3)δ0.88，0.92(dd，6H，J＝6.58)，1.81(m，1H)，2.03(s，3H)，2.16(s，6H)，2.88-3.18(m，6H)，3.94-4.26(m，4H)，6.90-6.98(m，4H)，7.25-7.29(m，4H)，7.66-7.75(m，4H).
Embodiment 3 (S)-N-((2S, 3R)-4-(4-acetylaminohydroxyphenylarsonic acid N-benzyl benzene sulfonamido)-3-hydroxyl-1-benzene butyl-2-)-2-(1,3-dioxy dihydro-iso indolyl-2-)-4-methylpent acid amides
Operation uses benzylamine as reactant in steps A with embodiment 1, and use (S)-2-in step (1,3-dioxo dihydro-iso indolyl-2-)-the 4-methylvaleric acid is a reactant.Productive rate is 82%.
FAB-MS：711.4(M+H)
+
1H-NMR：(CDCl
3)δ0.82，0.85(dd，6H，6.62)，1.45(m，1H)，1.88(m，1H)，2.13(s，3H)，2.30(m，1H)，2.82-3.05(m，4H)，3.90(m，1H)，4.15(m，1H)，4.49(m，1H)，6.32(d，1H)，7.01-7.10(m，5H)，7.12-7.28(m，5H)，7.60-7.83(m，8H).
The pharmacological research of The compounds of this invention.
Embodiment 5 anticancer shaker tests are tested with KB, Hela, HL-60, BGC and BEL-7402 tumour cell respectively, with mtt assay or srb assay.
Mtt assay: respectively with growth conditions HL-60 good, that be in logarithmic phase, Bel-7402, KB and Hela cell with 1 * 10
4Individual/mL concentration is inoculated in 96 orifice plates, 37 ℃ of 5%CO
2Cultivated 24 hours in the incubator.Abandon old liquid, renew nutrient solution, add the compound of sterilising treatment, continue to cultivate after 48 hours, discard nutrient solution, every hole adds RPMI 1640 (the containing 10% calf serum) nutrient solution that 20mL contains 5mg/mL MTT, continues to cultivate 4 hours.Centrifugal, 2500rpm, 20min, the sucking-off supernatant, room temperature is dried.Add a certain amount of dmso solution purple residue, on 570nm place microplate reader, measure absorption value.
Srb assay: the same with mtt assay.
Respectively with growth conditions HL-60 good, that be in logarithmic phase, Bel-7402, KB and Hela cell with 1 * 10
4Individual/mL concentration is inoculated in 96 orifice plates, 37 ℃ of 5%CO
2Cultivated 24 hours in the incubator.Abandon old liquid, renew nutrient solution, add the compound of sterilising treatment, continue to cultivate after 48 hours, get supernatant, add 100 μ l 10%TCA (Tricholroacetic Acid) in each aperture, leave standstill 5 minutes after, in 4 ℃ place 1 hour fixing.Outwell stationary liquid then, each aperture washes with water 5 times.After the drying at room temperature, every hole adds 0.4%SRB100 μ l, and room temperature was placed after 10 minutes, washes 5 times with 1%HOAc (acetic acid), and dry air adds the every hole of 10mMTris 200 μ l/, the vibration dissolving, and the place measures the OD value in the single wavelength of 540nm
Embodiment 6: suppress HIV-1 and duplicate in vitro tests.
Adopt MT
4Cell and HIV IIIB strain are tested, and the virus quantity of use is divided into 100TCID
50And 1000TCID
50(tissue cultured infection dose).MT
4Medicine under cell and HIV IIIB strain and the various dose was cultivated after 5 days, examined under a microscope CPE (cytopathy---cavity, swelling, fusion etc.).
Set up five groups of experiments:
Contrast: medicine+MT
4Cell
Blank: MT
4Cell+HIV IIIB
Negative control: water+MT
4Cell+HIV IIIB
Positive control: AZT+MT
4Cell+HIV IIIB
Experimental group: medicine+MT
4Cell+HIV IIIB
Claims (8)
1, formula (I) compound:
Wherein:
R
1The group of representative is selected from:
Phthalimide-based, 2-naphthyloxy, 3-naphthyloxy, phenoxy group, 2-methylphenoxy, 3-methylphenoxy, 4-methylphenoxy, 2-methoxyl group phenoxy group, 3-methoxyl group phenoxy group, 4-methoxyl group phenoxy group, 2,6-dimethyl phenoxy, 3-nitro-phenoxy, 3-amino-benzene oxygen, 4-nitrophenoxy, 4-amino-benzene oxygen, 2-nitro-phenoxy, 2-amino-benzene oxygen, indoles-3-methylene radical, tetrazole base, triazol radical, benzoic sulfimide base, 2-benzoxazoles ketone group;
R
2The group of representative is selected from:
Hydrogen, straight or branched (C
1-C
4) alkyl ,-CH
2OH ,=CH
2
R
3The group of representative is selected from:
Isobutyl-, the tertiary butyl, ring third methylene radical, benzyl, to methoxy-benzyl;
R
4The group of representative is selected from:
Hydrogen, straight or branched (C
1-C
4) alkyl, methoxyl group ,-NHCOCH
3,-COCH
3, fluorine, chlorine, bromine, nitro, amino;
Letter n represents any one integer among the 0-3.
2, according to formula (I) compound of claim 1, it is characterized in that R
1Represent 2-benzoxazoles ketone group or 2,6-dimethyl phenoxy or benzoic sulfimide base.
They or itself and pharmaceutically acceptable acid or the formed additive salt of alkali.
3, according to formula (I) compound of claim 1, it is characterized in that R
2Represent hydrogen or sec.-propyl or isobutyl-.It or itself and pharmaceutically acceptable acid or the formed additive salt of alkali.
4, according to formula (I) compound of claim 1, it is characterized in that R
3Represent isobutyl-or encircle third methyl.It or itself and pharmaceutically acceptable acid or the formed additive salt of alkali.
5, according to formula (I) compound of claim 1, it is characterized in that R
4Represent kharophen or amino.It or itself and pharmaceutically acceptable acid or the formed additive salt of alkali.
6,, it is characterized in that using (II) compound as raw material according to the preparation method of formula (I) compound of claim 1:
Epoxy alkalescence ring-opening reaction condition according to the routine in the organic synthesis makes this formula (II) compound and (III) compound reaction:
R
2NH
2 (III)
Wherein, R
3Suc as formula (I) definition,
Obtain formula (IV) compound:
R wherein
3Be as defined above,
According to conventional sulfonylation condition in the organic synthesis, react with (V) compound:
Wherein, R
4Suc as formula (I) definition,
Obtain formula (VI) compound,
R wherein
3And R
4Be as defined above,
According to the conventional condition that removes carbobenzoxy-(Cbz) in the organic synthesis, reaction obtains formula (VII)
R wherein
3And R
4Be as defined above,
According to the reaction conditions that peptide bond conventional in the organic synthesis generates, make this formula (VII) and the reaction of formula (VIII) compound:
R wherein
1, R
2With n be as defined above,
Obtain the compound of formula (I),
R wherein
1, R
2, R
3, R
4With n be as defined above.
7, at least a formula any according to claim 1 to 4 (I) compound is as activeconstituents, independent or pharmaceutically acceptable in conjunction with one or more, inert, the nontoxic pharmaceutical composition that vehicle or carrier constituted.
8, according to the pharmaceutical composition of claim 6 purposes in the preparation anti-AIDS drug.
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|---|---|---|---|
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|---|---|---|---|
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Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101062909A true CN101062909A (en) | 2007-10-31 |
Family
ID=38964221
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|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558883A (en) * | 2018-05-22 | 2018-09-21 | 中国医学科学院医药生物技术研究所 | A kind of nucleic acid base compound or its pharmaceutically acceptable salt and its preparation method and application |
-
2006
- 2006-04-28 CN CN 200610076169 patent/CN101062909A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558883A (en) * | 2018-05-22 | 2018-09-21 | 中国医学科学院医药生物技术研究所 | A kind of nucleic acid base compound or its pharmaceutically acceptable salt and its preparation method and application |
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