CN102406634A - Human immunodeficiency virus (HIV)-1 integrase inhibitor - Google Patents
Human immunodeficiency virus (HIV)-1 integrase inhibitor Download PDFInfo
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- CN102406634A CN102406634A CN201010288737XA CN201010288737A CN102406634A CN 102406634 A CN102406634 A CN 102406634A CN 201010288737X A CN201010288737X A CN 201010288737XA CN 201010288737 A CN201010288737 A CN 201010288737A CN 102406634 A CN102406634 A CN 102406634A
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- hiv
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- integrase inhibitor
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- 239000002850 integrase inhibitor Substances 0.000 title claims abstract description 53
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a human immunodeficiency virus (HIV)-1 integrase inhibitor, which is a ketonic acid integrase inhibitor with an inhibition effect on the HIV-1 integrase inhibitor. The integrase inhibitor has a structure shown in the following general formula (I) as the accompanying drawing. In the general formula (I), A represents hydrogen, or R and R' respectively represent hydrogen or alkyl groups with the carbon atom number being 1 to 5.
Description
Technical field
The present invention relates to the HIV-1 integrase inhibitor, especially keto acid class integrase inhibitor.
Background technology
AIDS (AIDS) is infected by HIV (HIV) and causes that HIV virus is divided into two types: HIV-1 and HIV-2, wherein worldwide 95% infects for HIV-1.The enzyme of encoding viral has three kinds among the HIV-1: reverse transcriptase (Reverse Transcriptase, RT), protease (Protease, PR) and intergrase (Intergrase, IN), these three kinds of enzymes are that HIV duplicates and infects necessary enzyme.Wherein, intergrase only is present in the virus, in mammiferous cell, does not have homologous protein, therefore thinks that integrase inhibitor possibly be nontoxic to human body, and the integrase inhibitor of clinical practice is found in expectation.
At present, being used to treat the medicine that HIV infects through U.S. FDA examining has 28 kinds, and wherein a kind be integrase inhibitor, and it is the Raltegravir (MK-0518) that is developed by U.S. Merck company shown in the formula (1).95% inhibition concentration (the IC of Raltegravir
95) be 33ng/mL (referring to non-patent literature 1).
And, still be in the known GS-9137 (50% inhibition concentration (IC that U.S. Gilead company shown in the formula (2) is arranged of HIV-1 integrase inhibitor in the clinical trial
50GSK-364735 (the IC of the Japanese Shionogi company shown in)＜30nm) and the formula (3)
50=8nM).In addition, also known two HIV-1 integrase inhibitors that get into clinical trials but ended at present: the S-1360 (IC of the Japanese Shionogi company shown in the formula (4)
50Be 20nmol/L) and formula (5) shown in the L-870810 (IC of Merck company
95Be 110ng/mL) (referring to non-patent literature 2～4).
On the other hand, beta-diketon acids and chemical equivalents thereof are identified and have the catalytic activity that suppresses intergrase in vivo.Beta-diketon acid structure have one common 1,3-dicarbonyl structure (but 3 carbonyl enolizations), acidic-group can be carboxyl and bioisostere triazole or tetrazolium.Jagged structure can form bonding with two bivalent metal ions of HIV-1 intergrase, suppresses the catalytic activity of intergrase.
Basic structure
As the beta-diketon acid compounds, can enumerate the for example chemical compound shown in the formula (6), it has integrase inhibiting activities (referring to non-patent literature 5) relatively preferably.
In addition, it is found that, the 7-acyl group-8-hydroxyl-1 among the L-870810 shown in the N-methyl of the MK-0518 shown in the above-mentioned formula (1)-5-hydroxyl-4-Methanamide pyrimidone structure, the above-mentioned formula (5), 6-naphthyridines structure etc. also can be used as substituting of two keto acid structures.
Non-patent literature 1: Yan Shifeng, Zhao Guisen, Sun Jian etc., the progress of HIV-1 integrase inhibitor, Chinese antibiotic magazine, 2007,32 (10), 577-598
Non-patent literature 2:Raltegravir, elvitegravir, and metoogravir:the birth of " me-too " HIV-1integrase inhibitors Erik Serrao; Srinivas Odde; Kavya Ramkumar, Retrovirology 2009,6:25
Non-patent literature 3:Billich A.S-1360Shionogi-GlaxoSmithKline.Curr Opin Investig Drugs, 2003,4 (2): 206-209
Non-patent literature 4:Boyle BA.Recent developments in HIV Research [J] .AIDS Read, 2002,12 (9): 390-394
Non-patent literature 5:Vasu Nair; A; Vinod Uchila and Nouri Neamati; B-Diketo acids with purine nucleobase scaffolds:Novel, selective inhibitors of the strand transfer step of HIV integrase, Bioorg.Med.Chem.Lett.16 (2006) 1920-1923
Summary of the invention
The objective of the invention is to design again one group of chemical compound that contains two keto acid structures, thereby a kind of novel HIV-1 integrase inhibitor is provided.
The inventor has designed one group of chemical compound that contains two two keto acid structures on the basis of understanding structure activity relationship and medicine and enzyme binding pattern in depth, the diverse location of two aromatic rings in the middle of two keto acid structures are connected.Thereby successfully synthesized a series of new chemical compounds, and observed integrase inhibiting activities.
Specifically, the present invention provides following technical scheme.
(1) a kind of HIV-1 integrase inhibitor, it is represented with following general formula (I):
In the general formula (I), A representes hydrogen or general formula (M),
General formula (I) and (M) in, R and R ' represent that independently of one another hydrogen or carbon number are 1～5 alkyl.
(2) like above-mentioned (1) described HIV-1 integrase inhibitor, wherein, the chemical compound shown in the general formula (I) is represented with following general formula (I-1):
In the general formula (I-1), A and R implication are the same.
(3) like above-mentioned (1) described HIV-1 integrase inhibitor, wherein, the chemical compound shown in the general formula (I) is represented with following general formula (I-2):
In the general formula (I-2I), A and R implication are the same.
(4) like above-mentioned (1) described HIV-1 integrase inhibitor, wherein, the chemical compound shown in the general formula (I) is represented with following general formula (I-3):
In the general formula (I-3), A and R implication are the same.
(5) like each described HIV-1 integrase inhibitor of above-mentioned (1)～(4), wherein, A representes hydrogen.
(6) like each described HIV-1 integrase inhibitor of above-mentioned (1)～(4), wherein, A representes general formula (M), and R and R ' represent hydrogen or ethyl independently of one another.
(7) like above-mentioned (6) described HIV-1 integrase inhibitor, wherein, R and R ' represent hydrogen or ethyl simultaneously.
(8) a kind of HIV-1 integrase inhibitor, it is represented with following general formula (II):
In the general formula (II); R representes that hydroxyl, carbon number are 1～6 alkyl amine group, to have or do not have substituent carbon number be 1～20 arylamine group or aralkyl amido; Said substituent group is that carbon number is that 1～6 straight chain shape or straight catenate alkyl or unsaturated alkyl, carbon number are 1～6 alkoxyl, halogen etc.; And, have under the substituent situation on the said aromatic ring, have more than one substituent group.
(9) like above-mentioned (8) described HIV-1 integrase inhibitor, wherein, R representes hydroxyl.
(10) like above-mentioned (8) described HIV-1 integrase inhibitor, wherein, R representes that carbon number is 1～6 alkyl amine group.
(11) like above-mentioned (10) described HIV-1 integrase inhibitor, wherein, R representes methylamino or ethylamino-.
(12) like above-mentioned (8) described HIV-1 integrase inhibitor, wherein, it is 1～12 arylamine group or aralkyl amido that R representes to have or do not have substituent carbon number.
(13) like above-mentioned (12) described HIV-1 integrase inhibitor, wherein, said aryl is a phenyl, and said aralkyl is the benzene alkyl.
(14) a kind of HIV-1 integrase inhibitor, it is represented with following general formula (III):
In the general formula (III); R representes that hydroxyl, carbon number are 1～6 alkyl amine group, to have or do not have substituent carbon number be 1～20 arylamine group or aralkyl amido; Said substituent group is that carbon number is that 1～6 straight chain shape or straight catenate alkyl or unsaturated alkyl, carbon number are 1～6 alkoxyl, halogen etc.; And, have under the substituent situation on the said aromatic ring, have more than one substituent group.
(15) like above-mentioned (14) described HIV-1 integrase inhibitor, wherein, R representes that carbon number is 1～6 alkyl amine group.
(16) like above-mentioned (15) described HIV-1 integrase inhibitor, wherein, R representes methylamino or ethylamino-.
(17) like above-mentioned (8) described HIV-1 integrase inhibitor, wherein, it is 1～12 arylamine group or aralkyl amido that R representes to have or do not have substituent carbon number.
(18) like above-mentioned (12) described HIV-1 integrase inhibitor, wherein, said aryl is a phenyl, and said aralkyl is the benzene alkyl.
(19) like above-mentioned (18) described HIV-1 integrase inhibitor, wherein, the substituent group that has on said phenyl or the benzene alkyl is a methoxyl group.
The specific embodiment
< first series compound >
The inventor has designed the two diketone acid compounds shown in a series of general formulas (I-4), wherein two keto acid structures link to each other with phenyl ring (below be also referred to as first series compound).Through two two keto acids of conversion different the position of substitution on phenyl ring, investigate two diketone acidic groups apart from the different caused variations of different angles to integrase inhibiting activities.
In the general formula (I-4), R and R ' represent that independently of one another hydrogen or carbon number are 1～5 alkyl.
As R and R ', can enumerate hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, tertiary pentyl, neopentyl etc.Wherein, preferred hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, more preferably hydrogen, methyl, ethyl are preferably hydrogen or ethyl especially.
Do not limit two two keto acid structures the position of substitution on phenyl ring is special, specifically can enumerate two diketone acidic groups and be ortho position, a position, para-position independently of one another.Substituent group on the wherein preferred benzyl phenyl ring is the situation of para-position, and also the substituent group on the phenyl ring of preferred phenoxy group is para-position or adjacent situation.
In addition, the inventor has also synthesized the chemical compound of list two keto acid structures, and it is the structure that two keto acids of above-claimed cpd (I-4) side are sloughed single ketones acid, and its structure is shown in general formula (I-5).
R and R ' implication in the general formula (I-5) are the same.
Below with 4-{3-[4-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester and 4-{3-[4-(3-carboxyl-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acid is example, and the synthetic route of of the present invention pair of diketone acid compound (I-4) is described.
[route 1]
A:K
2CO
3, 1-(3-hydroxy benzenes) ethyl ketone, DMF, 70 ℃
B: ethyl oxalate, NaH, toluene, 60 ℃
C:1N NaOH, dioxy hexane H
2O, room temperature.
In addition, single diketone acid compound of the present invention (I-5) for example can synthesize as follows.
[route 2]
Above route is merely example, and those skilled in the art can and suitably change at diketone acidic group the position of substitution on phenyl ring according to substituent group.
< second series chemical compound >
It is parent nucleus, the side chemical compound that is combined with two keto acid structures (below be also referred to as the second series chemical compound) with the quinolinone that the inventor has also synthesized a series of.This chemical compound is represented with following general formula (II).
In the general formula (II); R representes that hydroxyl, carbon number are that 1～6 alkyl amine group, carbon number are 1～20 and can have substituent arylamine group or aralkyl amido; The substituent group that can have on said arylamine group or the aralkyl amido is that carbon number is that 1～6 straight chain shape or straight catenate alkyl or unsaturated alkyl, carbon number are 1～6 alkoxyl, halogen etc.; And, can have more than one substituent group on the aromatic rings.
Chemical compound (II) has kept the architectural feature with intergrase catalytic center metal ion bonding.Select for use on the nitrogen of quinolinone luorobenzyl is replaced, help getting into the elastic ring zone.
Chemical compound (II) when being benzamido group or hydroxyl with R below is an example, provides the synthetic route of second series thing.
When R is benzamido group:
[route 3]
When R is hydroxyl:
[route 4]
< tertiary system row chemical compound >
On the basis of second series chemical compound, the inventor has further carried out structure of modification, has changed two keto acid structures into the keto acid structure, has synthesized chemical compound with following general formula (III) expression (below be also referred to as tertiary system row chemical compound).
In the general formula (III); R representes that hydroxyl, carbon number are that 1～6 alkyl amine group, carbon number are 1～20 and can have substituent arylamine group or aralkyl amido; The substituent group that can have on said arylamine group or the aralkyl amido is that carbon number is that 1～6 straight chain shape or straight catenate alkyl or unsaturated alkyl, carbon number are 1～6 alkoxyl, halogen etc.; And, can have more than one substituent group on the aromatic rings.
Chemical compound (III) is the keto acid structure with two keto acid structure of modification of a side of second series chemical compound, thereby has improved the biological stability of chemical compound greatly.
Chemical compound (III) when being hydroxyl or anilino-with R below is an example, provides the synthetic route of tertiary system rowization thing.
When R is hydroxyl:
[route 5]
When R is anilino-:
[route 6]
Or [route 7]
Embodiment
Below enumerate embodiment and illustrate in greater detail the present invention, but the present invention is not limited to these embodiment.
At first assay method of the present invention is described.
[fusing point]
Fusing point is measured with RY-1 type fusing point appearance (capillary tube method), and temperature is without rectification.
[nuclear magnetic resonance, NMR]
Nuclear magnetic resoance spectrum is with WYS-400 type nmr determination, and TMS is interior mark.
[mass spectrum]
Mass spectrum is measured with VG ZAB-2F and Autospec-Ultima ETOF mass spectrograph.
[infrared]
Infrared employing KBr pressed disc method utilizes Fourier transformation infrared spectrometer: the Nicolet of U.S. power & light company (Thermo) 5700 to measure.
[reagent]
Do not specify if having, be commercially available CP or AR level,, directly use without special processing.
Anhydrous tetrahydro furan: refluxing with sodium, is indicator with the benzophenone, steams after the change basket.
[chromatography]
TLC adopt E.Merck company overlay the silica gel aluminum foil coil (DC-alurolle Kieselgel 60GF254,0.2mm).
Silica gel H, 120-180 order and 200-300 order that VLC or decompression column chromatography adopt Haiyang Chemical Plant, Qingdao to produce.
[mensuration of integrase inhibiting activities]
Adopt the ELISA method to measure medicine and suppress HIV-1 intergrase activity and mechanism of action thereof.
Test material:
1.HIV-IN: this laboratory extracts and preserves.
2. sample treatment: face with before water-soluble or DMSO be made into debita spissitudo, remake 5 times of dilutions, 4 dilution factors.Positive control drug: achyranthes polysaccharide sulphate (S-y), the organic institute in Shanghai provides.
3. donor substrate and target substrate: it is synthetic that the worker is given birth in Shanghai.
Method of testing:
Add the donor substrate behind the diluted sample and encapsulate in 96 orifice plates, and add and contain among the reaction Buffer of genetic engineering target enzyme biotin target substrate, under optimum reaction condition, hatch,, measure 405nm absorption value OD value with biotin labeled alkaline phosphoric acid enzyme system colour developing.
[embodiment 1] 4-{2-[4-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HDL08003) synthetic
Synthesizing of operation (1-1): 1-(4-bromomethyl) 1-Phenylethanone. (HDL08001)
In the 100mL reaction bulb, add melilotal (13.4g, 0.1mol), acetonitrile (300mL), NBS (21.4,0.12mol) and azodiisobutyronitrile (2.7g); Stirring and dissolving, 50 ℃ of 6h of temperature (or the room temperature solar radiation stirred 3 days) in the illumination of reactant liquor 250W infrared lamp keeps, evaporated under reduced pressure; Add the 100mL ethyl acetate, separate out white solid and remove by filter, the mother solution concentrating under reduced pressure; Get light brown oily thing HDL08001 bullion 24.42g, need not make with extra care directly step reaction down.
Refining: column chromatography elution system petroleum ether: ethyl acetate=10: 1 obtains white solid.
(product document: bp105-107 ℃/1.8mm, mp38-39 ℃, yield 47.2%)
Thin layer system: petroleum ether: ethyl acetate=5: 1
1H-NMR(400MHz?CDCl
3)δ7.48～7.95(4H，2d，Ph)，4.50(2H，s，CH
2O)，2.60(3H，s，CH
3)
Synthesizing of operation (1-2): 2-[4-acetyl group benzyloxy] 1-Phenylethanone. (HDL08002)
In the 100mL reaction bulb, add HDL08001 bullion 24.4g, dry DMF 100mL, o-hydroxyacetophenone 13.1g, 55～60 ℃ of stirring reaction 2h of temperature in the porphyrize Anhydrous potassium carbonate 25.7g, mixture; Stop reaction, be chilled to room temperature, stir in the following impouring 800mL frozen water; Mixed liquor is placed solid to be separated out; Solid is separated out in filtration, the washing, dry HDL08002 product bullion brown solid 19.1g.
Refining: bullion adds the 200mL ethyl acetate, active carbon, and 50 ℃ are stirred decolouring in 30 minutes, and recrystallization gets the pure article of product, buff powder, mp113～114 ℃.
Thin layer system: petroleum ether: ethyl acetate=3: 1
1H-NMR (400MHz CD
3OD) δ 6.95～8.00 (8H, m, 2Ph), 5.25 (2H, s, CH
2O), 2.55,2.52 (6H, 2s, 2CH
3); IR: (KBr) v
Max(1667.9 ketone carbonyl)
Operation (1-3): 4-{2-[4-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HDL08003) synthetic
In the 100mL reaction bulb, add 3.22g (12mmol) HDL08002,42mL dry tetrahydrofuran, 4.38g (30mmol) ethyl oxalate, add 2.04g (30mmol) Sodium ethylate down, add the back and keep stirring at room reaction 2h, stop reaction in nitrogen environment.
Filter, residue washs 20mL * 3 with normal hexane, washes the back solid and is powder, goes into to add in the beaker 100mL1NHCl stirring at room 1h, and solids filtered is washed to PH5, dry the HDL08003 product, buff powder 5.1g, mp98～100 ℃, yield 90.8%.
Thin layer system: toluene: methanol=2: 1 (mixed liquor 1mL+1dHOAC)
1H-NMR (400MHz CD
3COCD
3) δ 7.13～8.16 (10H, m, 2Ph+2
CH=C (OH)), 5.47 (2H, s, CH
2O), 4.36 (2H, q,
CH 2 CH
3), 4.27 (2H, q,
CH 2 CH
3), 1.36 (3H, t, CH
2 CH 3 ), 1.24 (3H, t, CH
2 CH 3 ); ESI-MS:m/z 469 (M+H)
+IR: (KBr) v
Max(1724.8 ester carbonyl group), 1606.8 (ketone carbonyls)
[embodiment 2] 4-{2-[4-(3-carboxyl-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acid (HDL08004E) synthetic
In reaction bulb, add under 0.234g (0.5mmol) HDL08003,5mL oxolane/methanol=1: 1 mixed solution, the psychrolusia and drip the 2.5mL1N sodium hydroxide solution, add the back and keep stirring at room reaction 5 hours, stop reaction.
In the reactant liquor impouring 10mL water, wash 10mL * 3, wash the back water and under the ice-water bath cooling, be neutralized to PH2～3, filter the pale yellow powder of separating out with 2NHCl with ethyl acetate, a small amount of washing, vacuum is drained, and obtains the HDL08004E bullion.
Refining: bullion adds the 1N dissolution of sodium hydroxide, but the reuse ethyl acetate is washed in case of necessity, and with activated carbon decolorizing 30 minutes, 2NHCl transferred to PH3, a small amount of washing, and vacuum is drained, must pure article buff powder.
Thin layer system: toluene: methanol: glacial acetic acid=5: 5: 1
1H-NMR(400MHz?DMSO)δ7.06～8.00(8H，m，2Ph)，5.30(2H，s，CH
2O)；
FAB-MS:m/z 413 (M+H)
+ESI-high-resolution MS C
21H
16O
9
Synthesizing of [embodiment 3] 4-[2-(4-acetyl group benzyloxy) phenyl]-2-hydroxyl-4-oxygen but-2-ene acid (HDL08004D)
In reaction bulb, add under 1.404g (3mmol) HDL08003,30mL oxolane/methanol=1: 1 mixed solution, the psychrolusia and drip the 15mL1N sodium hydroxide solution, add the back and keep stirring at room reaction 4 days, stop reaction.
In the reactant liquor impouring 60mL water, wash 60mL * 3, wash the back water and under the ice-water bath cooling, be neutralized to PH3～4, filter the pale yellow powder of separating out with 2NHCl with ethyl acetate, a small amount of washing, vacuum is drained, and obtains the HDL08004D bullion.
Refining: bullion adds the 1N dissolution of sodium hydroxide, but the reuse ethyl acetate is washed in case of necessity, and with activated carbon decolorizing 30 minutes, 2NHCl transferred to PH3～4, a small amount of washing, and vacuum is drained, must pure article buff powder.
Thin layer system: toluene: methanol: glacial acetic acid=5: 5: 1
1H-NMR(400MHz?DMSO)δ7.14～8.15(8H，m，2Ph)，5.27(2H，d，CH
2O)，4.29(2H，q，
CH 2 CH
3)，1.30(3H，t，CH
2 CH 3 )；FAB-MS：m/z?485(M+2Na)
+；
Synthesizing of [embodiment 4] other pairs diketone acid compound
Synthetic mesophase chemical compound at first.
1-(3-bromomethyl) 1-Phenylethanone. (HJ08001) can be with reference to 1-(4-bromomethyl) 1-Phenylethanone. (HDL08001) synthetic, utilize that similarly method is synthetic with embodiment 1 operation (1-1);
4-[4-acetyl group benzyloxy] 1-Phenylethanone. (HDD08002),
2-[3-acetyl group benzyloxy] 1-Phenylethanone. (HJL08002),
3-[3-acetyl group benzyloxy] 1-Phenylethanone. (HJJ08002),
4-[3-acetyl group benzyloxy] 1-Phenylethanone. (HJD08002) can be with reference to 2-[4-acetyl group benzyloxy] 1-Phenylethanone. (HDL08002) synthetic, utilize that similarly method is synthetic with embodiment 1 operation (1-2), the spectrum analysis result sees table 1.
[table 1]
As A in the general formula (I) is the chemical compound that general formula (M) and R and R ' represent ethyl simultaneously,
4-{3-[4-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester,
4-{4-[4-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HDD08003),
4-{2-[3-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HJL08003),
4-{3-[3-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HJJ08003),
4-{4-[3-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HJD08003) can be with reference to 4-{2-[4-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HDL08003) synthetic; Utilize with the similar method of embodiment 1 operation (1-3) and synthesize, the spectrum analysis result sees table 2.
And, be the chemical compound that general formula (M) and R and R ' represent hydrogen simultaneously as A in the general formula (I),
4-{4-[4-(3-carboxyl-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acid (HDD08004),
4-{2-[3-(3-carboxyl-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acid (HJL08004),
4-{3-[3-(3-carboxyl-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acid (HJJ08004),
4-{4-[3-(3-carboxyl-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acid (HJD08004) can be with reference to 4-{2-[4-(3-carboxyl-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl }-2-hydroxyl-4-oxygen but-2-ene acid (HDL08004E) synthetic; Utilize with embodiment 2 similar methods and synthesize, the spectrum analysis result sees table 2.
[table 2]
Synthesizing of [embodiment 5] second series chemical compound
Synthesize according to following route.
Operation (5-1): 3-acetyl-6-Ethyl formate-4 (1H)-quinolizidine morpholine ketone synthetic
(1.65g, 10mmol) (1.87g 10mmol) mixes, and is heated to 120 ℃ of reaction 10min with the 2-ethoxymethyl methyl ethyl acetoacetate with the para amidocyanogen benzoic Acid ethyl ester.Be chilled to room temperature, form solid, in normal hexane, clay into power, cross and filter the little yellow solid of 2.76g, thick yield 90.5%.Needn't be further purified.
The solid gradation of last step joins in the diphenyl ether that 28mL refluxes (255 ℃), reaction 50min.After being chilled to below 50 ℃, add the 56mL normal hexane, the room temperature after-filtration obtains brown solid 1.66g, thick yield 70.7%.Needn't be further purified.
Operation (5-2): 3-acetyl-6-Ethyl formate-1-(4-fluorobenzene methyl)-4 (1H)-quinolizidine morpholine ketone synthetic
Last step solid adds among the exsiccant 50mL DMF, and (1.33g, 9.6mmol), (3.55g, 19.2mmol), suspension is heated to 100 ℃ of reaction 3h to the 4-fluorobenzyl bromide to add Anhydrous potassium carbonate.After being chilled to room temperature, add the 50mL saturated brine, with ethyl acetate 50mL * 3 time extraction, anhydrous sodium sulfate drying.Boil off solvent, obtain bullion dark brown solid 1.46g, thick yield 61.7%.
Operation (5-3): 3-acetyl-6-formic acid-1-(4-fluorobenzene methyl)-4 (1H)-quinolizidine morpholine ketone synthetic
Add 48mL acetone in the last step bullion, 24mL ethanol, the sodium hydroxide 24mL of 1N, stirring at room 1h, TCL show that raw material point disappears.Add the esterification of 2N hydrochloric acid in the reactant liquor to the PH=2, place in the refrigerator, solid filtering, faint yellow solid 1.31g, thick yield 97.4%.
Operation (5-4): 3-acetyl-6-anilino-formyl-1-(4-fluorobenzene methyl)-4 (1H)-quinolizidine morpholine ketone synthetic
Last step solid (0.08g, 0.25mmol) middle adding 5mL dry methylene chloride, 0.22mL triethylamine, nitrogen protection.Be cooled to-5 ℃, and adding isobutyl ester formyl chloride (0.08g, 0.45mmol), behind the 30min, adding aniline (0.07g, 0.75mmol), stirred overnight at room temperature.
Add 2N hydrochloric acid and transfer about PH=2, add the 20mL saturated aqueous common salt, the 20mL dichloromethane, separatory, organic facies is used anhydrous sodium sulfate drying.Cross column chromatography, obtain the 50mg white solid, yield 51.2%.
m.p.＝243-245℃。FAB-MS(m/z)：451(M+Na)
+。
Synthesizing of operation (5-5): 3-(1,3-diketone-4 butyric acid ethyl ester)-6-anilino-formyl-1-(4-fluorobenzene methyl)-4 (1H)-quinolizidine morpholine ketone
Last step gained solid (0.13mmol) is dissolved among the exsiccant 2mL THF, and the adding ethyl oxalate (33mg, 0.22mmol), nitrogen protection.(16mg 0.22mmol), is heated to 50 ℃ of reaction 30min to the sodium hydride of adding 50% under the room temperature.After being chilled to room temperature, add the 10mL ethyl acetate, 0.15N hydrochloric acid 10mL separatory, organic facies is used anhydrous sodium sulfate drying.
Fling to solvent, cross column chromatography (petrol ether/ethyl acetate) gradient elution, get the 35mg white solid, yield 62.0%.m.p.＝237-239℃。
1H-NMR(DMSO)：δ15.46(brs，1H，NH)，10.53(s，1H，OH)，9.07，7.88(2s，2H，quinolinone)，8.22，7.86(2d，2H，quinolinone)，7.76，7.40(2d，4H，Ph-F)，7.31，7.13，7.09(3m，5H，Ph)，5.83(s，2H，CH
2)，4.28(q，2H，
CH 2 CH
3)，1.30(t，3H，_CH
2 CH 3 )。
Synthesizing of operation (5-6): 3-(1,3-diketone-4 butyric acid)-6-anilino-formyl-1-(4-fluorobenzene methyl)-4 (1H)-quinolizidine morpholine ketone
Add 0.7mL (THF/ methanol=1/1) solution in the last step solid, add the sodium hydroxide solution of 0.35mL 1N, stirring at room 40min, adding 0.15N hydrochloric acid accent PH is about 4, separates out white precipitate.Filtration obtains white solid 25mg, yield 75.8%.Spectrum data is seen table 3.
Likewise synthesize other chemical compounds of second series, spectrum data is seen table 3.
[table 3]
Synthesizing of [embodiment 6] tertiary system row chemical compound
Synthesize according to following route.
Operation (6-1): para amidocyanogen benzoic Acid allyl ester synthetic
Para amidocyanogen benzoic Acid (2.74g, 20mmol) in, add 50mL methanol, 10mL water, (1.12g 20mmol), is stirred to dissolving to potassium hydroxide.Boil off solvent and obtain white solid.With above-mentioned white solid, and bromopropene (2.52g, 22mmol), 80mL DMF, stirred overnight at room temperature is to the complete obiteration of white suspension thing.Cross column chromatography (petroleum ether ethyl acetate) gradient elution, obtain the 3.2g yellow liquid, yield 90.4%.
Operation (6-2): 3-carbethoxyl group-6-allyl formate-4 (1H)-quinolizidine morpholine ketone synthetic
(1.77g, 10mmol) (2.16g 10mmol) mixes, and is heated to 120 ℃ of reaction 1h with 2-ethoxy methylene propanoic acid diethylester with aforesaid liquid.Be chilled to room temperature, form solid, in normal hexane, clay into power, cross and filter the 3.34g light yellow solid, thick yield 96.3%.Needn't be further purified.
The solid gradation of last step joins in the diphenyl ether that 33mL refluxes (255 ℃), reaction 50min.After being chilled to below 50 ℃, add the 66mL normal hexane, the room temperature after-filtration obtains dark brown solid 2.51g, thick yield 86.2%.Needn't be further purified.
Operation (6-3): 3-carbethoxyl group-6-allyl formate-1-(4-fluorobenzene methyl)-4 (1H)-quinolizidine morpholine ketone synthetic
Last step solid adds among the exsiccant 80mL DMF, and (1.60g, 11.4mmol), (5.41g, 25.1mmol), suspension is heated to 100 ℃ of reaction 2.5h to the 4-fluorobenzyl bromide to add Anhydrous potassium carbonate.After being chilled to room temperature, add the 100mL saturated brine, with ethyl acetate 100mL * 3 time extraction, anhydrous sodium sulfate drying.Boil off solvent, cross column chromatography (petroleum ether ethyl acetate) gradient elution, get white solid 2.1g, yield 61.6%.
m.p.＝176-178℃。ESI-MS(m/z)：410(M+H)
+
Operation (6-4): 3-carbethoxyl group-6-formic acid-1-(4-fluorobenzene methyl)-4 (1H)-quinolizidine morpholine ketone synthetic
Last step solid adds 140mL acetone and 140mL acetonitrile, adds triphenyl phosphorus palladium 0.42g, pyrrolidine 1.4g, stirred overnight.
Half solvent is flung in stirring, adds 0.15N hydrochloric acid and transfers about PH=1, separates out solid, crosses and filters khaki solid 1.55g, yield 82.0%.
Operation (6-5): 3-carboxylic acid-6-allyl formate-4 (1H)-quinolizidine morpholine ketone synthetic
Last step solid (0.50g, 1.36mmol) the middle 20mL dry methylene chloride that adds, triethylamine (0.28g, 2.72mmol), nitrogen protection.Be cooled to-10 ℃, and adding isobutyl ester formyl chloride (0.28g, 2.04mmol), behind the 30min, the adding o-chloraniline (0.58g, 4.08mmol), stirred overnight at room temperature.
Add 2N hydrochloric acid and transfer PH=3～4, add the 20mL saturated aqueous common salt, the 40mL dichloromethane, separatory, organic facies is used anhydrous sodium sulfate drying.Cross column chromatography, obtain the 50mg white solid, yield 51.2%.
m.p.＝243-245℃。FAB-MS(m/z)：451(M+Na)
+。
Carry out spectrum analysis, the result sees table 4.
Other chemical compounds of likewise synthetic tertiary system row, spectrum data is seen table 4.
[table 4]
The mensuration of [embodiment 7] integrase inhibiting activities
Adopt the ELISA method, each series compound of the foregoing description 1～6 is suppressed the active mensuration of HIV-1 intergrase.Positive control has used achyranthes polysaccharide sulphate (S-y).Wherein the result of first series compound and second series chemical compound sees table 5, and the result of tertiary system row chemical compound sees table 6.
[table 5]
[table 6]
Claims (19)
1. HIV-1 integrase inhibitor, it is represented with following general formula (I):
In the general formula (I), A representes hydrogen or general formula (M),
General formula (I) and (M) in, R and R ' represent that independently of one another hydrogen or carbon number are 1～5 alkyl.
2. HIV-1 integrase inhibitor as claimed in claim 1, wherein, the chemical compound shown in the general formula (I) is represented with following general formula (I-1):
In the general formula (I-1), A and R implication are the same.
3. HIV-1 integrase inhibitor as claimed in claim 1, wherein, the chemical compound shown in the general formula (I) is represented with following general formula (I-2):
In the general formula (I-2), A and R implication are the same.
4. HIV-1 integrase inhibitor as claimed in claim 1, wherein, the chemical compound shown in the general formula (I) is represented with following general formula (I-3):
In the general formula (I-3), A and R implication are the same.
5. like each described HIV-1 integrase inhibitor of claim 1～4, wherein, A representes hydrogen.
6. like each described HIV-1 integrase inhibitor of claim 1～4, wherein, A representes general formula (M), and R and R ' represent hydrogen or ethyl independently of one another.
7. HIV-1 integrase inhibitor as claimed in claim 6, wherein, R and R ' represent hydrogen or ethyl simultaneously.
8. HIV-1 integrase inhibitor, it is represented with following general formula (II):
In the general formula (II); R representes that hydroxyl, carbon number are 1～6 alkyl amine group, to have or do not have substituent carbon number be 1～20 arylamine group or aralkyl amido; Said substituent group is that carbon number is that 1～6 straight chain shape or straight catenate alkyl or unsaturated alkyl, carbon number are 1～6 alkoxyl, halogen etc.; And, have under the substituent situation on the said aromatic ring, have more than one substituent group.
9. HIV-1 integrase inhibitor as claimed in claim 8, wherein, R representes hydroxyl.
10. HIV-1 integrase inhibitor as claimed in claim 8, wherein, R representes that carbon number is 1～6 alkyl amine group.
11. HIV-1 integrase inhibitor as claimed in claim 10, wherein, R representes methylamino or ethylamino-.
12. HIV-1 integrase inhibitor as claimed in claim 8, wherein, it is 1～12 arylamine group or aralkyl amido that R representes to have or do not have substituent carbon number.
13. HIV-1 integrase inhibitor as claimed in claim 12, wherein, said aryl is a phenyl, and said aralkyl is the benzene alkyl.
14. a HIV-1 integrase inhibitor, it is represented with following general formula (III):
In the general formula (III); R representes that hydroxyl, carbon number are 1～6 alkyl amine group, to have or do not have substituent carbon number be 1～20 arylamine group or aralkyl amido; Said substituent group is that carbon number is that 1～6 straight chain shape or straight catenate alkyl or unsaturated alkyl, carbon number are 1～6 alkoxyl, halogen etc.; And, have under the substituent situation on the said aromatic ring, have more than one substituent group.
15. HIV-1 integrase inhibitor as claimed in claim 14, wherein, R representes that carbon number is 1～6 alkyl amine group.
16. HIV-1 integrase inhibitor as claimed in claim 15, wherein, R representes methylamino or ethylamino-.
17. HIV-1 integrase inhibitor as claimed in claim 8, wherein, it is 1～12 arylamine group or aralkyl amido that R representes to have or do not have substituent carbon number.
18. HIV-1 integrase inhibitor as claimed in claim 12, wherein, said aryl is a phenyl, and said aralkyl is the benzene alkyl.
19. HIV-1 integrase inhibitor as claimed in claim 18, wherein, the substituent group that has on said phenyl or the benzene alkyl is a methoxyl group.
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| CN1548413A (en) * | 2003-05-06 | 2004-11-24 | 中国科学院上海药物研究所 | Beta-diketoacid as dimer compound and its prepn and use |
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| CN1548413A (en) * | 2003-05-06 | 2004-11-24 | 中国科学院上海药物研究所 | Beta-diketoacid as dimer compound and its prepn and use |
Non-Patent Citations (6)
| Title |
|---|
| MARIO SECHI等: "Design and Synthesis of Novel Indole â-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| MARIO SECHI等: "Design and Synthesis of Novel Indole â-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 47, no. 21, 16 September 2004 (2004-09-16), pages 5298 - 5310, XP002515783, DOI: 10.1021/JM049944F * |
| ROBERTO DI SANTO等: "Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design,Synthesis, Biological Activities, and Mechanism of Action", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 49, no. 6, 17 February 2006 (2006-02-17), pages 1939 - 1945 * |
| ROBERTO DI SANTO等: "Novel Quinolinonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design, Synthesis,and Biological Activities", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 51, no. 15, 23 July 2008 (2008-07-23), pages 4744 - 4750 * |
| 陈晓芳 等: "HIV-1整合酶抑制剂的研究进展", 《国外医学药学分册》, vol. 31, no. 2, 30 April 2004 (2004-04-30), pages 65 - 69 * |
| 陈晓芳 等: "喹啉酮酸类化合物的设计合成与抗HIV-1整合酶活性研究", 《药学学报》, vol. 45, no. 2, 12 February 2010 (2010-02-12), pages 263 - 267 * |
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