CN102406634B - Hiv-1 integrase inhibitor - Google Patents
Hiv-1 integrase inhibitor Download PDFInfo
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- CN102406634B CN102406634B CN201010288737.XA CN201010288737A CN102406634B CN 102406634 B CN102406634 B CN 102406634B CN 201010288737 A CN201010288737 A CN 201010288737A CN 102406634 B CN102406634 B CN 102406634B
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- NINTYYVJSMXACR-WQRHYEAKSA-N O/C(/C(O)=O)=C\C(C(N(Cc1ccccc1)C1=O)=Nc2c1nc[n]2Cc1ccccc1)=O Chemical compound O/C(/C(O)=O)=C\C(C(N(Cc1ccccc1)C1=O)=Nc2c1nc[n]2Cc1ccccc1)=O NINTYYVJSMXACR-WQRHYEAKSA-N 0.000 description 1
Abstract
The invention provides HIV-1 integrase inhibitor, it is Mek-Tol Unit integrase inhibitor, inhibited to HIV-1 intergrase.Described integrase inhibitor has the structure described in following general formula (I).In general formula (I), A represent hydrogen or
r and R ' represents that hydrogen or carbon number are the alkyl of 1 ~ 5 independently of one another.
Description
Technical field
The present invention relates to HIV-1 integrase inhibitor, especially Mek-Tol Unit integrase inhibitor.
Background technology
Acquired immune deficiency syndrome (AIDS) (AIDS) is infected by HIV (human immunodeficiency virus) (HIV) and causes, and HIV virus is divided into two classes: HIV-1 and HIV-2, and wherein worldwide 95% is HIV-1 infection.In HIV-1, the enzyme of encoding viral has three kinds: reverse transcriptase (Reverse Transcriptase, RT), protease (Protease, PR) and intergrase (Intergrase, IN), these three kinds of enzymes are that HIV copies and infects necessary enzyme.Wherein, intergrase is only present in virus, in mammiferous cell, do not have homologous protein, therefore thinks that integrase inhibitor may be nontoxic to human body, expects the integrase inhibitor finding clinical practice.
At present, examined by U.S. FDA and the medicine that is used for the treatment of HIV has 28 kinds, wherein a kind is integrase inhibitor, and it is the Raltegravir (MK-0518) developed by Merck company of the U.S. shown in formula (1).95% inhibition concentration (the IC of Raltegravir
95) be 33ng/mL (see non-patent literature 1).
Further, the HIV-1 integrase inhibitor be still in clinical trial there will be a known the GS-9137 (50% inhibition concentration (IC of the Gilead company of the U.S. shown in formula (2)
50) < 30nm) and the GSK-364735 (IC of the Japanese Shionogi company shown in formula (3)
50=8nM).In addition, also known two enter clinical trial but the HIV-1 integrase inhibitor now stopped: the S-1360 (IC of the Japanese Shionogi company shown in formula (4)
50for 20nmol/L) and the L-870810 (IC of the Merck company shown in formula (5)
95for 110ng/mL) (see non-patent literature 2 ~ 4).
On the other hand, beta-diketon acids and chemical equivalents thereof are identified the catalytic activity having in vivo and suppress intergrase.Beta-diketon acid structure has common 1, a 3-dicarbonyl structure (3 carbonyl can enolization), and acidic-group can be carboxyl and bioisostere triazole thereof or tetrazolium.Jagged structure can form bonding with two of a HIV-1 intergrase bivalent metal ion, suppresses the catalytic activity of intergrase.
Basic structure
As beta-diketon acid compounds, can enumerate the such as compound shown in formula (6), it has integrase inhibiting activities (see non-patent literature 5) relatively preferably.
In addition; it is found that; 7-acyl group-8-hydroxyl-1,6-naphthyridines structure etc. in the N-methyl-5-hydroxyl-4-Methanamide pyrimidone structure of the MK-0518 shown in above-mentioned formula (1), the L-870810 shown in above-mentioned formula (5) 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 InvestigDrugs, 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 withpurine nucleobase scaffolds:Novel, selective inhibitors of the strand transfer step of HIVintegrase, Bioorg.Med.Chem.Lett.16 (2006) 1920-1923
Summary of the invention
The object of the invention is to the compound of redesign one group containing two keto acid structures, thus a kind of novel HIV-1 integrase inhibitor is provided.
The present inventor is on the basis of understanding structure activity relationship and medicine and enzyme binding pattern in depth, and devise one group of compound containing two two keto acid structures, two keto acid anatomical connectivity are at the diverse location of middle two aromatic rings.Thus successfully synthesized a series of new compound, and observed integrase inhibiting activities.
Specifically, the invention provides following technical scheme.
(1) a HIV-1 integrase inhibitor, it represents with following general formula (I):
In general formula (I), A represents hydrogen or general formula (M),
In general formula (I) and (M), R and R ' represents that hydrogen or carbon number are the alkyl of 1 ~ 5 independently of one another.
(2) the HIV-1 integrase inhibitor as described in above-mentioned (1), wherein, the compound shown in general formula (I) represents with following general formula (I-1):
In general formula (I-1), A and R implication is the same.
(3) the HIV-1 integrase inhibitor as described in above-mentioned (1), wherein, the compound shown in general formula (I) represents with following general formula (I-2):
In general formula (I-2I), A and R implication is the same.
(4) the HIV-1 integrase inhibitor as described in above-mentioned (1), wherein, the compound shown in general formula (I) represents with following general formula (I-3):
In general formula (I-3), A and R implication is the same.
(5) the HIV-1 integrase inhibitor as described in any one of above-mentioned (1) ~ (4), wherein, A represents hydrogen.
(6) the HIV-1 integrase inhibitor as described in any one of above-mentioned (1) ~ (4), wherein, A represents general formula (M), and R and R ' represents hydrogen or ethyl independently of one another.
(7) the HIV-1 integrase inhibitor as described in above-mentioned (6), wherein, R and R ' represents hydrogen or ethyl simultaneously.
(8) a HIV-1 integrase inhibitor, it represents with following general formula (II):
In general formula (II), R represent hydroxyl, carbon number be 1 ~ 6 alkyl amine group, there is or not have arylamine group or aralkyl amido that substituent carbon number is 1 ~ 20, described substituent group to be carbon number the be straight-chain of 1 ~ 6 or the alkyl of straight-chain or unsaturated alkyl, carbon number are the alkoxyl, halogen etc. of 1 ~ 6, and, under described aromatic ring has substituent situation, there is more than one substituent group.
(9) the HIV-1 integrase inhibitor as described in above-mentioned (8), wherein, R represents hydroxyl.
(10) the HIV-1 integrase inhibitor as described in above-mentioned (8), wherein, R represents that carbon number is the alkyl amine group of 1 ~ 6.
(11) the HIV-1 integrase inhibitor as described in above-mentioned (10), wherein, R represents methylamino or ethylamino-.
(12) the HIV-1 integrase inhibitor as described in above-mentioned (8), wherein, R represents to have or do not have arylamine group or the aralkyl amido that substituent carbon number is 1 ~ 12.
(13) the HIV-1 integrase inhibitor as described in above-mentioned (12), wherein, described aryl is phenyl, and described aralkyl is benzene alkyl.
(14) a HIV-1 integrase inhibitor, it represents with following general formula (III):
In general formula (III), R represent hydroxyl, carbon number be 1 ~ 6 alkyl amine group, there is or not have arylamine group or aralkyl amido that substituent carbon number is 1 ~ 20, described substituent group to be carbon number the be straight-chain of 1 ~ 6 or the alkyl of straight-chain or unsaturated alkyl, carbon number are the alkoxyl, halogen etc. of 1 ~ 6, and, under described aromatic ring has substituent situation, there is more than one substituent group.
(15) the HIV-1 integrase inhibitor as described in above-mentioned (14), wherein, R represents that carbon number is the alkyl amine group of 1 ~ 6.
(16) the HIV-1 integrase inhibitor as described in above-mentioned (15), wherein, R represents methylamino or ethylamino-.
(17) the HIV-1 integrase inhibitor as described in above-mentioned (8), wherein, R represents to have or do not have arylamine group or the aralkyl amido that substituent carbon number is 1 ~ 12.
(18) the HIV-1 integrase inhibitor as described in above-mentioned (12), wherein, described aryl is phenyl, and described aralkyl is benzene alkyl.
(19) the HIV-1 integrase inhibitor as described in above-mentioned (18), wherein, on described phenyl or benzene alkyl with substituent group be methoxyl group.
Detailed description of the invention
< First Series compound >
The present inventor devises the two diketone acid compounds shown in a series of general formula (I-4), and wherein two keto acid structures are connected (hereinafter also referred to First Series compound) with phenyl ring.By converting two two keto acids the position of substitution different on phenyl ring, investigate the change to integrase inhibiting activities caused by two diketone acidic group distance different angles differences.
In general formula (I-4), R and R ' represents that hydrogen or carbon number are the alkyl of 1 ~ 5 independently of one another.
As R and R ', hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, tertiary pentyl, neopentyl etc. can be enumerated.Wherein, preferred hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, more preferably hydrogen, methyl, ethyl, be particularly preferably hydrogen or ethyl.
Be not particularly limited two two keto acid structures the position of substitution on phenyl ring, specifically can enumerate two diketone acidic groups is ortho position, a position, para-position independently of one another.Substituent group wherein preferably on benzyl phenyl ring is the situation of para-position, and the substituent group on the phenyl ring of also preferred phenoxy group is the situation at para-position or ortho position.
In addition, the present inventor has also synthesized the compound of a list two keto acid structure, and it is the structure that single ketones acid sloughed by two keto acids of above-claimed cpd (I-4) side, and its structure is as shown in general formula (I-5).
R and R ' implication in general formula (I-5) is the same.
Below for 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 } acid of-2-hydroxyl-4-oxygen but-2-ene, 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 DEG C
B: ethyl oxalate, NaH, toluene, 60 DEG C
C:1N NaOH, dioxane H
2o, room temperature.
In addition, single diketone acid compound (I-5) of the present invention such as can be synthesized as follows.
[route 2]
Above route is only example, and those skilled in the art can come suitably to change according to substituent group and at diketone acidic group the position of substitution on phenyl ring.
< second series compound >
The present inventor also synthesize a series of take quinolinone as parent nucleus, side is combined with the compound (hereinafter also referred to second series compound) of two keto acid structures.This compound represents with following general formula (II).
In general formula (II), R represent hydroxyl, carbon number be 1 ~ 6 alkyl amine group, carbon number be 1 ~ 20 and substituent arylamine group or aralkyl amido can be had, the substituent group that described arylamine group or aralkyl amido can have to be carbon number the be straight-chain of 1 ~ 6 or the alkyl of straight-chain or unsaturated alkyl, carbon number are the alkoxyl, halogen etc. of 1 ~ 6, further, an aromatic rings can have more than one substituent group.
Compound (II) remains the architectural feature with intergrase catalytic center metal ion bonding.The nitrogen of quinolinone is selected luorobenzyl is replaced, be conducive to entering elastic ring region.
With R be below benzamido group or hydroxyl time compound (II) be example, provide the synthetic route of second series compound.
When R is benzamido group:
[route 3]
When R is hydroxyl:
[route 4]
< the 3rd series compound >
On the basis of second series compound, the present inventor has carried out structure of modification further, change two keto acid structures into keto acid structure, synthesize the compound (hereinafter also referred to the 3rd series compound) represented with following general formula (III).
In general formula (III), R represent hydroxyl, carbon number be 1 ~ 6 alkyl amine group, carbon number be 1 ~ 20 and substituent arylamine group or aralkyl amido can be had, the substituent group that described arylamine group or aralkyl amido can have to be carbon number the be straight-chain of 1 ~ 6 or the alkyl of straight-chain or unsaturated alkyl, carbon number are the alkoxyl, halogen etc. of 1 ~ 6, further, an aromatic rings can have more than one substituent group.
Two keto acid structure of modification of the side of second series compound are keto acid structure by compound (III), thus substantially increase the biological stability of compound.
With R be below hydroxyl or anilino-time compound (III) be example, provide the synthetic route of the 3rd serial compound.
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 embodiments.
First assay method of the present invention is described.
[fusing point]
Fusing point RY-1 type melting point apparatus (capillary tube method) measures, and temperature is without rectification.
[nuclear magnetic resonance, NMR]
Nuclear magnetic resoance spectrum WYS-400 type nmr determination, TMS is interior mark.
[mass spectrum]
Mass spectrum VG ZAB-2F and Autospec-Ultima ETOF mass spectrograph measure.
[infrared]
Infrared employing KBr pressed disc method, utilizes power & light company of the U.S. (Thermo) Fourier transformation infrared spectrometer: Nicolet 5700 to measure.
[reagent]
Unless otherwise noted, be commercially available CP or AR level, without special process, directly use.
Anhydrous tetrahydro furan: with sodium backflow, take benzophenone as indicator, steam after becoming basket.
[chromatography]
TLC employing E.Merck company overlays silica gel aluminum foil coil (DC-alurolle Kieselgel 60GF254,0.2mm).
The silica gel H that VLC or reduced pressure chromatography adopt Haiyang Chemical Plant, Qingdao to produce, 120-180 order and 200-300 order.
[mensuration of integrase inhibiting activities]
ELISA method is adopted to measure Drug inhibition HIV-1 intergrase activity and mechanism of action thereof.
Test material:
1.HIV-IN: this laboratory extracts and preserves.
2. sample treatment: water-soluble or DMSO is made into debita spissitudo before use, remakes 5 times of dilutions, 4 dilution factors.Positive control drug: achyranthes polysaccharide sulphate (S-y), Shanghai is organic to be provided.
3. donor substrate and target substrate: the raw work synthesis in Shanghai.
Method of testing:
Add donor substrate bag after diluted sample by 96 orifice plates, and add in the reaction Buffer containing genetic engineering target enzyme biotin target substrate, hatch under optimum reaction condition, develop the color with biotin labeled alkaline phosphoric acid enzyme system, measure 405nm absorption value OD value.
[embodiment 1] 4-{2-[4-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl } synthesis of-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HDL08003)
The synthesis of operation (1-1): 1-(4-bromomethyl) 1-Phenylethanone. (HDL08001)
Melilotal (13.4g is added in 100mL reaction bulb, 0.1mol), acetonitrile (300mL), bromo-succinimide (21.4,0.12mol) with azodiisobutyronitrile (2.7g), stirring and dissolving, temperature 50 DEG C of 6h (or ambient sunlight irradiates stirring 3 days) in the illumination of reactant liquor 250W infrared lamp keeps, evaporated under reduced pressure, add 100mL ethyl acetate, precipitation white solid is crossed and is filtered, mother solution concentrating under reduced pressure, light brown grease HDL08001 crude product 24.42g, do not need refining can direct the next step.
Refining: column chromatography elution system petroleum ether: ethyl acetate=10: 1 obtains white solid.
(product literature: bp105-107 DEG C/1.8mm, mp38-39 DEG C, 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)
The synthesis of operation (1-2): 2-[4-acetyl group benzyloxy] 1-Phenylethanone. (HDL08002)
HDL08001 crude product 24.4g, dry DMF 100mL, o-hydroxyacetophenone 13.1g is added in 100mL reaction bulb, porphyrize Anhydrous potassium carbonate 25.7g, temperature 55 ~ 60 DEG C of stirring reaction 2h in mixture, stop reaction, be chilled to room temperature, stir in lower impouring 800mL frozen water, mixed liquor is placed and is waited to separate out solid, filter and separate out solid, washing, dries to obtain HDL08002 product crude product brown solid 19.1g.
Refining: crude product adds 200mL ethyl acetate, active carbon, 50 DEG C are stirred decolouring in 30 minutes, and recrystallization obtains pure product, buff powder, mp113 ~ 114 DEG C.
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 } synthesis of-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HDL08003)
3.22g (12mmol) HDL08002,42mL dry tetrahydrofuran, 4.38g (30mmol) ethyl oxalate is added in 100mL reaction bulb, 2.04g (30mmol) Sodium ethylate is added under nitrogen environment, add rear maintenance room temperature stirring reaction 2h, stop reaction.
Filter, residue n-hexane 20mL × 3, washing rear solid is powder, enters in beaker to add 100mL1NHCl stirring at room temperature 1h, filtering solids, is washed to PH5, dries to obtain HDL08003 product, buff powder 5.1g, mp98 ~ 100 DEG C, 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
max1724.8 (ester carbonyl groups), 1606.8 (ketone carbonyls)
[embodiment 2] 4-{2-[4-(3-carboxyl-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl } synthesis of-2-hydroxyl-4-oxygen but-2-ene acid (HDL08004E)
In reaction bulb, add 0.234g (0.5mmol) HDL08003,5mL oxolane/methanol=1: under 1 mixed solution, psychrolusia, drip 2.5mL1N sodium hydroxide solution, add rear maintenance room temperature stirring reaction 5 hours, stop reaction.
In reactant liquor impouring 10mL water, wash 10mL × 3 by ethyl acetate, wash rear aqueous phase and be neutralized to PH2 ~ 3 with 2NHCl under ice-water bath cooling, filter the pale yellow powder of separating out, wash on a small quantity, vacuum is drained, and obtains HDL08004E crude product.
Refining: crude product adds 1N sodium hydroxide and dissolves, and can wash by ethyl acetate more if desired, with activated carbon decolorizing 30 minutes, 2NHCl was adjusted to PH3, washes on a small quantity, and vacuum is drained, and obtains sterling 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
The synthesis of [embodiment 3] 4-[2-(4-acetyl group benzyloxy) phenyl]-2-hydroxyl-4-oxygen but-2-ene acid (HDL08004D)
In reaction bulb, add 1.404g (3mmol) HDL08003,30mL oxolane/methanol=1: under 1 mixed solution, psychrolusia, drip 15mL1N sodium hydroxide solution, add rear maintenance room temperature stirring reaction 4 days, stop reaction.
In reactant liquor impouring 60mL water, wash 60mL × 3 by ethyl acetate, wash rear aqueous phase and be neutralized to PH3 ~ 4 with 2NHCl under ice-water bath cooling, filter the pale yellow powder of separating out, wash on a small quantity, vacuum is drained, and obtains HDL08004D crude product.
Refining: crude product adds 1N sodium hydroxide and dissolves, and can wash by ethyl acetate more if desired, with activated carbon decolorizing 30 minutes, 2NHCl was adjusted to PH3 ~ 4, washes on a small quantity, and vacuum is drained, and obtains sterling 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)
+；
The synthesis of [embodiment 4] other pair of diketone acid compound
First synthetic mesophase compound.
1-(3-bromomethyl) 1-Phenylethanone. (HJ08001) can, with reference to the synthesis of 1-(4-bromomethyl) 1-Phenylethanone. (HDL08001), utilize the method similar with embodiment 1 operation (1-1) to synthesize;
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 with reference to the synthesis of 2-[4-acetyl group benzyloxy] 1-Phenylethanone. (HDL08002); utilize the method similar with embodiment 1 operation (1-2) to synthesize, spectrum analysis the results are shown in Table 1.
[table 1]
Be general formula (M) as A in general formula (I) and R and R ' represents the compound of 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 with reference to 4-{2-[4-(3-ethoxy acyl group-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl } synthesis of-2-hydroxyl-4-oxygen but-2-ene acetoacetic ester (HDL08003); utilize the method similar with embodiment 1 operation (1-3) to synthesize, spectrum analysis the results are shown in Table 2.
Further, be general formula (M) as A in general formula (I) and R and R ' represents the compound of hydrogen simultaneously,
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 with reference to 4-{2-[4-(3-carboxyl-3-hydroxyl third-2-enoyl-) benzyloxy] phenyl } synthesis of-2-hydroxyl-4-oxygen but-2-ene acid (HDL08004E); utilize method synthesis similar to Example 2, spectrum analysis the results are shown in Table 2.
[table 2]
The synthesis of [embodiment 5] second series compound
Synthesize according to following route.
Operation (5-1): the synthesis of 3-acetyl-6-Ethyl formate-4 (1H)-quinolizidine morpholine ketone
By para amidocyanogen benzoic Acid ethyl ester (1.65g, 10mmol) and 2-ethoxymethyl methyl ethyl acetoacetate (1.87g, 10mmol) mixing, be heated to 120 DEG C of reaction 10min.Be chilled to room temperature, form solid, clay into power in normal hexane, filter to obtain the micro-yellow solid of 2.76g, thick yield 90.5%.Need not be further purified.
The gradation of upper step solid joins in the diphenyl ether of 28mL backflow (255 DEG C), reaction 50min.Be chilled to after below 50 DEG C, add 56mL normal hexane, filter after room temperature and obtain brown solid 1.66g, thick yield 70.7%.Need not be further purified.
Operation (5-2): the synthesis of 3-acetyl-6-Ethyl formate-1-(4-benzyl)-4 (1H)-quinolizidine morpholine ketone
Upper step solid adds in dry 50mL DMF, adds Anhydrous potassium carbonate (1.33g, 9.6mmol), 4-fluorobenzyl bromide (3.55g, 19.2mmol), and suspension is heated to 100 DEG C of reaction 3h.After being chilled to room temperature, add 50mL saturated brine, extract with ethyl acetate 50mL × 3 time, anhydrous sodium sulfate drying.Boil off solvent, obtain crude product dark brown solid 1.46g, thick yield 61.7%.
Operation (5-3): the synthesis of 3-acetyl-6-formic acid-1-(4-benzyl)-4 (1H)-quinolizidine morpholine ketone
Add 48mL acetone in upper step crude product, 24mL ethanol, the sodium hydroxide 24mL of 1N, stirring at room temperature 1h, TCL show raw material point and disappear.Add 2N salt in reactant liquor Esterification to about PH=2, place in refrigerator, solid filtering, obtain faint yellow solid 1.31g, thick yield 97.4%.
Operation (5-4): the synthesis of 3-acetyl-6-anilino-formyl-1-(4-benzyl)-4 (1H)-quinolizidine morpholine ketone
5mL dry methylene chloride is added, 0.22mL triethylamine, nitrogen protection in upper step solid (0.08g, 0.25mmol).Be cooled to-5 DEG C, add isobutyl ester formyl chloride (0.08g, 0.45mmol), after 30min, add aniline (0.07g, 0.75mmol), stirred overnight at room temperature.
Add 2N hydrochloric acid and adjust about PH=2, add 20mL saturated aqueous common salt, 20mL dichloromethane, separatory, organic facies anhydrous sodium sulfate drying.Cross column chromatography, obtain 50mg white solid, yield 51.2%.
m.p.＝243-245℃。FAB-MS(m/z)：451(M+Na)
+。
The synthesis of operation (5-5): 3-(1,3-diketone-4 butyric acid ethyl ester)-6-anilino-formyl-1-(4-benzyl)-4 (1H)-quinolizidine morpholine ketone
Upper step gained solid (0.13mmol) is dissolved in dry 2mL THF, adds ethyl oxalate (33mg, 0.22mmol), nitrogen protection.Add the sodium hydride (16mg, 0.22mmol) of 50% under room temperature, be heated to 50 DEG C of reaction 30min.After being chilled to room temperature, add 10mL ethyl acetate, 0.15N hydrochloric acid 10mL separatory, organic facies anhydrous sodium sulfate drying.
Fling to solvent, cross column chromatography (petrol ether/ethyl acetate) gradient elution, obtain 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 )。
The synthesis of operation (5-6): 3-(1,3-diketone-4 butyric acid)-6-anilino-formyl-1-(4-benzyl)-4 (1H)-quinolizidine morpholine ketone
Add 0.7mL (THF/ methanol=1/1) solution in upper step solid, add the sodium hydroxide solution of 0.35mL 1N, stirring at room temperature 40min, add 0.15N hydrochloric acid and adjust PH to be about 4, separate out white precipitate.Filtration obtains white solid 25mg, yield 75.8%.Spectrum data is in table 3.
Similarly synthesize other compounds of second series, spectrum data is in table 3.
[table 3]
[embodiment 6] the 3rd synthesis of series compound
Synthesize according to following route.
Operation (6-1): the synthesis of para amidocyanogen benzoic Acid allyl ester
In para amidocyanogen benzoic Acid (2.74g, 20mmol), add 50mL methanol, 10mL water, potassium hydroxide (1.12g, 20mmol), be stirred to dissolving.Boil off solvent and obtain white solid.By above-mentioned white solid, bromopropene (2.52g, 22mmol), 80mL DMF, stirred overnight at room temperature, disappears completely to white suspension thing.Cross column chromatography (petroleum ether ethyl acetate) gradient elution, obtain 3.2g yellow liquid, yield 90.4%.
Operation (6-2): the synthesis of 3-carbethoxyl group-6-allyl formate-4 (1H)-quinolizidine morpholine ketone
By aforesaid liquid (1.77g, 10mmol) and 2-ethoxy methylene propanoic acid diethylester (2.16g, 10mmol) mixing, be heated to 120 DEG C of reaction 1h.Be chilled to room temperature, form solid, clay into power in normal hexane, filter to obtain 3.34g light yellow solid, thick yield 96.3%.Need not be further purified.
The gradation of upper step solid joins in the diphenyl ether of 33mL backflow (255 DEG C), reaction 50min.Be chilled to after below 50 DEG C, add 66mL normal hexane, filter after room temperature and obtain dark brown solid 2.51g, thick yield 86.2%.Need not be further purified.
Operation (6-3): the synthesis of 3-carbethoxyl group-6-allyl formate-1-(4-benzyl)-4 (1H)-quinolizidine morpholine ketone
Upper step solid adds in dry 80mL DMF, adds Anhydrous potassium carbonate (1.60g, 11.4mmol), 4-fluorobenzyl bromide (5.41g, 25.1mmol), and suspension is heated to 100 DEG C of reaction 2.5h.After being chilled to room temperature, add 100mL saturated brine, extract with ethyl acetate 100mL × 3 time, anhydrous sodium sulfate drying.Boil off solvent, cross column chromatography (petroleum ether ethyl acetate) gradient elution, obtain white solid 2.1g, yield 61.6%.
m.p.＝176-178℃。ESI-MS(m/z)：410(M+H)
+
Operation (6-4): the synthesis of 3-carbethoxyl group-6-formic acid-1-(4-benzyl)-4 (1H)-quinolizidine morpholine ketone
Upper step solid adds 140mL acetone and 140mL acetonitrile, and add triphenyl phosphorus palladium 0.42g, pyrrolidine 1.4g, stirring is spent the night.
Half solvent is flung in stirring, adds 0.15N hydrochloric acid and adjusts about PH=1, separate out solid, filter to obtain khaki solid 1.55g, yield 82.0%.
Operation (6-5): the synthesis of 3-carboxylic acid-6-allyl formate-4 (1H)-quinolizidine morpholine ketone
20mL dry methylene chloride is added, triethylamine (0.28g, 2.72mmol), nitrogen protection in upper step solid (0.50g, 1.36mmol).Be cooled to-10 DEG C, add isobutyl ester formyl chloride (0.28g, 2.04mmol), after 30min, add o-chloraniline (0.58g, 4.08mmol), stirred overnight at room temperature.
Add 2N hydrochloric acid and adjust PH=3 ~ 4, add 20mL saturated aqueous common salt, 40mL dichloromethane, separatory, organic facies anhydrous sodium sulfate drying.Cross column chromatography, obtain 50mg white solid, yield 51.2%.
m.p.＝243-245℃。FAB-MS(m/z)：451(M+Na)
+。
Carry out spectrum analysis, the results are shown in Table 4.
Similarly synthesize other compounds of the 3rd series, spectrum data is in table 4.
[table 4]
The mensuration of [embodiment 7] integrase inhibiting activities
Adopt ELISA method, each series compound of above-described embodiment 1 ~ 6 is carried out to the mensuration of Inhibition of HIV-1 integrase activity.Positive control employs achyranthes polysaccharide sulphate (S-y).Wherein First Series compound and second series compound the results are shown in Table 5, the 3rd series compound the results are shown in Table 6.
[table 5]
[table 6]
Claims (7)
1. a HIV-1 integrase inhibitor, it represents with following general formula (I):
In general formula (I), A represents hydrogen or general formula (M),
In general formula (I) and (M), R and R ' represents that hydrogen or carbon number are the alkyl of 1 ~ 5 independently of one another.
2. HIV-1 integrase inhibitor as claimed in claim 1, wherein, the compound shown in general formula (I) represents with following general formula (I-1):
In general formula (I-1), A and R implication is the same.
3. HIV-1 integrase inhibitor as claimed in claim 1, wherein, the compound shown in general formula (I) represents with following general formula (I-2):
In general formula (I-2), A and R implication is the same.
4. HIV-1 integrase inhibitor as claimed in claim 1, wherein, the compound shown in general formula (I) represents with following general formula (I-3):
In general formula (I-3), A and R implication is the same.
5. the HIV-1 integrase inhibitor as described in any one of Claims 1 to 4, wherein, A represents hydrogen.
6. the HIV-1 integrase inhibitor as described in any one of Claims 1 to 4, wherein, A represents general formula (M), and R and R ' represents hydrogen or ethyl independently of one another.
7. HIV-1 integrase inhibitor as claimed in claim 6, wherein, R and R ' represents hydrogen or ethyl simultaneously.
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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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (5)
| Title |
|---|
| Design and Synthesis of Novel Indole â-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors;Mario Sechi等;《Journal of Medicinal Chemistry》;20040916;第47卷(第21期);第5298-5310页 * |
| HIV-1整合酶抑制剂的研究进展;陈晓芳 等;《国外医学药学分册》;20040430;第31卷(第2期);第65-69页 * |
| Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design,Synthesis, Biological Activities, and Mechanism of Action;Roberto Di Santo等;《Journal of Medicinal Chemistry》;20060217;第49卷(第6期);第1939-1945页 * |
| Novel Quinolinonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design, Synthesis,and Biological Activities;Roberto Di Santo等;《Journal of Medicinal Chemistry》;20080723;第51卷(第15期);第4744-4750页 * |
| 喹啉酮酸类化合物的设计合成与抗HIV-1整合酶活性研究;陈晓芳 等;《药学学报》;20100212;第45卷(第2期);第263-267页 * |
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