CN103130730A - Novel quinazoline derivative, and preparation method, anti-HIV activity and anti-TMV activity thereof - Google Patents
Novel quinazoline derivative, and preparation method, anti-HIV activity and anti-TMV activity thereof Download PDFInfo
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- CN103130730A CN103130730A CN2011103766517A CN201110376651A CN103130730A CN 103130730 A CN103130730 A CN 103130730A CN 2011103766517 A CN2011103766517 A CN 2011103766517A CN 201110376651 A CN201110376651 A CN 201110376651A CN 103130730 A CN103130730 A CN 103130730A
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- luorobenzyl
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Abstract
The invention relates to a novel quinazoline derivative, and a preparation method, anti-HIV activity and anti-TMV activity thereof. A general formula I has very good anti-human immunodeficiency virus activity, and can well inhibit the human immunodeficiency virus (HIV) and the tobacco mosaic virus (TMV). In the formula, specific representation contents of substituents R1, R2, R3, R4, R5 and R6 are defined in the specification.
Description
Technical field
The present invention relates to novel quinazoline oxazoline derivates I and preparation method thereof, HIV (human immunodeficiency virus)-resistant activity and anti-TMV activity.
Background technology
Acquired immune deficiency syndrome (AIDS) (acquired immunodeficiency syndrome, AIDS) is the communicable disease that has caused by human immunodeficiency virus (human immunodeficiency virus, HIV).Since American Studies personnel in 1981 find world's Patient With Aids case, acquired immune deficiency syndrome (AIDS) has totally seized more than 2,700 ten thousand people's life, becomes gradually the mankind's No.1 killer.Estimate to the year two thousand twenty, will have 200,000,000 people's infected by HIV (2010, UNAIDS/10.11E | JC1958E.).Therefore acquired immune deficiency syndrome (AIDS) is called as " century cancer ".HIV virus is the spherosome that a diameter is approximately 10nm, core have two sub-thread positive chain RNAs and by reversed transcriptive enzyme, intergrase and the proteolytic enzyme of encoding viral (J.Mol.Biol., 1999,285,1-32.).
Nineteen ninety-five, scientist Chinese descendant in America professor He great Yi has invented " drug cocktail therapy (treatment) " commonly used clinically at present, applies proteinase inhibitor and reverse transcriptase inhibitors combination, stops virus replication comprehensively, reduce the possibility of a single point sudden change in HIV, thereby delay resistance.Although " drug cocktail therapy (treatment) " treatment to AIDS when being born has brought a revolution, make the AIDS M & M all descend to some extent, but still some patient develops immunity to drugs to one or more medicines wherein, particularly this therapy can not be eradicated copying that under low-level state, virus continues to carry out, HIV still is present in some body tissue, needs to use medicine to carry out long-term treatment; In addition, be used in combination the medicine price very expensive, limited they the application of under-developed country (Science, 2002,296,2320-2324.).Owing to there being the problems referred to above, people wish to carry out more deep research by the life cycle to HIV and mechanism of causing a disease thereof, searching acts on the anti-AIDS drugs of other target spots in the HIV life cycle, thereby add a kind of medicine with new function in " drug cocktail therapy (treatment) ", reach the effect that increases combined therapy.
The integration of HIV-1 intergrase catalysis virus cDNA and host cell gene group is key enzyme essential in the HIV virus replication cycle.Human body is interior without the intergrase functional analogue.Therefore, intergrase is the desirable target spot of anti-AIDS drug research and development.In October, 2007, Merck & Co., Inc. optimized small-molecule drug Merck (raltegravir) the acquisition U.S. FDA approval screened, and becoming first is also current unique integrase inhibitor.Become the focus for the treatment of AIDS for the antiviral study of intergrase.2010, the people such as Stephen Hare delivered one piece " Retroviral intasome assembly and inhibition of DNA strand transfer " by name article (Nature, 2010,464,232-236).The researchist cultivates the intergrase crystal of prototype foamy virus (PFV).They,, by the X-ray diffraction to crystal, obtain its 3-d modelling.The meaning of this piece of article is that the intergrase of PFV and hiv integrase are the height homologies, and this has been equivalent to obtain be similar to very much the complete 3-d modelling of hiv integrase, and this difficult problem has perplexed scientist more than 20 year.By the research to this intergrase structure, be expected to design safer and more effective hiv integrase inhibitor, solve the virus drug resistance problem, improve method and the effect for the treatment of AIDS.
Although the exploitation of Merck has brought Gospel to the AIDS patient, along with AIDS patient's existence and administration time constantly extend, the problems such as adverse drug reaction, patient compliance, virus drug resistance engender.The best approach addressed this problem is exactly the research and development of new drug.
Tobacco mosaic virus (TMV) (tobacco mosaic virus, TMV) is a kind of plant positive chain RNA virus.Virion is shaft-like, and size 300 * 18nm (see photo), have a central empty district, radius 2nm.Virion mainly by capsid protein and RNA form (Annu.Rev.Phytopathol., 2004,42,13-34).
TMV vitality is quite indomitable, under passivation temperature 90-93 ℃ condition, through 10 minutes, dilutes 100 ten thousand times of point of accumulation, and the longevity in vitro can reach 72-96 hour.Under aseptic condition, virulence reaches the several years, and in the axersis tissue, survival is more than 30 years.This virus has different strains, and China mainly contains 4 strains such as common strain, tomato strain, macula lutea strain and pearl spot, because virulence difference reaches the diversity that causes symptom with other viral Combined Infections.
TMV can contaminate 38 section's 268 kind of plant, and this virus disease has hindered the further raising of tobacco production and quality, very big to the tobacco disserve to produce, and general time sickness rate is about 25%, and serious reaches more than 50%, the financial loss heaviness.Preventive effect is generally all lower than 60% under best spraying medicine concentration for the agent for preventing and treating plant virus of developing at present, and its prevention effect is undesirable, can not meet agriculture demand far away.
Quinazoline compounds is that a class has extensive bioactive nitrogen-containing heterocycle compound, it has EGF-R ELISA (EGFR) or its Tyrosylprotein kinase (EGFR-TK), vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), the inhibition activity of a plurality of action target spots such as trk C (NGFR), thereby at anti-inflammatory (Farmaco, 1999, 54, 780-784), antibiotic (Pharm.Acta.Helv., 1999, 74, 11-17), hypertension (Bioorg.Med.Chem., 2003, 11, 2439-2444), antitumor (J.Med.Chem., 2000, 43, 1910-1926) with anti-TMV, (deposit chemical machine, 2008, 28, 1785-1791) etc. aspect all demonstrates good activity.
Summary of the invention
The purpose of this invention is to provide novel quinazoline oxazoline derivates I (Fig. 2) and their preparation method, HIV (human immunodeficiency virus)-resistant activity and anti-TMV activity.The invention provides a kind of method for preparing easily quinazoline derivative I.The present invention finds that quinazoline derivative I has HIV (human immunodeficiency virus)-resistant activity and anti-TMV activity.
Quinazoline derivative of the present invention is the compound with structure shown in following general formula I, R
1represent the alkoxyl group of H, 1-10 carbon, the alkylamino radical of 1-10 carbon, the substituted benzyloxy of 1-10 carbon, the alpha substituted benzylamine base of 1-10 carbon, the alkyl of 1-10 carbon; R
2represent OH, F, Cl, Br, I
2, the alkoxyl group of 1-10 carbon, the alkylamino radical of 1-10 carbon, the substituted benzyloxy of 1-10 carbon, the alpha substituted benzylamine base of 1-10 carbon, 1-10 carbon acyloxy, 1-10 carbonamido, 1-10 carbon alkyl carbonyl; R
3represent the alkyl of H, 1-10 carbon, the substituted benzyl of 1-10 carbon; R
4represent H, the substituted benzyl of the alkylamino radical of the alkyl of 1-10 carbon, 1-10 carbon, the alpha substituted benzylamine base of 1-10 carbon, 1-10 carbon, the substituted aryl of 1-10 carbon, 1-10 carbon containing heterocyclic substituent; R
5represent singly-bound, H; R
6represent the alkyl of singly-bound, H, 1-10 carbon, the substituted aryl of the substituted benzyl of 1-10 carbon, 1-10 carbon, 1-10 carbon containing heterocyclic substituent.
Structural formula 1
The preparation of quinazoline derivative I of the present invention (equation 1) is as follows:
At first the 2-methyl-5-amino-phenol of take is raw material, through pivaloyl group protect 2, then after methylating 3.The ortho position carboxylation reaction obtains sour 4; obtain 5 with aminolysis after Vinyl chloroformate becomes acid anhydride; obtain 6 after potassium permanganate oxidation; with NSC 158269, react again 7; deprotection obtains crucial synthon 8; be dehydrated into and encircle to obtain I-1～11 with corresponding aldehyde again, next by the iodine oxidation style, make I-12～22, finally under aluminum chloride and pyridine condition, demethylation makes Compound I-23～30.
Equation 1
Equation 1 is used for illustrating the synthetic of general formula I indication compound, but do not limit the synthetic of compound in general formula I, R represents H, the substituted benzyl of the alkylamino radical of the alkyl of 1-10 carbon, 1-10 carbon, the alpha substituted benzylamine base of 1-10 carbon, 1-10 carbon, the substituted aryl of 1-10 carbon, 1-10 carbon containing heterocyclic substituent.
Novel quinazoline quinoline compounds I provided by the invention has good antiviral activity, can suppress well the infection of HIV and TMV.
Accompanying drawing explanation: TMV structural representation Fig. 1, RNA; 2, capsomere; 3, capsid.
embodiment
Following embodiment and Sheng test are tested result and be can be used to further illustrate the present invention, but do not mean that restriction the present invention.
Embodiment 1: quinazoline compounds I-1, synthetic (the square formula 2) of I-12 and I-23
Equation 2
Synthesizing of compound 2:
In the reaction flask of 1L, add the adjacent methyl of 20g (0.16mol)-5-amino-phenol (1), 41g (0.49mol) sodium bicarbonate, 350mL water, the 450mL ethyl acetate, drip 29g (0.24mol) pivaloyl chloride under mechanical stirring, reaction 3h, separatory, water is extracted with ethyl acetate (2 * 100mL), merge organic phase, with saturated sodium carbonate solution washing (2 * 200mL), anhydrous magnesium sulfate drying, add skim silica gel suction filtration, precipitation obtains white solid product 32.3g, yield 96%, fusing point 146-148 ℃;
1h NMR (400MHz, CDCl
3): δ=8.29 (s, 1H, OH), 7.89 (s, 1H, 6-H), 7.36 (brs, 1H, NH), 7.00 (d, J=7.9Hz, 1H, 4-H), 6.40 (d, J=7.9Hz, 1H, 3-H), 2.20 (s, 3H, ArCH
3), 1.33 (s, 9H, C (CH
3)
3) ppm;
13c NMR (100MHz, CDCl
3): δ=177.6,155.7,136.2,130.4,121.1,110.3,107.5,39.7,27.6,15.7ppm; Anal.Calcd.for C
12h
17nO
2: C, 69.54; H, 8.27; N, 6.76.Found:C, 69.58; H, 8.49; N, 6.65.
Synthesizing of compound 3:
In the reaction flask of 500mL, add 10g (48.3mmol) raw material 2, the tetrahydrofuran (THF) of 250mL Non-aqueous processing, the sodium hydride that in batches adds 2.5g (72.5mmol) 70% under magnetic agitation, stirring reaction 2h, drip the 12.2g methyl-sulfate, reaction 1h, the TLC detection reaction is complete, be chilled to room temperature, the methyl-sulfate that hydrolyzable is excessive, precipitation, the 300mL acetic acid ethyl dissolution, respectively with water (100mL), saturated aqueous common salt (100mL) washing, anhydrous magnesium sulfate drying, precipitation, obtain white needles solid 9.2g with the sherwood oil recrystallization after column chromatography, yield 86%, fusing point 124-126 ℃,
1hNMR (400MHz, CDCl
3): δ=7.49 (s, 1H, 6-H), 7.29 (brs, 1H, NH), 7.03 (d, J=7.9Hz, 1H, 4-H), 6.71 (dd, J=7.9Hz, 1.4Hz, 1H, 3-H), 3.84 (s, 3H, OMe), 2.17 (s, 3H, ArCH
3), 1.32 (s, 9H, C (CH
3)
3) ppm,
13c NMR (100MHz, CDCl
3): δ=176.6,157.9,137.1,130.2,122.3,110.9,102.8,55.4,39.6,27.7,15.8ppm, Anal.Calcd.for C
13h
19nO
2: C, 70.56, H, 8.65, N, 6.33.Found:C, 70.29, H, 8.77, N, 6.17.
Synthesizing of compound 4:
In the reaction flask of 2L, add 22g (0.1mol) raw material 3, the 1.2L anhydrous tetrahydro furan, under mechanical stirring, drip the hexane solution of 146mL (0.22mol) n-Butyl Lithium, reaction 10h, solution gradually becomes yellow viscous fluid by orange, slowly blasts high-purity CO
2gas, continue air-blowing 6h, and reaction solution gradually becomes the scarlet clear liquid, precipitation, add 10% potassium hydroxide solution 500mL, with ethyl acetate extraction (2 * 150mL), removes unreacted raw material, water slowly drips concentrated hydrochloric acid acid adjustment (pH=2-3), with ethyl acetate extraction (3 * 200mL), merge organic phase, anhydrous magnesium sulfate drying, suction filtration, precipitation obtains yellow solid 21g, yield 81%, fusing point 93-95 ℃;
1h NMR (400MHz, CDCl
3): δ=12.29 (brs, 1H, COOH), 11.72 (brs, 1H, NH), 8.63 (d, J=8.8Hz, 1H, 4-H), 7.40 (d, J=8.8Hz, 1H, 3-H), 3.92 (s, 3H, OMe), 2.32 (s, 3H, ArCH
3), 1.34 (s, 9H, C (CH
3)
3) ppm;
13c NMR (100MHz, CDCl
3): δ=178.2,168.1,157.4,141.6,137.3,124.5,118.0,107.9,62.9,40.5,27.5,15.5ppm; Anal.Calcd.for C
14h
19nO
4: C, 63.38; H, 7.22; N, 5.28.Found:C, 63.18; H, 7.37; N, 5.16.
Synthesizing of compound 5:
In the reaction flask of 500mL, add 7g (0.026mol) raw material 4, the tetrahydrofuran (THF) of 220mL Non-aqueous processing, 3.2g (0.032mol) triethylamine, under magnetic agitation, drip 4.95g (0.029mol) Vinyl chloroformate, a large amount of white precipitates appear, reaction 2h, drip 25% aqueous methylamine solution 7.86g (0.063mol), reaction 3h, precipitation, add the 200mL acetic acid ethyl dissolution, use respectively saturated sodium bicarbonate (100mL), water (100mL), saturated aqueous common salt (100mL) washing, anhydrous magnesium sulfate drying, precipitation obtains light yellow solid product 6.3g, yield 86%, fusing point 105-107 ℃,
1h NMR (400MHz, CDCl
3): δ=11.50 (brs, 1H, NH), 8.36 (d, J=8.6Hz, 1H, 4-H), 7.80 (d, J=0.8Hz, 1H, CH
3nH), 7.23 (d, J=8.6Hz, 1H, 3-H), 3.69 (s, 3H, OMe), 3.02 (d, J=4.8Hz, 3H, NMe), 2.24 (s, 3H, ArCH
3), 1.32 (s, 9H, C (CH
3)
3) ppm,
13c NMR (100MHz, CDCl
3): δ=177.6,168.0,156.3,139.2,134.0,125.5,117.5,114.0,61.3,40.1,27.6,26.6,15.5ppm, Anal.Calcd.for C
15h
22n
2o
3: C, 64.73, H, 7.97, N, 10.06.Found:C, 64.71, H, 8.12, N, 10.12.
Synthesizing of compound 6:
In the reaction flask of 1L, add 25g (0.09mol) raw material 5, 33.4g (0.42mol) pyridine, 109mL water, add 42.6g (0.27mol) potassium permanganate under magnetic agitation in batches, about 20min adds, react again 3h, add 10% vat powder aqueous solution 100mL to decompose the complete potassium permanganate of unreacted, add the diatomite suction filtration, respectively with 150mL water and 150mL methanol wash washing leaching cake, under concentrated latter 0 ℃ of filtrate with the concentrated hydrochloric acid acid adjustment, extraction (3 * 150mL) adds methylene chloride, merge organic phase, anhydrous sodium sulfate drying, suction filtration, precipitation, column chromatography obtains white solid product 23.3g, yield 84%, fusing point 192-194 ℃,
1h NMR (400MHz, CDCl
3): δ=11.59 (brs, 1H, NH), 8.59 (d, J=9.0Hz, 1H, 4-H), 8.11 (d, J=9.0Hz, 1H, 3-H), 7.54 (d, J=4.2Hz, 1H, CH
3nH), 3.90 (s, 3H, OMe), 3.06 (d, J=4.8Hz, 3H, NMe), 1.33 (s, 9H, C (CH
3)
3) ppm,
13c NMR (100MHz, CDCl
3): δ=178.2,168.5,167.0,159.5,145.8,135.9,117.2,116.8,114.9,63.8,40.5,27.5,26.8ppm, Anal.Calcd.for C
15h
20n
2o
5: C, 58.43, H, 6.54, N, 9.09.Found:C, 58.38, H, 6.61, N, 9.04.
Synthesizing of compound 7:
In the reaction flask of 500mL, add 11g (0.036mol) raw material 6, the tetrahydrofuran (THF) of 300mL Non-aqueous processing, 4.3g (0.043mol) triethylamine, under magnetic agitation, drip 6.7g (0.039mol) Vinyl chloroformate, a large amount of white precipitates appear, drip NSC 158269 10.71g (0.086mol), reaction 4h, precipitation, add the 200mL acetic acid ethyl dissolution, use respectively saturated sodium bicarbonate (100mL), water (100mL), saturated aqueous common salt (100mL) washing, anhydrous magnesium sulfate drying, the precipitation column chromatography obtains light yellow liquid, freezing curing 12.7g, yield 86%, fusing point 134-136 ℃,
1h NMR (400MHz, CDCl
3): δ=11.22 (brs, 1H, NH), 8.46 (d, J=9.0Hz, 1H, 4-H), 8.05 (d, J=9.0Hz, 1H, 3-H), 7.70-7.78 (m, 1H, NH), 7.40-7.44 (m, 1H, NH), 7.28-7.35 (m, 2H, ArH), 7.01-7.05 (m, 2H, ArH), 4.56 (d, J=5.6Hz, 2H, ArCH
2), 3.69 (s, 3H, OMe), 3.02 (d, J=4.8Hz, 3H, NMe), 1.30 (s, 9H, C (CH
3)
3) ppm,
13c NMR (100MHz, CDCl
3): δ=177.9,166.9,164.5,163.4,161.0,156.4,143.6,134.4,134.2,134.1,129.6,129.5,121.0,117.7,115.7,115.5,114.8,63.4,43.2,40.3,27.5,26.8ppm, Anal.Calcd.for C
22h
26fN
3o
4: C, 63.60, H, 6.31, N, 10.11.Found:C, 63.61, H, 6.51, N, 10.15.
Synthesizing of compound 8:
In the reaction flask of 500mL, add 6g (14.5mmol) raw material 7,120mL water, the 120mL concentrated hydrochloric acid, the about 1h of back flow reaction, TLC detection reaction to product point at any time no longer increases termination reaction, precipitation, lower alkalescence for 0 ℃, ethyl acetate extraction (3 * 100mL), merge the organic phase anhydrous magnesium sulfate drying, suction filtration, precipitation, column chromatography obtains light yellow solid product 2.9g, yield 61%, fusing point 170-172 ℃;
1h NMR (400MHz, CDCl
3): δ=7.92 (d, J=8.8Hz, 1H, 4-H), 7.80 (brs, 1H, NH), 7.32 (dd, J=5.5,8.1Hz, 2H, ArH), 7.15 (brs, 1H, NH), 7.02 (t, J=8.6Hz, 2H, ArH), 6.51 (d, J=8.8Hz, 1H, 3-H), 5.90 (brs, 2H, NH
2), 4.58 (d, J=5.6Hz, 2H, ArCH
2), 3.67 (s, 3H, OMe), 2.97 (d, J=4.8Hz, 3H, NMe) ppm;
13c NMR (100MHz, DMSO-d6): δ=166.0,164.9,157.1,149.6,143.0,135.5,131.8,129.3,129.3,129.3,115.0,114.8,111.2,62.8,62.4,41.9,27.0,26.0ppm; HRMS (ESI) calcd for C
17h
17fN
3o
3(M-H)
-: 330.1259, found:330.1257.
Synthesizing of Compound I-1:
In the reaction flask of 100mL, add 0.5g (1.5mmol) raw material 8,0.3g (2.3mmol) corresponding aldehyde, 0.05g (0.3mmol) tosic acid, 0.5g anhydrous magnesium sulfate, the ethanol of 60mL Non-aqueous processing, reaction 3h, precipitation, add the 100mL methylene dichloride, uses respectively saturated sodium bicarbonate solution (100mL), water (100mL), saturated aqueous common salt (100mL) washing, anhydrous sodium sulfate drying, suction filtration, precipitation, column chromatography obtains light yellow solid product 0.6g, yield 92%, fusing point 181-183 ℃;
1h NMR (400MHz, CDCl
3): δ=8.26 (s, 1H, CONH), 8.03 (d, J=8.7Hz, 1H, ArH), 7.28-7.37 (m, 4H, ArH), (6.99-7.06 m, 4H, ArH), 6.44 (d, J=8.7Hz, 1H, ArH), 5.66 (s, 1H, ArCH), 5.36 (s, 1H, ArNH), 4.56 (d, J=4.5Hz, 2H, ArCH
2), 3.85 (s, 3H, OMe), 2.92 (s, 3H, NMe) ppm; HRMS (ESI) calcd for C
24h
20f
2n
3o
3(M-H)
-: 436.1478, found:436.1477.
Synthesizing of Compound I-12:
In the reaction flask of 100mL, add 0.4g (1mmol) raw material amine, the 60mL dehydrated alcohol, 0.8g (3mmol) iodine, reaction 9h, the TLC detection reaction completes, and precipitation adds 30mL 10%Na
2s
2o
4the aqueous solution, the 50mL methylene dichloride, stirring at room 30min, separatory, organic phase is used respectively 30mL 10%Na
2s
2o
4the aqueous solution and 50mL water washing, anhydrous sodium sulfate drying, precipitation, column chromatography obtains white solid product 0.4g, yield 92%, fusing point 219-221 ℃;
1h NMR (400MHz, CDCl
3): δ=8.50 (d, J=8.7Hz, 1H, ArH), 8.35 (s, 1H, NH), 7.58-7.64 (m, 2H, ArH), 7.36 (dd, J=8.2,5.6Hz, 2H, ArH), 7.22-7.27 (m, 3H, ArH), (7.05 t, J=8.6Hz, 2H, ArH), 4.66 (d, J=5.6Hz, 2H, ArCH
2), 3.91 (s, 3H, OMe), 3.50 (s, 3H, NMe) ppm; HRMS (ESI) calcd for C
24h
18f
2n
3o
3(M-H)
-: 434.1322, found:434.1329.
Synthesizing of Compound I-23:
In the reaction flask of 100mL, add 0.17g (0.4mmol) raw material I-12,0.16g (1.2mmol) aluminum chloride, the 60mL methylene dichloride, drip 0.38g (4.8mmol) pyridine under magnetic agitation, reaction 28h, acid adjustment, thin up, dichloromethane extraction, anhydrous sodium sulfate drying, precipitation, column chromatography obtains white solid product 0.12g, yield 74%, fusing point 195-197 ℃;
1h NMR (400MHz, CDCl
3): δ=13.58 (s, 1H, OH), 8.60 (d, J=8.7Hz, 1H, ArH), 8.51 (s, 1H, NH), 7.62 (dd, J=8.6,5.2Hz, 2H, ArH), 7.38 (dd, J=8.3,5.6Hz, 2H, ArH), 7.23-7.30 (m, 3H, ArH), 7.04 (t, J=17.3Hz, 2H, ArH), 4.69 (d, J=5.6Hz, 2H, ArCH
2), 3.52 (s, 3H, NMe) ppm; HRMS (ESI) calcd for C
23h
16f
2n
3o
3(M-H)
-: 420.1165, found:420.1160.
Embodiment 2: chemical structural formula and the physical constant of part quinazoline compounds I, in Table 1:
Chemical structural formula and the physical constant of table 1. part quinazoline compounds I
Embodiment 3: the mensuration of HIV (human immunodeficiency virus)-resistant activity, and the mensuration program is as follows:
1 test material:
1. TZM cell: a kind of clone that can respond the HIV-1 virus infection;
2. HIV-1 pseudovirus: by the plasmid of HIV-1 coating disappearance with the plasmid of VSVG coating is provided (Proc.Natl.Acad.Sci.USA 1993,90,8033-8037) assemble after the transfection, are that to be prepared into viral liquid storage standby in experiment;
3. detection of drugs: positive control medicine AZT, positive control medicine Raltegravir (NIH provides), quinazoline compounds I.
2 testing method
1, (J.Immunol.Methods 1983,65, and 55-63): inoculation TZM-BL cell is in 96 orifice plates, and every hole spreads 10 in mtt assay cell toxicant test
4individual cell adds certain density medicine to be measured when cell grows to 50%-60% degree of converging, and detects cell survival rate after 48h.This experiment adopts SRB (sulphonyl rhodamine) staining to detect cell survival rate.After cell cultures 48h, use fixedly 1h (4 ℃) of 50%TCA (trichoroacetic acid(TCA)), then wash with water 5 times, room temperature is dried; Add 0.4%SRB dyeing, room temperature 0.5h, 1% acetic acid washing 5 times, room temperature is dried; Add the not Tris solution of the 10mM of buffering to dissolve the dyestuff of combination, photometry absorption value under 490nm-530nm.
Cell toxicant=(OD that only adds medicine
490the OD of the cell background of/not dosing
490) * 100%.
2, virus suppresses experiment: the TZM indicating clone is inoculated to 96 porocyte culture plates; Add medicine to be measured after 24h; After drug incubation 4h, add the HIV-1 pseudovirus to infect; Examining report genetic expression after infection 48h, indicator virus infection conditions (if medicine has restraining effect to virus, virus infection descends, and reporter gene activity reduces).
Annotate: the cell concentration identical (10 of inoculating in each every hole
4individual), medicine to be measured is established 3 holes and is repeated, and the every hole of pseudovirus adds 15 TCID
50amount.
Inhibiting rate=(only add viral uciferase activity-Jia virus and add the medicine uciferase activity)/(only adding viral uciferase activity-background fluorescence element enzymic activity) * 100%.
Because the medicine had has very strong cytotoxic activity, cell has all been killed, so uciferase activity is very low, the inhibiting rate recorded like this can not reflect real suppression efficiency, so use following formula to carry out the comprehensive evaluation to medicine:
Suppression efficiency=inhibiting rate * to the activation per-cent (cell toxicant) of background.
The inhibition active testing result that table 2 is part of compounds.
The HIV (human immunodeficiency virus)-resistant activity test result of table 2 part quinazoline compounds I under 10 μ M concentration
Data from table 2, majority of compounds has shown good HIV (human immunodeficiency virus)-resistant activity, absolutely prove that novel quinazoline quinoline compounds I can suppress the infection of HIV, especially Compound I-2, I-23, I-24 and I-29 can be used as new guide and further optimize.
Embodiment 4: the mensuration of anti-TMV activity, and the mensuration program is as follows:
1, virus is purified and concentration determination:
Virus is purified and concentration determination is given birth to and surveyed chamber establishment tobacco mosaic virus (TMV) SOP regulation enforcement with reference to Nankai University's element.The virus crude extract, after 2 polyoxyethylene glycol centrifugal treating, is measured concentration, and 4 ℃ of refrigerations are standby.
2, compound solution preparation:
After weighing, former medicine adds DMF to dissolve, and makes 1 * 10
5μ g/mL mother liquor, rear use is diluted to desired concn containing the 1 ‰ tween 80 aqueous solution; The Ningnanmycin preparation directly is watered dilution.
3, vitro treatment effect:
The of the right age blade of the western cigarette of frictional inoculation coral, rinse virus concentration 10 μ g/mL with flowing water.After receipts are dry, cut, along arteries and veins in leaf, to cuing open, left and right half leaf is dipped in respectively in 1 ‰ tween water and medicament, after 30min, takes out, and under suitable illumination temperature, moisturizing is cultivated, and every 3 leaves are to repeat for 1 time, repeat 3 times.Record the scab number after 3d, calculate preventive effect.
4, live body provide protection:
Select the western cigarette of 3-5 leaf phase coral of growing way uniformity, the complete stool spray pesticide, every processing repeats for 3 times, and establishes 1 ‰ tween 80 aqueous solution contrasts.After 24h, blade face spreading silicon carbide (500 order), dip virus liquid with writing brush, on full blade face, along the offshoot direction, dabs 2 times, and the blade below is supported with palm, and virus concentration 10 μ g/mL, rinse with flowing water after inoculation.Record the scab number after 3d, calculate preventive effect.
5, live body therapeutic action:
Select the western cigarette of 3-5 leaf phase coral of growing way uniformity, with the full leaf virus inoculation of writing brush, virus concentration is 10 μ g/mL, after inoculation, with flowing water, rinses.After blade face is received and is done, the complete stool spray pesticide, every processing repeats for 3 times, and establishes 1 ‰ tween 80 aqueous solution contrasts.Record the scab number after 3d, calculate preventive effect.
6, live body passivation:
Select the western cigarette of 3-5 leaf phase coral of growing way uniformity, by medicament with after isopyknic viral juice mixing passivation 30min, frictional inoculation, virus concentration 20 μ g/mL, rinse with flowing water after inoculation, repeats 3 times, establishes 1 ‰ tween 80 aqueous solution contrasts.Number scab number after 3d, calculation result.
Inhibiting rate (%)=[(contrast withered spot number-processing withered spot number)/contrast withered spot number] * 100%
The inhibition active testing result that table 3 is part of compounds.
The anti-TMV active testing result of table 3 part quinazoline compounds I
Data from table 3, part of compounds has shown good anti-TMV activity, though, not as good as the commercialization kind, can be used as new guide and further optimize.
Claims (7)
1. the novel quinazoline quinoline compounds I (Fig. 1) of structure shown in following general formula, in formula, R
1represent the alkoxyl group of H, 1-10 carbon, the alkylamino radical of 1-10 carbon, the substituted benzyloxy of 1-10 carbon, the alpha substituted benzylamine base of 1-10 carbon, the alkyl of 1-10 carbon; R
2represent OH, F, Cl, Br, I
2, the alkoxyl group of 1-10 carbon, the alkylamino radical of 1-10 carbon, the substituted benzyloxy of 1-10 carbon, the alpha substituted benzylamine base of 1-10 carbon, 1-10 carbon acyloxy, 1-10 carbonamido, 1-10 carbon alkyl carbonyl; R
3represent the alkyl of H, 1-10 carbon, the substituted benzyl of 1-10 carbon; R
4represent H, the substituted benzyl of the alkylamino radical of the alkyl of 1-10 carbon, 1-10 carbon, the alpha substituted benzylamine base of 1-10 carbon, 1-10 carbon, the substituted aryl of 1-10 carbon, 1-10 carbon containing heterocyclic substituent; R
5represent singly-bound, H; R
6represent the alkyl of singly-bound, H, 1-10 carbon, the substituted aryl of the substituted benzyl of 1-10 carbon, 1-10 carbon, 1-10 carbon containing heterocyclic substituent.
Fig. 1
It is characterized in that the compound shown in preferred general formula I is:
N-(4-luorobenzyl)-2-(4-fluorophenyl)-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-1;
N-(4-luorobenzyl)-2-(4-nitrophenyl)-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-2;
N-(4-luorobenzyl)-2-(2-furyl)-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-3;
N-(4-luorobenzyl)-2-(2-thienyl)-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-4;
N-(4-luorobenzyl)-2-(2-pyridyl)-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-5;
N-(4-luorobenzyl)-2-(3-pyridyl)-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-6;
N-(4-luorobenzyl)-2-normal-butyl-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-7;
N-(4-luorobenzyl)-2-tertiary butyl-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-8;
N-(4-luorobenzyl)-2-(4-luorobenzyl)-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-9;
N-(4-luorobenzyl)-2-(4-nitrobenzyl)-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-10;
N-(4-luorobenzyl)-2-(Z-styryl)-3-methyl-5-methoxyl group-4-oxo-1,2,3,4-tetrahydro quinazoline-6-methane amide I-11;
N-(4-luorobenzyl)-2-(4-fluorophenyl)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-12;
N-(4-luorobenzyl)-2-(4-nitrophenyl)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-13;
N-(4-luorobenzyl)-2-(2-furyl)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-14;
N-(4-luorobenzyl)-2-(2-thienyl)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-15;
N-(4-luorobenzyl)-2-(2-pyridyl)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-16;
N-(4-luorobenzyl)-2-(3-pyridyl)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-17;
N-(4-luorobenzyl)-2-normal-butyl-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-18;
N-(4-luorobenzyl)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-19;
N-(4-luorobenzyl)-2-(4-luorobenzyl)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-20;
N-(4-luorobenzyl)-2-(4-nitrobenzyl)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-21;
N-(4-luorobenzyl)-2-(Z-vinylbenzene)-3-methyl-5-methoxyl group-4-oxo-3,4-dihydroquinazoline-6-methane amide I-22;
N-(4-luorobenzyl)-2-(4-fluorophenyl)-3-methyl-5-hydroxyl-4-oxo-3,4-dihydroquinazoline-6-methane amide I-23;
N-(4-luorobenzyl)-2-(4-nitrophenyl)-3-methyl-5-hydroxyl-4-oxo-3,4-dihydroquinazoline-6-methane amide I-24;
N-(4-luorobenzyl)-2-(2-furyl)-3-methyl-5-hydroxyl-4-oxo-3,4-dihydroquinazoline-6-methane amide I-25;
N-(4-luorobenzyl)-2-(2-thienyl)-3-methyl-5-hydroxyl-4-oxo-3,4-dihydroquinazoline-6-methane amide I-26;
N-(4-luorobenzyl)-2-(2-pyridyl)-3-methyl-5-hydroxyl-4-oxo-3,4-dihydroquinazoline-6-methane amide I-27;
N-(4-luorobenzyl)-2-normal-butyl-3-methyl-5-hydroxyl-4-oxo-3,4-dihydroquinazoline-6-methane amide I-28;
N-(4-luorobenzyl)-2-(4-luorobenzyl)-3-methyl-5-hydroxyl-4-oxo-3,4-dihydroquinazoline-6-methane amide I-29;
N-(4-luorobenzyl)-2-(4-nitrobenzyl)-3-methyl-5-hydroxyl-4-oxo-3,4-dihydroquinazoline-6-methane amide I-30.
2. a method for preparing easily quinazoline compounds I, developed the synthetic method shown in equation 1: the 2-methyl-5-amino-phenol of at first take is raw material, through pivaloyl group protect 2, then after methylating 3.The ortho position carboxylation reaction obtains sour 4; obtain 5 with aminolysis after Vinyl chloroformate becomes acid anhydride; obtain 6 after potassium permanganate oxidation; with NSC 158269, react again 7; deprotection obtains crucial synthon 8; be dehydrated into and encircle to obtain I-1～11 with corresponding aldehyde again, next by the iodine oxidation style, make I-12～22, finally under aluminum chloride and pyridine condition, demethylation makes Compound I-23～30.
Equation 1
Equation 1 is used for illustrating the synthetic method of general formula I, but do not limit the application of this synthetic method, R represents H, the substituted benzyl of the alkylamino radical of the alkyl of 1-10 carbon, 1-10 carbon, the alpha substituted benzylamine base of 1-10 carbon, 1-10 carbon, the substituted aryl of 1-10 carbon, 1-10 carbon containing heterocyclic substituent.
3. according to the preparation method of quinazoline compounds I claimed in claim 2, it is characterized in that: the operation according to equation 1 can be prepared novel quinazoline quinoline compounds I-1～30 easily by 2-methyl-5-amino-phenol (1).
4. the application of quinazoline compounds I claimed in claim 1, is characterized in that their HIV (human immunodeficiency virus)-resistant activity suppressing well hiv virus (HIV).
5. according to the application of quinazoline compounds I claimed in claim 4, it is characterized in that N-(4-luorobenzyl)-2-(4-fluorophenyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-1, N-(4-luorobenzyl)-2-(4-nitrophenyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-2, N-(4-luorobenzyl)-2-(2-furyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-3, N-(4-luorobenzyl)-2-(2-thienyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-4, N-(4-luorobenzyl)-2-(2-pyridyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-5, N-(4-luorobenzyl)-2-normal-butyl-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-7, N-(4-luorobenzyl)-2-(4-luorobenzyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-9, N-(4-luorobenzyl)-2-(4-fluorophenyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-12, N-(4-luorobenzyl)-2-(2-furyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-14, N-(4-luorobenzyl)-2-(2-thienyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-15, N-(4-luorobenzyl)-2-(2-pyridyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-16, N-(4-luorobenzyl)-2-normal-butyl-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-18, N-(4-luorobenzyl)-2-(4-fluorophenyl)-3-methyl-5-hydroxyl-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-23, N-(4-luorobenzyl)-2-(4-nitrophenyl)-3-methyl-5-hydroxyl-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-24, N-(4-luorobenzyl)-2-(2-furyl)-3-methyl-5-hydroxyl-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-25, N-(4-luorobenzyl)-2-(2-thienyl)-3-methyl-5-hydroxyl-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-26, N-(4-luorobenzyl)-2-normal-butyl-3-methyl-5-hydroxyl-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-28, N-(4-luorobenzyl)-2-(4-luorobenzyl)-3-methyl-5-hydroxyl-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-29, N-(4-luorobenzyl)-2-(4-nitrobenzyl)-3-methyl-5-hydroxyl-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-30 has HIV and suppresses active.
6. the application of quinazoline compounds I claimed in claim 1, is characterized in that their anti-TMV activity suppressing well tobacco mosaic virus (TMV) (TMV).
7. according to the application of quinazoline compounds I claimed in claim 6, it is characterized in that N-(4-luorobenzyl)-2-(4-fluorophenyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-1, N-(4-luorobenzyl)-2-(4-nitrophenyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-2, N-(4-luorobenzyl)-2-(2-furyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-3, N-(4-luorobenzyl)-2-(2-thienyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-4, N-(4-luorobenzyl)-2-(2-pyridyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-5, N-(4-luorobenzyl)-2-(3-pyridyl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-6, N-(4-luorobenzyl)-2-tertiary butyl-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-8, N-(4-luorobenzyl)-2-(Z-styryl)-3-methyl-5-methoxyl group-4-oxo-1, 2, 3, 4-tetrahydro quinazoline-6-methane amide I-11, N-(4-luorobenzyl)-2-(4-fluorophenyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-12, N-(4-luorobenzyl)-2-(2-furyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-14, N-(4-luorobenzyl)-2-(2-thienyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-15, N-(4-luorobenzyl)-2-(2-pyridyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-16, N-(4-luorobenzyl)-2-(3-pyridyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-17, N-(4-luorobenzyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-19, N-(4-luorobenzyl)-2-(4-luorobenzyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-20, N-(4-luorobenzyl)-2-(4-nitrobenzyl)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-21, N-(4-luorobenzyl)-2-(Z-vinylbenzene)-3-methyl-5-methoxyl group-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-22, N-(4-luorobenzyl)-2-(2-thienyl)-3-methyl-5-hydroxyl-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-26, N-(4-luorobenzyl)-2-(4-nitrobenzyl)-3-methyl-5-hydroxyl-4-oxo-3, 4-dihydroquinazoline-6-methane amide I-30 has anti-TMV activity, though not as good as the commercialization kind, but can be used as new guide further optimizes.
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| CN108250152A (en) * | 2018-01-24 | 2018-07-06 | 浙江师范大学 | It is a kind of with the 3,4- dihydroquinazoline derivatives and its synthetic method of antibacterial activity and application |
| WO2021204669A1 (en) | 2020-04-07 | 2021-10-14 | Bayer Aktiengesellschaft | Substituted isophthalic acid diamides |
| WO2021204667A1 (en) | 2020-04-07 | 2021-10-14 | Bayer Aktiengesellschaft | Substituted isophthalic acid diamides |
| WO2021204665A1 (en) | 2020-04-07 | 2021-10-14 | Bayer Aktiengesellschaft | Substituted isophthalic acid diamides |
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| CN1270593A (en) * | 1997-09-12 | 2000-10-18 | 诺瓦提斯公司 | Pyrimidin-4-one and pyrimidin-4-thione as fungicide |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108250152A (en) * | 2018-01-24 | 2018-07-06 | 浙江师范大学 | It is a kind of with the 3,4- dihydroquinazoline derivatives and its synthetic method of antibacterial activity and application |
| CN108250152B (en) * | 2018-01-24 | 2021-04-13 | 浙江师范大学 | 3, 4-dihydroquinazoline derivative with antibacterial activity and synthetic method and application thereof |
| WO2021204669A1 (en) | 2020-04-07 | 2021-10-14 | Bayer Aktiengesellschaft | Substituted isophthalic acid diamides |
| WO2021204667A1 (en) | 2020-04-07 | 2021-10-14 | Bayer Aktiengesellschaft | Substituted isophthalic acid diamides |
| WO2021204665A1 (en) | 2020-04-07 | 2021-10-14 | Bayer Aktiengesellschaft | Substituted isophthalic acid diamides |
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Application publication date: 20130605 Assignee: TIANJIN QUANHECHENG TECHNOLOGY Co.,Ltd. Assignor: NANKAI University Contract record no.: X2024980002700 Denomination of invention: Quinazoline derivatives and their preparation methods, anti HIV activity and anti TMV activity Granted publication date: 20150408 License type: Common License Record date: 20240312 |