CN102267935B - Indoquinone derivatives, and preparation method and application thereof - Google Patents

Indoquinone derivatives, and preparation method and application thereof Download PDF

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CN102267935B
CN102267935B CN2011101579319A CN201110157931A CN102267935B CN 102267935 B CN102267935 B CN 102267935B CN 2011101579319 A CN2011101579319 A CN 2011101579319A CN 201110157931 A CN201110157931 A CN 201110157931A CN 102267935 B CN102267935 B CN 102267935B
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CN102267935A (en
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范志金
瓜勒姆·瓜弟尔
那斯姆·汗山·拉姆
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Nankai University
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention provides compounds containing indoquinone, and a preparation method and application thereof. The invention relates to heterocyclic compounds containing N, the chemical general formula of which is disclosed as V. The invention discloses a general formula and synthesis method of the compounds, and application of the compounds as bactericide, weedicide and plant growth regulator. The compounds can be mixed with agriculturally acceptable assistants or synergists to prepare bactericide, weedicide and plant growth regulator. The invention also discloses application of the compounds inthe fields of agriculture, forestry and horticulture when being combined with commercial bactericide, weedicide and plant growth regulator, and a preparation method of the compounds. The invention also discloses antivirus activity of the compounds, application of the compounds in preventing and treating mammal diseases when being combined with commercial antiviral agents, and a preparation methodof the compounds.

Description

One class isatin derivative and its production and use
Technical field
Technical scheme of the present invention relates to and contains the isatin derivative, is specifically related to the various isatin derivative of chlorine and bromine and their biological activitys of having.
Background technology
Isatin (1H-indoles-2,3-diketone) is the natural product of finding in the woaded blue platymiscium, and as an adrenergic metabolic derivative, it also is present among the human body.Some isatin derivatives have pharmacologically active (Pandeya, S.N., Smitha, S., Jyoti, M.﹠amp widely; Sridhar, S.K.Biological activities ofisatin and its derivatives.Acta Pharm.55 (2005), 27-46), discover, relevant (the Geronikaki with the activity of central nervous system of isatin and derivative thereof, A., Babaev, E., Dearden, J., et al.Design, synthesis, computational and biological evaluation of new anxiolytics.Bioorg.Med. Chem.12 (24), (2004) .6559-6568); Some isatin derivative also has antibiotic (Raj, A.A., Raghunathan, R., Sridevi Kumari, et al.Synthesis, antimicrobial and antifungal activity of a new class of spiro pyrrolidines.Bioorg.Med. Chem.11, (2003), 407-419), anticancer (Eshba, N.H.﹠amp; Salama, H.M.Pharmazie, 40, (1985) are 320-322) with anti-HIV (Pandeya, S.N., Sriram, D., Nath, G.﹠amp; De Clercq, E.Synthesis, antibacterial, antifungal and anti-HIV evaluation of schiff and mannich bases of isatin derivative with 3-amino-2-methylmercapto quinazolin-4 (3H)-one, Pharm.Acta Helv.74, (1999), 11-17) isoreactivity.Isatin also can be used as precursor compound (Bouhfid, R., Joly, N., Massoui, M., Ceechelli, R., Lequart, V., Martin, the P.﹠amp of the active heterocyclic system of synthesizing new potential source biomolecule; Essassi, E.M.Heterocycles, 56, (2005), 2949-2955).
Oxoindole (2-indolone) is present in multiple natural product (Hibino, S.; Choshi, T.Nat.Prod. Rep.2002,19,148.Somei, M.; Yamada, F.Simple indole alkaloids and those with a nonrearranged monoterpenoid unit.Nat.Prod. Rep.2003,20,216-242) with commercialization medicine (Howard, H.R.; Lowe J.A.; Seeger, T.F.; Et al.3-Benzisothiazolylpiperazine derivatives as potential a typical antipsychotic agents.J. Med. Chem.1996,29,143-148.Haynes, J.; Obiako, B.; Babal, P.; Stevens, T.; 5-(N-ethylcarboxamido) adenosine desensitizes the A2b-adenosine receptor in lung circulation.Am.J.Physiol.Heart Circul.Physiol, 1999,276,1877-1883.Liu, Y.; Liu, D.; Printzenhoff, D.; Et al.Tenidap, a novel antiinflammatory agent, is an opener of the inwardly rectifying K+ channel hKir 2.3.Eur. J.Pharmacol.2002,435,153-160.Maggio, R.; Scarselli, M.; Novi, F.; Et al.Potent activation of dopamine D3/D2 heterodimers by the antiparkinsonian agents, S32504, pramipexole and ropinirole.J. Neurochem.2003,87, the 631-641) heterogeneous ring compound in.
Patent documentation discloses multiple isatin derivative and important biological thereof, and these activity comprise anti-inflammatory activity, aldose reductase inhibition activity, tyrosine-kinase enzyme inhibition activity, weeding activity etc., and its chemical structure of general formula and biological activity see Table 1.
Consider that halogen is bioactive important activity group, the introducing of halogen atom has become newtype drug molecular designing synthetic main approaches and means, majority comprises halogen atom in commercial halo agricultural chemicals and the medical kind, and for example the disinfectant use in agriculture dimethomorph just contains the Cl atom; The introducing of bromine atoms also can improve the biological activity of target molecule greatly, for example, all contains the Br atom in bromothalonil and the bromopropylate molecule.Medicine fluconazole, Saperconazole, posaconazole etc. all contain the F atom.Therefore, in order to seek the more lead compound of high biological activity, the present invention introduces halogen atom F, Cl or Br in the isatin molecule, the full cyclohexadione compounds of halogeno indole that a class biologically active has been synthesized in design has carried out bioactive screening and the evaluation of system simultaneously.
Summary of the invention
Technical problem to be solved by this invention is: the synthetic method that new isatin compounds is provided, the biological activity and the measuring method thereof that this compounds inhibition agricultural and gardening and forestry plant harmful organism are provided and endanger mammiferous harmful organism provide the middle application of these compounds in agriculture field and gardening field and forestry and disease control field simultaneously.
The present invention solves this technical problem the technical scheme that adopts: have agriculture field, gardening field, field of forestry insecticidal activity, fungicidal activity, weeding activity, chemical structure of general formula plant growth regulating activity and resisting mammal virus activity isatin compounds and see formula V:
Figure BSA00000516057100021
Wherein, when X=0: R=3,5-F 2, R "=Cl; R=2,5-F 2, R "=Cl; R=2,4-(OCH 3) 2, R "=Cl; R=2,6-(OCH 3) 2, R "=Cl; R=2,5-F 2, R "=Br; R=3,5-F 2, R "=Br; R=2,4-(OCH 3) 2, R "=Br; R=2,6-(OCH 3) 2, R "=Br; Work as X=OCH 2CH 2The time: R=2,4-Cl 2, R "=Cl; As X=(CH 2) 2The time: R=3,4,5 (OCH 3) 3, R "=Cl; R=4-OCH 3, R "=Cl; R=3,4,5 (OCH 3) 3, R "=Br; R=4-OCH 3, R "=Br.
The synthetic method of isatin compounds V of the present invention is as follows:
Figure BSA00000516057100022
Wherein, when X=0, R=3,5-F 2, R "=Cl; R=2,5-F 2, R "=Cl; R=2,4-(OCH 3) 2, R "=Cl; R=2,6-(OCH 3) 2, R "=Cl; R=2,5-F 2, R "=Br; R=3,5-F 2, R "=Br; R=2,4-(OCH 3) 2, R "=Br; R=2,6-(OCH 3) 2, R "=Br; Work as X=OCH 2CH 2The time: R=2,4-Cl 2, R "=Cl; As X=(CH 2) 2The time: R=3,4,5 (OCH 3) 3, R "=Cl; R=4-OCH 3, R "=Cl; R=3,4,5 (OCH 3) 3, R "=Br; R=4-OCH 3, R "=Br.
Specifically be divided into following steps:
A. the preparation of isatin compounds V:
In 50 milliliters of round-bottomed flasks, add the full diketone IV of 10 mmole 5-halogeno indoles and 10 milliliters of ethanol, stir down and drip 10 mmole substituted formyl hydrazine III, after dropwising, stirred backflow 5-6 hour down, cooling leaches precipitation and washes with water, and recrystallization is carried out with ethanol in dry back; With the pure product calculated yield of gained, carry out the mensuration of fusing point, NMR, IR and MS, the amount of synthetic compound V enlarges by corresponding proportion or dwindles; The volume of respective reaction container enlarges in proportion or dwindles; Commercially available compound III also has effect same; Compound chemical structure sees Table 2.
B. the mensuration of isatin compounds V weeding activity:
The seed kind in the diameter that contains artificial mixed soil is 7.5 centimetres Disposable paper cup (250 milliliters), before plant sprouts, is covered dixie cup to keep moist with plastics film.Plant is placed in the greenhouse and grows, and 21 days mensuration overground part fresh weights suppress percentage after dispenser; Application method adopts the preceding soil treatment of bud, sprays the compound solution of preparation after the seed plantation immediately, and every processing repeats twice; Cauline leaf is handled behind the bud, launches the compound solution that preparation is sprayed in the back at first true leaf; The using dosage of each compound (effective constituent) is 1500 grams/hectare.At 100 microlitre N, dinethylformamide also adds a spot of tween 20, uses atomizers spray then with pure compound dissolution, and the sprinkling amount is 750 liters/hectare; Spray with the water of measuring in contrast; The test target be respectively swede type rape (Brassica napus) (BN), three-coloured amaranth (Amaranthus retroflexus.) (AR), barnyard grass grass (Echinochloa crusgalli (L.) Beauv.) (EC) and lady's-grass (Digitaria adscendens) (DA); Activity level is divided into: A: 〉=80%, B:60～79%, C:40～59%, D :≤39%.
C. the mensuration of isatin compounds V fungicidal activity:
Isatin compounds V sterilization of the present invention or bacteriostatic activity adopt thalli growth rate assay method, detailed process is: get 5 milligrams of sample dissolution in an amount of dimethyl formamide, then with containing the medicament that a certain amount of polysorbas20 emulsifier aqueous solution is diluted to 500 mcg/ml, reagent agent is respectively drawn under aseptic condition in 1 milliliter of injection culture dish, add 9 milliliters of substratum more respectively, make 50 mcg/ml pastille flat boards after shaking up, do blank with the flat board that adds 1 milliliter of aqua sterilisa, punch tool with 4 millimeters of diameters cuts the bacterium dish along the mycelia outer rim, move on the pastille flat board, being equilateral triangle puts, every processing repeats 3 times, culture dish is placed on cultivation in 24 ± 1 degrees centigrade of constant incubators, colony diameter to be contrasted expands to 2-3 centimetre of " Invest, Then Investigate " and respectively handles bacterium dish expansion diameter, average, relatively calculate relative bacteriostasis rate with blank, comprise frequently seen plants pathogenic bacteria on the various agricultural for the examination bacterial classification, its title and code name comprise AS: tomato early blight bacterium (Alternaria solani); CA: peanut Cercospora bacteria (Cercospora arachidicola); FO: cucumber wither (Fusarium oxysporum f.cucumerinum); GZ: fusarium graminearum (Gibberella zeae); PP: ring rot of apple bacterium (Physalospora piricola); These pathogenic fungies can represent the kind of most of pathogenic bacteria of the actual generation in field in agriculture production.
D. the mensuration of the mythimna separata insecticidal activity of isatin compounds V of the present invention:
The mythimna separata of isatin compounds V of the present invention (Mythimna separata, Walker) screening method of the insecticidal activity of (MSW) is as follows: adopt the blade medicine embrane method; Sample carries out active primary dcreening operation with 200 mg/litre earlier.Former medicine is earlier with the small amount of acetone dissolving, and with 0.5 ‰ Triton-100 dilution, 0.5 ‰ Triton-100 water are contrast then, and each concentration repeats for 4 times, and about 10 of each re-treatments try worm; Get fresh free of contamination maize leaf, in the soup of series concentration gradient, soaked 10 seconds, after indoor drying (about 2 hours), put into the culture dish of 9 centimetres of diameters, insert 2 initial stage in age of the mythimna separata larva of big or small basically identical respectively; Tighten with bungee and to be placed in the mythimna separata constant temperature insectary check result and calculation correction mortality ratio after 24 hours; Touching polypide with little writing brush or tweezers, can not coordinated movement be dead.
E. the mensuration of the aphid insecticidal activity of isatin compounds V of the present invention:
The screening method of the insecticidal activity of the aphid larva of isatin compounds V of the present invention is as follows: adopt pickling process, black bean aphid (Aphis laburni Kaltenbach) (ALK), the normal population of indoor feeding; Take by weighing 2.5 milligrams of test compounds in beaker, drip 1 N, dinethylformamide (DMF) adds 5 milliliters of acetone vibration dissolving samples, adds the solution to be measured that the water that tween 80 is arranged is mixed with 200 mcg/ml again; To have from basin, cutting for examination broad bean plant of at least 60 black bean aphids, in each soup to be measured, flooded for 5 seconds, take out and get rid of unnecessary soup gently, be inserted in and preserved moisture on the water saturated sponge, treat that the dried back of soup is with on the lens cover, the opening of lens upper end seals with gauze in case aphid escapes, check the aphid death state after raising placement 24h, standard is: can creep with the examination worm and maybe can stand or six legs can strenuous exercises is worm alive, be contrast with the clear water, each concentration repeats 3 times, with the mean value calculation corrected mortality; Activity level: A: 〉=80%, B:60～79%, C:40～59%, D :≤39%.
F. the cucumber cotyledons of the isatin compounds V of the present invention active mensuration of taking root:
The cucumber cotyledons of the isatin compounds V of the present invention active screening method of taking root is as follows: cucumber variety is that grind No. 4 in Tianjin; Take by weighing 1.0 milligrams of test compounds in small beaker, use N, dinethylformamide (DMF) is mixed with the mother liquor of 100 mcg/ml, the DMF drips of solution of getting 0.3 milliliter of 100 mcg/ml is on 6 centimetres the scraps of paper to diameter, air-dry being placed in the culture dish (6 centimetres), add 3 ml distilled waters and 10 cucumber cotyledons then in culture dish, finally measuring concentration is 10 mcg/ml; Cucumber cotyledons is in the dark soaked three days (26 ± 1 ℃) by seed and is cultivated preparation in agar.Also calculate the increase per-cent of taking root in the quantity of handling 5 days (26 ± 1 ℃) back inspection generation adventive root; Be contrast with the clear water, each concentration repeats 3 times; Activity level: A: 〉=80%, B:60～79%, C:40～59%, D :≤39%.
G. the mensuration of isatin compounds V antiviral activity of the present invention:
The method of the mensuration reference literature of the antiviral activity of the VZV of isatin compounds V of the present invention, CMV, HIV-1, HIV-2, vaccinia virus, vesicular stomatitis virus, Coxsackie B virus 4, respiratory syncytial virus, parainfluenza virus-3, reovirus-1, sindbis alphavirus and Punta Toro virus is carried out: Waitz, J.A; Deuve, C.G.Annu.Rep.Med.Chem., 1972,7,109; De Clercq, E.; M.Luczak, J.C.; Reepmeyer, K.; Kirk, L.; Cohen, L. A.Life Sci.1975,17,187; De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P. C.Nature, 1986,323,464.Virus: hsv-1 (KOS strain), hsv-2 (G strain), vaccinia virus, vesicular stomatitis virus, Coxsackie B virus 4, sindbis alphavirus, Measles virus and poliovirus-1, reovirus-1 (ATCC VR-230), Semliki Forest virus (ATCC VR-67), parainfluenza virus-3 (ATCC VR-93) (ATCC, Rockville, Md.); Viral growth is in former generation rabbit kidney cell (herpes simplex virus 1 and 2, vaccinia virus and vesicular stomatitis virus), HeLa cell (poliovirus), chick-embryo cell (sindbis alphavirus) or human embryonic lung cell (parainfluenza virus); Make regular check on Vero of the present invention and whether the HeLa cell strain has mycoplasma infection.
The cytopathogenic mensuration of virus induction exsomatizes
With the inoculation of the fused cell culture in microtiter tray dilution, so that 50% cell culture infects virus; Virus by cell absorption 1 hour after, residue virus is removed or is contained cell culture medium (the Yi Ge Er Shi basal component substratum) replacement of the test compounds of 3% foetal calf serum and various concentration; In case untreated virus infected cell culture is finished cytopathy and just recorded pathological changes caused by virus, herpetic stomatitis needs 1～2 day at once; Semliki Forest, COxsackie and poliovirus need 2 days; Bovine vaccine, herpes simplex virus 1 and 2 and sindbis alphavirus need 2～3 days; Exhale intestines orphan, parainfluenza and Measles virus to need 6～7 days; The antiviral activity of compound is expressed by suppressing the required concentration of 50% pathological changes caused by virus.
Cytotoxic mensuration
Cytotoxic measurement is based on following two parameters: the variation of normal cell form; To the synthetic restraining effect of host cell macromole (DNA, RNA and protein).In order to assess the metamorphosis of cell, the fused cell of handling with the test compounds of various different concns rather than the fused cell culture of infection carry out parallel breeding simultaneously and examine under a microscope, and the cell that record virus infected cell culture causes is pathogenic.The division of cell monolayer, cell rounding or separation are considered to the evidence of cytotoxic effect.In order to measure the restraining effect synthetic to the host cell macromole, cell is implanted to Yi Ge Er Shi basal component substratum (contains 10% foetal calf serum, [methyl-3H] thymidine of the test compounds of various concentration and 2.5 microcurie/milliliters, [5-3H] urea glycosides or [4,5-3H] leucine) in the Linbro microtiter well in (contain 300 in every hole, 000 to 400,000 cell), bred 16 hours down in 37 ℃.Handle with 5% ice-cold trichoroacetic acid(TCA) then, use 95% washing with alcohol again 5 times, the radioactive intensity in 7.5 milliliters of Lipoluma scintillation solutions is calculated in air-dry back.
The mensuration of live body antiviral activity
The live body antiviral activity is by measuring to newborn (be born two days) NMRI mouse vesicular stomatitis virus and Coxsackie B virus 4 and to the restraining effect of (being born 25 days) the NMRI mouse vesicular stomatitis virus that weans.Newborn (being born two days) mouse is adopted the hypodermis injection inoculation, and the vesicular stomatitis virus consumption is per 0.1 milliliter of every the mouse of 4PFU (PFU measures in the L-929 of mouse cell); Coxsackie B virus 4 consumptions are per 0.1 milliliter of every the mouse of 5CCID50 (CCID50 measures in the Vero of mouse cell).At this moment, mouse or accepted the single intraperitoneal injection of compound (0.1 ml physiological saline solution) in back 1 hour in infection, or back 1 hour of infection with accepted the repetition abdominal injection of compound in 1～2 day.Wean (the being born 25 days) mouse of body weight 11～13 grams is adopted collunarium inoculation vesicular stomatitis virus, consumption is per 0.02 milliliter of every the mouse of 40PFU, mouse or accepted the single intraperitoneal injection of compound (0.5 ml physiological saline solution) in back 1 hour in infection then, or back 1 hour of infection with accepted the repetition abdominal injection of compound in 1～4 day.
Anti-influenza virus activity in the mdck cell culture and Cytotoxic mensuration
Select three kinds of influenza virus sub-strains [A/Puerto Rico/8/34 (H1N1), A/Hong Kong/7/87 (H3N2) and B/Hong Kong/5/72] as viral for examination.By the cytopathic restraining effect of virus induction being measured the antiviral activity of compound, this restraining effect can be finished by microscopic examination and/or based on the MTS cytoactive assay method of formazan.The cytotoxicity of test compounds can cause the concentration (MCC) of cellular form subtle change to express by compound, perhaps determines to cause 50% cytotoxicity (CC by the MTS method of testing 50) time concentration express.
The invention has the beneficial effects as follows: the present invention has carried out the optimization of first guide structure to isatin compounds V, and synthetic new compound carried out the screening of desinsection, antibacterial and weeding and plant growth regulating activity, resisting mammal virus activity, this compounds can be used for the control of plant disease pest and weed in control agriculture field and field of forestry and gardening field and the control that Mammals is had harmful virus of damaging effect.
The present invention will more specifically describe synthetic and biological activity and the application thereof of isatin compounds V by specific preparation and biological activity determination embodiment, described embodiment only is used for specific description the present invention and unrestricted the present invention, especially its biological activity only illustrates, and unrestricted this patent, embodiment is as follows:
Embodiment 1:(E)-and N '-(5-chloro-2-oxindole alkane-3-subunit)-3,5-difluoro benzoyl hydrazine (10):
The full diketone of 5-chloro-indole (1.81 grams, 0.01 mole) and 3,5-difluoro benzoyl hydrazine (1.72 grams, 0.01 mole) are placed ethanol (10 milliliters), and back flow reaction cool off after 5 hours, leached precipitation and washed with water, carried out recrystallization with ethanol after the drying; Productive rate: 89%; M.p:178-179 degree centigrade; IR (KBr, v Max, cm -1): 3281 (NH stretching), 3084 (sp 2CH stretching), 1710 (C=O), 1677 (C=N), 1623,1460 (C=C); 1H NMR (DMSO-d6, ppm): 11.78 (1H, s, NH), 10.98 (1H, s, NH), 8.11 (1H, s, H-4), 7.68-7.43 (4H, m, H-6,2 ', 4 ', 6 '), 6.93 (1H, d, J=8.7Hz, H-7); 13C NMR (DMSO-d6, ppm): 171.3,164.7,164.2,143.3,141.7,136.7,132.8,127.4,127.1,126.0,116.8,112.9,108.0; EIMS (m/z, %): 335 (48, M +), 307 (14), 290 (2), 287 (1), 250 (2), 244 (2), 216 (1), 194 (100), 166 (53), 141 (91), 113 (56), 102 (10), 75 (7), 63 (6), 51 (2); Anal.Cald for C 15H 8ClF 2N 3O 2: C, 53.67; H, 2.40; N, 12.52; Found:C, 53.62; H, 2.45; N, 12.58.
Embodiment 2:(E)-and N '-(5-chloro-2-oxindole alkane-3-subunit)-3,5-difluoro benzoyl hydrazine (11):
With 2 of the full diketone of 5-chloro-indole (1.81 grams, 0.01 mole) and equivalent, 5-difluoro benzoyl hydrazine (1.72 grams, 0.01 mole) places ethanol (10 milliliters), and back flow reaction cool off after 5 hours, leaches precipitation and washes with water, carries out recrystallization with ethanol after the drying; Productive rate: 88%; M.p:165-166 degree centigrade; IR (KBr, max, cm -1): 3412-3237 (NH stretching), 3115 (sp 2CH stretching), 1719 (C=O), 1622 (C=N), 1308 (C-O); 1H NMR (DMSO-d6, ppm): 11.44 (1H, s, NH), 10.96 (1H, s, NH), 8.13 (1H, s, H-4), 7.72-7.41 (3H, m, H-3 ', 4 ', 6 '), 7.08-6.79 (2H, m, H-6,7); 13C NMR (DMSO-d6, ppm): 170.5,162.2,160.7,159.1,145.3,133.7,132.8,131.4,129.1,127.5,124.0,121.9,120.8,118.5,116.9; EIMS (m/z, %): 335 (24, M+), 307 (24), 291 (1), 290 (1), 250 (1), 232 (2), 224 (1), 194 (55), 166 (37), 141 (100), 113 (44), 102 (12), 75 (7), 63 (7), 51 (1); Anal.Cald for C 15H 8ClF 2N 3O 2: C, 53.67; H, 2.40; N, 12.52; Found:C, 53.66; H, 2.43; N, 12.53.
Embodiment 3:(E)-N '-(5-chloro-2-oxindole alkane-3-subunit)-2-(2,4 dichloro benzene oxygen base) propionyl hydrazine (12):
With the full diketone of 5-chloro-indole (1.81 grams, 0.01 mole) and 2-(2,4 dichloro benzene oxygen base) propionyl hydrazine (2.77 grams, 0.01 mole) place ethanol (10 milliliters), back flow reaction was cooled off after 5 hours, leached precipitation and washed with water, and recrystallization is carried out with ethanol in dry back; Productive rate: 82%; M.p:116-117 degree centigrade; IR (KBr, max, cm -1): 3226 (NH stretching), 3096 (sp 2CH stretching), 1735 (C=O), 1615 (C=N), 1473 (C=C), 1206 (C-O); 1H NMR (DMSO-d6, ppm): 11.34 (1H, s, NH), 10.90 (1H, s, NH), 7.95 (1H, s, H-4), 7.79 (1H, s, H-4,3 '), 7.60-7.36 (2H, m, H-6,5 '), 6.78 (1H, d, J=12.3Hz, H-7,6 '), 5.38 (1H, s, CH), 1.59 (2H, s, CH 3); 13C NMR (DMSO-d6, ppm): 173.6,169.7,151.6,144.7,133.4,132.3,131.2,129.2,125.6,123.5,119.9,117.8,75.9 (CH) 15.5 (CH 3); EIMS (m/z, %): 409 (4, M +), 394 (5), 366 (8), 352 (8), 323 (9), 295 (12), 253 (16), 239 (17), 197 (20), 183 (21), 155 (23), 113 (33), 99 (38), 85 (100), 71 (97), 57 (78), 43 (18); Anal.Cald for C 17H 12Cl 3N 3O 3: C, 49.48; H, 2.93; N, 10.18; Found:C, 49.46; H, 2.99; N, 10.15.
Embodiment 4:(E)-N '-(5-chloro-2-oxindole alkane-3-subunit)-3-(3,4,5-trimethoxyphenyl) propionyl (13):
3-(3,4 with the full diketone of 5-chloro-indole (1.81 grams, 0.01 mole) and equivalent, the 5-trimethoxyphenyl) propionyl hydrazine (2.54 grams, 0.01 mole) places ethanol (10 milliliters), and back flow reaction was cooled off after 5 hours, leach precipitation and wash with water, recrystallization is carried out with ethanol in dry back; Productive rate: 86%; M.p:150-151 degree centigrade; IR (KBr, max, cm -1): 3223 (NH stretching), 3107 (sp 2CH stretching), 1739 (C=O), 1614 (C=N), 1463 (C=C), 1342 (C-O); 1H NMR (DMSO-d6, ppm): 10.42 (1H, s, NH), 8.45 (1H, s, NH), 7.55 (1H, s, H-4), 7.39 (1H, dd, J=8.4,2.0Hz, H-6), 6.93 (1H, d, J=8.0Hz, H-7), 6.58 (1H, s, H-2 ', 6 '), 3.75-3.35 (12H, s, OCH 3), 2.88 (2H, s, CH2), 2.72 (2H, s, CH 2); 13CNMR (DMSO-d6, ppm): 169.1,168.4,152.5,145.8,137.2,134.5,133.3,132.0,130.5,129.8,124.2,120.5,106.5,40.2 (CH 2), 36.4 (CH 2); EIMS (m/z, %): 417 (32, M +), 400 (4), 372 (8), 358 (3), 341 (2), 313 (2), 236 (12), 223 (7), 194 (18), 181 (100), 166 (16), 138 (12), 102 (7), 77 (6), 65 (3), 51 (2); Anal.Cald for C 20H 20ClN 3O 5: C, 57.49; H, 4.82; N, 10.06; Found:C, 57.46; H, 4.89; N, 10.00.
Embodiment 5:(E)-N '-(5-chloro-2-oxindole alkane-3-subunit)-3-(4-p-methoxy-phenyl) propionyl hydrazine (14):
With the full diketone of 5-chloro-indole (1.81 grams, 0.01 mole) and 3-(4-p-methoxy-phenyl) the propionyl hydrazine of equivalent (1.94 restrain 0.01 mole) place ethanol (10 milliliters), back flow reaction was cooled off after 5 hours, leach precipitation and wash with water, recrystallization is carried out with ethanol in dry back; Productive rate: 83%; M.p:198-199 degree centigrade; IR (KBr, max, cm -1): 3256 (NH stretching), 3074 (sp 2CH stretching), 1746 (C=O), 1680 (C=N), 1645-1486 (C=C), 1391 (C-O); 1H NMR (DMSO-d6, ppm): 10.89 (1H, s, NH), 8.27 (1H, s, NH), 7.94 (1H, s, H-4), 7.40 (1H, dd, J=8.4,1.6Hz, H-6), 7.18 (1H, dd, J=6.8,2.0Hz, H-2 ', 6 '), 6.88 (1H, d, J=8.4Hz, H-7), 6.84 (1H, dd, J=6.4,1.6Hz, H-3 ', 5 '), 3.35 (3H, s, OCH 3), 2.88 (2H, s, CH 2), 2.72 (2H, s, CH 2); 13C NMR (DMSO-d6, ppm): 169.4,168.2,158.5,144.8,133.5,133.4,132.4,130.5,129.8,128.5,124.2,120.5,115.3,39.2 (CH 2), 36.0 (CH 2); EIMS (m/z, %): 357 (18, M +), 340 (7), 312 (17), 298 (4), 277 (5), 194 (8), 176 (12), 166 (11), 121 (100), 91 (13), 77 (9), 65 (3), 51 (1); Anal.Cald for C 18H 16ClN 3O 3: C, 60.42; H, 4.51; N, 11.74; Found:C, 60.46; H, 4.41; N, 11.75.
Embodiment 6:(E)-and N '-(5-chloro-2-oxindole alkane-3-subunit)-2,6-dimethoxy benzoyl hydrazine (15):
With 2 of the full diketone of 5-chloro-indole (1.81 grams, 0.01 mole) and equivalent, 6-dimethoxy benzoyl hydrazine (1.96 grams, 0.01 mole) place ethanol (10 milliliters), back flow reaction was cooled off after 5 hours, leached precipitation and washed with water, and recrystallization is carried out with ethanol in dry back; Productive rate: 85%; M.p:155-156 degree centigrade; IR (KBr, max, cm -1): 3255 (NH stretching), 3132 (sp 2CH stretching) 1712 (C=O), 1615 (C=N), 1592-1463 (C=C), 1342 (C-O); 1H NMR (DMSO-d6, ppm): 11.48 (1H, s, NH), 7.95 (1H, s, NH), 7.59 (1H, d, J=3.6Hz, H-4), 7.44 (1H, dd, J=16.8,4.0Hz, H-6), 7.09-6.81 (1H, m, H-7,3 ', 4 ', 5 '), 3.43 (6H, s, OCH 3); 13C NMR (DMSO-d6, ppm): 169.4,163.2,160.2,145.6,135.2,133.3,132.8,124.1,121.0,119.5,108.5,106.2,56.0 (OCH 3); EIMS (m/z, %): 359 (18, M +), 331 (17), 300 (2), 288 (1), 194 (5), 165 (100), 137 (24), 122 (29), 107 (6), 77 (4), 63 (4), 51 (2); Anal.Cald forC 17H 14ClN 3O 4: C, 56.75; H, 3.92; N, 11.68; Found:C, 56.74; H, 3.95; N, 11.73.
Embodiment 7:(E)-and N '-(5-chloro-2-oxindole alkane-3-subunit)-2,4-dimethoxy benzoyl hydrazine (16):
The full diketone of 5-chloro-indole (1.81 grams, 0.01 mole) and 2,4-dimethoxy benzoyl hydrazine (1.96 grams, 0.01 mole) are placed ethanol (10 milliliters), and back flow reaction cool off after 5 hours, leached precipitation and washed with water, carried out recrystallization with ethanol after the drying; Productive rate: 80%; M.p:201-202 ℃; IR (KBr, max, cm -1): 3345 (NH stretching), 3138 (sp 2CH stretching), 1715 (C=O), 1652 (C=N), 1594-1461 (C=C), 1350 (C-O); 1H NMR (DMSO-d6, ppm): 10.96 (1H, s, NH), 8.30 (1H, s, NH), 7.61 (1H, d, J=5.2Hz, H-4), 7.44 (2H, dd, J=14.2,2.4Hz, H-6,5 '), 7.35 (2H, d, J=13.2Hz, H-7,6 '), 6.94 (1H, d, J=2.4Hz, H-3 '), 3.36 (6H, s, OCH 3); 13C NMR (DMSO-d6, ppm): 169.0,164.2,161.6,145.4,134.5,133.3,132.0,129.1,124.1,120.3,118.5,111.2,107.2,101.3,56.4 (OCH 3); EIMS (m/z, %): 359 (5, M +), 331 (8), 309 (2), 281 (3), 264 (3), 194 (4), 165 (100), 138 (8), 122 (15), 111 (9), 71 (18), 57 (21), 43 (10); Anal.Cald for C 17H 14ClN 3O 4: C, 56.75; H, 3.92; N, 11.68; Found:C, 56.64; H, 3.95; N, 11.68.
Embodiment 8:(E)-N '-(5-bromo-2-oxindole alkane-3-subunit)-3-(3,4,5-trimethoxyphenyl) propionyl hydrazine (17):
With the full diketone of 5-bromo indole (2.26 grams, 0.01 mole) and 3-(3,4, the 5-trimethoxyphenyl) propionyl hydrazine (2.54 grams, 0.01 mole) places ethanol (10 milliliters), and back flow reaction was cooled off after 5 hours, leach precipitation and wash with water, recrystallization is carried out with ethanol in dry back; Productive rate: 84%; M.p:101-102 degree centigrade; IR (KBr, max, cm -1): 3272 (NH stretching), 2940,2833,1733 (C=O), 1654 (C=N), 1594-1460 (C=C), 1241 (C-O); 1H NMR (DMSO-d6, ppm): 10.90 (1H, s, NH), 8.37 (1H, s, NH), 7.65 (1H, s, H-4), 7.51 (1H, d, J=7.6Hz, H-7), 6.88 (1H, d, J=10.4Hz, H-6), 6.56 (1H, s, H-2 ', 6 '), 3.74-3.36 (12H, s, OCH 3), 2.87 (2H, s, CH2), 2.50 (2H, s, CH 2); 13C NMR (DMSO-d6, ppm): 169.3,168.4,152.6,142.3,137.5,134.6,134.0,133.8,123.7,122.9,119.5,105.5,55.7 (OCH 3), 36.4 (CH 2), 30.4 (CH 2); EIMS (m/z, %): 463 (33, M +, Br 81), 461 (33, M +, Br 79), 418 (7, Br 81), 416 (7, Br 79), 383 (5), 337 (2), 284 (1), 236 (13), 181 (100, Br 81), 179 (11, Br 79), 151 (4, Br 81), 149 (4., Br 79), 103 (4), 77 (3), 65 (2.); Anal.Cald for C 20H 20BrN 3O 5: C, 51.96; H, 4.36; N, 9.09; Found:C, 51.99; H, 4.39; N, 9.12.
Embodiment 9:(E)-N '-(5-bromo-2-oxindole alkane-3-subunit)-3-(4-p-methoxy-phenyl) propionyl hydrazine (18):
With the full diketone of 5-bromo indole (2.26 grams, 0.01 mole) and 3-(4-p-methoxy-phenyl) the propionyl hydrazine of equivalent (1.94 restrain 0.01 mole) place ethanol (10 milliliters), back flow reaction was cooled off after 5 hours, leach precipitation and wash with water, recrystallization is carried out with ethanol in dry back; Productive rate: 80%; M.p:130-131 degree centigrade; IR (KBr, max, cm -1): 3201 (NH stretching), 3092,2836,1734 (C=O), 1648 (C=N), 1597-1511 (C=C), 1375 (C-O); 1H NMR (DMSO-d6, ppm): 10.81 (1H, s, NH), 8.42 (1H, s, NH), 7.65 (1H, s, H-4), (7.49 1H, d, J=8.4Hz, H-6,7), 7.23 (1H, d, J=6.8Hz, H-2 ', 6 '), 6.91 (1H, d, J=6.4Hz, H-3 ', 5 '), 3.38 (3H, s, OCH 3), 2.92 (2H, s, CH 2), 2.45 (2H, s, CH 2); 13C NMR (DMSO-d6, ppm): 173.8,167.0,152.1,143.9,142.3,138.8,137.6,126.3,123.2,122.9,121.8,116.5,56.5 (OCH 3), 35.7 (CH 2), 30.7 (CH 2); EIMS (m/z, %): 403 (15, M +, Br 81), 401 (15, M +, Br 79), 358 (12, Br 81), 356 (12, Br 79), 277 (5), 241 (6, Br 81), 239 (6, Br 79), 214 (5, Br 81), 212 (5, Br 79), 176 (20), 121 (100), 91 (8) 77 (8), 57 (3); Anal.Cald for C 18H 16BrN 3O 3: C, 53.75; H, 4.01; N, 10.45; Found:C, 53.79; H, 4.11; N, 10.42.
Embodiment 10:(E)-and N '-(5-bromo-2-oxindole alkane-3-subunit)-3,5-difluoro benzoyl hydrazine (19):
The full diketone of 5-bromo indole (2.26 grams, 0.01 mole) and 3,5-difluoro benzoyl hydrazine (1.72 grams, 0.01 mole) are placed ethanol (10 milliliters), and back flow reaction cool off after 5 hours, leached precipitation and washed with water, carried out recrystallization with ethanol after the drying; Productive rate: 91%; M.p:158-159 degree centigrade; IR (KBr, max, cm -1): 3228 (NH stretching), 3042 (sp 2CH stretching), 2996-2834,1708 (C=O), 1595 (C=N), 1351 (C-O); 1H NMR (DMSO-d6, ppm): 11.53 (1H, s, NH), 10.49 (1H, s, NH), 7.76 (1H, s, H-4), 7.62-7.45 (4H, m, H-6,2 ', 4 ', 6 '), 6.97 (1H, d, J=8.7Hz, H-7); 13C NMR (DMSO-d6, ppm): 169.3,165.7,163.2,145.3,138.7,134.7,132.8,125.4,121.8,119.8,104.9; EIMS (m/z, %): 381 (25, M +Br 81), 379 (25, M +, Br 79), 353 (10, Br 81), 351 (10, Br 79), 301 (1), 240 (61, Br 81), 238 (61, Br 79), 212 (34, Br 81), 210 (35, Br 79), 184 (12, Br 81), 182 (12, Br 79), 141 (100), 113 (69), 103 (22), 63 (10); Anal.Cald for C 15H 8BrF 2N 3O 2: C, 47.39; H, 2.12; N, 11.05; Found:C, 47.38; H, 2.15; N, 11.02.
Embodiment 11:(E)-and N '-(5-bromo-2-oxindole alkane-3-subunit)-2,5-difluoro benzoyl hydrazine (20):
With 2 of the full diketone of 5-bromo indole (2.26 grams, 0.01 mole) and equivalent, 5-difluoro benzoyl hydrazine (1.72 grams, 0.01 mole) places ethanol (10 milliliters), and back flow reaction cool off after 5 hours, leaches precipitation and washes with water, carries out recrystallization with ethanol after the drying; Productive rate: 88%; M.p:139-140 degree centigrade; IR (KBr, max, cm -1): 3231 (NH stretching), 3052 (sp 2CH stretching), 2983-2856,1705 (C=O), 1625 (C=N), 1590-1359 (C=C), 1316 (C-O); 1H NMR (DMSO-d6, ppm): 11.23 (1H, s, NH), 10.79 (1H, s, NH), 7.81 (1H, s, H-4), 7.72-7.54 (3H, m, H-3 ', 4 ', 6 '), 7.16-6.72 (2H, m, H-6,7); 13C NMR (DMSO-d6, ppm): 169.2,164.2,159.2,158.1,144.3,132.7,130.8,130.4,127.5,124.0,121.9,120.8,119.3,118.5,116.9; EIMS (m/z, %): 381 (21, M +, Br 81), 379 (21, M +, Br 79), 353 (17, Br 81), 351 (17, Br 79), 301 (4), 273 (5), 240 (43, Br 81), 238 (43, Br 79), 212 (22Br 81), 210 (22, Br 79), 184 (5, Br 81), 182 (5, Br 79), 141 (100), 113 (39), 103 (12), 63 (6); Anal.Cald for C 15H 8BrF 2N 3O 2: C, 47.39; H, 2.12; N, 11.05; Found:C, 47.32; H, 2.11; N, 11.03.
Embodiment 12:(E)-and N '-(5-bromo-2-oxindole alkane-3-subunit)-2,4-dimethoxy benzoyl hydrazine (21):
With 2 of the full diketone of 5-bromo indole (2.26 grams, 0.01 mole) and equivalent, 4-dimethoxy benzoyl hydrazine (2.26 grams, 0.01 mole) place ethanol (10 milliliters), back flow reaction was cooled off after 5 hours, leached precipitation and washed with water, and recrystallization is carried out with ethanol in dry back; Productive rate: 86%; M.p:167-168 degree centigrade; IR (KBr, max, cm -1): 3486-3211 (NH stretching), 3075 (sp 2CH stretching), 2839,1717 (C=O), 1652 (C=N), 1492 (C=C), 1238 (C-O); 1H NMR (DMSO-d6, ppm): 11.54 (1H, s, NH), 10.24 (1H, s, NH), 7.72 (1H, s, H-4), 7.53 (1H, dd, J=8.4,2.0Hz, H-6), 7.24 (1H, d, J=8.4Hz, H-6 '), 6.99 (1H, d, J=8.0Hz, H-7), 6.70 (1H, dd, J=7.8,2.0Hz, H-5 '), 6.67 (1H, d, J=2.1Hz, H-3 '), 3.88 (6H, s, OCH 3); 13C NMR (DMSO-d6, ppm): 168.2,163.5,161.7,141.4,134.2,133.3,128.1,124.2,121.2,111.8,106.3,101.1,55.3 (OCH 3); EIMS (m/z, %): 405 (5, M +, Br 81), 403 (5, M +, Br 79), 377 (6, Br 81), 375 (6, Br 79), 325 (2), 297 (3), 240 (1), 165 (100), 122 (7), 107 (6), 77 (3); Anal.Cald for C 17H 14BrN 3O 4: C, 50.51; H, 3.49; N, 10.40; Found:C, 50.55; H, 3.45; N, 10.49.
Embodiment 13:(E)-and N '-(5-bromo-2-oxindole alkane-3-subunit)-2,6-dimethoxy benzoyl hydrazine (22):
The full diketone of 5-bromo indole (2.26 grams, 0.01 mole) and 2,6-dimethoxy benzoyl hydrazine (2.26 grams, 0.01 mole) are placed ethanol (10 milliliters), and back flow reaction cool off after 5 hours, leached precipitation and washed with water, carried out recrystallization with ethanol after the drying; Productive rate: 88%; M.p:128-129 degree centigrade; IR (KBr, max, cm -1): 3416-3311 (NH stretching), 3072 (sp 2CH stretching), 2839,1717 (C=O), 1606 (C=N), 1592 (C=C), 1308 (C-O); 1H NMR (DMSO-d6, ppm): 11.78 (1H, s, NH), 10.49 (1H, s, NH), 7.85 (1H, s, H-4), 7.62 (1H, dd, J=8.0,2.1Hz, H-6), 7.41 (1H, d, J=8.4Hz, H-6 '), 7.05 (1H, d, J=8.0Hz, H-7), 6.79 (1H, dd, J=7.8,2.0Hz, H-5 '), 6.71 (1H, d, J=2.1Hz, H-3 '), 3.80 (6H, s, OCH 3); 13C NMR (DMSO-d6,6, δ ppm): 169.6,164.5,161.7,145.4,134.2,133.3,124.7,121.2,119.8,106.3,56.4 (OCH 3); EIMS (m/z, %): 405 (5, M +, Br 81), 403 (6, M +, Br 79), 377 (4, Br 81), 375 (4, Br 79), 325 (1), 297 (2), 240 (1), 165 (100), 122 (9), 107 (4), 77 (2), 57 (2); Anal.Cald for C 17H 14BrN 3O 4: C, 50.51; H, 3.49; N, 10.40.Found:C, 50.50; H, 3.44; N, 10.47.
Embodiment 14
The weeding activity of isatin compounds V of the present invention:
The new compound that the present invention synthesizes sees Table 3 to the weeding activity measurement result of unifacial leaf and broadleaf weed, and table 3 shows, all target compounds (EC) do not have a weeding activity to barnyard grass grass (Echinochloa crusgalli (L.) Beauv.); 12 pairs of swede type rapes of compound (Brassica napus) (BN) have weeding activity preferably, and all the other compounds do not have weeding activity to BN; Compound 12,20,22 pairs of three-coloured amaranths (Amaranthus retroflexus.) (AR) have weeding activity preferably, and all the other compounds do not have weeding activity to AR; 22 pairs of lady's-grass of compound (Digitaria adscendens) (DA) have weeding activity preferably, and all the other compounds do not have weeding activity to DA.Therefore, part isatin compounds V of the present invention has shown weeding activity preferably.
Embodiment 15
Antibacterial or the fungicidal activity of isatin compounds V of the present invention:
Title and the code name of the frequently seen plants pathogenic fungi of the present invention's test comprise AS: tomato early blight bacterium (Alternaria solani); CA: peanut Cercospora bacteria (Cercospora arachidicola); FO: cucumber wither (Fusarium oxysporum f.cucumerinum); GZ: fusarium graminearum (Gibberella zeae); PP: ring rot of apple bacterium (Physalospora piricola), these bacterial classifications have good representativeness, can represent the kind of most of pathogenic bacteria that the field takes place in the agriculture production.Thalli growth rate method measurement result sees Table 4, and table 4 shows that when 50 mcg/ml, all new compounds that the present invention synthesizes all are lower than 10% to the fungicidal activity of AS; The fungicidal activity of compound 11,13,14,15,18,19,20 couples of CA is between 12% to 16%, and all the other compounds all are lower than 10% to the fungicidal activity of CA; The fungicidal activity of compound 12,13,19 couples of FO is between 10% to 15%, and all the other compounds all are lower than 10% to the fungicidal activity of FO; The new compound 14 that the present invention synthesizes, the fungicidal activity of 15,20,21 couples of GZ are between 12% to 16%, and all the other compounds all are lower than 10% to the fungicidal activity of GZ; The fungicidal activity of 22 couples of PP of compound is 16.5%, and all the other compounds all are lower than 10% to the fungicidal activity of PP; Therefore, part isatin compounds V of the present invention has shown certain fungicidal activity.
Embodiment 16
The insecticidal activity of isatin compounds V of the present invention:
The new compound that the present invention synthesizes is to mythimna separata (Mythimna separata, Walker) (MSW) and the measurement result of aphid (Aphis laburni Kaltenbach) insecticidal activity (ALK) see Table 4, table 4 shows, under the 200 mcg/ml concentration, compound of the present invention only 11 pairs of mythimna separatas of compound has 10% insecticidal activity, and all the other compounds all do not have insecticidal activity to two kinds of examination worms.
Embodiment 17
The plant growth regulating activity of isatin compounds V of the present invention:
The new compound that the present invention synthesizes sees Table 5 to the cucumber cotyledons active measurement result of taking root, and table 5 shows that the activity of compound 11 and 15 under 10mg/L concentration reached the C level, and the activity of compound 12,14,20 under 10mg/L concentration reached the B level.Therefore, part isatin compounds V of the present invention has shown the good cucumber cotyledons activity of taking root, and can be used as plant-growth regulator.And compound 16 and 20 has the activity that inhibition is taken root.
Embodiment 18
The antiviral activity of isatin compounds V of the present invention:
The activity of the anti-feline coronavirus of isatin compounds V that the present invention synthesizes and cat bag exanthema virus and the cytotoxic assay result of CRFK cell culture show (table 6), compound 12,19,22 couples the cytotoxicity CC of CRFK cell culture 50Value is lower than contrast medicament HHA, UDA and ganciclovir, and the measurement result of all the other compounds is suitable with the contrast medicament, all greater than 100 μ mol/L; To the activity of feline coronavirus, activity and the HHA of compound 12 are suitable, are higher than the activity of UDA and ganciclovir; The activity of compound 22 is significantly higher than the activity of 3 contrast medicaments; Compound 10 and 19 activity are between HHA, UDA and ganciclovir.To the activity of cat bag exanthema virus, the activity of the activity of compound 12 and HHA, UDA and ganciclovir is suitable substantially; The activity of compound 22 be significantly higher than 3 the contrast medicaments activity, the activity of all the other compounds all be lower than 3 the contrast medicaments.The isatin compounds V that the present invention synthesizes shows (table 7) in hel cell cells in culture toxicity and antiviral activity measurement result, compound 12, the smallest cell toxic concentration value of hel cell culture of 13,14,19,20,21,22 pairs are lower than contrast medicament brivudine, virazole, acyclovir and ganciclovir, the measurement result of all the other compounds is suitable with contrast medicament ganciclovir, is lower than the measurement result of contrast medicament brivudine, virazole, acyclovir.To the activity of hsv-1 (KOS), compound 12,13,14,19,21,22 activity are higher than the activity of virazole, are lower than the activity of brivudine, acyclovir and ganciclovir; The activity of all the other compounds all is lower than the contrast medicament of all mensuration.To the activity of hsv-2 (G), the activity of all target compounds all is higher than the activity of virazole, and compound 12,13,14,19,21,22 activity are higher than the activity of contrast medicament brivudine.To the activity of vaccinia virus, the activity of all target compounds all is higher than the activity of virazole, acyclovir and ganciclovir, and compound 12,13,14,19,21,22 activity are higher than the activity of contrast medicament brivudine.To the activity of vesicular stomatitis virus, the activity of all target compounds all is higher than the activity of virazole, acyclovir and ganciclovir, and compound 12,13,14,19,21,22 activity are higher than the activity of contrast medicament brivudine.Activity to hsv-1TK-KOSACVr, the activity of all target compounds all is higher than the activity of virazole, except the activity of compound 10 was lower than the activity of contrast medicament brivudine and acyclovir, the activity of all the other compounds all was higher than the activity of brivudine and acyclovir.Compound 12,14,19 activity be near the activity of ganciclovir, and compound 21,22 activity are higher than the activity of contrast medicament ganciclovir.The isatin compounds V that the present invention synthesizes shows (table 8) in hel cell cells in culture toxicity and antiviral activity measurement result, the smallest cell toxic concentration value of the hel cell culture that all compounds are right is lower than contrast medicament (S)-DHPA and virazole, and the measurement result of all the other compounds all is lower than contrast medicament D.S.-5000; Activity to vesicular stomatitis virus, Coxsackie B virus 4 and respiratory syncytial virus, except the activity of compound 20 was lower than the activity of contrast medicament, the activity of all the other compounds all was higher than the active or suitable with it of contrast medicament (S)-DHPA and virazole and D.S.-5000.Cytotoxicity and the antiviral activity measurement result of the isatin compounds V that the present invention synthesizes in the Vero cell culture shows (table 9), the smallest cell toxic concentration value of the Vero cell culture that all compounds are right be lower than the contrast medicament (S)-DHPA and virazole, the measurement result of part of compounds all be lower than the contrast medicament D.S.-5000 or with D.S-5000 or suitable with D.S-5000; Activity to parainfluenza virus-3, reovirus-1, sindbis alphavirus, Coxsackie B virus 4, Punta Toro virus, the activity of all target compounds all is higher than the activity of (S)-DHPA and virazole, compound 10 and 20 activity and D.S-5000 are suitable, and the activity of all the other compounds all is higher than the activity of D.S-5000.
Therefore, part isatin compounds V of the present invention has shown good antiviral activity, can be for the preparation of the medicament of resisting mammal virus.
Embodiment 19: the application in isatin compounds V of the present invention and combinations of herbicides control agricultural and forestry and the gardening plant crop smothering
In the weedicide of isatin compounds V of the present invention and following group one or more mix use: phenoxy carboxylic acid is as 2,4-D butyl ester, 2 first, 4 chlorine; Virtue phenoxy base propionic acid ester such as quizalofop, surely kill, cover grass energy etc.; Dinitroaniline such as trifluralin, pendimethalin; Triazine such as simazine, atrazine, prometryn, ametryn, bladex etc.; Amides such as alachlor, acetochlor, the third careless amine, Butachlor technical 92, propisochlor, metolachlor etc.; Substituted urea class such as Diuron Tech, methoxydiuron, chlorotoluron, isoproturon; Diphenyl ether such as acifluorfen, fomesafen, lactofen, fluoroglycofenethyl; Cyclic imide Lei such as the spirit of Evil grass, methylarsonic acid, flumioxazin; Kinds such as sulfonylurea such as metsulfuronmethyl, green sulphur swell, benbbensulfuronmethyl, tribenuron-methyl, monosulfmeturon, single phonetic sulphur ester, pyrazosulfuronmethyl, nicosulfuron, thifensulfuron methyl, azoles sulfometuron-methyl; Amino formate such as thiobencarb, Hydram; Organic phosphates such as glyphosate, careless ammonium phosphine; The bromoxynil of other classification weedicides such as nitrile, ioxynil, the dicamba 98 of benzoic acids, the Paraquat of bipyridyliums, the Imazethapyr of imidazolone type, imazamox, the pyrimidine Whitfield's ointment of pyrimidine salicylic acid, Nong Meili, the sethoxydim of cyclohexenone analog, clethodim etc., the bentazone of heterocyclic, quinclorac clomazone, fluroxypyr etc., the formulation of composition processing is selected from wettable powder, sustained release dosage, pulvis, micro-capsule suspension, the dispersible body preparation, the dispersible solid preparation, seed treatment emulsion, aqueous emulsion, big granula, granule, microemulsion, oil-suspending agent, finish, seed with coated pesticidal, suspended emulsion agent, water-soluble granule, soluble thick agent, water-dispersible granules, poison grain, aerosol, block poison bait, sustained-release block, dense poison bait, the capsule granula, capsule suspension, can disperse dense dose, pulvis, dry mixing kind pulvis, missible oil, the electrostatic spray agent, water-in-oil emulsion, seed treatment agent, oil-in-water emulsion, smoke candle, granula subtilis, smoke candle, smoke cartridge, the smog rod, the seed treatment suspension agent, the smog sheet, smoke substance, the smog ball, granular poison bait, foaming agent, big granula, the drift pulvis, granula, ointment, thermal fog, solid-liquid mixes the dress agent, liquid/liquid mixes the dress agent, cold mist agent, Gu Gu/mix and adorn agent, the medicine lacquer, the seed treatment liquor, microgranules, oil suspending agent, finish, the oil-dispersing property pulvis, paste, the sheet poison bait, dense jelly, sprinkle and water agent, stylus, plant the clothing agent, poison bait, basting agent, the fritter poison bait, suspension agent, suspension emulsion, water-soluble granule, soluble thick agent, the film forming finish, soluble powder, the seed treatment water solube powder, the ultra-low volume suspension agent, tablet, follow the trail of pulvis, ultra low volume liquids, the steam releasing agent, water-dispersible granules, wettable powder, in the wet-mixing kind water-dispersible powder any one; The total quality percentage composition of isatin compounds V of the present invention in composition is 1%-90%, and the ratio of isatin compounds V of the present invention and commercially available agricultural chemical is mass percent 1%: 99% to 99%: 1%; The herbicidal effect of composition is good, and these compositions have synergism and summation action, does not find to have the composition of antagonistic action.Above-mentioned medicament can be converted water spray and use; Controlling object comprises that the cereal that China extensively plants (comprises paddy, wheat, barley, oat, corn, millet, Chinese sorghum etc.), tuber crops (comprise sweet potato, potato, cassava etc.), beans (comprises soybean, broad bean, pea, mung bean, red bean etc.) and fiber (cotton, crudefiber crop, silkworm and mulberry etc.), oil plant (peanut, rape, sesame, soybean, Sunflower Receptacle etc.), sugar material (beet, sugarcane etc.), beverage (tealeaves, coffee, cocoa etc.), hobby (tobacco leaf etc.), medicinal (genseng, the bulb of fritillary etc.), the torrid zone (rubber, coconut, oil palm, sisal hemp etc.) food crop and fruit such as, flowers, oil plant, sugar material and cotton, fiber crops, tea, tobacco, cash crop and plantation melons such as Chinese medicinal materials, really, tea, silkworm and mulberry, vegetables (containing various wild vegetable etc.), bamboo shoots, flowers and ornamental plant, hops, medicinal material, pepper, garden crop such as tobacco (flue-cured tobaccos such as seedling and other garden crops, air-curing of tobacco leaves, suncured tabacco), vegetables, (tomato, capsicum, radish, cucumber, Chinese cabbage, celery, hot pickled mustard tube, beet, rape, green onion, garlic etc.), melon (watermelon, muskmelon, hami melon, pawpaw etc.), beans (soybean, broad bean, pea-pods etc.), potato, wheat, corn, paddy rice, peanut, fruit tree, (apple, banana, citrus, peach, papaya), flowers (as orchid), monocotyledon weed and broadleaf weed that fields such as potted landscape take place, and crop is all had good selectivity.
Embodiment 20: isatin compounds V of the present invention and plant-growth regulator are combined in the application in agricultural and forestry and the gardening plant
Isatin compounds V of the present invention is with triazole species or the other plant growth regulator of group mix the activity that use has plant growth regulating down; These plant-growth regulator are selected from growth hormone, jasmonic, the a-Nafusaku, zeatin, flumetralim, naphthylacetic acid, triapenthenol, maleic hydrazide (MH), phytokinin, general Lip river Malin, dormin, wallantoin, ancymidol, 6-benzyl aminopurine, brassinolide, carbaryl, chitosan, choline dichloride, choline chloride 60, drop-proof agent, swash and give birth to enzyme cocktail, 2,4-drips, alar-85,2,4-drips propionic acid, regulate peace, isopentennyladenine, ethrel, ethychlozate, flumetralim, forchlorfenuron, regulate phosphine, increase sweet phosphine, Plant hormones regulators,gibberellins, xanthohumic acid, indolylacetic acid, indolebutyric acid, production increasing agent, the chaff aminopurine, maleic hydrazide, the short peace that presses down, the first piperazine, naphthylacetic acid, naphthalene acetamide, Nucleotide, paclobutrazol, sweetener, rich pyridine alcohol, Whitfield's ointment, sodium nitrophenolate, thidiazuron, thiocarbamide, triacontanol price quote, Triiodobenzoic acid, uniconazole, xitix, cycocel, nitre naphthalene mixture, benzyl is to the chlorine mixture, Plant hormones regulators,gibberellins benzyl purine mixture, the second that rues mixture, quaternary ammonium hydroxyl quaternary ammonium mixture, quaternary ammonium second mixture, quaternary ammonium piperazine mixture, piperazine ketone hydroxyl quaternary ammonium mixture, hydroxyl quaternary ammonium naphthalene mixture, the fast mixture of second, second azoles mixture, red Yin mixture, yellow nuclear mixture, Yin ethylnaphthalene mixture, Yin fourth naphthalene mixture, piperazine second mixture, naphthalene naphthylamines thiocarbamide mixture, azoles piperazine mixture, multiple-effect alkene is imitated mixture, hymexazol, pyrocatechol, forulic acid, asccharin, phytomelin, chlorophenoxyacetic acid, Chlorlacetic Acid, sym-diphenylurea, forchlorfenuron, kantlex three, inhibition type fruit-setting agent, choline chloride 60, ancymidol, p-chlorophenoxyacetic acid, dormin, nicotinic acid, Fospinol, Paraquat, acephatemet, oxine, diquat, urea, ammonium persulphate, potassiumiodide, L-Ala, endothal, cycloheximide, 2,4-drips isopropyl ester, suberoyl, 2,4-Dichlorophenoxy propionic acid, calcium acetate, boric acid, short alkene is good, cyclodextrin, 2,4,5-tears propionic acid, Diuron Tech, citric acid, in the benomyl any one; The formulation of composition processing is selected from wettable powder, sustained release dosage, pulvis, micro-capsule suspension, the dispersible body preparation, the dispersible solid preparation, seed treatment emulsion, aqueous emulsion, big granula, granule, microemulsion, oil-suspending agent, finish, seed with coated pesticidal, suspended emulsion agent, water-soluble granule, soluble thick agent, water-dispersible granules, poison grain, aerosol, block poison bait, sustained-release block, dense poison bait, the capsule granula, capsule suspension, can disperse dense dose, pulvis, dry mixing kind pulvis, missible oil, the electrostatic spray agent, water-in-oil emulsion, seed treatment agent, oil-in-water emulsion, smoke candle, granula subtilis, smoke candle, smoke cartridge, the smog rod, the seed treatment suspension agent, the smog sheet, smoke substance, the smog ball, granular poison bait, foaming agent, big granula, the drift pulvis, granula, ointment, thermal fog, solid-liquid mixes the dress agent, liquid/liquid mixes the dress agent, cold mist agent, Gu Gu/mix and adorn agent, the medicine lacquer, the seed treatment liquor, microgranules, oil suspending agent, finish, the oil-dispersing property pulvis, paste, the sheet poison bait, dense jelly, sprinkle and water agent, stylus, plant the clothing agent, poison bait, basting agent, the fritter poison bait, suspension agent, suspension emulsion, water-soluble granule, soluble thick agent, the film forming finish, soluble powder, the seed treatment water solube powder, the ultra-low volume suspension agent, tablet, follow the trail of pulvis, ultra low volume liquids, the steam releasing agent, water-dispersible granules, wettable powder, in the wet-mixing kind water-dispersible powder any one; The total quality percentage composition of isatin compounds V of the present invention in composition is 1%-90%, and the ratio of isatin compounds V of the present invention and commercially available agricultural chemical is mass percent 1%: 99% to 99%: 1%; The plant growth regulating of composition is effective, does not find to have the composition of antagonistic action.The crop that these compositions are suitable for comprises that cereal (comprises paddy, wheat, barley, oat, corn, millet, Chinese sorghum etc.), tuber crops (comprise sweet potato, potato, cassava etc.), beans (comprises soybean, broad bean, pea, mung bean, red bean etc.) and fiber (cotton, crudefiber crop, silkworm and mulberry etc.), oil plant (peanut, rape, sesame, soybean, Sunflower Receptacle etc.), sugar material (beet, sugarcane etc.), beverage (tealeaves, coffee, cocoa etc.), hobby (tobacco leaf etc.), medicinal (genseng, the bulb of fritillary etc.), the torrid zone (rubber, coconut, oil palm, sisal hemp etc.) food crop and fruit such as, flowers, oil plant, sugar material and cotton, fiber crops, tea, tobacco, cash crop and plantation melons such as Chinese medicinal materials, really, tea, silkworm and mulberry, vegetables (containing various wild vegetable etc.), bamboo shoots, flowers and ornamental plant, hops, medicinal material, pepper, garden crop such as tobacco (flue-cured tobaccos such as seedling and other garden crops, air-curing of tobacco leaves, suncured tabacco), vegetables, (tomato, capsicum, radish, cucumber, Chinese cabbage, celery, hot pickled mustard tube, beet, rape, green onion, garlic etc.), melon (watermelon, muskmelon, hami melon, pawpaw etc.), beans (soybean, broad bean, pea-pods etc.), potato, wheat, corn, paddy rice, peanut, fruit tree, (apple, banana, citrus, peach, papaya), flowers (as orchid), potted landscape etc.
Embodiment 21
Application in isatin compounds V of the present invention and sterilant combination control agricultural and forestry and the gardening plant disease
bioassay results shows, all isatin compounds V of the present invention and existing bactericide such as diazosulfide, tiadinil, tisocromide, the first thiophene lures amine, the 4-methyl isophthalic acid, 2,3-thiadiazoles-5-formic acid, the 4-methyl isophthalic acid, 2,3-thiadiazoles-5-sodium formate, the 4-methyl isophthalic acid, 2,3-thiadiazoles-5-Ethyl formate, the DL-beta-aminobutyric acid, isotianil (isotianil), virazole, antofine, Ningnanmycin or salicylic acid, frost urea cyanogen, thiram, ziram, Mancozeb, aliette, thiophanate-methyl, Bravo, the enemy can be loose, procymidone, fenpropidin, thiophanate methyl, thiophanate, Metalaxyl-M, salicylic acid, flumorph, dimethomorph, efficient metalaxyl, efficient M 9834, two chlorine zarilamids, flusulfamide, the first flusulfamide, thiophene fluorine bacterium amine, flutolanil, tecloftalam, ring propionyl bacterium amine, cyflufenamid, fenhexamid, zarilamid, Silthiopham, furametpyr, the pyrrole metsulfovax, mandipropamid, zoxamide, fenfuram, carboxin, chlozolinate, iprodione, Fluoxastrobin, dimoxystrobin, fluoxastrobin, kresoxim-methyl, SSF 126, orysastrobin, ZEN 90160, pyraclostrobin, oxime bacterium ester, Enestroburin, alkene oxime amine, oxygen ring azoles, bromuconazole, Cyproconazole, Difenoconazole, alkene azoles alcohol, efficient alkene azoles alcohol, epoxiconazole, RH-7592, Fluquinconazole, Flusilazole, Flutriafol, own azoles alcohol, glyoxalin, plant the bacterium azoles, metconazole, nitrile bacterium azoles, penconazole, propiconazole, prothioconazoles, simeconazoles, Tebuconazole, tetraconazole, Triadimenol, triticonazole, bitertanol, probenazole, furidazol, imazalil, efficient imazalil, Prochloraz, fluorine bacterium azoles, cyazofamid, Fenamidone, the Evil imidazoles, pefurazoate, famoxadone, SYP-Z048, hymexazo, the spirit of Evil frost, Guardian, Grandox fumigant, octhilinone, benthiozole, dodemorph, butadiene morpholine, tridemorph, fenpiclonil, fludioxonil, fluazinam, pyrifenox, ring pyridine bacterium amine, Boscalid, fluopicolide, pyridine bacterium amine, cyprodinil, the fluorine mepanipyrim, ferimzone, mepanipyrim, phonetic mould amine, Fenarimol, nuarimol, chinomethionat, dithianon, ethoxyquin, oxyquinoline, the third oxygen quinoline, benzene oxygen quinoline, the mould prestige of second, iprovalicarb, the benzene metsulfovax, Propamocarb, methasulfocarb, edifenphos, IBP, pyrazophos, tolelofos-methyl, blasticidin-S, kasugarnycin, polyoxin, Polyoxin, valida, jinggangmeisu, streptomysin, metalaxyl, furalaxyl, M 9834, ofurace, mebenil, carbendazim, benomyl, thiophanate-methyl, triazolone, bupirimate, dimethirimol, the phonetic phenol of second, difoltan, captan, folpet, vinclozolin, fluoromide, dimethachlon, Bravo, Isoprothiolane, kitazine, Yekuzuo, pentachloronitrobenzene, Mancozeb, Propineb, phosethyl-Al, sulphur, Bordeaux mixture, copper sulphate, copper oxychloride, cuprous oxide, Kocide SD, metrafenone, Pencycuron, diclomezin, Rabcide, pyroquilon, volution bacterium amine, tricyclazole, triforine, the pyridine of many fruits, the hot salt of biguanides, iminoctadine, botran, the benzene flusulfamide, the toluene flusulfamide, K-281, fenaminosulf, oxolinic acide, probenazole, bronopol, iodomethane, metham-sodium, enemy's line ester, dazomet, nemamort, lythidathion, cadusafos, fensulfothion, thionazin, fenamiphos, phonamiphos, dichlofenthion, isazofos, fosthietan, oxamyl, Aldicarb, carbofuran, vikane, dichloropropylene, dichloro-isonicotinic acid, other known any any one or two kinds that can be used as in bactericide such as allyl isothiazole are used in combination, the total quality percentage composition of isatin compounds V of the present invention in composition is 1%-90%, and the ratio of isatin compounds V of the present invention and commercially available agricultural chemical is mass percent 1%: 99% to 99%: 1%, the prevention effect of composition is good, and these compositions have certain synergistic effect and summation action, does not find to have the composition of antagonistic action, above-mentioned composition can be used for the control of agricultural plant disease and gardening plant disease, controlling object comprises that more than 20 of the Achylas, Aphanomyces, pythium, Phytophthora, Sclerospora, Plasmopara, Pseudoperonospora, Peronospora of Oomycete etc. belong to the diseases that produce, as other diseases of plurality of cereals crop, industrial crops, gardening plant and the forestry plants such as seedling blight of rice, tomato root maize ear rot, the late blight of potato, black shank, millet powdery mildew, downy mildew of garpe, downy mildew of lettuce, cucumber downy mildew, cucumber anthracnose etc., the formulation of composition processing is selected from wettable powder, sustained release agent, pulvis, micro-capsule suspension, the dispersible body preparation, the dispersible solid preparation, seed treatment emulsion, aqueous emulsion, large granula, granule, microemulsion, oil-suspending agent, finish, seed with coated pesticidal, suspension emulsion, water-soluble granule, soluble thick agent, water-dispersible granules, poison grain, aerosol, block poison bait, sustained-release block, dense poison bait, CG/Encapsulated granule, capsule suspension, can disperse dense dose, pulvis, the Waterless Seed Dressing pulvis, missible oil, the electrostatic spray agent, water-in-oil emulsion, seed treatment, oil in water emulsion, smoke candle, granula subtilis, smoke candle, smoke cartridge, the smog rod, the seed treatment suspending agent, the smog sheet, smoke agent, the smog ball, granular poison bait, foaming agent, large granula, the drift pulvis, granula, ointment, thermal fog, solid-liquid mixes the dress agent, liquid/liquid mixes the dress agent, cold mist agent, Gu Gu/mix filling agent, the medicine paint, the seed treatment liquor, fine granule, oil suspending agent, finish, the oil-dispersing property pulvis, paste, the sheet poison bait, dense jelly, sprinkle and water agent, stylus, seed coat agent, poison bait, liniment, the fritter poison bait, suspending agent, suspended emulsion, water-soluble granule, soluble thick agent, the film forming finish, soluble powder, the seed treatment water solube powder, the ultra-low volume suspending agent, tablet, follow the trail of pulvis, ultra low volume liquids, the steam releasing agent, water-dispersible granules, wettable powder, any one in wet-mixing kind water-dispersible powder.
The crop that these compositions are suitable for comprises that cereal (comprises paddy, wheat, barley, oat, corn, millet, Chinese sorghum etc.), tuber crops (comprise sweet potato, potato, cassava etc.), beans (comprises soybean, broad bean, pea, mung bean, red bean etc.) and fiber (cotton, crudefiber crop, silkworm and mulberry etc.), oil plant (peanut, rape, sesame, soybean, Sunflower Receptacle etc.), sugar material (beet, sugarcane etc.), beverage (tealeaves, coffee, cocoa etc.), hobby (tobacco leaf etc.), medicinal (genseng, the bulb of fritillary etc.), the torrid zone (rubber, coconut, oil palm, sisal hemp etc.) food crop and fruit such as, flowers, oil plant, sugar material and cotton, fiber crops, tea, tobacco, cash crop and plantation melons such as Chinese medicinal materials, really, tea, silkworm and mulberry, vegetables (containing various wild vegetable etc.), bamboo shoots, flowers and ornamental plant, hops, medicinal material, pepper, garden crop such as tobacco (flue-cured tobaccos such as seedling and other garden crops, air-curing of tobacco leaves, suncured tabacco), vegetables, (tomato, capsicum, radish, cucumber, Chinese cabbage, celery, hot pickled mustard tube, beet, rape, green onion, garlic etc.), melon (watermelon, muskmelon, hami melon, pawpaw etc.), beans (soybean, broad bean, pea-pods etc.), potato, wheat, corn, paddy rice, peanut, fruit tree, (apple, banana, citrus, peach, papaya), flowers (as orchid), potted landscape etc.
Embodiment 22
Isatin compounds V of the present invention and antiviral agent are combined in the application that prevents and treats in the virus
Isatin compounds V and existing Antiphytoviral medicament metronidazole, virazole, rimantadine hydrochloride, brivudine, acyclovir, (S)-DHPA, D.S.-5000, Penciclovir, ganciclovir, Famciclovir, former times many furans Wei, take charge of his furan pyridine, neat many furans pyridine, lamivudine, didanosine, zalcitabine, riodoxol, Trisodium phosphonoformate hexahydrate, Sodium N,N-diethyldithiocarbamate, atovaquone, that furan pyridine of ground, Saquinavir, that Wei of Yin ground, Rui Tuonawei, nevirapine, the 3-nitrobenzamide, any 1 or 2 compound combinations among the Ai Faweirui; Be used for preventing and treating the disease that hsv-1 (KOS strain), hsv-2 (G strain), vaccinia virus, vesicular stomatitis virus, Coxsackie B virus 4, cytomegalovirus, sindbis alphavirus, Measles virus and poliovirus-1, reovirus-1, Semliki Forest virus, any virus of parainfluenza virus-3 cause; These compositions are suitable for and mammiferous virus disease.The total quality percentage composition of isatin compounds V of the present invention in composition is 1%-90%, and the ratio of isatin compounds V of the present invention and commercially available agricultural chemical is mass percent 1%: 99% to 99%: 1%; The formulation of composition processing is selected from the direction aqua, solution, injection, mucilage, liniment, emulsion, suspensoid, mixture, lotion, aerosol, powder, granule, tablet, capsule, microcapsule, the nanometer wafer, sol, aqueous injection, ointment, gelifying agent, powder, granule, tablet, capsule, pill, suppository, aerosol, sprays, tablet, chewable tablet, slow releasing tablet, effervescent tablet, dispersible tablet, capsule, oral solution, drops, syrup, granule, effervescent granule, slow releasing capsule, ointment, liniment, emulsion agent, in the gelifying agent any one; All show addition or synergism between these compositions, find no the composition of antagonistic action, the drug effect lasting period of composition is long.
Embodiment 23
Complete processing and the stability of isatin compounds V of the present invention and commercially available agricultural chemical compound preparation
The mixed preparation complete processing of isatin compounds V of the present invention and commercially available agricultural chemical sees Table 10, table 10 as seen, most medicament all can be processed according to the method for statement, the main component of liquid preparation is effective constituent and solubility promoter and tensio-active agent, synergistic agent, antifreezing agent, stablizer, other component etc. such as thickening material or permeate agent, the composition of solid preparation mainly includes the effect composition, other agriculturals such as tensio-active agent and filler go up the acceptable adjuvant component, the cold storage test of process preparation, liquid preparation is placed 1 week not have to precipitate at 0 ± 2 degree centigrade and is separated out, solid preparation placed for 2 weeks at 54 ± 2 degrees centigrade, caking phenomenon does not appear in medicament, the medicament drug effect that all preparations store before and after placing does not have significant difference, the rate of decomposition of composition effective constituent in 5%, the composite preparation qualified stability.
Embodiment 24
The complete processing of isatin compounds V of the present invention and commodity antiviral agent
The mixed preparation complete processing of isatin compounds V of the present invention and commercially available agricultural chemical sees Table 11, table 11 as seen, most medicament all can be processed according to the method for statement, the main component of liquid preparation is other component etc. of effective constituent and solubility promoter and tensio-active agent, synergistic agent, antifreezing agent, stablizer, thickening material or permeate agent etc., and the composition of solid preparation mainly includes other edible adjuvant components such as imitating composition, tensio-active agent and filler.
The various isatin derivatives of table 1 biologically active
Figure BSA00000516057100181
The various isatin derivatives (continuing) of table 1 biologically active
Figure BSA00000516057100191
The chemical structure of the active isatin compounds V that table 2 the present invention synthesizes
Figure BSA00000516057100201
The weeding activity of the isatin compounds V that table 3 the present invention synthesizes (/ %)
The sterilization of the isatin compounds V that table 4 the present invention synthesizes and insecticidal activity (/ %)
Compound Concentration (mcg/ml) AS CA FO GZ PP Concentration (mcg/ml) MSW ALK
10 50 6.2 0 7.1 8.3 3.3 200 0 0
11 50 6.2 16.0 0 5.6 6.7 200 10.0 0
12 50 3.1 0 14.2 0 0 200 0 0
13 50 9.3 12.9 10.8 0 5.1 200 0 0
14 50 0 13.5 7.1 12.1 0 200 0 0
15 50 0 16.0 0 22.3 0 200 0 0
16 50 0 0 7.1 0 5.1 200 0 0
17 50 6.2 0 7.1 8.3 3.3 200 0 0
18 50 6.2 16.0 0 5.6 6.7 200 0 0
19 50 9.3 12.9 10.8 0 5.1 200 0 0
20 50 0 13.5 7.1 12.1 0 200 0 0
21 50 0 4.0 0 15.4 5.1 200 0 0
22 50 9.3 0 0 0 16.5 200 0 0
The plant growth regulating activity of the isatin compounds V that table 5 the present invention synthesizes (/ %)
Compound Cucumber cotyledons adventive root method of testing (CCR)
10 23.3
11 46.6
12 70.0
13 12.5
14 61.7
15 40.0
16 -20.0
17 16.6
18 13.3
19 23.3
20 79.2
21 -20.0
22 0
The activity of the anti-feline coronavirus of isatin compounds V that table 6 the present invention synthesizes and cat bag exanthema virus and the cytotoxicity in the CRFK cell culture
Figure BSA00000516057100221
a50% cytotoxicity concentration is determined by the MTS colorimetric method for determining CRFK cytoactive based on formazan.
b50% effective concentration, or the concentration when the virus induction cytopathy produced 50% restraining effect are determined by the MTS colorimetric method for determining cytoactive based on formazan.
CRFK cells：Crandell-Rees Feline Kidney cells。
The isatin compounds V that table 7 the present invention synthesizes is at hel cell cells in culture toxicity and antiviral activity
Figure BSA00000516057100222
aMust cause microscopically can observe the variation of normal cell form. bThe virus induction cell of necessary minimizing 50% is pathogenic.
The isatin compounds V that table 8 the present invention synthesizes is at hel cell cells in culture toxicity and antiviral activity
Figure BSA00000516057100231
aMust cause microscopically can observe the variation of normal cell form. bThe virus induction cell of necessary minimizing 50% is pathogenic.
Cytotoxicity and the antiviral activity of isatin compounds V in the Vero cell culture that table 9 the present invention synthesizes
Figure BSA00000516057100232
aMust cause the variation of the observed normal cell form of microscopically energy. bThe virus induction cell of necessary minimizing 50% is pathogenic.
Table 10 isatin compounds of the present invention V mixes the preparation processing method of using with commercially available agricultural chemical
Figure BSA00000516057100241
Table 11 isatin compounds of the present invention V and antiviral agent are used in combination working method
Figure BSA00000516057100242

Claims (6)

1. a class isatin compounds is characterized in that: have suc as formula the general structure shown in the V:
V：
Figure FSB00001080226000011
Wherein,
X is key, R=3,5-F 2, R "=Cl;
X is key, R=2,5-F 2, R "=Cl;
X is key, R=2,4-(OCH 3) 2, R "=Cl;
X is key, R=2,6-(OCH 3) 2, R "=Cl;
X is key, R=2,5-F 2, R "=Br;
X is key, R=3,5-F 2, R "=Br;
X is key, R=2,4-(OCH 3) 2, R "=Br;
X is key, R=2,6-(OCH 3) 2, R "=Br
X＝OCH 2CH 2，R＝2，4-Cl 2，R″＝Cl；
X＝(CH 2) 2，R＝3，4，5-(OCH 3) 3，R″＝Cl；
X＝(CH 2) 2，R＝4-OCH 3，R″＝Cl；
X＝(CH 2) 2，R＝3，4，5-(OCH 3) 3，R″＝Br；
X＝(CH 2) 2，R＝4-OCH 3，R″＝Br。
2. the synthetic method of the described isatin compounds of claim 1 V, concrete synthetic route is as follows:
Wherein, substituent X, R and R are " for being selected from the group shown in claim 1;
Concrete steps are as follows:
In 50 milliliters of round-bottomed flasks, add the full diketone IV of 10 mmole 5-halogeno indoles and 10 milliliters of ethanol, stir down and drip 10 mmole substituted formyl hydrazine III, after dropwising, stirred backflow 5-6 hour down, cooling leaches precipitation and washes with water, and recrystallization is carried out with ethanol in dry back; With the pure product calculated yield of gained, carry out the mensuration of fusing point, NMR, IR and MS, the amount of synthetic compound V enlarges by corresponding proportion or dwindles; The volume of respective reaction container enlarges in proportion or dwindles.
3. the described isatin compounds of claim 1 V goes up the purposes of acceptable assistant in the preparation weedicide with agricultural.
4. the described isatin compounds of claim 1 V goes up the purposes of acceptable assistant in the preparation sterilant with agricultural.
5. the described isatin compounds of claim 1 V goes up the purposes of acceptable assistant in the preparation plant-growth regulator with agricultural.
6. claim 1 described isatin compounds V and the pharmaceutically acceptable auxiliary agent purposes in preparation resisting mammal viral agent.
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