CN1756744A - Pyridinium salts, compounds and methods of use - Google Patents

Pyridinium salts, compounds and methods of use Download PDF

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CN1756744A
CN1756744A CN 200480005708 CN200480005708A CN1756744A CN 1756744 A CN1756744 A CN 1756744A CN 200480005708 CN200480005708 CN 200480005708 CN 200480005708 A CN200480005708 A CN 200480005708A CN 1756744 A CN1756744 A CN 1756744A
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R·B·克来因
J·L·塞尔夫
J·J·帕特里奇
J·F·赖因哈德
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Mycosol Inc
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Abstract

Compounds of pyridinium salts and methods of their use in medicine, particularly in the prophylaxis and treatment of inflammatory conditions, infectious conditions, as well as immune disorders are disclosed. The present invention also relates to methods of controlling fungi and/or bacteria. Additionally, the present invention relates to controlling fungal or bacterial infestations relating to industrial and agricultural uses. The present invention may also be used to control insects.

Description

Pyridinium salt, compound and application method
Related application
Apply for right of priority below the application requires: the application number that on June 23rd, 2003 submitted is 60/480,995 U.S. Provisional Application, the application number that on November 25th, 2003 submitted is 60/524,775 U.S. Provisional Application, the application number of submitting on November 25th, 2003 is 60/525/075 U.S. Provisional Application, the application number that on November 25th, 2003 submitted is 60/524,784 U.S. Provisional Application, and the application number that on March 3rd, 2003 submitted is 60/450,599 U.S. Provisional Application, the content of these applications all is incorporated herein by reference.
Invention field
Briefly say, the present invention relates to the pyridinium salt compound and, particularly in the method for using them aspect prevention and treatment inflammation, allergic disease, infectious diseases and the immunological disease at medical field.The invention still further relates to the method for control fungi and/or bacterium.More precisely, the present invention relates to using the relevant fungi or the control of infectation of bacteria with industrial or agricultural.The present invention also can be used to prevent and treat insect.
Background of invention
The present invention relates to pyridine derivate, they the preparation method, comprise their pharmaceutical preparation and at medical field, particularly in the method for using them aspect prevention and treatment inflammation, infectious diseases and the immunological disease.
Stilbazium lodide is a kind of known insect repellent, allegedly can resist roundworm, nematode and whipworm effectively.United States Patent (USP) 3,075,975 and United States Patent (USP) 3,085,935 put down in writing the method for going out except that infecting due to the parasitic nematode of perch in enteron aisle.
Circulating leukocyte is key activities in the inflammatory reaction pathogeny to the adhesion of blood vessel endothelium.By activating, raise or introduce various adhesion molecules at cell surface, the adhesivity of leukocyte increasing or endotheliocyte, inflammatory, infectivity and immunity medium can stimulate the adhesion process.
The effectiveness of at present used anti-inflammatory drug is limited, all has side effect usually.There is theoretic shortcoming in the monoclonal antibody that test is used for antiblocking treatment for the treatment of chronic disease.Therefore, are interesting fields during therapeutics is disposed for the micromolecular research and development that can block to specificity or suppress inter-adhesive effect between white corpuscle and the endotheliocyte.
Also need in addition to use new compound to treat fungi and/or bacterium.Fungi comprises microbe, such as slime bacteria, Tan, smut-fungi, rest fungus, downy mildew (mildews), mould (molds), smelly angle bacterium (stinkhorns), Lasiosphaera nipponica(Kawam.)Y.Kobayasi, ferfas and yeast.Fungi is owing to be directly by the food in its cell walls absorbent solution and by sporogenesis, so be classified as independently boundary.Mould is a big class fungi, and they are common triggering factors of allergy, can influence farm crop, plant and food.Mould can so-called " mould spores " molecule form be present in the indoor outer air.Kind more than 100,000 is arranged in the world.Mouldly the growth Anywhere in moist source can be had.Common mould includes but not limited to that Cladosporium (Cladosporium), Penicillium (Penicillium), Aspergillus (Aspergillus), Alternaria (Alternaria), chain spore belong to (Fusarium), neurospora (Neurospora), Stachybotrys (Stachybotyrs) and Mucor (Mucor).
The plant epiphyte pathogenic agent of injuring soil and seed is to cause whole world agricultural and gardens industry to produce the major cause of serious financial loss.These pathogenic agent cause that plant produces disease, such as seed rots, root/foot rots, rice shoot is withered.These diseases usually can reduce seedling rate, the vitality that reduces plant and possible productive rate.Severe diseases infects the unearthed rice shoot that can kill whole plant populations, and the result causes the farm crop total crop failure.
Recent decades, people's unanimity was in the technical scheme of seeking to solve a phytopathogen recurrence difficult problem.Because extraordinary farm crop become abundant further, and divide the land area that is used in agricultural, thereby exist the nonnegotiable demands of the more effective agricultural measure of use also in expansion.In the face of the needs that increase progressively to crop yield, the peasant must be by planting farm crop inferior the choosing, perhaps by improving the conventional farming custom that the frequency of planting crop in specific area is abandoned them on the soil.Do the nutritive element that can exhaust the farm crop needs like this, and the crop pathogenic agent of some particular types (especially injuring the pathogenic agent of soil or seed) also becomes more general.Correspondingly, health and the reproductivity of keeping relevant crop also becomes more and more difficult.
In addition, in the field except that agricultural, also need a large amount of compounds to come controlling microbial.These comprise that handling fabric prevents mouldy and rotten; Suppress and the termination bacterial growth; For the purpose of medical science, industry, food processing and family, treat surface and matrix are to form anticorrosion environment; Handle the woodwork of ornament or buildings; Allotment ink and paint are used to prevent mould-growth and bacterial degradation; The disease of prevention and treatment humans and animals body; And spread all over the nearly all Application Areas relevant with our daily life.
People need to continue new antiseptic-germicide.Though known chemical compound lot can be used for treating Gram-positive and gram-negative bacterial infections and other infected by microbes, but the widely-used microorganism strains that can develop immunity to drugs in succession of these compounds, be antagonism certain antibiotics or the antibiotic microorganism strains of a class, so previous effective chemical composition is with no longer valid.Also have, known microbiotic and chemical ingredients are only effective to the certain micro-organisms bacterial strain, perhaps Gram-positive or Gram-negative, aerobic or anaerobion are had limited activity.
Summary of the invention
The present invention relates to certain methods and comprise the composition of department for shellfish ammonium (stibazium).One aspect of the invention is the composition that comprises formula (I) or its solvate:
Figure A20048000570800131
Wherein said compound is gone up substantially and is E, the E configuration.Amino part can be positioned at ortho position, a position or contraposition position.X -Can be anion salt, R 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino (pyrrolidino) or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And R 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.Replace and unsubstituted aryl moiety and replace and not substituted benzyl partly can include but not limited to low alkyl group, aryl, benzyl, acyl group, amido, amino, alkoxyl group, carboxyl, carboxyl ester, alcohol, nitro, thrihalothaneoxy, trifluoroalkyl and halogen.R 5Also can be organometallic compound, such as organotin, organosilicon, or organic germanium.In addition, R 5Can also be (CH 2) n-MR 6, wherein n is numerical value 1-6, M is an organometallic compound, such as tin, silicon or germanium, and R wherein 6Be selected from propyl group, butyl, or any alkylate.
The present invention also relates to control the method for fungi and/or bacterium, comprise and use the compound that comprises any tool following formula or the composition of its solvate:
X wherein -Be anion salt, R 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene, R that perhaps ought be wherein 1With R 2Or R 3With R 4When linking together with the nitrogen-atoms that they connected, they form pyrrolidino (pyrrolidino) or piperidino-(1-position only) ring.R 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene, alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.R 5Also can be organometallic compound, such as organotin, organosilicon, or organic germanium.In addition, R 5Can also be (CH 2) n-MR 6, wherein n is numerical value 1-6, M is an organometallic compound, such as tin, silicon or germanium, and R wherein 6Be selected from propyl group, butyl, or any alkylate.The compounds of this invention more commonly is called as department for shellfish ammonium (stibazium).
The invention still further relates to the method for control insect, comprise compound or its solvate of using any tool said structure formula.
In addition, the present invention also relates to treat the method for inflammation, allergic disease, infection and immunological disease, comprise and use compound or its solvate that comprises any said structure formula.The invention still further relates to the method for control fungi and/or bacterium, comprise compound or its solvate of using any tool said structure formula.
In addition, the invention still further relates to the stabilization microcapsule compositions of anti-environment degradable.
The accompanying drawing summary
Figure 1A-1G shows that the pyridine ring nitrogen atom site comprises all cpds of methyl.
Fig. 2 A-2G shows that the pyridine ring nitrogen atom site is connected with all cpds of trifluoroethyl.
Fig. 3 A-3F shows that the pyridine ring nitrogen atom site comprises all cpds of isobutyl-.
Fig. 4 A-4G shows that the pyridine ring nitrogen atom site is connected with all cpds of ethyl.
Detailed Description Of The Invention
Above-mentioned each side of the present invention and other aspect can illustrate in greater detail with reference to other embodiment described herein. Should be appreciated that the present invention can embody with different forms, and should not be regarded as being limited to described each embodiment in the Zhe. On the contrary, the purpose that a little embodiment of Zhe are provided is in order to make content of the present invention more fully and complete, and the abundant Zhuan of scope of invention is reached to this area Zhuan industry technical staff.
The term Zhi that specification Zhong of the present invention uses is that Yong Yu describes particular Zhi purpose, is not that Yong limits the present invention. Zheng used such as specification of the present invention and accessory claim Zhong, " one " and " one " of singulative also comprise plural form, but context Zhong in addition You offer some clarification on except.
Unless otherwise indicated, the implication of scientific and technical terminology used herein is identical Yu the implication that those skilled in the art understand usually.
This introducing do reference of full content Zai of all publications that this paper quotes, the sharp application of Zhuan, Zhuan profit and other document, Zuo is the explanation to the content of the relevant sentence at a little documents of Zhe place and/or paragraph.
The present invention also relates to pyridine derivate, Zhi is for their method, the Zu compound that uses their method and comprise a little derivatives of Zhe. Stilbazium iodide is a kind of known anthelmintic, and it is said can the ground opposing of You effect roundworm, nematode and whipworm. United States Patent (USP) 3,075,975 and United States Patent (USP) 3,085,935 put down in writing the method that infects due to the parasitic nematode of eliminating in the perch Zai enteron aisle. This compound can Yong Yu Zhen bacterium and/or the bacterium of control industrial use aspect.
One embodiment of the present invention comprises following formula: compound or its solvate:
X wherein-Anion salt, R1，R 2，R 3, or R4Independently be selected from methyl, ethyl, C1-10Alkyl (Zhi chain or Zhi chain), alkene (Zhi chain or Zhi chain) is perhaps worked as R1Yu R2Or R3Yu R4When the nitrogen-atoms that connects with them linked together, their formed pyrrolidino (pyrrolidino) or piperidino ring. X-Can be selected from fluoride, chloride, the Xiu compound, iodide halide, mesylate, toluene fulfonate (benzenesulfonate), naphthoate (napthylate), naphthalene sulfonate (nosylate), p-aminobenzoate, benzene sulfonate, benzene sulfonate (besylate), lauryl sulfate, 2,4-DihydroxyBenzophenone, 2-(2-Qiang base-5 '-aminomethyl phenyl) BTA, Uvinul N35 and salicylic acid 5-butyl phenyl ester. R5Be selected from methyl, ethyl, C1-10Alkyl (Zhi chain or Zhi chain), alkene (Zhi chain or Zhi chain), alkynes, the Zheng propyl group, isopropyl, the Zheng butyl, isobutyl group replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group. R5Also can be You machine metallic compound, such as organotin, organosilicon, or organic germanium. In addition, R5Can also be (CH2) n-MR 6, wherein n is numerical value 1-6, M is You machine metallic compound, such as tin, silicon or Zhe, and R wherein6Be selected from propyl group, butyl, or any alkyl compound.
Another embodiment of the invention comprises compound or its solvate of formula (II):
Figure A20048000570800161
X wherein -Be anion salt, R 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched) is perhaps worked as R 1With R 2Or R 3With R 4When linking together with the nitrogen-atoms that they connected, they form pyrrolidino (pyrrolidino) or piperidino-(1-position only) ring.R 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.X -Can be selected from fluorochemical, muriate, bromide, iodide halogenide, mesylate, tosylate, naphthoate (napthylate), naphthalenesulfonate (nosylate), p-aminobenzoate, lauryl sulfate, 2,4 dihydroxyl benzophenone, 2-(2-hydroxyl-5 '-aminomethyl phenyl) benzotriazole, benzene sulfonate (benzenesulfonate), benzene sulfonate (besylate), 2-cyano-3,3-diphenyl ethyl acrylate and Whitfield's ointment 5-butyl phenyl ester.R 5Also can be organometallic compound, such as organotin, organosilicon, or organic germanium.In addition, R 5Can also be (CH 2) n-MR 6, wherein n is numerical value 1-6, M is an organometallic compound, such as tin, silicon or germanium, and R wherein 6Be selected from propyl group, butyl, or any alkylate.The compounds of this invention usually abbreviates department as for shellfish ammonium (stibazium).One of embodiment of formula I is 2, two (to the pyrrolidino styryl) the pyridine methiodides of 6-.
On the other hand, shown in following compound, NR 1R 2And NR 3R 4Group can be at various different positionss.
Another embodiment comprises wherein NR 1R 2The locational formula III in position between being positioned at.
Formula IV shows NR 1R 2And NR 3R 4Position, position between group all is positioned at.
Figure A20048000570800172
X wherein -Be anion salt, R 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched) is perhaps worked as R 1With R 2Or work as R 3With R 4When linking together with the nitrogen-atoms that they connected, they form pyrrolidino (pyrrolidino) or piperidino-(1-position only) ring.R 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.In addition, R 5Can also be (CH 2) n-MR 6, wherein n is numerical value 1-6, M is an organometallic compound, such as tin, silicon or germanium, and R wherein 6Be selected from propyl group, butyl, or any alkylate.
Compound of the present invention can exist with the form of geometrical isomer.With regard to its industrial application, no matter all these isomer are single, or the form of mixture, all comprise within the scope of the present invention.E, E isomer are a kind of configurations of the present invention, E, the E-configuration forward with reverse 2, the 6-conformation all is possible.In addition, except that an above-mentioned contraposition and a bit architecture, also can form the ortho position, the structure of ortho position conformation.The ortho position conformational structure can comprise same salt and the group that above reaches description in the application's full text.
Embodiments more of the present invention comprise 1-ethyl-(E,-E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridinium chloride, the 1-ethyl-(E ,-E)-2,6-pair [right-(1-pyrrolidino styryl] pyridinium chloride, the 1-methyl-(E ,-E)-2, and two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridinium chloride and 1-methyl-(E,-E)-2,6-pair [right-(1-pyrrolidino styryl] pyridinium chloride.
In addition, the present invention can comprise compound or its solvate of following general formula V:
Wherein n is numerical value 1-5, and wherein Z may reside on a plurality of positions of phenyl ring, and is selected from C, N, O, S and halogen, wherein X -Be anion salt, R wherein 1, R 2, R 3, or R 4Independently be selected from do not exist, hydrogen, methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), nitrile, benzene, pyridine, thionaphthene, trifluoroalkyl, fluoroalkyl, replacement and unsubstituted aryl and replacement and unsubstituted benzyl moiety are perhaps wherein worked as R 1With R 2Or work as R 3With R 4When linking together with the nitrogen-atoms that they connected, they form pyrrolidino (pyrrolidino) or piperidino-(1-position only) ring.X -Can be selected from fluorochemical, muriate, bromide, iodide halogenide, mesylate, tosylate, naphthoate (napthylate), naphthalenesulfonate (nosylate), p-aminobenzoate, benzene sulfonate (benzenesulfonate), benzene sulfonate (besylate), lauryl sulfate, 2, the 4-dihydroxy benaophenonel, 2-(2-hydroxyl-5 '-aminomethyl phenyl) benzotriazole, 2-cyano-3,3-diphenyl ethyl acrylate and Whitfield's ointment 5-butyl phenyl ester.R 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.R 5Also can be organometallic compound, such as organotin, organosilicon or organic germanium.In addition, R 5Can also be (CH 2) n-MR 6, wherein n is numerical value 1-6, M is an organometallic compound, such as tin, silicon or germanium, and R wherein 6Be selected from propyl group, butyl, or any alkylate, condition be described compound can not be the 1-ethyl-(Z, Z), (Z, E) or (E, Z)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridinium chloride.But Fig. 1-4 for example understands the compound of the various combinations that the present invention can form.These compounds can be E, the E configuration, and can be used for any purposes of the present invention.
Compound of the present invention can be according to any proper method preparation in the organic chemistry.More particularly, formula I compound can be by United States Patent (USP) 3,085, the method preparation of describing in 935, and the content of the document is in these whole introducings.
In addition, embodiment of the present invention can comprise the compound that produces by following synthetic method, and this is synthetic to be by condensation two normal formula VI aldehyde:
Figure A20048000570800191
With 2, the quaternary ammonium salt of 6-lutidine prepares described compound:
Figure A20048000570800192
Above-mentioned condensation reaction can adopt the catalyzer such as quaternary ammonium (as piperidines) to carry out in lower alcohol.X in following formula -During for iodide ion (corresponding to the alkiodide salt of lutidine), condensation product (formula I) is undissolvable comparatively speaking, thereby can precipitation separate out in reaction process.The reaction yield of formula I is close to quantitatively.As United States Patent (USP) 3,085,935 is described, can use the catalyzer of triplication.Can adopt other method to prepare compound of the present invention, and also can use more volume or more a spot of catalyzer for the preparation of formula I compound.
For above-mentioned reaction, R can be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.In addition, R also can be (CH 2) n-MR 2, wherein n is numerical value 1-6, M is an organometallic compound, such as tin, silicon or germanium, and R2 wherein is selected from propyl group, butyl, any alkylate.
And, preferably iodide salt is converted into chloride salt.This conversion can utilize size exclusion (molecular sieve) chromatography to finish, and uses the appropriate solvent wash-out and the balance that contain the excess chlorination ammonium.By evaporating solvent, can obtain to contain the effluent and the ammonium iodide by product of chloride salt.Products therefrom is substantially free of iodide salt.On the other hand, make 2 in the presence of secondary amine (for example piperidines), the alkyl chloride salt of 6-lutidine and the aldehyde reaction of formula VI also can directly obtain the chloride salt of formula I.
Other method is, by with 2,6-lutidine ethyl iodide is dissolved in the methyl alcohol, slowly blasts anhydrous HCl (220 gram) subsequently in this solution, also can make compound of the present invention.In order to keep temperature of reaction to be lower than 30 ℃, can use ice/water-bath.After all HCl finish, will react at room temperature to stir and spend the night.After the stirring, should do near by concentration response, with 1000mL fresh methanol redilution.By feed anhydrous HCl in mixture, ethyl iodide can be converted into the diethylaluminum monochloride that needs.Stir after 10 minutes, utilize the rotatory evaporator concentration response, place the interior final drying of high-vacuum tube to spend the night to doing.
The present invention is surprised to find chloride salt and has high stability than iodide salt.Can use other method known in the art that these salt are converted into UV blocker salt or surfactant salt.Other salt comprises:
Formula A-department replaces shellfish ammonium para-aminobenzoate:
Formula B-department replaces shellfish ammonium dodecyl sulfate (department is for shellfish ammonium lauryl base vitriol):
In addition, " salt " can also comprise that the benzophenone of replacement is as 2, the 4-dihydroxy benzophenone, the benzotriazole such as 2-(2-hydroxyl-5 '-aminomethyl phenyl) benzotriazole that replace, the acrylate such as the 2-cyano group-2 that replace, 3-diphenylacrylate ester, ethyl salicylate, such as Whitfield's ointment 5-butyl phenyl ester.
These salt can comprise UV blockers or tensio-active agent." UV blockers " used herein is meant all " photoactive substance ", promptly is used for blocking-up and/or absorb ultraviolet all components and material.This term also refers to all bright protective agents and photoresist.
As mentioned above, compound of the present invention can be used for the treatment of inflammation, handle agricultural prods and Industrial products.
Inflammation
Have been found that these compounds can suppress one or more enzyme: 5-lipoxygenase, cyclooxygenase and molten-PAF: acetyl-CoA Transacetylase.In addition, we also are surprised to find this series pyridine derivate can suppress the expression of adhesion molecule on people's umbilical cord endothelial cell monolayer under lower concentration, illustrate that thus they can be used for the treatment of inflammation, infection and immunological disease.
The example of inflammation, infectious diseases or immunological disease comprises these diseases that lung, throat, oral cavity, joint, eyes, nose, intestines and skin are suffered from; These particularly relevant diseases with the infiltration of white corpuscle in Inflamed tissue.Lung symptoms comprises asthma, adult respiratory distress syndrome, bronchitis and cystic fibrosis of the pancreas (this disease is involved intestines or other tissue in addition or optionally).The throat symptom comprises laryngitis and oropharynx (orophoryngeal) mucositis.The oral cavity symptom comprises gingivitis and periodontitis.The joint symptom comprises rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and other sacroiliitis.Struvite illness in eye comprises uveitis (comprising iritis) and conjunctivitis.Struvite rhinopathy comprises rhinitis and chronic sinusitis.Inflammatory bowel comprises the Crohn disease, ulcerative colitis and tip rectitis (distalproctitis).Whether tetter comprises and the hyperplasia diseases associated, such as psoriasis, eczema and dermatitis (no matter being the allergy pathogeny), and allergy inductive pruritus, for example pruigo.Other inflammation and immunological disease comprise the tissue necrosis in the chronic inflammatory diseases process.
In addition, the present invention also provides prevention or treatment Mammals such as people's the inflammation or the method for immunological disease, and this method comprises formula (I) compound or its pharmaceutically acceptable solvate of administering therapeutic significant quantity.
Another embodiment of the invention also provides and has been used for medical purpose, especially for formula (I) compound that prevents or treat Mammals such as people's inflammation, allergic disease or immunological disease, or its pharmaceutically acceptable solvate.
In addition, we go back discoverable type I compound some bacteriums, yeast and fungi are had anti-infectious activity.This activity can not be expected, and this activity shows that formula I compound has the effectiveness of treatment local bacterium, yeast and fungi infestation.These infection comprise streptococcus aureus (Staphylococcus aureus) and streptococcus bacterial strain, for example streptococcus pyogenes and Candida albicans (Candida albicans), the yeast strain of Oidium tropicale (Candida tropicalis) and yeast saccharomyces cerevisiae equally also comprises following fungal bacterial strain: Cryptococcus neoformans (Cryptococcus neoformans), Aspergillus fumigatus (Aspergillus fumigatus), flavus (Aspergillus flavus), rhizopus arrhizus (Rhizopus arrihizus), fusarium solanae (Fusarium solani), microsporum gypseum (Microsporidiumgypseum), trichophyton equinum (Trichophyton equinium), trichophyton mentagrophytes (Trichophyton mentagrophyt), trichophyton rubrum (Trichophytonrubrum) and acrothesium floccosum (Epidermophyton floccsum).
Realize that formula (I) compound that the expection biological effect needs or the amount of its pharmaceutically acceptable solvate depend on multiple factor, for example predetermined purposes, the method for application and the person's that is subjected to the medicine situation.For example, the typical per daily dose used of treatment septic shock is expected to be 0.005mg/kg-100mg/kg, preferred 0.05-50mg/kg, and 0.5-20mg/kg most preferably.This dosage can be used by single unitary dose, perhaps with several independently unit dosage form use, perhaps use by the mode of continuous infusion.Estimate intravenous administration dosage in the 0.0025mg/kg-50mg/kg scope, and be typically mode administration with infusion.For other treatment of diseases, can use similar dosage.For by the pulmonary administration of aerosol, should use the compound of capacity, so that in curee's airway surface liquid, reach the concentration of about 2-1000numol to the curee.
Therefore, another aspect of the present invention provides pharmaceutical composition, and it comprises formula (I) compound or its salt or solvate pharmaceutically as activeconstituents, and at least a pharmaceutically useful carrier or vehicle (recipient).These pharmaceutical compositions can be used for prevention and treatment inflammation, allergic disease, infectious diseases and immunological disease.Carrier must be pharmaceutically acceptable for the recipient, and must be compatible with other composition in the composition, promptly can not have detrimental action to other composition.Carrier can be solid or liquid, and preferably is formulated as unit dosage, for example contains the tablet of 0.05-95% weight activeconstituents.If desired, also can in pharmaceutical composition of the present invention, mix other physiologically active ingredient.
Possible preparation comprises and is suitable in oral, cheek, rectum, part (comprising through the skin approach), the nose and the preparation of inhalation.For concrete patient, optimum administering mode depends on the character that is subjected to sanatory severity and active compound, but if possible, topical is preferred for for example local dermatitis of treatment or pruigo.Yet for this class treatment of conditions of picture asthma, suction is preferred route of administration.
The dosage form that is suitable for oral administration comprises discrete unit form, for example tablet, capsule, cachet, lozenge, and they contain the active compound of predetermined amount separately; Pulvis or granule form; Solution in water-based or non-aqueous liquid or suspension form; Or oil-in-water-type or water-in-oil emulsion form.
The preparation that is suitable for hypogloeeis or cheek administration comprises lozenge, the matrix that this formulation comprises active compound and is generally the process seasoning, such as sucrose and gum arabic or tragacanth gum.In addition, this type of preparation comprises that also activeconstituents is included in the pastille (pastille) in inert base such as gelatin and glycerine or sucrose and the gum arabic.
The preparation that is suitable for rectum glycerine is preferably the suppository of unitary dose, and this suppository comprises the activeconstituents that is in one or more solid carriers (as theobroma oil) that form suppository base.
The preparation that is suitable for using in part or the nose comprises ointment, creme, lotion, paste, gelifying agent, sprays, aerosol and finish.The appropriate carrier that is used for this class preparation comprises mineral jelly, lanolin, polyoxyethylene glycol, alcohol, DMSO and combination thereof.In this class preparation, the concentration that exists of activeconstituents is generally 0.1-15%w/w.
Preparation of the present invention can prepare with any suitable method, typical method comprises with activeconstituents and liquid or subdivided solids carrier or their the two ratios on demand evenly, mix densely, if desired the gained compound is shaped to the shape that needs then.
For example, the powder or the particulate dense mixture that comprise activeconstituents and one or more optional members such as tackiness agent, lubricant, inert diluent or surfactivity dispersion agent by compacting, the dense mixture of perhaps molded efflorescence activeconstituents and inert liquid diluent can make tablet.
The typical method of the preparation aqueous solution is a lytic activity composition in being added with the salt solution of cyclodextrin.
The suitable preparation that inhalation is used comprises particle pulvis in small, broken bits or mist agent, and the latter can utilize different types of quantitative pressurization aerosolizer, atomizer or insufflator to produce.
For the pulmonary administration via the oral cavity, in order to ensure being administered into bronchial tree, the particle diameter of powder or droplet is usually at 0.5-10 μ m, in the scope of preferred 1-5 μ m.For intranasal administration, preferable particle size rests on nasal cavity to guarantee medicine in the 10-500 mu m range.
Metered-dose inhaler is a kind of pressurization aerosol dispenser, contains suspension or the pharmaceutical solutions of activeconstituents in liquefied propellant usually.In use, these devices produce the fine particle sprays that contains activeconstituents by being suitable for transmitting the valve ejection preparation of quantitative volume (being generally 10-150 μ l).Suitable propelling agent comprises some chloro fluorocarbon compound, such as Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane and composition thereof.Can also comprise one or more solubility promoters in addition in the preparation, for example ethanol and lipid acid tensio-active agent, for example oleic acid or sorbitan trioleate, antioxidant and suitable seasonings.
Atomizer is the device that is commercially available.Dependence is passed the narrow Venturi mouth of pipe with pressurized gas (being generally air or oxygen) and is quickened, and perhaps relies on ultrasonic stirring, the aerosol mist that this device can change into treatment usefulness with the solution or the suspension of activeconstituents.The suitable formulations that supplies atomizer to use is made up of in liquid preparation activeconstituents, and comprises the preparation up to 40%w/w, preferably is less than 20%w/w.Typical carrier is water or diluted alcohol aqueous solution, preferably by adding for example sodium-chlor furnishing and the isoosmotic form of body fluid.Optional additives comprises sanitas (if preparation prepares) for example hydroxymethyl-benzoic acid methyl esters, antioxidant, seasonings, ethereal oil, buffer reagent and tensio-active agent under non-sterilizing condition.
The suitable formulations that inhalation is used comprises efflorescence powder in small, broken bits, and this powder can utilize insufflator to give, perhaps by taking in nasal cavity with the mode of snuffing gas.In insufflator, powder packets is contained in the gel or cartridge case that is made of plastics usually, and they are pierced on the spot or open, by inhalation or utilize manual pump to suck air and come delivery of powered.The powder that uses in the insufflator can be made up of separately activeconstituents, or is made up of the powdered mixture that comprises activeconstituents, suitable powder diluent such as lactose and optional tensio-active agent.Activeconstituents accounts for the 0.1-100%w/w of weight of formulation usually.
Therefore, another aspect of the present invention provides formula (I) mixture or its pharmaceutically acceptable solvate to be used for preventing or treat the application of the medicine of inflammation or immunological disease in preparation.
Further, the present invention can provide the microcapsule that has UV light absorber and optionally wherein seal organic solvent, and its cyst wall film is made of synthetic resins, and median size is 0.1-3 μ m.Ultraviolet ray can be blocked or suppress to these absorption agents.
Agricultural
The compounds of this invention is also to powdery mildew and rest fungus, the pathogenic agent of nuclear cavity Pseudomonas (pyrenophora), beak shape spore Pseudomonas (rhynchosporium), tapesia, fusarium and Leptosphaeria (leptosphaeria) fungi, especially monocotyledons such as cereal (comprising wheat and barley) is effective especially.And also downy mildew mushroom, Powdery Mildew, leaf spot and the rust to dicotyledons is effective for they.
The amount of application of The compounds of this invention depends on multiple factor, kind and the time of application of for example used compound, the main body (substrate, plant, soil, seed) of treatment, the mode of handling (for example spraying, dusting, seed dressing), the purpose of handling (prevention is treatment still), fungi to be processed and/or bacterium.
Be present in various Different Crop or its seed in order to control, especially the ornamental plant of wheat, rye, barley, oat, paddy rice, corn, lawn, cotton, soybean, coffee, sugarcane, fruit and gardening and viticulture aspect, vegetables such as cucumber, soybean and cucurbit, and, use fungicidal and/or kill bacterium mixture particularly important such as a large amount of fungies and/or bacterium on potato, peanut, tobacco and the beet field crop.
Term " control " is meant minimizing, suppresses, alleviates, containment, prevention etc.
Mixture is by with fungicidal and/or kill the mode that the bacterium effective amount of actives handles fungi and/or bacterium or be subjected to seed, plant or material that fungal infection threatens and use.
These preparations can be subjected to use before or after fungi and/or the bacterial invasion at material, plant or seed.
When imposing on plant, with 20-2000g/ha, what usually the dose of 20-1000g/ha was associated is, the amount of application of formula I compound is 25-250g/ha, is generally 50-150g/ha, for example 75,100,125 or 150g/ha.
In agricultural application, the formulation rate of mixture depends on desired effect kind, and changes in the scope of per hectare 0.02-3kg activeconstituents.
Plant a period of the day from 11 p.m. to 1 a.m when activeconstituents is used for handling, common every kilogram of seed uses the 0.001-50g activeconstituents, and the amount of general 0.01-10g just is enough to.
Composition of the present invention can be any conventionally form use, for example with agricultural on the form of acceptable assistant bonded double pack form, quick-acting granule, suspension agent, emulsifiable concentrate or wettable powder or tensio-active agent (for example Sodium Lauryl Sulphate BP/USP and lauryl sulfate sodium salt) use.This based composition can adopt ordinary method production, for example activeconstituents is mixed with suitable auxiliary (thinner or solvent and other optional processing preparation composition such as tensio-active agent).When the long-acting effectiveness of needs, also can use conventional slow release type preparation.
Specifically, preparation of using with Sprayable such as water emulsifiable concentrate or wettable powder can comprise the tensio-active agent such as wetting agent and dispersion agent, the for example condensation product of formaldehyde and naphthalenesulfonate, alkylaryl sulphonate, Sulfite lignin, aliphatic alkyl vitriol, and ethoxylated alkylphenol and ethoxylized fatty alcohol.
Use is the present composition and the thinner of suitable seed dressing formulation, in mode well known in the art this seed dressing is put on seed, these formulations such as aqueous suspension or seed is had the dry powder form of good adhesion.This class seed dressing is known in the art.Seed dressing can be the encapsulated form (as slow releasing capsule or microcapsule) that contains single-activity composition or various active constituents mixt.
In general, preparation of the present invention comprises 0.01-90% weight active substance, the solid of acceptable surfactant and 10-99.9% or liquid auxiliary agent on the 0-20% agricultural, active substance is by at least a formula I compound, and optional other active substance, particularly composition such as microbicide or sanitas.The conc forms of composition comprises 2-80% usually, is preferably the active substance of 5-70% weight.The administration form of preparation for example can contain 0.01-20% weight, is generally the active substance of 0.01-5% weight.Although the commercially available prod is mixed with the enriched material form usually, the end user often will use the dilution preparation.
In addition, the color of The compounds of this invention can be removed by the mode of " bleaching ".Art-recognized is (referring to B.C.Saunders etc., Peroxidase, London, 1964, p.10ff), the superoxide endonuclease capable acts on various amino and phenolic compound, thereby produces color.In view of the above, can think inevitably that peroxidase (and some oxide compound enzyme) also can apply effect to the coloring matter in the solution astoundingly, thereby suppress dye transfer.Although suppress the mechanism of the ability of dye transfer does not illustrate as yet about these enzymes, but think that at present these enzymes are to work by the coloring matter (donor matrix) that reduces hydrogen peroxide or molecular oxygen and oxidation dissolution or be dispersed in the washings, thereby produce colorless substance or form fabric or the non-adsorbable material of material of construction.
In addition, also can form the liquid composition of material of the present invention, they can dilute with mixed with excipients and/or with vehicle.When vehicle was used as thinner, it can be solid, semisolid or liquid substance, plays a part vehicle, carrier or medium as composition of matter of the present invention.Various appropriate excipients all are well known by persons skilled in the art, and are found in National Foumulary, 19:2404-2406 (2000) [full content of 2404-2406 page or leaf is hereby incorporated by].Preferred vehicle comprises butyleneglycol and EDTA.The example of proper excipient includes but not limited to starch, gum arabic, Calucium Silicate powder, Microcrystalline Cellulose, methacrylic ester, shellac, polyvinylpyrrolidone, Mierocrystalline cellulose, water, syrup and methylcellulose gum.Water medium can comprise one or more activeconstituentss, a certain amount of one or more tensio-active agents [this amount is enough to allow described activeconstituents to be dissolved or suspended in equably in the described medium] and other processing additives known in the art.The latter comprises particle binders such as gelatin; Natural gum such as gum arabic, tragacanth gum; Starch, sodiun alginate, sucrose, polyvinylpyrrolidone; Derivatived cellulose is Vltra tears for example, the polyethylene oxazolidone; Medicinal filler is lactose for example, Microcrystalline Cellulose, Lin Suanergai, tricalcium phosphate, calcium sulfate, glucose, mannitol, sucrose; Compressing tablet lubricant (if necessary), for example calcium stearate and Magnesium Stearate, stearic acid, talcum, sterotex (alkaline stearate).For a kind of composition of one of embodiment of the present invention, used term " water medium " has the usual implication of this area.It mainly is meant the water medium of carrying activeconstituents, is added with water-miscible solvent in case of necessity, such as Virahol or ethanol.
Industry
Compound of the present invention can be used to handle all places that growth has mould, fungi and bacterium.Example includes but not limited to woodwork, blast main, timber, deck, pipeline, stucco, brick and tile, paint, insulating material, top board, material of construction, metal, machine element, food pack, base material (substrates) etc.
Another embodiment of the invention can comprise that the department that capsule is sealed replaces the shellfish ammonium.Term used herein " microcapsule " is meant unit molecule, sealing discrete particles, many plastochondrias, the active ingredient of liquid polykaryon and uniform dissolution.Encapsulating method provides the water-soluble or oil soluble active ingredient that is sealed in water-soluble or the oil-soluble material conchiolin.The micro encapsulation seal active ingredient be owing to can avoiding oxidation and hydration to be protected, and can perhaps slowly diffuse through matrix by activeconstituents and discharge by the housing matrix that melts, breaks, biological degradation or dissolving are surrounded.The size of microcapsule is generally the 1-2000 micron, but greater or lesser size also is known in the art.
Compound of the present invention can place in the microcapsule or place and be used to distribute in their the fibrous type housing.They also can be dispersed in the polymer materials or with liquid form and preserve.
Activeconstituents can place in the microcapsule with compound of the present invention.Example with activeconstituents of repellent activity comprises triglycol one hexyl ether and N, the N-diethyl--triamide.Example with fragrant active activeconstituents comprises Geraniol, limonene, benzylalcohol, C 6-20The ester of hydrocarbon, ethers, aldehydes, and alcohol compound.Example with activeconstituents of insecticidal activity comprises sterilant such as salithion, diazinon and Chlorpyrifos 94 and bactericide such as thiophanate methyl and Vancide 89.
With regard to phase change material, also can seal these components when needing.These encapsulated ingredient can further be sealed in the microcapsule.Microcapsule can use multiple different material preparation, comprises polyethylene, polypropylene, polyester, polyvinyl chloride, three starch acetates, polyethylene oxide, polyoxytrimethylene, polyvinylidene dichloride or poly(vinylidene fluoride), polyvinyl alcohol, polyvinyl acetate, polycarbonate and polylactone.Can be about the detailed content of microencapsulation referring to USP5,589,194 and 5,433,953, their content is all incorporated at this.The diameter that is suitable for the microcapsule of base substance use of the present invention is about the 1.0-2000 micron.
Shape for the object of supported active composition does not have particular restriction.In other words, by supporting mixture (holding mixture) to have the form of multiple supported active composition.Concrete example comprises that wherein the activeconstituents surface has been supported the microcapsule that mixture coats; Be processed into the product that needs shape, they can be prepared as follows separately: mediate activeconstituents or form the homogeneous solution of supporting mixture and activeconstituents in supporting mixture, by removing composition such as desolvate activeconstituents is distributed in the support mixture, then dispersion is processed into the shape that needs, unit molecule for example, liquid, spheroid, sheet, film, rod, pipe, line, band shape or smear metal.In addition, as the example of these converted productss, can provide its surface and be coated with the product that is used to control the protective layer that activeconstituents discharges and be coated with and improve the product of suitability with tackiness agent.Further example comprises the product according to following method preparation: fill activeconstituents in being processed into the support mixture of capillary form, heated sealant two ends capillaceous are sealed in activeconstituents wherein then; Also comprise in addition by the above-mentioned kapillary of heart cutting become two and obtain thus have the product that an end is an opening form separately.
Container is sealed with the activeconstituents of liquid form by supporting that mixture constitutes in the container, so that obtain long-term evenly releasability.As this shape, generally be suitable for cast, bottle type or bag type container.
When mixture constituted container shapes, particulate was realized stable lasting release, and lasting releasing layer preferably has the thickness of 0.002mm at least.When the thickness that continues releasing layer is not less than 0.002mm, specific question can not take place, and can use the thickness of 0.005mm-5mm.When surpassing 5mm, it is very few that the burst size of compound tends to become.
For solid, the release surface area of the lasting delivery article that is made of this container is preferably 0.001cm 2Or it is bigger.Operable scope is 0.01cm 2-1cm 2
(described container is by supporting that compound constitutes) can seal them in batches when activeconstituents being encapsulated in the extended release preparation container.Retention volume can be 0.5mg-5mg, and can be 1mg, 2mg, 3mg, or 4mg.
As the shape of supporting the container that mixture constituted, can use pipe, bottle and bag.With regard to the cast goods, can use the pipe of internal diameter as 0.4mm-10mm.Internal diameter fills activeconstituents and become difficult in container, and internal diameter then is difficult to seal greater than 10mm less than 0.4mm.Bottle type goods are to utilize blow moulding or injection moulding to make, and internal volume is generally 0.1-200ml.Internal volume is not easy to make less than the bottle of 0.1ml, and internal volume then is uneconomic greater than the bottle of 200ml because wherein between the amount of the activeconstituents of Tian Chonging and the internal volume existence than big difference.For bag type goods, the amount of the activeconstituents of filling in the band is preferably 1mg-100g.
The lasting delivery article of first group biodegradable should keep its fundamental characteristics in application according to the present invention, therefore, in order to improve weathering resistance, can in supporting mixture, add pigment or dyestuff, or stablizer such as ultraviolet thinner and/or blocker or antioxidant separately.On the other hand, also can in being encapsulated in the activeconstituents of supporting in the container that mixture makes, add these additives.
Term used herein " sustained release " is to be used to refer to speed delivery of biologically active composition preselected or that need.This speed becomes according to using.Expected rate comprises fast or delivery mode and delay immediately, continue or delivery mode in order.The present invention also comprises the delivery mode of combination, and for example initial spike discharges, and lower level ground continues the delivery of biologically active composition subsequently.
Term used herein " bioactive ingredients " comprises therapeutical agent, such as medicine or pharmacological active substance, as medicine or medicament, and preventive, diagnostic reagent and be used for the treatment of or prevent other chemical or the material of uncomfortable, infection and/or disease.Composition of the present invention is effective especially to plant and other organism.
The invention provides microcapsule and kill bacterium and/or fungicide composition, it comprises having the polyureas housing separately and can slowly see through housing and comprise pyridinium salt and the microcapsule of the liquid filler material of biological potentiating agent.Wherein as the intrinsic part of described housing, also comprise stable ultraviolet radiation absorption immunomodulator compounds of light or blocker compound in the housing, with respect to the radiation of wavelength in the 270-350 nanometer range, these compounds have the logarithm molar extinction coefficient of 2-5.
" photochromics " used herein is meant and is used for blocking-up and/or absorbs ultraviolet all the components and material.All light protective agents and light stabilizer (photoresistantagent) also represented in this term.
" tensio-active agent " used herein is meant and comprises the tensio-active agent salt component by all the components such as can forming emulsion, microemulsion, suspension.
Complete microcapsule composition can comprise 60-90% liquid filler material and 40-10% housing, liquid filler material comprises 5-40% pyridinium salt, 25-50% biological potentiating agent and 20-40% and the immiscible organic solvent of water, and housing comprises the 0.5-20% light-stabilizing UV absorbent compound (all percentage number averages are benchmark with the weight of complete microcapsule composition) as its intrinsic part.
Because the dividing potential drop of pyridinium salt surrounds microcapsule, in the packing of composition and storage process, promptly place sealed vessel during, pyridinium salt is retained in the microcapsule.When product uses as bactericide and/or mycocide, slowly discharge pyridinium salt (actual release rate depends on the thickness and the porosity of cyst wall).Pyridinium salt is between the shelf lives and to use the back all be chemically stable up to its infiltrate micro-capsule cyst wall during this period of time.It becomes available bactericide and/or bactericide until degraded at that time.Because it is very slow that weighting material sees through the speed of shell wall, the micro-capsule product has long lasting killing bacterium and/or fungicidal drug effect phase, and can standing storage (for example reaching 6 months or the longer time).
Suitable weighting material stablizer absorbs the ultraviolet ray of 270-350 nanometer range, and it is converted into harmless form.They have high absorption coefficient in near-ultraviolet spectrum part (for example about 2-5 of logarithm molar extinction coefficient), but in their absorption minimum of visible light part.In the process for microencapsulation process, any substantial chemical reaction can not take place with isocyanato and the primary amine groups that housing constitutes compound in them.Wherein, can be used as and fill the benzophenone that compound that stablizer uses comprises replacement, 2,4 dihydroxy benzophenone for example, 2-hydroxyl-4-methoxyl group benzophenone, 2-hydroxyl-4-octyloxy benzophenone etc.; Benzotriazole category such as 2-(2-hydroxyl-5 '-aminomethyl phenyl) benzotriazole, 2-(3 ', 5 '-diallyl-2 '-hydroxy phenyl) benzotriazole etc.; The acrylate that replaces, 2-cyano-3,3-diphenyl ethyl acrylate for example, 2-ethylhexyl-2-cyano group-3,3-diphenyl acetic acid ester etc.; Salicylate, salol for example, Whitfield's ointment 5-butyl phenyl ester etc.; And the nickel organic compound, for example two (octyl phenol) nickelous sulfides etc.Other example of these kinds filling stablizers separately can be referring to Kirk-Othmer, encyclopedia of chemical technology (Encyclopeda of Chemical Technology).The filler stablizer accounts for 5% of microcapsule composition weight at most, accounts for 0.01-2% usually.
Embodiment of the present invention also provide the method for control fungi and bacterial activity, comprise make fungi and bacterium with comprising of significant quantity department described herein replace the composition of shellfish ammonium compound to contact.Contact can directly be carried out, for example, with spray form with composition spray in air.On the other hand, composition of the present invention can be made other various forms, and for example, load has the sheet material (such as microcapsule seal or flood ribbon) of microcapsule, and they are positioned over the place that fungi and bacterium may grow.
Another embodiment of the invention can comprise the have good storage stability thermo-sensitive material of (especially photostabilization), and the microcapsule that wherein is encapsulated with UV light absorber, and they are applicable to various fields.Can be present in needing component to comprise to absorb heat and can protect primer to avoid the superheated material in the substrate material.Heat energy is absorbed by the phase change process of this class material, thereby can not cause the increase in temperature of these materials.Suitable phase change material comprises paraffinic hydrocarbon, promptly by formula C nH N+2The straight chain hydrocarbon of expression, wherein n can be 13-28.Other compound that is applicable to phase change material comprises 2 (DMP), 2-methylol-2-methyl isophthalic acid, ammediol (HMP) and similar compound.Same fatty ester, for example Uniphat A60 in addition that is suitable for.Spendable phase change material comprises paraffinic hydrocarbon.
Thermal recording medium is known, and this material is the dye-forming reaction that utilizes between colourless or light basic dyestuff and the organic or inorganic dye acceptor (color acceptor), by making two kinds of chromonic material thermo-contacts each other, obtains recording image.This thermal recording medium is comparatively cheap, and the recording element that is fit to be easy to preserve with compressibility uses, and therefore has been found that they can be used as recording medium and are widely used in aspects such as facsimile system, various computers.In order to improve the photostabilization of thermal recording medium, can in heat sensitive recording layer or protective layer, add UV light absorber or blocker in small, broken bits.
Another embodiment of the invention provides a kind of microcapsule, and this microcapsule has good UV light absorber retention, be difficult to break under the normal pressure, and good ultraviolet radiation absorption is renderd a service.
Embodiment of the present invention can comprise thermal recording medium; it comprises base material; that form on the base material and comprise the recording layer of colourless or light basic material and dye acceptor; and the protective layer that on recording layer, forms, recording materials are characterised in that and mix the microcapsule that wherein is encapsulated with UV light absorber and does not have the quality ability basically in protective layers.
Further, the invention provides the microcapsule that wherein is encapsulated with UV light absorber and also is encapsulated with organic solvent on demand.This microcapsule has synthetic resins cyst wall film, and mean particle size is 0.1-3 μ m.
It below is the example of the UV light absorber that can use for the present invention.
Salol, Whitfield's ointment is right-tertiary butyl phenyl ester, and Whitfield's ointment is right-octyl octylphenyl and similar salicylic acid UV light absorber; 2, the 4-dihydroxy benzophenone, 2-hydroxyl-4-methoxyl group benzophenone, 2-hydroxyl-4-octyloxy benzophenone, 2-hydroxyl-4-dodecyloxy benzophenone, 2,2 '-dihydroxyl-4-methoxyl group benzophenone, 2,2 '-dihydroxyl-4,4 '-dimethoxy benzophenone, 2-hydroxyl-4-methoxyl group-5-diphenylsulfone ketone and similar Benzophenones UV light absorber; 2-cyano group-3,3-phenylbenzene-2-ethylhexyl acrylate, 2-cyano-3,3-diphenyl ethyl acrylate and similar cyanoacrylate UV light absorber; Sebacic acid two (2,2,6,6-tetramethyl--4-piperidyl ester), succsinic acid two (2,2,6,6-tetramethyl--4-piperidyl ester), 2-(3, the 5-di-tert-butyl-4-hydroxyl benzyl)-2-n-butylmalonic acid two (1,2,2,6,6-pentamethyl--4-piperidyl ester) and similarly hinder the amine UV light absorber; 2-(2 '-hydroxy phenyl) benzotriazole, 2-(2 '-hydroxyl-5 '-aminomethyl phenyl) benzotriazole, 2-(2 '-hydroxyl-5-tert-butyl-phenyl) benzotriazole, 2-(2 '-hydroxyl-3 ', 5 '-di-tert-butyl-phenyl) benzotriazole, 2-(2 '-hydroxyl-the 3 '-tertiary butyl-5 '-aminomethyl phenyl)-5-chlorobenzotriazole, 2-(2 '-hydroxyl-3 ', 5 '-di-tert-butyl-phenyl)-the 5-chlorobenzotriazole, 2-(2 '-hydroxyl-3 ', 5 '-di-tert-butyl-phenyl)-5-tertiary butyl benzo triazole, 2-(2 '-hydroxyl-3 ', 5 '-di-tert-pentyl-phenyl) benzotriazole, 2-(2 '-hydroxyl-3 ', 5 '-di-tert-pentyl-phenyl)-5-tert-pentyl benzo triazole, 2-(2 '-hydroxyl-3 ', 5 '-di-tert-pentyl-phenyl)-5-methoxyl group benzo triazole, 2-[2 '-hydroxyl-3 '-(3 "; 4 "; 5 "; 6 "-tetrahydrochysene phthalimido-methyl)-5 '-aminomethyl phenyl] benzotriazole, 2-(2 '-hydroxyl-5 '-uncle's octyl phenyl) benzotriazole, 2-(2 '-hydroxyl-3 '-sec-butyl-5 '-tert-butyl-phenyl) benzotriazole, 2-(2 '-hydroxyl-3 '-tert-pentyl-5 '-Phenoxyphenyl)-5-methyl] benzotriazole, 2-(2 '-hydroxyl-5 '-dodecyl phenyl) benzotriazole, 2-(2 '-hydroxyl-5 '-secondary octyloxyphenyl)-5-phenyl benzotriazole, 2-(2 '-hydroxyl-3 '-tert-pentyl-5 '-phenyl)-5-methoxyl group benzo triazole, 2-[2 '-hydroxyl-3 ', 5 '-two (α, α-Er Jiajibianji) phenyl] benzotriazole and similarly be solid benzotriazole category UV light absorber at normal temperatures; 2-(2 '-hydroxyl-3 '-dodecyl-5 '-aminomethyl phenyl)-benzotriazole, 2-(2 '-hydroxyl-3 '-undecyl-5 '-aminomethyl phenyl)-benzotriazole, 2-(2 '-hydroxyl-3 '-tridecyl-5 '-aminomethyl phenyl)-benzotriazole, 2-(2 '-hydroxyl-3 '-tetradecyl-5 '-aminomethyl phenyl)-benzotriazole, 2-(2 '-hydroxyl-3 '-pentadecyl-5 '-aminomethyl phenyl)-benzotriazole, 2-(2 '-hydroxyl-3 '-hexadecyl-5 '-aminomethyl phenyl)-benzotriazole, 2-[2 '-hydroxyl-4 '-(2 "-ethylhexyl) oxygen base phenyl]-benzotriazole; 2-[2 '-hydroxyl-4 '-(2 "-the ethyl heptyl) oxygen base phenyl]-benzotriazole, 2-[2 '-hydroxyl-4 '-(2 "-the ethyl octyl group) oxygen base phenyl]-benzotriazole; 2-[2 '-hydroxyl-4 '-(2 "-the propyl group octyl group) oxygen base phenyl]-benzotriazole, 2-[2 '-hydroxyl-4 '-(2 "-propylheptyl) oxygen base phenyl]-benzotriazole; 2-[2 '-hydroxyl-4 '-(2 "-the propyl group hexyl) oxygen base phenyl]-benzotriazole, 2-[2 '-hydroxyl-4 '-(1 "-ethylhexyl) oxygen base phenyl]-benzotriazole; 2-[2 '-hydroxyl-4 '-(1 "-the ethyl heptyl) oxygen base phenyl]-benzotriazole, 2-[2 '-hydroxyl-4 '-(1 "-the ethyl octyl group) oxygen base phenyl]-benzotriazole; 2-[2 '-hydroxyl-4 '-(1 "-the propyl group octyl group) oxygen base phenyl]-benzotriazole, 2-[2 '-hydroxyl-4 '-(1 "-propylheptyl) oxygen base phenyl]-benzotriazole; 2-[2 '-hydroxyl-4 '-(1 "-the propyl group hexyl) oxygen base phenyl]-benzotriazole, 2-(2 '-hydroxyl-3 '-sec-butyl-5 '-tert-butyl-phenyl)-5-normal-butyl benzo triazole, 2-(2 '-hydroxyl-3 '-sec-butyl-5 '-tert-butyl-phenyl)-5-tert-pentyl benzo triazole, 2-(2 '-hydroxyl-3 '-sec-butyl-5 '-tert-butyl-phenyl)-5-n-pentyl benzo triazole, 2-(2 '-hydroxyl-3 '-sec-butyl-5 '-tert-pentyl phenyl)-5-tertiary butyl benzo triazole, 2-(2 '-hydroxyl-3 '-sec-butyl-5 '-tert-pentyl phenyl)-5-normal-butyl benzo triazole, 2-(2 '-hydroxyl-3 ', 5 '-di-tert-butyl-phenyl)-5-sec-butyl benzo triazole, 2-(2 '-hydroxyl-3 ', 5 '-di-tert-pentyl-phenyl)-5-sec-butyl benzo triazole, 2-(2 '-hydroxyl-the 3 '-tertiary butyl-5 '-tert-pentyl phenyl)-5-sec-butyl benzo triazole, 2-(2 '-hydroxyl-3 ', 5 '-two secondary butyl phenenyls)-the 5-chlorobenzotriazole, 2-(2 '-hydroxyl-3 ', 5 '-two secondary butyl phenenyls)-5-methoxyl group benzo triazole, 2-(2 '-hydroxyl-3 ', 5 '-two secondary butyl phenenyls)-5-tertiary butyl benzo triazole, 2-(2 '-hydroxyl-3 ', 5 '-two secondary butyl phenenyls)-5-normal-butyl benzo triazole, the 5-tertiary butyl-3-(5-chloro-2H-benzotriazole-2-yl)-4-hydroxybenzene-n-octyl propionate, the 3-[3-tertiary butyl-5-(2H-benzotriazole-2-yl)-4-hydroxy phenyl] methyl propionate and polyoxyethylene glycol (molecular weight: condenses about 300), and be the benzotriazole category UV light absorber of liquid at normal temperatures similarly.Certainly, UV light absorber be not limited to top these, and optionally also can use the mixture of at least two kinds of these absorption agents.
Though the consumption to UV light absorber does not have particular restriction,, with respect to activeconstituents, the consumption that can control UV light absorber is the 10-500 weight part, is generally the 20-250 weight part.
The microcapsule that the present invention uses can prepare with various known method, but general method for making is: emulsification and dispersion core material (oily liquids) in water medium, and this core material comprises UV light absorber, and also comprises organic solvent if necessary; Form the high molecular weight material wall film that is sealing the oil microdroplets that forms then.
The example that is used to form the useful high molecular weight material of micro-capsule body wall film has polyurethane resin, carbamide resin, polyamide resin, vibrin, polycarbonate resin, amino aldehyde resin, melamine resin, polystyrene resin, the copolymer in cinnamic acrylic ester resin, vinylbenzene-methacrylate co-polymer resin, gelatin, polyvinyl alcohol etc.Especially; except other resin; its wall film is by synthetic resins; particularly the microcapsule made of carbamide resin, polyurethane resin and amino aldehyde resin has good UV light absorber retention and high heat resistance; thereby demonstrate outstanding additional effect; put the effect of the pigment that mixes in the protective layer to good use, be used for control adhering to heating head (thermal head).In addition; the microcapsule phase transformation of making by other material and common dye with the wall film; the microcapsule that the wall film is made by carbamide resin or polyurethane resin has lower refractive index; and be spherical; even if there are a large amount of microcapsules in the protective layer; because the irregular reflection of light, they very likely reduce the density (being so-called brightening) of recording materials, and it is particularly advantageous therefore using this microcapsule.Further, carbamide resin and polyurethane are widely used as the wall film of the microcapsule that can use under condition of high voltage.On the other hand, the advantage of the microcapsule that the wall film is made by amino aldehyde resin is that the thickness of wall film can control, and is irrelevant with the granularity of emulsion.Its reason is that this microcapsule can add into wall material afterwards by the emulsification core material and make.
The present invention also comprises and UV light absorber organic solvent together.Organic solvent does not have particular restriction, and the various hydrophobic solvents that use in the pressure sensitive manifold paper field can use.Representative examples of organic comprises tritolyl phosphate, phosphoric acid ester such as octyl diphenyl phosphate, dibutyl phthalate, phthalic esters such as dioctyl phthalate (DOP), carboxylic acid esters such as butyl oleate, various fatty acid amides, diethylene glycol dibenzoate, single isopropyl naphthalene, alkylated naphthalene classes such as diisopropylnaphthalene, 1-methyl isophthalic acid-phenyl-1-tolyl methane, 1-methyl isophthalic acid-phenyl-1-ditolylmethane, 1-phenyl-alkylated benzenes classes such as 1-tolyl methane, alkylated biphenyls classes such as isopropyl biphenyl, esters of acrylic acids such as Viscoat 295, ester, clorafin and kerosene that polyvalent alcohol and unsaturated carboxylic acid form.These solvents can use separately, perhaps use with at least two kinds of their form of mixtures.In these high boiling point hydrophobic mediums, preferably phosphoric acid front three phenolic ester and 1-phenyl-1-tolyl methane is because they have high resolution to the UV light absorber that the present invention uses.In general, the viscosity of core material is low more, and the granularity that emulsifying effect produces is just more little, and the distribution of granularity is just narrow more, therefore can unite and use lower boiling solvent to reduce the viscosity of core material.The example of this class low boiling point solvent comprises ethyl acetate, butylacetate, methylene dichloride etc.
The consumption of organic solvent should suitably be regulated according to the kind of used ultraviolet kind and quantity and organic solvent, does not do concrete qualification.For example, when using under the normal temperature UV light absorber as liquid, not necessarily must be with an organic solvent.But when used UV light absorber when being solid-state at normal temperatures, owing to require UV light absorber in microcapsule, preferably to exist with consoluet state, therefore the amount of organic solvent (for example, for carbamide resin or polyurethane resin class microcapsule) be controlled to be common 10-60wt.% usually, perhaps 20-60wt.% (with organic solvent, UV light absorber and to become the total amount of wall material be benchmark).Further, for the amino aldehyde resin microcapsule, by the weight of UV light absorber, the amount of control organic solvent is common 50-2000% weight, is generally 100-1000% weight.
Although cyst wall being formed the consumption of material also is not specifically limited, but the organic solvent that may make in the microcapsule of preserving over a long time oozes out, thereby reduce desired result or to thermal recording medium and other material production detrimental action of containing used microcapsule, so compare with the situation of the common microcapsule that uses in the materials such as pressure sensitive recording material, preferably use relatively large one-tenth wall material.Therefore, for the situation of using carbamide resin for example or polyurethane microcapsule, become the consumption of wall material to be preferably 20-70wt.%, more preferably 25-60wt.% is that organic solvent (using as required), UV light absorber and the gross weight that becomes wall material are benchmark with these three kinds of compositions.Under the situation of using the amino aldehyde resin microcapsule, the consumption of one-tenth wall material is generally the 30-300% weight of core material weight, preferred 35-200% weight, wherein said core material comprises the UV light absorber as main ingredient, also includes organic solvent on demand.
In addition, can use absorption agent.Selected absorption agent should be in the susceptibility in the following zone that can reduce its spectrum sensitive scope of microcapsule: promptly influence the zone (its non-active region) of the exposure effect of microcapsule under other wavelength, but selected absorption agent can not excessively reduce the susceptibility of microcapsule in the zone (its active region) of the spectrum sensitive scope of the microcapsule that is used for exposing.In some cases, may need the absorption characteristic of equilibrium activity zone and non-active region inner absorbent, to obtain the optimum exposure characteristic.Usually use and in the nonactive scope of microcapsule, have greater than about 100/Mcm optical extinction coefficient at the active region optical extinction coefficient less than about 100 the absorption agent of 000/Mcm.When absorption agent is directly mixed in the photosensitive composition, it is desirable to, it should not suppress radical polymerization, and should not produce free radical when exposure yet.
The absorption agent that the present invention uses can be selected from the known absorption agent of sensitization field.The example of this compounds is included in absorption agent (for example cyanine, part cyanines, half cyanines and styryl color) and the UV light absorber that is conventionally used as the silver halide sensitizing dye in the photochromy.In a large number microcapsule need to have outside the sensitive range absorb but within this scope coloured dyestuff of no strong absorption also can make the usefulness of absorption agent in the present invention.Wherein, the Sudan I, the Sudan II, Sudan III, sudan orange G, oil red O, oil blue N and Fast violet sauce GBC are the examples of very useful compound.
In addition, desirable UV light absorber comprises the absorption agent that is selected from hydroxy benzophenone class, hydroxy-phenyl-benzotriazole and formamidine.These absorption agents can be used alone or in combination, with the spectral response characteristic that need to obtain.
The representative example of useful hydroxy benzophenone class is 2-hydroxyl-4-n-octyloxy benzophenone (UV-CHEK AM-300 (Ferro Chemical Division), Mark 1413 (ArgusChemical Division, Witco Chem.Corp.), with Cyasorb UV-531 LightAbsorber (American Cyanamid)), 4-dodecyl-2-hydroxy benzophenone (Eastman Inhibitor DOBP (Eastman Kodak)), 2-hydroxyl-4-methoxyl group benzophenone (Cyasorb UV-9 Light Absorber (American Cyanamid)), with 2,2 '-dihydroxyl-4-methoxyl group benzophenone (Cyasorb UV-24 Light Absorber (American Cyanamid)).The representative example of useful hydroxy-phenyl-benzotriazole is 2-(2 '-hydroxyl-5 '-aminomethyl phenyl) benzotriazole (Tinuvin P (Ciba-GeigyAdditives Dept.)), 2-(3 ', 5 '-di-t-butyl-2 '-hydroxy phenyl)-5-chlorobenzotriazole (Tinuvin 327 (Ciba-Geigy)), and 2-(2-hydroxyl-uncle's 5-octyl phenyl) benzotriazole (Cyasorb UV-5411 Light Absorber (American Cyanamid)).The representative example of useful formamidine is recorded in U.S.P.4, in 021,471, and comprises N-(right-the ethoxy carbonyl phenyl)-N '-ethyl-N '-phenyl formamidine (Givsorb UV-2 (Givaudan Corp.)).For application-specific, the concentration of optimal absorption agent and absorption agent not only depends on the maximum absorption and the optical extinction coefficient of candidate's absorption agent, but also depends on the spectral response characteristic of the light trigger of associating use.
In addition, United States Patent (USP) 4,399, microcapsule, photosensitive composition, one-tenth imaging agents, photographic developer and the developing technique described in 209 and 4,440,846 all can be used among the present invention, and the content of introducing this document of two pieces in the present invention is as a reference.
Compound of the present invention is also to powdery mildew and rest fungus, nuclear cavity Pseudomonas (pyrenophora), beak shape spore Pseudomonas (rhynchosporium), tapesia, fusarium and Leptosphaeria (leptosphaeria) fungi, especially the pathogenic agent to monocotyledons such as cereal (comprising wheat and barley) is effective especially.And also downy mildew kind, Powdery Mildew, leaf spot and the rust to dicotyledons is effective especially for they.
The amount of application of The compounds of this invention depends on multiple factor, for example type and the time of application of the main body (substrate) of employed compound, treatment, the mode of handling (for example spraying, dusting, seed dressing), the purpose of handling (prevention is treatment still), fungi to be processed and/or bacterium.
Material of the present invention can be used before or after fungi and/or the listed material of bacterial invasion.
When bestowing plant, with 20-2000g/ha, what usually the dose of 20-1000g/ha was relevant is, the amount of application of formula I compound is 25-250g/ha, is generally 50-150g/ha, for example 75,100,125 or 150g/ha.
In industrial application, the formulation rate of mixture depends on desired effect kind, and changes in the scope of per hectare 0.02-3kg activeconstituents.
Plant a period of the day from 11 p.m. to 1 a.m when activeconstituents is used for handling, common every kilogram of seed uses the 0.001-50g activeconstituents, and the amount of general 0.01-10g just is enough to.
Composition of the present invention can be any conventionally form use, acceptable assistant bonded double pack form, quick-acting granule, suspension agent, emulsifiable concentrate or wettable powder form are used on example industry and the agricultural that comprises tensio-active agent (for example Sodium Lauryl Sulphate BP/USP and lauryl sulfate sodium salt).This based composition can be used ordinary method production, for example activeconstituents is mixed with suitable auxiliary (thinner or solvent and other optional processing preparation composition such as tensio-active agent).When the long-acting effectiveness of needs, also can use conventional slow release type preparation.
Specifically, preparation of using with Sprayable such as water emulsifiable concentrate or wettable powder can comprise the tensio-active agent such as wetting agent and dispersion agent, the for example condensation product of formaldehyde and naphthalenesulfonate, alkylaryl sulphonate, Sulfite lignin, aliphatic alkyl vitriol, and ethoxylated alkylphenol and ethoxylized fatty alcohol.
Use is the present composition and the thinner of suitable seed dressing formulation, in mode well known in the art this seed dressing is imposed on seed, these formulations such as aqueous suspension or the dry powder form that seed is had good adhesion.This class seed dressing is known in the art.Seed dressing can be for being the encapsulated form (as slow releasing capsule or microcapsule) that contains single-activity composition or various active constituents mixt.
In general, preparation of the present invention comprises 0.01-90% weight active substance, solid or the liquid auxiliary agent of industrial acceptable surfactant of 0-20% and 10-99.9%, active substance is by at least a formula I compound, and optional other active substance, particularly composition such as microbicide or sanitas.The conc forms of composition comprises 2-80% usually, is preferably the active substance of 5-70% weight.The administration form of preparation for example can contain 0.01-20% weight, is generally the active substance of 0.01-5% weight.Although the commercially available prod generally all is mixed with the enriched material form, the end user uses the preparation of dilution usually.
In addition, the color of The compounds of this invention can be removed by the mode of " bleaching ".And, have been found that, when in washings, adding the enzyme of catalyzing hydrogen peroxide or molecular oxygen oxidation organic or inorganic material (including color substance), coloring matter in the bleaching washing soln is possible, these coloring matters are to be formed or leached from be colored textiles that agent pollutes and material of construction by The compounds of this invention leaching in DYED FABRICS and the material of construction, have so just avoided described coloring matter to deposit on other fabric and material of construction in the washings.These enzymes are called peroxidase and oxydase usually respectively.Art-recognized is (referring to B.C.Saunders etc., Peroxidase, London, 1964, p.10ff), the superoxide endonuclease capable acts on various amino and phenolic compound, and the result produces color.In view of the above, can think inevitably that peroxidase (and some oxide compound enzyme) also can apply effect to the coloring matter in the solution astoundingly, thereby suppress dye transfer.Although suppress the mechanism of the ability of dye transfer does not illustrate as yet about these enzymes, but think that at present these enzymes are to work by the coloring matter (donor matrix) that reduces hydrogen peroxide or molecular oxygen and oxidation dissolution or be dispersed in the washings, thereby produce colorless substance or form fabric or the non-adsorbable material of material of construction.
In addition, also can form the liquid composition of material of the present invention, they can dilute with mixed with excipients and/or with vehicle.When vehicle was used as thinner, it can be solid, semisolid or liquid substance, plays a part vehicle, carrier or medium as composition of matter of the present invention.Various appropriate excipients all are well known by persons skilled in the art, and are found in National Foumulary, 19:2404-2406 (2000) [full content of 2404-2406 page or leaf is hereby incorporated by].Preferred vehicle comprises butyleneglycol and EDTA.The example of proper excipient includes but not limited to starch, gum arabic, Calucium Silicate powder, Microcrystalline Cellulose, methacrylic ester, shellac, polyvinylpyrrolidone, Mierocrystalline cellulose, water, syrup and methylcellulose gum.Water medium can comprise one or more activeconstituentss, a certain amount of one or more tensio-active agents [this amount is enough to allow described activeconstituents to be dissolved or suspended in equably in the described medium] and other processing additives known in the art.The latter comprises granulating tackiness agent such as gelatin; Natural gum such as gum arabic, tragacanth gum; Starch, sodiun alginate, sucrose, polyvinylpyrrolidone; Derivatived cellulose is Vltra tears for example, the polyethylene oxazolidone; Medicinal filler is lactose for example, Microcrystalline Cellulose, Lin Suanergai, tricalcium phosphate, calcium sulfate, glucose, mannitol, sucrose; Compressing tablet lubricant (if necessary), for example calcium stearate and Magnesium Stearate, stearic acid, talcum, sterotex (alkaline stearate).For a kind of composition of one of embodiment of the present invention, used term " water medium " has the usual implication of this area.It mainly is meant the water medium of carrying activeconstituents, is added with water-miscible solvent in case of necessity, such as Virahol or ethanol.
The present invention is described in more detail with the following example.But these embodiment are used for illustrating the present invention, but not are limitations of the present invention.
Embodiment 1: chlorination 1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine (6) synthetic
Figure A20048000570800391
1(2, the 6-lutidine) 2(iodoethane) 3(2,6-lutidine-ethyl iodide)
Figure A20048000570800392
4(2,6-lutidine diethylaluminum monochloride) 5(aromatic aldehyde)
Figure A20048000570800393
Step a:2,6-lutidine (1) and iodoethane (2) generate 2, the reaction of 6-lutidine ethyl iodide (3)
Mixing total amount is 2 of 69.7 grams (0.65 mole), 6-lutidine (1) and 202.8 gram iodoethane (2), 100 ℃ of heating gained mixture overnight.Reaction mixture then, filter collect separate out 2,6-lutidine ethyl iodide (3).To filter reheat to 100 a ℃ maintenance at night and spend the night, cooling afterwards, second batch of solid 2 of filtered and recycled, 6-lutidine ethyl iodide (3).Merge this two batches of products, they are dissolved in the hot dehydrated alcohol carry out recrystallization.Then the gained solid is dissolved in once more and carries out recrystallization in the hot ethanol.Air-dry these are purified 2, and 6-lutidine ethyl iodide (3) is to weight, and obtaining 107.5 grams needs product. 1H-NMR is consistent with the expectation product, and what measured is 205-206 ℃ without gauged fusing point.
Step b:2,6-lutidine ethyl iodide (3) is converted into 2, the reaction of 6-lutidine diethylaluminum monochloride (4)
With 107.5 grams 2,6-lutidine ethyl iodide is dissolved in 2.0 liters of methyl alcohol, cooling gained solution in ice-water bath.The anhydrous hydrogen chloride that in above-mentioned solution, slowly adds total amount 220 grams through the gas bubbler.In the process of reinforced hydrogenchloride, utilize ice-water bath to keep temperature to be lower than 30 ℃.After adding all hydrogenchloride, the stirring at room reaction mixture spends the night.Concentrated reaction mixture is done near, is dissolved in 1.0 liters of methyl alcohol again.Blasting total amount subsequently in mixture is the anhydrous hydrogen chloride of 103 grams.Stir after 10 minutes, the vacuum concentration reaction mixture obtains 2 of 94.3 gram needs, 6-lutidine diethylaluminum monochloride (4) to doing.
Step c:2,6-lutidine diethylaluminum monochloride (4) and 4-pyrrolidino phenyl aldehyde (5) generation chlorination 1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine (6)
Reflux 30.6 gram (0.22 moles) 2,6-lutidine diethylaluminum monochloride (4), 75 gram (0.54 mole) 4-pyrrolidino phenyl aldehydes (5), 12mL piperidines and about 2 liters of methanol mixture are spent the night. 1H NMR shows reactionless generation.Further the heating reflux reaction mixture did not still react after 96 hours.Add the 12mL piperidines again, continue reflux.Amount to reflux after 120 hours, have solid to begin to separate out, but 1H NMR shows that desired reaction remains unfulfilled.Add 12mL piperidines catalyzer more for this reason, and further heating reflux reaction mixture 24 hours.At this moment 1H NMR spectrum demonstration desired response is finished.Slowly reaction mixture is to room temperature, filter collect comprise chlorination 1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] solid sediment of pyridine (6).Solids is with ether development, the washing of three parts of each 100ml, to remove impurity and residual methanol solvate.Air-dry gained solid, and then vacuum-drying is to constant weight, the red crystallization chlorination 1-ethyl of 32.6 grams-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine (6)-high performance liquid chromatography area percent (HPLC area %)=98.1%, 1H NMR (DMSO, d 6); Ppm 8.16-8.14 (t, 1H); 8.08-8.07 (d, 2H); 7.71-7.68 (d, 1H); 7.69-7.67 (d, 2H, J=8.8Hz); 7.23-7.20 (d, 1H); 6.61-6.59 (d, 2H, J=8.8Hz); 4.75-4.74 (m, 2H); 3.31 (m, 2H); 1.98-1.96 (m, 2H); 1.48-1.45 (t, 3H).Concentrated filtrate is only about half of to its initial volume, adds the 10mL piperidines, the dark reaction of reflux filtrate 24 hours. 1H NMR spectroscopic analysis shows more chlorination 1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine (6) generation, this may be by due to the balanced reaction of olefinic isomer.Remove heating source, stirring at room reaction mixture 48 hours, during have throw out to generate.Solid collected by filtration is developed, is washed to remove impurity and residual methanol solvate with the ether of three parts of each 100ml.The red crystallization of air-dry gained, further vacuum-drying is to constant weight, further obtain 19.2 gram chlorination 1-ethyls-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine (6)-HPLC area %=97.4%, 1H NMR is consistent with first product (6).
Embodiment 2: chlorination 1-ethyl-(E, E)-2, two [2-[4-(dimethylamino) phenyl] vinyl of 6-] pyridine synthetic
Reflux restrains (0.07 moles) 2 by 9.0, the mixture that 6-lutidine diethylaluminum monochloride, 23.6 gram (0.16 mole) 4-dimethylaminobenzaldehydes, 14mL piperidines and 350mL methyl alcohol constitute 77 hours.Reflux after 77 hours, high performance liquid chromatography-mass spectroscopy (LC/MS analysis) shows to exist in the reaction mixture needs product.Slowly reaction mixture is filtered afterwards and is collected the solid of separating out to realize precipitation.These solids are with ether development and the washing of three parts of each 100ml, to remove impurity and residual methanol solvate.Air-dry gained solid, and then vacuum-drying is to constant weight, the red crystallization chlorination 1-ethyl of 2.8 grams-(E, E)-2, two [2-[4-(dimethylamino) phenyl] vinyl of 6-] pyridine-high performance liquid chromatography area percent (HPLC area %)=99.5%, 1H NMR (DMSO, d 6) consistent with the expectation product.Concentration response filtrate is only about half of to initial volume.The piperidines that adds total amount 10mL, the formed dark solution of reflux is 24 hours in addition.High performance liquid chromatography area percent analysis this moment (HPLC A% analysis) shows more product and generates, starting raw material 2, and 6-lutidine diethylaluminum monochloride exhausts basically.Remove thermal source, the vacuum concentration reactant obtains dense thick slurry.Filter and collect the solid of separating out, with the ether washing of three parts of each 100ml, air-dry gained solid, vacuum-drying is spent the night again, obtain 13.6 the gram red crystallization chlorination 1-ethyl-(E, E)-2, two [2-[4-(dimethylamino) phenyl] vinyl of 6-] pyridine-HPLC area %=99% 1H NMR is consistent with the product of expectation.
Embodiment 3: chlorination 1-ethyl-(E, E)-2, two [2-[4-(diethylamino) phenyl] vinyl of 6-] pyridine synthetic
Figure A20048000570800421
Reflux is by 9.0 gram (0.07 moles) 2, the mixture that 6-lutidine diethylaluminum monochloride, 28.1 gram (0.16 mole) 4-diethyl amino benzaldehydes, 14mL piperidines and 350mL methyl alcohol are formed 96 hours, LC/MS analyzed to exist in the demonstration reaction mixture and needed product this moment.Reaction mixture, vacuum concentration obtains jelly.Solid collected by filtration is with ether development and the washing of three parts of each 50ml.Air-dry gained purifying solid, and then vacuum-drying, the red crystallization chlorination 1-ethyl of acquisition 17.3 grams-(E, E)-2, two [2-[4-(diethylamino) phenyl] vinyl of 6-] pyridine-high performance liquid chromatography area percent (HPLC area %)=95%, 1H NMR (DMSO, d 6) consistent with the expectation product, wherein there is the raw material 4-diethyl amino benzaldehyde of trace.
Embodiment 4:1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine 4-aminobenzoate synthetic
Figure A20048000570800422
With the chlorination 1-ethyl of 52.8g (0.12 mole)-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] sodium salt (sodium salt of Para-Aminobenzoic, the Na of pyridine and 18.6 gram (0.12 mole) 4-benzaminic acid +PABA -) be dissolved in 1.3 liters of methyl alcohol, in this mixture of stirring at room 4 days, during have precipitation to generate.Filter reaction mixture then, air-dry gained solid salt, vacuum-drying again, obtain first 28.0 gram 1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine 4-aminobenzoate (also claiming PABA salt).Vacuum concentrated filtrate produces more throw out.Second batch of throw out of filtering separation, follow air-dry and vacuum-drying gained solid, thereby obtain second crowd 42.6 gram 1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine 4-aminobenzoate (also claiming PABA salt)-high performance liquid chromatography area percent (HPLC A%), first=99.6%, (except the PABA); HPLC A% second crowd=99.9% (except the PABA); 1These two batches of products of H NNR and mass spectroscopy, the structure of finding them with need product 1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine 4-aminobenzoate (also claiming PABA salt) unanimity.This product be also referred to as the 1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine p-aminobenzoate or 1-ethyl-(E, E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine PABA salt.
According to the described method of embodiment 1-3, at polar aprotic solvent such as methyl alcohol, ethanol, 2-propyl alcohol equal solvent or polar aprotic solvent such as acetonitrile (CAN), N,N-DIMETHYLACETAMIDE (DMA), dimethyl formamide (DMF), in methyl-sulphoxide (DMSO) equal solvent, make and replace and unsubstituted aromatic aldehyde or replacement and unsubstituted heteroaromatic aldehyde and replacement and unsubstituted lutidine diethylaluminum monochloride salt, lutidine isobutyl-chlorination thing salt, lutidine iodine muriate, lutidine 1,1,1-trifluoroethyl chloride salts etc. and secondary amine catalyst such as piperidines and tetramethyleneimine reaction generate any compound that may make up as being put down in writing in the application and claims.In addition, the applicant provides a large amount of compounds (shown in Fig. 1-4) that some of the present invention may combinations are described.
In following examples, " activeconstituents " can be any compound or its pharmaceutically useful salt or the solvate of above-mentioned formula (I).
Embodiment 5: anti-microbial activity
Utilize continuous half grade of (half-step) dilution method, with sterilized water dilution formula I compound, chlorination department is for the solution (1% dimethyl sulfoxide solution) of shellfish ammonium (stilbazium chloride).For every kind of weaker concn, draw 40 microlitre solution and be put on the vaccinated Mueller-Hinton agar plate.Agar plate was cultivated 24 hours down at 35 ℃ then, the record inhibition zone.Minimum inhibitory concentration (MIC) is meant the substances minimum concentration that the microorganisms inhibition zone is needed.Following table is listed the MIC of the anti-a series of microorganisms of formula I compound.
The anti-microbial activity of table 1: formula I
Bacterial strain MIC
Streptococcus pyogenes 1.0
Streptococcus faecium 1.0
Streptococcus agalactiae 1.0
Streptococcus aureus 0.3
Bordetella bronchiseptica 1.0
Vibrio cholerae 10.0
Pasteurella multocida 3.0
Intestinal bacteria ＞100
Pseudomonas aeruginosa ＞100
* data representation formula I suppresses the minimum inhibitory concentration of vitro culture bacterial growth, is unit with μ g/mL.
Embodiment 6: anti-mycotic activity
Fungal bacterial strain (being obtained from ATCC) was cultivated 18 hours in 35 ℃ in Mueller-Hinton meat soup.Then plate is inoculated room temperature (22 ℃) air-dry about 10-15 minute with broth culture.Draw 40 microlitre formula I compounds (in 1% methyl-sulphoxide) then and continuous half grade of (half-step) diluent in water is added on the vaccinated Mueller-Hinton agar plate.Agar plate was cultivated the record inhibition zone 34 hours in 35 ℃ subsequently.Minimum inhibitory concentration (MIC) is meant the formula I compound minimum concentration that the microorganisms inhibition zone is needed.Following table is listed the anti-microbial activity of formula I compound to various fungal bacterial strains.
Table 2: formula I compound is to the vitro inhibition effect of yeast and fungal growth
Microorganism MIC
Candida albicans ＜0.006
Oidium tropicale ＜0.4
Novel Cryptococcus ＜0.4
Saccharomyces cerevisiae (Saccharomyces cervisciae) ＜0.4
Aspergillus fumigatus ＜0.006
Yellow aspergillus 6.25
Fusariun solani ＜0.4
Unrooted rhizopus 6.25
Sabouraudites lanosus 1.6
Gypsum shape sporidiole bacteria 1.6
Trichophyton equinum 1.6
Along Trichophyton 1.6
Trichophyton rubrum 1.6
Acrothesium floccosum 1.6
*Data representation formula I compound suppresses the minimum inhibitory concentration of vitro culture bacterial growth, is unit with μ g/mL.
Embodiment 7
At the relevant fungal strain test of one group of plant stilbazium lodide (Stilbaziumiodide).The stock solution of preparation The compounds of this invention in DMSO, concentration 10,000ppma.i..Utilize water to prepare further diluent.Test is carried out under following concentration: 125,31,8,21,0.5 and 0.125ppm a.i..The spore suspension of preparation fungi.Test is carried out in microtiter plate, and for every kind of fungi and each concentration, prepares 3 holes.Cultivated the inoculation plate down 7 days at 18 ℃.Then, measure the mycelial optical density(OD) that produces in each hole in the 405nm place.
Gained data (being shown in Table 3) are used to estimate IC90 value (comparing the concentration that is reduced by at least 90% fungal growth needs with control group).
Table 3
Microorganism Corresponding plants IC90
Target chain lattice spore Potato ＞125
Gray botrytis Vegetables 0.5
It is mould that spore is revolved in palace portion Corn ＞125
Curcurbitaceae hair disc spore Muskmelon 31
Machete sickle spore Wheatear ＞125
Phytophthora infestan Tomato 2
The circle nuclear cavity bacteria Barley 31
Pyricularia oryzae Paddy rice 8
The Solanum rhizoctonia Rice leaf sheath (Rice Sheath) 2
Wheat septoria Wheat leaf 2
Embodiment 8
Data list shown in the following table 4 available the department various bacteriums and the fungi of handling for the shellfish ammonium compound.The various departments of these data declarations are for total effectiveness of shellfish ammonium compound.
Table 4
Kind Separate kind # MIC 80％ MIC 100％ MFC
The yellow aspergillus aspergillus fumigatus of the yellow aspergillus of the yellow aspergillus of the yellow aspergillus of the yellow aspergillus of the yellow aspergillus of chain lattice Bao QC aspergillus fumigatus QC aspergillus fumigatus aspergillus fumigatus 128.89 112.96 194.99 107.96 141.88 178.03 173.03 168.95 168.95 168.95 111.02 6.25 3.12 3.12 6.25 12.5 12.5 25 3.12 3.12 3.12 3.12 12.5 6.25 3.12 12.5 25 25 25 6.25 6.25 6.25 6.25 ＞100 6.25 12.5 25 25 ＞25 ＞25 ＞25 ＞100 ＞100 12.5
Aspergillus fumigatus Aspergillus fumigatus aspergillus sydowi aspergillus versicolor 153.90 182.99 165.02 120.02 12.5 12.5 0.78 1.56 25 25 1.56 3.12 25 ＞25 3.12 6.25
Bipolaris spicifera Candida albicans Candida albicans QC Candida albicans QC Candida albicans Candida albicans Candida albicans Candida albicans Candida albicans Candida albicans Candida albicans Candida albicans Candida albicans Candida albicans Candida albicans Candida albicans Candida parapsilosis Candida parapsilosis Candida parapsilosis Candida parapsilosis Candida parapsilosis 155.89 A39 117.00 117.00 117.00 117.00 116.98 126.97 149.97 159.95 156.97 203.03 204.03 205.03 206.03 202.03 110.01 ATCC 22019 109.96 118.02 123.00 3.12 0.39 0.39 1.56 3.12 0.78 0.39 0.39 0.39 0.39 1.56 1.56 1.56 1.56 3.12 3.12 0.78 0.78 1.56 1.56 1.56 3.12 0.39 0.39 1.56 3.12 1.56 0.39 0.78 0.39 0.39 1.56 1.56 1.56 1.56 3.12 3.12 0.78 0.78 1.56 1.56 1.56 ＞100 0.39 0.39 3.12 6.25 3.12 1.56 0.78 0.78 1.56 1.56 3.12 1.56 6.25 12.5 3.12 3.12 3.12 3.12 6.25 6.25
The yellow grey mould penicillium chrysogenum Rhizopus oryzae Rhizopus oryzae Rhizopus oryzae Rhizopus oryzae Rhizopus oryzae Rhizopus oryzae Nian rhodotorula Nian rhodotorula Nian rhodotorula Nian rhodotorula Nian rhodotorula of the new long-radius elbow Bao of the new long-radius elbow Bao of the hair gram new long-radius elbow Bao of the new long-radius elbow Bao of mould novel Cryptococcus aerobic-type mutation T217 H99 141.90 110.90 104.89 146.90 135.02 119.02 172.86 182.88 318.86 117.89 127.88 181.88 213.03 207.03 209.03 210.03 211.03 1.56 0.012 1.56 3.12 3.12 6.25 6.25 0.78 1.56 3.12 3.12 6.25 12.5 12.5 1.56 3.12 3.12 3.12 6.25 3.12 0.024 3.12 3.12 6.25 6.25 12.5 0.78 6.25 6.25 6.25 6.25 12.5 12.5 3.12 3.12 6.25 3.12 6.25 ＞100 1.56 ＞100 ＞100 ＞100 ＞100 ＞100 12.5 ＞100 ＞100 ＞100 12.5 ＞25 ＞25 6.25 3.12 6.25 3.12 6.25
Embodiment 9
(1) tablet formulation
(i) oral tablet
The mg/ sheet
A B C
Activeconstituents
25 25 25
Avicel TM 13 0 7
Starch (corn) 0 9 0
Starch (pregelatinized, NF15 0 0 32
Explotab 5 0 0
Povidone TM 3 3 0
Magnesium Stearate 1 1 1
(ii) sublingual tablet
The mg/ sheet
D E
Activeconstituents
25 25
Avicel TM 0 10
Lactose 0 36
N.F,USP MANNITOL 51 75
Sucrose 0 3
Gum arabic 0 3
Povidone TM 3 0
Magnesium Stearate 1 1
The method for making of preparation A-E: the first six is planted composition and Povidone TMWet granulation adds Magnesium Stearate subsequently together, and compacting forms.
(iii) buccal tablet
The mg/ sheet
Activeconstituents
25
Vltra tears (HPMC) 25
Polycarbophil TM 39
Magnesium Stearate 1
Said preparation can each preparation that becomes to assign to by direct compacting blended.
(2) capsule preparations
(i) powder-type
The mg/ capsule
F G
Activeconstituents
25 25
Avicel TM 45 0
Lactose 153 0
Starch (1500NF) 0 117
Explotab 0 6
Magnesium Stearate 2 2
By mixing above-mentioned each composition, then the gained mixture is inserted in the two joint hard gelatin capsules, can prepare preparation F and G.
(ii) liquid filler material type
The mg/ capsule
H I
Activeconstituents
25 25
Macrogol TM.4000BP 200 0
Yelkin TTS 0 100
Peanut oil 0 100
Preparation H can be by fusing Macrogol TM.4000BP, and then activeconstituents is dispersed in the melts, is filled into immediately in the two joint hard gelatin capsules and makes.Preparation I can be by being distributed to activeconstituents in Yelkin TTS and the peanut oil, and the delayed filling dispersion liquid is in the elasticity soft gelatin capsule and make.
(iii) control release type
The mg/ sheet
Activeconstituents
25
Avicel 123
Lactose 62
Triethyl citrate 3
Ethyl cellulose 12
The method for making of said preparation comprises mixes and the above-mentioned preceding four kinds of compositions of extruding, with extrudate ball granulating, drying.Dried particles, is filled in the two joint hard gelatin capsules as release-controlled film then with the ethyl cellulose dressing.
The sterile injection powder capsule
Activeconstituents (0.5-7.0 μ m powder) 1.0mg
Lactose (30-90 μ m powder) 49.0mg
Mix above-mentioned two kinds of powder until evenly, be filled to the hard gelatin capsule interior (every capsules 50mg) of suitable size then.
Inhalation aerosol
Activeconstituents (0.5-7.0 μ m powder) 50mg
Sorbitol olein 100mg
Soluble saccharin (0.5-7.0 μ m powder) 5mg
Menthol 2mg
Trifluoromethane 4.2mg
Refrigerant
12 In right amount to 10Ml
With sorbitol olein and dissolve with methanol in trichlorofluoromethane.In this mixture, disperse soluble saccharin and activeconstituents, transfer to then in the suitable aerosol container, inject dichlorofluoromethane by valve system.Said composition can provide 0.5mg activeconstituents in per 100 μ l dosage.
Topical solution
Component Consumption
Formula I compound 200mg
Ethanol, USP (95%v/v) 100mL
Formula I compound directly is dissolved in ethanol, in the amber glass bottle of packing into.Utilize cotton swab or permeable absorption valve protection cap, 0.2% solution of gained is coated on the infection epidermis, can realize medication skin.
Embodiment 10
Biological activity
The aqueous cream that is used for outside (skin), vagina and rectal application
Formula I compound
Component Consumption
Formula I compound 500mg
Butyleneglycol 100mL
By mixing formula I compound is suspended in the butane.The gained emulsifiable paste is used by the topical mode.
The test of carrageenin tuberculous pleurisy
According to Vinegar, R etc., Proc.Soc.Exp.Biol.Med., 1981,168, the method for 24-32, the male Lewis rat of using 150.+-.20 to restrain is measured the anti-inflammatory activity of The compounds of this invention.Carrageenin dosage is the 0.075mg/ rat.Four hours collection pleural space transudates behind the injection carrageenin.According to respect to the restraining effect of negative (vehicle) control group, measure acute anti-inflammatory activity to pleura oedema and inflammatory cell (neutrophilic leukocyte).
2) acetic acid colitis test
According to Fretland, D etc., 1990, the method for 255:572-576 is utilized acetic acid colitis rat model, restrains the anti-inflammatory activity of measuring The compounds of this invention in the male Lewis rat at 275+25.Behind the oral or rectal administration compound 24,16 or 4 hours under slight anesthesia at colon near-end 6cm place instillation 3% acetic acid solution (lasting for 40 seconds).Colon is used the water washing of 5cc salt immediately.Put to death rat after 24 hours, excision 6cm proximal colonic, weighing is used for oedema mensuration.By measuring the MPO concentration in the mucous membrane of colon that scrapes in these rat bodies, measure the inflammation neutrophilic leukocyte.Compare with negative (vehicle) control group,, measure acute anti-inflammatory activity according to restraining effect to oedema formation and mucous membrane MPO concentration.
3) anti-microbial activity
Utilize continuous half grade of dilution method, further dilute the solution (1% methyl-sulphoxide) of formula I compound with aqua sterilisa.For every kind of weaker concn, draw 40 microlitre solution and place on the vaccinated Mueller-Hinton agar plate.Agar plate was cultivated 24 hours down at 35 ℃ then, the record inhibition zone.Minimum inhibitory concentration (MIC) is meant the minimum concentration of the substances that the microorganisms inhibition zone is needed.Last table 2 is listed the MIC of the anti-a series of microorganisms of formula I compound.
4) anti-mycotic activity
Fungal bacterial strain (being obtained from ATCC) was cultivated 18 hours in 35 ℃ in Mueller-Hinton meat soup.Then plate is inoculated with broth culture, descended air-dry about 10-15 minute in room temperature (22 ℃).Draw 40 microlitre formula I compound solutions (in 1% methyl-sulphoxide) then and continuous half grade of (half-step) diluent in water is added on the vaccinated Mueller-Hinton agar plate.Agar plate was cultivated the record inhibition zone 24 hours in 35 ℃ subsequently.Minimum inhibitory concentration (MIC) is meant the formula I compound minimum concentration that the microorganisms inhibition zone is needed.Below table 6 list the anti-microbial activity of formula I compound to various fungal bacterial strains.
Table 5: the male Lewis mouse carrageenin tuberculous pleurisy test-results of formula I compound and other anti-inflammatory drug relatively
Compound Dosage (μ g/ mouse; In the pleura) % inhibiting rate WBC % inhibiting rate transudate
Formula I formula I formula I dexamethasone dexamethasone dexamethasone prednisolone prednisolone 0.2 1.0 5.0 2.0 10.0 50.0 50 250 32 41 76 8 29 68 23 32 25 40 60 10 41 83 25 30
Ultracortene-H 1250 97 55
The result is to represent complete blood cell (wbc) penetrating fluid (iniltration) of instillation carrageenin generation in the pleura and the % inhibiting rate of transudate volume.Medicine give to be used behind the instillation carrageenin in 1 hour; Measurement was carried out after 4 hours.
Table 6: the male Lewis mouse acetic acid colitis test-results of formula I compound and other anti-inflammatory drug relatively
Compound Dosage (mg/kg (po)) % inhibiting rate swollen tissue (oedema) % inhibiting rate MP0 (μ/cm)
Formula I formula I sulfasalazine sulfasalazine Ultracortene-H Ultracortene-H 5 20 100 300 3 12 36 47 10 14 44 40 39 37 20 16 41 46
Table 7: the result that formula I compound and another kind of antifungal drug are treated female Charles River mouse vaginal candidiasis compares
Compound Eliminate Improve
Thinner (butyleneglycol) 4/10 0/10
Formula I 9/10 1/10
Clotrimazole (Chlortrimazole) 7/10 2/10
Behind the vaginal infection Candida albicans 6 hours, every day was handled mice infected with the above-mentioned therapeutant of 0.025mL in beginning, handles continuously 4 days.Formula I compound concentrations is 0.5% (w/v), and clotrimazole is 1% (w/v).
Table 8: formula I compound is to the vitro inhibition effect of yeast and fungal growth
Microorganism MIC
Candida albicans ＜0.006
Oidium tropicale ＜0.4
Novel Cryptococcus ＜0.4
Saccharomyces cerevisiae (Saccharomyces cervisciae) ＜0.4
Aspergillus fumigatus ＜0.006
Yellow aspergillus 6.25
Fusariun solani ＜0.4
Unrooted rhizopus 6.25
Sabouraudites lanosus 1.6
Gypsum shape sporidiole bacteria 1.6
Trichophyton equinum 1.6
Along Trichophyton 1.6
Trichophyton rubrum 1.6
Acrothesium floccosum 1.6
These data representation formulas I compound suppresses the minimum inhibitory concentration of the bacterial growth of vitro culture, is unit with μ g/mL.
Table 9: department is for pharmacology and toxicology effect in the body of shellfish ammonium salt
Test, species, route of administration, volume injected Active dose (concentration) Signs of toxicity Remarks
Candidal vaginitis, mouse, part, 25 μ l 100μM Do not have, histology is normal Under 100 μ M, do not have and infect
The allergy pleuritis, rat, part, 250 μ l 12μM 82uM Do not have Suppress transudate and generate ﹠LTs inhibition late response (neutrophilic leukocyte)
The allergy synovitis, rat, part, 5 μ L 230μM Do not have Neutrophilic leukocyte reduces # in the joint
Anti-inflammatory activity, Hindlimb mouse, topical application, 100 μ l 0.5％ Do not have The oedema that suppresses the neutrophilic leukocyte mediation forms
Anthelmintic activity, people, oral capsule 1-10mg/kg Slight gastric irritation There is not disadvantageous general influence
Mastocyte discharges, rat, intradermal, 100 μ l 2mM Mild edema
Leukotriene is synthetic, rat pleura cell, part, 25 μ l 0.008mg/kg Do not have ED 50Dosage
Eye irritation, rabbit, part, 30 μ l 2mM Non-stimulated
Table 10: the department for the shellfish ammonium salt+/-4 hours carrageenin tuberculous pleurisies of the effectiveness of Ultracortene-H in grinding tooth substrate inflammatory model
Compound Dosage mg/kg % inhibiting rate oedema % inhibiting rate neutrophilic leukocyte
Ultracortene-H 0.02 31 21
Department is for the shellfish ammonium salt 0.0004 38 18
Ultracortene-H+department is for the shellfish ammonium salt 0.02 + 0.0004 67 56
The result Adduction Adduction
4 hours allergy pleuritis
Compound Dosage mg/kg % inhibiting rate oedema % inhibiting rate neutrophilic leukocyte
Ultracortene-H 0.004 33 25
Department is for the shellfish ammonium salt 0.002 19 10
Ultracortene-H+department is for the shellfish ammonium salt 0.004 + 0.002 57 40
The result Adduction Adduction
4 hours allergy synovitis
Compound Dosage mg/kg % inhibiting rate oedema % inhibiting rate neutrophilic leukocyte
Ultracortene-H 0.05 36 37
Department is for the shellfish ammonium salt 0.002 24 28
Ultracortene-H+department is for the shellfish ammonium salt 0.05 + 0.02 67 72
The result Adduction Adduction
Embodiment 11
Body outer screening test
The stock solution of each compound of preparation in DMSO, concentration 10,000ppm a.i..Utilize water to prepare further diluent.Test is carried out under following concentration: 125,31,8,21,0.5 and 0.125ppm a.i..The spore suspension of the following fungi of preparation: target chain lattice spore, gray botrytis, it is mould that spore is revolved in palace portion, Curcurbitaceae hair disc spore, machete sickle spore, phytophthora infestan, circle nuclear cavity bacteria, Pyricularia oryzae, Solanum rhizoctonia and wheat septoria.
Test is carried out in microtiter plate, and for every kind of fungi and each concentration, prepares 3 holes.Cultivated the inoculation plate 7 days at 18 ℃.Then, measure the mycelial optical density(OD) of growing in each hole in the 405nm place.
The gained data are used to estimate IC90 value (comparing the concentration that is reduced by at least 90% fungal growth needs with control group)
External-test of detached leaf sheet
In this model, the detached leaf sheet of suitable host plant is placed on the water agar.Blade is with 20 μ L cm 2, the solution-treated of every kind of compound of 15ppm a.i., these solution are by 10, and the DMSO stock solution of 000ppm a.i. prepares.With dry 24 hours of the leaf natural handled, then with following kind fungi inoculation (host plant place bracket interior); That make an exception is puccinia triticinia (wheat septoria (Puccinia triticina)), before using test compound, inoculated blade with it in 24 hours: Blumeria graminis f.sp.tritici (wheat), machete sickle spore (barley), Phaeophaeria nodorum (wheat), phytophthora infestan (tomato), leaf rust (wheat) and Pyricularia oryzae (Pyricularia oyrzae) (paddy rice).
Blade is cultivated 12 hours photoperiod down at 18 ℃ subsequently.Incubation period was up to 7 days.Replicate(determination) 3 times.
In the body-the greenhouse shaker test
To the test plant spray concentration be 250,63 and the compound of 16ppm a.i. run off until drop, handle and inoculated handling plant in back 24 hours, as the test of front, exception be the brown rest fungus of wheat (it is seeded in to handle and carried out in preceding 24 hours).Test comprises following pathogenic agent/host plant combination: target chain lattice spore/tomato, gray botrytis/bell pepper, phytophthora infestan/tomato and leaf rust/wheat.
Then under the weather condition that help the fungal pathogens growth, cultivate.Inoculate back 7 days and estimate incidence.
Overall result
Most of test-compounds demonstrate the remarkable vitro activity, in some cases, also observe this activity under extremely low concentration.
Under the situation of greenhouse experiment and the complete plant of use, can observe limited activity down in high test concentrations (250ppma.i.).Show active to target chain lattice spore and phytophthora infestan.
Embodiment 12
At the relevant fungal strain test of one group of plant stilbazium lodide (Stilbaziumiodide).The stock solution of preparation The compounds of this invention in DMSO, concentration 10,000ppma.i..Utilize water to prepare further diluent.Test is carried out under following concentration: 125,31,8,21,0.5 and 0.125ppm a.i..The spore suspension of preparation fungi.Test is carried out in microtiter plate, and for every kind of fungi and each concentration, prepares 3 holes.Cultivated the inoculation plate down 7 days at 18 ℃.Then, measure the mycelial optical density(OD) that produces in each hole in the 405nm place.
Gained data (being shown in Table 11) are used to estimate IC90 value (comparing the concentration that is reduced by at least 90% fungal growth needs with control group).
Table 11
Microorganism Corresponding plants IC90
Target chain lattice spore Potato ＞125
Gray botrytis Vegetables 0.5
It is mould that spore is revolved in palace portion Corn ＞125
Curcurbitaceae hair disc spore Muskmelon 31
Machete sickle spore Wheatear ＞125
Phytophthora infestan Tomato 2
The circle nuclear cavity bacteria Barley 31
Pyricularia oryzae Paddy rice 8
The Solanum rhizoctonia Rice leaf sheath (Rice Sheath) 2
Wheat septoria Wheat leaf 2
In this manual, typical preferred embodiment of the present invention is disclosed, although wherein used some particular term, they only are to use from general and illustrative meaning, are not to be used for limiting the scope of the present invention that the back claim is proposed.

Claims (47)

1. comprise:
Or the compound of its solvate,
Wherein said compound is E, the E configuration;
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.
2. the compound of claim 1, wherein X -Be selected from fluorochemical, muriate, bromide, iodide halogenide, mesylate, tosylate, naphthoate, naphthalenesulfonate, p-aminobenzoate, lauryl sulfate, 2,4 dihydroxyl benzophenone, 2-(2-hydroxyl-5 '-aminomethyl phenyl) benzotriazole, benzene sulfonate, benzene sulfonate, 2-cyano-3,3-diphenyl ethyl acrylate and Whitfield's ointment 5-butyl phenyl ester.
3. the compound of claim 1-2, wherein R 5Be (CH 2) n-MR 6, wherein n is numerical value 1-6, M is the organometallic compound that is selected from tin, silicon and germanium, and R wherein 6Be selected from propyl group, butyl, or alkyl, they are replacements or unsubstituted.
4. the compound of claim 1-3, wherein said compound is selected from 1-ethyl-(E,-E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridinium chloride, 1-ethyl-(E,-E)-2, and two [2-[4-(dimethylamino) phenyl] vinyl of 6-] pyridinium chloride, 1-ethyl-(E,-E)-2, two [2-[4-(diethylamino) phenyl] vinyl of 6-] pyridinium chloride, the 1-ethyl-(E ,-E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridine 4-aminobenzoate and 1-methyl-(E,-E)-2, and two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridinium chloride, and be substantially free of any other configurational isomer.
5. handle the method that growth has the Industrial products of fungi, this method comprises the compound of growth site to be processed being used the claim 1-4 of significant quantity.
6. according to the method for claim 5, wherein said Industrial products are selected from woodwork, blast main, timber, deck, pipeline, stucco, brick and tile, paint, insulating material, top board, material of construction, metal, machine element, food pack and base material.
7. the composition that comprises following formula: compound or its solvate and vehicle:
Figure A2004800057080003C1
Wherein said compound is E, the E configuration;
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.
8. be used to prepare the synthetic method of the composition of claim 7, comprise in composition, adding HCl.
9. the composition of claim 7, wherein X -Be selected from fluorochemical, muriate, bromide, iodide halogenide, mesylate, tosylate, naphthoate, naphthalenesulfonate, p-aminobenzoate, lauryl sulfate, 2,4 dihydroxyl benzophenone, 2-(2-hydroxyl-5 '-aminomethyl phenyl) benzotriazole, 2-cyano-3,3-diphenyl ethyl acrylate, benzene sulfonate, benzene sulfonate and Whitfield's ointment 5-butyl phenyl ester.
10. the composition of claim 7, wherein said compound be the 1-ethyl that is substantially free of any other configurational isomer-(E ,-E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridinium chloride.
11. the composition of claim 7, wherein R 5Be (CH 2) n-MR 6, wherein n is numerical value 1-6, M is the organometallic compound that is selected from tin, silicon and germanium, and R wherein 6Be selected from propyl group, butyl, or alkyl, they are replacements or unsubstituted.
12. the composition of claim 7, wherein said compound be the 1-methyl-(E ,-E)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridinium chloride.
13. the composition of claim 7 further comprises mycocide and/or bactericide.
14. the composition of claim 7 further comprises sterilant.
15. the composition of claim 7, wherein said composition is encapsulated in emulsion or the microcapsule.
16. the composition of claim 15, wherein said microcapsule are timed release capsule.
17. the composition of claim 7, wherein said composition are slowly-releasing form or non-slowly-releasing form.
18. a method of controlling fungi and/or bacterium comprises and uses the composition that comprises following formula: compound or its solvate:
Figure A2004800057080004C1
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.
19. a method for the treatment of curee's inflammation comprises the composition that curee's topical application of needs is comprised formula (I) or its solvate:
Figure A2004800057080005C1
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.
20. a method for the treatment of curee's infection comprises that the curee to needs uses the composition that comprises formula (I) or its solvate:
Figure A2004800057080005C2
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.
21. a method for the treatment of curee's immunological disease comprises that the curee to needs uses the composition that comprises formula (I) or its solvate:
Figure A2004800057080006C1
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.
22. treat curee's the fungi or the method for infectation of bacteria for one kind, comprise that the curee to needs uses the composition that comprises formula (I) or its solvate:
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.
23. a protective plant is avoided the method for fungal infection, the growth phase that is included in described plant makes plant contact with following formula: compound or its solvate:
Figure A2004800057080007C1
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group.
24. according to the method for claim 18-23, wherein N-R partly is positioned at contraposition, X is Cl -And R 5Be methyl or ethyl.
25. according to the method for claim 18 and 22-23, the method for wherein said control fungi and/or bacterium further is included in identical zone combination and contains fungi and/or bacterium.
26. according to the method for claim 18 and 22-23, wherein said composition was used before the fungi of growth occurs.
27. according to the method for claim 18-23, wherein R 5Be (CH 2) n-MR 6, wherein n is numerical value 1-6, M is the organometallic compound that is selected from tin, silicon and germanium, and R wherein 6Be selected from propyl group, butyl, or alkyl, they are replacements or unsubstituted.
28. according to the method for claim 18 and 22-23, wherein said composition is used after the fungi of growth occurs.
29. according to the branch of claim 18 and 22-23, wherein said composition is applied to Industrial materials.
30. according to the method for claim 29, wherein said Industrial materials are selected from Thistle board, timber, deck, pipeline, flooring material, material of roof plate, carpet, wallpaper, panelling, cloth matter seam sealer, mortar, brick and tile, grouting, fastening parts, tackiness agent, paint, coating, sealing agent and stucco.
31. according to the method for claim 18, wherein said method comprises that the fungi and/or the bacterium that are grown in food Package system, pharmaceutical prod, base material, plastics, paper and the foam by minimizing control fungi and/or bacterium.
32. according to the method for claim 19, wherein said inflammation is selected from allergic rhinitis, external otitis, uveitis, sinusitis, asthma, adult respiratory distress syndrome, bronchitis, laryngitis, mycodermatitis and cystic fibrosis of the pancreas.
33. according to the method for claim 221, wherein said immunological disease is selected from allergic rhinitis, external otitis, sinusitis, asthma, adult respiratory distress syndrome, bronchitis, laryngitis, mycodermatitis, cystic fibrosis of the pancreas, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis, uveitis, conjunctivitis, inflammatory bowel, Crohn disease, ulcerative colitis, tip rectitis, psoriasis, eczema, dermatitis, the allergy pruigo, local fungal infects, oulitis, periodontitis, the damage of coronary artery infraction, chronic inflammatory diseases, asthma, adult respiratory distress syndrome, rhinitis, chronic sinusitis, oropharynx moniliosis, bronchitis, laryngitis, cystic fibrosis of the pancreas and unstriated muscle proliferative disease.
34. according to the method for claim 18-23, wherein said method further comprises uses organotin, organosilicon or organic germanium.
35. according to the method for claim 23, the seed of wherein said plant was immersed in the composition that comprises described bacterial strain before planting the substratum of going into to be used for described plant, and cultivated described plant.
36. according to the method for claim 23, wherein said plant comprises seedling or seed.
37. according to the method for claim 19-21, wherein said fungi infestation is selected from the ringworm of the foot, favus of the scalp, ringworm of the body, tinea versicolor, nail fungi disease, porrigo, jock itch, moniliosis, sinusitis paranasal sinusitis and allergic rhinitis, and wherein said infectation of bacteria is selected from acne, uveitis, sinusitis paranasal sinusitis and rhinallergosis.
38. according to the method for claim 18-23, wherein R 6Be UV blockers or UV light absorber.
39. according to the method for claim 38, wherein said UV blockers or UV light absorber are selected from:
40. a microcapsule, it comprises the composition that comprises formula (I) component or its solvate:
Figure A2004800057080009C1
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected;
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-replaces and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group;
Vehicle; And
Photochromics.
41. the microcapsule of claim 40, wherein photochromics absorbs ultraviolet ray.
42. the microcapsule of claim 40, wherein photochromics ultraviolet blocking-up.
43. the microcapsule of claim 40, wherein photochromics is 1: 10 in the ratio of formula I component.
44. the method for control insect comprises and uses the composition that comprises formula (I) or its solvate:
Figure A2004800057080009C2
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkene, alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-and benzyl group.
45. according to the method for claim 44, wherein said composition is applied to waste water.
46. comprise:
Or the compound of its solvate, wherein n is numerical value 1-5;
Wherein Z is selected from C, N, O, S and halogen;
NR wherein 1R 2And NR 3R 4Part is positioned at ortho position, a position or contraposition position;
X wherein -It is anion salt;
R wherein 1, R 2, R 3, or R 4Independently be selected from do not exist, hydrogen, methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), perhaps R wherein 1With R 2Or R 3With R 4Form pyrrolidino or piperidino-(1-position only) ring together with the nitrogen-atoms that they connected; And
R wherein 5Be selected from methyl, ethyl, C 1-10Alkyl (straight or branched), alkene (straight or branched), alkynes, n-propyl, sec.-propyl, normal-butyl, isobutyl-, replace and unsubstituted aromatic yl group and replacement and unsubstituted benzyl group, condition be described compound can not be the 1-ethyl-(Z, Z), (Z, E) or (E, Z)-2, two [2-[4-(pyrrolidyl) phenyl] vinyl of 6-] pyridinium chloride.
47. the compound of claim 46, wherein said compound are E, the E configuration.
CN 200480005708 2003-03-03 2004-03-03 Pyridinium salts, compounds and methods of use Pending CN1756744A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108157405A (en) * 2018-02-06 2018-06-15 上海应用技术大学 One kind is gone out cockroach bait formulation and its preparation method and application

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108157405A (en) * 2018-02-06 2018-06-15 上海应用技术大学 One kind is gone out cockroach bait formulation and its preparation method and application
CN108157405B (en) * 2018-02-06 2020-10-02 上海应用技术大学 Cockroach killing bait and preparation method and application thereof

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