CN1224717A - Quinoxaline-1,4-dioxide derivative and its synthesis - Google Patents
Quinoxaline-1,4-dioxide derivative and its synthesis Download PDFInfo
- Publication number
- CN1224717A CN1224717A CN 98105030 CN98105030A CN1224717A CN 1224717 A CN1224717 A CN 1224717A CN 98105030 CN98105030 CN 98105030 CN 98105030 A CN98105030 A CN 98105030A CN 1224717 A CN1224717 A CN 1224717A
- Authority
- CN
- China
- Prior art keywords
- group
- compound
- quinoxaline
- formula
- replace
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the synthesis and application of medicine, especially of one quinoxaline derivative. The derivative of the present invention is used as antimicrobial and growth promoting medicine and is synthesized by leading active substituent to the benzene ring of parent nucleus and changing the substitute in the second position of parent nucleus. The said compounds have expanded antimicrobial spectrum, lowered toxicity and increased antiseptic activity.
Description
The present invention relates to the synthetic and Application Areas of medicine.
In recent years, the antimicrobial drug for animals of external listing, as " olaquindox " of Bayer A.G (Bayer) development (Olaquindox), " mequidox " of Pfizer Inc. (Pfizer) development (Mequidox) etc. all has-anti-microbial activity of Ding, some other digestive tract diseases effects such as certain growth promoting function and prevention pig bloody flux.And all owing to toxicity is higher, in clinical treatment, be subjected to certain restriction, and, poison for poult especially and constantly take place because poisoning appears in the clinical use of bird in olaquindox.
The objective of the invention is can cause the generation of Resistant strain in view of the shared antimicrobial drug of people and animals, unfavorable to the protection in new drug kind work-ing life, and influence people's diseases prevention and treatment and HUMAN HEALTH and the broad spectrum antibiotic a kind of for animals studied.It is by the Dui quinoxaline-1, the research of 4-titanium dioxide class drug molecule, quantitative structure-activity relation, introducing substituent change on two of active substituent and the parent nucleus on the phenyl ring of its parent nucleus, the antimicrobial spectrum of this compounds is expanded, toxicity reduces, anti-microbial activity significantly increases, and some other pathogenic micro-organisms such as mycoplasma, chlamydozoan are had the obvious suppression effect.
Motif compound of the present invention can be represented by formula I:
Wherein: R
1For ketone group, ester group, carboxy and amide groups, oximido, hydrazone or fragrance replace ketone group;
R
2, R
3Be nitrogenous substituting group or heterocyclic substituents such as hydrogen, halogen, amino, nitro, nitroso-group, and R
2, R
3Be not hydrogen simultaneously;
R
4Be hydrogen, lower paraffin hydrocarbons, alkoxyl group or aromatic substituent;
This compound derivatives is as antibiotic and promotes growth medicine.
The derivative of formula I can be prepared with following method:
Method A:
A (ⅰ), substituted o nitroaniline and suitable oxygenant, as: reactions such as potassium bichromate, potassium permanganate, perchloric acid, hydrogen peroxide, hypochlorous acid, obtain replacing the benzo furazan, represent with the general formula II
R in the III formula
2, R
3Has R in the formula I
2, R
3The meaning that is had.This reaction is at suitable solvent, as alcohols, 1, reacts in 4-dioxane, the chloroform, and reaction is preferably under the alkaline environment to be carried out, and temperature, was stirred 1-12 hour to the solvent refluxing temperature by zero.
A (ⅱ), replace the benzo furazan and contain the compound that the methylene compound reaction obtains, represent with formula I
Wherein methylene compound comprises and contains methylene radical: the ketoxime that ketone, aldehyde, acid amides, oxime or fragrance replace.
Reaction is (promptly to be solvent at suitable solvent as containing the methylene radical fluid cpds, be again reactant) carry out under the appropriate catalyst, as reacting in Trimethylamine 99, triethylamine, diethylamine, pyridine, sodium hydroxide and some organic acid, to the solvent refluxing temperature, the time is 1-48 hour to temperature in room temperature.
Method B
B (ⅰ), benzo furazan as alcohol, ether, 1, with the compound reaction that contain " active replace group ", obtain replace benzo furazan in 4-dioxane, the chloroform at suitable solvent, represent with the general formula II
Temperature of reaction, stirred 1-24 hour to the solvent refluxing temperature from room temperature.Wherein " the active group that replaces " is R in the formula I
2, R
3The meaning that has.
B (ⅱ), replacement benzo furazan are carried out A (ⅱ) reaction.
Method C
C (ⅰ), make 2-formyl quinoxaline-1,4-dioxide and the compound reaction that contains " the active group that replaces " must replace 2-formyl quinoxaline-1, the 4-dioxide, and wherein " the active group that replaces " has R in the formula I
2, R
3The meaning that is had.
C (ⅱ), replacement 2-formyl quinoxaline-1,4-dioxide and " nucleophilic reagent " reaction, as: substituted-amino, hydroxyl, urea, hydrazine hydrate, thiocarbamide reaction, reaction is preferably in alkalescence as carrying out in Trimethylamine 99, triethylamine, pyridine or its mixture, optimum temperuture can change between the reflux temperature of solvent in room temperature, stirred 1-48 hour, wherein " nucleophilic reagent " has R in the formula I
2, R
3The meaning that has.
According to derivative preparation method of the present invention, in the following example, provide, the following examples are simply to provide in the mode that illustrates, but should not limit the scope of the invention by any way.
Method A
Embodiment 1,6-chloro-3-methyl-2-ethanoyl quinoxaline-1, the 4-dioxide
1.1,4-chloro-2-N-methyl-p-nitroaniline 34.5 g (0.20ml) add 100ml ethanol, 50ml methyl alcohol, heating for dissolving, add small amounts of sodium hydroxide therein, make alkalize, add the oxygenant potassium bichromate, until color by the red stain Huang, produce yellow mercury oxide, need time 1-4 hour, filter, the nitrogen gas stream drying, get 27.3g, productive rate 80%, 146 ℃ of fusing points.
1.2, the 6-chlorobenzene that produces in 1.1 and furazan added the 50ml methyl ethyl diketone add 3gNaOH, the heat production phenomenon is arranged, temperature raises at once, stirs 24 hours, there is yellow crystal to separate out, filters the nitrogen gas stream drying, alcohol or chloroform recrystallization get 21g, productive rate 52%, 165 ℃ of fusing points.
Embodiment 2,6-chloro-3-methyl-2-ethoxycarbonyl quinoxaline-1, the 4-dioxide
2.1,4-chloro-2-N-methyl-p-nitroaniline 34.5g (0.20ml), carry out among the embodiment 1 1.1 reactions, the chloro benzo furazan.
2.2, the chloro benzo furazan adds the 50ml methyl aceto acetate and NaOH makes alkalize, is heated to boiling, stirs 48 hours, has yellow crystal to produce, filtration, the nitrogen gas stream drying, alcohol or chloroform recrystallization get 21.2g, productive rate 47%, 159 ℃ of fusing points.
Method B
Embodiment 3,6-piperazine-quinoxaline-1s, the 4-dioxide
3.1, benzo furazan thermosol does in the methanol mixed solution, adds piperazine, stirs 24 hours, has yellow crystal to separate out, filtration drying.
3.2,6-piperazine-quinoxaline-1s, the 4-dioxide carry out A (ⅱ) react 6-piperazine-2-ethanoyl quinoxaline-1, the 4-dioxide.
Embodiment 4
According to embodiment 3, can synthesize following one group of compound according to method B:
Method C:
Embodiment 5
7-fluoro-6-chloro-3-methyl-2-methyl carbamoyl oxime based quinoxaline-1, the 4-dioxide
5.1,3-fluoro-4-chloro-2-N-methyl-p-nitroaniline 28.8g (0.2mol) thermosol is in 100ml ethanol and 50ml methyl alcohol, adds alkali and makes alkalize, adds KMnO again
4, color reddens immediately, up to its colour changed into yellow, has yellow crystal to produce, and adds water and is reflected at below 20 ℃, stirred 8 hours, and filtration, drying, ethyl alcohol recrystallization gets 3-fluoro-4-chlorobenzene and furazan 30.6g, productive rate 81%.
5.2,3-fluoro-4-chlorobenzene and furazan add the methyl ethyl diketone dissolving and add pyridine, stirred 48 hours, and the yellow crystal generation is arranged, filtration, dry, ethyl alcohol recrystallization, get 7-fluoro-6-chloro-3-methyl-2-acetyl quinoxaline-1, the 4-dioxide adds oxammonium hydrochloride with it, in acidity or alkaline environment, stirred 20 hours, temperature is controlled at room temperature, has crystallization to separate out, filtration, dry, ether recrystallization, get 7-fluoro-6-chloro-3-methyl-2-methyl carbamoyl oxime based quinoxaline-1, the 4-dioxide.
Embodiment 6
According to embodiment 5,, can synthesize following one group of compound according to method C
R
1 R
2 R
3 R
4 -CL -H -CH
3 -CL -H -H
-CL -H -CH
3 -CL -H -CH
3 -CL -H -CH
3 -CL -H -CH
3 -CL -H -CH
3 -CL -H -CH
3 -CL -H -CH
3
Pharmacologically active
1, anti-microbial activity
In the laboratory, adopt doubling dilution, to the livestock and poultry The main pathogenic fungi, make external bacteriostatic experiment and show the: quinoxaline-1, the has a broad antifungal spectrum of 4-dioxide novel derivative, toxicity is lower, its antimicrobial spectrum comprises gram-positive microorganism and Gram-negative bacteria, especially the inside and outside Gram-negative bacteria is had extremely strong anti-microbial activity, respond well for control digestive tube and respiratory tract infection, and to the good restraining effect of some other pathogenic micro-organism also tool.
2, growth promoting function
Clinical experiment shows that this compounds has the promotion growth of animal, improves food conversion ratio, and improves the effect of feeding effect.
Claims (2)
1, a kind of quinoxaline-1, the 4-dioxide derivative is characterized in that they represent with formula I:
Wherein:
R
1Be ketone group, ester group, carboxyl, amide group, oximido, hydrazone or fragrance replace ketone group;
R
2, R
3Be nitrogenous substituting group or heterocyclic substituents such as hydrogen, halogen, amino, nitro, nitroso-group, and R
2, R
1Be not hydrogen simultaneously;
R
4Be hydrogen, lower paraffin hydrocarbons, alkoxyl group or aromatic substituent;
This derivative is as antibiotic and promotes growth medicine.
2, a kind of quinoxaline-1, the synthetic method of 4-dioxide derivative is characterized in that it comprises:
Method A:
(ⅰ), replace adjacent nitre aniline and oxidant reaction, obtain replacing the benzo furazan, represent with the general formula II:
Wherein: adjacent nitre aniline substituent is represented with the general formula III:
R in the III formula
2, R
3Be nitrogenous substituting group or heterocyclic substituents such as hydrogen, halogen, amino, nitro, nitroso-group, and R
2, R
3Be not hydrogen simultaneously;
(ⅱ), making the general formula II replace the benzo furazan reacts with containing " methylene compound ", obtains compound and represent with formula I
Wherein: " methylene compound " comprises and contains methylene radical: the ketoxime that ketone, aldehyde, acid, acid amides, oxime or fragrance replace;
Method B
(ⅰ), make benzo furazan and the compound reaction that contains " active substituent group ", obtain replacing the benzo furazan, represent with the general formula II
Wherein: " the active group that replaces " has R in the claim 1
2, R
3The meaning that is had;
(ⅱ) make the general formula II replace the benzo furazan and react, obtain compound and represent with formula I with containing " methylene compound "
Wherein: " methylene compound " comprises the ketoxime of the ketone, aldehyde, acid, acid amides, oxime or the fragrance replacement that contain methylene radical;
Method C
(ⅰ), make 2-formyl quinoxaline-1,4-dioxide and the compound reaction that contains " the active group that replaces "
Wherein: " the active group that replaces " has R in the claim 1
2, R
3The meaning that is had;
(ⅱ), make replacement 2-formyl quinoxaline-1,4-dioxide and " nucleophilic reagent " reaction
Wherein: " nucleophilic reagent " comprises R in the claim 1
1The substituent compound that is had.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 98105030 CN1224717A (en) | 1998-01-24 | 1998-01-24 | Quinoxaline-1,4-dioxide derivative and its synthesis |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 98105030 CN1224717A (en) | 1998-01-24 | 1998-01-24 | Quinoxaline-1,4-dioxide derivative and its synthesis |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1224717A true CN1224717A (en) | 1999-08-04 |
Family
ID=5218650
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 98105030 Pending CN1224717A (en) | 1998-01-24 | 1998-01-24 | Quinoxaline-1,4-dioxide derivative and its synthesis |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1224717A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103145631A (en) * | 2013-03-18 | 2013-06-12 | 广州英赛特生物技术有限公司 | Antibacterial derivative of quinoxaline-1,4-dioxide and application in animal production thereof |
CN110551072A (en) * | 2019-10-18 | 2019-12-10 | 华中农业大学 | quinoxaline-N 1, N 4 -dioxide derivative with DNA topoisomerase activity inhibition function, preparation method and application |
CN111171013A (en) * | 2020-01-08 | 2020-05-19 | 华中农业大学 | quinoxaline-N containing thiazolidone structure1,N4-dioxide derivatives, preparation method and application thereof |
-
1998
- 1998-01-24 CN CN 98105030 patent/CN1224717A/en active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103145631A (en) * | 2013-03-18 | 2013-06-12 | 广州英赛特生物技术有限公司 | Antibacterial derivative of quinoxaline-1,4-dioxide and application in animal production thereof |
CN103145631B (en) * | 2013-03-18 | 2015-08-19 | 广州英赛特生物技术有限公司 | Germ resistance quinoxaline-1, the derivative of 4-dioxide and the application in animal productiong thereof |
CN110551072A (en) * | 2019-10-18 | 2019-12-10 | 华中农业大学 | quinoxaline-N 1, N 4 -dioxide derivative with DNA topoisomerase activity inhibition function, preparation method and application |
CN111171013A (en) * | 2020-01-08 | 2020-05-19 | 华中农业大学 | quinoxaline-N containing thiazolidone structure1,N4-dioxide derivatives, preparation method and application thereof |
CN111171013B (en) * | 2020-01-08 | 2021-03-16 | 华中农业大学 | quinoxaline-N containing thiazolidone structure1,N4-dioxide derivatives, preparation method and application thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Turan‐Zitouni et al. | Synthesis of Some 1‐[(N, N‐Disubstituted thiocar bamoylthio) acetyl]‐3‐(2‐thienyl)‐5‐aryl‐2‐pyrazoline Derivatives and Investigation of Their Antibacterial and Antifungal Activities | |
US4599418A (en) | Benzoquinolizine carboxylic acid derivatives, and process for preparation thereof | |
JPS59118774A (en) | Substituted phenylsulfonyloxybenzimidazole carbamates and manufacture | |
CN1224717A (en) | Quinoxaline-1,4-dioxide derivative and its synthesis | |
Sensi et al. | Rifamycins. 1 XXXV. 2 Amides and hydrazides of rifamycin B3 | |
CN112442084B (en) | Preparation method of antibacterial drug intermediate | |
CN105646392A (en) | 1,3,4-oxadiazole compounds containing oxime carboxylate and preparation method and application of 1,3,4-oxadiazole compounds containing oxime carboxylate | |
US4044130A (en) | Compositions for the control of microorganisms | |
US3948913A (en) | New 5-nitrofuryl derivatives | |
EP0060573B1 (en) | Thiolic derivatives of erythromycin having therapeutic activity, process for their preparation and pharmaceutical compositions containing them | |
Jensen et al. | Use of acetylacetone to prepare a prodrug of cycloserine | |
US3947441A (en) | Substituted 2-amino-4-(hydroxyamino)-pyrimidines | |
US4593024A (en) | Dihydroisoxazole compounds and anthelmintic use | |
OZAWA et al. | Synthesis and antimicrobial activity of salicylanilide derivatives. II | |
CN112409410A (en) | Application of silver catalyst in preparation of antibacterial intermediate | |
CN116730942B (en) | 1,3, 4-Oxadiazole-2 (3H) -thioketone compound and preparation method and application thereof | |
US4036849A (en) | 1-(Para-substituted-phenyl)-1H-tetrazoles | |
US20240217917A1 (en) | Photolytically degradable compounds and methods | |
CN116730941B (en) | 5-Phenyl-1, 3, 4-oxadiazole compound and preparation method and application thereof | |
RU2136679C1 (en) | 2-amino-5,6,7,8-tetrahydroquinoline-3-carboxylic acid 5-nitrofurfurylidenehydrazide | |
RU2671573C1 (en) | 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide of maleic acid having antimicrobial activity | |
US4038392A (en) | 3-(heterocyclicthiomethyl) quinoxaline-1,4-dioxides | |
US3528971A (en) | Cycloalkyl nitrofuryl nitrones | |
CN109232543A (en) | A kind of fungicide and its application | |
CN112028854B (en) | Benzothiazole phenylurea compounds and preparation and sterilization application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C01 | Deemed withdrawal of patent application (patent law 1993) | ||
WD01 | Invention patent application deemed withdrawn after publication |