CN101407499A - Triazine compounds having coccidiostat activity and preparation thereof - Google Patents
Triazine compounds having coccidiostat activity and preparation thereof Download PDFInfo
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Abstract
The invention discloses triazine compounds of formula (I) which have anti-coccidia activity and the pharmaceutically acceptable acid or alkali salts of the compounds, wherein, A stands for oxygen or sulfur, R1 and R2 stand for one or several groups of hydrogen, halogen atoms, alkyl, naphthene base, alkoxy, nitryl, trifluoromethyl, trichloromethyl, COR5, naphthene base and heterocyclic rings; R1 and R2 stand for same or different groups; R3 stands for hydrogen atoms, alkyl or naphthene base; R4 stands for hydrogen atoms, CO2R5 or CONHR6; and the compounds have good inhabitation effect for animal coccidiosis.
Description
Technical field
The present invention relates to new compound in triazine class and its salt at pharmaceutically acceptable acid or alkali; The present invention relates to the preparation method of the new compound of this class; The compound that the present invention relates to has anti-chicken coccidia activity.
Background technology
Coccidia be a kind ofly parasitize in bile duct and the intestinal epithelial cells, very wide protozoon distributes.Animals such as horse, ox, sheep, pig, camel, dog, rabbit, mink, chicken, turkey, duck, goose, dove can both suffer from coccidiosis, and the easy infection of chick, turkey wherein endangers the heavyliest, is one of most important disease in the intensification poultry husbandry.Because of immunization prevention and control coccidiosis of chicken still has many technology barriers and condition restriction, medicine is the topmost measure of this disease of control for a long time.Anticoccidial drug mainly contains several big classes such as sulfamido, polyethers ion carrier antibiotic, triazines.
But also there is defective in anticoccidial drug commonly used, and the ionophore medicine has being subjected to following or contacting or take in the toxicity hazard that is caused unintentionally of medicine animal and other farming animals and people, and drug safety is low, the drug effect narrow range.Polyether antibiotics Salinomycin. and Luo Luo mycin etc. can reduce the hatching rate of laying hen; The Robenidine life-time service has peculiar smell in the chicken.Be exactly residues of antibiotics in addition, the European Union and the U.S. require very strict to the antibiotic residual quantity in the animal-derived food product, if the microbiotic improper use will inevitably cause residual the exceeding standard in chicken and the egg and influence outlet.In addition, enter the nineties in 20th century, the life-time service of anticoccidial drug and cause clinically that drug-resistant worm plant constantly occurs, cause the chemical sproof generation of coccidia, cause anticoccidial drug shortening working life, control failure or poor effect cause clinical or subclinical coccidiosis of chicken, bring a difficult problem, the effect of serious threat medical treatment for chicken coccidia or the sick medical treatment of abuse.So probing into the anticoccidial drug of novel, efficient, low toxicity, safety has great importance.
Summary of the invention
The objective of the invention is to provide an a kind of class new compound of coccidiostat activity at the deficiencies in the prior art, this compounds has tangible anti-animal coccidia activity, contain the formed salt at pharmaceutical acceptable acid or alkali of at least a formula (I) compound or these compounds as activeconstituents, can be used for the prevention of animal's coccidiosis.
The concrete technical scheme that realizes the object of the invention is:
A kind of compound in triazine class with coccidiostat activity, characteristics are: the compound of formula (I) and their formed salt at pharmaceutically acceptable acid or alkali;
Wherein:
A represents oxygen or sulphur;
R
1, R
2Represent hydrogen, halogen atom, alkyl, cycloalkyl, alkoxyl group, nitro, trifluoromethyl, trichloromethyl, COR
5, cycloalkyl, one or more groups of heterocyclic, R
1, R
2Identical or different;
R
3Represent hydrogen atom, alkyl or cycloalkyl;
R
4Represent hydrogen atom, CO
2R
5, CONHR
6Or nitrogen heterocyclic ring group:
Wherein: CO
2R
5In R
5Represent 3-trifluoromethyl, 3,5-bis trifluoromethyl phenyl, trifluoromethyl, trichloromethyl, trisbromomethyl, CHCl
2, CHBr
2, OR
6Or SR
6
CONHR
6In R
6Represent hydrogen atom, alkyl or cycloalkyl;
-" halogen atom " is defined as fluorine, chlorine, bromine, iodine;
-" alkyl " is defined as C
1-C
6The saturated group of straight or branched;
The end that-" alkoxyl group " is defined as oxygen is connected with the group of alkyl;
-" cycloalkyl " is defined as C
3-C
6Cyclic group;
-" heterocycle " is defined as saturated or undersaturated single or bicyclic groups, have aromatics or non-aromatic character, have 5-12 annular atoms, contain 1-3 identical or different heteroatoms, heteroatoms is selected from oxygen, nitrogen, p and s, heterocycle is randomly replaced by one or more identical or different substituting groups, and substituting group is selected from halogen, hydroxyl, alkyl, alkoxyl group or nitro; In heterocycle, symbolic and do not add any pyridyl, thienyl, thiazolyl, furyl, imidazolyl, pyrazinyl, pyrimidyl, tetrazyl, pyrazolyl, quinolyl, isoquinolyl, quinazolyl, pyrrolidyl, piperazinyl, dioxygen ethylene imine Ji, oxazolyl, isoxazolyl, purine radicals, different purine radicals restrictedly mentioned.
The salt of described pharmaceutically acceptable acid is meant salt crystal water or that do not contain crystal water that contains of hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid, carbonic acid, formic acid, acetate, propionic acid, Succinic Acid, citric acid, lactic acid, fumaric acid, tartrate or gluconic acid formation.
The salt of described pharmaceutically acceptable alkali is meant salt crystal water or that do not contain crystal water that contains of sodium hydroxide, potassium hydroxide, triethylamine or TERTIARY BUTYL AMINE formation.
Phenyl ring in the described formula (I) also is aromaticity or non-aromaticity heterocycle that replace or non-replacement.
The preparation method of a kind of formula (I) compound, use the compound of formula (II) and the compound of formula (III) to be raw material:
Formula (II) formula (III)
R wherein
1, R
2Be as defined above, X is a halogen atom;
Add the closed loop agent in formula (III) compound, obtain crucial intermediate formula (IV) compound through diazonium coupling, cyclization, hydrolysis, decarboxylic reaction:
Wherein A, R
1, R
2, R
3, R
4Be as defined above.
According to the reaction conditions of the Liv Ullmann in the organic synthesis (Ullmann) reaction, make the reaction of formula (IV) compound and formula (II) compound obtain the formula V compound:
Wherein A, R
1, R
2, R
4Be as defined above, R
3=H.
Formula V compound and haloalkane effect obtain formula (I) compound:
Wherein A, R
1, R
2, R
3, R
4Be as defined above.
According to a kind of favourable change example, preferred compound is: R wherein
1Be trifluoromethyl, trichloromethyl, halogen atom, heterocycle, R
3Be alkyl, cycloalkyl.
According to the present invention, be for the preferred compound of formula (I):
Be A=O; R
1=methyl, methoxyl group; R
2=methyl, methoxyl group; R
3, R
4=hydrogen.
Be A=S; R
1=methyl, methoxyl group; R
2=hydrogen; R
3, R
4=hydrogen.
Be A=S; R
1=chlorine; R
2=methyl, methoxyl group; R
3, R
4=hydrogen.
Be A=O; R
1=chlorine, bromine; R
2=hydrogen; R
3, R
4=hydrogen.
Be A=O; R
1=chlorine, bromine; R
2=chlorine, bromine; R
3, R
4=hydrogen.
Be A=S; R
1=methyl, methoxyl group; R
2=hydrogen; R
3=methyl, R
4=hydrogen.
Be A=O; R
1=methyl, methoxyl group; R
2=hydrogen; R
3=methyl, R
4=CO
2R
5, R
5=hydrogen atom, alkyl.
Be A=S; R
1=methyl, methoxyl group; R
2=hydrogen; R
3=methyl, R
4=CONHR
6, R
6=hydrogen atom, alkyl, nitrogen heterocyclic ring.
Be A=O; R
1=trifluoromethyl, methoxyl group; R
2=hydrogen, methyl; R
3, R
4=hydrogen.
Be A=S; R
1=bromine; R
2=chlorine; R
3=hydrogen, methyl; R
4=CO
2R
5, R
5=hydrogen atom, alkyl.
Be A=O; R
1=trifluoromethyl, methoxyl group; R
2=hydrogen, methyl; R
3=methyl; R
4=hydrogen.
Be A=O; R
1=chlorine, bromine; R
2=hydrogen, methyl; R
3=methyl, cycloalkyl; R
4=CONHR
6, R
6=hydrogen atom, alkyl, nitrogen heterocyclic ring.
Be A=O; R
1=trifluoromethyl, chlorine; R
2=hydrogen, methyl; R
3=methyl; R
4=CO
2R
5, R
5=hydrogen atom, alkyl.
Be 2-[4-(4 '-4-trifluoromethylphenopendant)-3-methyl-phenyl]-4-methyl-6-formyl piperazine base-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone.
Be 2-[4-(4 '-bromine phenoxy group)-3-methyl-phenyl]-4-methyl-6-formyl piperazine base-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone.
These compounds and at pharmaceutically acceptable acid or the formed additive salt of alkali.Easier acquisition or higher biological activity is arranged.
The part of preferred compound and they and pharmaceutically acceptable acid or the formed additive salt formation of alkali complete content of the present invention.
The compounds of this invention has tangible anti-animal coccidia activity, contains the formed salt at pharmaceutical acceptable acid or alkali of at least a formula (I) compound or these compounds as activeconstituents, therefore can be used for the prevention of animal's coccidiosis.
Embodiment
The following example is used for further specifying the present invention and limits the present invention absolutely not:
Raw materials used and (or) reagent is known product, or according to the product of known operation preparation.
The structure of compound described in embodiment and the synthesis step be according to routine spectroscopic techniques (infrared, UV, NMR MS) measures.
Embodiment 1
2-[4-(4 '-4-trifluoromethylphenopendant) phenyl]-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone synthetic
22.0g para hydroxybenzene amine, 25ml water and 100ml concentrated hydrochloric acid are joined in the reaction flask, stir, lower the temperature, 15 ~ 20 ℃ of droppings contain the aqueous solution of 30.0g Sodium Nitrite, and 30min drips off, and insulation reaction 2h gets diazonium salt, and is stand-by.In another reaction flask, add 60.0g malonyl-diamino acid ethyl ester, 300ml pyridine, 300g trash ice and 200ml water, be cooled to below 10 ℃ after, slowly pour above-mentioned diazonium salt under the vigorous stirring into.Finish 10 ~ 15 ℃ of reaction 5h.Filter, be washed to neutrality, get 2-(4 hydroxyl phenylhydrazone)-malonyl-diamino acid ethyl ester 70.3g, yield 95.1%.
33.2g2-(4 hydroxyl phenylhydrazone)-malonyl-diamino acid ethyl ester, 20g sodium acetate, anhydrous and 250ml Glacial acetic acid are added in the reaction flask, stir heating reflux reaction 5h down, cooling, the reaction solution concentrating under reduced pressure filters, filter cake wash 2-(4 hydroxy phenyl)-3,5-(2H, 4H)-dioxo-6-formamido group ethyl formate-1,2,4-triazine 25.2g, yield 86.9%.
With 20.0g 2-(4 hydroxy phenyl)-3, and 5-(2H, 4H)-dioxo-6-formamido group ethyl formate-1,2,4-triazine, 300ml concentrated hydrochloric acid and 200ml Glacial acetic acid add in the reaction flask, stir back flow reaction 5h down.The reaction solution concentrating under reduced pressure filters, and the water recrystallization gets 2-(4 hydroxy phenyl)-3,5-diketone-2H-[1,2,4]-triazine-6-carboxylic acid 12.5g, yield 80.3%.
With 3.0g 2-(4 hydroxy phenyl)-3,5-diketone-2H-[1,2,4]-triazine-6-carboxylic acid and 50ml Thiovanic acid add in the reaction flask, is heated to 180 ℃ of reaction 5h under nitrogen protection.Cooling adds saturated sodium bicarbonate aqueous solution, stirs 30min, filters, and uses recrystallizing methanol behind the filtration cakes torrefaction, gets key intermediate 2-(4 hydroxy phenyl)-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone 2.0g, yield 81.0%.
With 1.0g 2-(4 hydroxy phenyl)-[1,2,4]-triazine-3, (2H 4H)-diketone, 1.5g Anhydrous potassium carbonate and 200ml DMSO add in the reaction flask, stirs and is warming up to 80 ℃ down and reacts 30min 5-, cooling is dissolved in 1.0g among the 20ml DMSO to the trifluoromethyl chlorobenzene slightly, drops in the reaction flask, be warming up to 100 ℃ of reaction 10h, cooling changes it in beaker over to, add water (300ml), dilute hydrochloric acid is transferred pH=4, filters, washing, dry off-white powder product 1.52g, the yield 85.2% of getting.
Embodiment 2
2-[4-(4 '-4-trifluoromethylphenopendant) phenyl]-4-methyl-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone synthetic
With 0.73g 2-[4-(4 '-4-trifluoromethylphenopendant) phenyl]-[1,2,4]-triazine-3,5-(2H, 4H)-diketone, 0.1g sodium hydroxide and 20ml dimethyl sulfoxide (DMSO) join in the reaction flask, stirring at room 0.5h drips the mixing solutions of 0.83g methyl iodide and 10ml dimethyl sulfoxide (DMSO), drips to finish to be warming up to 100 ℃, reaction 5h, reaction finishes, and reduces to room temperature, add the about 100ml of water under stirring, filter, washing, dry product 0.67g, the yield 88.5% of getting.
Embodiment 3
2-[4-(4 '-nitro-phenoxy) phenyl]-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone synthetic
With 1.0g 2-(4 hydroxy phenyl)-[1,2,4]-triazine-3, (2H 4H)-diketone, 0.75g Anhydrous potassium carbonate and 40ml DMSO add in the reaction flask, stirs and is warming up to 80 ℃ down and reacts 30min 5-, the 0.8g p-Nitrophenyl chloride is dissolved in 10ml DMSO, drops in the reaction flask, be warming up to 150 ℃ of reaction 10h, cooling adds water (300ml), and dilute hydrochloric acid is transferred pH=4, filter, washing, dry off-white powder product 1.5g, the yield 90.2% of getting.
Embodiment 4
2-[4-(4 '-nitro-phenoxy) phenyl]-4-methyl-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone synthetic
With 0.65g 2-[4-(4 '-nitro-phenoxy) phenyl]-[1,2,4]-triazine-3,5-(2H, 4H)-diketone, 0.08g sodium hydride and 8ml dimethyl sulfoxide (DMSO) join in the reaction flask, stirring at room 0.5h drips the mixing solutions of 0.43g methyl iodide and 3ml dimethyl sulfoxide (DMSO), drips to finish to be warming up to 100 ℃, reaction 3h, reaction finishes, and reduces to room temperature, add the about 10ml of water under stirring, filter, washing, dry product 0.6g, the yield 88.5% of getting.
Embodiment 5
2-[4-(2 '-quinoline oxy) phenyl]-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone synthetic
With 4.0g 2-(4 hydroxy phenyl)-[1,2,4]-triazine-3,5-(2H, 4H)-diketone, 3.4g Anhydrous potassium carbonate and 75ml DMF join in the reaction flask, magnetic agitation, oil bath are heated to 80 ℃ of reaction 0.5h, reduce to room temperature, 3.5g 2-chloroquinoline is dissolved in 15ml DMF, drip finishes and to be warming up to 150 ℃ of reactions and to spend the night, add the about 400ml of water, dilute hydrochloric acid is transferred pH=4, separates out white cotton-shaped product, filters, washing, dry white products 2.1g, the yield 32.4% of getting.
Embodiment 6
2-[4-(2 '-thiophene oxy) phenyl]-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone synthetic
With 1.0g 2-(4 hydroxy phenyl)-[1,2,4]-triazine-3, (2H 4H)-diketone, 1.5g Anhydrous potassium carbonate and 200ml DMSO add in the reaction flask, stirs and is warming up to 80 ℃ down and reacts 30min 5-, cooling slightly adds to 0.95g2-bromothiophene and the mixed drop of 20ml DMSO in the reaction flask, is warming up to 150 ℃ of reaction 10h, cooling changes it in beaker over to, adds water 300ml, dilute hydrochloric acid is transferred pH=4, filters washing, dry off-white powder product 1.15g, the yield 82.2% of getting.
Embodiment 7
2-[4-(4 '-bromine phenoxy group) phenyl]-6-formyl piperazine base-3,5-diketone-2H-[1,2,4]-triazine synthetic
With 3.0g 2-(4 hydroxy phenyl)-3,5-diketone-2H-[1,2,4]-triazine-6-carboxylic acid and 50ml sulfur oxychloride add in the reaction flask, back flow reaction 3h removes solvent under reduced pressure, gets 2-(4-hydroxy phenyl)-3,5-diketone-2H-[1,2,4]-and triazine-6-formyl chloride 2.9g, yield 90.0%.
With 2.68g 2-(4-hydroxy phenyl)-3,5-diketone-2H-[1,2,4]-and triazine-6-formyl chloride, 50ml anhydrous tetrahydro furan and 1.5ml triethylamine add in the reaction flask, stir cooling, the 0.90g Piperazine anhydrous is dissolved in the 20ml tetrahydrofuran (THF), slowly is added drop-wise in the reaction flask, drip and finish, rise to room temperature, reaction is spent the night, and filters, filtrate concentrate 2-(4-hydroxy phenyl)-6-formyl piperazine base-3,5-diketone-2H-[1,2,4]-and triazine 2.59g, yield 81.6%.
With 1.55g 2-(4-hydroxy phenyl)-6-formyl piperazine base-3,5-diketone-2H-[1,2,4]-and triazine, 1.5g Anhydrous potassium carbonate and 200ml DMSO add in the reaction flask, are warming up to 80 ℃ of reaction 30min under stirring, cooling slightly adds to 1.20g paradibromobenzene and the mixed drop of 20ml DMSO in the reaction flask, is warming up to 150 ℃ of reaction 10h, cooling changes it in beaker over to, adds water 200ml, dilute hydrochloric acid is transferred pH=6, filters washing, dry off-white powder product 1.3g, the yield 56.3% of getting.
Embodiment 8
2-[4-(4 '-chlorobenzene sulfenyl) phenyl]-3,5-diketone-2H-[1,2,4]-triazine synthetic
With 2.65g 2-(4 sulfydryl phenyl)-3,5-diketone-2H-[1,2,4]-triazine-6-carboxylic acid and 30ml Thiovanic acid add in the reaction flask, is heated to 180 ℃ of reaction 4h under nitrogen protection.Cooling adds saturated sodium bicarbonate aqueous solution, stirs 30min, filters, and uses ethyl alcohol recrystallization behind the filtration cakes torrefaction, gets 2-(4-sulfydryl phenyl)-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone 1.69g, yield 76.4%.
With 1.08g 2-(4 sulfydryl phenyl)-[1,2,4]-triazine-3, (2H 4H)-diketone, 0.75g Anhydrous potassium carbonate and 50ml DMSO add in the reaction flask, stirs and is warming up to 80 ℃ down and reacts 30min 5-, the 0.8g santochlor is dissolved in 15ml DMSO, drops in the reaction flask, be warming up to 160 ℃ of reaction 10h, cooling adds water (400ml), and dilute hydrochloric acid is transferred pH=6, filter, washing, dry off-white powder product 1.43g, the yield 88.3% of getting.
Embodiment 9
2-[4-(4 '-chlorobenzene sulfenyl) phenyl]-6-formyl piperazine base-3,5-diketone-2H-[1,2,4]-triazine synthetic
With 2.65g 2-(4 sulfydryl phenyl)-3,5-diketone-2H-[1,2,4]-triazine-6-carboxylic acid and 40ml sulfur oxychloride add in the reaction flask, back flow reaction 3h, concentrating under reduced pressure gets 2-(4-sulfydryl phenyl)-3,5-diketone-2H-[1,2,4]-and triazine-6-formyl chloride 2.34g, yield 82.7%.
With 1.42g 2-(4-sulfydryl phenyl)-3,5-diketone-2H-[1,2,4]-and triazine-6-formyl chloride, 50ml anhydrous tetrahydro furan and 0.8ml triethylamine add in the reaction flask, stir cooling, the 0.45g Piperazine anhydrous is dissolved in the 25ml tetrahydrofuran (THF), slowly is added drop-wise in the reaction flask, drip and finish, rise to room temperature, reaction is spent the night, and filters, filtrate concentrate 2-(4-sulfydryl phenyl)-6-formyl piperazine base-3,5-diketone-2H-[1,2,4]-and triazine 1.34g, yield 80.0%.
With 1.33g 2-(4-sulfydryl phenyl)-6-formyl piperazine base-3,5-diketone-2H-[1,2,4]-and triazine, 0.55g Anhydrous potassium carbonate and 100ml DMSO add in the reaction flask, are warming up to 80 ℃ of reaction 30min under stirring, cooling slightly adds to 0.58g santochlor and the mixed drop of 20ml DMSO in the reaction flask, is warming up to 150 ℃ of reaction 10h, cooling changes it in beaker over to, adds water 200ml, dilute hydrochloric acid is transferred pH=6, filters washing, dry off-white powder product 1.1g, the yield 62.0% of getting.
Embodiment 10
2-[4-(2 '-thiophene oxy) phenyl]-4-methyl-[1,2,4]-triazine-3, and 5-(2H, 4H)-diketone synthetic
With 0.57g 2-[4-(2 '-thiophene oxy) phenyl]-[1,2,4]-triazine-3,5-(2H, 4H)-diketone, 0.08g sodium hydride and 10ml dimethyl sulfoxide (DMSO) join in the reaction flask, stirring at room 0.5h drips the mixing solutions of 0.42g methyl iodide and 3ml dimethyl sulfoxide (DMSO), drips to finish to be warming up to 100 ℃, reaction 3h, reaction finishes, and reduces to room temperature, add the about 10ml of water under stirring, filter, washing, dry product 0.49g, the yield 81.6% of getting.
Claims (3)
1, a kind of compound in triazine class with coccidiostat activity is characterized in that: the compound of formula (I) and their formed salt at pharmaceutically acceptable acid or alkali;
Wherein:
A represents oxygen or sulphur;
R
1, R
2Represent hydrogen, halogen atom, alkyl, cycloalkyl, alkoxyl group, nitro, trifluoromethyl, trichloromethyl, COR
5, cycloalkyl, one or more groups of heterocyclic, R
1, R
2Identical or different;
R
3Represent hydrogen atom, alkyl or cycloalkyl;
R
4Represent hydrogen atom, CO
2R
5, CONHR
6Or nitrogen heterocyclic ring group:
Wherein: CO
2R
5In R
5Represent 3-trifluoromethyl, 3,5-bis trifluoromethyl phenyl, trifluoromethyl, trichloromethyl, trisbromomethyl, CHCl
2, CHBr
2, OR
6Or SR
6
CONHR
6In R
6Represent hydrogen atom, alkyl or cycloalkyl;
-" halogen atom " is defined as fluorine, chlorine, bromine, iodine;
-" alkyl " is defined as C
1-C
6The saturated group of straight or branched;
The end that-" alkoxyl group " is defined as oxygen is connected with the group of alkyl;
-" cycloalkyl " is defined as C
3-C
6Cyclic group;
-" heterocycle " is defined as saturated or undersaturated single or bicyclic groups, have aromatics or non-aromatic character, have 5-12 annular atoms, contain 1-3 identical or different heteroatoms, heteroatoms is selected from oxygen, nitrogen, p and s, heterocycle is randomly replaced by one or more identical or different substituting groups, and substituting group is selected from halogen, hydroxyl, alkyl, alkoxyl group or nitro; In heterocycle, the group that can relate to is: pyridyl, thienyl, thiazolyl, furyl, imidazolyl, pyrazinyl, pyrimidyl, tetrazyl, pyrazolyl, quinolyl, isoquinolyl, quinazolyl, pyrrolidyl, piperazinyl, dioxygen ethylene imine Ji, oxazolyl, isoxazolyl, purine radicals, different purine radicals;
The salt of described pharmaceutically acceptable acid is meant salt crystal water or that do not contain crystal water that contains of hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid, carbonic acid, formic acid, acetate, propionic acid, Succinic Acid, citric acid, lactic acid, fumaric acid, tartrate or gluconic acid formation;
The salt of described pharmaceutically acceptable alkali is meant salt crystal water or that do not contain crystal water that contains of sodium hydroxide, potassium hydroxide, triethylamine or TERTIARY BUTYL AMINE formation.
2, compound according to claim 1 is characterized in that the phenyl ring in the described formula (I) also is aromaticity or non-aromaticity heterocycle that replace or non-replacement.
3, the preparation method of a kind of formula (I) compound is characterized in that using the compound of formula (II) and the compound of formula (III) to be raw material:
Formula (II) formula (III)
R wherein
1, R
2Be as defined above, X is a halogen atom;
Add the closed loop agent in formula (III) compound, obtain crucial intermediate formula (IV) compound through diazonium coupling, cyclization, hydrolysis, decarboxylic reaction:
Wherein A, R
1, R
2, R
3, R
4Be as defined above;
According to the reaction conditions of the ullmann reaction in the organic synthesis, make the reaction of formula (IV) compound and formula (II) compound obtain the formula V compound:
Wherein A, R
1, R
2, R
4Be as defined above, R
3=H;
Formula V compound and haloalkane effect obtain formula (I) compound:
Wherein A, R
1, R
2, R
3, R
4Be as defined above.
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