CN101469001A - 6H-thiochromeno[4,3-d] [1,2,4] triazole [4,3-a] pyridine compound with antiphlogistic activity and antifungal activity - Google Patents
6H-thiochromeno[4,3-d] [1,2,4] triazole [4,3-a] pyridine compound with antiphlogistic activity and antifungal activity Download PDFInfo
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- CN101469001A CN101469001A CNA2007103015780A CN200710301578A CN101469001A CN 101469001 A CN101469001 A CN 101469001A CN A2007103015780 A CNA2007103015780 A CN A2007103015780A CN 200710301578 A CN200710301578 A CN 200710301578A CN 101469001 A CN101469001 A CN 101469001A
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Abstract
The invention discloses new nitrogen sulfur containing combined tetracycle heterocyclic compounds with anti-inflammatory and antifungal activity, namely a 6H-tetrahydrothiochromeno[4,3-d][1,2,4] triazolo [4,3-a] pyrimidine compounds. Aiming at the R&D status quo of few antifungal medicines and high toxicity in the prior art, the invention carries out the design and synthesis of the new 6H-tetrahydrothiochromeno[4,3-d][1,2,4] triazolo [4,3-a] pyrimidine compounds and carries out antifungal experiments. The experimental results show that the compounds have good antifungal activities. The compounds have a simple synthesis method, and easily obtained raw materials. The synthesis method is shown in an instructional book. The products can be used for anti-inflammatory and antifungal medicines.
Description
Technical field
Patent of the present invention relates to the heterogeneous ring compound of nitrogenous sulphur, particularly relates to also also [4,3-a] pyrimidine serial anti-inflammatory, antimycotic synthetic drugs of [4,3-d] [1,2,4] triazole of a kind of 6H-thiochromene.
Background technology
Fungi is the eucaryotic organism that a kind of and host cell have analog structure and physiological metabolism process, according to fungus-caused infection site difference, is divided into that the superficial part bacterium infects and the infection of deep bacterium.Mycotic infection of superficial part mainly is to be caused by various tinea bacterium, as tinea manus and pedis, favus of the scalp, ringworm of the body etc., at present often with grey mold rhzomorph, nystatin, KETOKONAZOL etc. as medicine.Deep fungal infection harm is big; even crisis life; it is mainly caused by pathomycete; it comprises Candida albicans, Cryptococcus neoformans, aspergillus tubigensis, mucormycosis etc.; these fungies belong to flora member in the normal body; do not cause disease under the normal circumstances, still, long-term a large amount of Broad spectrum antibiotics, hormone and immunosuppressor etc. used can cause morbidity.In recent years, the sickness rate of deep fungal infection has the trend that rises year by year.
Because the biological nature of fungi, general antifungal drug often destroying the fungal cell simultaneously, can damage host cell again, adds the continuous appearance of Resistant strain, makes the fungi infestation treatment of diseases sink into the border of facing a difficult choice.So far, can be applicable to clinical good effect, toxic side effect little, safety coefficient (safety Index, LD
5/ ED
95) high medicine is very few.Amphotericin B and triazole species fluconazole class medicine are also big limited in application facet because of its toxic side effect.Therefore, develop and seek a kind of high-efficiency low-toxicity, have the wide spectrum of treatment prevention double effects and the new compound of narrow spectrum anti-mycotic activity, become when last significant research work.
Summary of the invention
The objective of the invention is to remedy above-mentioned weak point of the prior art, and also [4,3-d] [1,2,4] triazole antimycotic synthetic drugs of [4,3-a] pyrimidine serial also of simple, the effective 6H-thiochromene of synthetic method is provided.
Target compound of the present invention can reach by following measure: anti-inflammatory, antimycotic 6H-thiochromene be [4,3-d] [1,2,4] triazole [4,3-a] pyrimidines also also, it is characterized in that representing compound with general formula (I), (II):
Wherein:
Work as R
1, R
2, R
3In when having one or two to be H, two other or one are respectively:
R
1=X (halogenic substituent) ,-OH ,-OMe ,-OEt ,-Me ,-Et ,-NMe
2,-NEt
2, C
3-C
6Alkyl or substituted hydrocarbon radical
R
2=X (halogenic substituent) ,-OH, Me ,-Et ,-OMe ,-OEt ,-CF
3,-NMe
2,-NEt
2, C
3-C
6Alkyl or substituted hydrocarbon radical
R
3=X (halogenic substituent) ,-OMe ,-OEt ,-Me, Et ,-NMe
2,-NEt
2, C
3-C
6Alkyl or substituted hydrocarbon radical
R
4=H, C
1-C
6Chain alkylene or cyclic hydrocarbon radical, phenyl or substituted-phenyl, hetero-aromatic ring base or replace the hetero-aromatic ring base
R
5＝H、-Me、-Et
Halogenic substituent is meant: fluorine, chlorine, bromine, iodine.
The 6H-thiochromene also [4,3-d] [1,2,4] triazole also the synthetic method of [4,3-a] miazines medicine be thiophenol to be dissolved in the 2M NaOH solution (can add adequate amount of ethanol).In addition β-chloropropionic acid (or its methyl ester, ethyl ester) is dissolved in the Na of calculated amount
2CO
3In the solution, mix ultrasonicly then with above-mentioned solution, refluxed 6～8 hours, eliminate alcohol back suction filtration.Filtrate is used 4M H
2SO
4Acidifying, suction filtration then.The filter cake that washing obtains also is dried, and gets compound i, and compound i is used the vitriol oil (or polyphosphoric acid) condensation again, and separation and purification obtains the crude product of compound i i.Under the room temperature,, add the back and continue reaction 1 hour at the ethanol and the above-mentioned compound i i that obtains of 10% NaOH mixed solution and dripping of aromatic aldehyde (substituted aroma aldehyde).Reaction solution is cooled off suction filtration.The washing filter cake also is dried, and gets compound i ii.In 150～154 ℃ DMF, compound i ii and 3-amino-1,2,4-triazole reacted respectively 2 and 10 hours.In 2 hours reaction system of reaction, add benzene then, separate out solid filtering; Filter cake with benzene and DMF recrystallization, is obtained solid chemical compound I; Add methyl alcohol to 10 hours system of reaction and separate out solid filtering, collect filter cake and obtain solid chemical compound II.
The 6H-thiochromene also [4,3-d] [1,2,4] triazole also the synthetic method of [4,3-a] pyrimidines is as follows:
R
1, R
2, R
3, R
4, R
5Define the same.
The present invention has following advantage compared to existing technology: the 6H-thiochromene also [4,3-d] [1,2,4] triazole also [4,3-a] miazines series compound be the heterogeneous ring compound that contains the nitrogen sulphur atom, have extensive biological activity.It not only has better inhibited activity to common superficial fungal infection, and deep fungal is had good fungicidal activity.Raw material of the present invention is easy to get, synthetic method is simple, yield is higher, has excellent research to be worth and application prospect.
Embodiment
Enumerate embodiment below, associative list A is further specified the present invention.
Embodiment 1 (preparation of compound 3 in the Table A)
The preparation of compound 1 in the Table A (6-fluoro-thiochromanone): 50mmol fluorobenzene thiophenol is dissolved in the 2mol/L NaOH solution (can adds adequate amount of ethanol).In addition 8.2g β-chloropropionic acid (or its methyl ester of 10g) is dissolved in 50mmol Na
2CO
3In the solution, mix with above-mentioned solution then, ultrasonic, backflow 6-8 hour.Most of solvent, suction filtration are removed in underpressure distillation then.Filtrate is used 4mol/L H
2SO
4Suction filtration after 1～2 hour is stirred in acidifying.The washing filter cake is also dry, gets β-(6-fluoro-thiophenyl)-propionic acid, productive rate 65～75%.At room temperature, 13mmol β-(6-fluoro-thiophenyl)-propionic acid is dissolved in the 20ml vitriol oil, places 18h.Then reaction solution ice is separated, filtered, filter cake is with 5～10% NaHCO
3Solution washing is washed till neutrality, suction filtration.Filtration cakes torrefaction gets light yellow solid 6-fluoro-thiochromanone, productive rate 80～85%.
The preparation of compound 2 in the Table A (3-benzylidyne-6-fluoro-thiochromanone): controlled temperature is under 22～30 ℃ of conditions, in 38mmol 10%KOH solution and 7.4ml dehydrated alcohol, stir adding 30mmol6-fluoro-thiochromanone down, add the 30mmol phenyl aldehyde then, reaction 3.5h.After then reaction solution being placed 10h in 0 ℃ of refrigerator, suction filtration, the washing filter cake is to neutral.Filter cake dry light yellow 3-benzylidyne-6-fluoro-thiochromanone, the productive rate 85～92% of getting of ethanol/water recrystallization.
(the 2-fluoro-7-(4-p-methoxy-phenyl)-7 of compound 3 in the Table A, 12-dihydro-6H-thiochromene [4,3-d] [1,2,4] preparation triazole [4,3-a] pyrimidine): in 150～154 ℃ 5ml DMF, 6mmol 3-benzylidyne-6-fluoro-thiochromanone and 7mmol 3-amino 1,2,4-triazole reaction 2h.In reaction solution, add an amount of benzene then, to there being a large amount of solids to separate out suction filtration.Filtration cakes torrefaction with DMF and benzene recrystallization, obtains solid chemical compound 3.
The preparation technology of other compounds of I class is with the preparation technology of compound 3.
Embodiment 2 (preparation of compound 13 in the Table A)
(the 2-fluoro-7-(4-p-methoxy-phenyl)-6H-thiochromene [4,3-d] [1,2 of compound 13 in the Table A, 4] triazole [4,3-a] pyrimidine) preparation method 1:6mmol 3-benzylidyne-6-fluoro-thiochromanone and 7mmol 3-amino 1,2, the 4-triazole is reflux 15h in 5ml DMF.In reaction solution, add an amount of methyl alcohol then, suction filtration, the filtration cakes torrefaction that obtains, promptly compound 13.
(the 2-fluoro-7-(4-p-methoxy-phenyl)-6H-thiochromene [4 of compound 13 in the Table A, 3-d] [1,2,4] triazole [4,3-a] pyrimidine) preparation method 2: controlled temperature is under 45～60 ℃ of conditions, the 2.5mmol bromo-succinimide is added in the methanol suspension of 2mmol compound 3 reflux 2h.Reaction solution is cooled to room temperature, and most of reaction solution is removed in underpressure distillation, to there being a large amount of solids to separate out, adds a small amount of DMF recrystallization, filter, and the filtration cakes torrefaction that obtains, promptly compound 13.
The preparation technology of other compounds of II class is with the preparation technology 1 or the technology 2 of compound 13.
The physicochemical constant of Table A partial synthesis compound
Bacteriostatic test
6H-thiochromene of the present invention also [4,3-d] [1,2,4] triazole also [4,3-a] pyrimidine serial medicine by to 10 belong to, 18 kind of 18 fungal strain, adopts two times of concentration dilution methods to carry out external bacteriostatic experiment, the result is referring to showing B.
Strains tested: Candida albicans (C.albicas), Oidium tropicale (C.tropicalis), saccharomyces cerevisiae (C.cecerisiae), cryptococcus neoformans (C.neoformans), acrothesium floccosum (E.floccosum), trichophyton gypseum (T.gypsoum), trichophyton (T.vubrum), trichophyton (T.tonsurans), microsporon gypseum (M.gypseum), Trichoderma (trichoderum), black-koji mould (A.niger), grayish green aspergillus (A.glaucus), penicillium commune (P.commune), Pei Shi Saksenaea vasiformis bacterium (P.pedrosoi), Cladosporium carrionii bacterium (C.carionii), phialophora compacta (P.comaitum), phialophora verrucosa (P.verrcosa) and Sporothrix schenckii (S.schenekn).
The preparation of bacterium liquid: what will reach full growth moves in the 5ml stroke-physiological saline solution for the examination bacterial classification, smashs the ultrasonic abundant concussion in back to pieces, removes block insoluble substance, mixing, and as original bacteria liquid, adjusting its concentration during test is 10
6Use behind individual cell/ml.
Test compound is the compound 3～13 among the subordinate list B.
Experimental technique: test compound dissolves with an amount of methyl-sulphoxide, again with sterile distilled water dilution, adds death of monks or nuns and crosses in the glucose peptone nutrient agar of 1% (heat) of bacterium, and sample concentration is 200,100,50,25,12.5,6.25,3.12,1.60mg/mL.Inoculation for the examination bacterium after, putting constant temperature oven, to cultivate 5-7 day be minimal inhibitory concentration MIC with the highly diluted concentration of no fungal growth.
From experimental result as can be seen, 6H-thiochromene [4,3-d] [1 also, 2,4] triazole also [4,3-a] pyrimidine fungi is all had in various degree inhibition activity, the anti-mycotic activity of some of them compound is suitable with the reference substance clotrimazole, some in addition be better than the anti-mycotic activity of clotrimazole.
In a word, the medicine that the present invention relates to all is synthesized as raw material with thiophenol, the various chemical reagent of using in the synthetic reaction process all be common and be simple and easy to, the yield of reaction is also more satisfactory.Learn experiment by pharmacological toxicology, show that series compound all has in various degree inhibition activity to fungi.
The compounds of this invention is widely used in antimycotic field, and wide researching value and application prospect are arranged.
Claims (4)
1. the 6H-thiochromene that has anti-inflammatory, an anti-mycotic activity is [4,3-d] [1,2,4] triazole [4,3-a] pyrimidines also also.
2. according to claim 1, the 6H-thiochromene is [4,3-d] [1,2,4] triazole [4,3-a] pyrimidines also also, it is characterized in that representing compound with general formula (I), (II):
Wherein:
Work as R
1, R
2, R
3In when having one or two to be H, two other or one are respectively:
R
1=X (halogenic substituent) ,-OH ,-OMe ,-OEt ,-Me ,-Et ,-NMe
2,-NEt
2, C
3-C
6Alkyl or substituted hydrocarbon radical
R
2=X (halogenic substituent) ,-OH, Me ,-Et ,-OMe ,-OEt ,-CF
3,-NMe
2,-NEt
2, C
3-C
6Alkyl or substituted hydrocarbon radical
R
3=X (halogenic substituent) ,-OMe ,-OEt ,-Me, Et ,-NMe
2,-NEt
2, C
3-C
6Alkyl or substituted hydrocarbon radical
R
4=H, C
1-C
6Chain alkylene or cyclic hydrocarbon radical, phenyl or substituted-phenyl, hetero-aromatic ring base or replace the hetero-aromatic ring base
R
5＝H、-Me、-Et
Halogenic substituent is meant: fluorine, chlorine, bromine, iodine.
3. according to claim 1, the 6H-thiochromene also [4,3-d] [1,2,4] triazole also [4,3-a] pyrimidines be characterised in that have anti-inflammatory, anti-mycotic activity.
4. according to claim 1, the 6H-thiochromene also [4,3-d] [1,2,4] triazole also [4,3-a] pyrimidines can be used for anti-inflammatory, antifungal drug.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007103015780A CN101469001A (en) | 2007-12-25 | 2007-12-25 | 6H-thiochromeno[4,3-d] [1,2,4] triazole [4,3-a] pyridine compound with antiphlogistic activity and antifungal activity |
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|---|---|---|---|
| CNA2007103015780A CN101469001A (en) | 2007-12-25 | 2007-12-25 | 6H-thiochromeno[4,3-d] [1,2,4] triazole [4,3-a] pyridine compound with antiphlogistic activity and antifungal activity |
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|---|---|
| CN101469001A true CN101469001A (en) | 2009-07-01 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408476A (en) * | 2013-08-23 | 2013-11-27 | 河北大学 | Mono-aryl thioether compound as well as preparation method and application thereof |
-
2007
- 2007-12-25 CN CNA2007103015780A patent/CN101469001A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408476A (en) * | 2013-08-23 | 2013-11-27 | 河北大学 | Mono-aryl thioether compound as well as preparation method and application thereof |
| CN103408476B (en) * | 2013-08-23 | 2014-10-15 | 河北大学 | Mono-aryl thioether compound as well as preparation method and application thereof |
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Open date: 20090701 |