CN107151242A - 一种2-氮唑硫色酮类化合物及其合成方法和在制备抗真菌药物中的应用 - Google Patents
一种2-氮唑硫色酮类化合物及其合成方法和在制备抗真菌药物中的应用 Download PDFInfo
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- CN107151242A CN107151242A CN201610119072.7A CN201610119072A CN107151242A CN 107151242 A CN107151242 A CN 107151242A CN 201610119072 A CN201610119072 A CN 201610119072A CN 107151242 A CN107151242 A CN 107151242A
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- Prior art keywords
- oxyl
- alkyl
- formula
- phenoxy group
- hydrogen
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Links
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- 239000003429 antifungal agent Substances 0.000 title abstract description 11
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- 238000006467 substitution reaction Methods 0.000 claims abstract description 32
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- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 24
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 22
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 21
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
- A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
本发明涉及一种2-氮唑硫色酮类化合物(式I)具有如下结构,其中R1是被氢或C1-C3烷基取代的五元氮唑环;R2为羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基;R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基。本发明的化合物具有制备抗真菌药物用途,对常见致病真菌以及深部真菌感染都具有较强的抑菌活性,并且毒性低,稳定性好、抗真菌谱广。
Description
技术领域
本发明涉及一种抗真菌的2-氮唑硫色酮类化合物,这种化合物的合成方法及其在制备抗真菌药物中的应用。
背景技术
真菌在自然界大量存在,很多真菌可引起动植物的多种病害,不仅危害动植物的生长,更主要的是影响人类健康,威胁人类生命安全。
近年来,由于免疫受损人群,包括恶性肿瘤、恶性血液病、艾滋病、SARS、糖尿病、严重烧伤等发病快速增多,以及广谱抗生素和免疫抑制剂的广泛使用,导管、插管和器官移植等新技术的开展,使机会性深部脏器的真菌感染发病率越来越高,也越来越严重。资料显示,上述人群中深部真菌感染发生率约为11%~40%,病死率为40%。据文献报道,通过对上世纪80年代至90年代医院内细菌和真菌感染导致败血症的统计结果分析显示,其中真菌感染导致败血症的发病率明显渐增,并且真菌性败血症的病死率最高,高达71.43%。通过对149例真菌感染的分析显示,真菌感染呈逐年上升趋势。因此,抗真菌药物的研究和开发越来越受到重视。
而现在临床上应用的抗真菌药物按结构可以分为抗真菌抗生素、唑类抗真菌药及其他抗真菌药。抗真菌抗生素,主要为多烯类抗生素,是作用于真菌膜上麦角甾醇的药物,近年来虽然各国报道的新抗真菌抗生素种类繁多,但是其中有一部分抗生素专抗植物真菌,而大多数抗动物真菌的抗生素抗真菌谱过窄,或体内活性微弱,或细胞毒性较强等,具有开发前景者不多。唑类抗真菌药为麦角甾醇生物合成抑制剂,是临床上应用最广泛的药物,包括咪唑和三氮唑类,现有的唑类抗真菌药物一般都有相对较宽的抗真菌谱,但是每个药物之间仍有差异,同时也存在一定的毒副作用和耐药性。而其他抗真菌药物也同样伴随这抗真菌广谱窄,一定抗药性和毒性等问题。
色酮类化合物是一类广泛存在且具有生物活性的物质,早在十九世纪末,人们便已经从广泛分布于地中海东部国家的伞形科阿米芹的果实中提取出了Khellin,并被作为第一个色酮类药物临床应用。活性研究表明,无论是天然存在的还是合成得到的色酮类化合物,具有抗过敏、抗菌、抗癌、抗病毒、降血压血脂等广泛生理活性,尤其作为抗真菌药物,目前研究较为活跃,已成为抗真菌药物研发的热点之一。而硫色酮结构在药物合成中是一种重要的结构基序,比相应的色酮,其表现出较高的生物活性。硫色酮类化合物主要通过合成的方式获得,它相对于色酮的生理活性都有较大的增强,更是在抗真菌药物研究领域有着广泛的研究。
发明内容
本发明的目的是提供一种硫色酮类抗真菌化合物,该化合物对常见治病真菌以及深部真菌感染都具有较强的抑菌活性,而且具有毒性低,稳定性好、抗真菌谱广,安全性好等特点。本发明还提高该硫色酮类抗真菌化合物的制备方法及其在制备治疗系统性真菌感染的药物中的应用。
一种2-氮唑硫色酮类化合物,化学结构如式(I)
式(I)中,R1选自如式(II)五元氮唑环中的一种:
其中:J、K、L分别独立地选自氢、C1-C3的烃基;
R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基。
本发明2-氮唑硫色酮类化合物合成方法,按下步骤:
用化合物(V)与CS2在碱性化合物作用下缩合、环合形成2-巯基硫色酮衍生物的盐即化合物(VI),然后与碘乙烷或溴乙烷反应得式(IIIa)化合物。所述的碱性化合物选自氢氧化钠、氢氧化钾、碳酸钾、碳酸铯或三乙胺。其反应式如下:
其中:R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基;
M表示无机盐金属离子;
X表示F或Cl。
将式(IIIa)化合物溶于有机溶剂中,在1-1.3当量的氧化剂存在下进行氧化反应而得式(IIIb)化合物。所述有机溶剂选自乙腈、乙酸、二氯甲烷、二氯乙烷中的至少一种;所述氧化剂选自二氧化锰、过氧化氢、过氧苯甲酸、间氯过氧苯甲酸、单过氧邻苯二甲酸镁或过氧乙酸。其反应式如下:
其中:R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基。
将式(IIIa)化合物溶于有机溶剂中,在2-3当量的氧化剂存在下进行氧化反应而得式(IIIc)化合物。所述有机溶剂选自乙腈、乙酸、二氯甲烷、二氯乙烷中的至少一种;所述氧化剂选自二氧化锰、过氧化氢、过氧苯甲酸、间氯过氧苯甲酸、单过氧邻苯二甲酸镁或过氧乙酸。其反应式如下:
其中:R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基。
以式(III)化合物为原料,在有机溶剂中,在碱性化合物存在条件下,与式(IV)化合物反应而得2-氮唑硫色酮类化合物。所述的有机溶剂选自N,N-二甲基甲酰胺、二甲亚砜、二氧六环、乙腈、四氢呋喃、丙酮、乙酸乙酯中的至少一种;所述的碱性化合物选自氢化钠、氢化钾、碳酸钟或碳酸铯。所述式(III)化合物结构如下:
所述式(IV)化合物选自以下结构化合物中的一种,
其中:Z选自硫(S)、亚硫酰基磺酰基
J、K、L分别独立地选自氢、C1-C3的烃基;
R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基。
本发明式(I)化合物还包括其在药物制剂学上所容许的盐。
本发明提供所述2-氮唑硫色酮类化合物在制备治疗真菌感染疾病的人用药物或动物用药物中的应用。
所述药物中除含有活性成分2-氮唑硫色酮类化合物外,还含有与药物上可接受的载体、助剂和/或稀释剂,组成组合物。
所述药物的剂型是溶液、霜剂、栓剂、膏剂或溶液剂。
本发明还提供所述2-氮唑硫色酮类化合物作为农业和园艺杀菌剂的应用。
所述杀菌剂中除含有活性成分2-氮唑硫色酮类化合物外,还含有与药物上可接受的载体、助剂和/或稀释剂,组成组合物。
通过测定最低抑菌浓度MIC(即化合物能抑制试验微生物生长的浓度),对本发明2-氮唑硫色酮类化合物的抗真菌活性进行了体外评价。试验证实,本发明2-氮唑硫色酮类化合物具有广谱抗真菌活性,在人体及动物(特别是哺乳动物)体内具有药理学活性,可与普通化疗可接受的稀释剂或载体相混合,或用其他的赋形剂,制成溶液、霜剂、栓剂、软膏、溶液等剂型,以药物的形式进行局部涂抹使用,对于真菌感染病具有明显的疗效。除了用于制备抗真菌的人用或动物用抗真菌药物外,本发明2-氮唑硫色酮类化合物还可以用于农业和园艺的植物杀菌剂,对各种植物病原体疾病如稻瘟病、大麦和小麦的粉霉病及其他各种寄主植物(如黄瓜、苹果、葡萄)的粉霉病、小麦的锈病、燕麦的冠锈和其他各种寄主的锈病,西红柿的晚疫病及其他寄主植物的病原性腐烂等的防治非常有效。
具体实施方式
下面通过实施例对本发明的上述内容进一步进行详细说明。需要说明的是,本发明的范围不受实施例限制,而以权利要求为准。
实施例1,式III1的合成制备反应式如下:
按下步骤制备:
单口烧瓶中加入2,4-二氯-5氟苯甲酰乙酸甲酯22.4mmol,DMSO 30mL、NaOH 45mmol,搅拌下升温至40℃,在此温度下滴加CS2 26.3mmol的5mL DMSO的溶液。滴毕,控温40℃搅拌反应。反应毕,冷却至室温,滴加碘乙烷26.3mmol的10mL DMSO溶液,滴毕,室温反应至反应毕,将反应液搅拌下倒入50mL冰水中,有大量固体析出,过滤收集固体,乙醇中重结晶,得式(III1)产物2-乙硫基-6-氟-7氯硫色酮-3-甲酸甲酯16.8mmol,收率75%。
1HNMR(DMSO-d6):1.36(t,3H),3.16(q,2H),4.81(s,3H),8.22(d,1H),8.55(d,1H)。
实施例2-实施例20:式(III)硫色酮类化合物的制备
以(IV)化合物为原料,制备产物式(III)化合物(目标产物为表1中的式(III2)~(III15)各化合物),制备步骤同实施例1,反应式如下:
实施例2~实施例15中,产物式(III)硫色酮类化合物各基团选择及制备用试剂和检测数据均列于表1。
表1
实施例16:式III16的合成制备反应式如下:
按下面步骤制备:
向100mL单口烧瓶中,依次加入2-乙硫基-6-氟-7氯硫色酮-3-甲酸甲酯10mmol,乙酸20mL,加热至65℃,滴加30%的H2O2 12mmol搅拌反应6小时,加入亚硫酸钠萃灭,减压蒸馏除去溶剂乙酸,然后50mL二氯甲烷和50mL水萃取,取二氯甲烷层,用水洗涤两次(50mL×2),回收有机层,减压蒸馏得式(III16)产物2-乙亚硫酰基-6-氟-7氯硫色酮-3-甲酸甲酯9.5mmol,收率95%。
1HNMR(DMSO-d6):1.28(t,3H),3.06-3.18(m,1H),3.31-3.43(m,1H),3.87(s,3H),8.16(d,1H),8.60(d,1H)。
实施例17:式III17的合成制备反应式如下
按下面步骤制备:
向100mL单口烧瓶中,依次加入2-乙硫基-6-氟-7氯硫色酮-3-甲酸甲酯10mmol,二氯甲烷20mL,加热至回流,滴加间氯过氧苯乙酸mCPBA 22mmol,搅拌反应毕,加入亚硫酸钠萃灭,减压蒸馏除去溶剂乙酸,然后50mL二氯甲烷和50mL水萃取,取二氯甲烷层,用水洗涤两次(50mL×2),回收有机层,减压蒸馏得式(III17)产物2-乙磺基-6-氟-7氯硫色酮-3-甲酸甲酯9.7mmol,收率97%。
1HNMR(DMSO-d6):1.38(t,3H),3.20(q,2H),4.83(s,3H),7.54(d,1H),8.15(d,1H)。
实施例18~实施例31:式(III)硫色酮类化合物的制备
分别以(III2-III15)化合物为原料,制备产物式(III18-III31)化合物(目标产物为表1中的式(III18)~(III31)各化合物),制备步骤同实施例16或17,反应式如下:
实施例18~实施例31中,产物式(III18-III31)硫色酮类化合物各基团选择及制备用试剂和检测数据均列于表2。
表2
实施例32:式(I1)的合成制备反应如下:
按下面步骤制备:
向100mL单口烧瓶中,依次加入2-乙硫基-6-氟-7-氯硫色酮-3-甲酸甲酯1mmol,NaH2.5mmol和5mL的DMF,然后称取1.5mmol的咪唑溶于2-3mL的DMF中,室温下缓慢滴加,搅拌反应。待反应毕,用20mL二氯甲烷和20mL水萃取,取二氯甲烷层,用水洗涤两次(20mL×2),回收有机层减压蒸馏,得式(I1)产物2-(1H-咪唑-1-基)-6-氟-7-氯硫色酮-3-甲酸甲酯0.51mmol,收率51%。
1HNMR(DMSO-d6):3.71(s,3H),7.28(s,1H),7.62(s,1H),8.16(s,1H),8.23(d,1H),8.58(d,1H)。
实施例33:式(I2)的合成制备反应如下:
按下面步骤制备:
向100mL单口烧瓶中,依次加入2-乙亚硫酰基-6-氟-7-氯硫色酮-3-甲酸甲酯1mmol,NaH2.5mmol和5mL的DMF,然后称取1.5mmol的1H-1,2,4-三唑溶于2-3mL的DMF中,室温下缓慢滴加,搅拌反应。待反应毕,用20mL二氯甲烷和20mL水萃取,取二氯甲烷层,用水洗涤两次(20mL×2),回收有机层减压蒸馏,得式(I2)产物2-(1H-1,2,4-三唑-1-基)-6-氟-7-氯硫色酮-3-甲酸甲酯0.62mmol,收率62%。
1HNMR(DMSO-d6):3.7(s,3H),8.22(d,1H),8.49(s,1H),8.58(d,1H),9.12(s,1H)。
实施例34:式(I3)的合成制备反应如下:
按下面步骤制备:
向100mL单口烧瓶中,依次加入2-乙磺酰基-6-氟-7-氯硫色酮-3-甲酸甲酯1mmol,碳酸钾2.5mmol和5mL的乙腈,然后称取1.5mmol的1H-1,2,3-三唑溶于2-3mL的乙腈中,缓慢滴加,搅拌反应,HPLC跟踪反应。待反应结束后,用20mL二氯甲烷和20mL水萃取,取二氯甲烷层,用水洗涤两次(20mL×2),回收有机层减压蒸馏,得式(I3)产物2-(1H-1,2,3-三唑-1-基)-6-氟-7-氯硫色酮-3-甲酸甲酯0.85mmol,收率85%。
1HNMR(DMSO-d6):3.85(s,3H),8.15(d,1H),8.44(s,2H),8.55(d,1H)。
实施例35~实施例51:式(I)硫色酮类化合物的制备
分别以(III)化合物为原料,制备产物式(I)化合物(目标产物为表1中的式(I2)~(I20)各化合物),制备步骤同实施例31,32或33,反应式如下:
实施例35~实施例51中,产物式(I)硫色酮类化合物各基团选择及制备用试剂和检测数据均列于表3。
表3
实施例61:体外抗真菌活性实验
1、实验用菌株
近平滑念珠菌、孢子丝菌、啤酒酵母菌曲霉菌、白色念珠菌、光滑念珠菌、热带念珠菌、红色毛癣菌、青霉菌、疣状毛癣菌、紫色毛癣菌、新生隐球菌、克柔氏念珠菌、絮状表皮癣菌、石膏样毛癣菌。
2、试药及材料
试验用材料:
改良马丁培养基、96孔培养板、DMSO
对照药物:氟康唑
3、实验方法
(1)抗菌药液的制备
将受试药物分别用DMSO溶解,配成25.6g/L的溶液,于-20℃以下保存备用。试验前将低温冷藏的受试药液取出,在35℃恒温箱中融化,用RPMI1640稀释10倍,备用。
(2)接种液的制备
哥受试念珠菌株(近平滑念珠菌,白色念珠菌,光滑念珠菌,热带念珠菌)在改良马丁培养基上转种,将其用质量分数为0.85%的无菌盐水制成悬液。用血细胞计数板计数孢子,调整含菌量,使集落形成单位为1×106~5×106CFU/mL。接种时用RPMI-1640培养液将其稀释200倍后,再稀释10倍,CFU值调至0.5×103~6.0×103CFU/mL,备用。
(3)MIC板制备
无菌操作下,在灭菌的96孔聚乙烯板的第1号孔加RPMI-1640培养液100μL,作为空白对照。第2号孔加菌液190μL,第3-12号孔加配置好的菌液100μL。然后在2号孔中加入10μL受试药液,按10级倍比稀释2-11号孔的浓度,使各孔的最终浓度为128,64,32,16,8,4,2,1,0.5,0.25mg/L,第12号孔不加受试药液作为生长对照。各MIC板密闭后置于35℃普通空气孵箱中,孵育满24h判断结果。
(4)结果判断
用酶标分析仪于620nm测各孔的OD值,以OD值下降80%以上的最低浓度作为MIC值。当MIC值高于128mg/L时计为>128mg/L;当MIC值低于0.25mg/L时计为≤0.25mg/L。
(5)重复观察与统计
上述试验需要至少重复三次,当出现MIC值单一跳孔时,则记录为最大的抑制细菌浓度,当MIC值出现两个或两个以上跳孔时,则重新进行试验。
4、抗真菌敏感性试验结果
通过初步的MIC测定发现,受试化合物具有广谱抗真菌活性,其中实施例(32)~实施例(51)的硫色满类化合物抑制真菌活性更为显著,对以上受试菌株的MIC值均小于10mg/L。
Claims (10)
1.一种如式(I)的2-氮唑硫色酮类化合物,其化学结构如下:
R1选自如式(II)五元氮唑环中的一种:
其中:J、K、L分别独立地选自氢、C1-C3的烃基;
式(I)中的R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
式(I)中的R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
式(I)中的R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基。
2.一种权利要求1所述的2-氮唑硫色酮类化合物的合成方法,其特征是以式(III)化合物为原料,在有机溶剂中,在碱性化合物存在条件下,与式(IV)化合物反应而得2-氮唑硫色酮类化合物。所述的有机溶剂选自N,N-二甲基甲酰胺、二甲亚砜、二氧六环、乙腈、四氢呋喃、丙酮、乙酸乙酯中的至少一种;所述的碱性化合物选自氢化钠、氢化钾、碳酸钾或碳酸铯。所述式(III)化合物结构如下:
所述式(IV)化合物选自以下结构化合物中的一种:
其中:Z选自硫(S)、亚硫酰基磺酰基
J、K、L分别独立地选自氢、C1-C3的烃基;
R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基。
3.根据权利要求2所述的式(III)结构化合物,当Z为硫时(结构为式IIIa),其合成方法为:用化合物(V)与CS2在碱性化合物作用下缩合、环合形成2-巯基硫色酮衍生物的盐,即化合物(VI),然后与碘乙烷或溴乙烷反应得式(IIIa)化合物。所述的碱性化合物选自氢氧化钠、氢氧化钾、碳酸钾、碳酸铯或三乙胺。其反应式如下:
其中:R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基;
M表示无机盐金属离子;
X表示F或Cl。
4.根据权利要求2所述的式(III)结构化合物,当Z为亚硫酰基时(结构为式IIIb),其合成方法为:将式(IIIa)化合物溶于有机溶剂中,在1-1.3当量的氧化剂存在下进行氧化反应而得式(IIIb)化合物。所述有机溶剂选自乙腈、乙酸、二氯甲烷、二氯乙烷中的至少一种;所述氧化剂选自二氧化锰、过氧化氢、过氧苯甲酸、间氯过氧苯甲酸、单过氧邻苯二甲酸镁或过氧乙酸。其反应式如下:
其中:R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基。
5.根据权利要求2所述的式(III)结构化合物,当Z为磺酰基时(结构为式IIIc),其合成方法为:将式(IIIa)化合物溶于有机溶剂中,在2-3当量的氧化剂存在下进行氧化反应而得式(IIIc)化合物。所述有机溶剂选自乙腈、乙酸、二氯甲烷、二氯乙烷中的至少一种;所述氧化剂选自二氧化锰、过氧化氢、过氧苯甲酸、间氯过氧苯甲酸、单过氧邻苯二甲酸镁或过氧乙酸。其反应式如下:
其中:R2选自羟基、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯基、被1个或多个C1-C6烃基或烃氧基取代的苯基、苯氧基、被1个或多个C1-C6烃基或烃氧基取代的苯氧基;
R3、R4、R6分别独立地选自氢、氟、氯、溴或碘;
R5选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基。
6.一种权利要求1或2所述的2-氮唑硫色酮类化合物在制备治疗真菌感染疾病的人用或动物用药物中的应用。
7.根据权利要求6所述的应用,其特征是所述药物中除含有活性成分2-氮唑硫色酮类化合物外,还含有药物上可接受的载体、助剂和/或稀释剂,组成组合物。
8.根据权利要求7所述的应用,其特征是所述药物的剂型是溶液、霜剂、栓剂或软膏剂。
9.一种权利要求1或2所述2-氮唑硫色酮类化合物作为农业和园艺杀菌剂的应用。
10.根据权利要求9所述的应用,其特征是所述杀菌剂中除含有活性成分2-氮唑硫色酮类化合物外,还含有药物上可接受的载体、助剂和/或稀释剂,组成组合物。
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