CN88100346A - 3-芳基-5-烷硫基-4h-1,2,4,-三唑 - Google Patents
3-芳基-5-烷硫基-4h-1,2,4,-三唑 Download PDFInfo
- Publication number
- CN88100346A CN88100346A CN88100346.8A CN88100346A CN88100346A CN 88100346 A CN88100346 A CN 88100346A CN 88100346 A CN88100346 A CN 88100346A CN 88100346 A CN88100346 A CN 88100346A
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- Prior art keywords
- methyl
- triazole
- phenyl
- mole
- alkyl group
- Prior art date
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- SOGBOGBTIKMGFS-UHFFFAOYSA-N thiophene-2-carbohydrazide Chemical class NNC(=O)C1=CC=CS1 SOGBOGBTIKMGFS-UHFFFAOYSA-N 0.000 description 1
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 1
- 229960000488 tizanidine Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
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Abstract
本发明涉及3-芳基-5-烷硫基-4H-1,2,4-三唑的衍生物,它们的药学性质及其作为肌驰剂,解痉剂,抗惊厥剂,抗惊厥剂和抗焦虑剂的应用。
Description
本申请为1987年1月27日递交的美国专利申请系列号7,063的部分继续申请。
本发明涉及3-芳基-5-烷硫基-4H-1,2,4-三唑衍生物,其中间体及它们的制备方法,涉及它们的药理性质和作为肌驰剂,解痉剂,抗惊厥剂和抗焦虑剂(anxiolytics)的应用。
更具体地说,本发明涉及通式Ⅰ化合物及其药学上可接受的盐作为肌驰剂,解痉剂,抗惊厥剂和抗焦虑剂的应用。
式中
Ar是苯基,萘基或选自噻吩基,吡啶基,吡咯基和N-(C1-6低级烷基)吡咯基的单环杂芳基;
R1是C1-6低级烷基;
R2是氢或C1-6低级烷基;
R是C1-6低级烷基,C1-6烷氧基,羟基,卤素或三氟甲基和n是0,1或2,或者Rn-(Ar)是亚甲基二氧苯基;和m和q各自为0,1或2。
本发明还涉及通式为Ⅱ的新的5-芳基-3-烷基亚磺酰基-4H-1,2,4-三唑:
式中Ar,R1,R2,R,m和n的定义同上。
本发明还涉及通式为Ⅲ的新的5-芳基-3-烷基磺酰基-4H-1,2,4-三唑:
式中Ar,R1,R2,R,m和n的定义同上,条件是(1)Rn-Ar-(CH2)m不为2-乙氧基苯基;(2)当Rn-Ar-(CH2)m为苯基和R1是甲基时,R2是C1-6低级烷基;(3)当Rn-Ar-(CH2)m为4-氯苯基时,R2不为乙基。
在通式Ⅰ,Ⅱ和Ⅲ中,卤素最好是氯或氟,尽管低级烷基包括所有直链和支链烷基,但最好是甲基和乙基。低级烷氧基包括C1-6烷基的醚。当Ar为苯基时,n最好是1,代表R取代在邻,间或对位的单取代苯基。当n是2时,则是在2,3-,2,4-,2,5-,2,6-,3,4-或3,5-位上。最好R1和R2各自代表甲基或乙基。
Ar代表的杂环是2-,3-或4-吡啶基,2-或3-噻吩基,2-吡咯基和N-烷基-3-吡咯基。最好是有或无R取代基的2-噻吩基。这些三唑的盐可以是常规应用的盐酸盐。这些盐通过该技术领域所熟知的标准技术而制成。
当Ar代表萘基时,最好是2-萘基,R基可取代在任一位置,不过,不论是单取代的还是双取代的通式为Ⅰ的萘基化合物,5-,6-,7-或8-位是最合适的:
通式Ⅰ的硫醚可以通过反应方程A表示的类似方法和过程来制备。
反应方程A:
式中R1,R2和Rn-(Ar)-(CH2)m的定义同通式Ⅰ,X是适宜的离去基团。
通式Ⅰ表示的亚砜和砜可以用过酸最好是间-氯过苯甲酸(MCPBA)氧化通式Ⅰa表示的烷基硫醚来制备,如下面反应方程B所示。
反应方程B:
式中R1,R2和Rn-(Ar)-(CH2)m的定义同通式Ⅰ。
R2取代的氨基硫尿通过肼与异硫氰酸酯在适合的溶剂中反应很容易制备。此反应十分迅速并可在0℃和室温之间进行。虽然反应迅速,但反应混合物放置24小时产率不明显减少。可以使用回流条件,但最好不这样。几乎可应用所有溶剂。最好用无水醇(最好是乙醇或甲醇),也可以用二甲基甲酰胺(DMF),CHCl3,CH2Cl2,四氢呋喃(THF)和乙醚。所用的肼和异硫氰酸酯可以买到,也可用由熟悉本领域的人员所熟知的技术来制备。一旦得到该氨基硫尿,就通过在非质子溶剂如吡啶,CHCl3,THF等中与合适的酰氯(Ⅴ)反应转化成相应的芳酰基取代的氨基硫尿(Ⅵ)。尽管可采用升温反应(例如,回流温度),然而,在0℃至室温下,在3至24小时内,酰化作用很容易完成。再有,酰卤(Ⅴ)一般是可以买到的,但也可以由相应的酸来制备。
芳酰基氨基硫尿(Ⅵ)经环代反应得到通式为(Ⅶ)的3-芳基-3H-1,2,4-三唑-5-硫酮。在碱例如碳酸氢钠或氢氧化钠水溶液中,加热化合物(Ⅵ)完成环化反应。也可以应用醇碱,但一般是不大合意的。此反应在大约溶剂的回流温度,最好是约65°-100℃下进行。
通过标准的烷基化方法很容易制备烷基硫醚(1a)。最好是在中度碱存在下,3-芳基-3H-1,2,4-三唑-5-硫酮(Ⅶ)与相应的卤代烷(R1X)或它们的功能等价物反应来制备。适宜的碱是碱金属碳酸盐或碳酸氢盐或者碱金属氢氧化物,最好是K2CO3或NaOH水溶液。烷基化反应最好用碘代烷,不过,任何适宜的离去基(例如,溴化物或-OSO2CF3)都可用来代替碘化物。适宜的溶剂是丙酮,乙醇水溶液,THF,吡啶等等。反应可以在室温至反应混合物的回流温度下进行,一般需要15小时或更长。
3-芳基-4-烷基-5-烷硫基-4H-1,2,4-三唑(Ⅰa)转化成更高氧化态,最好是按已知条件用过酸氧化此烷基硫醚(Ⅰa)来完成。
适宜的氧化剂是H2O2和NaIO4,但最好用间-氯过苯甲酸。为了氧化成通式(Ⅰb)的亚磺酰基衍生物,应用1摩尔当量的过酸;如应用二当量的过酸,会得到通式(Ⅰc)的磺酰基衍生物。氧化反应在温度约为0℃至室温下,对氧化作用不敏感的溶剂中进行。最适合的溶剂是CH2Cl2,CHCl3,乙酸和乙酸乙酯。
以前已经发现,通式(Ⅰa)的硫醚是有用的杀虫剂,杀菌剂和杀真菌剂,但以前还没有指出具有肌肉松驰,解痉、抗惊厥或抗焦虑作用。M.Y.Mhasalkar等(J.Med.Chem,14(3),260-2(1971))已经发现3-(4-氯苯基)-4-乙基-5-甲磺酰基-4H-1,2,4-三唑具有降血糖活性,但是,不论此化合物还是通式(Ⅰc)的其它砜类化合物,以前还没有报告过有肌肉松驰,解痉,抗惊厥或抗焦虑活性。
业已发现,以前知道的通式(Ⅰ)的硫醚和砜,以及通式(Ⅱ)和(Ⅲ)的新的亚砜和砜,具有一般属于肌肉松弛药,解痉药,抗惊厥和抗焦虑药物所呈现的药理效应。这样,本发明的化合物会缓解患者的肌紧张,肌肉痉挛及由此引起的疼痛和惊厥发作和焦虑。
对抗由士的宁引起的伸肌强直发作的化合物,已经显示对人有肌肉松弛、解痉,抗惊厥和抗焦虑活性。这些化合物的活性可以通过R.A.Turner(Screening Methods in Pharmacology,第14章,1965年)的方法证实。10至20只雄性小鼠为一组,在适宜赋形剂中的受试化合物以一个或多个剂量给药,并以赋形剂作对照。于选定的时间,以2.7mg/kg剂量腹腔注射硫酸士的宁水溶液。用这种剂量的士的宁,会使99%的赋形剂处理过的小鼠出现惊厥。在注射士的宁后,15分钟以内不出现强直伸肌症状的认为是有效保护。以氯苯氨丁酸(一种已知的抗痉挛药/肌驰剂)剂量范围12.5至200mg/kg腹腔注射处理小鼠,可以对士的宁诱发的惊厥产生50%以上的拮抗作用,但是,不能100%的保护。Tizanidine(一种已知的肌驰剂,腹腔注射3.1mg/kg时,可产生60%的最大保护,但即使50mg/kg剂量也不会引起更大的效果。安定(一种已知的具有肌驰和抗惊厥活性的抗焦虑剂)的ED50为腹腔注射1.2mg/kg;但要全部抑制士的宁诱发的惊厥需要非常高的剂量。可是,本发明的许多化合物在4倍于此ED50剂量的范围内,可100%解除士的宁诱发的惊厥。在本发明的化合物中,4-甲基-3-苯基-5-乙亚磺酰基-4H-1,2,4-三唑腹腔注射的ED50是8.1mg/kg;4-甲基-3-苯基-5-乙磺酰基-4H-1,2,4-三唑是8.5mg/kg,4-甲基-3-苯基-5-甲磺酰基-4H-1,2,4-三唑是12.8mg/kg;4-甲基-3-(2-氟苯基)-5-乙硫基-4H-1,2,4-三唑是18.6mg/kg。
在使用中,本发明的化合物作用开始较快并持续有较长的活性。最好是用于治疗肌肉痉挛和肌肉紧张。一般,化合物在每天约0.25-25mg/kg剂量水平就可发挥其治疗效果,当然,症状的严重程度,患者的年令和由诊断者决定的其它因素会对适宜每一位患者的正确疗程和剂量设置有影响。活性化合物的肠胃外给药剂量一般等于口服给药剂量。
口服给药时,活性化合物可以配制成固体或液体制剂,如胶囊,丸剂,片剂,锭剂,粉剂,溶液,悬浮液或乳液。固体单位剂型可以是胶囊。这种胶囊可以是普通明胶型,含有例如润滑剂和惰性填充剂如乳糖,蔗糖或玉米淀粉。通式(Ⅰ)的化合物可以用常规片基质如乳糖,蔗糖和玉米淀粉与粘合剂如阿拉伯树胶,玉米淀粉或明胶,崩解剂如马铃薯淀粉或藻酸,润滑剂如硬脂酸或硬脂酸镁一起制成片剂。
为了肠胃外给药,以该化合物在生理学上可接受的稀释剂与药学载体中的溶液或悬浮液注射剂型给药,也可以加或不加表面活性剂,和其它药学上可接受的佐剂。所说的药学载体可以是无菌液体,如水,醇类,油类和其它可接受的有机溶剂。也可以用于这些制剂中的油类有来自石油,动物,植物或合成的油类,例如花生油,豆油和矿物油。一般来说,液体载体最好是水,盐水,右旋糖水溶液,和有关的糖溶液,乙醇,二元醇如丙二醇或聚乙二醇或2-吡咯烷酮,这些溶剂特别用于注射剂。
这些化合物可按贮存注射剂或植入制剂形式给药,这时可按控制释放活性组分的方法配成。活性组分可以压成小丸或小圆柱状并作为贮存注射剂或植入剂进行皮下或肌肉注射。植入剂可以使用惰性物质如生物可降解的聚合物或合成硅酮,例如Silas tic ,Dow-Corning公司制造的一种硅酮橡胶。
事实上,在有药理活性和治疗价值的许多类化合物中,最好是用某些次类化合物和某些特殊化合物,这是由于它们的总的治疗指数及其生化和药理作用状况较好。在这种情况下,最优选的通式(Ⅰ)化合物是这样的化合物,即式中R1和R2是甲基或乙基;R是氯或氟;Rn是一个单氯或单氟取代基,n是0,m是0和Ar是苯基的化合物。特别优选的化合物是:
4-甲基-3-苯基-5-甲磺酰基-4H,-1,2,4三唑,
5-乙亚磺酰基-4-甲基-3-苯基-4H-1,2,4-三唑,
5-乙磺酰基-4-甲基-3-苯基-4H-1,2,4-三唑,
4-甲基-5-甲亚磺酰基-3-苯基-4H-1,2,4三唑,
5-乙硫基-3-(2-氟苯基)-4-甲基-4H-1,2,4-三唑,
3-(2-氟苯基)-4-甲基-5-甲磺酰基-4H-1,2,4-三唑,
3-(2-氟苯基)-4-甲基-5-甲硫基-4H-1,2,4-三唑,
3-(2-氟苯基)-4-甲基-5-甲亚磺酰基-4H-1,2,4-三唑,
3-(4-氟苯基)-4-甲基-5-甲硫基-4H-1,2,4-三唑,
3-(2-氯苯基)-4-甲基-5-甲硫基-4H-1,2,4-三唑,
4-乙基-3-(2-氟苯基)-5-甲硫基-4H-1,2,4-三唑和
5-乙硫基-4-甲基-3-苯基-4H-1,2,4-三唑。
为了进一步阐明本发明化合物的制备,下面给出一些实例,不过,例举的化合物的范围并不限制本发明,只是为了说明通式(Ⅰ)化合物容易制备。必要中间体和溶剂的变换、改进和使用,对于普通化学工作者是显而易见的。
实例1
1-(2-氟苯甲酰基)-4-甲氨基硫脲
在室温下,滴加9.4ml(7.9×10-2mole)2-氟苯甲酰氯到搅拌着的7.9g(7.5×10-2mole)4-甲基氨基硫脲于190mlCHCl3的悬浮液中。在室温下搅拌过夜后,过滤收集沉淀,用乙醇洗两次。抽气干燥,得到11.3g(66%)无色粉末,不必提纯可直接用于下步环化反应。
另一方法:在室温下,滴加11.9ml(1.00×10-1mole)2-氟苯甲酰氯到搅拌着的10.5g(1.00×10-1mole)4-甲基氨基硫脲于250ml吡啶的溶液中。在室温下搅拌过夜后,首先在旋转蒸发器中减压蒸除过量的吡啶,然后,高真空蒸发,得到所需要产物和吡啶盐酸盐的混合物,不必提纯可直接用于下一步的环化反应。
实例2
1-(4-吡啶甲酰基)-4-甲基氨基硫脲
在150ml吡啶中的10.0g(5.62×10-2mole)4-吡啶甲酰氯盐酸盐和5.91g(5.62×10-2mole)4-甲基氨基硫脲。室温。搅拌过夜后,减压蒸出吡啶并用水洗浓缩物。过滤收集不溶的产物,并抽气干燥。
实例3
1-(2-噻吩甲酰基)-4-甲基氨基硫脲
4.75g(3.34×10-2mole)2-噻吩羧酸酰肼和115ml THF的混合物,搅拌并以空气加热枪温热至均态。然后,滴加2.56g(3.51×10-2mole)新蒸的异硫氰酸甲酯和5ml THF的溶液。搅拌约14小时后,过滤收集沉淀,用少量乙醚洗,抽气干燥,得到无色粉末,7.1g(99%)。
实例4
4-甲基-1-(2-萘甲酰基)氨基硫脲
在室温搅拌下,将10.7g(5.61×10-2mole)2-萘甲酰氯加到5.91g(5.62×10-2mole)4-甲基氨基硫脲与150ml吡啶的溶液中。搅拌过夜后,减压蒸出吡啶。用水处理浓缩物,过滤收集不溶的产物并抽气干燥。
实例5
5-(2-氟苯基)-2,4-二氢-4-甲基
-3H-1,2,4-三唑-3-硫酮
1-(2-氟苯甲酰基)-4-甲基氨基硫脲或者11.3g(4.97×102mole)上面的化合物和吡啶盐酸盐的混合物和4.80ml 1摩尔的NaHCO3水溶液(4.80×10-1mole),搅拌下加热至回流。回流过夜后冰浴中冷却反应混合物后,滴加浓盐酸(40ml,4.8×10-1mole),过滤收集所得沉淀,以少量水洗,抽气干燥。得到无色粉末5.0g(48%)。此物质的纯度对于下一步反应已足够,如果需要,可以用乙酸乙酯/己烷重结晶,得到无色针状结晶,m.p137-139℃。
实例6
2,4-二氢-4-甲基-5-(4-吡啶基)
-3H-1,2,4-三唑-3-硫酮
10.4g(4.97×10-2mole)1-(4-吡啶甲酰基)-4-甲基氨基硫脲和480ml 1摩尔的NaHCO3水溶液(4.80×10-1mole)搅拌并加热回流。回流过夜后,冰浴中冷却反应混合物,滴加浓盐酸(40ml,4.8×10-1mole)酸化,过滤收集产物,抽气干燥。
实例7
2,4-二氢-4-甲基-5-(2-噻吩基)
-3H-1,2,4-三唑-3-硫酮
7.1g(3.3×10-2mole)1-(2-噻吩甲酰基)-4-甲基氨基硫脲和330ml 1摩尔的NaHCO3水溶液(3.30×10-1mole)搅拌并加热回流,回流约14小时后,趁热过滤,然后,在冰浴中冷却滤液。滴加浓盐酸(28ml,3.4×10-1mole)酸化,得到无色沉淀,过滤收集沉淀,用少量水洗,抽气干燥。异丙醇重结晶,得到无色片状结晶,5.0g(77%),mp155-157℃。
实例8
2,4-二氢-4-甲基-5-(2-萘基)
-3H-1,2,4-三唑-3-硫酮
12.9g(4.97×10-2mole)4-甲基-1-(2-萘甲酰基)氨基硫脲和480ml 1摩尔的NaHCO3水溶液(4.80×10-1mole)搅拌并加热回流。回流过夜后,冰浴中冷却反应混合物并滴加浓盐酸(40ml,4.8×10-1mole)酸化。过滤收集所得产物,抽气干燥。m.p223-225℃。
实例9
3-(2-氟苯基)-4-甲基-5-甲硫基
-4H-1,2,4-三唑
4.56g(2.18×10-2mole)5-(2-氟苯基)-2,4-二氢-4-甲基-3H-1,2,4-三唑-3-硫酮,3.01g(2.18×10-2mole)K2CO3,1.5ml(2.4×10-2mole)碘甲烷和65ml丙酮的混合物,搅拌并加热至回流。回流过夜后,蒸发溶剂并用水处理浓缩物。用乙酸乙酯萃取水溶液三次。合并萃取液,用饱和NaCl水溶液洗,无水Na2SO4干燥。过滤除去干燥剂,减压蒸发滤液,得到浅黄色油状物,色谱提纯并用球管蒸馏,得到浅黄色油状物,3.55g(73%),bp=190-197℃(0.3mm)。
实例10
4-甲基-5-甲硫基-3-(4-吡啶基)
-4H-1,2,4-三唑
4.19g(2.18×10-2mole)2,4-二氢-4-甲基-5-(4-吡啶基)-3H-1,2,4-三唑-3-硫酮,3.01g(2.18×10-2mole)K2CO3,1.5ml(2.4×10-2mole)碘甲烷和65ml丙酮的混合物,搅拌并加热至回流。回流过夜后,减压蒸出溶剂并用水处理浓缩物。用乙酸乙酯提取此水溶液三次。合并乙酸乙酯提取液,用饱和NaCl水溶液洗,无水Na2SO4干燥。过滤出干燥剂,减压蒸发滤液,得到所需产物。
实例11
3-(2-噻吩基)-4-甲基-5-甲硫基
-4H-1,2,4-三唑
将6.3ml(1.0×10-1mole)碘甲烷与32ml乙醇的溶液,在室温下滴加到搅拌着的12.5g(6.34×10-2mole)2,4-二氢-4-甲基-5-(2-噻吩基)-3H-1,2,4-三唑-3-硫酮和142ml 1摩尔的NaOH水溶液(1.42×10-1mole)的溶液中。搅拌约14小时后,用乙酸乙酯提取反应混合物四次。合并乙酸乙酯提取液,用饱和NaCl水溶液洗,无水Na2SO4干燥。过滤出干燥剂,减压蒸发滤液,经快速色谱(乙酸乙酯)提纯。得到粘性黄色固体。乙酸乙酯重结晶,得到无色结晶,10.5g(78%),mp,83-85℃。
实例12
4-甲基-5-甲硫基-3-(2-萘基)
-4H-1,2,4-三唑
5.26g(2.18×10-2mole)2,4-二氢-4-甲基-5-(2-萘基)-3H-1,2,4-三唑-3-硫酮,3.01g(2.18×10-2mole)K2CO3,1.5ml(2.4×10-2mole)碘甲烷和65ml丙酮的混合物,搅拌下加热至回流。回流过夜后,减压蒸除溶剂,用水处理浓缩物。用乙酸乙酯提取水溶液三次。合并乙酸乙酯提取液,用饱和NaCl水溶液洗,无水Na2SO4干燥。过滤除去干燥剂,减压蒸发滤液,得到所需产物。mp 177-179℃。
实例13
3-(2-氟苯基)-4-甲基-5-甲亚磺酰基
-4H-1,2,4-三唑
在0℃和搅拌下,向5.0g(2.2×10-2mole)3-(2-氟苯基)-4-甲基-5-甲硫基-4H-1,2,4-三唑的125mlCH2Cl2的溶液中分批加入4.83g(2.24×10-2mole),80%活性MCPBA)间氯过苯甲酸。室温下搅拌过夜,用CH2Cl2稀释成均相,然后,用饱和NaHCO3水溶液洗两次,用饱和NaCl水溶液洗一次。用无水Na2SO4干燥后,蒸除CH2Cl2,剩下的油状物,慢慢变成结晶。乙酸乙酯/己烷重结晶,得到无色固体,3.7g(68%),m.p 95-97℃。
实例14
4-甲烷-5-甲亚磺酰基-3-(4-吡啶基)
-4H-1,2,4-三唑
在0℃和搅拌下,向4.54g(2.2×10-2mole)4-甲基-5-甲硫基-3-(4-吡啶基)-4H-1,2,4-三唑于125ml CH2Cl2的溶液中,分批加入4.83g(2.24×10-2mole,80%活性MCPBA)间氯过苯甲酸。搅拌过夜后,用CH2Cl2稀释至均相。然后,用饱和NaHCO3水溶液洗涤,并用饱和NaCl水溶液洗涤。用无水Na2SO4干燥后,减压蒸除CH2Cl2,得到所需产物。
实例15
3-(2-噻吩基)-4-甲基-5-甲亚磺酰基-
-4H-1,2,4-三唑
在0℃和搅拌下,向4.85g(2.29×10-2mole)4-甲基-5-甲硫基-3-(2-噻吩基)-4H-1,2,4-三唑于170ml CH2Cl2的溶液中,分批加入4.95g(2.29×10-2mole)间一氯过苯甲酸。室温下搅拌过夜后,用饱和NaHCO3水溶液洗二次,饱和NaCl水溶液洗一次,并用无水Na2SO4干燥。过滤掉干燥剂,减压蒸发滤液,经快速色谱(40%丙酮/乙酸乙酯)提纯后得到灰白色固体。乙酸乙酯重结晶,得到无色的小片状结晶,2.78g(53%)m.p 105-107℃。
实例16
4-甲基-5-甲亚磺酰基-3-(2-萘基)
-4H-1,2,4-三唑
在0℃和搅拌下,向4.00g(1.57×10-2mole)4-甲基-5-甲硫基-3-(2-萘基)-4H-1,2,4-三唑于110ml CH2Cl2的溶液中,分批加入3.38g(1.57×10-2mole)间一氯过苯甲酸。室温下搅拌过夜后,用200ml CH2Cl2稀释,饱和NaHCO3水溶液洗两次,饱和NaCl水溶液洗一次,无水Na2SO4干燥。过滤掉干燥剂,减压蒸发滤液余下灰白色固体,并经快速色谱(4%CH3OH/CH2Cl2)提纯,甲苯重结晶,得到无色的小片状结晶,2.5g(59%),m.p.224-226℃。
实例17
3-(2-氟苯基)-4-甲基-5-甲磺酰基
-4H-1,2,4-三唑
在0℃和搅拌下,向5.0g(2.2×10-2mole)3-(2-氟苯基)-4-甲基-5-甲硫基-4H-1,2,4-三唑于125mlCH2Cl2的溶液中,分批加入12.1g(5.6×10-2mole,80%活性MCPBA)间一氯过苯甲酸,于室温下搅拌过夜后,用CH2Cl2稀释成均相,然后,用饱和NaHCO3水溶液洗两次,饱和NaCl水溶液洗一次。无水Na2SO4干燥后,减压蒸除CH2Cl2,余下的固体,经色谱提纯,然后乙酸乙酯/己烷重结晶,得到无色无光泽针状结晶,3.6g(63%)m.p 128-130℃。
实例18
4-甲基-5-甲磺酰基-3-(4-吡啶基)
-4H-1,2,4-三唑
在0℃和搅拌下,向4.54g(2.2×10-2mole)4-甲基-5-甲硫基-3-(4-吡啶基)-4H-1,2,4,-三唑于125ml CH2Cl2的溶液中,分批加入9.49g(4.4×10-2mole,80%活性MCPBA)间一氯过苯甲酸。于0℃下搅拌1小时,然后,温热至室温。搅拌过夜后,用CH2Cl2稀释至均相。顺序用饱和NaHCO3水溶液和NaCl水溶液洗涤。无水Na2SO4干燥,减压蒸发CH2Cl2,得到所需产物。
实例19
5(2-噻吩基)-4-甲基-5-甲磺酰基
-4H-1,2,4-三唑
在0℃和搅拌下,向3.00g(1.42×10-2mole)4-甲基-5-甲硫基-3-(2-噻吩基)-4H-1,2,4-三唑于105mlCH2Cl2的溶液中,分批加入6.42g(2.98×10-2mole)间一氯过苯甲酸。在室温下搅拌过夜后,用饱和NaHCO3水溶液洗两次,饱和NaCl水溶液洗一次,无水Na2SO4干燥。过滤掉干燥剂,减压蒸发滤液,余下灰白色固体,经快速色谱(20%乙酸乙酯/二氯甲烷)提纯,乙酸乙酯/己烷重结晶,得到无色固体,3.5g(76%),m.p 157-159℃。
实例20
4-甲基-5-甲磺酰基-3-(2-萘基)-4H-1,2,4-三唑
在0℃和搅拌下,向5.62g(2.20×10-2mole)4-甲基-5-甲硫基-3-(2-萘基)-4H-1,2,4-三唑于125mlCH2Cl2的溶液中,分批加入12.1g(5.6×10-2mole,80%活性MCPBA)间一氯过苯甲酸。于0℃下搅拌反应混合物1小时,然后,温热至室温。搅拌过夜后,用CH2Cl2稀释成均相。顺序用饱和NaHCO3水溶液和饱和NaCl水溶液洗涤。无水Na2SO4干燥后,减压蒸发CH2Cl2,重结晶后得到所需产物,m.p.204-206℃。
变更实例1方法中相应的酰氯,得到的氨基硫脲按照实例5,9,13,17的方法反应,得到下表所列的通式(Ⅰ)化合物。
Rn-(Ar)-(CH2)mq R1R2mp(℃)
苯基 0 CH3CH3134-136
苯基 1 CH3CH3144-146
苯基 2 CH3CH3158-160
苯基 0 C2H5CH394-99
苯基 1 C2H5CH3131-133
苯基 2 C2H5CH3141-143
4-氟苯基 0 CH3H 145-146
4-氟苯基 0 CH3CH3193-195
2-氟苯基 0 CH3C2H5oil
2-氟苯基 0 C2H5CH395-97
2-氟苯基 1 C2H5CH363-67
2-氟苯基 2 C2H5CH3145-147
2-氯苯基 0 CH3CH3oil
4-氯苯基 0 CH3CH3105-107
4-氯苯基 0 CH3C2H5113-115
4-甲氧苯基 0 CH3CH3149-151
4-甲氧苯基 1 CH3CH3168-170
4-甲氧苯基 2 CH3CH3187-189
4-甲苯基 0 CH3CH3140-142
4-甲苯基 1 CH3CH3161-163
4-甲苯基 2 CH3CH3170-172
Claims (8)
2、权利要求1的方法,其中所说的过酸氧化剂是间-氯过苯甲酸。
3、权利要求1的方法,其中Ar是苯基,n是0或1,m是0,R是卤素,R1和R2各自独立地为甲基或乙基。
4、权利要求1的方法,其中的化合物选自4-甲基-3-苯基-5-乙亚磺酰基-4H-1,2,4-三唑和3-(2-噻吩基)-4-甲基-5-甲亚磺酰基-4H-1,2,4-三唑。
5、通式如下化合物或其药学上可接受的盐的制备方法,
式中
Ar是苯基,萘基或选自噻吩基,吡啶基,吡咯基和N-(C1-6烷基)吡咯基的杂环基;
R1是C1-6低级烷基;
R2是氢或C1-6低级烷基;
R是C1-6低级烷基,C1-6烷氧基,羟基,卤素或三氟甲基,和n是0,1或2,或者Rn-(Ar)-是亚甲基二氧苯基,和
m是0,1或2;
条件是(1)Rn-(Ar)-不为2-乙氧基苯基;(2)当Rn-(Ar)-(CH2)m代表苯基和R1代表甲基时,R2是C1-6低级烷基;和(3)当Rn-(Ar)-(CH2)m代表4-氯苯基时,R2不为乙基,该方法包括相应的通式如下的硫醚,该方法包括相应的通式如下的硫醚,
式中Ar,R1,R2,R,m和n的定义同上,与2摩尔当量的过酸氧化剂在对氧化剂不敏感的溶剂中,于0℃至室温下反应。
6、权利要求5的方法,其中所说的过酸氧化剂是间-氯过苯甲酸。
7、权利要求5的方法,其中n是0或1,m是1,R是卤素,R1和R2各自独立地为甲基或乙基。
8、权利要求5的方法,所说的化合物选自4-甲基-3-苯基-5-甲磺酰基-4H-1,2,4-三唑,3-(2-氟苯基)-4-甲基-5-甲磺酰基-4H-1,2,4-三唑,4-甲基-3-苯基-5-乙磺酰基-4H-1,2,4-三唑和3-(2-噻吩基)-4-甲基-5-甲磺酰基-4H-1,2,4-三唑。
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US007,063 | 1987-01-27 | ||
US126,191 | 1987-12-04 | ||
US07/126,191 US4900743A (en) | 1987-01-27 | 1987-12-04 | 3-aryl-5-alkylthio-4H-1,2,4-triazoles |
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US (1) | US4900743A (zh) |
EP (1) | EP0276793B1 (zh) |
JP (1) | JP2537651B2 (zh) |
KR (1) | KR960007166B1 (zh) |
CN (1) | CN1023480C (zh) |
AR (1) | AR244682A1 (zh) |
AU (1) | AU601013B2 (zh) |
CA (1) | CA1312605C (zh) |
DE (1) | DE3881712T2 (zh) |
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HU (1) | HU205747B (zh) |
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CN1736381B (zh) * | 2005-08-11 | 2010-09-08 | 沈阳药科大学 | 吗啉甲基萘满酮用于制备平滑肌解痉剂的用途 |
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WO1989006125A1 (en) * | 1987-12-31 | 1989-07-13 | Smithkline Beckman Corporation | 4-aralkyl-5-substituted-1,2,4-triazole-5-thiols |
AU644500B2 (en) * | 1990-12-20 | 1993-12-09 | Merrell Dow Pharmaceuticals Inc. | 3-aryl-5-alkylthio-4h-1,2,4-triazoles for treatment of hyperreflexia due to spinal trauma |
DE4339412A1 (de) * | 1993-11-18 | 1995-05-24 | Bayer Ag | Verfahren und neue Zwischenprodukte zur Herstellung von Triazolinonen |
AR032653A1 (es) | 2001-02-09 | 2003-11-19 | Telik Inc | Inhibidores heterociclicos del trasportador de glicina 2 composiciones farmaceuticas, uso y metodos. |
KR20110089868A (ko) * | 2008-12-12 | 2011-08-09 | 아스트라제네카 아베 | 4-[4-메틸-5-(c1-10알킬티오/c5-10아릴-c1-6알킬티오)-4h-1,2,4-트리아졸-3-일]피리딘을 제조하기 위한 신규 방법 |
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CN1736381B (zh) * | 2005-08-11 | 2010-09-08 | 沈阳药科大学 | 吗啉甲基萘满酮用于制备平滑肌解痉剂的用途 |
Also Published As
Publication number | Publication date |
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FI91526B (fi) | 1994-03-31 |
IL85185A (en) | 1996-03-31 |
FI91526C (fi) | 1994-07-11 |
ES2058144T3 (es) | 1994-11-01 |
FI880282A (fi) | 1988-07-28 |
DK171599B1 (da) | 1997-02-17 |
DK35488A (da) | 1988-07-28 |
PT86623A (pt) | 1988-02-01 |
IL85185A0 (en) | 1988-07-31 |
PH24513A (en) | 1990-07-18 |
IE61188B1 (en) | 1994-10-19 |
HU205747B (en) | 1992-06-29 |
NZ223260A (en) | 1991-07-26 |
KR960007166B1 (ko) | 1996-05-29 |
DE3881712D1 (de) | 1993-07-22 |
JPS63201176A (ja) | 1988-08-19 |
NO166642B (no) | 1991-05-13 |
HUT47257A (en) | 1989-02-28 |
AU601013B2 (en) | 1990-08-30 |
AR244682A1 (es) | 1993-11-30 |
AU1072888A (en) | 1988-07-28 |
CN1023480C (zh) | 1994-01-12 |
PT86623B (pt) | 1993-01-29 |
US4900743A (en) | 1990-02-13 |
FI880282A0 (fi) | 1988-01-22 |
KR880008999A (ko) | 1988-09-13 |
JP2537651B2 (ja) | 1996-09-25 |
EP0276793B1 (en) | 1993-06-16 |
DE3881712T2 (de) | 1993-12-23 |
CA1312605C (en) | 1993-01-12 |
EP0276793A3 (en) | 1988-09-21 |
EP0276793A2 (en) | 1988-08-03 |
NO880337L (no) | 1988-07-28 |
NO880337D0 (no) | 1988-01-26 |
DK35488D0 (da) | 1988-01-26 |
NO166642C (no) | 1991-08-21 |
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