CN1071420A - 4-[4-[4-(4-羟苯基)-1-哌嗪基]苯基]-5-甲基-3h-1，2，4-三唑-3-酮衍生物 - Google Patents
4-[4-[4-(4-羟苯基)-1-哌嗪基]苯基]-5-甲基-3h-1，2，4-三唑-3-酮衍生物 Download PDFInfo
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- CN1071420A CN1071420A CN92110869A CN92110869A CN1071420A CN 1071420 A CN1071420 A CN 1071420A CN 92110869 A CN92110869 A CN 92110869A CN 92110869 A CN92110869 A CN 92110869A CN 1071420 A CN1071420 A CN 1071420A
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- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
2-[2-(4-氯苯基)-2-(羟基或氧代)乙基]-2，4-
二氢-4-[4-[4-(4-羟苯基)-1-哌嗪基]苯基]-5-，甲
基-3H-1，2，4-三唑-3-酮，如通式(I)。
其中X代表C＝O或CHOH，它用作5-脂肪
氧合酶抑制剂。药物组合物，所述化合物及药物组合
物的制备方法以及治疗白三烯引起的疾病的方法。
Description
美国专利US-4，791，111公开了许多4-（4-苯基-1-哌嗪基）酚衍生物，它们作为制备具有抗真菌性能化合物的中间体。随后，上述中间体以及公开在美国专利US-4，267，179和US-4，619，931中的有关衍生物在美国专利US-4，931，444中作为5-脂肪氧合酶抑制剂被披露。目前意外地发现，和具有类似结构的以前公知的化合物相比，用本发明的化合物可以获得优异的血浆浓度。
本发明涉及具有下式的5-脂肪氧合酶抑制化合物2-[2-（4-氯苯基）-2-（羟基或氧代）乙基]-2，4-二氢-4-[4-[4-（4-羟苯基）-1-哌嗪基]苯基]-5-甲基-3H-1，2，4-三唑-3-酮：
及药学上可接受的酸加成盐及它们的对映体，其中X表示C＝O或CHOH。
式（Ⅰ）化合物具有碱性，因此用合适的酸处理可以将它们转化成其有治疗活性的无毒酸加成盐，上述酸例如无机酸如盐酸，氢溴酸等，硫酸，硝酸，磷酸等;或有机酸如乙酸，丙酸，羟基乙酸，2-羟基丙酸，2-氧代丙酸，草酸，丙二酸，丁二酸，（Z）-2-丁烯二酸，（E）-2-丁烯二酸，2-羟基丁二酸，2，3-二羟基丁二酸，2-羟基-1，2，3-丙烷三羧酸，甲磺酸，乙磺酸，苯磺酸，4-甲基苯磺酸，环己烷氨基磺酸，2-羟基苯甲酸，4-氨基-2-羟基苯甲酸等。相反，用碱处理能将其盐的形式转化成游离碱。
上述酸加成盐这一术语也包括式（1）化合物能形成的溶剂化物，所述的溶剂化物属于本发明的范围之内。这些溶剂化物例如水合物，醇合物等。
X代表CHOH的式（1）化合物在其结构中有一个不对称碳原子。上述碳原子的绝对构型可以用立体化学表示符号R和S指出。外消旋体，对映体混合物及上述化合物的纯对映体全部属于本发明的范围之内。
上述“纯对映体”这一术语是指其一种对映体的量超过至少96%直到100%的对映体，特别是超过98%-100%的对映体。
最令人感兴趣的化合物是2-[2-（4-氯苯基）-2-氧代乙基]-2，4-二氢-4-[4-[4-（4-羟基苯基）-1-哌嗪基]苯基]-5-甲基-3H-1，2，4-三唑-3-酮。
制备本发明中通式（1）化合物的方法已经在美国专利US-4，267，179，US-4，619，731，US-4，791，111及US-4，931，444中披露过。
具体地说，通式（1）化合物可以通过适当的脱烷基化反应从通式（Ⅱ）的烷氧基衍生物来制备，例如，上述反应在酸性介质中使用强的无氧化性的酸，例如三氟乙酸来完成，或者特别是无机酸如浓氢卤酸，例如氢溴酸，氢碘酸，优选氢溴酸在冰醋酸中的饱和溶液，路易士酸，例如三溴化硼。
在通式（Ⅱ）中，R1代替烷基，特别是C1-6烷基，优选是甲基。当采用氢溴酸时，在溴的清除剂如亚硫酸钠或亚硫酸存在下进行上述脱烷基化反应是有利的。
其中X代表C＝O的通式（Ⅰ）化合物可按照公知的还原工艺转变成其中X代表CHOH的通式（1）化合物。例如上述还原反应用金属氢化物或络合金属氢化物如硼氢化钠，氰基硼氢化钠等，在水或醇如甲醇，乙醇等介质中能方便地进行。
其中X代表CHOH的化合物通过采用手性固定相如适当衍生的纤维素例如三（二甲基氨基甲酰基）纤维素（ChiralcelOD
）及其它类似的手性固性相的柱色谱技术能很容易地分离为它各自对映体。
式Ⅱ中间体可以通过式（Ⅲ）的胺与式（Ⅳ）的衍生物进行环化得到中间体（Ⅴ）再与烷基化试剂进行N-烷基化来制备。在式（Ⅳ）中，R2代表C1-6烷基例如甲基或乙基，L代表离去基团如C1-6烷氧基或二（C1-6烷基）氨基，例如甲氧基，乙氧基，二甲氨基，在式（Ⅵ）中，卤素代表氯，溴或碘，优选溴。
上述环化反应在适当的溶剂中搅拌并加热上述试剂的混合物能顺利进行。所采用的溶剂是偶极非质子溶剂如N，N-二甲基甲酰胺，N，N-二甲基乙酰胺，1，3-二甲基-2-咪唑啉酮，1-甲基-2-吡咯啉酮，四氢噻吩1，1-二氧化物等。最好将反应混合物在约100℃以上加热，并且进一步升高到约150-160℃是有利的。在反应过程中游离出的醇或胺最好被蒸馏掉。式（Ⅵ）化合物与式（Ⅴ）化合物的N-烷基化反应能通过在适当碱存在下，在合适溶剂中搅拌并加热上述化合物的混合物方便地完成。合适的溶剂例如酮，如丙酮，4-甲基-2-戊酮，偶极非质子溶剂如N，N-二甲基甲酰胺，N，N-二甲基乙酰胺，1，3-二甲基-2-咪唑啉酮等，合适的碱例如碱金属和碱土金属的碳酸盐或碳酸氢盐，例如碳酸钠或碳酸钾，或者有机碱，例如三乙胺等。优选反应在过量约1.5-2.5当量的烷基化剂，约40-120℃温度，最好是约45-65℃条件下进行。
另外，三唑酮衍生物（Ⅴ）还可按US-4，267，179中所述的方法来制备。在上述情况下，式（Ⅲ）的胺和氯甲酸苯酯反应得到相应的氨基甲酸酯，随后再将其用肼处理，然后将所得到的肼基甲酰胺例如用亚氨代乙酰胺环化成式（Ⅴ）中间体。
式（Ⅲ）中间体是公知的（US4，267，179）。其中L代表C1-6烷氧基的式（Ⅳ）中间体可以通过将C1-6烷醇加到乙腈中，然后用C1-6烷基肼基甲酸酯处理所得到的亚胺醚来制备。其中L代表二（C1-6烷基）氨基的式（Ⅳ）中间体可由N，N-二甲基乙酰胺-二（C1-6烷基）乙缩醛和C1-6烷基肼基甲酸酯来制备。
式（Ⅰ）化合物在体外和体内均是5-脂肪氧合酶的有效的并有选择性的抑制剂。抑制5-脂肪氧合酶有效地阻断了从花生四烯酸到白三烯的新陈代谢途径，据了解后者具有潜在的生理活性并认为和各种变应性，过敏性及炎性的反应有关（Science，220，568-575，1983;Science，237，1171-1176，1987;N.Engl.J.Med.，323;645-655，1990;Drugs Future，16，547-558，1991;Pharmac.Ther.，46 57-66，1990）。
白三烯C4，D4和E4（LTC4，LTD4和LTE4）强烈地诱发平滑肌收缩，并且尤其显示有力的支气管收缩性。进一步地，上述白三烯能增加血管的渗透性，导致血管内的流体及蛋白质漏入到组织内而造成水肿。白三烯B4对白细胞是一种潜在的化学增活剂及趋化性剂，在急性和亚急性过敏反应及发炎过程中被认为是一种重要介体（The New England Journal of Medicine，303，822-825，1980;“The Leukotri-enes：Chemistry and Biology”，ed.L.W.Chakrin，D.M.Bailey，Academic Press，Orlando，195-214，1984）。上述白三烯全可从普通的中间体5-过氧化氢基花生四烯酸（5-HPETE）得到，后者从花生四烯酸通过5-脂肪氧合酶的活性形成。其它脂肪氧合酶，例如12-及15-脂肪氧合酶能把花生四烯酸转变成具有相反或协同生理活性的单及双羟基衍生物。另外，还报道了从牛皮癣及特异性皮炎患者的受损伤的皮肤中能释放出过量的5-脂肪氧合酶和12-脂肪氧合酶酶活性的产物（Prostaglandins 29，611-619，1985;J.Invest.Dermatol 83，70-73，1983;Lancet，i，222-223，1984）。
因此认为，调节花生四烯酸的新陈代谢途径的脂肪氧合酶抑制剂，特别是5-脂肪氧合酶抑制剂对于减低白三烯的上述有害作用是一种有效的治疗药物。有关的疾病和/或机能障碍例如包括：支气管哮喘，变态反应（N.Eng.J.Med.323，1736-1739，1990;Lancet，337，690-694，1991;N.Eng.J.Med.323，1740-1744，1990），过敏反应，表皮角化症如鱼鳞癣及牛皮癣（J.Am.Acad.Dermatol.22，751-755，1990;J.Invest.Dermatol.95 50-54，1990），肠炎例如溃疡性结肠炎及节段性回肠炎，以及其它炎性反应如（类风湿）关节炎及皮炎特别是特异性皮炎。由于以目前方法使用的式（1）化合物对于5-脂肪氧合酶是有效和有选择性的抑制剂，这一事实使本发明十分重要。很多被报道的抑制剂缺乏选择性并且伴随抑制其它脂肪氧合酶和/或环氧合酶，后者调节花生四烯酸到前列腺素的新陈代谢。式（1）化合物不明显地抑制大豆15-脂肪氧合酶，人血小板12-脂肪氧合酶，人血小板环氧合酶及血小板A2合成酶。
5-脂肪氧合酶抑制活性用“Beagle狗的血液中A23187诱导的5-脂肪氧合酶活性的抑制“试验（实施例15）来阐明（一个类似的试验记载在J.Pharmacol.Exp.Ther.，256 929-937，1991中）。本发明的另一个重要特点是，如在“鼠耳中葡聚糖诱发的水肿的抑制”试验中所看到的，式（1）化合物具有口服活性。
本发明化合物对于以前公知的化合物的主要优点是我们惊异地发现，用本发明化合物，特别是其中X代表C＝O的化合物可以获得十分高的血浆浓度。
同样有趣的是，我们发现上述化合物主要被代谢为活性代谢产物，即其中X代表CHOH的式（1）化合物。
本发明还涉及通过施用有效的5-脂肪氧合酶抑制量的式（1）化合物或其药学上可接受的酸加成盐，治疗患白三烯引起的疾病和/或机能障碍的温血动物的方法。相关领域中的技术人员从下文所述中能够很容易地确定5-脂肪氧合酶抑制剂的有效量。一般认为，对患者合适的日用药剂量约为0.1mg/kg-50mg/kg体重，优选约1mg/kg-10mg/kg体重。本发明化合物可以配制成适于用药的各种剂型。通常对于系统或局部给药所用的所有组合物均可作为合适的组合物。为了制备本发明的药物组合物，将作为活性组份的有效量的特定化合物以及任意的酸加成盐形式和药学上可接受的载体以紧密混合物的形成相结合。根据用药所需的制剂形式，载体可以采用各种各样的形式。这些药物组合物以单位剂量形式特别适用于口服，直肠给药，皮表给药或非肠道注射。例如，为了制备口服剂形的组合物，可采用任何有用的药物载体，例如，当采用口服液体制剂如悬浮剂，糖浆，酏剂及溶液时，可采用水，二甘醇，油及醇等。当采用粉末、丸剂、胶囊及片剂时，可用固体载体如淀粉，蔗糖，高岭土，润滑剂，粘合剂，崩解剂等。由于易于给药，片剂和胶囊是最好的口服单位剂形。此时，很明显应采用固体的药物载体。为了制备肠外给药的组合物，载体通常包括至少绝大部分的无菌水，虽然也包括例如助溶的其它组份。例如制备注射溶液时，其载体可以是盐水溶液，葡萄糖溶液或它们的溶液混合物。当制备注射用悬浮液时，可使用适当的液体载体，悬浮剂等。还可以制备在使用前可迅速转变成液体形式制剂的固体形式制剂。在制备适用于表皮给药的组合物时，载体选择性地包括增进渗透剂和/或合适的润湿剂，以及对皮肤无有害反应的，少量的任何种类的合适的添加剂。作为局部使用的适合的组合物，通常适于局部给药的所有组合物都可被采用。例如乳脂、冻胶、敷剂、香波、酊剂、糊剂、软膏、油膏及粉剂等。上述组合物能以气雾剂形式使用，例如以氯-二氧化碳，氟利昂为推进剂，或者不要推进剂，例如泵喷洒剂，滴剂，洗剂或者半固态稠的组合物（装在管中使用）。在某些特殊组合物中，半固态组合物如油膏，乳脂，冻胶，软膏等使用起来是十分方便的。
配制成易于给药，剂量均匀的单一剂量形式的药物组合物是十分有好处的。这里所述的单一剂量形式是指作为单位剂量外观能分开的单位，每一单位合有计算出能产生预期治疗效果的预定量的有效成分，它们和所需的药物载体结合在一起。这些单位剂量形式的例子有片剂（包括有刻痕的片剂及包衣的片剂），胶囊，丸剂，粉剂包，糯米纸囊剂，注射溶液或悬浮液等以及它们个别的复合物。
下述实施例用以阐明本发明，但并不限制本发明的范围。
实施例1
a）于温度低于10℃下，往400ml乙醇中鼓入气态盐酸3小时，滴加162ml乙腈（t≤5℃），于0℃搅拌过夜，滤除沉淀，用一些乙醇洗涤，于40℃在氮气保护下，真空干燥，得到251g（65%）亚氨代乙酸乙酯单氢氯化物（中间体1）
b）将330.5g中间体（1）和2500ml乙醇的混合物于室温下搅拌1/2小时，在1 1/2小时内滴加事先温热至±50℃的230g肼基甲酸甲酯的1500ml乙醇溶液，室温搅拌过夜后，过滤反应混合物并蒸发滤液，将残留物溶在500ml二氯甲烷中，溶液用硅藻土过滤并蒸发滤液，得到375.5g（92%）2-（1-乙氧亚乙基）肼基甲酸甲酯（中间体2）。
c）将400g 4-[4-（4-甲氧苯基）-1-哌嗪基]苯胺（按US-4，627，179实施例1所述制备）的1000ml四氢噻吩1，1-二氧化物溶液在100℃下搅拌1小时，再于100℃下用4小时滴加预先预热至60℃的382.8g中间体（2）的200ml四氢噻吩1，1-二氧化物溶液。将混合物于100℃搅拌过夜，在160℃搅拌3小时。冷至50℃后，滤除沉淀，用丙酮洗涤，于氮气保护下于60℃真空干燥，得到290g（56%）2，4-二氢-4-[4-[4-（4-甲氧苯基）-1-哌嗪基]苯基]-5-甲基-3H-1，2，4-三唑-3-酮（中间体3）。
实施例2
a）将5.5g中间体（3）（也可以按US-4267179的实施例ⅩⅢ所述制备），4g 2-溴-1-（4-氯苯基）乙酮，10g碳酸钠-单水化合物及200ml 1，3-二甲基-2-咪唑啉酮的混合物于80℃下搅拌1.5小时。把反应混合物倒入水中，滤除沉淀，用水洗涤并溶在二氯甲烷中。分出有机层，干燥，过滤，蒸发，残留物用柱色谱法提纯（硅胶;CH2Cl2/CH3OH98∶2），将所需组分的洗脱液蒸发，用乙酸乙酯研磨，过滤产物并干燥，得到5.1g（65.6%）2-[2-（4-氯苯基）-2-氧代乙基]-2，4-二氢-4-[4-[4-（4-甲氧苯基）-1-哌嗪基]苯基]-5-甲基-3H-1，2，4-三唑-3-酮。mp.229.5℃（中间体4）。
b）将4.8g中间体（4）在333份二氯甲烷中的溶液滴加到冷至0-5℃的50ml三溴化硼的1M二氯甲烷溶液中，室温搅拌2小时后，用二氯甲烷萃取产品。萃取液用水洗，干燥，过滤并蒸发。残留物用柱色谱法提纯（硅胶;CH2Cl2/CH3OH99∶1→98∶2）。蒸发所需组份的洗脱液，将残余物用乙酸乙酯研磨。将产品过滤干燥得1.4g（30.9%）2-[2-（4-氯苯基）-2-氧代乙基]-2，4-二氢-4-[4-[4-（4-羟苯基）-1-哌嗪基]苯基]-5-甲基-3H-1，2，4-三唑-3-酮。mp.251.7℃（化合物1）
实施例3
将25g中间体（4），350ml48%氢溴酸和200ml乙酸的混合物回流5小时。室温下将反应混合物搅拌过夜并用100ml水稀释。滤除沉淀，用水洗，将其溶在700ml甲醇和100ml水的混合物中，在回流温度下滴加20ml氨。室温下搅拌反应混合物5小时。滤除沉淀，用甲醇洗涤，于氮气保护下于50℃真空干燥，得到20g（82%）2-[2-（4-氯苯基）-2-氧代乙基]-2，4-二氢-4-[4-[4-（4-羟苯基）-1-哌嗪基]苯基]-5-甲基-3H-1，2，4-三唑-3-酮;mp.251.7℃（化合物1）。
实施例4
往55g化合物（1）的1000ml N，N-二甲基甲酰胺的混合物中滴加8.3g硼氢化钠的30ml水混合物。搅拌过夜后，连续加50ml乙酸和1500ml水，放置反应混合物至结晶。过滤产物，用水洗并真空干燥，得到54.1g（94.7%）2-[2-（4-氯苯基）-2-羟乙基]-2，4-二氢-4-[4-[4-（4-羟苯基）-1-哌嗪基]苯基]-5-甲基-3H-1，2，4-三唑-酮单水合物，mp.264.4℃（化合物2）。
实施例5
用柱色谱法（Chiralcel OD
;C2H5OH/2-C3H7OH 80∶20）将4.5g化合物（2）拆分为（+）和（-）两种异构体。将第一组分浓缩至约100ml，滤出形成的沉淀，于80℃真空干燥，得到1.64g（36.4%）（+）-2-[2-（4-氯苯基）-2-羟乙基]-2，4-二氢-4-[4-[4-（4-羟苯基）-1-哌嗪基]苯基]-5-甲基-3H-1，2，4-三唑-3-酮。mp.251.2℃（化合物3）。
第二组分用和第一组分同样的方法处理，得到2.13g（47.3%）（-）-2-[2-（4-氯苯基）-2-羟乙基]-2，4-二氢-4-[4-[4-（4-羟苯基）-1-哌嗪基]苯基]-5-甲基-3H1，2，4-三唑-3-酮。mp.249.2℃（化合物4）
实施例6：口服滴剂
于60-80℃将500g活性成分（A.I）溶解于0.5l 2-羟基丙酸和1.5l聚乙二醇中。冷至30-40℃后，加35l聚乙二醇并充分搅拌混合物，然后加1750g糖精钠的2.5l纯水溶液，搅拌下加2.5l可可香味剂和聚乙二醇足量至50l，制得含10mg/mlA.I.的口服滴剂。将所得溶液装入合适的容器中。
实施例7：口服溶液
将9g 4-羟基苯甲酸甲酯和1g. 4-羟基苯甲酸丙酯溶于4l沸纯水中。在3l上述溶液中，先溶入10g 2，3-二羟基丁二酸，再溶入20g.A.I.。将后者与前面的剩余溶液合并，再加入12l1，2，3-丙三醇和3l70%的山梨醇溶液。将40g糖精钠溶在0.5l水中，加入2ml覆盆子和2ml鹅莓香精，将后一溶液和前一溶液合并，加水足量至体积为20l，得每茶匙（5ml）含5mg活性成分的口服溶液。将所得溶液装进适当容器。
实施例8：胶囊
将20g A.I.，6g十二烷基硫酸钠，56g淀粉，56g乳糖，0.8g胶状二氧化硅和1.2g硬脂酸镁放在一起剧烈搅拌，随后将所得混合物装进1000支合适的硬胶囊中，每支含20mg活性成分。
实施例9：包衣片剂
片芯的制备
将100g A.I.，570g乳糖和200g淀粉充分混合，然后用5g十二烷基硫酸铜和10g聚乙烯吡咯烷酮（Kollidon-K90
）的约200ml水溶液润湿。过筛湿的粉状混合物，干燥，再过筛。然后加100g微晶纤维素（Avicel
）和15g氢化植物油（Sterotex
）。充分混合整个溶液，压片，做得10，000片，每片含10mg活性成分。
包衣
往10g甲基纤维素（Methocel 60HG
）的75ml变性乙醇的溶液中加5g乙基纤维素（Ethocel 22 Cps
）的150ml二氯甲烷溶液。然后加75ml二氯甲烷和2.5ml 1，2，3-丙三醇。将10g聚乙二醇熔化并溶解在75ml二氯甲烷中，再将其加到前一个溶液中。然后加2.5g十八烷羧酸镁，5g聚乙烯吡咯烷酮和30ml浓的着色悬浮液（Opaspray K-1-2109
），并使每个溶液均匀。在包衣装置中用所得混合物给片芯包衣。
实施例10：注射溶液
将1.8g 4-羟基苯甲酸甲酯和0.2g 4-羟基苯甲酸丙酯溶于约0.51注射用沸水中。冷至约50℃后，在搅拌下加入4g乳酸，0.05g丙二醇和4g A.I.。将溶液冷至室温，用注射用水补充至足量约1l，得到含4mg/ml A.I.的溶液。将该溶液过滤灭菌（US.P ⅩⅦ P.811）并装入无菌容器。
实施例11：栓剂
3g A.I.溶于3g 2，3-二羟基丁二酸的25ml聚乙二醇400溶液中，将12g表面活性剂（SPAN
）和足量甘油三酯至300g（Witepsol 555
）一起熔化，将该混合物和前面的溶液充分混合，于37-38℃将所得混合物注入模具中，形成100支栓剂，每支含30mg/ml A.I.。
实施例12：注射溶液
将60g A.I.和12g苄醇充分混合，加芝麻油足量至约1l.。得到含60mg/ml A.I.的溶液。杀菌后装入无菌容器。
实施例13：2%乳脂
将75mg硬脂醇，20mg十四烷醇，20mg脱水山梨糖醇单硬脂酸酯和10mg十四烷酸异丙酯加入到双层套筒的容器中，加热至混合物全部熔化。将该混合物加入到另外制备好的纯水，200mg丙二醇和15mg聚山梨酸酯60的混合物中，使用液体匀化器，70-75℃。所得乳液冷至25℃以下，同时继续混合。20mg式（1）化合物的A.I.1mg聚山梨酸酯80和637mg纯水溶液和2mg无水亚硫酸钠的纯水溶液随后加入到上述乳液中，同时继续混合。将该乳脂匀化并装进合适的管子里。
实施例14：气雾剂。
a）往2.5mg A.I.的0.7ml蒸馏水溶液中加入730μg 0.1N盐酸溶液。室温下搅拌10分钟后，加0.1N氢氧化钠溶液将所得溶液的PH值调至5.5。然后连续加入4mg氯化钠和0.15mg乙酸苯汞，搅拌得到一完全的溶液。加蒸馏水使体积达1.0ml。将溶液装入用机械泵喷嘴封口的玻璃瓶中，每压一次释放0.1ml。
b）往2mg A.I.的0.7ml蒸馏水溶液中加入600μg0.1N盐酸溶液。室温下搅拌10分钟后，将10mg聚乙烯醇溶于该混合物中，加0.1N氢氧化钠溶液将所得溶液PH值调至5.5。连续加入4mg氯化钠和2mg苯乙醇，搅拌得一完全的溶液。加蒸馏水使体积达1.0ml。装入用机械泵喷嘴封口的玻璃瓶中，每压一次喷0.1ml。
实施例15
“在Beagle狗血液中抑制A23187-诱发的白三烯B4产生”的试验
将Beagle狗禁食一夜，试验化合物的聚乙二醇溶液（2ml/kg）通过食道插管直接给至胃内。在给药前以及给药后适当的时间间隔，从颈静脉抽取血样。将这些血样收集在肝素上，将全部血样（1ml）迅速分配到试管中，试管中含已知浓度的钙离子载体A23187（25μm），后者已知能刺激白三烯B4（LTB4）的形成。试管中的物质用涡流经短时间混合后于37℃培养60分钟，在冰上使试管冷却停止培养，以10000g离心力离心5分钟。通过放射免疫测定法（RIA），使用Amersham Int（英）的LTB4试验体系测定LBT4。放射免疫测定用在未萃取的适当稀释的样品中补加了0.1%明胶的TRIS HCl（50mM，PH8.6）来完成。抗体用RIA缓冲剂稀释，等分成几份与（0.1ml）标准样品或试样（0.1ml）混合。加入3H标记的抗原，用缓冲液将体积调至0.5ml，并将混合物培养18-24小时，用葡聚糖的活性炭将其从无放射性材料中分离。旋沉下活性炭，取一部分上清液用液体闪光计数器计数。对LBT4的平均抑制效果的测定方法（以%计）如下：施用试验化合物1小时和4小时后采血样，分别测定各血样的LTB4数量。将血样中LTB4的数量和给试验化合物前血液中存在的LTB4的数量相比较以确定抑制的程度。当给药剂量为1.25mg/kg时，本发明化合物在至少4小时内能抑制约80%的离子载体A-23187诱发LBT4的产生。
Claims (4)
1、如下式的化合物，
及其药学上可接受的酸加成盐，或它们的对映体形式，其中X代表C=0或CHOH。
2、按照权利要求1的化合物，其中化合物是2-[2-（4-氯苯基）-2-氧代乙基]-2，4-二氢-4-[4-[4-（4-羟苯基）-1-哌嗪基]苯基]-5-甲基-3H-1，2，4-三唑-3-酮或其药学上可接受的酸加成盐。
3、5-脂肪氧合酶抑制组合物，它包括药学上可接受的载体和作为活性组分的治疗有效量的如权利要求1所定义的化合物。
4、制备在权利要求1中请求保护的化合物的方法，其特征在于在酸性介质或使用强的亲核试剂将式（Ⅱ）的烷氧基衍生物脱烷基化：
其中R1是C1-6烷基，以及任意地将X为C＝O的式（Ⅰ）化合物还原成X为CHOH的式（Ⅰ）化合物，并且如果需要，分离X为CHOH的式（Ⅰ）化合物成为它的对映体，并且如果需要通过用酸处理将式（Ⅰ）化合物转变成有治疗活性的无毒酸加成盐或者反之通过用碱处理将酸加成盐变成自由碱的形式。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP91202351 | 1991-09-13 | ||
| EP91202351.2 | 1991-09-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1071420A true CN1071420A (zh) | 1993-04-28 |
Family
ID=8207873
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92110869A Pending CN1071420A (zh) | 1991-09-13 | 1992-08-21 | 4-[4-[4-(4-羟苯基)-1-哌嗪基]苯基]-5-甲基-3h-1，2，4-三唑-3-酮衍生物 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US5254553A (zh) |
| EP (1) | EP0532091A1 (zh) |
| JP (1) | JPH05194436A (zh) |
| KR (1) | KR930006009A (zh) |
| CN (1) | CN1071420A (zh) |
| AU (1) | AU652069B2 (zh) |
| BG (1) | BG96815A (zh) |
| CA (1) | CA2076257A1 (zh) |
| FI (1) | FI923723A (zh) |
| HU (1) | HUT62884A (zh) |
| IL (1) | IL102863A (zh) |
| MX (1) | MX9205186A (zh) |
| NO (1) | NO923532L (zh) |
| NZ (1) | NZ244297A (zh) |
| ZA (1) | ZA926967B (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW279864B (zh) * | 1993-02-19 | 1996-07-01 | Janssen Pharmaceutica Nv | |
| CA2185552A1 (en) * | 1994-04-06 | 1995-10-19 | Jan Heeres | Anti-helicobacter ester and carbamate derivatives of azolones |
| US5607932A (en) * | 1994-07-12 | 1997-03-04 | Janssen Pharmaceutica N.V. | Heterocyclic derivatives of azolones |
| US5571811A (en) * | 1994-07-12 | 1996-11-05 | Janssen Pharmaceutica N.V. | Sulfonamide derivatives of azolones |
| US6001866A (en) * | 1995-10-05 | 1999-12-14 | Warner-Lambert Company | Method for treating and preventing inflammation and atherosclerosis |
| CN102413825A (zh) | 2009-04-29 | 2012-04-11 | 阿马里纳股份公司 | 含有epa和心血管剂的药物组合物以及使用其的方法 |
| BR112013007389B1 (pt) * | 2010-10-01 | 2022-03-22 | Taisho Pharmaceutical Co., Ltd | Derivado de 1,2,4-triazolona, substância e composição farmacêutica |
| KR101715448B1 (ko) * | 2014-07-16 | 2017-03-20 | 주식회사 큐리언트 | 염증성 질환 치료용 화합물 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1292472C (en) * | 1985-12-03 | 1991-11-26 | Alfonsus Guilielmus Knaeps | Derivatives of ¬¬4-¬4-(4-phenyl-1-piperazinyl)- phenoxymethyl|-1,3-dioxolan-2-yl|methyl|-1h-imidazoles and 1h-1,2,4-triazoles |
| US4791111A (en) * | 1985-12-23 | 1988-12-13 | Janssen Pharmaceutica, N.V. | [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles having anti-microbial properties |
| CA1331757C (en) * | 1988-02-29 | 1994-08-30 | Janssen Pharmaceutica Naamloze Vennootschap | 5-lipoxygenase inhibiting 4-(4-phenyl-1-piperazinyl)phenols |
-
1992
- 1992-08-17 CA CA002076257A patent/CA2076257A1/en not_active Abandoned
- 1992-08-19 IL IL10286392A patent/IL102863A/en not_active IP Right Cessation
- 1992-08-19 FI FI923723A patent/FI923723A/fi not_active Application Discontinuation
- 1992-08-21 CN CN92110869A patent/CN1071420A/zh active Pending
- 1992-08-24 US US07/933,848 patent/US5254553A/en not_active Expired - Fee Related
- 1992-08-25 BG BG096815A patent/BG96815A/bg unknown
- 1992-08-27 JP JP4250403A patent/JPH05194436A/ja not_active Withdrawn
- 1992-09-03 EP EP92202663A patent/EP0532091A1/en not_active Withdrawn
- 1992-09-07 AU AU22819/92A patent/AU652069B2/en not_active Ceased
- 1992-09-09 KR KR1019920016515A patent/KR930006009A/ko not_active Application Discontinuation
- 1992-09-10 NZ NZ244297A patent/NZ244297A/en unknown
- 1992-09-11 NO NO92923532A patent/NO923532L/no unknown
- 1992-09-11 MX MX9205186A patent/MX9205186A/es unknown
- 1992-09-11 HU HU9202914A patent/HUT62884A/hu unknown
- 1992-09-11 ZA ZA926967A patent/ZA926967B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BG96815A (bg) | 1993-12-24 |
| KR930006009A (ko) | 1993-04-20 |
| IL102863A0 (en) | 1993-01-31 |
| AU2281992A (en) | 1993-03-18 |
| NO923532D0 (no) | 1992-09-11 |
| HUT62884A (en) | 1993-06-28 |
| ZA926967B (en) | 1994-03-11 |
| IL102863A (en) | 1996-05-14 |
| EP0532091A1 (en) | 1993-03-17 |
| AU652069B2 (en) | 1994-08-11 |
| NO923532L (no) | 1993-03-15 |
| JPH05194436A (ja) | 1993-08-03 |
| FI923723A (fi) | 1993-03-14 |
| US5254553A (en) | 1993-10-19 |
| CA2076257A1 (en) | 1993-03-14 |
| HU9202914D0 (en) | 1992-11-30 |
| NZ244297A (en) | 1994-03-25 |
| FI923723A0 (fi) | 1992-08-19 |
| MX9205186A (es) | 1993-03-01 |
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