CN1105716C - 具有抗组胺的新苯并咪唑衍生物 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
其中，R1是氢或短链烃基，例如甲基、乙基、异丙基、环丙基或乙烯基等，R2是选自CH2OH、COOH、COOR3和4，4-二甲基-2-噁唑啉基中的一个基团，R3是如前所述的短链烷基，例如甲基、乙基等。还描述了制备这样一类的化合物的方法，这些化合物有高H1抗组胺和抗过敏活性并避免了对中枢神经和心血管系统的作用。
Description
本发明涉及具有H1抗组胺活性、没有心脏中毒作用的新的苯并咪唑衍生物。
最接近本发明化合物的现有技术是西班牙专利9201512，它描述了一些下列通式的具有抗组胺效能和抗过敏效能的哌啶苯并咪唑衍生物：
本发明的化合物与上述专利的化合物之间主要的结构区别在于苯基取代过程中出现了氧化了的官能。而且已经发现了这些氧化了的官能有重要的药效基团特性，这个药效基团特性主要包括作用的选择性并具有与其它已知组织胺药理学性能不同的药理学性能。在本发明中公开的这些化合物有几乎是专一的H1抗组胺药理学活性，因而甚至在比治疗剂量高得多的情况下仍能避免对其它药理学受体起作用。由于这种作用的选择性，本发明的化合物在治疗过敏型病况中是很有价值的手段，尤其是能够允许任何其它不管是什么样的伴行的药剂治疗人员以及有病理心脏循环障碍的病人不受限制地使用。
很久以前就知道组织胺在过敏性疾病--例如过敏性鼻炎、结膜炎、荨麻疹和哮喘--中起非常重要的作用；以H1-受体组织胺剂量作用的抗组胺化合物对于治疗这类症状是有用处的。
第一代H1抗组胺存在几种有害的影响，例如因其对中枢神经系统和胆碱能受体的作用而导致镇静作用和口干感。
对于不和血脑屏障交叉的分子的探寻导致用已经克服了与它们对中枢神经系统作用相关的副作用的其它第二代抗组胺代替早期抗组胺。这种新一代的抗组胺--而其中由于广泛而大量使用引人注意的是特那非定和阿司咪唑--在对心血管作用方面表现出一种危险的相反作用，扩大了QT间隔和心率失常，这就要求其使用避免下列的情形：病人容易感受这种失调或当病人使用这类药物时可能会干扰其代谢。
近年来一直加倍努力以图获得安全和有效的H1抗组胺，而这种研究在几个近年的专利申请中有了结果，这几个专利要求了对治疗过敏性疾病的含有抗组胺、而不产生心律失常作用的药物组合物的保护，美国专利申请924 156(03/08/92)和国际专利申请95/00480(05/01/95)就是这样的。
本发明涉及一组具有苯并咪唑结构的新化合物，其具有有效选择性的H1抗组胺活性，对中枢神经系统和对心血管系统缺乏活性。
本发明的这些化合物具有以下的通式：
其中，R1是氢或短链烃基，例如甲基、乙基、异丙基、环丙基或乙烯基，R2选自CH2OH、COOH、COOR3和4，4-二甲基-2-噁唑啉基，R3是如前所述的短链烷基，以及它们与药物学可接受的酸或碱的加成盐。
R1是短链烷基和R2是4，4-二甲基-2-噁唑啉基的化合物I可以按照传统的方法制备：通过在一种有机溶剂中的无机碱(例如碱金属的碳酸盐或碳酸氢盐)存在下，2-(4-哌啶基)-1H-苯并咪唑与化学式In的烷基化试剂的烷基化反应来制备，这里，X是在亲核取代反应中的一个良好的离去基团，例如Cl、Br、I、R4SO2、R2SO3等，然后在一种氢化物或一种碱金属碳酸盐的存在下，把生成的苯并咪唑IV与分子式为XCH2CH2OR1的醚进行另一次N-烷基化反应，这里，X的定义同上，R1是短链烷基，例如甲基(Me)、乙基(Et)、异丙基(i-Pr)、环丙基或乙烯基，等。
R1是短链烷基，R2是羧基的化合物I可以按照传统的方法通过把苯并咪唑Ia与一种无机酸如HCl或H2SO4的水解反应制备。
R1是短链烷基，R2是COOR3(这里的R3是短链烷基)的化合物I可以通过苯并咪唑Ia在一种醇溶剂R3OH的存在下，在合适的脂转移条件下的酸解来制备。
R1是短链烷基，R2是CH2OH基的化合物I可以通过苯并咪唑Ib或Ic与一种适当的还原剂，例如铝和锂的氢化物的还原反应来制备。
R1是氢，R2是4，4-二甲基-2-噁咪啉基的化合物I可以通过苯并咪唑IV-与氯代乙酸乙酯在一种氢化物或一种碱金属的碳酸盐存在下生成酯V，然后再用还原剂如铝和锂的氢化物的还原来制备。
R1是氢，R2是COOH基的化合物I按传统的方法通过化合物Ie与一种无机酸例如HCl或H2SO4的水解反应制备。
所得的这些新苯并咪唑I可以通过用适当的酸或碱处理转化成药物学上可接受的盐。
化学式I的化合物具有有用的药理学性质。尤其是它们具有有效的H1抗组胺作用。这种活性清晰地表现于在体外阻断离体豚鼠回肠中组织胺诱发的收缩(Magnus，pflugers，Arch，Ges.Physionl.，102，123(1904)；Arunlakshana，O.and Sohild，H.O.，Br.J.Pharmacol14，48-58(1959))和在体内阻止对于大鼠的组织胺诱发皮肤毛细渗透力增大(Lefebvre，P.，Salmon，J.，Leconte and Cauwenberge，V.H.，C.R.Soc.Biol.156，183-186(1962)；Udaka，K.，Takeuchi，Y.and Morat，H.Z.，Proc.Soc.Exp.Biol.Med.133，1384-1387(1970))。
这样，证明了化合物Ib(R1＝Et)是一种有效的豚鼠回肠H1受体组织胺混合性拮抗剂，其计算的pA2＝7.98-8.10，而pD’2＝6.50。同样的这种化合物以口服DE50接近2mg/kg时在体内阻止大鼠的毛细渗透能力的增大。在口服剂量为5mg/kg时，这种化合物保持明显效力(超过50％)的时间至少6小时。
这些化合物在其药物学作用方面有高选择性，表现为既没有显著抗胆碱能活性也没有对中枢神经和心血管系统的活性。因此，化合物Ib(R＝Et)在0.1M浓度不能够有效地对抗乙酰胆碱诱发的在离体豚鼠回肠中的收缩作用，口服100mg/kg不提高大鼠的自发性运动原活性，此外，同样这种化合物，以20mg/kg的剂量静脉用药不会引起大鼠的形态学心电图紊乱也不会增大QTc间隔。
鉴于它们的有用的药物学抗组胺和抗过敏方面特性，本发明所述的化合物可以配制成口服、皮肤给药、注射和直肠用药几种药物剂型。口服制剂是把一种本发明中所述产品的有效剂量的抗组胺剂与例如乳糖、纤维素、滑石粉等的赋形剂直接混合配成片剂或胶囊、或与水、甘醇、醇类，油类等直接混合来制备糖浆、溶液和悬浮液。皮肤制剂可以制成乳膏、软膏、凝胶、溶液和经皮肤给药的膏药形式，使用例如凡士林、聚乙二醇等作为载体。对于注射制剂，虽然为了增大溶解度可以加入其它的赋形剂，诸如含盐溶液、葡萄糖溶液等或它们的混合物，不过至少占绝大部分的赋形剂应该是灭菌水。
下面详述的实施例具体说明本发明而不限制其范围。
实施例1
制备1-(2-乙氧基乙基)-2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-(甲乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑。(Ia，R1＝Et)
把3.57g碳酸钠加到在60ml DMF的14g的2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)乙基对甲苯磺酸酯和6.78g的2-(4-哌啶基)-1H-苯并咪唑悬浮液中，生成的悬浮液在80℃加热14小时。DMF被浓缩，把反应物倒入水/冰中，此后把结晶固体过滤、水洗，并在50℃干燥而生成10g的2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑。生成的固体溶于25ml DMF中并在其中加入1.2g在60％的油悬浮液中的氢化钠。生成的悬浮液在室温下搅拌2小时再加入2.44g 2-氯乙基乙醚。反应物在80℃下加热16小时，冷却，倒入水/冰中，用乙醚萃取，并用水和饱和氯化钠溶液洗涤。含醚溶液用无水硫酸钠干燥、浓缩后生成11.2g 1-(2-乙氧基乙基)-2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑。RMN-1H(CDCl3)，δ：1.1(t，3H)；1.3(s，6H)；1.5(s，6H)，1.9(m，2H)；2.1(m，4H)，2.6(t，2H)；2.8(t，2H)；3.0(m，1H)；3.1(d，2H)；3，4(c，2H)；3.7(t，2H)；3.9(s，2H)；4.3(t，2H)；7.1-7.3(m，7H)；7.7-7.8(m，1H).RMN-13C(CDCl3)3，δ：14，96；27.38；28.15；31.06；33.10；34.53；40.18；43.60；53.71；60.46；66.74；66.83；68.59；79.14；109.09；119.41；121.71；121.88；125.30；128.73；134.78；138.72；142.72；143.04；158.41和177.70.
实施例2
制备2-[4-(2-(4-(1-(2-乙氧基乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基[-2-甲基丙酸。(Ib，R1＝Et)
把6.72g的1-(2-乙氧基乙基)-2-[1-(2-(4-(1-(4，4-二甲基-△2-恶唑啉-2-基)-1-甲乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑(Ia)溶于170ml 3N的HCL中并回流1小时。把它冷却并用50％氢氧化钠溶液调节至pH7。溶液用正-丁醇萃取，水洗，用无水硫酸钠干燥并浓缩。往剩余物中加入甲醇(30ml)和50％的氢氧化钠溶液(40ml)并回流30分钟。蒸发掉甲醇，加水至完全溶解时为止。用乙醚提取之后把含水层用20％HCl调节至pH7及用氯化钠溶液饱和，此后把沉淀出来的固体过滤、反复用水洗涤、在50℃的真空干燥器中生成3.5g的2-[4-(2-(4-(1-(2-乙氧基乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基]-2-甲基丙酸。MP：199-201℃RMN-1H(DMSO-d6)，δ：1.0(t，3H)；1.4(s，6H)；1.8(m，4H)，2.2(m，2H)；2.5(t，2H)；2.7(t，2H)；3.0(m，3H)；3.3(c，2H)；3.6(t，2H)；4.4(t，2H)；7.0-7.3(m，6H)；7.4-7.6(m，2H).RMN-13C(DMSO-d6)，δ：14.90；26.59；30.97；32.22；33.39；43.04；45.50；53.08；60.05；65.70；68.43；110.18；118.40；121.16；121.35；125.47；128.42；134.72；138.33；142.29；143.03；158.60；和177.87.
实施例3
制备2-[4-(2-(4-(1-(2-乙氧基乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基]-2-甲基丙酸乙酯。(Ic，R1＝Et，R3＝Et)
把浓硫酸(20ml)加到在250ml乙醇里的10g 1-(2-乙氧基乙基)-2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑溶液中，回流16小时。冷却后加入1升乙醚。分离出有机层后用水、10％碳酸氢钠溶液洗涤，然后再次用水洗涤。经无水硫酸钠干燥后浓缩，生成7g的油状物，用快速色谱法纯化，使用95/5氯仿/乙醇混合物作为洗脱液，生成5g油状的2-[4-(2-(4-(1-(2-乙氧基乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基]-2-甲基丙酸乙酯。RMN-1H(CDCl3)，δ：1.1(t，3H)；1.2(t，3H)；1.5(s，6H)；2.0(m，2H)；2.2(m，4H)；2.6(t，2H)；2.8(t，2H)；3.0(m，1 H)；3.2(m，2H)；3.4(c，2H)；3.7(t，2H)；4.1(c，2H)；4.3(t，2H)；7.1-7.3(m，7H)；7.6-7.7(m，1H).RMN-13C(CDCl3)，δ：13.86；14.80；26.35；30.62；32.73；33.87；43.48；45.91；53.26；60.11；60.49；66.61；68.40；109.02；119.16；121.55；121.75；125.40；128.50；134.56；138.40；142.29；142.51；158.13和176.53.
实施例4
制备1-(2-乙氧基乙基)-2-[1-(2-(4-(1，1-二甲基2-羟乙基)苯基)-乙基)哌啶-4-基]-1H-苯并咪唑。(Id，R1＝Et)
把1g的铝和锂的氢化物溶解在30ml THF中，并滴入3g的2-[4-(2-(4-(1-(2-乙氧基乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基]-2-甲基丙酸乙酯。在室温下把反应物搅拌4小时，并加入几毫升水以便消除过量的氢化物。把溶液过滤并用饱和氯化钠溶液洗涤滤液。干燥并浓缩。浓缩物重新溶解在氯仿中并用水洗涤，干燥和浓缩。残余物用快速色谱法纯化，使用己烷/乙醚/异丙胺混合液(2/7.5/0.5)作为洗脱液，生成1.5g的1-(2-乙氧基乙基)-2-[1-(2-(4-(1， 1-二甲基-2-羟乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑。MP：112-114℃RMN-1H(CDCl3，δ：1.0(t，3H)；1.4(s，6H)；1.9-2.1(m，2H)；2.1-2.3(m，4H)；2.6(t，2H)；2.8(t，2H)；3.0(m，1H)；3.2(d，2H)；3.4(c，2H)；3.6(s，2H)；3.7(t，2H)；4.3(t，2H)；7.1-7.4(m，7H)；7.8(m，1H).RMN-13C(CDCl3)，δ：15.01；25.34；31.07；33.07；34.53；39.78；43.64；53.72；60.52；66.88；68.62；73.07；109.13；119.44；121.77；121.94；126.22；128.80；134.78；138.39；142.71；143.90；158.45.
实施例5
制备1-(2-羟乙基)-2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑。(Ie)
把5g的2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)哌啶-4-基]-1H-苯并咪唑溶于30ml DMF中，并把0.54g在油悬浮液中的氢化钠加入其中。生成的悬浮液在室温下搅拌2小时并滴入1.19ml的氯乙酸乙酯。反应物在70℃加热16小时、冷却并倒入300ml的水中。再用乙醚萃取并水洗其含醚层，用无水硫酸钠干燥并过滤。把0.8g的铝和锂的氢化物溶于30ml乙醚中，把预先过滤的含醚相滴入这个溶液中。在室温下搅拌4小时，再加入20ml 10％氢氧化钠溶液。加入氯化钠达到饱和后分离出含醚层。含水相用乙醚萃取。各个含醚相混合在一起，用水和饱和氯化钠溶液洗涤。再用无水硫酸钠干燥并浓缩，生成2.6g呈油状的1-(2-羟乙基)-2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑。RMN-1H(CDCl3)，δ：1.3(s，6H)；1.6(s，6H)；1.8-2.2(m，6H)；2.6(t，2H)；2.8(t，2H)；2.9(m，1H)；3.0-3.1(m，2H)；3.7(s，2H)；4.0(s，2H)；4.3(t，2H)；7.1-7.4(m，7H)；7.7(m，1H).RMN-13C(CDCl3)，δ：15.01；25.34；31.07；33.07；34.53；39.78；43.64；53.72；60.52；66.88；68.62；73.07；109.13；1 19.44；121.77；121.94；126.22；128.80；134.78；138.39；142.71；143.90；158.45.
实施例6
制备2-[4-(2-(4-(1-(2-羟乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基]-2-甲基丙酸。(If)
把5g 1-(2-羟乙基)-2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑(Ie)溶于45ml的3NHCl中并回流1小时。用50％氢氧化钠溶液调节至碱性pH值，加入20ml乙二醇。在190℃加热3小时同时进行蒸馏，然后真空浓缩。加入水并用乙醚萃取。含水层用稀HCl调节至pH7，用氯化钠饱和后用正-丁醇提取。含醚的提取物被干燥并浓缩。浓缩物在丙酮/甲醇中结晶生成2.7g 2-[4-(2-(4-(1-(2羟乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基]-2-甲基丙酸。MP：218℃(分解)RMN-1H(CDCl3)，δ：1.4(s，6H)；2.0-2.1(m，4H)；2.7-2.9(m，4H)；2.9-3.1(t，2H)；3.2-3.5(m，3H)；3.7(t，2H)；4.3(t，2H)；6.7-7.1(m，2H)；7.1-7.2(m，2H)；7.2-7.3(m，2H)；7.3-7.4(m，1H)；7.4-7.5(m，1H).
Claims (9)
1、苯并咪唑衍生物，具有如下的化学式：
其中，R1是氢、甲基或乙基，R2选自CH2OH、COOH、COOR3和4，4-二甲基-2-噁唑啉基，R3是甲基或乙基，以及它们与药物学可接受的酸或碱的加成盐。
2、根据权利要求1所述的化合物，它是1-(2-乙氧基乙基)-2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)乙基)哌啶-4-基]1H-苯并咪唑或它与一种药物学可接受的酸或碱的加成盐。
3、根据权利要求1所述的化合物，它是2-[4-(2-(4-(1-(2-乙氧基乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基]-2-甲基丙酸或它与一种药物学可接受的酸或碱的加成盐。
4、根据权利要求1所述的化合物，它是2-[4-(2-(4-(1-(2-乙氧基乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基]-2-甲基丙酸乙酯或它与一种药物学可接受的酸或碱的加成盐。
5、根据权利要求1所述的化合物，它是1-(2-乙氧基乙基)-2-[1-(2-(4-(1，1-二甲基-2-羟甲基-乙基)苯基-乙基)哌啶-4-基]-1H-苯并咪唑或它与一种药物学可接受的酸或碱的加成盐。
6、根据权利要求1所述的化合物，它是1-(2-羟乙基)-2-[1-(2-(4-(1-(4，4-二甲基-△2-噁唑啉-2-基)-1-甲乙基)苯基)乙基)哌啶-4-基]-1H-苯并咪唑或它与一种药物学可接受的酸或碱的加成盐。
7、根据权利要求1所述的化合物，它是2-[4-(2-(4-(1-(2-羟乙基)苯并咪唑-2-基)哌啶-1-基)乙基)苯基)-2-甲基丙酸或它与一种药物学可接受的酸或碱的加成盐。
8、一种抗组胺药物组合物，其特征在于，它含有有效剂量的作为活性剂的一种权利要求1-7中的化合物，与一种或几种赋形剂相混合。
9、权利要求1-7任一项中的化合物用于制备治疗过敏性疾病的药物的用途。
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