CN1120838A - 治疗局部缺血和相关疾病的杂环衍生物 - Google Patents
治疗局部缺血和相关疾病的杂环衍生物 Download PDFInfo
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- CN1120838A CN1120838A CN94191728A CN94191728A CN1120838A CN 1120838 A CN1120838 A CN 1120838A CN 94191728 A CN94191728 A CN 94191728A CN 94191728 A CN94191728 A CN 94191728A CN 1120838 A CN1120838 A CN 1120838A
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- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
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- 239000003365 glass fiber Substances 0.000 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 230000003993 interaction Effects 0.000 description 1
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- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- UFXSGSYKGLMMJU-UHFFFAOYSA-N methanesulfonic acid;morpholine Chemical compound CS([O-])(=O)=O.C1COCC[NH2+]1 UFXSGSYKGLMMJU-UHFFFAOYSA-N 0.000 description 1
- RSJDPRFLMBXMFO-UHFFFAOYSA-N methanesulfonic acid;piperazine Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.C1CNCCN1 RSJDPRFLMBXMFO-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000003757 neuroblast Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical group O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- AUYNWRLEXAPZAJ-UHFFFAOYSA-N piperazine;trihydrochloride Chemical compound Cl.Cl.Cl.C1CNCCN1 AUYNWRLEXAPZAJ-UHFFFAOYSA-N 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000002795 scorpion venom Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000003195 sodium channel blocking agent Substances 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 229940001516 sodium nitrate Drugs 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000003568 synaptosome Anatomy 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
新的取代的哌啶和哌嗪或其药物上可接受的酸加成盐为钙和/或钠通道拮抗剂,该化合物用于治疗患有各种疾病如中风,癫痫,高血压,心绞痛,偏头痛,心率失常,血栓,栓塞的哺乳动物以及治疗脊椎损伤。
Description
本发明涉及式(I)的取代杂环衍生物,其药物上可接受的盐,制备这些化合物的方法及含有它们的药物组合物。本发明化合物是钙和/或钠通道拮抗剂,并且可有效地治疗局部缺血和其它疾病症状,并具有保护活性以抵御产生大脑局部缺血的一些有害因素。
本发明化合物是各种氨基的杂环衍生物,有几个结构上相关的化合物公开在美国专利4,829,065,5,043,447,5,091,428,英国专利1,434,854和日本专利49,093,379中。
n是0或1;
p是0,1,2或3;
q是0或1;
R4是氢,低级烷基,环烷基,或任意取代的苯基;
R5是任意取代的苯基;
X是(CH2)p,或4-哌啶-1-基;
Y是CH,CH-O-,CH-S-,或氮;
Z是CH2,NH,硫,或氧;及A选自下式基团:其中:
R9是低级烷基,或任意取代的苯基;
R10是氢,或低级烷基;
R11是低级烷基,或任意取代的芳基;
R12是氢,低级烷基,低级烷氧基,卤,或三氟甲基;及
W是氧,硫,或NR15;
其中:R15是氢,或低级烷基;条件是R9,R10,R12和其侧链不能连接在杂原子上。
本发明第二方面涉及含有至少一个式(I)化合物和一种或多种药物上可接受的赋形剂的药物组合物。
本发明第三方面涉及用式(I)化合物治疗哺乳动物的某些疾病,这些疾病为通过直接神经元保护或钙通道抑制剂,钠通道抑制剂,或钙和钠通道抑制剂治疗的疾病,这些疾病包括:
通过直接神经元保护治疗的疾病如:局部和全面性脑缺血,脑缺血包括由神经变性引起的缺血,产期窒息,脊柱损伤,末梢神经缺血,末梢神经损伤,神经病患者疼痛,头损伤,原发性大脑内出血,脑病,癫痫或癫痫神经病症状,和神经病学疾病如阿尔茨海默氏病,亨廷顿舞蹈病,帕金森病和痴呆;
通过钙通道抑制剂,钠通道抑制剂,或钙和钠通道抑制剂治疗的疾病,这些疾病包括:
通过抑制脑血管痉挛和脑血管舒张治疗的疾病,如偏头痛,休克,由蛛网膜下出血引起的痉挛,和由滥用***引起的脑血管缺血;
通过抑制细胞水肿治疗的疾病,如脑水肿和低钠血脑病;
心血管疾病,如高血压,心绞痛,稳定和不稳定心绞痛,梗死性心绞痛,心律失常,血栓,心肌梗死,栓塞,充血性心脏衰竭如慢性或急性心力衰竭;
由末梢血管疾病引起的小腿缺血的疾病,包括间隙性跛行;
以平滑肌痉挛为特征的疾病,包括可逆性气道阻塞,哮喘,输尿管痉挛,膀胱痉挛,子宫痉挛,和过敏性肠综合征;
预防在外科手术期间如移植物分流术,血管造影术,血管成形术,移植期间器官保存的血管收缩和/或缺血性组织损伤,高血压危象,和手术后高血压;
通过利尿治疗的疾病;和***脑病;
该方法包括将有效量的式(I)化合物或含有式(I)化合物的药物组合物给药予哺乳动物。
本发明第四方面涉及式(I)化合物的制备方法。定义
在本文中:
“烷基”意指支链或直链含有1-12个碳原子的饱和烃的单基团,如甲基,乙基,丙基,叔-丁基,正-己基,正-辛基,正-壬基等,除非其它说明。
“低级烷基”意指支链或直链含有1-6个碳原子的饱和烃的单基团,如甲基,乙基,丙基,异丙基,叔-丁基,丁基,正-己基等,除非其它说明。
“环烷基”意指饱和的单价单环含有3-8个碳原子的烃基,如环丙基,环丁基,环戊基,环己基,环庚基和环辛基,并可被上述低级烷基任意取代。
“低级烷氧基”意指-O-R基团,其中R为如上定义的低级烷基。
术语“卤”意指氟、溴、氯或碘,除非其它说明。
术语“惰性有机溶剂”或“惰性溶剂”意指在所述反应条件下为惰性的溶剂,[包括,例如,苯,甲苯,乙腈,四氢呋喃(“THF”),二甲基甲酰胺(“DMF”),氯仿(“CHCl3”),二氯甲烷(或“CH2Cl2”),***,乙酸乙酯,丙酮,甲乙酮,甲醇,乙醇,丙醇,异丙醇,叔-丁醇,二恶烷,吡啶,等等]。除非有相反的说明,在本发明反应中所用溶剂均为惰性溶剂。
碱性氮原子的存在使式(I)化合物形成酸加成盐。“药物上可接受的盐”意指保持式(I)化合物的生物效力和性质的那些盐,而且它们没有其它不希望的生物活性。酸加成盐可以是与无机酸和有机酸形成的盐,无机酸如盐酸,氢溴酸,硫酸,硝酸,磷酸等,有机酸如乙酸,丙酸,乙二酸,丙酮酸,草酸,苹果酸,丙二酸,琥珀酸,马来酸,富马酸,酒石酸,柠檬酸,苯甲酸,肉桂酸,扁桃酸,甲磺酸,乙磺酸,对-甲苯磺酸,水杨酸等等。
本发明化合物可以具有一个或多个手性中心(例如当R1不是氢,或当q是0及R4是低级烷基时)并且可以得到外消旋混合物或一种立体异构体。通过在适当的合成步骤拆分中间体的外消旋或非外消旋混合物,或拆分式(I)化合物可以得到一种立体异构体。可以理解某种立体异构体及某些立体异构体的外消旋和非外消旋混合物均属于本发明的范围。
术语“芳基”意指单环芳香环,包括碳环和杂环。芳基的实例为苯基,噻吩,呋喃,咪唑,吡啶,嘧啶等等。
“选择的”或“任意地”意指下面所述的事情或情况发生或不发生,说明书中包括的叙述事情或情况的例子发生或不发生。例如“任意取代的苯基”或“任意取代的芳基”意指可以被取代基取代或不取代,其中取代基选自低级烷基,低级烷氧基,羟基,硝基,三氟甲基,和卤,并且包括所有可能单,二或三取代的苯基。
术语“哺乳动物”包括人和所有家养和野生哺乳动物,对此没有限制,包括牛,马,猪,羊,山羊,狗,猫,兔等等。
在此所用术语“治疗”包括对哺乳动物,特别是人的疾病的任何治疗,包括:
(i)对于易于感染某些疾病但是尚未诊断出患有这类疾病的患者进行预防;
(ii)抑制疾病,即阻止其发展;及
(iii)解除疾病,即治愈疾病。
术语“有效量”意指足以提供治疗所述疾病的剂量。该剂量将依据患者,疾病和治疗效果而变化。
本发明化合物的命名和编号将在以下说明。
4-二苯基甲基-1-[(5-(4-三氟甲基苯基)-3-甲基呋喃-2-基)甲基]哌啶。
因此,当R11是4-甲氧基苯基;R12为4-甲基;和侧链在3位,其中m为0;R1为氢;和-NR2R3代表下式基团:其中p和q为0,R4为氢;R5为2,3,4-三甲氧基苯基时式(IDA)化合物命名为:1-(2,3,4-三甲氧基苯基)甲基-4-[4-甲基-4’-甲氧基联苯基-3-基甲基]哌嗪。
优选的具体化合物
在本发明化合物家族中,一种优选的类型包括其中A为下列基团的式(I)化合物:在这组中优选下列化合物:R2和R3与其连接的氮原子一起表示下式基团:特别是其中m为0,q为0,R1为氢或低级烷基,R9为任意取代的苯基和R10为低级烷基。该组中优选下列分组化合物:p为0,R1为氢,R4和R5均为苯基,更特别是Y为氮。
在这类中另一优选的组包括下列化合物:R2和R3与其连接的氮原子一起表示下式基团:特别是其中Z为氧,R4和R5均为苯基。
另一类优选的为包括A为下列基团的式(I)化合物:在这类中优选下列化合物中:R2和R3与其连接的氮原子一起代表如(II)所示的基团,特别是其中m为0,q为0,R1为氢或低级烷基,R11为任意取代的苯基和R12为低级烷基。
式(IB)化合物的制备
式(I)化合物,其中A为呋喃,噻吩或吡咯衍生物,所示式(IB)化合物可以由式(9)或式(10)化合物制备,如下面反应流程IIIA和IIIB所示。
A.其中m为0和R1为氢的式(IB)化合物的制备
反应流程IIIA其中m为0,R1为氢,R2,R3,R9和R10如本发明概要中定义。
起始原料
式(9)化合物为商品,或可以依照Utimato et al.,
Tet.Lett.,Vol.22,pp4277-8(1981),Evans et al.,
J.O.C.,Vol.39,pp914-7(1974),
Zh.Ob.Khimi,Vol.43,p2749(1973),Mikaiyama et al.,Chem.Lett.,pp527,Compaigne et al.,
J.Het.Chem.,Vol.25,p367(1988),J.O.C.,Vol.25,p392,(1960),和Shridhar et al.,Synthesis,pp1061-2(1982)中公开的方法制备。
步骤1式(9a)化合物的制备
为制备式(9a)化合物,首先在-10到10℃,优选在0℃,将约1摩尔当量的三氯氧化磷与约1摩尔当量的N,N-二甲基甲酰胺反应10分钟到2小时,优选30分钟,最好不用溶剂。然后加人约1摩尔当量溶解于惰性溶剂(如二氯甲烷,氯仿,二氯乙烷,优选二氯乙烷)的式(9)化合物。反应在0到40℃,优选在约25℃进行30分钟到5小时,优选1.5小时。当反应基本完成时,式(9a)甲酰胺化合物被分离并用常规方法纯化,优选快速色谱法。
步骤2 其中m为0和R1为氢的式(IB)化合物的制备
为制备其中m为0和R1为氢的式(IB)化合物,在钛(IV)催化剂(例如四氯化钛,乙醇钛(IV),异丙醇钛(IV),优选异丙醇钛(IV))存在下,将式HNR2R3胺与约1到3摩尔当量,优选1.2摩尔当量的式(9a)化合物反应。反应在0到40℃,优选在约25℃,在极性溶剂(例如甲醇,乙醇,丙醇,优选乙醇)中进行10分钟到4小时,优选约1小时。然后将还原剂(例如硼氢化钠,氰基硼氢化钠,优选氰基硼氢化钠)加到反应混合物中,继续反应10分钟到4小时,优选约1小时。当反应基本完成时,分离式(IB)产物并用常规方法纯化,优选快速色谱法,接着转化成酸盐,优选盐酸盐。此类反应在Mattson,
J.O.C.,Vol.55,p2552(1990)也有描述。
替换步骤2 其中m为0和R1为低级烷基的式(IB)化合物的制备
为制备其中m为0和R1为低级烷基的式(IB)化合物,首先在钛(IV)催化剂存在下,将式(9a)化合物与式HNR2R3的胺反应,如上面反应流程IIIA所示,然后中间体亚胺与式R1MgBr的格利雅(Grignard)试剂(代替还原剂)按已知方法反应。当反应基本完成时,分离其中m为0和R1为低级烷基的式(IB)产物并用常规方法纯化,优选快速色谱法,接着转化成酸加成盐,优选盐酸盐。
B.其中m为1和R1为羟基的式(IB)化合物的制备
起始原料
式(10)化合物为商品,或可以依照在
J.A.C.S.Vol.75,5956,(1953),
Tetrahedron,Vol.44,3343(1988),和
Ber.,616(1964)中公开的方法制备。
其中m为1和R1为羟基的式(IB)化合物的制备
为了制备其中m为1和R1为羟基的式(IB)化合物,首先将式(10)化合物与卤化剂例如溴,吡咯烷氢三溴化物,优选吡咯烷氢三溴化物反应。该反应在醚溶剂(例如***,二甲氧基甲烷,四氢呋喃,优选四氢呋喃)中,温度为0-40℃优选25℃进行约4-48小时,优选进行约16小时。当反应基本完成时,将产物(酰溴化物)分离,并与约1-3摩尔当量,优选1.1摩尔当量的式HNR2R3的胺在过量碱优选碳酸钾的存在下反应。该反应在极性溶剂(甲醇,乙醇,丙醇,优选丙醇)中,温度为约40-100℃优选回流温度进行约30分钟到4小时,优选进行约2小时。当反应基本完成时,将式(11)产物分离并用常规方法优选快速色谱法纯化。
然后将式(11)化合物优选与硼氢化钠在甲醇中进行常规还原得到其中m为1和R1为羟基的式(IB)化合物。
式(ID)化合物的制备式(IDA)化合物的制备
起始原料
例如,式(15)和(16)化合物可从Aldrich购到,或用
Tet.Tett.,Vol.29(11),pp1293-1294(1988)和
J.Med.Chem.,Vol.32,pp105-118(1989)中公开的方法制备,或用如下反应流程VA的方法制备。
用现有技术中的已知方法,例如用钯-碳催化剂氢化的方法,将硝基酯还原为氨基酯。然后用现有技术中的已知方法,例如用胺与硝酸钠进行重氮化反应,然后再用碘化钾处理的方法,将胺转化为碘化物。
步骤1-式(17)化合物的制备
为了制备式(17)化合物,将式(16)化合物与约1-3摩尔当量优选约1.5摩尔当量的式(15)化合物在Grignard反应催化剂(例如约0.05摩尔当量氯化镍(II),[1,3-二(三苯基膦基)丙烷]氯化镍(II),或从[1,3-二(二苯基膦基)氯化钯(II)制备的还原性钯(II)和二丁基氢化铝,优选氯化镍(II))存在下反应。该反应在醚溶剂(例如***,二甲氧基甲烷,四氢呋喃,优选四氢呋喃)中,温度为0-40℃优选25℃进行约4-48小时,优选进行约16小时。当反应基本完成时,将式(17)产物分离并用常规方法纯化,优选快速色谱法。
步骤2-式(18)化合物的制备
为了制备式(18)化合物,将式(17)化合物进行常规水解,例如,通过用强碱在极性溶剂,用氢氧化钠在醇的水溶液中加热,并且用常规方法分离和纯化式(18)的酸。
步骤3-式(19)化合物的制备
为了制备式(19)化合物,首先将式(18)化合物与约1-1.5摩尔当量,优选1.2摩尔当量的卤化剂(例如三氯氧化磷,三氯化磷,五氯化磷,亚硫酰氯,优选亚硫酰氯)反应。该反应在惰性溶剂(例如氯仿,乙酸乙酯,二氯甲烷,优选二氯甲烷)和二甲基甲酰胺的混合物中,温度约40-80℃,优选回流温度反应直到完成。然后将该混合物与1-3摩尔当量,优选1.5摩尔当量的式HNR2R3的胺反应。该反应在温度为约0-40℃优选25℃进行约4-48小时,优选进行约16小时。当反应基本完成时,将式(19)的胺分离并用常规方法优选快速色谱法纯化。
式(IDA)化合物的制备
式(ID)化合物从式(19)的衍生物用如反应流程VI所示方法进行制备。
步骤4-其中m为0和R1为氢的式(IDA)化合物的制备
为了制备其中m为0和R1为氢的式(IDA)化合物的制备,将式(19)化合物与约1-3摩尔当量,优选1.5摩尔当量的适宜的还原剂(例如硼,三乙基氧翁氟硼酸盐加硼氢化钠,或优选氢化铝锂)反应。该反应在醚溶剂(例如***,二甲氧基甲烷,四氢呋喃,优选***和四氢呋喃的混合物)中,温度为0-40℃优选25℃进行约30分钟-8小时,优选进行约1.5小时。当反应基本完成时,将式(IDA)的胺分离并用常规方法优选快速色谱法纯化,然后转化为酸的盐,优选盐酸盐。
式(ID)化合物的替代制备
另外,其中m为0和R1为氢的式(IDA)的化合物可用如反应流程VII所示方法从式(17)化合物进行制备。
步骤1-式(20)化合物的制备
式(20)化合物是从式(17)化合物制备的。将式(17)化合物与约1-3摩尔当量,优选1.5摩尔当量的适宜的还原剂(例如硼,三乙基氧翁氟硼酸盐加硼氢化钠,在羧酸存在下的硼氢化钠,或优选氢化铝锂)反应。该反应在醚溶剂(例如***,二甲氧基甲烷,四氢呋喃,优选***和四氢呋喃的混合物)中,温度为0-40℃优选25℃进行约30分钟-8小时,优选进行约1.5小时。当反应基本完成时,将式(20)的醇分离并用常规方法纯化,优选快速色谱法。
步骤2-其中m为0和R1为氢的式(IDA)的化合物的制备
为了制备其中m为0和R1为氢的式(IDA)的化合物,首先将式(20)化合物的-CH2OH部分的羟基转化为离去基团,例如用现有技术中的已知方法转化为卤,或优选通过与约1-1.5摩尔当量,优选约1.2摩尔当量的磺酰化试剂(例如对-甲苯磺酰氯或优选甲磺酰氯),在含有1-10摩尔当量,优选约1.3摩尔当量无机碱(如碳酸钠,碳酸氢钾等等),或优选含叔有机碱(如吡啶,N-甲基哌啶等等,优选三乙胺)的惰性有机溶剂(如苯,甲苯,乙酸乙酯,乙腈,四氢呋喃,***,氯仿或二氯甲烷,优选二氯甲烷)中,在0-40℃,优选25℃反应2-24小时,优选16小时。产物用常规方法分离和纯化,然后与1-3摩尔当量,优选1.2摩尔当量的式HNR2R3的胺反应。反应在上述惰性溶剂,优选乙腈中,在约1-3摩尔当量,优选1.2摩尔当量上述有机碱或无机碱,优选碳酸氢钾存在下,在约20-100℃,优选25℃下进行约1-8小时,优选3小时。当反应基本完成时,将式(IDA)化合物分离和用常规方法纯化,优选快速色谱法,接着将其转化为酸加成盐,优选盐酸盐。
化合物的分离和纯化
如果需要,用任何适当的分离和纯化方法,例如过滤,萃取,结晶,柱色谱法,薄层色谱法,厚层色谱法,制备低或高压液相色谱法或这些方法的结合,对这里所说的化合物和中间体进行分离和纯化。特别说明的是,适宜的分离和离析方法可以参考下列实施例。然而,其它等价的分离或离析方法当然也可以使用。
式(I)化合物的盐
式(I)化合物可以借助于碱性氮原子的存在而转化为相应的酸加成盐。转化过程通过用至少化学当量适宜的酸处理来完成,酸如盐酸,氢溴酸,硫酸,硝酸,磷酸等等,有机酸如乙酸,丙酸,乙二酸,丙酮酸,草酸,苹果酸,丙二酸,琥珀酸,马来酸,富马酸,酒石酸,柠檬酸,苯甲酸,肉桂酸,扁桃酸,甲磺酸,乙磺酸,对-甲苯磺酸,水杨酸等等。典型地,将游离碱溶解于惰性有机溶剂中,如***,乙酸乙酯,氯仿,乙醇或甲醇等等,以及将酸加到类似的溶剂中。温度保持在0-50℃。所得盐自然沉淀出或可以用弱极性溶剂从溶液中取出。
总之,本发明化合物是用下面概括的方法制备:
n是0或1;
p是0,1,2或3;
q是0或1;
R4是氢,低级烷基,环烷基,或任意取代的苯基;
R5是任意取代的苯基;
X是(CH2)p,或4-哌啶-1-基;
Y是CH,CH-O-,CH-S-,或氮;
Z是CH2,NH,硫,或氧;及A选自下式基团:其中:
R9是低级烷基,或任意取代的苯基;
R10是氢,或低级烷基;
R11是低级烷基,或任意取代的芳基;
R12是氢,低级烷基,低级烷氧基,卤,或三氟甲基;及
W是氧,硫,或NR15;
其中:R15是氢,或低级烷基;条件是R9,R11,R12和其侧链不能连接在杂原子上,该方法包括:
a)下式化合物其中R9和R10定义如上,在钛(IV)催化剂存在下与式HNR2R3的胺反应,其中R2和R3定义如上,接着加入还原剂(如果R1为氢)或Grignard试剂(如果R1为低级烷基),生成式I化合物;或
c)下式化合物其中R11,R12,R2和R3定义如上,与还原剂反应生成式I化合物;或
e)式I化合物的游离碱与酸反应,得到药物上可接受的酸加成盐;或
f)式I化合物的酸加成盐与碱反应,得到相应的游离碱;或
g)将式I化合物的酸加成盐转变成另一药物上可接受的酸加成盐。
应用和给药方法一般应用
本发明化合物对治疗患有多种血管疾病的哺乳动物是有用的,并具有保护活性以抵御产生大脑局部缺血的一些有害因素。这些化合物对治疗哺乳动物通过直接神经元保护或钙通道抑制剂,钠通道抑制剂,或钙和钠通道抑制剂治疗的疾病是有用的,这些疾病包括:
通过直接神经元保护治疗的疾病如:局部和全面性脑缺血,脑缺血包括由神经变性引起的缺血,产期窒息,脊柱损伤,末梢神经缺血,末梢神经损伤,神经病患者疼痛,头损伤,原发性大脑内出血,脑病,癫痫或癫痫神经病症状,和神经病学疾病如阿尔茨海默氏病,亨廷顿舞蹈病,帕金森病和痴呆;
通过钙通道抑制剂,钠通道抑制剂,或钙和钠通道抑制剂治疗的疾病,这些疾病包括:
通过抑制脑血管痉挛和脑血管舒张治疗的疾病,如偏头痛,休克,由蛛网膜下出血引起的痉挛,和由滥用***引起的脑血管缺血;
通过抑制细胞水肿治疗的疾病,如脑水肿和低钠血脑病;
心血管疾病,如高血压,心绞痛,稳定和不稳定心绞痛,梗死性心绞痛,心律失常,血栓,心肌梗死,栓塞,充血性心脏衰竭如慢性或急性心力衰竭;
由末梢血管疾病引起的小腿缺血的疾病,包括间隙性跛行;
以平滑肌痉挛为特征的疾病,包括可逆性气道阻塞,哮喘,输尿管痉挛,膀胱痉挛,子宫痉挛,和过敏性肠综合征;
预防在外科手术期间如移植物分流术,血管造影术,血管成形术,移植期间器官保存的血管收缩和/或缺血性组织损伤,高血压危象,和手术后高血压;
通过利尿治疗的疾病;和***脑病。
总之,发现有血管疾病的哺乳动物包括:家养商品化动物如马,牛,羊和猪;家养室内动物如狗,猫等等;特别是人。
活性试验
对钠通道的亲和力以及与钠和钙电流的相互作用可以在体外测定,治疗脑血管疾病的活性可以通过研究神经保护效果而在体内测定。通过测量[3H]-南美蟾毒的替换在其钠通道上的结合位置(便可在)在体外测定钠通道的亲和力,如实施例13所示。
通过记录整个细胞钠的钳位电压和通道电流在体外测定钠和钙通道活性,如实施例14所示。
体外活性可以根据鼠局部缺血模型(鼠中部大脑动脉阻塞或“MCA”型)测定,Gotti,B.et al.,Brain Res,1990,522,290-307。MCA模型间接测量了局部缺血发生后的神经细胞坏死(即左中部大脑动脉阻塞),如下面实施例16所述。
一般给药
本发明化合物以治疗效果给药,即足以提供治疗上述各种疾病的有效剂量。活性化合物和这里所说的盐可以通过类似用途的任何可接受的制剂给药方式给药。
一般来说,日剂量为0.02-50mg/kg/天式I活性化合物。大多数治疗为0.1-4mg/kg/天的剂量水平。因此,对70kg的人给药剂量范围约为每天1.4-3500mg,优选每天7.0-280mg。
对于特殊疾病,给药可以通过任何可接受的***途径,例如,通过胃肠外,口服,静脉内,或鼻途径,以固体,半固体或液体制剂形式,比如片剂,栓剂,丸剂,胶囊,粉剂,溶液,悬浮液,喷雾剂,乳胶等等,优选以单位剂量形式,因其适合于精细剂量的简单给药。组合物包含常规药物载体或赋性剂以及活性式I化合物,另外,可以包含其它医学制剂,药物制剂,载体,辅剂等。
如果需要,用于给药的药物组合物还可以含有少量无毒辅助物,如湿润剂或乳化剂,pH缓冲剂等等,比如乙酸钠,单月桂酸脱水山梨醇,油酸三乙醇胺等。
本发明化合物一般以含有式(I)化合物和与其结合的药物赋性剂的药物组合物形式给药。制剂中的药量可以在现有技术中所用药量的整个范围内变化,例如,基于全部制剂的药量从约0.01%wt至约99.99%wt和约0.01%wt-99.99%wt赋性剂。优选制剂为约3.5-60%wt药物活性化合物,其余部分为合适的药物赋性剂。
口服给药
根据上面所述疾病,用常规日剂量安排口服给药是优选方式,因为它便于根据病情进行调节。对于口服给药,任何正常使用的赋性剂,例如药物级甘露糖醇,乳糖,淀粉,硬脂酸镁,糖精钠,滑石,纤维素,葡萄糖,明胶,蔗糖,碳酸镁等等,结合形成药物上可接受的无毒的组合物。这些组合物可以是溶液,悬浮液,片剂,丸剂,胶囊,粉剂,缓释剂等等形式。这些组合物可以含有0.01-99.99%wt式(I)化合物,但优选25-80%wt。
组合物优选丸剂或片剂形式,因此该组合物含有活性组分,稀释剂如乳糖,蔗糖,亚磷酸钙等等;分散剂如淀粉或其衍生物;润滑剂如硬脂酸镁等等,粘合剂如淀粉,聚乙烯吡咯烷酮,***树胶,明胶,纤维素及其衍生物等等。
栓剂
对于通过栓剂进行***给药,传统的粘合剂包括比如聚碱乙二醇或三甘油酯[例如PEG1000(96%)和PEG4000(4%)]。这些栓剂可以由含有约0.5-10%wt活性组分的混合物形成,优选1-2%wt。
液体
液体药物可服用组合物可以通过比如溶解分散上述活性化合物(约0.5-20%)和任意药物辅剂于溶液或悬浮液形式的载体比如水,盐水,右旋糖水,甘油,乙醇等等来制备。
这些制剂形式的实际制备方法是已知的,或对本领域技术人员来说是明显的;例如见
Reminqton′s Pharmaceutical Sciences,Mackpublishing Company,Easton,Pennsylvania,16th Ed.,1980。要给药的组合物在任何情况下都含有具有药物疗效的定量的活性化合物以减轻本发明所述的要治疗的特殊疾病。
实施例
下面给出的制备例和实施例可以使本领域技术人员更加了解和实现本发明。本发明不应被认为仅限于这些制备例和实施例,它们只是本发明优选实例的说明和代表。
除非作出相反的说明,这些制备例和实施例均在惰性气体中进行,例如氮或氩气。制备例1
式(9a)化合物的制备
A.其中R9为5-(4-甲基苯基),R10为3-甲基,W为氧,
-CHO在2-位的(9a)的制备
在0℃搅拌的同时将三氯氧化磷(12ml)缓慢加入二甲基甲酰胺(9.85ml),并将混合物在0℃搅拌30分钟。用15分钟在上述溶液中滴入3-甲基-5-(4-甲基苯基)呋喃(22g)的50ml二氯乙烷溶液,并保持0℃。然后在室温下搅拌1.5小时。加入冰水,用稀氢氧化钠将水相的pH调至8。分离有机相,用二氯甲烷萃取水相,减压条件下合并有机相并去掉溶剂。减压条件下从滤液中去掉溶剂,剩余物用快速硅胶色谱法分离,用10%乙酸乙酯的庚烷洗脱,得到19.2g 2-甲酰基-3-甲基-5-(4-甲基苯基)呋喃。
B.改变R9,R10,W和甲酰基位置的(9a)的制备
类似地,依照上述制备例1A的方法,只是用其它式的(9)化合物代替3-甲基-5-(4-甲基苯基)呋喃,制备下列式(9a)的中间体:
2-甲酰基-3-甲基-5-(正-丁基)呋喃,为油状物;
2-甲酰基-3-甲基-5-(叔-丁基)呋喃,为油状物;
2-甲酰基-3-甲基-5-苯基呋喃,m.p.55℃;
2-甲酰基-3-甲基-5-(4-三氟甲基苯基)呋喃,m.p.80℃;
2-甲酰基-3-甲基-5-环己基呋喃,为油状物;
2-甲酰基-3-甲基-5-苯基吡咯,m.p.152-153℃;
3-甲酰基-2-甲基-5-苯基吡咯,m.p.150℃;
3-甲酰基-1,2-二甲基-5-苯基吡咯,m.p.97℃;
2-甲酰基-1,3-二甲基-5-苯基吡咯,为油状物;
2-甲酰基-3-甲基-5-苯基噻吩,m.p.110℃;
3-甲酰基-2-甲基-5-苯基噻吩,m.p.82-83℃。制备例2
式(17)化合物的制备
A.其中R11为4-甲基苯基,R12氢,R为乙基的(17)的制备
将镁(1.6g)和对-溴甲苯(10.26g)的60ml四氢呋喃搅拌并加温直至反应开始。放热反应结束后将混合物回流过夜。在另一烧杯中将4mlDIBAL(1M于甲苯中)加入二(三苯基磷)氯化钯(II)(1.4g)的100ml四氢呋喃悬浮液中,接着加入3-碘苯甲酸乙酯(11.04g)。将上面制备的镁试剂滴入该混合物,引起放热反应。在室温下将反应混合物搅拌过夜,然后加入稀盐酸淬灭。混合物用***萃取,然后用水和饱和盐水洗涤有机相。分离有机相,用硫酸钠干燥,减压蒸发溶剂,剩余物用硅胶色谱法分离,用5%乙酸乙酯的庚烷洗脱,得到5.69g 4′-甲基联苯基-3-羧酸乙酯,即式(17)化合物,为淡黄色油。
B.其中R为乙基并改变R11和R12的(17)的制备
类似地,依照上面制备例2A的方法,只是用式(15)的其它芳基卤前体任意代替对-溴甲苯,用其它式(16)化合物任意代替3-碘苯甲酸乙酯,制备下列式(17)的中间体:
4,4′-二甲基联苯基-3-羧酸乙酯;
4-甲基-4′-氟联苯基-3-羧酸乙酯;
4-甲基-4′-三氟甲基联苯基-3-羧酸乙酯;
4-甲基-4′-甲氧基联苯基-3-羧酸乙酯;
4′-甲氧基联苯基-3-羧酸乙酯;
4′-二甲基氨基联苯基-3-羧酸乙酯;
4-甲基-3′-甲氧基联苯基-3-羧酸乙酯。制备例3
式(18)化合物的制备
A.其中R11为4-甲基苯基,R12为氢的(18)的制备
将10ml 10%氢氧化钠水溶液加到4′-甲氧基联苯基-3-羧酸乙酯(4.0g)的乙醇(50ml)溶液中,将混合物回流2小时。减压除去溶剂,剩余物中加水,过滤溶液。滤液用稀盐酸酸化,滤掉白色固体并真空干燥,得到2.4g 4′-甲基联苯基-3-羧酸,m.p.192℃。
B.改变R11和R12的(18)的制备
类似地,依照上面制备例3A的方法,只是用其它式(17)化合物代替3-(4-甲基苯基)苯甲酸乙酯,制备下列式(18)的中间体:
4,4′-二甲基联苯基-3-羧酸;
4-甲基-4′-氟联苯基-3-羧酸;
4-甲基-4′-三氟甲基联苯基-3-羧酸;
4-甲基-4′-甲氧基联苯基-3-羧酸;
4′-甲氧基联苯基-3-羧酸;
4′-二甲基氨基联苯基-3-羧酸;
4-甲基-3′-甲氧基联苯基-3-羧酸。制备例4
式(19)化合物的制备
A.其中-NR2R3为代表二苯基甲基哌嗪,R11为4-甲基苯基,
R12为氢的(19)的制备
将亚硫酰氯(1.48g)加到4′-甲基联苯基-3-羧酸(2.2g)的二氯甲烷(20ml)和二甲基甲酰胺(0.5ml)混合物的悬浮液中。将该混合物回流至悬浮物溶解,之后可冷却使温度降至室温。向该溶液中滴加1-(二苯基甲基)哌嗪(3.94g)的二氯甲烷,并将反应混合物放置过夜。加入氢氧化钠(30ml,1N)和50ml二氯甲烷,分离有机相,用盐水洗涤,用硫酸钠干燥,减压除去溶剂。剩余物用硅胶色谱法分离,用25%乙酸乙酯的庚烷洗脱,得到3.8g 1-二苯基甲基-4-(4′-甲基联苯基-3-羰基)哌嗪。制备二盐酸盐并从乙醇中重结晶,m.p.226℃。
B.改变-NR2R3,R11和R12的(19)的制备
类似地,依照上面制备例4A的方法,只是用其它式(18)化合物代替4′-甲基联苯基-3-羧酸,制备下列式(19)的中间体:
1-二苯基甲基-4-(4,4′-二甲基联苯基-3-羰基)哌嗪;
1-二苯基甲基-4-(4-甲基-4′-氟联苯基-3-羰基)哌嗪;
1-二苯基甲基-4-(4-甲基-4′-三氟甲基联苯基-3-羰基)哌嗪;
1-二苯基甲基-4-(4-甲基-4′-甲氧基联苯基-3-羰基)哌嗪;
1-二苯基甲基-4-(4′-甲氧基联苯基-3-羰基)哌嗪;
1-二苯基甲基-4-(4′-二甲氨基联苯基-3-羰基)哌嗪;
1-二苯基甲基-4-(4-甲基-3′-甲氧基联苯基-3-羰基)哌嗪;制备例5
式(20)化合物的制备
A.其中R11为4-甲基苯基,R12为4-甲基的(20)的制备
在0℃将4,4′-二甲基联苯基-3-羧酸乙酯(2g)的***溶液滴加到氢化铝锂(0.2g)的50ml***悬浮液中。滴加完成后将混合物缓慢升温至室温,搅拌2小时。过量试剂用湿硫酸钠水解。过滤该混合物,减压从滤液中蒸发掉溶剂,剩余物用快速硅胶色谱法分离,用25%乙酸乙酯的庚烷洗脱,得到3-羟甲基-4,4′-二甲基联苯基为油状物。
B.改变R11和R12的(20)的制备
类似地,依照上面制备例5A的方法,只是用其它式(17)化合物代替4,4′-二甲基联苯基-3-羧酸乙酯,制备下列式(20)的中间体:
3-羟甲基-4-甲基-4′-氟联苯基,为油状物;
3-羟甲基-4-甲基-4′-三氟甲基联苯基,m.p.92℃;
3-羟甲基-4′-甲氧基联苯基,m.p.91℃;
3-羟甲基-4-甲基联苯基,为油状物;
3-羟甲基-4′-甲基联苯基,为油状物;
3-羟甲基-4′-二甲氨基联苯基,m.p.94℃;
3-羟甲基-4-甲基-3′-甲氧基联苯基,为油状物;
3-羟甲基-4-甲基-4′-甲氧基联苯基,m.p.85℃;
4-羟甲基-4′-甲基联苯基,m.p.130℃;
4-羟甲基-4,4′-二甲基联苯基,为油状物。实施例1
式(IB)化合物的制备
A.其中m为0,R1为氢,-NR2R3代表1-二苯基甲基哌啶,
R9为4-三氟甲基苯基,R10为3-甲基的(IB)的制备
将2-甲酰基-3-甲基-5-(4-三氟甲基苯基)呋喃(0.5g),1-二苯基哌啶(0.54g)和异丙醇钛(IV)(0.73g)的溶液在室温下放置1小时。加入乙醇(10ml),将所得溶液搅拌1小时。然后加入氰基硼氢化钠(90mg),将混合物搅拌过夜。加入氢氧化钠使pH值超过7,减压除去溶剂,将剩余物在二氯甲烷和水之间分配。过滤混合物,分离有机相,用无水硫酸镁干燥,过滤并蒸发。剩余物用快速硅胶色谱法分离,用乙酸乙酯/甲醇/氨(97/3/0.5)洗脱,得到4-二苯基甲基-1-[(5-(4-三氟甲基苯基)-3-甲基呋喃-2-基)甲基]哌啶。在乙醇中用无水盐酸处理将该碱转化成其盐酸盐,m.p.240℃。
B.其中m为0,R1为氢,改变-NR2R3,R9和R10的(IB)的制备
类似地,依照上面实施例1A的方法,只是用其它式(9a)化合物代替2-甲酰基-3-甲基-5-(4-三氟甲基苯基)呋喃,用式HNR2R3的胺任意代替1-二苯基甲基哌啶,制备下列式(IB)化合物:
1-二苯基甲基-4-[(5-苯基-3-甲基呋喃-2-基)甲基]哌嗪二盐酸化物,m.p.170℃;
1-二苯基甲基-4-[(5-正-丁基-3-甲基呋喃-2-基)甲基]哌嗪二盐酸化物,m.p.145℃;
1-二苯基甲基-4-[(5-叔-丁基-3-甲基呋喃-2-基)甲基]哌嗪二盐酸化物,m.p.160℃;
1-二苯基甲基-4-[(5-环己基-3-甲基呋喃-2-基)甲基]哌嗪二盐酸化物,m.p.120℃;m.p.二盐酸化物184℃;
1-二苯基甲基-4-[(5-(4-三氟甲基苯基)-3-甲基呋喃-2-基)甲基]哌嗪,m.p.150℃;m.p.二盐酸化物1 80℃;
1-二苯基甲基-4-[(5-(4-甲基苯基)-3-甲基呋喃-2-基)甲基]哌嗪二盐酸化物,m.p.225℃;
1-二苯基甲基-4-[(5-(4-甲氧基苯基)-3-甲基呋喃-2-基)甲基]哌嗪富马酸盐,m.p.216-218℃;
4-二苯基甲基-1-[(5-苯基-3-甲基呋喃-2-基)甲基]哌嗪二盐酸化物,m.p.250℃;
1-(2,3,4-三甲氧基苯基)甲基-4-[(5-(4-三氟甲基苯基)-3-甲基呋喃-2-基)甲基]哌嗪二盐酸化物,m.p.230℃;
4-(4-氟苯基)甲基-1-[(5-(4-甲基苯基)-3-甲基呋喃-2-基)甲基]哌嗪二盐酸化物,m.p.210℃;
2,2-二(4-氟苯基)-4-[(5-(4-甲基苯基)-3-甲基呋喃-2-基)甲基]二盐酸化物,m.p.210℃;
1-二苯基甲基-4-[(5-苯基-3-甲基吡咯-2-基)甲基]哌嗪,m.p.60-63℃;马来酸盐,m.p.149-152℃;
1-二苯基甲基-4-[(5-苯基-2-甲基吡咯-3-基)甲基]哌嗪马来酸盐,m.p.180℃;
1-二苯基甲基-4-[(5-苯基-1,2-二甲基吡咯-3-基)甲基]哌嗪二盐酸化物,m.p.225℃;
1-(2,3,4-三甲氧基苯基)甲基-4-[(5-苯基-1,2-二甲基吡咯-3-基)甲基]哌嗪二盐酸化物,m.p.205℃;
1-二苯基甲基-4-[(5-苯基-1,3-二甲基吡咯-2-基)甲基]哌嗪,m.p.151-152℃;马来酸盐,m.p.159-162℃;
1-(2,3,4-三甲氧基苯基)甲基-4-[(3-甲基-5-苯基噻吩基-2-基)甲基]哌嗪二盐酸化物,m.p.180℃;
1-二苯基甲基-4-[(3-甲基-5-苯基噻吩基-2-基)甲基]哌嗪二盐酸化物,m.p.179℃;
4-二苯基甲基-1-[(3-甲基-5-苯基噻吩基-2-基)甲基]哌啶二盐酸化物,m.p.250℃;
4-二苯基甲基-1-[(5-(4-甲基苯基)-3-甲基呋喃-2-基)甲基]哌啶盐酸化物;
4-二苯基甲基-1-[(5-(4-甲氧基苯基)-3-甲基呋喃-2-基)甲基]哌啶盐酸化物;
4-二(4-氟苯基)甲基-1-[(3-甲基-5-苯基噻吩基-2-基)氧甲基]哌啶二盐酸化物,m.p.135℃;
1-二苯基甲基-4-[(2-甲基-5-苯基噻吩基-3-基)甲基]哌嗪二盐酸化物,m.p.179-181℃;
4-二苯基甲基-1-[(2-甲基-5-苯基噻吩基-3-基)甲基]哌啶二盐酸化物,m.p.155℃;实施例2
式(IB)化合物的制备
A.其中m为0,R1为甲基,-NR2R3代表1-二苯基甲基哌嗪,
R9为2-苯基,R10为4-甲基的(IB)的制备
将2-苯基-4-甲基-5-甲酰基呋喃(1.1g),二苯基甲基哌嗪(1.5g)和异丙醇钛(IV)(1.76g)的溶液搅拌1.25小时。加入***(20ml),将所得溶液搅拌30分钟。然后滴加甲基碘化镁(6ml 3M的***),将混合物在室温搅拌1小时。然后加入氯化铵(20ml的水饱和溶液),接着加入300ml二氯甲烷,用碳酸氢钠溶液使该混合物碱化。将剩余物在二氯甲烷和水之间分配,分离有机相,用无水硫酸镁干燥,过滤并蒸发。剩余物用快速硅胶色谱法分离,用15%乙酸乙酯的庚烷洗脱,用氨示踪,得到0.51g 1-(二苯基甲基)-4-[(2-苯基-4-甲基呋喃-5-基)乙基-1-基]哌嗪。在乙醇中用无水盐酸处理将该碱转化成其盐酸盐,m.p.205-208℃。实施例3
式(IB)化合物的制备
A.其中m为1,R1为羟基,-NR2R3代表1-(二苯基甲基)哌嗪,
R9为3-苯基,R10为2-甲基的(IB)的制备
1.其中R9为3-苯基,R10为2-甲基的(11)的制备
用紫外线保护5-乙酰基-2-甲基-3-苯基呋喃(3.8g)的50ml四氢呋喃,搅拌的同时加入少量吡咯烷酮氢三溴化物(9.4g)。将该混合物搅拌过夜,保持紫外线,在室温下滤掉结晶,用四氢呋喃洗涤,减压蒸发滤液。
将产物与二苯基甲基哌嗪(4.8g)和碳酸钾(3g)的异丙醇(50ml)合并,将该混合物回流2小时。减压除去溶剂,剩余物中加入100ml二氯甲烷,滤除沉淀。固体用二氯甲烷洗涤,合并合并的有机相并减压除去溶剂。剩余物用快速色谱法分离,用20%乙酸乙酯的庚烷洗脱,得到3.8g 1-(二苯基甲基)-4-[(2-甲基-3-苯基呋喃-5-基)乙酰-2-基]哌嗪式(11)化合物。
2.其中R1为羟基,R9为3-苯基,R10为2-甲基,
-NR2R3代表1-(二苯基甲基)哌嗪的(IB)的制备
在5到10℃,将式(11)化合物(制备于第一部分)溶解于100ml乙醇,并加入1.3g硼氢化钠。将混合物搅拌30分钟,再加入1.3g硼氢化钠,再在5到10℃搅拌30分钟,然后在室温搅拌30分钟。加入50ml水,减压除去溶剂。将剩余物在二氯甲烷和水之间分配,分离有机相,用无水硫酸镁干燥,过滤并蒸发。产物为淡黄色油状物,用异丙醚研制,得到2.9g 1-(二苯基甲基)-4-[(2-甲基-3-苯基呋喃-5-基)-1-羟基乙烷-2-基]哌嗪。在乙醇中用无水盐酸处理将该碱转化成其盐酸盐,m.p.190℃。
B.其中m为1,R1为羟基,改变R2,R3,R9和R10的(IB)的制备
类似地,依照上面实施例3A第1和第2部分的方法,只是用其它式(10)化合物代替5-乙酰基-2-甲基-3-苯基呋喃,用式HNR2R3的胺任意代替二苯基甲基哌啶,制备下列其中R1为羟基和m为1的式(IB)化合物:
1-(二苯基甲基)-4-[(2-苯基-5-甲基呋喃-4-基)-1-羟基乙烷-2-基]哌嗪,m.p.140℃;
1-(二苯基甲基)-4-[(2-甲基呋喃-5-基)-1-羟基乙烷-2-基]哌嗪二盐酸化物,m.p.197℃;
1-(二苯基甲基)-4-[(2,5-二甲基呋喃-4-基)-1-羟基乙烷-2-基]哌嗪二盐酸化物,m.p.195℃;和
1-(二苯基甲基)-4-[(2-苯基-4-甲基呋喃-5-基)-1-羟基乙烷-2-基]哌嗪二盐酸化物,m.p.144-154℃。实施例4
式(ID)化合物的制备
A.其中m为0,R1为氢,-NR2R3代表1-(二苯基甲基)哌嗪,
R11为4-甲基苯基,和R12为氢的(IDA)的制备
在0℃向氢化铝锂(0.13g)的50ml***的悬浮液中滴加1-二苯基甲基-4-(4′-甲基联苯基-3-羰基)哌嗪(1g)的***和四氢呋喃的混合溶液。滴加完成后,使混合物慢慢升至室温,并搅拌1.5小时。用湿硫酸钠水解过量的试剂。过滤混合物,蒸发溶解,并将剩余物在硅胶上进行快速色谱分离,用25%乙酸乙酯的庚烷洗脱产生1-二苯基甲基-4-[4′-甲基联苯基-3-甲基]哌嗪,将其用无水盐酸的乙醇处理转化为其二盐酸化物,m.p.206℃。
B.其中m为0,R1为氢,改变-NR2R3,R11和R12的(IDA)的制备
类似地,用上述实施例4A的方法,只是用其它式(19)化合物代替1-二苯基甲基-4-(4′-甲基联苯基-3-羰基)哌嗪,制备式(IDA)的下列化合物:
1-二苯基甲基-4-(4,4′-二甲基联苯基-3-甲基)哌嗪;
1-二苯基甲基-4-(4-甲基-4′-氟联苯基-3-甲基)哌嗪;
1-二苯基甲基-4-(4-甲基-4′-三氟甲基联苯基-3-用基)哌嗪;
1-二苯基甲基-4-(4-甲基-4′-甲氧基联苯基-3-甲基)哌嗪;
1-二苯基甲基-4-(4′-甲氧基联苯基-3-甲基)哌嗪;
1-二苯基甲基-4-(4,4′-二甲氨基联苯基-3-甲基)哌嗪;
1-二苯基甲基-4-(4-甲基-3′-甲氧基联苯基-3-甲基)哌嗪。实施例5
式(ID)化合物的制备A.其中m为0,R1为氢,-NR2R3为3-位的1-(二苯基甲基)哌嗪甲基,
R11为4-甲基苯基,和R12为甲基的(IDA)的制备
将3-羟甲基-4,4′-二甲基联苯基(1.3g)和三乙胺(0.8g)的二氯甲烷(50ml)溶液冷却至0℃,滴加甲磺酰氯(0.84g)的二氯甲烷。将混合物升温至室温,并搅拌过夜。然后加入冰/水,分离有机相,水相用二氯甲烷洗涤,有机相用盐水洗涤,用硫酸钠干燥,减压除去溶剂,得到3-氯甲基-4,4′-二甲基联苯基为油状物。
将该产物溶解于乙腈并加到1-(二苯基甲基)哌嗪(1.85g)和碳酸钾(1g)的乙腈(60ml)溶液中。将混合物回流过夜,滤除固体,用二氯甲烷洗涤,减压从滤液中除去溶剂,将剩余物在硅胶上进行快速色谱分离,用30%乙酸乙酯的庚烷洗脱,产生1-二苯基甲基-4-[4,4′-二甲基联苯基-3-基甲基]哌嗪为纯白色固体,将其用无水盐酸的乙醇处理转化为二盐酸化物,m.p.177℃。
B.其中m为0,R1为氢,改变-NR2R3,R11和R12的(IDA)的制备
类似地,用上述实施例5A的方法,只是用其它式(17)化合物任意代替3-羟甲基-4,4′-二甲基联苯基,用1-(2,3,4-三甲氧基苯基-甲基)哌嗪任意代替1-(二苯基甲基)哌嗪,制备式(IDA)的下列化合物:
1-(2,3,4-三甲氧基苯基甲基)-4-[4,4′-二甲基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.193℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4-甲基-4′-氟联苯基-3-基甲基]哌嗪二盐酸化物,m.p.198℃;
1-二苯基甲基-4-[4-甲基-4′-三氟甲基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.157℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4-甲基-4′-三氟甲基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.185℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4-甲基-4′-甲氧基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.230℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4′-甲氧基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.204℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4-甲基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.204℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4′-二甲氨基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.232℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4-甲基-3′-甲氧基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.194℃;
1-(3,4,5-三甲氧基苯基甲基)-4-[4-甲基-3′-甲氧基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.220℃;
N-[4-甲基-4′-甲氧基联苯基-3-甲基]-N-甲基-4,4-二苯基丁基胺盐酸化物,m.p.93℃;
N-[4-甲基-4′-甲氧基联苯基-3-甲基]-N-甲基-3-(2,3,4-三甲氧基苯基)丙胺富马酸盐,m.p.185℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[3,4′-二甲基联苯基-4-基甲基]哌嗪二盐酸化物,m.p.220℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4′-甲基联苯基-4-基甲基]哌嗪二盐酸化物,m.p.235℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4′-甲基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.125℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[3-(3-呋喃基)苯基甲基]哌嗪二盐酸化物,m.p.183℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[3-(4-吡啶基)苯基甲基]哌嗪三盐酸化物,m.p.189℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[5-甲基-4′-甲氧基联苯基-3-基甲基]哌嗪二盐酸化物,m.p.230℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4-氯-4′-甲氧基联苯基-3-基甲基]哌嗪盐酸化物,m.p.190℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[4′-氯联苯基-3-基甲基]哌嗪二盐酸化物,m.p.201℃;
2,2-二-(4-氟苯基)-4-[4′-甲氧基联苯基-3-基甲基]吗啉甲磺酸盐,m.p.202℃;
1-(4-氟苯基甲基)-4-[4′-甲氧基联苯基-3-基甲基]哌嗪二甲磺酸盐,m.p.202℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[3-(正-丁基苯基)-甲基]哌嗪二盐酸化物,m.p.177℃;
1-(2,3,4-三甲氧基苯基甲基)-4-[3-(3-噻吩基)苯基甲基]哌嗪二盐酸化物,m.p.210℃。实施例6-12
下列实施例说明了含有活性式I化合物,例如:(±)-1-(2,3,4-三甲氧基苯基甲基)-4-[4-甲基-4′-甲氧基联苯基-3-基甲基]哌嗪二盐酸化物的有代表性的药物制剂的制备。式I的其它化合物和盐如根据实施例1-5制备的那些也可以作为实施例6-12制剂中的活性化合物。实施例6 I.V.制剂
活性化合物 0.14g
丙二醇 20.0g
聚乙二醇400 20.0g
吐温(Tween)80 1.0g
0.9%盐水溶液 100.0ml
这里也可用其它式I化合物及其药物上可接受的盐。实施例7
组分 每片含量,mqs
活性化合物 25
玉米淀粉 20
乳糖,喷雾干燥 153
硬脂酸镁 2
将上述组分充分混合并压制成单个药片。实施例8
组分 每粒含量,mqs.
活性化合物 100
乳糖,喷雾干燥 148
硬脂酸镁 2
将上述组分混合并装入硬壳明胶胶囊。实施例9
组分 每片含量,mqs.
活性化合物 1
玉米淀粉 50
乳糖 145
硬脂酸镁 5
将上述组分紧密混合并压制成单个药片。实施例10
组分 每粒含量,mqs.
活性化合物 150
乳糖 92
将上述组分混合并装入硬壳明胶胶囊。实施例11
用下列组合物制备缓冲pH至7的可注射制剂:
组分
活性化合物 0.2g
KH2PO4缓冲液(0.4M溶液) 2ml
KOH(1N) q.s.至pH7
水(蒸馏,灭菌) q.s.至20ml实施例12
含有下列组合物的口服悬浮剂的制备:
组分
活性化合物 0.1g
富马酸 0.5g
氯化钠 2.0g
羟苯甲酸甲酯 0.1g
糖粒 25.5g
山梨糖醇(70%溶液) 12.85g
Veegum K(Vanderbilt Co.) 1.0g
调味剂 0.035ml
色素 0.5mg
蒸馏水 q.s.至100ml实施例13
Na+通道结合部位亲和力的测定([3H]-南美蟾毒)
将冲洗过的鼠脑突触体匀浆与3H]-南美蟾毒(3H]BTX,2nM)和试验化合物(或没有)浓度为1010-104的Hepes缓冲溶液(氯化钾5.4mM,MgSO4 0.8mM,葡萄糖5.5mM,Hepes 50mM,胆碱130mM,pH7.4),其中含有河豚毒素(最终测定浓度1μM)和蝎毒素(最终测定浓度100mg),最终体积为500μl,一起培养。用饱和的蔡芦次碱浓缩物(0.3mM)定义没有特定结合。将测定试管在25℃培养90分钟然后在Whatam GF/B玻璃纤维过滤垫用Brandel细胞采集器过滤。用液体闪烁光谱测定结合放射性。将试验化合物对于Na+通道的亲和力与pIC50值比较。式(I)化合物对于Na+通道亲和力如下所示。
化合物 pIC50vs[3H]BTX
A 6.47+0.1
B 7.76+0.09
A=1-(2,3,4-三甲氧基苯基甲基〕-4-[4-甲基-4′-
甲氧基联苯基-3-基甲基]哌嗪二盐酸化物
B=4-二苯基甲基-1-[5-(4-三氟甲基苯基)-3-甲基
呋喃-2-基甲基]哌啶盐酸化物实施例14
N1E115成神经细胞瘤细胞的钠电流(INa)的整个细胞钳位电压记录
这是整个细胞变异的修补钳位(patch clamp)技术的一种整个细胞变型(Hammill et al.,Pflugers Arch.(1981)391,85-100)。
内溶液的离子组合物(以mM表示)为:120CsF,10NaCl,11EGTA,10HEPES,10氯化四乙铵,1CaCl2,1MgCl2(用CsOH调节pH至7.3)和含有145NaCl,3KCl,10HEPES,1CaCl2,1MgCl2,0.5CdCl2,5葡萄糖(用NaOH调节pH至7.3)的外溶液。
将细胞放在膜电位为-80mV,通过去极化过程降至0mV引起INa直到可记录稳定的电流。然后用一系列去极化过程使膜电压为-60-+70mV(增量10mV)作出电流/电压曲线。使试验化合物1μM,3μM,或10μM作用10分钟,记录第二次电流/电压曲线。
试验化合物产生如下所示对固有钠电流(INa)(从电流/电压曲线测量)的峰的抑制。
化合物 浓度[μM] 对钠电流的抑制% n IC50
A 1 12.9±7.7 3 3μM
3 51.2±6.1 3
10 100 1A=1-(2,3,4-三甲氧基苯基甲基〕-4-[4-甲基-4′-
甲氧基联苯基-3-基甲基]哌嗪二盐酸化物n=试验细胞的数量实施例15
T-型钙电流(ICa(T))的整个细胞钳位电压记录
这是修补钳位技术的一种整个细胞变型(Hammill et al.,PflugersArch.(1981)391,85-100)。
内溶液的离子组合物(以mM表示)为:120CsCl,10NaCl,11EGTA,10HEPES,10氯化四乙铵,1CaCl2,1MgCl2,40蔗糖(用CsOH调节pH至7.4)和含有110Tris碱,20BaCl,5CsCl2,5KCl,20HEPES,30葡萄糖(用HCl调节pH至7.4)的外溶液。
将细胞定位在膜电位为-80mV,通过200ms去极化过程降至-10mV引起ICa(T)直到可产生稳定的电流。然后用一系列去极化过程使膜电压为-60-+40mV(增量10mV)作出电流/电压曲线。将试验化合物放在过冷介质中得到最终浓度为3μM或10μM。使药物作用10分钟后,得到第二次记录电流/电压曲线。
试验化合物抑制T-型Ca电流如下所示。
化合物 浓度 对钠电流的抑制% n IC50
A 3μM 30±3.3 3 8μM
10μM 59.2±5.8 1
A=1-(2,3,4-三甲氧基苯基甲基〕-4-[4-甲基-4′-
甲氧基联苯基-3-基甲基]哌嗪二盐酸化物
n=试验细胞的数量实施例16
用MCA模型测定活性
将成年雄性小鼠(CD1种),体重30-40g,用5%的卤代烷的二氧化氮∶氧气为70%比30%的混合物进行麻醉。
将左中部大脑动脉暴露在介于眼睛和外耳道间的弯曲切口中部,将该动脉用热烙术封住。
剂量表如下:将试验化合物的第一剂量(腹膜内0.05-1.0mg/kg)在局部缺血15分钟后给药。然后将小鼠恢复7天,在此期间,每天在约上午9点和下午4点用相同试验化合物剂量给药二次。
在最后剂量4小时后将小鼠处死。从缺血左半球解剖梗塞面积并且将对面的右半球作为非缺血组织进行对照。
通过测量结合[3H] PK 11195定量缺血半球的损伤,这种结合提供了缺血损作的指标即与[3H] PK 11195(由Bmax评价)的结合的升高间接地反应了神经的损伤情况能防止增加一些结合部位的化合物被认为是神经保护剂。
用对照剂处理的动物显示在缺血半球增加了[3H] PK 11195的结合的Bmax,结果增加了左半球(缺血):右半球(非缺血)结合的比例。此时,被认为100%损伤,并以此为根据,可计算出化合物的效果。
在这个研究中的各结合部位对[3H] PK 11195的亲和力没有改变。
在这个模型中式(I)化合物显示的神经保护效果如下所示。a.有效剂量范围化合物 剂量ip 15min后局部缺血 剂量ip bid 7天 %保护A 50μg/kg 50μg/kg 59%与对照组比较
500μg/kg 500μg/kg 73%与对照组比较B 50μg/kg 50μg/kg 63%与对照组比较
500μg/kg 500μg/kg 66%与对照组比较b. 剂量响应曲线
化合物 剂量 %保护
A 50μg/kg 52n.s.
100μg/kg 64)
250μg/kg 62)p<0.05
500μg/kg 76)
1mg/kg 87)A=1-(2,3,4-三甲氧基苯基甲基〕-4-[4-甲基-4′-
甲氧基联苯基-3-基甲基]哌嗪二盐酸化物B=4-二苯基甲基-1-[5-(4-三氟甲基苯基)-3-甲基
呋喃-2-基甲基]哌啶盐酸化物实施例17
鼠静脉内毒性
每天一次,连续5天,通过尾部静脉给体重150-180g的成年雄鼠和雌鼠(Hsd Ola:sprague Dawley SD,种)静脉内给药。所用化合物A[1-(2,3,4-三甲氧基苯基甲基)-4-(4-甲基-4′-甲氧基联苯基-3-基甲基)哌嗪二盐酸化物]的剂量为6和10mg/kg/天。
每日评定动物的临床状态,未见相反效果。后mortem检查显示无***毒性的证据。
虽然本发明已通过它们的特殊具体实例加以描述,但是,本领域技术人员应该理解的是,在不脱离本发明真实精神和范围的条件下,会有各种变化和用等价物取代。另外,可以对特定条件,材料,物质组合,方法步骤或步骤等进行修改以使它们适用于本发明的目的,精神和范围。所有这些修改都将在随后附上的权利要求的范围之内。
Claims (10)
n是0或1;
p是0,1,2或3;
q是0或1;
R4是氢,低级烷基,环烷基,或任意取代的苯基;
R5是任意取代的苯基;
X是(CH2)p,或4-哌啶-1-基;
Y是CH,CH-O-,CH-S-,或氮;
Z是CH2,NH,硫,或氧;及A选自下式基团:其中:
R9是低级烷基,或任意取代的苯基;
R10是氢,或低级烷基;
R11是低级烷基,或任意取代的芳基;
R12是氢,低级烷基,低级烷氧基,卤,或三氟甲基;及
W是氧,硫,或NR15;
其中:R15是氢,或低级烷基;
条件是R9,R10,R12和其侧链不能连接在杂原子上。
4.权利要求3的化合物,其中W是氧,Y是CH,R9是5-(4-三氟甲基苯基),R10是3-甲基,且侧链在2-位上,即4-二苯基甲基-1-[(5-(4-三氟甲基苯基)-3-甲基呋喃-2-基)甲基]哌啶或其药物上可接受的酸加成盐。
6.权利要求5的化合物,其中R2和3与其连接的氮原子一起代表下式基团:或其药物上可接受的酸加成盐。
7.权利要求6的化合物,其中Y是氮,R4是氢,5是2,3,4-三甲氧基苯基,且侧链在3-位上,即1-(2,3,4-三甲氧基苯基甲基)-4-[4-甲基-4′-甲基联苯基-3-基甲基]哌嗪或其药物上可接受的酸加成盐。
8.权利要求1的化合物对于治疗哺乳动物的某些疾病的用途,这些疾病包括:
局部缺血包括局部和全面性脑缺血,脑缺血包括由神经变性引起的缺血,产期窒息,脊柱损伤,末梢神经缺血,末梢神经损伤,神经病患者疼痛,头损伤,原发性大脑内出血,脑病,癫痫或癫痫神经病症状,和神经病学疾病如阿尔茨海默氏病,亨廷顿舞蹈病,帕金森病和痴呆;或
偏头痛,休克,由蛛网膜下出血引起的痉挛,和由滥用***引起的脑血管缺血;
脑水肿和低钠血脑病;
高血压,心绞痛,稳定和不稳定心绞痛,梗死性心绞痛,心律失常,血栓,栓塞,充血性心脏衰竭如慢性或急性心力衰竭;
间隙性跛行;
可逆性气道阻塞,哮喘,输尿管痉挛,膀胱痉挛,子宫痉挛,和过敏性肠综合征;
在外科手术期间如移植物分流术,血管造影术,血管成形术,移植期间器官保存的血管收缩和/或缺血性组织损伤,高血压危象,和手术后高血压;
通过利尿治疗的疾病;和***脑病。
9.一种药物组合物,含有治疗剂量权利要求1化合物或其药物上可接受的盐,以及与其混合的一个或多个药物上可接受的无毒载体。
m为0或1;
R1为氢,羟基或低级烷基;
R2为氢或低级烷基;
R3为
n是0或1;
p是0,1,2或3;
q是0或1;
R4是氢,低级烷基,环烷基,或任意取代的苯基;
R5是任意取代的苯基;
X是(CH2)P,或4-哌啶-1-基;
Y是CH,CH-O-,CH-S-,或氮;
Z是CH2,NH,硫,或氧;及
R9是低级烷基,或任意取代的苯基;
R10是氢,或低级烷基;
R11是低级烷基,或任意取代的芳基;
R12是氢,低级烷基,低级烷氧基,卤,或三氟甲基;及
W是氧,硫,或NR15;
其中:R15是氢,或低级烷基;条件是R9,R10,R12和其侧链不能连接在杂原子上,它们包括:a)式化合物
其中R9和R10定义如上,在钛(IV)催化剂存在下与式HNR2R3的胺反应,其中R2和R3定义如上,接着加入还原剂(如果R1为氢)或Grignard试剂(如果R1为低级烷基),生成式I化合物;或b)下式化合物其中R9,R10,R12和R13定义如上,与还原剂反应生成其中R1为羟基的式I化合物;或c)下式化合物其中R11,R12,R2和R3定义如上,与还原剂反应生成式I化合物;或d)下式化合物其中R11,R12定义如上,L为离去基团,与式HNR2R3的胺反应,其中R2和R3定义如上,生成式I化合物;或e)式I化合物的游离碱与酸反应,得到药物上可接的酸加成盐;或f)式I化合物的酸加成盐与碱反应,得到适当的游离碱;或g)将式I化合物的酸加成盐转变成另一药物上可接受的酸加成盐。
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US4829065A (en) * | 1987-04-24 | 1989-05-09 | Syntex Pharmaceuticals, Ltd. | Substituted imidazolyl-alkyl-piperazine and -diazepine derivatives |
US5043447A (en) * | 1987-04-24 | 1991-08-27 | Syntex Pharmaceuticals, Ltd. | Substituted imidazolyl-alkyl-piperazine and -diazepine derivatives |
US4921863A (en) * | 1988-02-17 | 1990-05-01 | Eisai Co., Ltd. | Cyclic amine derivatives |
-
1993
- 1993-04-09 US US08/045,568 patent/US5428037A/en not_active Expired - Fee Related
-
1994
- 1994-04-06 WO PCT/EP1994/001085 patent/WO1994024116A1/en not_active Application Discontinuation
- 1994-04-06 CA CA002160113A patent/CA2160113A1/en not_active Abandoned
- 1994-04-06 AU AU65660/94A patent/AU6566094A/en not_active Abandoned
- 1994-04-06 EP EP94913550A patent/EP0693062A1/en not_active Withdrawn
- 1994-04-06 JP JP6522707A patent/JPH08508741A/ja active Pending
- 1994-04-06 CN CN94191728A patent/CN1120838A/zh active Pending
- 1994-04-06 BR BR9406209A patent/BR9406209A/pt not_active Application Discontinuation
-
1995
- 1995-03-09 US US08/401,486 patent/US5545645A/en not_active Expired - Fee Related
- 1995-04-24 HU HU95P/P00109P patent/HU210880A9/hu unknown
- 1995-10-04 FI FI954718A patent/FI954718A0/fi not_active Application Discontinuation
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105683163A (zh) * | 2013-10-04 | 2016-06-15 | 诺华股份有限公司 | RNA干扰中使用的RNAi剂的3’端帽 |
US10227588B2 (en) | 2013-10-04 | 2019-03-12 | Novartis Ag | 3′end caps for RNAi agents for use in RNA interference |
US10519446B2 (en) | 2013-10-04 | 2019-12-31 | Novartis Ag | Organic compounds to treat hepatitis B virus |
US11008570B2 (en) | 2013-10-04 | 2021-05-18 | Novartis Ag | 3′ end caps for RNAi agents for use in RNA interference |
Also Published As
Publication number | Publication date |
---|---|
FI954718A (fi) | 1995-10-04 |
JPH08508741A (ja) | 1996-09-17 |
HU210880A9 (en) | 1995-09-28 |
BR9406209A (pt) | 1996-02-06 |
WO1994024116A1 (en) | 1994-10-27 |
EP0693062A1 (en) | 1996-01-24 |
US5545645A (en) | 1996-08-13 |
FI954718A0 (fi) | 1995-10-04 |
AU6566094A (en) | 1994-11-08 |
US5428037A (en) | 1995-06-27 |
CA2160113A1 (en) | 1994-10-27 |
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