CN1202104A - 刺激轴突生长的方法和组合物 - Google Patents
刺激轴突生长的方法和组合物 Download PDFInfo
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- CN1202104A CN1202104A CN96195690A CN96195690A CN1202104A CN 1202104 A CN1202104 A CN 1202104A CN 96195690 A CN96195690 A CN 96195690A CN 96195690 A CN96195690 A CN 96195690A CN 1202104 A CN1202104 A CN 1202104A
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- alkyl
- phenyl
- alkenyl
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Classifications
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Abstract
本发明涉及刺激神经细胞的轴突生长的方法和药物组合物。该组合物包含神经营养量的与FK-506结合蛋白(FKBP)结合的化合物和神经营养因子,例如神经生长因子NGF。该方法包括使用上述的组合物和含有FKBP结合的化合物但不含有神经营养因子的组合物治疗神经细胞。本发明的方法可用于促进由疾病或自然性损伤引起的神经元损伤的修复。
Description
本发明涉及刺激神经细胞的轴突生长的方法和药物组合物。该组合物包含神经营养量的与FK-506结合蛋白(FKBP)结合的化合物和神经营养因子,例如神经生长因子NGF。该方法包括使用上述的组合物和含有FKBP结合的化合物但不含有神经营养因子的组合物治疗神经细胞。本发明的方法可用于促进由疾病或自然性损伤引起的神经元损伤的修复。
亲免疫因子是一类可溶性蛋白,它们介导免疫抑制剂药物如环孢菌素A、FK506和雷帕霉素发生作用。特别令人感兴趣的是12 kDa的亲免疫因子,FK-506结合蛋白(FKBP12)。FKBP12与FK-506和雷帕霉素结合,结果抑制T细胞的激活和增殖。有趣的是,FK-506和雷帕霉素的作用机理不同。参见S.H.Solomon等,天然药物,1,第32-37页(1995)。
FK-506和FKBP12结合,所得的配合物与钙调磷酸酶,一种胞质磷酸酶结合并将其抑制。该钙调磷酸酶的磷酸酶活性是脱磷酸作用和随后移位进入转录因子NF-AT的核所必需的。NF-AT引起白细胞介素-2基因的激活,该基因随后介导T细胞的增殖。
另一方面,雷帕霉素-FKBP12配合物与称为RAFT1/FRAP的未知功能蛋白有关。已知该三重(tripartite)配合物抑制多种细胞激酶(即p70S6,p34cdc2,cdk2),这些激酶为T细胞的细胞循环过程所必需。雷帕霉素也已知是FK-506蛋白拮抗剂,还假设它是作为FKBP12结合的竞争性抑制剂而起作用的。
最近发现FKBP在机体中还起着其它的重要作用。业已发现FKBP12与胞内钙离子通道的ryanodine受体(RyR)和1,4,5-三磷酸肌醇酯受体(IP3R)结合形成配合物,[T.Jayaraman等,生物化学杂志,267,9474-77(1992);A.M.Cameron等,美国国立科学院学报,92,1784-44(1995)],有助于稳定钙的释放。该ryanodine受体发现于骨骼肌、心肌、脑和其它可兴奋组织中。IP3R介导由激素和神经递质而引出的胞内钙释放,它们作用于细胞表面,激活磷酸脂酶C,并产生1,4,5-三磷酸肌醇(IP3)。绝大多数IP3R发现于内质网,但也有少数发现于细胞表面,它们介导钙迁入细胞。
现已证明,无论对于RyR和IP3R,FK506和雷帕霉素都能够使FKBP12与受体解离。在每种情况下,“解离出”的FKBP12致使钙通道的外泄增强,从而降低胞内钙的浓度。
FKBP12的另一种作用是调节神经细胞的轴突生长。W.E.Lyons等[美国国立科学院学报,91,3191095(1994)]证明在大鼠副神经节瘤细胞系中,FK506与神经生长因子(NGF)具有协同刺激轴突生长的作用。有趣的是,雷帕霉素并不抑制FK-506对轴突的生长作用,而是神经营养因子本身与FK-506表现出加合作用。在感觉神经节中,证明FK-506有类似的神经营养作用,但这些作用不被雷帕霉素阻断。由这些结果,作者推测FK-506通过其与FKBP12和钙调磷酸酶的配合抑制后者磷酸酶的活性而产生神经营养作用。另外,作者假设FK-506是通过“解离”机制,例如包括从RyR和IP3R脱除FKBP12而起作用的。
基于通过刺激轴突生长可治疗的疾病有许多种,而已知具有该性质的FKBP12结合化合物又相对较少,因此仍需要其它具有神经营养作用的FKBP12结合化合物。
本发明者通过发现两类新的FKBP12结合化合物解决了上述问题,他以前就已发现了它们具有神经营养活性。本发明者先前还在WO 92/19593和WO 94/07858中描述过一系列与FKBP12结合的酰基化氨基酸衍生物。其它系列的FKBP12配体记载于本发明者的美国专利5192773和5330993及PCT专利公开WO 92/00278中。各种系列的化合物在外源性或内源性NGF的存在下均刺激轴突的生长。
所提供的组合物包括上述两类中的一类化合物和神经元生长因子。本文描述的方法使用那些先前所述的化合物和含有它们的组合物以实现轴突的生长,可用于治疗由各种疾病和自然性损伤引起的神经损伤。
根据实施方案,本发明提供药物组合物,含有:
a)具有FKBP12亲和性的式(I)化合物:和其可药用衍生物,其中A是O,NH或N-(C1-C4烷基);
其中B是氢,CHL-Ar,(C1-C6)-直链或支链烷基,(C2-C6)-直链或支链链烯基,(C5-C7)-环烷基,(C5-C7)-环链烯基或者被(C1-C6)-烷基或(C2-C6)-链烯基取代的Ar,或者
其中L和Q独立地是氢,(C1-C6)-直链或支链烷基或者(C2-C6)-直链或支链链烯基;
其中T是Ar或者在3和4位带有取代基的环己基,所述取代基独立地选自氢,羟基,O-(C1-C4)-烷基或O-(C2-C4)-链烯基和羰基;
其中Ar选自具有一至三个取代基的1-萘基,2-萘基,2-呋喃基,3-呋喃基,2-噻吩基,2-吡啶基,3-吡啶基,4-吡啶基和苯基,所述取代基独立地选自氢、卤素、羟基、硝基、CF3、(C1-C6)-直链或支链烷基或(C2-C6)-直链或支链链烯基,O-(C1-C4)-直链或支链烷基或O-((C2-C4)-直链或支链链烯基),O-苄基,O-苯基,氨基或苯基;其中D是U;E是氧或CH-U,条件是如果D是氢,则E是HC-U或者如果E是氧,则D不是氢;
其中每个U独立地选自氢,O-(C1-C4)-直链或支链烷基或者O-((C2-C4)-直链或支链链烯基),(C1-C6)-直链或支链烷基或(C2-C6)-直链或支链链烯基,被(C1-C4)-直链或支链烷基或(C2-C4)-直链或支链链烯基取代的(C5-C7)-环烷基或者(C5-C7)-环链烯基,2-吲哚基,3-吲哚基,[(C1-C4)-烷基或(C2-C4)-链烯基]-Ar或者Ar;
其中J是氢或者C1或C2烷基;K是(C1-C4)直链或支链烷基,苄基或环己基甲基;或者其中J和K可以一起形成其中包含O、S、SO或SO2的5-7元杂环;其中1位碳的立体化学是R或S构型;
b)神经营养因子;和
c)药学上适用的载体。
更优选的是,在药物组合物中具有FKBP12亲和性的化合物为:A是氧;J是氢或者C1或C2烷基;K是(C1-C4)直链或支链烷基,苄基或环己基甲基;或者J和K一起形成吡咯烷基或哌啶基;并且1位碳的立体化学是S构型。
在上述优选的化合物中,其中J和K一起形成吡咯烷基或哌啶基并且E是CH-U,U优选是二甲氨基苯基、甲氧基苯基、二甲氧基苯基、三甲氧基苯基、硝基苯基、呋喃基、吲哚基、吡啶基或亚甲二氧苯基。
在上述优选的化合物中,其中J和K一起形成吡咯烷基或哌啶基并且E是氧:B优选是苄基,萘基,叔丁基,氢,E-3-苯基-2-甲基-丙-2-烯基,E-3-(4-羟基苯基)2-甲基-丙-2-烯基,E-3-[反(4-羟基环己基)]-2-甲基-丙-2-烯基,环己基乙基,环己基丙基,环己基丁基,环戊基丙基,E-3-(4-甲氧基苯基)-2-甲基-丙-2-烯基,E-3-(3,4-二甲氧基苯基)-2-甲基-丙-2-烯基或E-3-[顺(4-羟基环己基)]-2-甲基-丙-2-烯基;并且D优选是苯基,甲氧基苯基,环己基,乙基,甲氧基,硝基苄基,苯硫基,吲哚基,呋喃基,吡啶基,吡啶基-N-氧化物,硝基苯基,氟苯基,三甲氧基苯基或二甲氧基苯基。
在本发明的组合物和方法中使用的最优选的式(I)化合物是在下面实施例1的表1a-1d中分别列出的式Ia、Ib、Ic和Id化合物。
具有FKBP12亲和性的式(I)化合物的合成记载于美国专利5192773和5330993及PCT专利公开WO 92/00278中,这些文献的公开内容均引入本文以供参考。根据另一个实施方案,本发明提供了药物组合物,含有:
其中A′是CH2,氧,NH或N-(C1-C4烷基);
其中B′和W独立地是:
(i)氢,Ar′,(C1-C10)-直链或支链烷基,(C2-C10)-直链或支链链烯基或炔基,(C1-C6)-直链或支链烷基、(C2-C6)直链或支链链烯基或炔基取代的(C5-C7)-环烷基,(C1-C6)-直链或支链烷基、(C2-C6)直链或支链链烯基或炔基取代的(C5-C7)-环链烯基,或者(C1-C6)-直链或支链烷基、(C2-C6)直链或支链链烯基或炔基取代的Ar′,在各种情况下,其中所述烷基、链烯基或炔基链中的任一个CH2基可任意地被选自O、S、SO、SO2、N和NR的杂原子取代,其中R选自氢、(C1-C4)-直链或支链烷基、(C2-C4)-直链或支链链烯基或烧基,和(C1-C4)桥烷基,其中桥是由形成环的所述含杂原子的链中的氮原子和碳原子形成的,并且其中所述的环可任意地与Ar′基稠合;或者
(ii)其中Q′是氢,(C1-C6)-直链或支链烷基或者(C2-C6)-直链或支链链烯基或炔基;
其中T′是Ar′或者在3位和4为带有取代基的5-7元环烷基,所述取代基独立地选自氧、氢、羟基、O-(C1-C4)-烷基和O-(C2-C4)-链烯基;
其中Ar′是碳环芳香基,选自苯基,1-萘基,2-萘基,茚基,甘菊环基,芴基和蒽基;或者杂环芳香基,选自2-呋喃基,3-呋喃基,2-噻吩基,3-噻吩基,2-吡啶基,3-吡啶基,4-吡啶基,吡咯基,噁唑基,噻唑基,咪唑基,吡唑基,异噁唑基,异噻唑基,1,2,3-噁二唑基,1,2,3-三唑基,1,3,4-噻二唑基,哒嗪基,嘧啶基,吡嗪基,1,3,5-三嗪基,1,3,5-三噻烷基,中茚氮基,吲哚基,异吲哚基,3H-吲哚基,二氢吲哚基,苯并[b]呋喃基,苯并[b]噻吩基,1H-吲唑基,苯并咪唑基,苯并噻唑基,嘌呤基,4H-喹嗪基,喹啉基,异喹啉基肉啉基,2,3-二氮杂萘基,喹唑啉基,喹喔啉基,1,8-二氮杂萘基,蝶啶基,咔唑基,吖啶基,吩嗪基,吩噻嗪基和吩噁嗪基;
其中Ar′可带有一至三个取代基,所述取代基独立地选自氢,卤素,羟基,羟甲基,硝基,三氟甲基,三氟甲氧基,(C1-C6)-直链或支链烷基,(C2-C6)直链或支链链烯基,O-[(C1-C4)-直链或支链烷基],O-[(C2-C4)-直链或支链链烯基],O-苄基,O-苯基,1,2-亚甲二氧基,氨基,羧基,N-[(C1-C5)-直链或支链烷基或者(C2-C5)-直链或支链链烯基)甲酰胺,N,N-二-[(C1-C5)-直链或支链烷基或者(C2-C5)-直链或支链链烯基)]甲酰胺,N-吗啉代甲酰胺,N-苄基甲酰胺,N-硫代吗啉代甲酰胺,N-甲基二氢吡啶基(picolinoyl)甲酰胺,O-X,CH2-(CH2)q-X,O-(CH2)q-X,(CH2)q-O-X和CH=CH-X;
其中X是4-甲氧基苯基,2-吡啶基,3-吡啶基,4-吡啶基,吡嗪基(pyrazyl),喹啉基,3,5-二甲基异噁唑基,异噁唑基,2-甲基噻唑基,噻唑基,2-噻吩基,3-噻吩基或嘧啶基;并且
q是0-2;其中G是U′;M是氧或CH-U′;条件是如果G是氢,则M是CH-U′;或者如果M是氧,则G是U′;
其中U′是氢,O-[(C1-C4)-直链或支链烷基]或O-[(C2-C4)-直链或
支链链烯基],(C1-C6)-直链或支链烷基或者(C2-C6)-直链或支链链烯
基,被(C1-C4)-直链或支链烷基或者(C2-C6)-直链或支链链烯基取代
的(C5-C7)-环烷基或者(C5-C7)-环链烯基,[(C1-C4)-烷基或(C2-C4)-
链烯基]-Y或Y;
其中Y选自苯基,1-萘基,2-萘基,茚基,甘菊环基,芴基,蒽
基,2-吡咯啉基,3-吡咯啉基,吡咯烷基,1,3-间二氧杂环戊烯基,
2-咪唑啉基,咪唑烷基,2H-吡喃基,4H-吡喃基,哌啶基,1,4-二噁
烷基,吗啉基,1,4-二噻烷基,硫代吗啉基,哌嗪基,奎宁环基和如
上述为Ar′所定义的杂环芳香基;
其中Y可带有一至三个取代基,所述取代基独立地选自氢,卤素,
羟基,羟甲基,硝基,三氟甲基,三氟甲氧基,(C1-C6)-直链或支链
烷基,(C2-C6)直链或支链链烯基,O-[(C1-C4)-直链或支链烷基],
O-[(C2-C4)-直链或支链链烯基],O-苄基,O-苯基,1,2-亚甲二氧
基,氨基和羧基;
其中J′是氢,(C1-C2)烷基或苄基;
K是(C1-C4)-直链或支链烷基,苄基或环己基甲基,或者其中J′和K一
起形成5-7元杂环,该杂环可含有选自O、S、SO和SO2的杂原子;
并且
其中m是0-3;
b)神经营养因子;和
c)药学上适用的载体。式(II)化合物排除了所有式(I)化合物。
更优选的是,在这些药物组合物中的具有FKBP12亲和性的化合物中:
B′和W独立地是:
(i)氢,Ar′,(C1-C10)-直链或支链烷基,(C2-C10)-直链或支链链烯基或炔基,(C1-C6)-直链或支链烷基、(C2-C6)-直链或支链链烯基或炔基取代的(C5-C7)-环烷基,(C1-C6)-直链或支链烷基、(C2-C6)-直链或支链链烯基或炔基取代的(C5-C7)-环链烯基,或者(C1-C6)-直链或支链烷基、(C2-C6)-直链或支链链烯基或炔基取代的Ar′,在各种情况下,其中所述烷基、链烯基或炔基链中的任一个CH2基可任意地被选自O、S、SO、SO2的杂原子取代;或者
(ii)
Ar′可带有一至三个取代基,所述取代基独立地选自氢,卤素,羟基,羟甲基,硝基,三氟甲基,三氟甲氧基,(C1-C6)-直链或支链烷基,(C2-C6)直链或支链链烯基,O-[(C1-C4)-直链或支链烷基],O-[(C2-C4)-直链或支链链烯基],O-苄基,O-苯基,1,2-亚甲二氧基,氨基和羧基;并且
Y选自苯基,1-萘基,2-萘基,茚基,甘菊环基,芴基,蒽基,和如上述为Ar′所定义的杂环芳香基;
根据其它优选实施方案,在具有FKBP12亲和性的式(II)化合物中:至少B′或W中的一个独立地选自(C2-C10)-直链或支链炔基;被(C2-C6)-直链或支链炔基取代的(C5-C7)-环烷基;被(C2-C6)-直链或支链炔基取代的(C5-C7)-环链烯基;和被(C2-C6)-直链或支链炔基取代的Ar′。
或者,至少B′或W中的至少一个独立地选自式-(CH2)r-(Z)-(CH2)r-Ar′,其中:Z独立地选自CH2、O、S、SO、SO2、N和NR;r是0-4;s是0-1;并且Ar′和R如式II中所定义。
在另外的实施方案中,式II中的B′或W中的至少一个独立地选自Ar′,被(C1-C6)-直链或支链烷基取代的Ar′和被(C2-C6)-直链或支链链烯基或炔基取代的Ar′;其中Ar′被一至三个取代基取代,所述取代基独立地选自N-(直链或支链(C1-C5)-烷基或者(C2-C5)-链烯基)甲酰胺,N,N-二-(直链或支链(C1-C5)烷基或(C2-C5)烯基)甲酰胺,N-吗啉代甲酰胺,N-苄基甲酰胺,N-硫代吗啉代甲酰胺,N-甲基二氢吡啶基(picolinoyl)甲酰胺,O-X,CH2-(CH2)q-X,O-(CH2)q-X,(CH2)q-O-X和CH=CH-X;并且Ar′、X和q如上述所定义。
用于药物组合物中最优选的式(II)化合物选自下面实施例1的表2中列出的那些式(II′)化合物。
式II化合物的合成方法详细记载在本发明者的PCT专利公开WO92/19593和WO 94/07858中,这些文献均引入本文以供参考。
用于本发明的药物组合物和方法中的FKBP12结合化合物的定义包括其可药用衍生物。“可药用衍生物”是指本发明化合物或者经给药于患者后能够提供(直接地或间接地)本发明化合物的任意其它化合物或者其代谢物或残余物(特征在于能够促进或增进轴突生长)的可药用盐、酯或这类酯的盐。
如果使用FKBP12结合化合物的可药用盐,那些盐优选由无机或有机酸和碱衍生。与酸成的盐包括下述:乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐(digluconate)、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐(glucoheptanoate)、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、棕榈酸盐(pamoate)、果胶酸盐、过二硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一烷酸盐。碱盐包括铵盐,碱金属盐如钠盐和钾盐,碱土金属盐如钙盐和镁盐,与有机碱形成的盐,如二环己基铵盐、N-甲基-D-葡糖胺以及与氨基酸如精氨酸和赖氨酸等形成的盐。再有,含氮碱性基团可与试剂发生季胺化,所述试剂是例如烷基卤化物,如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二烷基硫酸酯,例如二甲基、二乙基、二丁基和二戊基硫酸酯;长链卤化物,例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物;芳烷基卤化物,如苄基和苯乙基溴等。由此可获得水溶性、油溶性或可分散性产物。
用于本发明组合物和方法的FKBP12结合化合物还可通过附加适当的功能基修饰以提高生物选择性。这类修饰是本领域中已知的,包括增强向给定生物系统(如血液、淋巴系统、中枢神经系统)的生物渗透性,提高口服生物利用度,提高溶解度以通过注射给药,改变代谢和排泄率。
本发明的FKBP12结合化合物的神经营养活性与它们对FKBP12的亲和性和它们抑制FKBP12 rotomase活性的能力有直接关系。为确定这些性质,采用了本领域中已知的几种分析方法。例如,M.W.Harding等在自然,341,758-60(1989)和J.J.Siekierka等在自然,341,755-57(1989)中描述的竞争性LH20结合分析法。
优选分析测定FKBP12旋转异构酶(rotomase)活性。M.W.Harding等和J.J.Siekierka等在上述文献中也描述了这种分析方法。该分析中,进行分光光度测定后,将人工底物-N-琥珀酰-Ala-Pro-Phe-对硝基苯胺异构化。该分析包括顺式的底物、FKBP12、抑制剂和糜蛋白酶。糜蛋白酶可使对硝基苯胺从反式底物上裂解下来,但不能使其从顺式底物上裂解下来。测定释放的对硝基苯胺。
在上述各药物组合物中的第二种成分是神经营养因子。本文采用的术语“神经营养因子”是指可刺激神经组织生长或增殖的化合物。本申请中采用的术语“神经营养因子”不包括本文所述的FKBP12结合化合物,以及FK-506和雷帕霉素。
在本领域中已鉴别出许多神经营养因子,它们均可用于本发明的组合物。这些神经营养因子包括,但不限于神经生长因子(NGF)、胰岛素生长因子(IGF-1)和其活性截断衍生物如gIGF-1、酸性和碱性成纤维细胞生长因子(分别为aFGF和bFGF)、血小板衍生的生长因子(PDGF),脑衍生的神经营养因子(BDNF)、睫神经营养因子(CTNF)、神经胶质细胞系衍生的神经营养因子(GDNF)、向神经素-3(NT-3)和向神经素4/5(NT-4/5)。在本发明的组合物中最优选的神经营养因子是NGF。
本发明的可药用组合物的第三种成分是药学上适用的载体。可用于这些组合物的药学上适用的载体包括,但不限于离子交换剂,矾土,硬脂酸铝,卵磷脂,血清蛋白如人血清白蛋白,缓冲物质例如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠,锌盐,胶态硅石,三硅酸镁,聚乙烯吡咯烷酮,纤维素基的物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜡,聚乙烯-聚氧丙烯嵌段聚合物,聚乙二醇和羊毛脂。
本发明的组合物可经口服、非胃肠道、吸入喷雾、局部、直肠、鼻、颊、阴道给药或者经植入储库给药。本文使用的术语“非胃肠道”包括皮下、静脉内、肌内、关节内、滑液内、胸骨内、鞘内、肝内、损伤区内和颅内注射或输注技术。组合物优选经口服、腹膜内或静脉内给药。
本发明组合物的无菌注射形式可以是水或油悬浮液。这些悬浮液可按照本领域已知的技术,使用适用的分散或润湿剂和悬浮剂配制。无菌注射制剂也可以是在无毒的非胃肠道可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如在1,3-丁二醇中的溶液。在可接受的载体和溶剂中,可使用的是水、林格氏溶液和等渗氯化钠溶液。此外,无菌的固定油也常用作溶剂或悬浮介质。为此,可使用包括合成一或二甘油酯的钡白(blandfix)固定油。在注射剂中可使用脂肪酸,例如油酸和其甘油酯衍生物,同样可使用天然可药用油,例如橄榄油或蓖麻油,尤其是它们的多氧乙基化油。这些油溶液或悬浮液还可含有长链醇稀释剂或分散剂,例如Ph.Hely或类似的醇。
本发明的可药用组合物可以任意口服可接受的剂型给药,剂型包括,但不限于胶囊、片剂、水悬浮液或水溶液。在口服用片剂的情况下,常用的载体包括乳糖和玉米淀粉。典型地,还加入润滑剂,例如硬脂酸镁。为以胶囊形式给药,可用的稀释剂包括乳糖和干玉米淀粉。当需使用水悬浮液口服时,将活性成分与乳化剂和悬浮剂混合。如果需要,可加入某些甜味剂、芳香剂或着色剂。
另外,本发明的药物组合物可以栓剂形式用于直肠给药。栓剂可通过将药物与适宜的无刺激性赋形剂混合制备,所述赋形剂在室温下是固体,但在直肠温度下是液体,因而会在直肠熔化释放出药物。这类物质包括可可脂、蜂蜡和聚乙二醇。
本发明的药物组合物还可局部给药,尤其是当靶向治疗包括局部用药易达到的患面或器官时,包括眼病、皮肤病或下部肠道疾病。对于这些患面和器官,很容易制备适宜的局部制剂。
直肠栓剂制剂(见上)或适宜的灌肠制剂可用于下部肠道给药。也可使用局部透皮的贴剂。
为局部给药,可将药物组合物配制成适宜的软膏,包括将活性成分悬浮或溶解在一种或多种载体中。用于本发明的化合物局部给药的载体包括,但不限于矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯化合物、乳化蜡和水。另外,可将药物组合物配制成适宜的洗剂或霜剂形式,包括将活性成分悬浮或溶解在一种或多种可药用载体中。适宜的载体包括,但不限于矿物油、山梨糖醇酐单硬脂酸酯、吐温60、鲸蜡醇酯蜡、十六烷(cetearyl)醇、2-辛基十二烷醇、苄醇和水。
为眼科应用,药物组合物在使用或不用防腐剂,例如氯化苄基烷鎓的情况下,可配制成微粉化的等渗的调节了pH的无菌盐水悬浮液,或者优选配制成等渗的调节了pH的无菌盐水溶液。另外,为眼科应用,药物组合物可配制成软膏形式,例如使用凡士林。
本发明的药物组合物还可经鼻气雾或吸入给药。这类组合物可按照药物制剂领域熟知的技术制备,可使用苄醇或其它适宜的防腐剂、提高生物利用度的吸收促进剂、氟烃和/或其它常用的增溶剂或分散剂制备成盐水溶液。
可与载体材料混合生产单一剂量的FKBP12结合化合物和神经营养因子的量取决于所医治的患者和特定的给药方式。本发明药物组合物的两种活性成分协同刺激轴突的生长。因此,该类组合物中神经营养因子的量应少于仅使用该因子单独治疗所需的量。
优选将组合物配制成使接受该组合物的患者每日可服用0.01-100mgFKBP12结合蛋白/kg体重和0.01-100μg神经营养因子/kg体重。
还应理解对任一特定患者的具体剂量和治疗方案取决于许多因素,包括所使用具体化合物的活性、年龄、体重、健康状况、性别、饮食、给药时间、排泄率、药物联用及治疗医师的判断和所医治的特定疾病的严重性。活性成分在组合物中的量也取决于特定的FKBP12结合化合物和神经营养因子。
根据另一个实施方案,本发明提供刺激轴突生长的方法。这类方法包括使用上述的任意FKBP12结合化合物处理神经细胞的步骤。优选地,该方法用于刺激患者轴突的生长,将FKBP12结合化合物配制成组合物,该组合物另外包含可药用载体。这些方法中FKBP12结合化合物的用量为0.01-100mg/kg/日。
根据另一个实施方案,刺激轴突生长的方法包括另外使用神经营养因子,例如本发明的药物组合物中含有的那些因子处理神经细胞的步骤。该实施方案包括一单剂量形式或分开或者多剂量形式服用FKBP12结合化合物和神经营养药物。如果采用分开的药剂形式,它们可同时、先后或在彼此不超过5小时的时间内服用。
本发明的方法优选用于刺激患者轴突的生长。
本发明的方法和组合物可用于治疗由广泛的各种疾病或自然损伤引起的神经损伤。这些包括,但不限于阿尔茨海默氏症、巴金森氏病、ALS、中风和与中风有关的局部缺血、神经病变(paropathy)、其它神经退化性疾病、运动神经疾病、坐骨神经痛疾病、脊索损伤和面神经疾病。
为对本发明进行全面的描述,给出如下实施例。应该理解这些实施例仅是说明性的,而不是以任何方式对本发明构成限制。
实施例1
FKBP12结合测定
测定本发明组合物中优选的FKBP12结合化合物对FKBP旋转异构酶活性的抑制。在该测定中,在FKBP12和糜蛋白酶的存在下,将不同量的FKBP12结合化合物(0.1nM-10μm)加到顺-N-琥珀酰-Ala-Ala-Pro-Phe-对硝基苯胺。FKBP12将顺式的底物转化为反式。这使糜蛋白酶将对硝基苯胺从底物上裂解下来。用分光光度法测定释放的对硝基苯胺。该测定测量了作为FKBP12结合化合物浓度函数的旋转异构酶活性的一级速率常数的变化并得到了表观概算值Ki。下表列出了本发明的组合物和方法中使用的最优选的FKBP12结合化合物和它们的计算Ki。表1a
表1b
表1c
表1d
B | D | n | Ki(μM) |
苄基 | 苯基 | 1 | 25 |
苄基 | 苯基 | 2 | 1.5 |
烯丙基 | 苯基 | 2 | 8 |
1-萘基 | 苯基 | 2 | 0.9 |
2-萘基 | 苯基 | 2 | 7 |
苄基 | 2-甲基丙基 | 2 | 0.9 |
苄基 | 2-甲氧基苯基 | 2 | 17 |
苄基 | 3-甲氧基苯基 | 2 | 0.3 |
苄基 | 4-甲氧基苯基 | 2 | 5 |
苄基 | 3,5-二甲氧基苯基 | 2 | 2 |
苄基 | 2,6-二甲氧基苯基 | 2 | 50 |
苄基 | 3,4,5-三甲氧基苯基 | 2 | 0.1 |
苄基 | 4-氟苯基 | 2 | 4 |
苄基 | 3-硝基苯基 | 2 | 160 |
苄基 | 4-硝基苯基 | 2 | 160 |
苄基 | 2-吡啶基 | 2 | 130 |
苄基 | 2-吡啶基N-氧化物 | 2 | >500 |
叔丁基 | 2-呋喃基 | 1 | 200 |
苄基 | 2-呋喃基 | 2 | 3 |
苄基 | 3-吲哚基 | 2 | 25 |
苄基 | 2-噻吩 | 2 | 0.8 |
E-3-苯基-2-甲基-丙-2-烯基 | 苯基 | 2 | 1.5 |
E-3-(4-羟基苯基)-2-甲基-丙-2-烯基 | 苯基 | 2 | 6 |
E-3-[顺-(4-羟基环己基)]-2-甲基-丙-2-烯基 | 苯基 | 2 | 0.6 |
E-3-[反-(4-羟基环己基)]-2-甲基-丙-2-烯基 | 苯基 | 2 | 0.5 |
B | D | n | Ki(μM) |
苄基 | 2-硝基苄基 | 2 | 26 |
氢 | 甲氧基 | 2 | ND |
叔丁基 | 甲氧基 | 1 | 600 |
烯丙基 | 甲氧基 | 2 | 190 |
苄基 | 甲氧基 | 2 | 80 |
2-环己基乙基 | 甲氧基 | 2 | 45 |
3-环己基丙基 | 甲氧基 | 2 | 20 |
4-环己基丁基 | 甲氧基 | 2 | 6 |
3-环戊基丙基 | 甲氧基 | 2 | 35 |
E-3-(4-甲氧基苯基)-2-甲基-丙-2-烯基 | 甲氧基 | 2 | 40 |
E-3-(3,4-二甲氧基苯基)-2-甲基-丙-2-烯基 | 甲氧基 | 2 | 10 |
E-3-(4-羟基苯基)-2-甲基-丙-2-烯基 | 甲氧基 | 2 | 60 |
E-3-[顺-(4-羟基环己基)]-2-甲基-丙-2-烯基 | 甲氧基 | 2 | 70 |
苄基 | 环己基 | 2 | 1.3 |
苄基 | 乙基 | 1 | 400 |
苄基 | 3-甲氧基苯基 | 1 | 5 |
苄基 | 2-吡啶基 | 1 | 300 |
苄基 | 3,4-二氟苯基 | 2 | 3 |
苄基 | (E)-2-(4-甲氧基苯基)-乙烯基 | 2 | 1 |
苄基 | 1-羟基-1-环己基 | 2 | 1 |
苄基 | 2-萘基 | 2 | 1.5 |
苄基 | 1-萘基 | 2 | 1 |
(S)-α-甲基苄基 | 苯基 | 2 | 0.5 |
苄基 | 2-羟基-2-四氢吡喃基 | 2 | 12 |
(R)-α-甲基苄基 | 苯基 | 2 | 1.5 |
苄基 | 3-三氟甲基苯基 | 2 | 1.5 |
苄基 | 3-苄氧基苯基 | 2 | 0.5 |
苄基 | (E)-2-叔丁基乙烯基 | 2 | 9 |
苄基 | 2-三氟甲基苯基 | 2 | 5 |
4-环己基丁基 | 苯基 | 2 | 0.4 |
4-环己基丁基 | 3,4,5-三甲氧基苯基 | 2 | 0.04 |
4-苯基苄基 | 苯基 | 2 | 5 |
4-苯基苄基 | 3,4,5-三甲氧基苯基 | 2 | 2 |
苄基 | 3-乙氧基苯基 | 2 | 0.56 |
3-苯氧基苄基 | 3,4,5-三甲氧基苯基 | 2 | 0.018 |
3-苯氧基苄基 | 苯基 | 2 | 0.09 |
4-苯基丁基 | 3,4,5-三甲氧基苯基 | 2 | 0.019 |
4-苯基丁基 | 苯基 | 2 | 0.35 |
B | D | n | Ki(μM) |
苄基 | 3-(3-丙烯氧基)苯基 | 2 | 1 |
苄基 | 3-(2-丙氧基)苯基 | 2 | 0.5 |
苄基 | 1-甲基丙基 | 2 | 1 |
2-苯乙基 | 苯基 | 2 | 1.1 |
6-苯己基 | 苯基 | 2 | 0.5 |
5-苯戊基 | 3,4,5-三甲氧基苯基 | 2 | 0.07 |
6-苯己基 | 3,4,5-三甲氧基苯基 | 2 | 0.1 |
6-环己基己基 | 3,4,5-三甲氧基苯基 | 2 | 0.05 |
4-苯氧基苄基 | 3,4,5-三甲氧基苯基 | 2 | 0.8 |
5-环己基苯基 | 3,4,5-三甲氧基苯基 | 2 | 0.09 |
苄基 | 3-(1-丁氧基)苯基 | 2 | 0.36 |
4-苯丁基 | 3-(2-丙氧基)苯基 | 2 | 0.1 |
4-(4-碘苯基)丁基 | 3,4,5-三甲氧基苯基 | 2 | 0.016 |
4-碘苄基 | 3,4,5-三甲氧基苯基 | 2 | 1.4 |
2-(2-萘基)乙基 | 3,4,5-三甲氧基苯基 | 2 | 0.22 |
2-(1-萘基)乙基 | 3,4,5-三甲氧基苯基 | 2 | 0.5 |
4-苯丁基 | 4-碘苯基 | 2 | 0.8 |
4-苯丁基 | 3-碘苯基 | 2 | 0.13 |
3-苯丙基 | 3,4,5-三甲氧基苯基 | 2 | 0.11 |
3-(3-吲哚基)丙基 | 3,4,5-三甲氧基苯基 | 2 | 0.017 |
4-(4-甲氧基苯基)丁基 | 3,4,5-三甲氧基苯基 | 2 | 0.013 |
4-苯丁-2-烯基 | 3,4,5-三甲氧基苯基 | 2 | 0.8 |
4-苯丁-3-烯基 | 3,4,5-三甲氧基苯基 | 2 | 0.5 |
4-(4-烯丙氨基(allocamino)苯基)丙基 | 3,4,5-三甲氧基苯基 | 2 | 0.011 |
4-苯基丙基 | 1-环己烯基 | 2 | 0.78 |
4-(4-甲氧基苯基)丁-3-烯 | 3,4,5-三甲氧基苯基 | 2 | 0.011 |
基 | |||
4-苯丙基 | 1-氟-1-环己基 | 2 | 0.54 |
4-苯丙基 | 3-丁氧苯基 | 2 | 1.4 |
3-[3-(N-甲酰基吲哚基)]丙基 | 3,4,5-三甲氧基苯基 | 2 | 0.015 |
4-(3-吲哚基)丁基 | 3,4,5-三甲氧基苯基 | 2 | 0.016 |
4-苯丁基 | 苄基 | 2 | 0.35 |
4-苯丁基 | 3-联苯基 | 2 | 0.04 |
4-苯丁基 | 4-叔丁基苯基 | 2 | 0.6 |
4-苯丁基 | 环己基 | 2 | 0.08 |
4-苯丁基 | 环己基甲基 | 2 | 0.12 |
4-苯丁基 | 3,4-亚甲二氧基苯基 | 2 | 0.25 |
4-苯丁基 | 4-四氢吡喃基 | 2 | 0.44 |
4-苯丁基 | 3-环己基-4-甲氧基苯基 | 2 | 14 |
4-苯丁基 | 4-(4-甲氧基苄氧基-甲基)-2-呋喃基 | 2 | 0.7 |
B | D | n | Ki(μM) |
4-苯丁基 | 叔丁基 | 2 | 0.18 |
4-苯丁基 | 乙基 | 2 | 1.6 |
3-(N-苯并咪唑基)丙基 | 3,4,5-三甲氧基苯基 | 2 | 0.11 |
3-(N-嘌呤基)丙基 | 3,4,5-三甲氧基苯基 | 2 | 0.13 |
(S,S)-2-甲基-3-羟基-4-苯丙基 | 3,4,5-三甲氧基苯基 | 2 | 0.25 |
B | U | n | Ki |
苄基 | 3,4-亚甲二氧基苯基 | 1 | 3 |
苄基 | 3,4-亚甲二氧基苯基 | 2 | 3 |
苄基 | 4-甲氧基苯基 | 1 | 6 |
苄基 | 4-甲氧基苯基 | 2 | 4 |
苄基 | 2,5-二甲氧基苯基 | 1 | 10 |
苄基 | 2,4,5-三甲氧基苯基 | 1 | 25 |
苄基 | 3,4,5-三甲氧基苯基 | 1 | 450 |
苄基 | 4-二甲氨基苯基 | 2 | 20 |
苄基 | 4-硝基苯基 | 2 | 14 |
苄基 | 1-呋喃基 | 2 | 2.5 |
苄基 | 2-呋喃基 | 2 | 2.5 |
苄基 | 3-吲哚基 | 2 | >60 |
苄基 | 3-吡啶基 | 2 | 25 |
苄基 | 氢 | 2 | 300 |
苄基 | 苯基 | 2 | 11 |
B | D | J | K | Ki(μM) |
苄基 | 甲氧基 | 甲基 | 氢 | 1000 |
苄基 | 甲氧基 | 甲基 | S-甲基 | 400 |
苄基 | 甲氧基 | 甲基 | S-异丙基 | 170 |
乙基 | 甲氧基 | 苄基 | 氢 | >1200 |
叔丁基 | 甲氧基 | 乙基 | S-甲基 | >400 |
(式1d)
B | U | J | K | Ki(μM) |
苄基 | 4-甲氧基苯基 | 甲基 | S-甲基 | 80 |
苄基 | 4-甲氧基苯基 | 甲基 | S-异丙基 | 30 |
苄基 | 3,4-亚甲二氧基苯基 | 甲基 | S-甲基 | 50 |
苄基 | 3,4-亚甲二氧基苯基 | 氢 | S-甲基 | 60 |
表2
化合物 | n | m | B′ | W | Ar′ | Ki(nM) |
2 | 1 | 0 | 3-(吡啶-2-基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 95. |
3 | 2 | 0 | 3-苯基丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 1. |
4 | 2 | 0 | 3-苯氧基苯基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 220. |
5 | 2 | 0 | 苯基 | 3-苯氧基苯基 | 3,4,5-三甲氧基苯基 | 4000. |
6 | 2 | 0 | 苯基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 80. |
7 | 2 | 0 | 2-(吡啶-3-基)乙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 3. |
8 | 2 | 0 | E-3-[反-(4-羟基环己基)]-2-甲基-乙-2-烯基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 27. |
9 | 2 | 0 | 3-(吡啶-3-基) | 3-苯基丙基 | 3,4,5-三甲氧 | 0.5 |
丙基 | 基苯基 | |||||
10 | 2 | 0 | 苄基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 32. |
11 | 2 | 0 | 苄基 | 3-(吲哚-3-基)丙基 | 3,4,5-三甲氧基苯基 | 24. |
12 | 2 | 0 | 2-苯乙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 83. |
13 | 2 | 0 | 2-(4-甲氧基苯基)乙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 3.5 |
14 | 2 | 0 | 2-(4-甲氧基苯基)乙基 | 3-苯基丙基 | 苯基 | 270. |
15 | 2 | 0 | 3-(N-苯并咪唑基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 5. |
16 | 2 | 0 | 苄基 | 3-苯基乙基 | 3,4,5-三甲氧基苯基 | 57. |
17 | 2 | 0 | 3-(4-甲氧基苯基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 3. |
18 | 2 | 0 | 3-(吡啶-3-基)丙基 | 3-苯基丙基 | 苯基 | 56. |
19 | 2 | 0 | 3-(吡啶-2-基)丙基 | 3-苯基丙基 | 苯基 | 50. |
20 | 2 | 0 | 3-(吡啶-2-基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 6.5 |
21 | 2 | 0 | 3-(吡啶-2-基)丙基 | 3-苯基丙基 | 叔丁基 | 36. |
22 | 2 | 0 | 3-(吡啶-3-基)-丙基-N-氧化物 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 7. |
23 | 2 | 0 | 3-IN-(7-氮杂 | 3-苯基丙基 | 3,4,5-三甲氧 | 9. |
吲哚基)-丙基 | 基苯基 | |||||
24 | 2 | 0 | 3-(吡啶-3-基)丙基 | 3-(4-甲氧基苯基)丙基 | 3,4,5-三甲氧基苯基 | ND |
25 | 2 | 0 | 3-(N-嘌呤基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 2.2 |
26 | 2 | 0 | 3-(4-羟甲基苯基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 4. |
27 | 2 | 0 | 3-(吡啶-3-基)丙基 | 3-苯基丙基 | 3-苄氧基苯基 | 15. |
化合物 | n | m | B′ | W | Ar′ | Ki(nM) |
28 | 2 | 0 | 3-(吡啶-3-基)丙基 | 3-苯基丙基 | 3-烯丙氧基苯基 | 11. |
29 | 2 | 0 | 3-(吡啶-3-基)丙基 | 3-苯基丙基 | 3-异丙氧基苯基 | 2. |
30 | 2 | 0 | 3-(噻吩-2-基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 4. |
31 | 2 | 0 | 3-(4-羧基苯基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 2. |
32 | 2 | 0 | 3-苯基丁基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 20. |
33 | 2 | 0 | 2-羟甲基苯基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 89. |
34 | 2 | 0 | 2-烯丙氧基苯基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 150. |
35 | 2 | 0 | 3-(3-羟甲基苯基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 1. |
36 | 2 | 0 | 3-(3-羧基苯基)丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 4. |
37 | 2 | 0 | 3-羟甲基苯基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 6.8 |
38 | 2 | 0 | 2-羟基苯基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | ND |
39 | 2 | 0 | 吡啶-3-基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | ND |
40 | 2 | 0 | 3-(噻吩-2-基)丙基 | 4-苯基丁基 | 3,4,5-三甲氧基苯基 | 1100 |
41 | 2 | 0 | 5-苯基戊基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 45. |
42 | 2 | 0 | 3-烯丙氧基丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | ND |
43 | 2 | 0 | 3-[4-(N,N-二甲氨基羰基)-苯基]-丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 5. |
44 | 2 | 0 | 3-[4-(吗啉-4-羰基)苯基]-丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 6. |
45 | 2 | 0 | 4-烯丙氧基丁基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 7. |
46 | 2 | 0 | 3-烯丙氧基-丙-1-炔基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 5. |
47 | 2 | 0 | 3-[4-(哌啶-1-羰基)苯基]-丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 7. |
48 | 2 | 0 | 5-烯丙氧基壬基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | ND |
49 | 2 | 0 | 甲基 | 3,5-二(苄氧基)苯基 | 3,4,5-三甲氧基苯基 | 3400. |
50 | 2 | 0 | 2-烯丙乙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 11. |
51 | 2 | 0 | 3-烯丙乙基-(E)-丙-1-炔基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 2.8 |
52 | 2 | 0 | 3-[3-(吗啉-4-羰基)苯基]丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 1.5 |
53 | 2 | 0 | 癸-9-烯基 | 3-苯基丙基 | 3,4,5-三甲氧 | ND |
基苯基 | ||||||
54 | 2 | 0 | 3-[4-(N-苄基-氨基羰基)-苯基]丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 1.6 |
55 | 2 | 0 | 3-[4-(硫代吗啉-4-羰基)苯基]丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 2.4 |
56 | 2 | 0 | 3-(吗啉-4-羰基)苯基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 6.1 |
57 | 2 | 0 | 3-[4-(1-甲基哌嗪-4-羰基)苯基]丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 5.6 |
58 | 2 | 0 | 3-[4-(1-苄基哌嗪-4-羰基)苯基]丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 30. |
化合物 | n | m | B′ | W | Ar′ | Ki(nM) |
59 | 2 | 0 | 3-[3-(N-苄基胺-羰基)苯基]丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 40. |
60 | 2 | 0 | 3-[4-(N-吡啶-2-基胺羰基)-苯基]丙基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 2. |
61 | 2 | 0 | 吡啶-3-基 | 3-(吡啶-3-基)丙基 | 3,4,5-三甲氧基苯基 | 10. |
62 | 2 | 0 | 丙-2-烯基 | 3,4-二-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 62. |
63 | 2 | 0 | 吡啶-3-基 | 3-(吡啶-4-基-甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 13. |
64 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基-甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 1.4 |
65 | 2 | 0 | 3-苯基丙基 | 3,4-二-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 4.1 |
66 | 2 | 0 | 甲基 | 3,4-二-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 35. |
67 | 2 | 0 | 3-苯基丙基 | 2,3,4-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 46. |
68 | 2 | 0 | 3-苯基丙基 | 3-(吗啉-4-羰基)-4-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 2. |
69 | 2 | 0 | 甲基 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 36. |
70 | 2 | 0 | 3-苯基丙基 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 5. |
71 | 2 | 0 | 甲基 | 3,5-二-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 14. |
72 | 2 | 0 | 3,5-二-(吡啶-4-基甲氧基)苯基 | 甲基 | 3,4,5-三甲氧基苯基 | 12. |
73 | 2 | 0 | 甲基 | 3,5-双-(吡啶-4-基甲氧基)-4-甲基苯基 | 3,4,5-三甲氧基苯基 | 36. |
74 | 2 | 0 | 乙基 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 18. |
75 | 2 | 0 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 乙基 | 3,4,5-三甲氧基苯基 | 12. |
76 | 2 | 0 | 丙-2-烯基 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 14. |
77 | 2 | 0 | 甲基 | 3,4,6-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 24. |
78 | 2 | 0 | 乙烯基 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 73. |
化合物 | n | m | B′ | W | Ar′ | Ki(nM) |
79 | 2 | 0 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 乙烯基 | 3,4,5-三甲氧基苯基 | 2.3 |
80 | 2 | 0 | 丙基 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 17. |
81 | 2 | 0 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 丙基 | 3,4,5-三甲氧基苯基 | 5. |
82 | 2 | 0 | 甲基 | 3,4,5-三-(噻吩-3-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | >5000 |
83 | 2 | 0 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 甲基 | 3,4,5-三甲氧基苯基 | >1000 |
84 | 2 | 0 | 甲基 | 2-异丙氧基-3,4-二-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 54. |
85 | 2 | 0 | 2-异丙氧基-3,4-二-(吡啶-4-基甲氧基)苯基 | 甲基 | 3,4,5-三甲氧基苯基 | 3.5 |
86 | 1 | 0 | 甲基 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 280 |
87 | 1 | 0 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 甲基 | 3,4,5-三甲氧基苯基 | 360 |
88 | 2 | 0 | 甲基 | 3,4,5-三-(嘧啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 19. |
89 | 2 | 0 | 苄氧甲基 | 苄氧基苯基 | 3,4,5-三甲氧基苯基 | 5. |
90 | 2 | 0 | 甲基 | 3,4,5-三-(苄氧基)苯基 | 3,4,5-三甲氧基苯基 | 2600 |
91 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-3-基羰基)苯基 | 3,4,5-三甲氧基苯基 | 24. |
92 | 2 | 0 | 3-(吡啶-3-基羰基)苯基 | 3-苯基丙基 | 3,4,5-三甲氧基苯基 | 9. |
93 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 7.5 |
94 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基羰基)苯基 | 4-苄氧基-3,5-二甲氧基苯基 | 25. |
95 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基羰基)苯基 | 4-烯丙氧基-3,5-二甲氧基苯基 | 3.6 |
96 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基羰基)苯基 | 3-苄氧基-4-甲氧基苯基 | 25. |
97 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基羰基)苯基 | 3-烯丙氧基-4-甲氧基苯基 | 17. |
98 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基羰基)苯基 | 3-[3-苯基-(E)-丙-2-烯 | 380. |
基]-4-甲氧基苯基 | ||||||
99 | 2 | 0 | 3-苯基丙基 | 4-(吡啶-4-基羰基)苯基 | 4-苄氧基-3,5-二甲氧基苯基 | 15000. |
化合物 | n | m | B′ | W | Ar′ | Ki(nM) |
100 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基羰基)苯基 | 3-苄氧基-4-甲氧基苯基 | >5000 |
101 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基羰基)苯基 | 3,4,5-三甲氧基苯基 | ND |
102 | 2 | 0 | 3-苯基丙基 | 3-(吡啶-4-基羰基)苯基 | 3,4-二甲氧基苯基 | ND |
103 | 2 | 0 | 3-苯基丙基 | 苯基 | 3-苄氧基-4-甲氧基苯基 | 24000. |
104 | 2 | 0 | 3-苯基丙基 | 苯基 | 4-苄氧基-3,5-二甲氧基苯基 | 1700. |
105 | 1 | 0 | 3-(吡啶-3-基)丙基 | 3-苯基丙基 | 叔丁基 | 340. |
106 | 2 | 0 | 3-(吡啶-3-基)丙基 | 3-(吡啶-3-基)丙基 | 3,4,5-三甲氧基苯基 | 3.7 |
107 | 1 | 0 | 苄氧甲基 | 苄氧甲基 | 3,4,5-三甲氧基苯基 | 75000. |
108 | 1 | 0 | 3-(吡啶-3-基)丙基 | 3-(吡啶-3-基)丙基 | 3,4,5-三甲氧基苯基 | 89. |
109 | 2 | 0 | 3-(吡啶-3-基)丙基 | 3-(吡啶-3-基)丙基 | 异丙基 | 1500. |
110 | 2 | 0 | 3-(吡啶-3-基)- | 3-(吡啶-3-基)- | 噻吩-2-基 | ND |
111 | 2 | 0 | 3-(吡啶-3-基)丙基 | 3-(吡啶-3-基)丙基 | 3,4-亚甲二氧基苯基 | ND |
112 | 2 | 0 | 3-(吡啶-3-基)丙-2-炔基 | 3-(吡啶-3-基)丙-2-炔 | 3,4-亚甲二氧基苯基 | ND |
基 | ||||||
113 | 2 | 0 | 3-(吡啶-3-基)丙-2-炔基 | 3-(吡啶-3-基)苯-2-炔基 | 3,4,5-三甲氧基苯基 | ND |
114 | 2 | 0 | 3-(吡啶-2-基)丙基 | 3-(吡啶-2-基)丙基 | 3,4,5-三甲氧基苯基 | ND |
115 | 2 | 0 | 异丙基 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 3,4,5-三甲氧基苯基 | 0.39 |
116 | 2 | 0 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 异丙基 | 3,4,5-三甲氧基苯基 | 13. |
118 | 2 | 0 | 3,4,5-三-(吡啶-4-基甲氧基)苯基 | 丙-2-烯基 | 3,4,5-三甲氧基苯基 | 12. |
实施例2
轴突在PC12培养基中的生长测定
为直接测定本发明使用的FKBP12结合化合物的神经营养活性,按照W.E.Lyons等在美国国立科学院学报,91,3191-95(1994)所述进行测定。
使PC12大鼠嗜铬细胞在37℃下、5%CO2中在Dulbecco′s改性Eagle′s培养基(DMEM)中保温,该培养基中加有10%加热活化的马血清(HS)和5%加热活化的胎牛血清(FBS)。然后将细胞以105/培养孔加到培养板中,所述培养孔包被有5μg/cm2的大鼠尾胶原并使其附着。然后用DMEM+2%HS和1%、NGF(1-100ng/ml)和各种浓度的FKBP12结合化合物(0.1nM-10μM)代替培养基。对照培养物仅给予不含FKBP12结合化合物的NGF。
本发明使用的FKBP12结合化合物与对照培养物相比,能够明显增进轴突的生长。
实施例3
背根部神经节轴突的生长测定
直接测定本发明使用的FKBP12结合化合物的神经营养活性的另一种方法也是W.E.Lyons等在Proc.Natl.Acad.Sci.USA,91,3191-95(1994)上描述的背根部神经节培养测定法。
在该测定中,从16天的大鼠胚胎中分离背根部神经节并使其在胶原包被的35mm培养皿中在N2培养基中在37℃和15%CO2环境中培养。然后将感觉神经节用各种浓度的NGF(0-100ng/ml)和FKBP12结合化合物(0.1nM-10μM)处理。在相相反显微镜下每两天观察一次神经节并测定轴突的长度。对照培养基不含FKBP12结合化合物或者不含FKBP12结合化合物和NGF。
本发明使用的FKBP12结合化合物与存在或不存在NGF的不含该类化合物的对照培养基相比明显增进轴突的生长。
上文的化合物I表示了本发明的多种实施方案,显然该基本的结构可以有所变化以提供本发明的其它实施方案。因此,十分清楚本发明的的范围由附录的权利要求书限定,而不是由上文以实施例方式表示的实施方案限定。
Claims (25)
1.药物组合物,其包括:
a)神经营养量的具有FKBP12亲和性的式(I)化合物:和其可药用衍生物,其中A是O、NH或N-(C1-C4烷基);
其中B是氢,CHL-Ar,(C1-C6)-直链或支链烷基,(C2-C6)-直链或支链链烯基,(C5-C7)-环烷基,(C5-C7)-环链烯基或者被(C1-C6)-烷基或(C2-C6)-链烯基取代的Ar,或者
其中L和Q独立地是氢,(C1-C6)-直链或支链烷基或者(C2-C6)-直链或支链链烯基;
T是Ar或者在3和4位带有取代基的环己基,所述取代基独立地选自氢,羟基,O-(C1-C4)-烷基或O-(C2-C4)-链烯基和基;
其中Ar选自具有一至三个取代基的1-萘基,2-萘基,2-呋喃基,3-呋喃基,2-噻吩基,2-吡啶基,3-吡啶基,4-吡啶基和苯基,所述取代基独立地选自氢、卤素、羟基、硝基、CF3、(C1-C6)-直链或支链烷基或(C2-C6)-直链或支链链烯基,O-(C1-C4)-直链或支链烷基或O-((C2-C4)-直链或支链链烯基),O-苄基,O-苯基,氨基或苯基;
其中D是U;
E是氧或CH-U,条件是如果D是氢,则E是HC-U或者如果E是氧,则D不是氢;
其中每个U独立地选自氢,O-(C1-C4)-直链或支链烷基或者O-((C2-C4)-直链或支链链烯基),(C1-C6)-直链或支链烷基或(C2-C6)-直链或支链链烯基,被(C1-C4)-直链或支链烷基或(C2-C4)-直链或支链链烯基取代的(C5-C7)-环烷基或者(C5-C7)-环链烯基,2-吲哚基,3-吲哚基,[(C1-C4)-烷基或(C2-C4)-链烯基]-Ar或者Ar;
J是氢或者C1或C2烷基;
K是(C1-C4)直链或支链烷基,苄基或环己基甲基;或者其中J和K可以一起形成其中包含O、S、SO或SO2的5-7元杂环;
1位碳的立体化学是R或S构型;
b)神经营养因子;和
c)药学上适用的载体。
2.根据权利要求1的组合物,其中:
A是氧;
J是氢或者C1或C2烷基;
K是(C1-C4)直链或支链烷基,苄基或环己基甲基;或者J和K一起形成吡咯烷基或哌啶基;并且
1位碳的立体化学是S构型。
3.根据权利要求2的组合物,其中:
J和K一起形成吡咯烷基或哌啶基;
E是CH-U;并且
U是二甲氨基苯基、甲氧基苯基、二甲氧基苯基、三甲氧基苯基、硝基苯基、呋喃基、吲哚基、吡啶基或亚甲二氧苯基。
4.根据权利要求2的组合物,其中:
J和K一起形成吡咯烷基或哌啶基;
E是氧:
B是苄基,萘基,叔丁基,氢,E-3-苯基-2-甲基-丙-2-烯基,E-3-(4-羟基苯基)2-甲基-丙-2-烯基,E-3-[反(4-羟基环己基)]-2-甲基-丙-2-烯基,环己基乙基,环己基丙基,环己基丁基,环戊基丙基,E-3-(4-甲氧基苯基)-2-甲基-丙-2-烯基,E-3-(3,4-二甲氧基苯基)-2-甲基-丙-2-烯基或E-3-[顺(4-羟基环己基)]-2-甲基-丙-2-烯基;并且
D优选是苯基,甲氧基苯基,环己基,乙基,甲氧基,硝基苄基,噻吩基,吲哚基,呋喃基,吡啶基,吡啶基-N-氧化物,硝基苯基,氟苯基,三甲氧基苯基或二甲氧基苯基。
5.药物组合物,其包括:
其中B′和W独立地是:
(i)氢,Ar′,(C1-C10)-直链或支链烷基,(C2-C10)-直链或支链链烯基或炔基,(C1-C6)-直链或支链烷基、(C2-C6)直链或支链链烯基或炔基取代的(C5-C7)-环烷基,(C1-C6)-直链或支链烷基、(C2-C6)直链或支链链烯基或炔基取代的(C5-C7)-环链烯基,或者(C1-C6)-直链或支链烷基、(C2-C6)直链或支链链烯基或炔基取代的Ar′,在各种情况下,其中所述烷基、链烯基或炔基链中的任一个CH2基可任意地被选自O、S、SO、SO2、N和NR的杂原子取代,
其中R选自氢、(C1-C4)-直链或支链烷基、(C2-C4)-直链或支链链烯基或炔基,和(C1-C4)桥烷基,其中桥是由形成环的所述含杂原子的链中的氮原子和碳原子形成的,并且其中所述的环可任意地与Ar′基稠合;或者
(ii)其中Q′是氢,(C1-C6)-直链或支链烷基或者(C2-C6)-直链或支链链烯基或炔基;并且
T′是Ar′或者在3位和4为带有取代基的5-7元环烷基,所述取代基独立地选自氧、氢、羟基、O-(C1-C4)-烷基和O-(C2-C4)-链烯基;
其中Ar′是碳环芳香基,选自苯基,1-萘基,2-萘基,茚基,甘菊环基,芴基和蒽基;或者杂环芳香基,选自2-呋喃基,3-呋喃基,2-噻吩基,3-噻吩基,2-吡啶基,3-吡啶基,4-吡啶基,吡咯基,噁唑基,噻唑基,咪唑基,吡唑基,异噁唑基,异噻唑基,1,2,3-噁二唑基,1,2,3-三唑基,1,3,4-噻二唑基,哒嗪基,嘧啶基,吡嗪基,1,3,5-三嗪基,1,3,5-三噻烷基,中茚氮基,吲哚基,异吲哚基,3H-吲哚基,二氢吲哚基,苯并[b]呋喃基,苯并[b]噻吩基,1H-吲唑基,苯并咪唑基,苯并噻唑基,嘌呤基,4H-喹嗪基,喹啉基,异喹啉基,肉啉基,2,3-二氮杂萘基,喹唑啉基,喹喔啉基,1,8-二氮杂萘基,蝶啶基,咔唑基,吖啶基,吩嗪基,吩噻嗪基和吩噁嗪基;
其中Ar′可带有一至三个取代基,所述取代基独立地选自氢,卤素,羟基,羟甲基,硝基,三氟甲基,三氟甲氧基,(C1-C6)-直链或支链烷基,(C2-C6)直链或支链链烯基,O-[(C1-C4)-直链或支链烷基],O-[(C2-C4)-直链或支链链烯基],O-苄基,O-苯基,1,2-亚甲二氧基,氨基,羧基,N-[(C1-C5)-直链或支链烷基或者(C2-C5)-直链或支链链烯基)甲酰胺,N,N-二-[(C1-C5)-直链或支链烷基或者(C2-C5)-直链或支链链烯基)]甲酰胺,N-吗啉代甲酰胺,N-苄基甲酰胺,N-硫代吗啉代甲酰胺,N-甲基二氢吡啶基甲酰胺,O-X,CH2-(CH2)q-
X,O-(CH2)q-X,(CH2)q-O-X和CH=CH-X;
其中X是4-甲氧基苯基,2-吡啶基,3-吡啶基,4-吡啶基,
吡嗪基,喹啉基,3,5-二甲基异噁唑基,异噁唑基,2-甲基噻唑基,
噻唑基,2-噻吩基,3-噻吩基或嘧啶基;并且
q是0-2;
G是U′;
M是氧或CH-U′;条件是如果G是氢,则M是CH-U′;或者如果M是氧,则G是U′;
其中U′是氢,O-[(C1-C4)-直链或支链烷基]或O-[(C2-C4)-直链或
支链链烯基],(C1-C6)-直链或支链烷基或者(C2-C6)-直链或支链链烯
基,被(C1-C4)-直链或支链烷基或者(C2-C6)-直链或支链链烯基取代
的(C5-C7)-环烷基或者(C5-C7)-环链烯基,[(C1-C4)-烷基或(C2-C4)-
链烯基]-Y或Y;
其中Y选自苯基,1-萘基,2-萘基,茚基,甘菊环基,芴基,
蒽基,2-吡咯啉基,3-吡咯啉基,吡咯烷基,1,3-间二氧杂环戊烯
基,2-咪唑啉基,咪唑烷基,2H-吡喃基,4H-吡喃基,哌啶基,1,4-
二噁烷基,吗啉基,1,4-二噻烷基,硫代吗啉基,哌嗪基,奎宁环基
和如上述为Ar′所定义的杂环芳香基;并且
其中Y可带有一至三个取代基,所述取代基独立地选自氢,卤
素,羟基,羟甲基,硝基,三氟甲基,三氟甲氧基,(C1-C6)-直链或
支链烷基,(C2-C6)直链或支链链烯基,O-[(C1-C4)-直链或支链烷
基],O-[(C2-C4)-直链或支链链烯基],O-苄基,O-苯基,1,2-亚甲
二氧基,氨基和羧基;
J是氢,(C1-C2)烷基或苄基;
K是(C1-C4)-直链或支链烷基,苄基或环己基甲基,或者其中J′和K一
起形成5-7元杂环,该杂环可含有选自O、S、SO和SO2的杂原子;
m是0-3;并且
其中所述的化合物不是式(I)化合物;
b)神经营养因子;和
c)药学上适用的载体。
6.根据权利要求5的组合物,其中:
B′和W独立地是:
(i)氢,Ar′,(C1-C10)-直链或支链烷基,(C2-C10)-直链或支链链烯基或炔基,(C1-C6)-直链或支链烷基、(C2-C6)-直链或支链链烯基或炔基取代的(C5-C7)-环烷基,(C1-C6)-直链或支链烷基、(C2-C6)-直链或支链链烯基或炔基取代的(C5-C7)-环链烯基,或者(C1-C6)-直链或支链烷基、(C2-C6)-直链或支链链烯基或烧基取代的Ar′,在各种情况下,其中所述烷基、链烯基或炔基链中的任一个CH2基可任意地被选自O、S、SO、SO2的杂原子取代;或者
(ii)
Ar′可带有一至三个取代基,所述取代基独立地选自氢,卤素,羟基,羟甲基,硝基,三氟甲基,三氟甲氧基,(C1-C6)-直链或支链烷基,(C2-C6)直链或支链链烯基,O-[(C1-C4)-直链或支链烷基],O-[(C2-C4)-直链或支链链烯基],O-苄基,O-苯基,1,2-亚甲二氧基,氨基和羧基;并且
Y选自基,1-萘基,2-萘基,茚基,甘菊环基,芴基,蒽基,和如上述为Ar′所定义的杂环芳基。
7.根据权利要求5的组合物,其中
至少B′或W中的一个独立地选自(C2-C10)-直链或支链炔基;被(C2-C6)-直链或支链炔基取代的(C5-C7)-环烷基;被(C2-C6)-直链或支链炔基取代的(C5-C7)-环链烯基;和被(C2-C6)-直链或支链炔基取代的Ar′。
8.根据权利要求5的组合物,其中:
至少B′或W中的至少一个独立地选自式-(CH2)r-(Z)-(CH2)r-Ar′,其中:
Z独立地选自CH2、O、S、SO、SO2、N和NR;
r是0-4;
s是0-1。
9.根据权利要求5的组合物,其中:
至少B′或W中的一个独立地选自Ar′,被(C1-C6)-直链或支链烷基取代的Ar′和被(C2-C6)-直链或支链链烯基或炔基取代的Ar′;
其中Ar′被一至三个取代基取代,所述取代基独立地选自N-(直链或支链(C1-C5)-烷基或者(C2-C5)-链烯基)甲酰胺,N,N-二-(直链或支链(C1-C5)烷基或-(C2-C5)烯基-)甲酰胺,N-吗啉代甲酰胺,N-苄基甲酰胺,N-硫代吗啉代甲酰胺,N-甲基二氢吡啶基甲酰胺,O-X,CH2-(CH2)q-X,O-(CH2)q-X,(CH2)q-O-X和CH=CH-X。
10.根据权利要求1或5的组合物,其中所述的神经营养因子选自神经生长因子(NGF)、胰岛素生长因子(IGF-1)和其活性截断衍生物如gIGF-1、酸性和碱性成纤维细胞生长因子(分别为aFGF和bFGF)、血小板衍生的生长因子(PDGF),脑衍生的神经营养因子(BDNF)、睫神经营养因子(CTNF)、神经胶质细胞系衍生的神经营养因子(GDNF)、向神经素-3(NT-3)和向神经素4/5(NT-4/5)。
11.根据权利要求10的组合物,其中所述的神经营养因子是NGF。
其中B是氢,CHL-Ar,(C1-C6)-直链或支链烷基,(C2-C6)-直链或支链链烯基,(C5-C7)-环烷基,(C5-C7)-环链烯基或者被(C1-C6)-烷基或(C2-C6)-链烯基取代的Ar,或者
其中L和Q独立地是氢,(C1-C6)-直链或支链烷基或者(C2-C6)-直链或支链链烯基;
T是Ar或者在3和4位带有取代基的环己基,所述取代基独立地选自氢,羟基,O-(C1-C4)-烷基或O-(C2-C4)-链烯基和羰基;
其中Ar选自具有一至三个取代基的1-萘基,2-萘基,2-呋喃基,3-呋喃基,2-噻吩基,2-吡啶基,3-吡啶基,4-吡啶基和苯基,所述取代基独立地选自氢、卤素、羟基、硝基、CF3、(C1-C6)-直链或支链烷基或(C2-C6)-直链或支链链烯基,O-(C1-C4)-直链或支链烷基或O-((C2-C4)-直链或支链链烯基),O-苄基,O-苯基,氨基或苯基;
其中D是U;
E是氧或CH-U,条件是如果D是氢,则E是HC-U或者如果E是氧,则D不是氢;
其中每个U独立地选自氢,O-(C1-C4)-直链或支链烷基或者O-((C2-C4)-直链或支链链烯基),(C1-C6)-直链或支链烷基或(C2-C6)-直链或支链链烯基,被(C1-C4)-直链或支链烷基或(C2-C4)-直链或支链链烯基取代的(C5-C7)-环烷基或者(C5-C7)-环链烯基,2-吲哚基,3-吲哚基,[(C1-C4)-烷基或(C2-C4)-链烯基]-Ar或者Ar;
J是氢或者C1或C2烷基;
K是(C1-C4)直链或支链烷基,苄基或环己基甲基;或者其中J和K可以一起形成其中包含O、S、SO或SO2的5-7元杂环;
1位碳的立体化学是R或S构型。
13.根据权利要求12的方法,其中所述具有FKBP12亲和性的化合物中:
A是氧;
J是氢或者C1或C2烷基;
K是(C1-C4)-直链或支链烷基、苄基或环己基甲基;或者J和K一起形成吡咯烷基或哌啶基;并且
1位碳的立体化学是S构型。
14.根据权利要求13的方法,其中所述的具有FKBP12亲和性的化合物中:
J和K一起是形成吡咯烷基或哌啶基;并且
E是CH-U;并且
U是二甲氨基苯基,甲氧基苯基,二甲氧基苯基,三甲氧基苯基,硝基苯基,呋喃基,吲哚基,吡啶基或亚甲二氧基苯基。
15.根据权利要求13的方法,其中所述的具有FKBP12亲和性的化合物中:
J和K一起形成吡咯烷基和哌啶基;
E是氧;
B是苄基,萘基,叔丁基,氢,E-3-苯基-2-甲基-丙-2-烯基,E-3-(4-羟基苯基)2-甲基-丙-2-烯基,E-3-[反(4-羟基环己基)]1-2-甲基-丙-2-烯基,环己基乙基,环己基丙基,环己基丁基,环戊基丙基,E-3-(4-甲氧基苯基)-2-甲基-丙-2-烯基,E-3-(3,4-二甲氧基苯基)-2-甲基-丙-2-烯基或E-3-[顺(4-羟基环己基)]-2-甲基-丙-2-烯基;并且
D优选是苯基,甲氧基苯基,环己基,乙基,甲氧基,硝基苄基,噻吩基,吲哚基,呋喃基,吡啶基,吡啶基-N-氧化物,硝基苯基,氟苯基,三甲氧基苯基或二甲氧基苯基。
16.一种刺激神经细胞轴突生长的方法,包括使所述神经细胞于含有神经营养量的具有FKBP12亲和性的式(II)化合物:a)神经营养量的具有FKBP12亲和性的式(II)化合物:和其可药用衍生物的组合物接触的步骤,式II中A′是CH2,氧,NH或N-(C1-C4烷基);
其中B′和W独立地是:
(i)氢,Ar′,(C1-C10)-直链或支链烷基,(C2-C10)-直链或支链链烯基或炔基,(C1-C6)-直链或支链烷基、(C2-C6)直链或支链链烯基或炔基取代的(C5-C7)-环烷基,(C1-C6)-直链或支链烷基、(C2-C6)直链或支链链烯基或炔基取代的(C5-C7)-环链烯基,或者(C1-C6)-直链或支链烷基、(C2-C6)直链或支链链烯基或炔基取代的Ar′,在各种情况下,其中所述烷基、链烯基或炔基链中的任一个CH2基可任意地被选自O、S、SO、SO2、N和NR的杂原子取代,
其中R选自氢、(C1-C4)-直链或支链烷基、(C2-C4)-直链或支链链烯基或炔基,和(C1-C4)桥烷基,其中的桥是由形成环的所述含杂原子的链中的氮原子和碳原子形成的,并且其中所述的环可任意地与Ar′基稠合;或者
(ii)其中Q′是氢,(C1-C6)-直链或支链烷基或者(C2-C6)-直链或支链链烯基或炔基;并且
T′是Ar′或者在3位和4为带有取代基的5-7元环烷基,所述取代基独立地选自氧、氢、羟基、O-(C1-C4)-烷基和O-(C2-C4)-链烯基;
其中Ar′是碳环芳香基,选自苯基,1-萘基,2-萘基,茚基,甘
菊环基,芴基和蒽基;或者杂环芳香基,选自2-呋喃基,3-呋喃基,
2-噻吩基,3-噻吩基,2-吡啶基,3-吡啶基,4-吡啶基,吡咯基,
噁唑基,噻唑基,咪唑基,吡唑基,异噁唑基,异噻唑基,1,2,3-噁
二唑基,1,2,3-三唑基,1,3,4-噻二唑基,哒嗪基,嘧啶基,吡嗪基,
1,3,5-三嗪基,1,3,5-三噻烷基,中茚氮基,吲哚基,异吲哚基,3H-
吲哚基,二氢吲哚基,苯并[b]呋喃基,苯并[b]噻吩基,1H-吲唑基,
苯并咪唑基,苯并噻唑基,嘌呤基,4H-喹嗪基,喹啉基,异喹啉基,
肉啉基,2,3-二氮杂萘基,喹唑啉基,喹喔啉基,1,8-二氮杂萘基,
蝶啶基,咔唑基,吖啶基,吩嗪基,吩噻嗪基和吩噁嗪基;
其中Ar′可带有一至三个取代基,所述取代基独立地选自氢,卤
素,羟基,羟甲基,硝基,三氟甲基,三氟甲氧基,(C1-C6)-直链或
支链烷基,(C2-C6)直链或支链链烯基,O-[(C1-C4)-直链或支链烷
基],O-[(C2-C4)-直链或支链链烯基],O-苄基,O-苯基,1,2-亚甲
二氧基,氨基,羧基,N-[(C1-C5)-直链或支链烷基或者(C2-C5)-直链
或支链链烯基)甲酰胺,N,N-二-[(C1-C5)-直链或支链烷基或者(C2-
C5)-直链或支链链烯基)]甲酰胺,N-吗啉代甲酰胺,N-苄基甲酰胺,
N-硫代吗啉代甲酰胺,N-甲基二氢吡啶基甲酰胺,O-X,CH2-(CH2)q-X
,O-(CH2)q-X,(CH2)q-O-X和CH=CH-X;
其中X是4-甲氧基苯基,2-吡啶基,3-吡啶基,4-吡啶基,
吡嗪基(pyrazyl),喹啉基,3,5-二甲基异噁唑基,异噁唑基,2-甲
基噻唑基,噻唑基,2-噻吩基,3-噻吩基或嘧啶基;并且
q是0-2;
G是U′;
M是氧或CH-U′;条件是如果G是氢,则M是CH-U′;或者如果M是氧,则G是U′;
其中U′是氢,O-[(C1-C4)-直链或支链基]或O-[(C2-C4)-直链或
支链链烯基],(C1-C6)-直链或支链烷基或者(C2-C6)-直链或支链链烯
基,被(C1-C4)-直链或支链烷基或者(C2-C6)-直链或支链链烯基取代
的(C5-C7)-环烷基或者(C5-C7)-环链烯基,[(C1-C4)-烷基或(C2-C4)-
链烯基]-Y或Y;
其中Y选自苯基,1-萘基,2-萘基,茚基,甘菊环基,芴基,
蒽基,2-吡咯啉基,3-吡咯啉基,吡咯烷基,1,3-间二氧杂环戊烯
基,2-咪唑啉基,咪唑烷基,2H-吡喃基,4H-吡喃基,哌啶基,1,4-
二噁烷基,吗啉基,1,4-二噻烷基,硫代吗啉基,哌嗪基,奎宁环基
和如上述为Ar′所定义的杂环芳香基;并且
其中Y可带有一至三个取代基,所述取代基独立地选自氢,卤
素,羟基,羟甲基,硝基,三氟甲基,三氟甲氧基,(C1-C6)-直链或
支链烷基,(C2-C6)直链或支链链烯基,O-[(C1-C4)-直链或支链烷
基],O-[(C2-C4)-直链或支链链烯基],O-苄基,O-苯基,1,2-亚甲
二氧基,氨基和羧基;
J是氢,(C1-C2)烷基或苄基;
K是(C1-C4)-直链或支链烷基,苄基或环己基甲基,或者其中J′和K一
起形成5-7元杂环,该杂环可含有选自O、S、SO和SO2的杂原子;
m是0-3;并且
其中所述的化合物不是式(I)化合物。
17.根据权利要求16的方法,其中所述的具有FKBP12亲和性的化合物中:
B′和W独立地是:
(i)氢,Ar′,(C1-C10)-直链或支链烷基,(C2-C1O)-直链或支链链烯基或炔基,(C1-C6)-直链或支链烷基、(C2-C6)-直链或支链链烯基或炔基取代的(C5-C7)-环烷基,(C1-C6)-直链或支链烷基、(C2-C6)-直链或支链链烯基或炔基取代的(C5-C7)-环链烯基,或者(C1-C6)-直链或支链烷基、(C2-C6)-直链或支链链烯基或炔基取代的Ar′,在各种情况下,其中所述烷基、链烯基或炔基链中的任一个CH2基可任意地被选自O、S、SO、SO2的杂原子取代;或者
(ii)
Ar′可带有一至三个取代基,所述取代基独立地选自氢,卤素,羟基,羟甲基,硝基,三氟甲基,三氟甲氧基,(C1-C6)-直链或支链烷基,(C2-C6)直链或支链链烯基,O-[(C1-C4)-直链或支链烷基],O-[(C2-C4)-直链或支链链烯基],O-苄基,O-苯基,1,2-亚甲二氧基,氨基和羧基;并且
Y选自苯基,1-萘基,2-萘基,茚基,甘菊环基,芴基,蒽基,和如上述为Ar′所定义的杂环芳基。
18.根据权利要求16的方法,其中所述的具有FKBP12亲和性的化合物中:
至少B′或W中的一个独立地选自(C2-C10)-直链或支链炔基;被(C2-C6)-直链或支链炔基取代的(C5-C7)-环烷基;被(C2-C6)-直链或支链炔基取代的(C5-C7)-环链烯基;和被(C2-C6)-直链或支链炔基取代的Ar′。
19.根据权利要求16的方法,其中所述的具有FKBP12亲和性的化合物中:
至少B′或W中的至少一个独立地选自式-(CH2)r-(Z)-(CH2)r-Ar′,其中:
Z独立地选自CH2、O、S、SO、SO2、N和NR;
r是0-4;
s是0-1。
20.根据权利要求16的方法,其中所述的具有FKBP12亲和性的化合物中:
至少B′或W中的一个独立地选自Ar′,被(C1-C6)-直链或支链烷基取代的Ar′和被(C2-C6)-直链或支链链烯基或烧基取代的Ar′;
其中Ar′被一至三个取代基取代,所述取代基独立地选自N-(直链或支链(C1-C5)-烷基或者(C2-C5)-链烯基)甲酰胺,N,N-二-(直链或支链(C1-C5)烷基或-(C2-C5)烯基-)甲酰胺,N-吗啉代甲酰胺,N-苄基甲酰胺,N-硫代吗啉代甲酰胺,N-甲基二氢吡啶基(picolinoyl)甲酰胺,O-X,CH2-(CH2)q-X,O-(CH2)q-X,(CH2)q-O-X和CH=CH-X。
21.根据权利要求12或16的方法,其中所述方法包括另外的使所述神经细胞与神经营养因子接触的步骤。
22.根据权利要求21的方法,其中所述神经营养因子选自神经生长因子(NGF)、胰岛素生长因子(IGF-1)和其活性截断衍生物如gIGF-1、酸性和碱性成纤维细胞生长因子(分别为aFGF和bFGF)、血小板衍生的生长因子(PDGF),脑衍生的神经营养因子(BDNF)、睫神经营养因子(CTNF)、神经胶质细胞系衍生的神经营养因子(GDNF)、向神经素-3(NT-3)和向神经素4/5(NT-4/5)。
23.根据权利要求22的方法,其中所述神经营养因子是NGF。
24.根据权利要求24的方法,其中所述方法用于治疗阿尔茨海默氏症、巴金森氏病、ALS、中风和与中风有关的局部缺血、神经病变、其它神经退化性疾病、运动神经疾病、坐骨神经痛疾病、脊索损伤和面神经疾病。
25.根据权利要求21的方法,其中所述的方法用于治疗阿尔茨海默氏症、巴金森氏病、ALS、中风和与中风有关的局部缺血、神经病变、其它神经退化性疾病、运动神经疾病、坐骨神经痛疾病、脊索损伤和面神经疾病。
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- 1995-06-08 US US08/486,004 patent/US6037370A/en not_active Expired - Lifetime
-
1996
- 1996-06-06 RU RU98100456/14A patent/RU2197240C2/ru not_active IP Right Cessation
- 1996-06-06 KR KR1019970709288A patent/KR100480662B1/ko not_active IP Right Cessation
- 1996-06-06 EP EP05026521A patent/EP1666037A3/en not_active Withdrawn
- 1996-06-06 EP EP96918469A patent/EP0831812B1/en not_active Expired - Lifetime
- 1996-06-06 DE DE69635550T patent/DE69635550T2/de not_active Expired - Lifetime
- 1996-06-06 PL PL96328723A patent/PL185798B1/pl not_active IP Right Cessation
- 1996-06-06 CN CN96195690A patent/CN1202104A/zh active Pending
- 1996-06-06 DK DK96918469T patent/DK0831812T3/da active
- 1996-06-06 IL IL12234696A patent/IL122346A/en not_active IP Right Cessation
- 1996-06-06 BR BR9609333-1A patent/BR9609333A/pt not_active IP Right Cessation
- 1996-06-06 NZ NZ310339A patent/NZ310339A/xx unknown
- 1996-06-06 CA CA002222430A patent/CA2222430A1/en not_active Abandoned
- 1996-06-06 AT AT96918469T patent/ATE311875T1/de not_active IP Right Cessation
- 1996-06-06 WO PCT/US1996/010123 patent/WO1996041609A2/en active IP Right Grant
- 1996-06-06 ES ES96918469T patent/ES2255077T3/es not_active Expired - Lifetime
- 1996-06-07 ZA ZA964852A patent/ZA964852B/xx unknown
-
1997
- 1997-02-28 US US08/795,956 patent/US6124328A/en not_active Expired - Lifetime
-
2000
- 2000-07-14 US US09/616,539 patent/US6326387B1/en not_active Expired - Lifetime
-
2007
- 2007-09-03 JP JP2007227995A patent/JP2007308517A/ja active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003048150A1 (fr) * | 2001-12-06 | 2003-06-12 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. | Composes n-heterocycliques a 5 elements substitues et leurs utilisations dans le traitement ou la prevention de maladies neurodegeneratives |
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EP0831812A2 (en) | 1998-04-01 |
EP1666037A3 (en) | 2006-06-21 |
PL328723A1 (en) | 1999-02-15 |
CA2222430A1 (en) | 1996-12-27 |
JP2007308517A (ja) | 2007-11-29 |
ZA964852B (en) | 1996-07-29 |
RU2197240C2 (ru) | 2003-01-27 |
IL122346A0 (en) | 1998-04-05 |
EP1666037A2 (en) | 2006-06-07 |
ES2255077T3 (es) | 2006-06-16 |
US6037370A (en) | 2000-03-14 |
BR9609333A (pt) | 1999-10-13 |
ATE311875T1 (de) | 2005-12-15 |
US6124328A (en) | 2000-09-26 |
WO1996041609A2 (en) | 1996-12-27 |
DE69635550T2 (de) | 2006-08-24 |
KR100480662B1 (ko) | 2005-09-12 |
NZ310339A (en) | 2000-03-27 |
KR19990022819A (ko) | 1999-03-25 |
US6326387B1 (en) | 2001-12-04 |
IL122346A (en) | 2002-05-23 |
DK0831812T3 (da) | 2006-07-17 |
PL185798B1 (pl) | 2003-07-31 |
EP0831812B1 (en) | 2005-12-07 |
DE69635550D1 (de) | 2006-01-12 |
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