CN1882565A - 哌啶取代的吲哚或其杂环衍生物以及它们作为趋化因子-受体(ccr-3)调节剂的用途 - Google Patents
哌啶取代的吲哚或其杂环衍生物以及它们作为趋化因子-受体(ccr-3)调节剂的用途 Download PDFInfo
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Abstract
本发明的目的之一是提供式(1)新的哌啶取代的吲哚或其杂环衍生物,其中R1、R5、R6、A、B、D-E、X-W-V、Y、i、j、n及m的定义如说明书中所述。本发明另一目的是提供CCR-3的激动剂或拮抗剂,或其药学上可接受的盐类,优选的是提供包含药学上可接受的载体及至少一种治疗有效量的本发明化合物或其药学上可接受的盐类的药物组合物。
Description
发明领域
本发明一般而言是关于经哌啶取代的吲哚或其杂环衍生物及其作为趋化因子(chemokines)受体或其调节剂的用途、含有该化合物的药物组合物及使用该化合物作为治疗及预防发炎性疾病例如气喘和过敏性疾病,以及自体免疫病例如类风湿关节炎和动脉硬化药剂的方法。
发明背景
趋化因子为趋化性细胞激素,分子量6-15kDa,它是由各种不同细胞所释放用以吸引或活化细胞,其中的细胞类型为(但不限于),巨噬细胞、T及B淋巴细胞、嗜伊红细胞(eosinophils)、嗜碱白血球(basophil)及中性细胞(neutrophil)(参见Luster,New Eng.J Med.,338,436-445(1998)及Rollins,Blood,90,909-928(1997))。
有两种主要的趋化因子,CXC及CC,是依照在胺基酸序列中前两个半胱胺酸是否被单一的氨基酸(CXC)分隔开或是相邻(CC)。CXC趋化因子例如介白素-8(IL-8)、中性细胞活化蛋白-2(NAP2)及黑素瘤生长刺激活性蛋白(MGSA),主要为中性细胞及T淋巴细胞的趋化因子,而CC趋化因子例如RANTES、MIP-1a、MIP-1(3,单核细胞趋化蛋白(MCP-1、MCP-2、MCP-3、MCP-4及MCP-5)及嗜伊红粒细胞趋化蛋白(eotaxin)(-1,-2,及-3),于其它各种细胞类型中,为巨噬细胞、T淋巴细胞、嗜伊红细胞(eosinophils)、树突细胞及嗜碱白细胞(basophil)的趋化因子。另外还存在的趋化因子有淋巴细胞趋化因子-1、淋巴细胞趋化因子-2(两者皆为C趋化因子)、及膜结合趋化因子(fractalkine)(CXXXC趋化因子)其并不在主要的趋化因子亚族中。
与特定细胞表面受体结合的趋化因子是属于G-蛋白偶合的七跨膜结构域蛋白(G-protein-coupled seventransmembrane-domain proteins)的家族(参见Horuk,Trends Pharm.Sci.,15,159-165(1994)),其是称为“趋化因子受体”。在与其同源配体结合时,趋化因子受体将通过相关的三聚体G蛋白转换胞内信息,连同其它反应一起导致快速增加胞内钙离子浓度、改变细胞形状、增加细胞的黏附分子表达、细胞去颗粒作用及细胞迁移变快。至少有十种可结合或对CC趋化因子有反应的人类趋化因子受体具有下列特性模式:CCR1(或“CKR-1”或“CC-CKR-1”)[MIP-1a,MCP-3,MCP-4,RANTES](Ben-Barruch等人,Cell,72,415-425(1993),Luster,New Eng.J.Med.,338,436-445(1998));CCR-2A及CCR-2B(或“CKR-2A”/“CKR-2B”或“CC-CKR-2A”/“/CC-CKR-2B”)[MCP-1,MCP2,MCP-3,MCP-4,MCP-5](Charo等人,Proc.Natl.Acad.Sci.USA,91,2752-2756(1994)),Luster,New Eng.J.Med.,338,436-445(1998));CCR-3(或“CKR-3”或“CC-CKR-3”)[嗜伊红粒细胞趋化蛋白-1,嗜伊红粒细胞趋化蛋白-2,RANTES,MCP-3,MCP-4](Combadiere等人,J.Biol.Chem.,270,16491-16494(1995),Luster,New Eng.J.Med.,338,436-445(1998));CCR-4(或“CKR-4”或“CC-CKR-4”)[TARC,MIP-1a,RANTES,MCP-1](Power等人,J.Biol.Chem.,270,19495-19500(1995),Luster,New Eng.J.Med.,338,436-445(1998));CCR-5(或“CKR-5”或“CCCKR-5”)[MIP-1a,RANTES,MIP-1p](Sanson等人,Biochemistry,35,3362-3367(1996));CCR-6(或“CKR-6”或“CC-CKR-6”)[LARC](Baba等人,J.Biol.Chem.,272,14893-14898(1997));CCR-7(或“CKR-7”或“CC-CKR-7”)[ELC](Yoshie等人,J.Leukoc.Biol.62,634-644(1997));CCR-8(或“CKR-8”或“CC-CKR-8”)[1-309,TARC,MIP-1p](Napolitano等人,J.Immunol.,157,2759-2763(1996),Bernardini等人,Eur.J.Immunol.,28,582-588(1998));及CCR-10(或“CKR-10”或“CC-CKR-10”)[MCP-1,MCP-3](Bonini等人,DNA and Cell Biol.,16,1249-1256(1997))。
除了哺乳动物趋化因子受体外,哺乳动物巨细胞病毒、疱疹病毒及痘病毒已显示,于受感染的细胞中表达具有与趋化因子受体结合特性的蛋白(参见Wells及Schwartz,Curr.Opin.Biotech.,8,741-748(1997))。人类CC趋化因子,例如RANTES及MCP-3可造成钙通过这些病毒所编码受体而快速移动。受体表达可容许通过破坏正常免疫体系监督及对感染的反应来感染。此外,人类趋化因子受体,例如CXCR-4、CCR-2、CCR-3、CCR-5及CCR-8可作为哺乳动物细胞被微生物感染与例如人类免疫缺陷病毒(HIV)的共受体。
趋化因子受体已显示为一重要的发炎性、感染性及免疫调节性症状和疾病的介质,包括气喘及过敏性疾病以及自体免疫病例如类风湿关节炎及动脉硬化。例如,趋化因子受体CCR-3在吸引嗜伊红细胞至过敏发炎部位及随后活化这些细胞上起了关键的作用。CCR-3的趋化因子配体诱导胞内钙浓度快速增加、增加细胞粘附分子表达、细胞去颗粒作用、及嗜伊红细胞迁移变快。因此,可调节趋化因子受体的药剂应可有效用于这些症状和疾病。此外,可调节趋化因子受体的药剂也可有效用于感染性疾病例如通过阻断由HIV引起CCR-3表达细胞的感染,或用于预防由病毒(例如巨细胞病毒)引起的免疫细胞反应的操作。
现有技术
-US 5,521,197公开了哌啶取代的吲哚作为5-HT1F激动剂。
-国际专利申请WO 98006402公开了这些化合物用于治疗感冒或过敏性鼻炎的用途。
-WO 98011895公开了这些化合物用于治疗偏头痛。
-WO 2001043740公开了用类似的化合物作为5-HT调节剂。
-WO 2002008223公开了与肽取代的芳基环相连接的哌啶取代的吲哚作为D4调节剂,而同时对5-HT2A或5-HT2C受体亦具有部分效用。
-WO 99037304公开了抑制XA因子的取代的哌啶-及吡嗪-衍生物。
-WO 2000075130公开吲哚基哌啶衍生物作为抗组织胺剂及抗过敏剂,其包括治疗慢性气喘。
本发明主要的目的是提供新颖的CCR-3调节剂。令人意外的发现某些哌啶取代的吲哚非常适合作为CCR-3调节剂。
发明内容
因此,本发明的目的之一是提供式1的哌啶取代的吲哚或其杂环衍生物:
其中R1、R5、R6、A、B、D-E、X-W-V、Y、i、j及m的定义如下。
本发明另一个目的是提供CCR-3的激动剂或拮抗剂,或其药学上可接受的盐,更具体地说是提供包含药学上可接受的载体及治疗有效量的至少一种本发明化合物或其药学上可接受的盐类的药物组合物。这些目的及其他目的将于下列详细说明中变得更加明显。
具体实施方式
本发明是关于式(I)化合物及其药学上可接受的盐,
其中
R1为芳基、het或其稠合的环,其中het为杂环,而稠合部分包括芳基-het-、het-芳基-或het-het-稠合的环,每一个所述芳基或het可被一、二或三个R2取代;
R2各自独立地为C1-6-烷基、C3-6-环烷基、C1-6-卤代烷基、C1-6-芳烷基卤素、CN、COOR3、COR3、CONR3R4、NR3R4、NR3SO2R4、OR3、NO2、SR3、SOR3、SO2R3或SO2NR3R4;
R3为H、C1-6烷基、C3-8-环烷基或(C3-8-环烷基)-C1-6-烷基;
R4为H、C1-6-烷基、C3-8-环烷基或(C3-8-环烷基)-C1-6-烷基;或
R3及R4与在中间的氮原子或N-SO2-基团一起形成可任选被取代的含有氮的3至8员杂环;
R5为C1-6-烷基、C1-6-烷氧基、C1-6-酰氧基、C1-6-芳烷基、C3-6-环烷基、(-C3-6-环烷基)-C1-6-烷基、C1-6-卤代烷基、C1-6-硫烷基、卤素、NO2、CN;
R6各自独立地为C1-6-烷基、C1-6-烷氧基、C1-6-酰氧基、C1-6-芳烷基、C3-6-环烷基、C1-6-卤代烷基、C1-6-硫烷基、卤素、OR3、SR3、CN、NO2、COOR3、COR3、CONR3R4、NR3R4、NR3COR4、NR3SO2R4、SOR3、SO2R3、SO2NR3R4、芳基或het;
A为(C3-6环烷基)-C2-8-亚烷基、直链或支链C2-8-亚烷基,可任选被卤素或OH取代;
B为芳基或het;
D-E为CH-CH2-或C=CH-;
X-W-V为N-C=CR7或C=C-NR7;
R7为H或C1-6-烷基;
Y为CF2、NR4、O、S(O)n;
i、j各自独立地为0、1或2;
n为0、1或2;
m为0、1、2、3或4。
本文所描述的化合物可具有不对称中心。含有一不对称经取代原子的本发明化合物,可分离成光学活性及外消旋的形式。如何制备光学活化形式是本领域中众所周知的,例如将外消旋形式分解或由光学活性的起始物质来合成。烯类的许多几何异构体及其类似物也可存在于本文所描述的化合物中,且所有这样的稳定异构体均属于在本发明的构思。本发明化合物的顺式和反式几何异构体已有报导,且可分离为异构体的混合物或分开的异构体形式。除非有特别指出特定的立体化学或异构体形式,否则所有的结构都是指手性形式、非对映形式、外消旋形式和所有的几何异构体形式的结构。
所用的术语及定义
对本文中未特别定义的术语应解释为具有本领域技术人员根据本发明公开的内容和上下文能理解的含义。然而,在本说明书中,除非特别指出其反面的意思,否则下列术语具有其所指出的含义,并附有下列的习惯用法。
在如下定义的基团、基或部分中,碳原子数通常是指前面的基团,例如C1-6烷基是指一个具有1至6个碳原子的烷基基团。一般而言,含有两个或多个亚基的基团,最后命名的基团是基的连接点,例如,“硫烷基”是指式HS-烷基-的单价基。除非下列另有指明,否则术语的参照含义及通常是稳定的原子价的常用定义被认为是表示所有化学式及基团。
除了在化合物名称或结构上特别指出有其特定的立体化学或异构体形式之外,一般都是指所有的互变异构形式及异构形式及混合形式的化学结构或化合物,无论是单独的几何异构体或光学异构体或外消旋或非外消旋异构体的混合物均是如此。
本文所用的术语“取代的”是指在指定原子上任何一个或多个氢被选自指定的基团取代,但是不能超过所指定的原子的正常价,且该取代作用是产生稳定的化合物。
本文所用的“药学上可接受的”一词是指在明确的医学判断范围内与合理的疗效/风险比的适合用于与人及动物组织接触而无太大毒性、刺激性、过敏反应或其他问题或并发症的那些化合物、物质、组合物和/或剂型。
本文所用“药学上可接受的盐类”是指所公开化合物的衍生物,其中该母体化合物是被其酸或碱盐修饰过的。药学上可接受的盐类的实施例包括(但不限于)碱性残基的无机或有机酸盐例如胺;酸性残基的碱盐或有机盐类,例如羧酸,及其类似物。药学上可接受的盐类包括,例如由无毒无机或有机酸所形成的母体化合物的常用无毒盐类或第四铵盐。例如这些常用的无毒盐类包括由无机酸例如盐酸、氢溴酸、硫酸、磺胺酸、硫酸、硝酸及其类似物所衍生的盐类;及由有机酸,例如乙酸、丙酸、琥珀酸、甘醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、延胡索酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、异硫羰酸(isothionic)等的盐类。
本发明药学上可接受的盐类可由含有碱性或酸性基团的母体化合物利用常用的方法来制备。一般而言,这些盐类可通过将游离酸或碱形式的这些化合物与化学剂量的适合的酸或碱于水或有机溶剂或两者的混合物中反应而制备;通常非水性的介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈为优选。合适的盐类可参见Remingto中所列的表,当该前药给药于哺乳动物体时,其在体内会释出一种本发明化合物的活性原药。本发明的前药可通过修饰存在于化合物的官能基来制备,而该方法可在常规操作中或在体内将该修饰物裂解形成母体化合物。前药包括本发明化合物,其中羟基、氨基或巯基(sulfhydryl)可键合至任何基团上,当本发明前药给药于哺乳动物体时,其将断裂分别形成游离的羟基、游离的氨基或游离的巯基。前药的实施例包括(但不限于)本发明化合物的醇及胺官能基团的乙酸盐、甲酸盐及苯甲酸盐衍生物。
本文所用的术语“芳基”,单独或与其他取代基组合,是指含有碳原子的芳香族单环体系或芳香族多环体系。例如,芳基是包括苯基或萘基环系,其中芳基一般是指一芳香体系,例如苯基。
本文所用的术语“het”,单独或与其他取代基组合时,是指单价的取代基,其是从含有碳原子及一、二、三或四个选自氮、氧及硫的杂环原子的五、六或七元的饱和或不饱和(包括芳香系)杂环中将氢移除所衍生的。适合杂环的实施例包括:四氢呋喃、噻吩、二氮杂、异唑、哌啶、二烷、吗啉、哌嗪或
虽然本文所用的术语“杂芳基”是涵盖在术语“het”之中,但严格来说其是指不饱和杂环,而其双键形成芳香体系。适合的杂芳香体系的实例包括吡啶、嘧啶、
本文所用的术语“芳基或het稠合的环”,单独或与其他取代基组合,其中以芳基-het(a)、het-芳基(b)或het-het(c)的稠合存在的稠合环是指单价取代基,其是从下列各基中移除一个氢所衍生的
a)从含有碳原子的芳香单环体系或芳香多环体系中移除氢,该芳香单环体系或芳香多环体系是与含有碳原子及一、二、三或四个选自氮、氧及硫的杂环原子的五、六或七元的饱和或不饱和(包括芳香系)杂环稠合,或
b)从含有碳原子及一、二、三或四个选自氮、氧及硫的杂环原子的五、六或七元的饱和或不饱和(包括芳香系)杂环中移除氢,其中该杂环是与含有碳原子的芳香单环体系或芳香多环体系稠合,或
c)从含有碳原子及一、二、三或四个选自氮、氧及硫的杂环原子的五、六或七元的饱和或不饱和(包括芳香系)杂环中移除氢,其中该杂环是与含有碳原子及一、二、三或四个选自氮、氧及硫的杂环原子的五、六或七元的饱和或不饱和(包括芳香系)杂环相稠合。
适合的芳基或het稠合的环的实例包括:喹啉基、1-吲哚基、3-吲哚基、5-吲哚基、6-吲哚基、中氮茚基(indolizinyl)、苯并咪唑基(benzimidazyl)或嘌呤基。
本文所用的术语“卤素”是指选自氟、氯、溴或碘的卤素取代基。
本文所用的术语“-C1-6-烷基”,单独或与其他取代基组合,是指含有一至六个碳原子的环状、直链或支链的烷基取代基,其包括甲基、乙基、丙基、丁基、己基、1-甲基乙基、1-甲基丙基、2-甲基丙基或1,1-二甲基乙基。
本文所用的术语“-C3-8-环烷基”,单独或与其他取代基组合,是指含有三至六个碳原子的环烷基取代基,其包括环丙基、环丁基、环戊基或环己基。
本文所用的术语“-C1-6-卤代烷基”,单独或与其他取代基组合,是指含有多至六个碳原子的环状、直链或支链的烷基取代基,该碳原子具有一或多个选自溴、氯、氟或碘的卤素取代的氢原子。因此,“C2-6-卤代烷基”除了链上含有二至六个碳原子外,亦具有相同的含义。优选的是,C1-6-卤代烷基是代表C1-6-氟烷基,例如三氟甲基、2,2,2-三氟乙基或全氟乙基。
本文所用的术语“-C1-6-烷氧基”,单独或与其他取代基组合,是指取代基C1-6-烷基-O-,其中烷基是如上述定义含有多至六个碳原子。烷氧基包括甲氧基、乙氧基、丙氧基、1-甲基乙氧基、丁氧基、1,1-二甲基乙氧基。最后一个取代基一般是称为叔丁氧基。
本文所用的术语“-C1-6-酰氧基”单独或与其他取代基组合,是指取代基C1-6-烷基-(CO)O-,其中烷基是如上述定义含有高至六个碳原子。酰氧基包括MeCOO-、EtCOO-、正PrCOO-、异PrCOO-、正BuCOO-、仲BuCOO-或叔BuCOO-。
本文所用的术语“-C1-6-芳烷基”单独或与其他取代基组合时是指取代基-芳基-C1-6-烷基-,其中烷基是如上述定义含有多至六个碳原子。芳烷基包括苯甲基、苯基乙基、苯基丙基、1-苯基-1-甲基乙基、苯基丁基或1-苯基-1,1-二甲基乙氧基。
本文所用的术语“-C1-6-硫代烷基”,单独或与其他取代基组合,是指环状、直链或支链烷基取代基,其含有多至六个碳原子及硫氢(HS)基团作为取代基。硫代烷基基团的实施例有硫代丙基,例如HS-CH2CH2CH2-。
本文所用的术语“-C2-8-亚烷基”是指从每个含有二至八个碳原子的饱和直链或支链脂族烃基末端移除一个氢原子所衍生的二价烷基取代基,其包括例如CH2CH2C(CH3)2CH2CH2-。因此,“-C1-3-亚烷基”除了链上含有一至三个碳原子外,具有相同的含义。
优选实施例
优选的为式1化合物,其中Y为S或S=O,R1、R5、R6、A、B、D-E、X-W-V、i、j及m如上述的含义。特别优选的为式1a或1b的化合物,
其中R1、R5、R6、A、B、D-E、X-W-V及m如上述的定义。
还优选的为式1、1a或1b的化合物,其中:
R1为芳基或het,两者均任选地被一、二或三个R2取代,及
B为苯基。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基。
还优选的为式1、1a或1b的化合物,其中:
B为苯基及
D-E为CH-CH2-。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基及
D-E为CH-CH2-。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基及
D-E为CH-CH2-及
A为CH2-CH2-CH2-。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基及
D-E为CH-CH2-及
A为C(CH3)2-CH2-CH2-。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代及
B为苯基及
D-E为CH-CH2-及
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基及
D-E为CH-CH2-及
A为
及
R7为H。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,可任选地被一、二或三个R2取代,及
B为苯基及
D-E为CH-CH2-及
A为
及
R7为Me。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,可任选地被一、二或三个R2取代,及
B为苯基及
D-E为C=CH-。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基及
D-E为C=CH-及
A为CH2-CH2-CH2-。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基及
D-E为C=CH-及
A为C(CH3)2-CH2-CH2-。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基及
D-E为C=CH-及
A为
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基及
D-E为C=CH-及
R7为H。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
B为苯基及
D-E为C=CH-及
A为
及
R7为Me。
还优选的为式1、1a或1b的化合物,其中:
R1为苯基,任选地被一、二或三个R2取代,及
R2各自独立地为COOR3、COR3、CONR3R4、NR3SO2R4、SOR3、SO2R3或SO2NR3R4;特别是COOR3或SO2R3;
R3为H或C1-6-烷基;特别是H或甲基;
R4为H或C1-6-烷基;特别是H或甲基;
还优选的为式1、1a或1b的化合物,其中
R1为苯基,任选地被一个R2取代及
R2为COOR3或SO2R3;
R3为H或甲基;
R4为H或甲基;
还优选的为式1、1a或1b的化合物,其中:
-R5为C1-6-烷基、C3-6-环烷基或C2-6-卤代烷基;或
-R2为CF3或卤素,特别是氟;或
-R6优选的为卤素,特别是氟;或
还优选的是为制备式1或1a的方法,其特征为将式2化合物
与式3化合物反应
其中R1、R5、R6、A、B、X-W-V、i、j及m如上述的定义而LG为一适合的游离基,特别是卤素、甲磺酸基(mesylate)、三氟甲磺酸基(triflate)、甲苯磺酸基(tosylate)或对溴苯磺酸基(brosylate)。
式1或1a的化合物可使用下列所述的反应或技术来制备。该反应是在与反应剂和物质相适应并适合于发生转化的溶剂中进行。有机合成领域中的技术人员都知道,分子上的官能度应与所要进行的转化一致。有时需要判断修改合成步骤的顺序或选择一种比别的方法具体的处理方案,以便可得到所需的本发明化合物。也认识到在本领域中设计的任何合成路径的另一个主要考虑的因素是准确选择用于本发明所述化合物中反应性官能基团保护作用的保护基团。供专业医师作许多其他选择的权威性报告为Greeneand Wuts(Protective Groups In Organic Synthesis,Wiley and Sons,1991)。
本申请的化合物可有效的用于制造供预防和/或治疗与CCR-3-受体相关疾病的药物。
优选制备的药物是用于预防和/或治疗各种发炎性、感染性及免疫调节的症状或疾病,该症状或疾病包括气喘及过敏性疾病、病理性微生物感染(依照定义包括病毒),以及自体免疫疾病例如类风湿关节炎及动脉硬化。
最优选制备的药物是用于预防和/或治疗例如发炎性或过敏性疾病和症状,该症状或疾病包括呼吸过敏疾病例如气喘、过敏性肺炎、过敏性肺部疾病、高过敏性局限性肺炎、嗜伊红性蜂窝组织炎(例如威尔氏(Well′s)综合征)、嗜伊红性肺炎(例如吕弗勒氏(Loeffler′s)肺炎、慢性嗜伊红性肺炎)、嗜伊红性肌膜炎(例如舒尔曼(Shulman′s)综合征)、迟发性过敏反应、间质性肺病(ILD)(例如先天性肺纤维化、或与类风湿关节炎有关的ILD、全身性红斑狼疮、僵直性脊椎炎、全身性硬化症、修格连氏(sjogren′s)综合征、多肌炎或皮肌炎);全身性过敏反应或超敏反应、药物过敏(例如对盘尼西林或头孢菌素(cephalosporins)过敏)、因摄入受污染的色胺酸所引起的嗜伊红细胞增多性肌肉痛综合征、昆虫叮咬过敏、自动免疫性疾病例如类风湿关节炎、干癣性关节炎、多发性硬化症、全身性红斑狼疮、重症肌无力、青少年糖尿病;肾小球肾炎、自体免疫性甲状腺炎、贝氏症;移植排斥(例如移植)包括异体移植物的排斥或移植物抗宿主病、发炎性肠道疾病例如克隆氏症(Crohn′s disease)及溃疡性结肠炎;脊椎关节病变;硬皮病;牛皮癣(包括T细胞所介导的牛皮癣)及发炎性皮肤病例如皮肤炎、湿疹、异位性皮肤炎、过敏型接触性皮肤炎、荨麻疹、血管炎(例如坏死性、皮肤性及过敏性血管炎)、嗜伊红性肌炎、嗜伊红性肌膜炎、与皮肤或器官的白血球浸润有关的癌症。
制备
式2a的氮取代化合物的制备是通过至少由一个氨官能基和邻位的氢取代的B环,与保护的氮杂环的酮官能基的还原性缩合反应;
偶合后,该氢原子经过Friedel Crafts酰基化作用被α-卤代-乙酰卤化物或取代的α-卤代-乙腈化合物取代之后被水解成α-酮基化合物;
(Hal是代表Cl或Br)酰基化反应后,在酸存在下迅速闭环;
其中整个制备过程中的R5、R6、B、i、j及m是如上述的定义,及PG为一氮保护基,优选的为苯甲基基团。
式2c或2d的碳取代的化合物的制备是通过至少被一个硝基官能基和邻位的卤取代的B环在布赫瓦尔德(Buchwald)条件下与酮官能基的α-C-原子进行C-C偶合;
(Hal是代表Cl或Br),该偶合反应后,在还原条件下迅速闭环
之后,新形成的环与氮杂环的酮功能基在酸的存在下迅速缩合
接着,在化合物2d的情况下,氮杂环上的双键氢化
其中整个制备过程中R5、R6、B、D-E、i、j及m是如上述的定义。
式1b-d的化合物可通过将化合物2b-d与式3的化合物反应来制备,
其中R1、R5、R6、A、B、Y、i、j及m是如上述的定义,及
LG为适合的离去基,特别是卤素、甲磺酸根、三氟甲磺酸根、甲苯磺酸根或对溴苯磺酸根。
式1e或1f的N-甲基化化合物可通过将式1c或1d甲基化来制备。
其中R1、R5、R6、A、B、Y、i、j及m是如上述的定义。
本领域技术人员都知道,根据上述教导,可对本发明作许多修饰或变化。因此,在所附的权利要求的范畴内,本发明可以用本文具体描述之外的方法来实施。
实施例1
1-(3-溴-丙基硫基)-4-氟-苯
向对-氟-硫酚(thiophenole)(20.8ml)及1-3-二溴丙烷(60ml)的乙腈(250ml)溶液中以少量加入K2CO3(55.0g)并将混合物回流3小时。然后将所产生的盐及溶剂移除并将产物蒸馏。沸点112-115℃/1毫巴(mbar)。
实施例2
(1-苯甲基-哌啶-4-基)-(4-氟-苯基)-胺
将4-氟苯胺(32.7g)、N-苯甲基哌啶酮(106.0g)及乙酸(106.0g)的1,2-二氯乙烷(1200ml)溶液置于15℃以下的温度中。向搅拌的溶液中缓慢的加入乙酸(495.0g)及硼氢化钠(31.2g)的悬浮液。于15℃下搅拌2小时并于室温再搅拌2小时后,真空移除溶剂。于搅拌下加入乙酸乙酯(500ml)及水(700ml)并用碳酸钠(约250g)中和所产生的混合物。将有机相分离出,用2M NaHCO3溶液(100ml)及水(100ml)冲洗,硫酸钠干燥。移除溶剂及由乙醚/石油醚再结晶后,得到53.8g的橙色晶体产物。熔点:90-92℃。
实施例3
1-[2-(1-苯甲基-哌啶-4-基氨基)-苯基]-2-氯-丁-1-酮
将(1-苯甲基-哌啶-4-基)-(4-氟-苯基)-胺(51.2g)溶于180ml苯中并用冰浴冷却。于30分钟内逐滴加入三氯化硼(180ml,1M己烷溶液)。加入2-氯丁腈(18.6g)及三氯化铝(24.0g)并将产生的化合物加热回流15小时。然后将混合物冷却,加入180ml的2N HCl,将混合物再回流。加入200ml水及200mlCH2Cl2,用几份碳酸钠将生成的混合物调整至pH=5。进行相分离,有机相用硫酸钠干燥并移除溶剂。用快速柱色谱法(96∶4 CH2Cl2∶MeOH)将所生成的油状物纯化得到20.7g的无色油状物。
1H NMR(300MHz,CDCl3):1.10(3H,t),1.62-1.79(3H,m),2.01-2.36(6H,m),2.80-2.92(2H,m),3.43-3.57(1H,m),3.59(2H,s),5.03(1H,dd),6.75(1H,dd),7.16-7.22(1H,m),7.23-7.42(4H,m),7.43(1H,dd),8.92(1H,br d)。
实施例4
1-(1-苯甲基-哌啶-4-基)-2-乙基-5-氟-1H-吲哚
将1-[2-(1-苯甲基-哌啶-4-基氨基)-苯基]-2-氯-丁-1-酮(20.7g)与250ml二烷、27ml水及2.3g硼氢化钠混合并加热至120℃。回流12小时后,另外再加入3.3g的硼氢化钠并将混合物再回流16小时。移除溶剂后,加入200ml的水并以150ml CH2Cl2进行混合物萃取,接着用硫酸钠干燥并真空浓缩。用快速柱色谱法(96∶4 CH2Cl2∶MeOH)将所生成的油状物纯化得到11.9g淡黄色的油状物。
1H NMR(400MHz,DMSO):1.25(3H,t),1.72(2H,br d),2.19(2H,br t),2.39-2.48(2H,m),2.79(2H,q),2.98(2H,br d),3.59(2H,s),4.12-4.25(1H,m),6.19(1H,s),6.88(1H,td),7.19(1H,dd),7.21-7.31(1H,m),7.31-7.39(4H,m),7.49-7.52(1H,m)。
实施例5
1-(哌啶-4-基)-2-乙基-5-氟-1H-吲哚
将1-(1-苯甲基-哌啶-4-基)-2-乙基-5-氟-1H-吲哚(11.9g)及乙酸(4.1ml)的甲醇(250ml)溶液氢化8小时(50℃/1013毫巴)。然后将混合物过滤并真空浓缩。加入CH2Cl2(250ml)、NaHCO3(100ml)及水(300ml)并将混合物搅拌10分钟。用CHCl3萃取有机层并将其干燥(MgSO4)及真空浓缩。由乙醚/石油醚再结晶后,得到6.4g纯产物(73%)的无色的结晶。
1H NMR(400MHz,DMSO):1.25(3H,T),1.65(2H,BR D),1.83(1H,S),2.22-2.37(2H,M),2.62(2H,TD),2.79(2H,Q),3.10(2H,BR D),4.20-4.31(1H,M),6.18(1H,S),6.83(1H,TD),7.19(1H,DD),7.59-7.14(1H,M)。
实施例6
2-乙基-5-氟-1-{1-[3-(4-氟-苯基硫基)-丙基]-哌啶-4-基}-1H-吲哚
将1-(1-苯甲基-哌啶-4-基)-2-乙基-5-氟-1H-吲哚(2.4g)、1-(3-溴-丙基硫基)-4-氟-苯(2.4g)、乙腈及碳酸钾的混合物加热回流5小时。移除溶剂并用快速柱色谱法(1∶1乙酸乙酯∶石油醚)将所生成的油状物纯化。将含有产物的级分(fraction)的溶剂释出并以乙醇将产生的油状物结晶。得到1.2g(30%)的无色结晶。
Mp:82-84℃;1H NMR(300MHz,CDCl3):1.33(3H,t,J7.5),1.77-1.87(4H,m),2.10(2H,td,J 12.5,J 2.5),2.48-2.66(4H,m),2.75(2H,q,J7.5),2.94-3.08(4H,m),4.02-4.15(1H,m),6.20(1H,s),6.83(1H,td,J9.5 J2.5),6.98-7.04(2H,m),7.16(1H,dd,J9.5,J2.5),7.36-7.40(2H,m),7.47(1H,dd,J9.0,J4.0).13CNMR(75MHz,CDCl3):13.23,21.12,26.95,30.62,33.10,53.88,54.11,57.10,98.85,104.70,105.00,108.12,108.46,112.07,115.98,116.27,129.30,132.22,132.33,144.20,156.05,159.15,160.21,163.48。
实施例7
1-(2-硝基-4-氟-苯基)-丁-2-酮
向1-溴-2-硝基-4-氟-苯基(6.2g)、Pd2dba3(260mg)、2-二环己基膦-2′-(N,N-二甲基氨基)联苯(455mg)、K3PO4(13.7g)及4-甲氧基酚(700mg)的甲苯(60ml)溶液中加入2-丁酮(5.6ml)并于氩气下将反应混合物加热至60℃24小时。之后以水及乙酸乙酯(1∶1)萃取混合物,并用2M NaOH及水冲洗。移除溶剂,用快速色谱法(9∶1环己烷∶乙酸乙酯)将残余产物纯化得到2.6g(44%)淡黄结晶的纯物质。
1H NMR(400MHz,DMSO):0.98(3H,t),2.56(2H,q),4.22(2H,s),7.51(1H,dd),7.63(1H,td),7.98(1H,dd)。
实施例8
2-乙基-6-氟-1H-吲哚
将1-(2-硝基-3-氟-苯基)-丁-2-酮(2.5g)的乙醇(25ml)溶液加热至70℃。加入Na2S2O4(10.7g)的水(30ml)溶液并将生成的混合物加热回流1小时。蒸馏将乙醇移除,用乙酸乙酯萃取残余物两次,然后用水冲洗有机层并干燥。移除溶剂,并用快速色谱法(9∶1环己烷∶乙酸乙酯)将残余物的杂质去除。得到1.3g(67%)白色结晶固体的纯产物。
1H NMR(400MHz,DMSO):1.26(3H,t),2.72(2H,q),6.12(1H,s),6.73-6.80(1H,m),7.02(1H,br d),7.37(1H,dd),10.98(1H,br s)。
实施例9
2-乙基-6-氟-3-(1,2,3,6-四氢-吡啶-4-基)-1H-吲哚
向2-乙基-5-氟-1H-吲哚(1.2g)的乙酸(21ml)悬浮液中于90℃加入4-哌啶酮(3.4g)及2N磷酸(7ml)的混合物。于95℃将反应混合物搅拌4小时,然后加入水(50ml)并让反应冷却至室温。用浓NaOH溶液将pH调整至11,并用乙酸乙酯萃取混合物。以水冲洗,置于硫酸镁上干燥并真空浓缩。冲洗产物(乙醚)并以抽气过滤器干燥,得到1.5g(84%)白色结晶固体的产物。熔点194-6℃。
实施例10
2-乙基-6-氟-3-[1-(4-氟-苯基-硫基-丙基)-1,2,3,6-四氢-吡啶-4-基]-1H-吲哚
将2-乙基-6-氟-3-(1,2,3,6-四氢-吡啶-4-基)-1H-吲哚(1.5g)、1-(3-溴-丙基硫基)-4-氟-苯(1.7g)、碘化钾(20mg)和碳酸钾(1.1g)的DMF(10ml)溶液加热至95℃1小时。然后加入乙酸乙酯(80ml)及水(35ml)并用乙酸乙酯进一步萃取有机层。用水冲洗萃取液,干燥(MgSO4)并真空浓缩。用快速色谱法(100∶2 CH2Cl2∶MeOH)纯化粗产物,并于丙酮中与适量的含醚的(ethereal)HCl反应来制备其盐酸盐,得到1.7g(55%)白色结晶的纯产物。熔点135℃。
实施例11
2-乙基-6-氟-3-哌啶-4-基-1H-吲哚
于10%Pd/C催化剂(0.3g)及甲醇(25ml)的存在下,将3-(1-苯甲基-1,2,3,6-四氢-吡啶-4-基)-2-乙基-6-氟-1H-吲哚(1.4g)氢化1小时(室温/1013毫巴)。过滤将催化剂移除,蒸发溶剂并以小量的乙醚冲洗残余物。得到1.2g(85%)纯产物。
1H NMR(400MHz,DMSO):1.20(3H,t),1.52(2H,br d),1.90-2.04(2H,m),2.59-2.71(4H,m),2.71-2.83(1H,m),3.07(2H,br d),6.74(1H,t),6.99(1H,d),7.52-7.60(1H,m),10.72(1H,br s)。
实施例12
2-乙基-6-氟-3-{1-[3-(4-氟-苯基硫基)-丙基]-哌啶-4-基}-1H-吲哚
将2-乙基-6-氟-3-哌啶-4-基-1H-吲哚(0.9g)、1-(3-溴-丙基硫基)-4-氟-苯(1.0g)、碘化钾(20mg)及碳酸钾(0.7g)的DMF(10ml)混合物于100℃加热3小时,并放至隔夜冷却至室温。加入乙酸乙酯(50ml)及水(25ml)并以水冲洗有机相,干燥并真空浓缩。快速色谱法(95∶5 CH2Cl2∶MeOH)纯化粗产物并于丙酮中与适量的含醚的HCl反应来制备其盐酸盐,从乙醚中再结晶后得到1.1g(70%)白色结晶的纯产物。
1H NMR(400MHz,DMSO):1.19(3H,t),1.75(2H,br d),1.92-2.02(2H,m),2.35(2H,br q),2.59(2H,q),2.92-3.09(5H,m),3.10-3.20(2H,m),3.47(2H,br d),6.71-6.79(1H,m),7.01(1H,dd),7.22(2H,br t),7.44-7.49(2H,m),7.58-7.62(1H,m),10.87(1H,br s)。
实施例13
2-乙基-6-氟-3-{1-[3-(4-氟-苯基硫基)-丙基]-哌啶-4-基}-1-甲基-1H-吲哚
向2-乙基-6-氟-3-{1-[3-(4-氟-苯基硫基)-丙基]-哌啶-4-基}-1H-吲哚(0.4g)的DMF(5ml)溶液中于5℃加入氢化钠(0.1g)并将生成的混合物于室温下搅拌15分钟。之后将混合物冷却至5℃,加入MeI(0.1ml),并于室温下将混合物搅拌30分钟。加入乙酸乙酯(50ml)及水(50ml),用水冲洗有机层,用MgSO4干燥并真空浓缩。于丙酮中与适量的含醚的HCl反应来制备其盐酸盐,从乙醚中再结晶后得到0.2g纯产物(46%)的白色结晶。
1H NMR(400MHz,DMSO):1.12(3H,t),1.74(2H,br d),1.92-2.01(2H,m),2.29-2.42(2H,m),2.78(2H,q),2.92-3.08(5H,m),3.10-3.17(2H,m),3.46(2H,brd),3.62(3H,s),6.79(1H,br t),7.18-7.27(3H,m),7.47(2H,dd),7.66(1H,dd)。
实施例14-17
2-乙基-6-氟-3-{1-[3-(4-氟苯基硫基)-丙基]-1,2,3,6-四氢-吡啶-4-基}-1-甲基-1H-吲哚
1H NMR(400MHz,DMSO):1.19(3H,t),1.19-2.10(2H,m),2.50-2.62(1H,m),2.75-2.90(3H,m),3.05(2H,t),3.31-3.39(3H,m),3.56-3.63(1H,m),3.68(3H,s),3.70-3.81(1H,m),3.93-4.02(1H,m),5.62(1H,br s),6.86(1H,br t),7.22(2H,t),7.29(1H,dd),7.45-7.50(3H,m)。
2-乙基-5-氟-1-1-(3-对三氟甲基-苯基-硫基-丙基)-哌啶-4-基]-1H-吲哚
1H NMR(400MHz,DMSO):1.25(3H,t),1.90(2H,br d),2.00-2.12(2H,m),2.66-2.83(4H,m),2.99-3.23(6H,m),3.51(2H,br d),4.47-4.60(1H,m),6.20(1H,s),6.83(1H,td),7.21(1H,dd),7.54(2H,dd),7.62-7.70(3H,m)。
2-乙基-5-氟-1-{1-[3-(4-氟-苯基硫基)-3-甲基-丁基]-哌啶-4-基}-1H-吲哚
2-乙基-5-氟-1-(1-{2-[1-(4-氟-苯基硫基)-环丙基]-乙基]-哌啶-4-基)-1H-吲哚
实施例18-20
2-乙基-6-氟-3-[1-(3-对三氟甲基-苯基-硫基-丙基)-哌啶-4-基]-1H-吲哚
2-乙基-6-氟-3-{1-[3-(4-氟-苯基硫基)-3-甲基-丁基]-哌啶-4-基}-1H-吲哚
2-乙基-6-氟-3-(1-{2-[1-(4-氟-苯基硫基)-环丙基]-乙基}-哌啶-4-基)-1H-吲哚
实施例21-23
2-乙基-6-氟-1-甲基-3-[1-(3-对三氟甲基-苯基-硫基-丙基)-哌啶-4-基]-1H-吲哚
2-乙基-6-氟-3-{1-[3-(4-氟-苯基硫基)-3-甲基-丁基]-哌啶-4-基}-1-甲基-1H-吲哚
2-乙基-6-氟-3-(1-{2-[1-(4-氟-苯基硫基)-环丙基]-乙基}-哌啶-4-基)-1-甲基-1H-吲哚
实施例24-26
2-乙基-6-氟-3-[1-(3-对三氟甲基-苯基-硫基-丙基)-1,2,3,6-四氢-吡啶-4-基]-1H-吲哚
2-乙基-6-氟-3-{1-[3-(4-氟-苯基硫基)-3-甲基-丁基]-1,2,3,6-四氢-吡啶-4-基}-1H-吲哚
2-乙基-6-氟-3-(1-{2-[1-(4-氟-苯基硫基)-环丙基]-乙基}-1,2,3,6-四氢-吡啶-4-基)-1H-吲哚
实施例27-29
2-乙基-6-氟-1-甲基-3-[1-(3-对三氟甲基-苯基-硫基-丙基)-1,2,3,6-四氢-吡啶-4-基]-1H-吲哚
2-乙基-6-氟-3-{1-[3-(4-氟-苯基硫基)-3-甲基-丁基]-1,2,3,6-四氢-吡啶-4-基}-1-甲基-1H-吲哚
2-乙基-6-氟-3-(1-{2-[1-(4-氟-苯基硫基)-环丙基]-乙基}-1,2,3,6-四氢-吡啶-4-基)-1-甲基-1H-吲哚
实施例30-37
3-{3-[4-(2-乙基-5-氟-吲哚-1-基)-3,6-二氢-2H-吡啶-1-基]-丙基硫基}-[1,2,4]三唑并[4,3-a]吡啶
1H NMR(400MHz,DMSO):1.22(3H,t),1.63(2H,br d),1.73-1.83(2H,m),1.98-2.11(2H,m),2.19-2.34(2H,m),2.43(2H,t),2.73(2H,q),2.83(2H,br d),3.15(1H,t),3.25-3.31(1H,m),4.08-4.19(1H,m),6.18(1H,s),6.86(1H,td),7.12(1H,t),7.17(1H,dd),7.37(1H,dd),7.42(1H,dd),7.82(1H,d),8.48(1H,d).
2-{3-[4-(2-乙基-5-氟-吲哚-1-基)-3,6-二氢-2H-吡啶-1-基]-丙基硫基}-噻唑并[5,4-b]吡啶
1H NMR(400MHz,DMSO):1.25(3H,t),1.75(2H,br d),1.97-2.08(2H,m),2.20-2.33(2H,m),2.41-2.51(2H,m),2.56-2.65(2H,m),2.87(2H,q),3.12(2H,brd),3.49(2H,t),4.18-4.30(1H,m),6.20(1H,s),6.87(1H,td),7.19(1H,dd),7.48-7.53(2H,m),8.21(1H,dd),8.50(1H,dd).
5-氯-2-{3-[4-(2-乙基-5-氟-吲哚-1-基)-哌啶-1-基]-丙基硫基}-苯并噻唑
1H NMR(400MHz,DMSO):1.25(3H,t),1.93(2H,br d),2.30-2.42(2H,m),2.81(2H,q),2.99(2H,br q),3.13-3.32(4H,m),3.56(2H,t),3.60-3.81(2H,m),4.53-4.65(1H,m),6.22(1H,m),6.82(1H,br t),7.21(1H,dd),7.43(1H,dd),7.91-8.02(2H,m),8.08(1H,dd).
2-{3-[4-(2-乙基-5-氟-吲哚-1-基)-3,6-二氢-2H-吡啶-1-基]-丙基硫基}-苯并唑
1H NMR(400MHz,DMSO):1.27(3H,t),1.76(2H,br d),1.99-2.09(2H,m),2.19-2.27(2H,m),2.40-2.53(2H,m),2.59(2H,t),2.77(2H,q),3.11(2H,br d),3.43(2H,t),4.17-4.28(1H,m),6.20(1H,s),6.85(1H,td),7.18-7.22(2H,m),7.30-7.35(2H,m),7.47-7.55(1H,m),7.62-7.67(1H,m).
2-乙基-5-氟-1-{1-[3-(5-三氟甲基-吡啶-2-基硫基)-丙基]-1,2,3,6-四氢-吡啶-4-基}-1H-吲哚
1H NMR(400MHz,DMSO):1.25(3H,t),1.73(2H,br d),1.73-1.82(2H,m),2.12(2H,br t),2.32-2.44(3H,m),2.78(2H,q),3.02(2H,br d),3.24-3.32(3H,m),4.13-4.23(1H,m),6.20(1H,s),6.85(1H,td),7.20(1H,dd),7.46-7.51(1H,m),7.53(1H,m),7.99(1H,dd),8.81(1H,s).
2-乙基-6-氟-3-{1-[3-(4-氟苯基硫基)-丙基]哌啶-3-基}-1H-吲哚
1H NMR(400MHz,DMSO):1.19(3H,t),1.51-1.85(6H,m),1.96(1H,br.t),2.30-2.44(3H,m),2.64-2.72(3H,m),2.83-2.90(2H,m),2.93(2H,t),6.70-6.78(1H,m),6.99(1H,dd),7.13(2H,t),7.35-7.41(2H,m),7.49-7.54(1H,m),10.77(1H,s).
3-{3-[4-(2-乙基-5-氟-吲哚-1-基)-哌啶-1-基]-丙基硫基}-苯甲酸乙酯
熔点179-181℃
3-{3-[4-(2-乙基-5-氟-吲哚-1-基)-哌啶-1-基]丙基硫基}-苯甲酸
1H NMR(400MHz,DMSO):1.25(3H,t),1.90(2H,br.d),1.98-2.10(2H,m),2.72-2.88(4H,m),3.02-3.21(7H,m),3.44-3.60(2H,m),4.53(1H,br.s),6.21(1H,s),6.88(1H,td),7.22(1H,dd),7.49(1H,t),7.68(1H,br.d),7.70-7.80(2H,m),7.88(1H,s).
治疗方法
因此,本发明是关于可有效用于预防和/或治疗各种发炎性、感染性及免疫调节症状或疾病的化合物,该症状或疾病包括气喘及过敏性疾病、病理性微生物感染(按定义,包括病毒),以及自体免疫疾病例如类风湿关节炎及动脉硬化。
例如,抑制一种或多种哺乳动物趋化因子受体(例如人类趋化因子受体)的本发明化合物可将其用来抑制(亦即降低或预防)发炎性或感染性疾病。因此,一种或多种发炎过程例如白血球迁移、黏附、趋化性、胞泌作用(例如酵素、组织胺的分泌)或炎症介质的释放受到了抑制。例如发炎部位的嗜伊红细胞浸润(如于气喘或过敏性鼻炎)可根据本方法来抑制。特别是,在上述分析中,使用适当趋化因子,则下列实例化合物具有阻断表达CCR-3受体细胞的迁移的活性。
同样,增进一种或多种哺乳动物趋化因子受体(例如人类趋化因子受体)功能的本发明化合物,可被用来刺激(引发或增进)免疫或发炎反应,例如白血球迁移、黏附、趋化性、胞泌作用(例如酵素、组胺的胞泌作用)或炎症介质的释放,导致有效刺激发炎过程。例如可召集嗜伊红细胞来对抗寄生虫的感染。此外,在送入足量化合物使得通过诱导趋化因子受体内在化而造成表达在细胞上的受体流失的情况下,或在送入化合物使得细胞迁移方向错误的情况下,增进哺乳动物趋化因子受体的一种或多种功能的本发明化合物亦被认为能治疗前述的发炎性、过敏性及自体免疫性疾病。
除了灵长类(例如人类)外,其他各类的哺乳动物亦可根据本发明方法来治疗。例如,可治疗的哺乳动物包括(但不限于)乳牛、绵羊、山羊、马、狗、猫、天竺鼠、老鼠及其他牛类、绵羊、马类、犬科、猫科、啮齿科或海中物种。然而,该方法亦可在其他物种,例如禽类动物中实施。以上述方法治疗的对象是需要调节趋化因子受体活性的雄性或雌性的哺乳动物。本文所用的“调节”是指包含拮抗作用、激动作用、部分拮抗作用和/或部分激动作用。
用趋化因子受体功能抑制剂可治疗的人类或其他物种的疾病或症状,包括(但不限于):发炎或过敏性疾病,包括呼吸过敏疾病例如气喘、过敏性肺部疾病、过敏性肺炎、嗜伊红性蜂窝组织炎(例如威尔氏综合征(Well′ssyndrome))、嗜伊红性肺炎(例如吕弗勒氏肺炎(Loeffler′s syndrome)、慢性嗜伊红性肺炎)、嗜伊红性肌膜炎(例如舒尔曼综合征(Shulman′s syndrome))、迟发性过敏反应、间质性肺病(ILD)(例如先天性肺纤维化、或与类风湿关节炎有关的ILD、全身性红斑狼疮、僵直性脊椎炎、全身性硬化症、修格连氏综合征、多肌炎或皮肌炎);全身性过敏反应或超敏反应、药物过敏(例如对盘尼西林或头孢菌素(cephalosporins)过敏)、因摄入受污染的色胺酸所引起的嗜伊红细胞增多性肌肉痛综合征、昆虫叮咬过敏、自动免疫性疾病例如类风湿关节炎、干癣性关节炎、多发性硬化症、全身性红斑狼疮、重症肌无力、青少年糖尿病、肾小球肾炎、自体免疫性甲状腺炎、贝氏症;移植排斥(例如移植)包括异体移植物的排斥或移植物抗宿主症、发炎性肠道疾病例如克隆氏症(Crohn′s disease)及溃疡性结肠炎;脊椎关节病变;硬皮病;牛皮癣(包括T细胞所介导的牛皮癣)及发炎性皮肤病例如皮肤炎、湿疹、异位性皮肤炎、过敏型接触性皮肤炎、荨麻疹、血管炎(例如坏死性、皮肤性及过敏性血管炎)、嗜伊红性肌炎、嗜伊红性肌膜炎、与皮肤或器官的白血球浸润有关的癌症。由抑制不良发炎反应来治疗的其它疾病或症状包括(但不限于)再灌注损伤、动脉硬化、某些血液恶性肿瘤、细胞激素诱发的毒性(例如败血性休克、内毒素性休克)、多发性肌炎、皮肌炎。可用趋化因子受体功能抑制剂治疗的人类或其他物种的感染性疾病或症状包括(但不限于)HIV。
可用趋化因子受体功能促进剂治疗的人类或其他物种的疾病或症状包括(但不限于):免疫抑制,例如免疫缺乏综合征如AIDS或其他病毒感染,进行放射线治疗、化学治疗、自体免疫疾病的治疗或药物治疗(例如类固醇治疗)者的免疫抑制;先天性受体功能障碍或其他因素所引起的免疫抑制;及感染性疾病,例如寄生虫病,其包括(但不限于)蠕虫感染疾病,例如线虫(蛔虫);(鞭虫病(Trichuriasis)、蛲虫病(Enterobiasis)、蛔虫病(Ascariasis)、钩虫病(Hookworm)、杆线虫症(Strongyloidiasis)、旋毛虫病(Trichinosis)、丝虫病(filariasis));吸虫病(trematodes)(吸虫(flukes))(肝吸虫病(Schistosomiasis)、肺吸虫病(Clonorchiasis))、条虫(cestodes)(条虫(tape worms))(胞虫症(Echinococcosis)、牛肉条虫(Taeniasis saginata)、囊虫病(Cysticercosis))、内脏寄生虫、内脏性幼虫移行症(visceral larva migraines)(例如弓浆虫(Toxocara))、嗜伊红细胞性胃肠炎(例如Anisaki属、复管线虫属(Phocanemasp))、皮肤幼虫移行症(cutaneous larva migraines)(巴西钩虫(Ancylostonabraziliense)、犬钩虫(Ancylostoma caninum))。本发明化合物因此可有效用于预防和治疗各种发炎性、感染性及免疫调节性障碍和疾病。此外,在送入足量化合物使得通过诱导趋化因子受体内在化而造成表达在细胞上的受体流失的情况下或在送入化合物使得细胞迁移方向错误的情况下,趋化因子受体功能促进剂亦被认为能治疗前述的发炎性、过敏性及自体免疫性的疾病。
在另一方面,本发明可用于评估推定的特异性G蛋白偶合受体激动剂或拮抗剂。本发明涉及这些化合物在制备及筛选化合物以调节趋化因子受体活性中的用途。再者,本发明化合物可有效用于确定及测定其他化合物与趋化因子的结合位置,例如利用竞争性的抑制作用或参照分析报告将未知活性的化合物与已知活性的化合物比较。在开发新的测定或分析方法中,本发明化合物可用于检验它们的效果。
具体地说,这些化合物可以按商品试剂盒方式提供以用于与前述疾病有关的医药研究上。本发明化合物亦可有效地用于评估推定的特异性趋化因子受体调节剂。此外,人们可利用本发明化合物,作为不结合的化合物的实例或作为在有助于确定互相作用的特定位置的这些受体上活化的化合物的结构变体,来检验不被认为是趋化因子受体的G蛋白偶合受体的特异性。
药物剂型
式1化合物以治疗有效量给药于哺乳动物。“治疗有效量”是指当单独或与其他治疗剂联合用药时为有效预防或缓解与CCR-3受体的活性有关的疾病或该疾病的恶化所用的式1化合物的量。
本发明化合物可以口服剂型的方式给药,例如片剂、胶囊(包括持续释放或定时释放的制剂)、丸剂、散剂、粒剂、酏剂、酊剂、悬浮剂、糖浆及乳剂。其亦可以静脉内(推注或输液剂)、腹腔内、皮下或肌肉内形式给药,所有使用的剂型是为本项技术人员所熟知。其可单独给药,但通常是与药用载体一起给药,而该药用载体是依所选择的给药路径及标准用药实践为基准所选出的。
本发明化合物的剂量方法,当然是依各种已知的因素而定,例如特定药剂的药物动力学特性及给药的方式和路径;接受者的物种、年龄、性别、健康、医疗状况及体重、症状性质及程度;协同治疗种类;治疗频率、给药路径、病患的肾脏及肝功能、和所希望的效果。医师或兽医师可决定并开立预防疾病、对抗疾病或阻止疾病恶化所需的有效药量。
根据一般规则,用于指定效果的每种活性成分的每日口服剂量范围是在约0.001至1000mg/kg体重之间,优选的是在每天约0.01至100mg/kg体重之间,最优选的是1.0至20mg/kg/天。静脉给药最佳的剂量是介于约1至约10mg/kg/分钟的固定流速的输液。本发明化合物可以每日单一剂型给药,或将每日总剂量分成每日二、三或四次给予。
本发明化合物可以鼻内形式通过适合鼻内的介质局部给药,或通过皮肤透皮路径而使用透皮贴剂给药。当以透皮递送体系的形式给药时,整个剂量疗程的给药剂量当然为连续的而不是间断的。
式1化合物典型的是与适合的药用稀释剂、赋形剂或载体(在此统称为药用载体)混合给药,该药用稀释剂、赋形剂或载体是适当地以符合所需给药方式来选择,如口服片剂、胶囊、酏剂、糖浆及其类似物,并符合常规的医药实践。
例如,以口服给药的片剂或胶囊而言,活性药物组分可与口服、无毒性、药学上可接受、惰性载体组合,例如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露醇、山梨糖醇及其类似物;以液体形式口服给药而言,口服药物组分可与任何口服的、无毒性、药学上可接受的惰性载体组合,例如乙醇、甘油、水及其类似物。再者,当希望或必须时,适合的粘结剂、润滑剂、分裂剂及着色剂亦可并入混合物中。适合的粘结剂包括淀粉、明胶、天然糖类如葡萄糖或β-乳糖、玉米甜味剂、天然及合成胶如阿拉伯胶、黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡及其类似物。用于这些剂型的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠、氯化钠及其类似物。崩解剂包括(但不限于)淀粉、甲基纤维素、糖、膨润土、黄原胶及其类似物。
本发明化合物亦可以脂质体递送体系的形式来给药,例如小单层泡、大单层泡、多层束泡。脂质体可由各种磷脂质形成,例如胆固醇、硬脂胺或卵磷脂。
本发明化合物亦可与作为标的药物载体的适合的聚合物偶合。这些聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基丙基甲基丙烯酰胺-酚、聚羟基乙基天门冬酰胺酚、或经棕榈酰基残基取代的聚环氧乙烷多熔素。
再者,本发明化合物亦可与一种可有效控制药物释放的生物可降解聚合物偶合,例如聚乳酸、聚乙醇酸、聚乳酸及聚乙醇酸的共聚物、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚乙醛、聚二氢吡喃、聚氰丙烯酸酯、及交链或两亲嵌段共聚物凝胶。
适合给药的剂型(药物组合物)每剂量单位可含有约1毫克至约100毫克的活性成分。
在这些药物组合物中,活性成分一般是以该组合物总重量的0.5-95%重量比的量存在。
明胶胶囊可含有活性成分及散剂载体,例如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸及其类似物。类似的稀释剂亦可用于压制片剂。片剂和胶囊两者皆可以制成持续释放的形式,以提供几小时期间内持续释放的药物治疗。压制的片剂可包上糖衣或膜衣以掩饰任何不良的味道并保护片剂免受空气侵害,或包上可于肠胃道中选择性分解的肠衣。
口服给药的液体剂型可含有调色及调味剂以增加病患的接受度。
一般而言,水、适合的油脂、食盐水、右旋糖水溶液(葡萄糖)及相关的糖溶液及甘油醇例如乙二醇或聚乙二醇皆为适合的肠外溶液的载体。肠外给药的溶液优选的是含有一活性成分的水溶性盐类、合适的稳定剂,若需要可含有缓冲物质。抗氧化剂例如亚硫酸氢钠、亚硫酸钠、或抗坏血酸(单独或组合)皆为适合的安定剂。亦可使用柠檬酸及其盐类和EDTA钠。此外,肠外溶液可含有防腐剂例如氯苄烷铵、对羟基苯甲酸甲酯或丙酯、及氯丁醇。
适合的医药载体被记载在本领域标准的参考文献,Mack出版公司的Reminqton′s Pharmaceutical Sciences中。
当二种或多种前述的第二治疗剂与式1化合物一起联合给药时,相对于单独给药时的一般药剂的剂量,通常,典型的每日剂量及剂型中每种组分的量可降低,当联合给药时,需考虑治疗药剂的附加及协同效应。
具体地说,当单一剂量单位提供时,在联合的活性成分间存在着潜在的化学相互作用。因此,当式1化合物及第二治疗药剂组合成单一剂量时,虽然活性成分是组合于单一剂量单位中,但也可以按减少(亦即降低)活性物质间的物理性接触的方式来配制。例如,其中一个活性成分可包覆肠衣。通过其中一种成分包覆肠衣,不仅降低联用的活性成分之间的接触,亦可控制其中一种组分在肠胃道中释放,使其中一种组分不是在胃中释放,而是在肠内释放。其中亦可使一种组分包覆上一种可在整个肠胃道中持续释放的物质,并亦可减少联用的活性成分之间的物理性接触。
再者,持续释放组分可额外包覆肠衣,使该组分只能在肠中释放。另一方面有关联用药物制剂,其中一种组分是包覆一种持续和/或肠中释放的聚合物,而另一种组分亦包覆上一种低黏度的羟丙基甲基纤维素(HPMC)的聚合物,或其他本领域中已知的适合的物质,以便进一步将活性组分分开。该聚合物膜衣可在组合的活性物质成分之间形成另外的屏障。
本文中所公开的本发明联合药物组分之间减少接触的这些方法及其他方法,无论以单一剂型给药或以分开剂型而以同样方式在相同时间给药,都是本领域技术人员已知的。
Claims (17)
1.式1的化合物及其药学上可接受的盐,
其中
R1为芳基、het或其稠合的环,其中het为杂环,而稠合部分包括芳基-het-、het-芳基-或het-het-稠合的环,每一个所述芳基或het可被一、二或三个R2取代;
R2各自独立地为C1-6-烷基、C3-6-环烷基、C1-6-卤代烷基、C1-6-芳烷基、卤素、CN、COOR3、COR3、CONR3R4、NR3R4、NR3SO2R4、OR3、NO2、SR3、SOR3、SO2R3或SO2NR3R4;
R3为H、C1-6烷基、C3-8-环烷基或(C3-8-环烷基)-C1-6-烷基;
R4为H、C1-6-烷基、C3-8-环烷基或(C3-8-环烷基)-C1-6-烷基;或
R3及R4与在中间的氮原子或N-SO2-基团一起形成可任选被取代的含有氮的3至8员杂环;
R5为C1-6-烷基、C1-6-烷氧基、C1-6-酰氧基、C1-6-芳烷基、C3-6-环烷基、(-C3-6-环烷基)-C1-6-烷基、C1-6-卤代烷基、C1-6-硫烷基、卤素、NO2、CN;
R6各自独立地为C1-6-烷基、C1-6-烷氧基、C1-6-酰氧基、C1-6-芳烷基、C3-6-环烷基、C1-6-卤代烷基、C1-6-硫烷基、卤素、OR3、SR3、CN、NO2、COOR3、COR3、CONR3R4、NR3R4、NR3COR4、NR3SO2R4、SOR3、SO2R3、SO2NR3R4、芳基或het;
A为(C3-6环烷基)-C2-8-亚烷基、直链或支链C2-8-亚烷基,可任选被卤素或OH取代;
B为芳基或het;
D-E为CH-CH2-或C=CH-;
X-W-V为N-C=CR7或C=C-NR7;
R7为H或C1-6-烷基;
Y为CF2、NR4、O、S(O)n;
i、j各自独立地为0、1或2,其中0≤i+j≤4;
n为0、1或2;
m为0、1、2、3或4。
4.根据权利要求1-3中任一项的化合物,其中
R1为芳基或het,两者均任选地被一、二或三个R2取代及
B为苯基。
5.根据权利要求1-4中任一项的化合物,其中
R1为苯基,任选地被一、二或三个R2取代。
6.根据权利要求1-5中任一项的化合物,其中
D-E为CH-CH2-。
7.根据权利要求1-6中任一项的化合物,其中
A为CH2-CH2-CH2-。
8.根据权利要求1-6中任一项的化合物,其中
A为C(CH3)2-CH2-CH2-。
9.根据权利要求1-6中任一项的化合物,其中
A为
10.根据权利要求1-9中任一项的化合物,其中
R5为C1-6-烷基、C3-6-环烷基、C2-6-卤代烷基。
11.根据权利要求1-10中任一项的化合物,其中
X-W-V为N-C=CR7。
11.根据权利要求1-11中任一项的化合物,其中
R1为苯基,其任选地被一、二或三个R2取代,及
R2各自独立地为COOR3、COR3、CONR3R4、NR3SO2R4、SOR3、SO2R3或SO2NR3R4;
R3为H或C1-6-烷基;
R4为H或C1-6-烷基。
13.制备式1、1a或1b化合物的方法,其特征为使式2的化合物
与式3的化合物反应,
其中R1、R5、R6、A、B、D-E、X-W-V、i、j及m如权利要求1中所定义及
LG为适当的离去基,其选自卤素、甲磺酸基、三氟甲磺酸基、甲苯磺酸基或对溴苯磺酸基。
14.药物组合物,其特征为该组合物含有一种或多种根据权利要求1-12中任一项的式1、1a或1b的化合物。
15.作为药物的根据权利要求1-12中任一项的式1、1a或1b化合物。
16.根据权利要求1-12中任一项的式1、1a或1b化合物在制备用于预防和/或治疗其中CCR3活性调节剂具有治疗效益的疾病的药物中的用途。
17.CCR3活性调节剂有疗效的疾病的治疗或预防方法,该方法包括给有此需要的患者用治疗或预防有效量的权利要求1-12中任一项的式1、1a或1b的化合物。
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EP03026170 | 2003-11-17 | ||
EP03026170.5 | 2003-11-17 |
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CN1882565A true CN1882565A (zh) | 2006-12-20 |
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US (1) | US7544806B2 (zh) |
EP (1) | EP1687294B1 (zh) |
JP (1) | JP4825679B2 (zh) |
KR (1) | KR20060127000A (zh) |
CN (1) | CN1882565A (zh) |
AR (1) | AR047123A1 (zh) |
AU (1) | AU2004291297B2 (zh) |
BR (1) | BRPI0416665A (zh) |
CA (1) | CA2545261C (zh) |
IL (1) | IL175678A (zh) |
MX (1) | MXPA06004626A (zh) |
MY (1) | MY143862A (zh) |
NZ (1) | NZ547314A (zh) |
PE (1) | PE20051007A1 (zh) |
RU (1) | RU2382037C2 (zh) |
TW (1) | TW200526622A (zh) |
UY (1) | UY28618A1 (zh) |
WO (1) | WO2005049559A2 (zh) |
ZA (1) | ZA200601800B (zh) |
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WO2006117314A2 (en) * | 2005-04-30 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Novel piperidin- substituted indoles and their use as ccr-3 modulators |
CA2667548C (en) * | 2006-10-27 | 2015-02-03 | Boehringer Ingelheim International Gmbh | Substituted piperidyl-propane-thiols |
JP5581055B2 (ja) * | 2006-10-27 | 2014-08-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ピペリジル−プロパン−チオールccr3モジュレーター |
WO2010129351A1 (en) | 2009-04-28 | 2010-11-11 | Schepens Eye Research Institute | Method to identify and treat age-related macular degeneration |
US10213421B2 (en) | 2012-04-04 | 2019-02-26 | Alkahest, Inc. | Pharmaceutical formulations comprising CCR3 antagonists |
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FR2533924A1 (fr) * | 1982-10-05 | 1984-04-06 | Roussel Uclaf | Nouveaux derives du 4-(1h-indol-3-yl)a-methyl piperidine-1-ethanol, leurs sels, le procede de preparation, l'application a titre de medicaments et les compositions les renfermant |
US5521197A (en) | 1994-12-01 | 1996-05-28 | Eli Lilly And Company | 3-<1-alkylenearyl>-4-<1,2,3,6-tetrahydropyridinyl>-and 3-<1-alkylenearyl>-4-piperidinyl-1h-indoles: new 5-HT1F agonists |
US5576321A (en) * | 1995-01-17 | 1996-11-19 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
CA2259927A1 (en) * | 1996-07-12 | 1998-01-22 | Leukosite, Inc. | Chemokine receptor antagonists and methods of use therefor |
US5962473A (en) | 1996-08-16 | 1999-10-05 | Eli Lilly And Company | Methods of treating or ameliorating the symptoms of common cold or allergic rhinitis with serotonin 5-HT1F |
WO1998011895A1 (en) | 1996-09-18 | 1998-03-26 | Eli Lilly And Company | A method for the prevention of migraine |
AR013669A1 (es) * | 1997-10-07 | 2001-01-10 | Smithkline Beecham Corp | Compuestos y metodos |
EP1051176B1 (en) | 1998-01-27 | 2006-11-22 | Aventis Pharmaceuticals Inc. | SUBSTITUTED OXOAZAHETEROCYCLYL FACTOR Xa INHIBITORS |
ES2165274B1 (es) * | 1999-06-04 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de indolilpiperidina como agentes antihistaminicos y antialergicos. |
AU3789901A (en) | 1999-12-17 | 2001-06-25 | Bristol-Myers Squibb Company | Antipsychotic heterocycle compounds |
DE60112725T2 (de) * | 2000-02-18 | 2006-06-01 | Meiji Seika Kaisha Ltd. | Phenoxyalkylaminderivate als agonisten des opioid-delta rezeptors |
AU2001281738B2 (en) | 2000-07-21 | 2006-12-21 | H.Lundbeck A/S | Indole derivatives useful for the treatment of cns disorders |
ES2201899B1 (es) * | 2002-04-01 | 2005-06-01 | Almirall Prodesfarma, S.A. | Derivados de la azaindolilpiperidina como agentes antihistaminicos y antialergicos. |
US7157471B2 (en) * | 2003-08-25 | 2007-01-02 | Boehringer Ingelheim International Gmbh | Haloalkyl- and piperidine-substituted benzimidazole-derivatives |
WO2006117314A2 (en) * | 2005-04-30 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Novel piperidin- substituted indoles and their use as ccr-3 modulators |
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Publication number | Publication date |
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BRPI0416665A (pt) | 2007-01-16 |
ZA200601800B (en) | 2007-05-30 |
KR20060127000A (ko) | 2006-12-11 |
US20050153979A1 (en) | 2005-07-14 |
TW200526622A (en) | 2005-08-16 |
CA2545261A1 (en) | 2005-06-02 |
WO2005049559A3 (en) | 2006-04-13 |
IL175678A0 (en) | 2006-09-05 |
RU2006121328A (ru) | 2008-01-10 |
AU2004291297A1 (en) | 2005-06-02 |
AU2004291297B2 (en) | 2011-06-23 |
PE20051007A1 (es) | 2005-12-26 |
AR047123A1 (es) | 2006-01-11 |
MXPA06004626A (es) | 2006-06-27 |
RU2382037C2 (ru) | 2010-02-20 |
US7544806B2 (en) | 2009-06-09 |
JP4825679B2 (ja) | 2011-11-30 |
WO2005049559A2 (en) | 2005-06-02 |
UY28618A1 (es) | 2005-06-30 |
MY143862A (en) | 2011-07-15 |
CA2545261C (en) | 2013-07-23 |
NZ547314A (en) | 2010-02-26 |
EP1687294A2 (en) | 2006-08-09 |
IL175678A (en) | 2012-08-30 |
EP1687294B1 (en) | 2014-05-21 |
JP2007511480A (ja) | 2007-05-10 |
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