CN101014347B - 抗炎剂 - Google Patents
抗炎剂 Download PDFInfo
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- CN101014347B CN101014347B CN2005800301864A CN200580030186A CN101014347B CN 101014347 B CN101014347 B CN 101014347B CN 2005800301864 A CN2005800301864 A CN 2005800301864A CN 200580030186 A CN200580030186 A CN 200580030186A CN 101014347 B CN101014347 B CN 101014347B
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- Prior art keywords
- amino
- hexanolactam
- compound
- carbonyl
- diamantane
- Prior art date
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Abstract
本发明提供通式(I)化合物或其药学上可接受的盐的化合物、组合物和用途,它们是3-氨基己内酰胺衍生物,用于制备治疗炎性障碍的药物,其中,X是-CO-Y-(R1)n或SO2-Y-(R1)n;Y是环烷基或多环烷基(例如金刚烷基、金刚烷甲基、双环辛基、环己基、环丙基);或者是环烯基或多环烯基。
Description
本发明涉及3-氨基己内酰胺衍生物的用途,用于制备预防或治疗炎症的药品。
发炎是生理性宿主防御的重要组分。不过日益明显的是,在时间或空间上不适当的炎性应答在广泛的疾病中扮演角色,包括具有明显的白细胞组分的那些(例如自身免疫疾病、哮喘或动脉粥样硬化),以及在传统上不被认为牵涉白细胞的疾病(例如骨质疏松或阿尔茨海默氏病)。
趋化因子是一大家族具有白介素-8同源性的信号传导分子,它们在调节生理和病理条件下的白细胞运输中都有牵连。鉴于五十多种配体和二十种受体参与趋化因子信号传导,该系统具有必需的信息密度,以通过复杂的免疫调节过程为白细胞寻址,从骨髓到外周,然后通过次级淋巴样器官返回。不过,趋化因子系统的这种复杂性首先妨碍通过阻滞趋化因子受体来调控炎性应答的药理手段。已经证实难以确定在既定炎性疾病中应当抑制何种趋化因子受体以产生治疗益处。
最近,已经描述了同时阻滞多种趋化因子信号传导的成分家族:Reckless et al.,Biochem J.(1999)340:803-811。第一种这样的成分是一种被称为“肽3”的肽,被发现抑制由5种不同趋化因子诱导的白细胞移行,而响应于其他化学引诱剂(例如fMLP或TGF-β)的移行没有改变。这种肽及其类似物、例如NR58-3.14.3(也就是序列ID No.1 c(DCys-DGln-DIle-DTrp-DLys-DGln-DLys-DPro-DAsp-DLeu-DCys)-NH2),统称为“广谱趋化因子抑制剂”(BSCI)。Grainger et al.,Biochem.Pharm.65(2003)1027-1034随后指出BSCI在广泛的动物疾病模型中具有潜在有用的抗炎活性。有趣地,同时阻滞多种趋化因子在表面上与急性或慢性毒性无关,提示了这种手段可能是可用于开发新的抗炎药物的策略,它们具有与甾类相似的益处,但是减少了副作用。
不过,肽类和类肽衍生物、例如NR58-3.14.3可能不是体内使用的优选。合成它们相当昂贵,并且具有相对不可取的药动学和药效学性质。例如,NR58-3.14.3不是口服可生物利用的,在静脉内注射后从血浆中廓清的半衰期小于30分钟。
为鉴定保留肽3和NR58-3.14.3的抗炎性质、但是改进作为药物使用的特征的新颖制剂已经采取两种平行策略。首先开发一系列肽类似物,有些具有比NR58-3.14.3更长的血浆半衰期,有些合成起来相当便宜。其次进行详细的肽结构:活性分析,以鉴定关键的药效基因,并设计保留原始肽的有益性质的小型非肽结构。
这种第二种手段产出若干结构不同的保留肽类抗炎性质的化合物系列,包括生物碱育亨宾的16-氨基和16-氨基烷基衍生物,以及一些N-取代的3-氨基戊二酰亚胺(参考文献:Fox et al.,J Med Chem45(2002)360-370:WO 99/12968和WO 00/42071)。所有这些化合物都是保留非趋化因子类化学引诱剂之外选择性的广谱趋化因子抑制剂,它们当中有些已经显示体内阻滞急性炎症。
这些化合物中最有效力和选择性的是(S)-3-(十一碳-10-烯酰基)-氨基戊二酰亚胺(NR58,4),它体外抑制趋化因子-诱导移行的ED50为5nM。不过,进一步的研究揭示氨基戊二酰亚胺环易感于血清中的酶促开环作用。所以,就有些应用而言(例如其中所治疗的炎症是慢性的,例如在自身免疫疾病中),这些化合物可能不具有最优的性质,并且具有相似抗炎性质的更稳定的化合物可能是更优的。
作为鉴定这类稳定类似物的手段,已经测试了(S)-3-(十一碳-10-烯酰基)-氨基戊二酰亚胺的各种衍生物在血清中的稳定性。一种这类衍生物、即6-脱氧类似物(S)-3-(十一碳-10-烯酰基)-四氢吡啶-2-酮,在37℃人血清中完全稳定达至少7天,但是与母体分子相比,效力也有相当的减少。
本领域已经公开了3-氨基己内酰胺的酰胺衍生物。例如:
-日本专利申请No.09087331描述了3-氨基己内酰胺酰胺衍生物,其中酰胺烷基侧链可以含有2至30个碳原子。这些化合物已经作为油-胶化剂存在。
-美国专利No.6,395,282描述了致免疫性缀合物,包含与革兰氏阴性细菌自诱导剂偶联的载体分子,其中所述自诱导剂可以是3-氨基己内酰胺酰胺衍生物,其中酰胺烷基侧链可以含有至多34个碳原子。不过,仅公开了缀合物而非所分离的酰胺衍生物的治疗用途。
-Weiss等的文章(Research Communications in Psychology,Psychiatry and Behavior(1992),17(3-4),153-159)公开了一系列3-氨基己内酰胺酰胺衍生物,其中有3-己酰氨基-DL-e-己内酰胺和3-十二烷酰氨基-DL-ε-己内酰胺。这些化合物仅有体外活性,没有显著的体内效果。
换句话说,尽管本领域确实已经知晓3-氨基己内酰胺的一些烷基酰胺衍生物,不过没有描述过3-氨基己内酰胺酰胺衍生物的实际药学用途。
本发明提供通式(I)化合物或其药学上可接受的盐的用途,用于制备治疗炎性障碍的药物:
其中
X是-CO-Y-(R1)n或SO2-Y-(R1)n;
Y是环烷基或多环烷基(例如金刚烷基、金刚烷甲基、双环辛基、环己基、环丙基);
或者是环烯基或多环烯基;
每个R1独立地选自氢或者烷基、卤代烷基、烷氧基、卤代烷氧基、链烯基、炔基或烷基氨基原子团,具有1至20个碳原子(例如5至20个碳原子、8至20个碳原子、9至20个碳原子、10至18个碳原子、12至18个碳原子、13至18个碳原子、14至18个碳原子、13至17个碳原子);
或者每个R1独立地选自氟、氯、溴、碘、羟基、氧基烷基、氨基、氨基烷基或氨基二烷基原子团;
n是1至m的任意整数,其中m是环状基团Y上可允许的最大取代数。
作为替代选择,R1可以选自肽基原子团,例如具有1至4个肽片段(peptidicmoieties),通过肽键连接在一起(例如1至4个氨基酸残基的肽基原子团)。
己内酰胺环3位碳原子是不对称的,所以,根据本发明的化合物具有两种可能的对映体形式,也就是“R”和“S”构型。本发明涵盖这两种对映体形式和这些形式的所有组合,包括外消旋的“RS”混合物。为了简便起见,当没有在结构式中指出具体构型时,应当理解这代表两种对映体形式和它们的混合物。
优选地,按照这方面发明所使用的通式(I)化合物或其药学上可接受的盐将是通式(I’)化合物:
其中x具有上述相同含义。
优选地,通式(I)或(I’)化合物或它们药学上可接受的盐将是这样的,Y的一个或多个环限制α-碳的键角为本质上四面体的(也就是sp3杂化键)。“α-碳”位于2-位(相对于酰胺羰基而言)或者1-位(相对于磺酰胺磺酰基而言)。
任何取代基R1都可以是环状基团Y的一个或多个环上任意可允许位置上的取代基。特别要注意的是,本发明包括其中“α-碳”是环状基团一部分和本身被取代的化合物。(R1)n的定义涵盖没有取代(也就是R1=氢)的本发明化合物、具有单取代(也就是R1不是氢,并且n=1)和多取代(也就是至少两个R1基团不是氢,并且n=2或以上)的本发明化合物。
本发明也提供药物组合物,包含作为活性成分的通式(I)化合物或其药学上可接受的盐和至少一种药学上可接受的赋形剂和/或载体:
其中
X是-CO-Y-(R1)n或SO2-Y-(R1)n;
Y是环烷基或多环烷基(例如金刚烷基、金刚烷甲基、双环辛基、环己基、环丙基);
或者是环烯基或多环烯基;
每个R1独立地选自氢或者烷基、卤代烷基、烷氧基、卤代烷氧基、链烯基、炔基或烷基氨基原子团,具有1至20个碳原子(例如5至20个碳原子、8至20个碳原子、9至20个碳原子、10至18个碳原子、12至18个碳原子、13至18个碳原子、14至18个碳原子、13至17个碳原子);
或者每个R1独立地选自氟、氯、溴、碘、羟基、氧基烷基、氨基、氨基烷基或氨基二烷基原子团;并且
n是1至m的任意整数,其中m是环状基团Y上可允许的最大取代数。
作为替代选择,R1可以选自肽基原子团,例如具有1至4个肽片段,通过肽键连接在一起(例如1至4个氨基酸残基的肽基原子团)。
优选地,按照本发明这方面所使用的通式(I)化合物或其药学上可接受的盐将是通式(I’)化合物
其中x具有上述相同含义。
药学上可接受的盐确切地表示无机酸或有机酸的加成盐,前者例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、二磷酸盐和硝酸盐,后者例如乙酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对-甲苯磺酸盐、棕榈酸盐和硬脂酸盐。在本发明的范围内,当它们可以使用时,还有从碱生成的盐,例如钠或钾的氢氧化物。关于药学上可接受的盐的其他实例,可以参见″Saltselection for basic drugs″,Int.J.Pharm.(1986),33,201-217。
药物组合物可以是固体形式,例如粉剂、颗粒剂、片剂、明胶胶囊、脂质体或栓剂。适当的固体载体例如可以是磷酸钙、硬脂酸镁、滑石、糖类、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷和蜡。其他适当的药学上可接受的赋形剂和/或载体将是本领域技术人员已知的。
根据本发明的药物组合物也可以以液体形式呈递,例如溶液、乳液、悬浮液或糖浆。适当的液体载体例如可以是水、有机溶剂(例如甘油或二醇)以及它们在水中的可变比例混合物。
本发明也提供通式(I)化合物及其盐
其中
X是-CO-Y-(R1)n或SO2-Y-(R1)n;
Y是环烷基或多环烷基(例如金刚烷基、金刚烷甲基、双环辛基、环己基、环丙基);
或者是环烯基或多环烯基;
每个R1独立地选自氢或者烷基、卤代烷基、烷氧基、卤代烷氧基、链烯基、炔基或烷基氨基原子团,具有1至20个碳原子(例如5至20个碳原子、8至20个碳原子、9至20个碳原子、10至18个碳原子、12至18个碳原子、13至18个碳原子、14至18个碳原子、13至17个碳原子);
或者每个R1独立地选自氟、氯、溴、碘、羟基、氧基烷基、氨基、氨基烷基或氨基二烷基原子团;
n是1至m的任意整数,其中m是环状基团Y上可允许的最大取代数。
作为替代选择,R1可以选自肽基原子团,例如具有1至4个肽片段,通过肽键连接在一起(例如1至4个氨基酸残基的肽基原子团)。
优选地,按照本发明这方面所使用的通式(I)化合物或其盐将是通式(I’)化合物
其中x具有上述相同含义。
优选地,当用在本发明中时,通式(I)或(I’)化合物或它们的盐将是这样的,Y的一个或多个环限制α-碳的键角为本质上四面体的(也就是sp3杂化键)。
确切而言,按照本发明任意方面所优选的通式(I)或(I’)化合物和它们的盐选自下组:
-(S)-3-(环己烷羰基)氨基-己内酰胺;
-(S)-3-(1’-甲基环己烷羰基)氨基-己内酰胺;
-(S)-3-(环己-1’-烯羰基)氨基-己内酰胺;
-(S)-3-(反式-4’-戊基环己烷-1-羰基)氨基-己内酰胺;
-(S)-3-(4’-戊基[2,2,2]双环-辛烷-1-羰基)氨基-己内酰胺;
-(S)-3-(1’-金刚烷羰基)氨基-己内酰胺;
-(S)-3-(1’-金刚烷基甲烷羰基)氨基-己内酰胺;
-(S)-3-(3’-氯-1’-金刚烷羰基)氨基-己内酰胺;
-(S)-3-(3’,5’-二甲基-1’-金刚烷羰基)氨基-己内酰胺;
-(S)-3-(3’,5’,7’-三甲基-1’-金刚烷羰基)氨基-己内酰胺;
及其盐。
最优选的化合物是(S)-3-(1’-金刚烷羰基)氨基-己内酰胺及其盐。
本发明也提供所例证的化合物的磺酰胺类似物:也就是所述化合物的磺酰基-氨基-己内酰胺等价物。
正如上文在先技术讨论所提到的,3-氨基己内酰胺的某些烷基酰胺衍生物作为化合物本身可能是已知的(不过目前未知任何已在抗炎方面被描述为药物组合物或医药用途者)。
本发明包括所定义的化合物、组合物及其用途,其中该化合物是水合或溶剂化形式。
这里所述3-氨基己内酰胺的酰胺衍生物是功能性BSCI。采用本文提供的灵巧合成途径,它们合成起来相对便宜;它们在人血清中是稳定的,所以具有优异的药动学性质;它们是口服可生物利用的;它们是非常有力的体外广谱趋化因子抑制剂,具有优异的非趋化因子类化学引诱剂之外选择性;它们在啮齿动物炎症模型中是非常有力和有效的体内抗炎剂;它们的给药在达到最大治疗效果所需的剂量下不与任何显著的急性毒性有关。总之,这些性质提示了3-氨基己内酰胺的酰胺衍生物代表了优于前述化合物的抗炎药物。
与在先技术相比,本发明的改进在于带侧链3-氨基己内酰胺片段的提供,该侧链具有一个或多个烷基/烯基环,限制了该侧链α-碳的键角。本发明化合物显著优于带线性烯丙基链的化合物(无论烷基酰胺还是烷基磺酰胺)。
在先技术的肽类(例如NR58-3.14.3)具有如下缺点:(a)它们是昂贵的,并需要固相合成(至少对于更长者而言),并且(b)它们经由肾脏非常快速地廓清,和(c)它们一般是不太有效的。
在先技术的氨基戊二酰亚胺是便宜的,不经由肾脏快速廓清,也更加有效,但是它们不显示代谢稳定性。
这里所述的改进、即氨基己内酰胺,是便宜的,不被肾脏廓清,甚至更加有效,也是代谢稳定的。
按照本发明,旨在用通式(I)或(I’)化合物或其药学上可接受的盐或者含有它们作为活性成分的药物组合物或药物预防或治疗的炎症尤其包括:
-自身免疫疾病,例如多发性硬化;
-血管障碍,包括中风、冠状动脉疾病、心肌梗塞、不稳定型心绞痛、动脉粥样硬化或脉管炎,例如贝切特氏综合征、巨细胞性动脉炎、风湿性多肌痛、韦格内氏肉芽肿病、Churg-Strauss综合征结节性脉管炎、Henoch-Schnlein紫癜和川崎病;
-病毒感染或复制,例如由病毒引起的感染或者病毒的复制,所述病毒包括痘病毒、疱疹病毒(例如Herpesvirus samiri)、巨细胞病毒(CMV)或lentivirus;
-哮喘;
-骨质疏松(低骨矿质密度);
-肿瘤生长;
-类风湿性关节炎;
-器官移植排斥和/或移植物或器官功能迟缓,例如在肾移植患者中;
-以TNF-α水平升高为特征的障碍;
-牛皮癣;
-皮肤伤口;
-由细胞内寄生虫导致的障碍,例如疟疾或结核;
-变态反应;或者
-阿尔茨海默氏病。
按照本发明,进一步的炎性障碍包括:
-ALS;
-纤维化(特别是肺纤维化,但是不限于肺中的纤维化);
-粘连的形成(特别是在腹膜和骨盆区域中);
-抗原诱发的回忆应答;
-免疫应答抑制。
这些临床适应症满足炎症或以TNFα水平升高为特征的障碍的一般定义。
只要法律允许,本发明也提供治疗、改善或预防炎性疾病症状(包括对于任何药物的不良炎性反应)的方法,该方法对患者给予抗炎量的如本文所要求保护的化合物、组合物或药物。
根据本发明的药物的给药可以借助局部、口服、肠胃外途径、通过肌内注射等进行。
适用于根据本发明的药物的给药剂量在0.1mg与10g之间,这依赖于所用活性化合物的类型。
按照本发明,通式(I)或(I’)化合物可以利用下文所述过程制备。
通式(I)或(I’)化合物的制备
所有通式(I)或(I’)化合物都可以按照本领域技术人员已知的一般方法容易地制备。
尽管如此,建议下列优选的合成途径:
简图1
简图1所示反应可以在例如氯仿或二氯甲烷中进行。最优选的反应溶剂是二氯甲烷。
上述反应优选地是在碱存在下进行的,例如Na2CO3。
上述反应可以在环境温度(约25℃)下进行,或者更一般为20与50℃之间的温度。
定义
术语“约”表示在所考虑的数值左右的区间。正如本专利申请所使用的,“约X”表示从X减去X的10%到X加上X的10%的区间,优选从X减去X的5%到X加上X的5%的区间。
数字范围在本说明书中的使用旨在在本发明范围内明确包括在该范围内的所有个别整数和在既定范围最宽范围内的上下限数字的所有组合。因此例如,(尤其)关于式I所指定的1至20个碳原子的范围旨在包括4与20之间的所有整数和上下限数字的每种组合的所有子范围,无论明示与否。
本文所用的术语“包含”被理解为表示包含和由......组成。所以,若本发明涉及“包含作为活性成分的化合物的药物组合物”,这种术语旨在涵盖其中可能存在其他活性成分的组合物以及仅由一种所定义的活性成分组成的组合物。
本文所用的术语“肽片段”旨在包括下列20种天然存在的蛋白质生成性氨基酸残基:
符号 | 含义 |
Ala | 丙氨酸 |
Cys | 半胱氨酸 |
Asp | 天冬氨酸 |
Glu | 谷氨酸 |
Phe | 苯丙氨酸 |
Gly | 甘氨酸 |
His | 组氨酸 |
Ile | 异亮氨酸 |
Lys | 赖氨酸 |
Leu | 亮氨酸 |
Met | 甲硫氨酸 |
Asn | 天冬酰胺 |
Pro | 脯氨酸 |
Gln | 谷氨酰胺 |
Arg | 精氨酸 |
Ser | 丝氨酸 |
Thr | 苏氨酸 |
Val | 缬氨酸 |
Trp | 色氨酸 |
Tyr | 酪氨酸 |
改性和非寻常氨基酸残基以及拟肽类也打算涵盖在“肽片段”的定义内。
除非另有定义,这里使用的所有科学技术术语都具有通常为本发明所属领域普通专业人员所理解的相同含义。与之相似,所有出版物、专利申请、所有专利和所有其他这里提到的参考文献都引用在此作为参考(只要法律允许)。
下列实施例供阐述上述工艺,绝不应被解释为限制发明的范围。
附图
图1显示根据本发明的化合物实例的化学结构。
实施例
起始化合物的一般合成工艺
按照文献合成(R)与(S)-3-氨基-己内酰胺的盐酸盐和(R,R)与(S,S)-3-氨基-己内酰胺的氢-吡咯烷-5-甲酸盐(cf.Boyle et al.,J.Org.Chem,(1979),44,4841-4847;Rezler et al.,J.Med.Chem.(1997),40,3508-3515)。
实施例1:(S)-3-(环己烷羰基)氨基-己内酰胺:
在环境温度下,将(S,S)-3-氨基-己内酰胺氢-吡咯烷-5-甲酸盐2(5mmol)与Na2CO3(15mmol)的水(25ml)溶液加入到环己烷碳酰氯(5mmol)的二氯甲烷(25ml)溶液中,将反应搅拌12小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×25ml)。合并有机层,经Na2CO3干燥,在真空中浓缩。残余物经过EtOAc/己烷重结晶纯化,得到内酰胺(540mg,45%);m.p.(EtOAc/己烷)180-181℃;[α]D 25(c=1,CHCl3)+42.0;vmax/cm-1 3294(NH),1668,1614(CO),1537(NH);δH(500MHz,CDCl3)6.89(1H,d,J 5.5,CHNH),6.51(1H,brs,CH2NH),4.48(1H,dd,J 11,6,CHNH),3.30-3.17(2H,m,CH2NH),2.11(1H,tt,J 11.5,3.5,(CH2)CHCO),2.01(1H,brd,J 13,内酰胺环CH),1.98-1.92(1H,m,内酰胺环CH),1.87-1.70(6H,m,内酰胺环CH×2+己环CH×4),1.66-1.59(1H,m,己环CH),1.47-1.30(4H,brm,内酰胺环CH×2+己环CH×2)和1.23-1.15(3H,m,己环CH×3);δC(125MHz,CDCl3)175.9,175.3(CO),51.8(NHCHCO),45.2(CH),42.1,31.7,29.6,29.4,28.9,27.9,25.7(×2),25.6(CH2);m/z(M+C13H22N2O2需要238.16813)238.16768.
实施例2:(S)-3-(1’-甲基环己烷羰基)氨基-己内酰胺:
在环境温度下,将(S,S)-3-氨基-己内酰胺氢-吡咯烷-5-甲酸盐2(5mmol)与Na2CO3(15mmol)的水(25ml)溶液加入到1-甲基环己烷碳酰氯(5mmol)的二氯甲烷(25ml)溶液中,将反应搅拌12小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×25ml)。合并有机层,经Na2CO3干燥,在真空中浓缩。残余物经过EtOAc/己烷重结晶纯化,得到内酰胺(540mg,43%);m.p.(EtOAc/己烷)168-169℃;[α]D 25(c=1,CHCl3)+33.0;vmax/cm-13380,3241(NH),1674,1638(CO),1501(NH);δH(500MHz,CDCl3)7.12(1H,d,J 5,CHNH),6.52(1H,brs,CH2NH),4.48(1H,ddd,J 11,5.5,1.5 CHNH),3.30-3.16(2H,m,CH2NH),2.01(1H,br d,J 13,内酰胺环CH),1.98-1.86(3H,m,内酰胺环CH+己环CH×2),1.85-1.73(2H,m,内酰胺环CH×2),1.56-1.47(2H,m,己环CH×2),1.47-1.33(5H,br m,内酰胺环CH×2+己环CH×3)和1.33-1.25(3H,m,己环CH×3);δC(125MHz,CDCl3)176.9,167.0(CO),52.0(NHCHCO),42.5(C quat),42.1,35.5(×2),31.6,28.9,27.9(CH2),26.4(CH3),25.8,22.9(×2)(CH2);m/z(M+C14H24N2O2需要252.18378)252.18323.
实施例3:(S)-3-(环己-1’-烯羰基)氨基-己内酰胺:
在环境温度下,将(S,S)-3-氨基-己内酰胺氢-吡咯烷-5-甲酸盐2(5mmol)与Na2CO3(15mmol)的水(25ml)溶液加入到环己-1-烯-1-碳酰氯(5mmol)的二氯甲烷(25ml)溶液中,将反应搅拌12小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×25ml)。合并有机层,经Na2CO3干燥,在真空中浓缩。残余物经过EtOAc/己烷重结晶纯化,得到内酰胺(431mg,36%);m.p.(EtOAc/己烷)151-152℃;[α]D 25(c=1,CHCl3)+57.5;vmax/cm-13219(NH),1652,1628(C=O,C=C),1515(NH);δH(500MHz,CDCl3)7.12(1H,d,J5,CHNH),6.67(1H,qn,J 1.5,CH=C),6.52(1H,br s,CH2NH),4.54(1H,ddd,J 11,5.5,1.5CHNH),3.32-3.18(2H,m,CH2NH),2.30-2.17(2H,m,CH2CH=C),2.16-2.10(2H,m,CH=CCH2),2.07(1H,br d,J 15,内酰胺环CH),2.00-1.92(1H,m,内酰胺环CH),1.87-1.76(2H,m,内酰胺环CH×2),1.68-1.60(2H,m,己环CH×2),1.60-1.52(2H,m,己环CH×2)和1.50-1.31(2H,br m,内酰胺环CH×2);δC(125MHz,CDCl3)175.9,167.4(CO),134.0(CH=C),132.8(CH=C),52.1(NHCHCO),42.1,31.6,28.9,27.9,25.3,24.0,22.1,21.5(CH2);m/z(M+C13H20N2O2需要236.15248)236.15208.
实施例4:(S)-3-(反式-4-’-戊基环己烷-1-羰基)氨基-己内酰胺:
在环境温度下,将(S,S)-3-氨基-己内酰胺氢-吡咯烷-5-甲酸盐2(7mmol)与Na2CO3(21mmol)的水(25ml)溶液加入到反式-4-戊基环己烷-1-碳酰氯(6mmol)的二氯甲烷(25ml)溶液中,将反应搅拌12小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×25ml)。合并有机层,经Na2CO3干燥,在真空中浓缩。残余物经过EtOAc/己烷重结晶纯化,得到内酰胺(977mg,53%);m.p.182-184℃;[α]D 25(c=1,CHCl3)+32.2;vmax/cm-1 3326(NH),1670,1636(CO),1511(NH);δ(500MHz,CDCl3)6.91(1H,d,J 5.5,CHNH),6.87-6.70(1H,brm,CH2NH),4.44(1H,ddd,J 11,6.0,1.5,CHNH),3.28-3.15(2H,m,CH2NH),2.08-1.90(3H,br m,环CH×2+(CH2)2CHCO),1.88-1.72(6H,m,环CH+链CH2×4),1.45-1.28(4H,br m,环CH+链CH2×2+链CH(CH2)3),1.27-1.07(9H,br m,环CH+链CH2×8)t0.90-0.79(5H,m,链CH2+CH3);δC(125MHz,CDCl3)176.0,175.3(CO),51.8(NHCHCO),45.4(CH),41.0(CH2),37.1(CH2),36.9(CH),32.5,32.4,32.1,31.7,29.6,29.4,28.9,27.9,26.5,22.6(CH2)and 14.0(CH3);m/z(M+C18H32N2O2需要308.24638)308.24566.
实施例5:(S)-3-(4’-戊基[2,2,2]双环-辛烷-1-羰基)氨基-己内酰胺:
在环境温度下,将(S,S)-3-氨基-己内酰胺氢-吡咯烷-5-甲酸盐2(5.5mmol)与Na2CO3(16.5mmol)的水(25ml)溶液加入到反式-4-戊基环己烷-1-碳酰氯(4.4mmol)的二氯甲烷(25ml)溶液中,将反应搅拌12小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×25ml)。合并有机层,经Na2CO3干燥,在真空中浓缩。残余物经过EtOAc/己烷重结晶纯化,得到内酰胺(868mg,57%);m.p.195-196℃;[α]D 25(c=1,CHCl3)+28.7;vmax/cm-1 3395,3254(NH),1677,1626(CO),1501(NH);δH(500MHz,CDCl3)6.98(1H,d,J 5.5,CHNH),6.77-6.63(1H,br m,CH2NH),4.41(1H,dd,J 11,5.5,CHNH),3.27-3.15(2H,m,CH2NH),2.00-1.88(2H,br m,环CH×2),1.81-1.73(2H,brm,环CH×2),1.69(6H,br t,J 7.5,链CCH2CH2C×6),1.43-1.30(8H,br m,环CH×2+链CCH2CH2C×6),1.24(2H,sext,J 7,CH2CH3),1.19-1.07(4H,m,CH2CH2CH2CH3)1.05-0.98(2H,m,CH2Bu)和0.82(3H,t,J 7,CH3);δC(125MHz,CDCl3)177.4,176.1(CO),51.9(NHCHCO),42.0,41.2(CH2),39.0(C quat),32.7,31.6,30.6(×3)(CH2),30.4(C quat),28.9,28.8(×3),27.9,23.3,22.6(CH2)and 14.0(CH3);m/z(M+C20H34N2O2需要334.26203)334.26352.
实施例6:(S)-3-(1’-金刚烷羰基)氨基-己内酰胺:
在环境温度下,将(S)-3-氨基-己内酰胺盐酸盐2(1mmol)与Na2CO3(3mmol)的水(15ml)溶液加入到1-金刚烷碳酰氯(1mmol)的二氯甲烷(15ml)溶液中,将反应搅拌2小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×25ml)。合并有机层,经Na2CO3干燥,在真空中浓缩。残余物经过CH2Cl2/己烷重结晶纯化,得到(S)-3-(1’-金刚烷羰基)氨基-己内酰胺(171mg,59%);m.p.256-258℃;[α]D 25(c=1,CHCl3)+29.5;vmax/cm-1 3411,3259(NH),1678,1626(CO),1505(NH);δH(500MHz,CDCl3)7.08(1H,d,J 5.5,CHNH),6.67(1H,br s,CH2NH),4.47(1H,ddd,.J 11,5.5,1.5,CHNH),3.32-3.17(2H,m,CH2NH),2.06-1.94(5H,m,2×环CH+3×金刚烷CH),1.90-1.75(8H,m,2×环CH+3×金刚烷CH2),1.72(3H,brd,J 14.5,3×金刚烷CHH),1.68(3H,br d,J 14.5,3×金刚烷CHH)和1.47-1.32(2H,m,2×环CH);δC(125MHz,CDCl3)177.2,175.9(CO),51.9(NHCHCO),42.2(CH2N),40.5(CCO),39.0(3×CH2金刚烷),36.5(3×CH2金刚烷),31.7,28.9,28.0(CH2内酰胺),28.1(3×CH金刚烷);m/z(MH+C17H27N2O2需要291.2073)291.1994.
实施例7:(S)-3-(1’-金刚烷基甲烷羰基)氨基-己内酰胺:
在环境温度下,将(S)-3-氨基-己内酰胺盐酸盐2(4mmol)与Na2CO3(12mmol)的水(50ml)溶液加入到1-金刚烷甲烷碳酰氯(4mmol)的二氯甲烷(50ml)溶液中,将反应搅拌2小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×50ml)。合并有机层,经Na2SO4干燥,在真空中浓缩。残余物经过EtOAc/己烷重结晶纯化,得到(S)-3-(1’-金刚烷基甲烷羰基)氨基-己内酰胺,从EtOAc中重结晶,得到白色晶体(688mg,56%);m.p.258-260℃;[α]D 25(c=1,CHCl3)+30.7;vmax/cm-1 3409,3255(NH),1682,1611(CO),1539(NH);δH(500MHz,CDCl3)6.82(1H,d,J 5.5,CHNH),6.77(1H,br t,J 5.5,CH2NH),4.48(1H,ddd,J 11,6,1.5,CHNH),3.28-3.14(2H,m,CH2NH),2.04(1H,br d,J 13.5,C-4H),1.97-1.86(6H,m,C-5H+3×金刚烷CH+CH2CO),1.84-1.72(2H,m,C-5H+C-6H),1.63(3H,br d,J 12,金刚烷3×CH2),1.60-1.54(9H,m,9×金刚烷CH2)和1.47-1.27(2H,m,C-4H+C-6H);δC(125MHz,CDCl3)175.9(内酰胺CO),170.1(酰胺CO),52.0(NHCHCO),51.4(CH2CO),42.6(3×金刚烷CH2),42.0(NCH2),36.7(3×CH2金刚烷),32.7(Cquat金刚烷),31.7(C-4),28.8(C-6),28.6(3×CH金刚烷),28.5(C-5);m/z(M+C18H28N2O2需要304.2151)304.21430.
实施例8:(S)-3-(3’-氯-1’-金刚烷羰基)氨基-己内酰胺:
在环境温度下,将(S)-3-氨基-己内酰胺盐酸盐2(3mmol)与Na2CO3(9mmol)的水(15ml)溶液加入到3-氯-1-金刚烷碳酰氯(3mmol)的二氯甲烷(15ml)溶液中,将反应搅拌12小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×25ml)。合并有机层,经Na2CO3干燥,在真空中浓缩。残余物经过EtOAc/己烷重结晶纯化,得到(S)-3-(3’-氯-1’-金刚烷羰基)氨基-己内酰胺(621mg,64%);m.p.204-206℃;[α]D 25(c=0.5,CHCl3)+26.2;vmax/cm-1 3411,3267(NH),1679,1630(CO),1508(NH);δH(500MHz,CDCl3)7.07(1H,d,J 5.5,CHNH),6.65-6.44(1H,br m,CH2NH),4.43(1H,dd,J 11,5.5,CHNH),3.24-3.17(2H,m,CH2NH),2.24(2H,br s,金刚烷CH),2.20(2H,br s,金刚烷CH),2.12-2.03(4H,m,金刚烷CH),2.02-1.91(2H,m,2×内酰胺环CH),1.85-1.72(6H,m,2×环CH+4×金刚烷CH),1.66-1.55(2H,m,2×金刚烷CH)and 1.45-1.31(2H,m,2×环CH);δC(125MHz,CDCl3)175.9,174.9(CO),67.4(CCl),51.9(NHCHCO),48.6,46.2(×2)(3×CH2金刚烷),44.5(CCO),42.1(CH2N),37.4,37.3,34.5(3×CH2金刚烷),31.5(CH2内酰胺),31.1(2×CH金刚烷),28.8,27.9(CH2内酰胺);m/z(MH+C17H26N2O2Cl需要325.1683)325.1696.
实施例9:(S)-3-(3’,5’-二甲基-1’-金刚烷羰基)氨基-己内酰胺:
在环境温度下,将(S)-3-氨基-己内酰胺盐酸盐2(1mmol)与Na2CO3(3mmol)的水(15ml)溶液加入到3,5-二甲基-1-金刚烷碳酰氯(1mmol)的二氯甲烷(15ml)溶液中,将反应搅拌12小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×25ml)。合并有机层,经Na2CO3干燥,在真空中浓缩。残余物从己烷中重结晶,得到(S)-3-(3’,5’-二甲基-1’-金刚烷羰基)氨基-己内酰胺(200mg,63%);m.p.157-158℃;[α]D 25(c=0.5,CHCl3)+26.8;vmax/cm-1 3206(NH),1647(CO),1548(NH);δH(500MHz,CDCl3)7.05(1H,d,J 5.0,CHNH),6.49-6.24(1H,br m,CH2NH),4.45(1H,ddd,J 11,5.5,1.5,CHNH),3.30-3.16(2H,m,CH2NH),2.12-2.07(1H,m,金刚烷CH),2.04-1.90(2H,m,2×内酰胺环CH),1.86-1.73(2H,m,2×内酰胺环CH),1.67(2H,br s,2×金刚烷CH),1.51-1.26(10H,br m,8×金刚烷CH+2×内酰胺环CH)1.17-1.09(2H,m,金刚烷CH)和0.81(6H,s,2×CH3);δC(125MHz,CDCl3)176.9,176.0(CO),51.9(NHCHCO),50.6,45.2(×2),42.7(×2)(CH2金刚烷),42.4(CCO),42.1(CH2N),37.7(CH2金刚烷),31.6(CH2内酰胺),31.0(2×CCH3),30.4,29.3(CH3),28.9 and 27.9(CH2内酰胺);m/z(MH+C19H31N2O2需要319.2386)319.2372.
实施例10:(S)-3-(3’,5’,7’-三甲基-1’-金刚烷羰基)氨基-己内酰胺:
在环境温度下,将(S)-3-氨基-己内酰胺盐酸盐2(1mmol)与Na2CO3(3mmol)的水(15ml)溶液加入到3,5,7-三甲基-1-金刚烷碳酰氯(1mmol)的二氯甲烷(15ml)溶液中,将反应搅拌12小时。然后分离有机层,水相用另外的二氯甲烷萃取(2×25ml)。合并有机层,经Na2CO3干燥,在真空中浓缩。残余物经过EtOAc/己烷重结晶纯化,得到(S)-3-(3’,5’,7’-三甲基-1’-金刚烷羰基)氨基-己内酰胺(188mg,56%);m.p.177-178℃;[α]D 25(c=0.5,CHCl3)+25.6;vmax/cm-1 3377,3220(NH),1677,1623(CO),1514(NH);δH(500MHz,CDCl3)7.06(1H,d,J 5.0,CHNH),6.40-6.15(1H,br m,CH2NH),4.46(1H,ddd,J 11,5.5,1.5,CHNH),3.32-3.17(2H,m,CH2NH),2.03-1.92(2H,m,2×内酰胺环CH),1.86-1.74(2H,m,2×内酰胺环CH)1.47-1.32(8H,m,2×环CH+6×金刚烷CH)1.06(3H,br d,J 12,3×金刚烷CHH),1.04(3H,br d,J 12,3×金刚烷CHH)和0.83(9H,s,3×CH3);δC(125MHz,CDCl3)176.8,176.0(CO),51.9(NHCHCO),50.0(3×CH2金刚烷),44.6(3×CH2金刚烷),43.4(CCO),42.1(CH2N),31.8(3×CCH3),31.7(CH2内酰胺),30.0(3×CH3),28.9,27.9(CH2内酰胺);m/z(MH+C20H33N2O2需要333.2542)333.2528.
本发明产物的药理研究
抑制MCP-1诱导的白细胞移行
测定原理
本发明化合物的生物活性可以利用任何多种体外白细胞移行功能测定法加以证明,包括但不限于Boyden室与相关跨孔移行测定法、琼脂糖下移行测定法和直接肉眼观察室,例如Dunn室。
例如,为了证明抑制响应于趋化因子(而非其他化学引诱剂)的白细胞移行,使用来自Neuroprobe(Gaithersburg,MD,USA)的96-孔微量跨孔测定系统。原则上,这种测定法由被多孔膜隔开的两个室组成。将化学引诱剂放置在下部室内,将细胞放置在上部室内。在37℃下温育一段时间后,细胞朝向化学引诱剂移动,下部室内的细胞数与化学引诱剂活性成比例(相对于一系列对照而言)。
这种测定法可以适用一些不同的白细胞种群。例如,可以使用新鲜制备的人外周血白细胞。作为替代选择,利用本领域技术人员熟知的方法,例如密度梯度离心或磁性珠粒分离,可以制备白细胞亚群,包括多形核细胞或淋巴细胞或单核细胞。作为替代选择,可以使用已被广泛验证为人外周血白细胞模型的无限增殖化细胞系,包括但不限于作为单核细胞模型的THP-1细胞或者作为幼稚T细胞模型的Jurkat细胞。
尽管有一些测定条件是证明抑制趋化因子-诱导的白细胞移行可接受的,不过提供具体的实例。
材料
跨孔移行系统是由Neuroprobe,Gaithersburg,MD,USA制造的。
所用平板为ChemoTx平板(Neuroprobe 101-8)和30μl透明平板(Neuroprobe MP30)。
Geys平衡盐溶液是从Sigma购买的(Sigma G-9779)。
无脂肪酸BSA是从Sigma购买的(Sigma A-8806)。
MTT、即3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物是从Sigma购买的(Sigma M-5655)。
不含酚红的RPMI-1640是从Sigma购买的(Sigma R-8755)。
使用THP-1细胞系(European Cell culture Collection)作为白细胞种群。
试验方案
利用下列工艺测试本发明化合物对MCP-1诱导的白细胞移行的影响:
首先,制备所要放置在上部室内的细胞悬液。离心(770xg;4min)沉淀出THP-1细胞,用含有1mg/ml BSA的Geys平衡盐溶液(GBSS+BSA)洗涤。然后重复这种洗涤,重新使细胞沉淀,然后重新悬浮在少量GBSS+BSA中供计数,例如利用标准血细胞计数器。
然后根据细胞数调整GBSS+BSA的体积,以便细胞的最终浓度为4.45×106细胞每ml GBSS+BSA。这样确保在每25μl将要放置在平板上部室内的溶液中存在100,000 THP-1细胞。
为了测试单一化合物抑制MCP-1诱导的移行的能力,有必要准备两批细胞。将4.45×106细胞/ml的THP-1细胞悬液分成两批。向其中一批加入适当最终浓度的供试抑制剂在适当载体中的溶液(例如1μM,载体为不超过1%的DMSO)。向第二批加入等体积的GBSS+BSA,酌情加上载体(例如不超过1%的DMSO),作为对照。
下面,制备所要放置在下部室内的化学引诱剂溶液。将MCP-1稀释在GBSS+BSA中,得到最终浓度为25ng/ml。将其分成两批,与细胞悬液一样。向其中一批加入供试化合物,最终浓度与向细胞悬液中加入的相同,向另一批加入等体积的GBSS+BSA,酌情加上载体(例如不超过1%的DMSO)。
注意,在建立下部室内溶液中MCP-1的最终浓度和上部室内细胞的最终浓度时,需要考虑为加入供试化合物所加入的液体体积。
一旦已经制备用于下部小孔的化学引诱剂溶液和用于上部室的细胞溶液,应当装配移行室。将29μl适当的化学引诱剂溶液放置在下部小孔内。每种条件应当进行至少一式三份测定。一旦已经填充所有下部室,按照厂商指导向该室安装多孔膜。最后,向每一上部室加入25μl适当的细胞溶液。将塑料盖放置在整个装置上,防止蒸发。
将装配好的室在37℃、5%CO2下温育2小时。在试管中也在等同条件下温育细胞在GBSS+BSA中的悬液:这些细胞将用于构建标准曲线,供测定在每一条件下移行至下部室的细胞数。
在温育结束时,小心地从上部室除去液体细胞悬液,向上部室加入20μl冰冷的20mM EDTA的PBS溶液,将装置在4℃下温育15min。这种工艺导致所有细胞粘附于膜的下侧,落入下部室内。
这种温育之后,将滤器小心地用GBSS+BSA冲洗,以洗去EDTA,然后除去滤器。
然后可以借助多种方法测定在每种条件下移行至下部室的细胞数,包括直接计数、用荧光或放射性标志物标记或者使用活体染剂。通常,我们采用活体染剂MTT。向每孔加入3μl储备MTT溶液,然后将平板在37℃下温育1-2小时,在此期间细胞内的脱氢酶转化可溶性MTT为不溶性蓝色甲产物,可以用分光光度法量化。
并列设置8-点标准曲线。开始于向每一上部室加入的细胞数(100,000),继之以在GBSS+BSA中的2-倍系列稀释液,向平板加入25μl细胞,并且加入3μl MTT储备溶液。沿着移行平板温育标准曲线平板。
在这种温育结束时,小心地从下部室除去液体,注意不要扰乱已沉淀的甲产物。简单风干后,向每一下部室加入20μl DMSO,以增溶蓝色染剂,利用96-孔平板读数器测定在595nm下的吸光度。然后向标准曲线插入每孔吸光度,以估计每一下部室中的细胞数。
从到达含有25ng/ml MCP-1的下部室的平均细胞数中减去到达没有加入MCP-1的小孔下部室的平均细胞数,测定MCP-1刺激的移行。
通过比较在有或没有各种浓度供试物质的存在下发生的MCP-1诱导的移行,计算供试物质的影响。通常,抑制移行以总MCP-1诱导的移行因化合物的存在而受阻滞的百分比表示。就大多数化合物而言,通过测定抑制在一定范围的不同化合物浓度下(通常从1nM至1μM,或者更高,在弱活性化合物的情况下)发生的MCP-1诱导的移行,构建剂量-响应图。然后,每种化合物的抑制活性以减少MCP-1诱导的移行达50%所需化合物浓度(ED50浓度)表示。
结果
测试了实施例1至8和10化合物,在本试验中其显示100nM或以下的ED50。
对映体选择性
可以合成氨基己内酰胺系列的两种不同成员的(S)-和(R)-对映体,以测定生物活性是否显示对映体选择性。
利用跨孔移行测定法可以测定每种化合物作为MCP-1诱导的THP-1细胞移行抑制剂的剂量-响应曲线。
就本发明化合物作为体内抗炎剂的应用而言,优选使用化合物的纯(S)-对映体,而不是两种对映体的外消旋混合物或者纯(R)-对映体。
Claims (9)
1.通式(I)的化合物或其药学上可接受的盐:
其中
X是-CO-Y-(R1)n;
Y是金刚烷基、金刚烷甲基、双环辛基、环己基或环丙基;
每个R1独立地选自氢或者烷基,该烷基具有1至20个碳原子;
或者每个R1独立地选自氟、氯、溴、碘、羟基或氨基;以及
n是1至m的任意整数,其中m是环状基团Y上可允许的最大取代数。
3.根据权利要求1或2的化合物或它们药学上可接受的盐,其中Y的一个或多个环限制α-碳的键角为本质上四面体的。
4.根据权利要求1的的化合物,其中该化合物选自下组:
-(5)-3-(环己烷羰基)氨基-己内酰胺;
-(5)-3-(1’-甲基环己烷羰基)氨基-己内酰胺;
-(S)-3-(反式-4’-戊基环己烷-1-羰基)氨基-己内酰胺;
-(S)-3-(4’-戊基[2,2,2]双环-辛烷-1-羰基)氨基-己内酰胺;
-(5)-3-(1’-金刚烷羰基)氨基-己内酰胺;
-(5)-3-(1’-金刚烷基甲烷羰基)氨基-己内酰胺;
-(S)-3-(3’-氯-1’-金刚烷羰基)氨基-己内酰胺;
-(S)-3-(3’,5’-二甲基-1’-金刚烷羰基)氨基-己内酰胺;
-(S)-3-(3’,5’,7’-三甲基-1’-金刚烷羰基)氨基-己内酰胺;
以及它们的药学上可接受的盐。
5.根据权利要求1的化合物,其中该化合物是(S)-3-(1’-金刚烷羰基)氨基-己内酰胺及其药学上可接受的盐。
6.权利要求1至5任一项的化合物或其药学上可接受的盐的用途,用于制备治疗炎性障碍的药物。
7.根据权利要求6的用途,其中该炎性障碍选自自身免疫疾病、血管障碍、病毒感染或复制、哮喘、骨质疏松、肿瘤生长、以TNF-α水平升高为特征的障碍、皮肤伤口、由细胞内寄生虫导致的障碍、阿尔茨海默氏病、抗原诱导的回忆应答、免疫应答抑制、纤维化和粘连形成。
8.根据权利要求6的用途,其中所述炎性障碍选自类风湿性关节炎、器官移植排斥和/或移植物或器官功能迟缓、牛皮癣、变态反应、多发性硬化和ALS。
9.药物组合物,其包含作为活性成分的根据权利要求1至5任一项的化合物或其药学上可接受的盐和至少一种药学上可接受的赋形剂。
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US7803794B2 (en) | 2005-06-15 | 2010-09-28 | Cambridge Enterprise Limited | Anti-inflammatory agents |
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EP0093949A1 (de) * | 1982-05-08 | 1983-11-16 | Bayer Ag | Sulfinyl- und Sulfonyl-azacycloheptan-2-one, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Futterzusatzstoffe |
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