CN1430597A - 新颖的mmp-2/mmp-9抑制剂 - Google Patents
新颖的mmp-2/mmp-9抑制剂 Download PDFInfo
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- CN1430597A CN1430597A CN01810068A CN01810068A CN1430597A CN 1430597 A CN1430597 A CN 1430597A CN 01810068 A CN01810068 A CN 01810068A CN 01810068 A CN01810068 A CN 01810068A CN 1430597 A CN1430597 A CN 1430597A
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- Prior art keywords
- nonyl
- succsinic acid
- pain
- acid
- amides
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Abstract
本发明提供了新颖的MMP-2/MMP-9抑制剂以及使用它们的方法。
Description
发明领域
本发明涉及基质金属蛋白酶-2(在此称“MMP-2”)和基质金属蛋白酶-9(在此称“MMP-9”)的新颖二元抑制剂。本发明还涉及治疗病人疼痛的方法,此方法包括向病人给药减轻疼痛有效量的本发明化合物。
发明背景
细胞外基质(ECM)是蛋白质与以高度的组织形式组合起来的蛋白多糖的多官能络合物,它导致在器官体系内的细胞及组织的结构完整性。对脉管系统提供结构支持的基底膜由ECM分子如IV型胶原、层粘连蛋白和纤连蛋白组成。在维持ECM和它支持的组织的完整性方面包括各种因素。但是,在某些病理情况下,ECM被调整,使得组织的结构变成被损伤的或被破坏的。基质金属蛋白酶(MMPs)是一组使细胞外基质分子降解的依赖于锌的酶。MMP家族中的两个成员,即MMP-2(72KDa明胶酶/Gelatinase A)和MMP-9(92KDa明胶酶/Gelatinase B)使基底膜的ECM组分降解。它们的底物包括IV型和V型胶原,纤连蛋白、弹性蛋白及变性间质胶原。已经表明,基于这些蛋白酶的基质降解在疾病如动脉粥样硬化、炎症、中风以及瘤的生长和转移的加重方面,起重要作用。
因狭窄引起的神经损伤会导致神经组织的缺血并最终使神经元细胞死亡。神经损伤之后的变狭窄由于微血管受压迫首先导致血流减少和能量缺失,而这些微血管支持着神经组织。这些因素加上因为兴奋、酶活化、水肿及炎症,使神经组织变梗塞。神经受损伤后引发明显的炎症应答。例如,中性白细胞浸润受损组织,并使得神经受损伤,这进一步加重受损应答。此外,研究人员已证明,中性白细胞利用MMPs以进行它们的移行。人们相信,MMP抑制会防止或改善因神经受损而发生的组织损伤。此外,MMP抑制还会防止或降低炎症细胞浸润入受损组织内部的程度。
因此很清楚,有必要对MMP-2和MMP-9的二元拮抗剂进行鉴定和表征,而这些二元拮抗剂对防止、改善或治愈下列疾病起重要作用:中风;出血;再灌注损伤;脑局部缺血;脑梗塞;对疼痛的高的或超常敏感如痛觉过敏、灼痛和异常性疼痛;急性疼痛;灼烧痛;典型的面部痛;神经病痛;背痛;复杂的局部疼痛综合症I和II;关节炎痛;运动损伤痛;涉及病毒如HIV感染的疼痛、脊髓灰质炎后综合症及疱疹后神经痛;幻象肢痛;分娩痛;癌痛;化疗后痛;中风后痛;手术后痛;生理性痛;炎症痛;急性炎症环境/内脏痛例如因痛、应激性肠综合症(IBS)及炎性肠疾病;神经病痛;神经痛;疼痛性糖尿病神经病;创伤神经痛;脊索损伤;以及对麻醉药的耐受性或从麻醉药的病理性退隐,这些仅是其中的一些。
一方面,本发明涉及新颖的MMP-2/MMP-9抑制剂,并涉及治疗病人疼痛的方法,该方法包括将治疗疼痛有效量的本发明化合物与载体一起给药于病人,其中这些病人患上了下列疾病:对疼痛的高的或超常敏感如痛觉过敏、灼痛和异常性疼痛;急性疼痛;灼烧痛;典型的面部痛;神经病痛;背痛;复杂的局部疼痛综合症I和II;关节炎痛;运动损伤痛;涉及病毒如HIV感染的疼痛、脊髓灰质炎后综合症及疱疹后神经痛;幻象肢痛;分娩痛;癌痛;化疗后痛;中风后痛;手术后痛;生理性痛;炎症痛;急性炎症环境/内脏痛例如咽痛、应激性肠综合症(IBS)及炎性肠疾病;神经病痛;神经痛;疼痛性糖尿病神经病;创伤神经痛;脊索损伤;以及对麻醉药的耐受性或从麻醉药的病理性退隐。
第二方面,本发明涉及本发明化合物以及需治疗神经组织损伤的病人的治疗方法,该方法包括将减少神经组织损伤有效量的本发明化合物与载体一起给药于病人,其中这些病人患上了下列疾病:中风;出血;再灌注损伤;脑局部缺血;脑梗塞;对疼痛的高的或超常敏感如痛觉过敏、灼痛和异常性疼痛;急性疼痛;灼烧痛;典型的面部痛;神经病痛;背痛;复杂的局部疼痛综合症I和II;关节炎痛;运动损伤痛;涉及病毒如HIV感染的疼痛、脊髓灰质炎后综合症及疱疹后神经痛;幻象肢痛;分娩痛;癌痛;化疗后痛;中风后痛;手术后痛;生理性痛;炎症痛;强烈的炎症环境/内脏痛例如咽痛、应激性肠综合症(IBS)及炎性肠疾病;神经病痛;神经痛;疼痛性糖尿病神经病;创伤神经痛;脊索损伤;以及对麻醉药的耐受性或从麻醉药的病理性退隐,这些仅是其中的一些。
第三方面,本发明涉及本发明化合物以及治疗患了下列疾病的患者的方法:中风,出血,再灌注损伤,脑的局部出血及脑梗塞,该方法包括向病人给药有效量的本发明化合物的步骤。
本发明的概括
本发明包括下面通式(I)所代表的新颖化合物以及其作为MMP2/9抑制剂的用途。
本发明还提供在包括人类的动物中抑制MMP2/9的方法,该方法包括向需要治疗的患者给药有效量的如下面通式(I)所示的化合物。
本发明的详细描述
适用于本发明方法的化合物选自下列通式(I)。
通式(I)的化合物具有下列结构:
通式(I)
其中:
R选自烷基,芳基,芳烷基,杂芳基,杂环烷芳基,烷硫基烷基,羟烷基,及氨烷基;而R1选自烷基,环烷基,芳基,杂芳基,芳烷基,杂环芳烷基,氨烷基,及(N-取代的氨磺酰基)氨烷氨基,其中氨烷基中的氨基可以是未取代的,被烷基或芳基单取代的或双取代的,或者是杂环的一部分,而(N-取代的氨磺酰基)中的N-取代氨基可以是未取代的,被烷基或芳基单取代或双取代的,或者是杂环的一部分。
R和R1的芳基可以被例如下列基团所取代:例如烷基,烯基,芳烷基,酰基,芳酰基,卤烷基,卤,羧基,烷氧羰基,氨基甲酰基,烷基氨基甲酰基,芳基氨基甲酰基,氰基,烷氧基,羟基,苯基偶氮基,氨基,硝基,烷氨基,芳氨基,芳烷氨基,酰氨基,芳酰氨基,烷硫基,芳烷硫基,芳硫基,烷基亚磺酰基,芳基亚磺酰基,芳烷基亚磺酰基,烷基磺酰基,芳基磺酰基,芳烷基磺酰基,氨磺酰基,芳基磺酰胺基或烷基磺酰胺基。
这里所用的“烷基”指用碳-碳单键相连在一起的任选被取代的烃基。此烷烃基可以是直链的、支化的或环状的,饱和的或不饱和的。此基团优选是未取代的。此基团优选是饱和的。优选的烷基部分是C1-5烷基。
这里所用的“芳基”指一种也任选被取代的芳基,它被至少一个具有共轭π-电子体系、含高达两个共轭的或稠合的环体系的环所取代。“芳基”包括碳环芳基、杂环芳基及双芳基。它们全部都任选被取代。优选的芳基部分是苯基,未取代的,单取代的,双取代的或三取代的。
具有通式(I)的适用于本发明的优选化合物选自:
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-3-(N-吗啉代)丙基酰胺
N-[2(R)-壬基琥珀酸]-L-苯甘氨酸-N-3-(N-吗啉代)丙基酰胺
N-[2(R)-壬基琥珀酸]-L-亮氨酸-N-3-(N-吗啉代)丙基酰胺
N-[2(R)-壬基琥珀酸]-L-蛋氨酸-N-3-(N-吗啉代)丙基酰胺
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-2-(N-吗啉代)乙基酰胺
N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-3-(N-吗啉代)丙基酰胺
N-[2(R)-壬基琥珀酸]-L-缬氨酸-N-2-(N-吗啉代)乙基酰胺
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-(4-甲氧基苯基)酰胺
N-[2(R)-壬基琥珀酸]-L-苯基丙氨酸-N-(4-甲氧基苯基)酰胺
N-[2(R)-壬基琥珀酸]-L-正缬氨酸-N-(4-甲氧基苯基)酰胺
N-[2(R)-壬基琥珀酸]-L-精氨酸-N-(4-甲氧基苯基)酰胺
N-[2(R)-壬基琥珀酸]-L-苯基甘氨酸-N-甲基酰胺
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-环戊基酰胺;以及
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-3-二甲氨基丙基酰胺。
在本发明中,本发明化合物药物上可接受的盐及络合物也包括在内。优选的是锌、铜、镍、钴和铑络合物,盐酸盐,氢溴酸盐及三氟乙酸盐。本发明的化合物可含有一个或多个不对称碳原子,并且可以以外消旋体或施光体存在。所有这些化合物以及非对映体均应理解为包括在本发明的范围之内。
合成
N-[2(R)-壬基琥珀酸]-L-苯基甘氨酸-N-甲基酰胺的合成如方案1所示进行,包括使4(s)苄基-2-噁唑烷与丁基锂反应,生成氮阴离子,然后它与十一烷酰氯反应,给出(s)-4-苄基-3-十一烷酰基-噁唑烷-2-酮(2)。将它与二异丙基氨基锂反应生成阴离子,又用溴乙酸叔丁酯进行熄灭,生成4(s)-苄基3-[2-(R)-[(叔丁氧基羰基)甲基]十一烷酰基]-2-噁唑烷酮(3),用色谱法进行提纯。在过氧化氢存在下用氢氧化锂使此产物水解,转化为2(R)-[(叔丁氧羰基)甲基]十一羧酸(4)。L-苯基甘氨酸甲酯与甲胺反应,制备L-苯甘氨酸-N-甲基酰胺,在标准的酰胺形成反应中使它与(4)缩合,生成2-(R)-[(叔丁氧羰基)甲基]十一烷酰基-L-苯基甘氨酸-N-甲基酰胺(5)。用色谱法提纯后,用90%三氟乙酸处理它,使之水解,生成所需的N-[2(R)-壬基琥珀酸]-L-苯基甘氨酸-N-甲基酰胺,用乙腈将它结晶。
本发明的这些化合物也可以在聚苯乙烯树脂上制成排布形式。为制备N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-3-(N-吗啉代)丙基酰胺,将N-(3-氨丙基)吗啉与(4-甲酰基-3,5-二甲氧基苯氧基)甲基聚苯乙烯树脂缩合,使用三乙氧基硼氢化钠作为还原剂。利用1-羟基-7-氮杂苯并三氮唑(0.25毫摩尔)和二异丙基碳二亚胺,使此产物与(s)-Fmoc苯丙氨酸偶合。用哌淀将Fmoc保护基除去,并使用1-羟基-7-氮杂苯并三唑和二异丙基碳二亚胺,使所得产物与R-2-壬基琥珀酸4-叔丁酯偶合。通过用三氟乙酸处理此树脂和用自动制备型HPLC进行提纯,得到N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-3-(N-吗啉代)丙基酰胺。LCMS分析测出此产物的预期分子量为517。
采用相似制法,使用甲胺,2-氨基甲基吡啶,二甲氨基丙胺,4-甲氧基苯乙胺,环戊胺,对茴香胺,4-(3-氨丙基)吗啉,及2-氨乙基吗啉作为胺类,以及使用Fmoc-甘氨酸,Fmoc-丝氨酸,Fmoc-缬氨酸,Fmoc-正缬氨酸,Fmoc-亮氨酸,Fmoc-异亮氨酸,Fmoc-苯丙氨酸,t-BuO-Fmoc-酪氨酸,Fmoc-蛋氨酸,Fmoc-D-均苯丙氨酸,Fmoc-苯甘氨酸及Fmoc-赖氨酸作为FMOC氨基酸,制得了这些化合物。使用其他胺类于还原胺化反应之中和使用FMOC氨基酸类,可制备相似化合物。
方案2
利用合适的操作和对任何化学官能团的保护,采用与上述那些以及实验部分中描述的那些相似的方法,可以进行通式(I)和(II)中余下的那些化合物的合成。
为了使用通式(I)的化合物或其药物上可接受的盐类来治疗人类或其他哺乳动物,通常根据标准药物实践配制药物组合物。
这里所用的疾病“治疗”包括但不限于对疾病的治疗、缓解和预防。本发明化合物,用于治疗包括但不限于下列疾病:中风;出血;再灌注损伤;脑局部缺血;脑梗塞;对疼痛的高的或超常敏感如痛觉过敏、灼病和异常性疼痛;急性疼痛;灼烧痛;典型的面部病;神经病痛;背痛;复杂的局部疼痛综合症I和II;关节炎痛;运动损伤痛;涉及病毒如HIV感染的疼痛、脊髓灰质炎后综合症及疱疹后神经病;幻象肢痛;分娩痛;癌痛;化疗后痛;中风后痛;手术后病;生理性病;炎症痛;强烈的炎症环境/内脏痛例如咽痛、应激性肠综合症(IBS)及炎肠疾病;神经病痛;神经痛;疼痛性糖尿病神经病;创伤神经痛;脊索损伤;以及对麻醉药的耐受性或从麻醉药的病理性退隐。
通式(I)或(II)的化合物或它们的药物上可接受的盐类可以以治疗上述疾病的标准方式给药,例如口服,胃肠外,舌下,皮肤,经皮,直肠给药,通过吸入给药或通过面颊给药。
通式(I)或(II)的化合物及它们的口服时有活性的药物上可接受盐类可配制成糖浆,片剂,胶囊,乳膏及锭剂。糖浆制剂通常由此化合物或其盐在液体载体(例如带芳香剂或着色剂的乙醇、花生油、橄榄油、甘油或水)中的悬浮液或溶液组成。当此组合物是片剂时,可以使用任何日常用于制备固体制剂的药物载体。这类载体的例子包括硬脂酸镁,石膏粉,滑石粉,明胶,阿拉伯胶,硬脂酸,淀粉,乳糖及蔗糖。当此组合物是胶囊时,任何胶囊化法均可使用,例如在硬明胶胶囊壳中使用上述载体。当此组合物是软明胶壳胶囊时,可以考虑使用任何通常用于制造分散液或悬浮液的药物载体,例如含水树胶,纤维素,硅酸盐或油类,并将它们加入软明胶胶囊壳中。
典型的胃肠外用的组合物由此化合物或其盐在无菌的含水或无水载体(它们还任选含有胃肠外可接受的油如聚乙二醇、聚吡咯烷酮、卵磷脂,花生油或芝麻油)中的溶液或悬浮液组成。
典型的吸入用组合物处于溶液、悬浮液或乳液状态,它们可以以干粉或以气溶胶形式使用,气溶胶中使用通常的气雾剂基质如二氯二氟甲烷或三氯一氟甲烷。
典型的栓剂包含通式(I)或(II)的化合物,或者它们的药物上可接受的盐,这种盐当以任何方式与粘结剂和/或润滑剂如聚乙二醇、明胶、可可脂或其他低熔点植物蜡或植物脂或者它们的合成类似物一起给药时是活性的。
典型的皮肤用和经皮用制剂包含通常的含水或无水载体,例如,乳膏、软膏、洗液或糊剂,或呈含药石膏形、贴剂或膜。
此组合物优选呈单位剂型,例如片剂、胶囊或计量的气溶胶剂量,使得病人使用单一剂量。
每一口服剂量单位合适地含有0.1mg~500mg/Kg,优选含有1mg~100mg/Kg,每一胃肠外给药剂量单位合适地含有0.1mg~100mg/Kg通式(I)或(II)的化合物或其药物上可接受的盐(以游离酸计算)。每一鼻内给药剂量单位合适地含有1~400mg、优选含有10-200mg/人。局部给药制剂合适地含有0.01~5.0%通式(I)或(II)化合物。
口服的每日剂量方案合适地为约0.01mg/Kg~40mg/Kg通式(I)或(II)化合物或其药物上可接受的盐类(以游离酸计算)。胃肠外给药每日剂量方案合适地为约0.001mg/Kg~40mg/Kg通式(I)或(II)化合物或其药物上可接受的盐类(以游离酸计算)。经鼻给药或口吸给药每日剂量方案合适地为约10~500mg/人。活性组份的给药可以为每日1~6次,这足以显示所需活性。
当根据本发明给药本发明化合物时未发现不可接受的毒害作用。
通式(I)或(II)的化合物的生物活性用下列方法检验。
MMP-2/MMP-9筛选测定记录
利用高输出的96穴筛选法来测定MMP-9活性及检测潜在的MMP-9的抑制剂。此筛选法是熄灭荧光测定法。这些被测定组份包括已提纯的重组体人MMP-9(由SB生成,最终浓度为3nM)和荧光团肽底物(产自PeptidesInternational,Louisville,ky,10(M)最终浓度,底物在有或没有本化合物存在下温育过。简略地说,在37℃温育30分钟后测定酶活性,并使用肽底物测定数量,所述肽底物是(Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMa)-NH2)或者(2,4-二硝基苯基-L-丙基-L-环己基丙氨酰-甘氨酰(甲基-L-半胱氨酰-L-组氨酰-L-丙氨酰-N(-甲基氨茴酰-L-赖氨酸酰胺),它在肽的一端含有荧光团,而在另一端则含有熄灭剂Dnp。当肽完整时,荧光团熄灭。当肽被MMP-9裂解后,熄灭剂从荧光团离解出来,荧光信号消失,这可容易地用荧光板阅读仪测出。以MMP-1,-2,-3,-9和-13识别的肽之内的普遍裂解位是Gly-Cys键。将对MMP-9显示的IC50小于1nm的化合物进行再一次筛选,筛选时使用已提纯的重组体人MMP-2(由SB生产,10nM),MMP-13(产自Chemicon,Temecula,加利福尼亚州),MMP-3(产自Biogenesis,Sandown,新罕布什尔州)及MMP-1(产自Biogenesis,Sandown,新罕布什尔州),以证实对MMP-9的选择性。这些筛选与上述对MMP-9的描述一样,使用相同的荧光团肽底物。使用这一筛选记录,证实N-[2(R)-(n-壬基)琥珀酰基-L-苯基甘氨酸-N-甲基酰胺与MMP-2/MMP-9二元抑制剂相同,此化合物的合成详述于实施例3中。
测定羧酸化合物对MMP-9和MMP-2的抑制的Ic50
背景
使用96穴熄灭荧光测定法来测定MMP-9和MMP-2的活性和检测潜在的MMP-9及MMP-2的抑制剂。检测的组份包括已提纯的重组体人MMP-2或-9以及在本化合物存在或不存在下温育过的荧光团肽底物。这些化合物针对MMP-9首先在1μm进行筛选,而抑制MMP-9>95%的那些化合物则针对已提纯的重组体人MMP-2,MMP-1和MMP-3再进行筛选。为了这些另外的筛选,测定IC50值。
MMP-9和MMP-2筛选
用肽底物2,4-二硝基苯-L-丙基-L-环己基丙氨酰基-甘氨酰基(甲基-L-半胱氨酰基-L-组氨酰基-L-丙氨酰基-N(甲基氨茴酰基-L-赖氨酸酰胺,(Dnp-(Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMa)-NH2,产自Peptides International,目录号SDP-3815),在肽的一端含有荧光团Nma,而在另一端含有熄灭剂Dnp(见Bickett等人的著作,1993)。当肽完整时,将荧光团熄灭。当肽被MMP裂解时,熄灭剂从荧光团离解出来,可用荧光板阅读仪测出荧光信号(Ex.355nm Em.460nM)。被MMP-2和MMP-9识别的肽之中的裂解位是Gly-Cys键。
为每一化合物制备了3μM(500μl)工作储备液。所有的工作储备液均在含有100mM Tris;pH7.5,100mM NaCl;10mM CaCl2;0.01% NaN3的测定用缓冲液中制备。由这一工作储备液,用测定用缓冲液进行对数稀释,而且在1μM,300nM,100nM,30nM,10nM,3nM及1nM,测定每一化合物,重复三次。肽底物浓度是10μM。用于此测定的MMP-9的浓度为0.3nM,而MMP-2浓度为10nM。在这些浓度,肽的裂解是最大的,在37℃温育30分钟达到平稳期。于37℃在t=0和t=30分钟时测定荧光。测定每一反应相对于载体对比物的δ荧光,并计算抑制百分数。然后用这些数值相对于化合物浓度作图,并外推出IC50。
MMP-1筛选
从英国伦敦T.Cawston以活性形式得到MMP-1。为测定MMP-1活性和化合物抑制性,往96穴板中加入10μl在测定用缓冲液中的20% DMSO,或加入10μl在20% DMSO中的10倍最终浓度的化合物抑制剂。然后,往每个穴中加入70μl测定用缓冲液,10μlSDP-3815肽底物(产自PeptidesInternational)其浓度在测定用缓冲液中的10% DMSO之中为500μM,以及10μl MMP-1(在测定用缓冲液中最终浓度为24μg/ml)。
用荧光板阅读仪(360/460nm滤光片对)在长达30分钟内测定荧光,时间间隔为10分钟。如果时间终了时为非直线的,则用直线部分测定斜率。为测定MMP-1抑制百分数,绘出所产生的荧光信号的斜率相对于时间的图。
MMP-3筛选
从Biogenesis(目录号5980-0357)购得的Pro-MMP-3(prostromelysin)230μg/ml,按照Lark等人在《Connective Tissue Res.25,52(1990)》中所述进行活化。简单地说,往5μl of 230μg/ml原溶基质素(pro-stromelysin)中,加入在0.15M Tris HCl、15mM CaCl2 0.2M NaCl,pH7.6(测定用缓冲液)中的5μl 160nM胰蛋白酶(产自Fluka)。使此反应混合物在37℃温育30分钟,然后,加入在琼脂糖珠(产自Sigma)上的豆油胰蛋白酶抑制剂的1/6稀释液(在0.5M NaCl中)3.3μl,比胰蛋白酶抑制剂过量100倍。随后让此反应混合物在37℃温育另30分钟,然后在14000rpm转速(微离心机)下离心5分钟以便把颗粒甩掉。然后把此样品贮存在冰之上以便马上使用,或者等分并在-80℃下贮存。MMP-3的最终浓度为1.5μM。
为测定MMP-3的活性和化合物的抑制性,往96穴板中加入在测定用缓冲液中的20% DMSO 10μl,或在20% DMSO中的最终浓度为10倍的化合物抑制剂10μl。随后,往每个穴中,加入测定用缓冲液70μl,在10% DMSO/测定用缓冲液中的浓度为500μM的NFF-3肽底物(产自InternationalPeptides)10μl,及溶基质素(在测定用缓冲液中的最终浓度为75nM)10μl。
用荧光板阅读器(320/405nm滤光片对)在长达1小时内测定荧光,时间间隔10分钟。为测定MMP-3抑制百分数,绘出所产生的荧光信号斜率相对于时间的图。
下面实施例是说明性的,但不限制本发明的具体实施方案。
实施例1
N-[2(R)-壬基琥珀酸]-L-苯基甘氨酸-N-甲基酰胺
制备(S)-4-苄基-3-十一烷酰基噁唑烷-2-酮(2)。将21.5克(0.122毫升)(S)-4-苄基噁唑烷-2-酮在THF(250毫升)中的溶液冷却至-78℃,并用61毫升(0.128摩尔)在己烷中的2.1M叔丁基锂进行处理。在-78℃将此混合物搅拌45分钟,然后逐滴加入27.5克(0.134摩尔)十一烷酰氯在50毫升THF中的溶液。此混合物在-78℃搅拌1小时,然后使之加热到室温保持18小时。逐滴加入20ml 0.1N HCl,然后加入乙酸乙酯以产生相分离。用水、饱和NaHCO3及饱和盐水洗涤有机层,在真空下浓缩之,得到产物。LC/MS分析:计算的分子量:345;实测值:M+1 346;停留时间(RT)3.20分钟,1×40mm C18柱子,4.5%~90% CH3CN(0.02%TFA),在3.2分钟内,保持0.4K分钟并再平衡1.4分钟,UV和MS检测。
制备R-3-[1-(1S)-4-苄基-2-氧代-噁唑烷-3-基)甲酰基]-十二烷酸叔丁酯(3)。将18.1毫升(13.07克,0.129摩尔)二异丙胺在200毫升THF中的溶液用48.2毫升(0.121摩尔)2.5M正丁基锂在THF中的溶液进行处理。30分钟后,加入40.69克(0.117摩尔)S-4-苄基-3-十一烷酰基-噁唑烷-2-酮在150毫升THF中的溶液,并把此混合物在-78℃搅拌90分钟,然后加入20.75毫升(27.4克,0.14摩尔)溴乙酸叔丁酯,随后用同一漏斗加入50毫升THF。把此混合物在室温下放置18小时,然后加入300毫升0.5N HCl,用乙酸乙酯萃取此混合物。有机层用水、5% NaHCO3及饱和盐水洗涤,然后用MgSO4干燥。真空下干燥得粗品。粗品用SiO2进行色谱提纯,以5%乙酸乙酯/己烷洗脱产物。LC/MS分析:计算的分子量459;实测值M+1 460,RT3.45分钟。
制备R-2-壬基-琥珀酸4-叔丁酯(4)。将7.9克(17.2毫摩尔)产物(3)在175毫升THF中的溶液冷至0℃,逐滴加入9毫升30%过氧化氢(80毫摩尔)及1.24克(29.5毫摩尔)氢氧化锂一水合物溶在50毫升水中的溶液。然后把此混合物在室温搅拌2小时,冷至0℃,加入5.2克(75毫摩尔)亚硝酸钠。30分钟后,把此混合物在真空下浓缩,并加入更多的水。用乙醚洗涤此碱性溶液,用12N HCl调整pH至2.5,并用EtOAc萃取3次,把此有机溶液用MgSO4干燥,并在真空下浓缩,得到产物,此产物具有所希望的NMR谱图。LC/MS分析:计算的分子量300;实测值:m+1 301,RT 2.90分钟。
制备N-[叔丁基-2(R)-壬基琥珀酸]-L-苯基甘氨酸-N-甲基酰胺(5)。将L-苯基甘氨酸-N-甲基酰胺(7.25克,44.2毫摩尔)及产物(4)(13.27克,44.2毫摩尔)在125毫升DMF中的溶液用EDC-HCl(8.47克,44.2毫摩尔)进行处理,并搅拌48小时。用EtOAc将此反应混合物稀释,并用0.5N HCl、水、饱和NaHCO3及饱和盐水洗涤。用MgSO4干燥,浓缩。所得产物用色谱法(SiO2,用30% EtOAc/乙烷洗脱)提纯。LC/MS分析:计算的分子量:446;实测值M+1 447,RT 3.02分钟。
制备N-[2(R)-壬基琥珀酸]-L-苯基甘氨酸-N-甲基酰胺(6)。将产物(5)(10.36克,23.2毫摩尔)在80毫升90% TFA中的溶液搅拌2.5小时,然后在真空下浓缩。残留物与EtOAc一起研磨,然后在真空下浓缩。加入CH3CN,得到结晶,将它收集并用新鲜的CH3CN洗涤。将合并的母液和洗出液在真空下浓缩,并把残留物溶在EtOAc中,用水洗,用MgSO4干燥,并在真空下干燥,得到第二批产物。往残留物中加入CH3CN得另外的结晶,把它与第一批产物合并,得到无色结晶,mp156-158℃。LC/MS分析:计算的分子量390;实测值M+1 391,RT 2.17分钟。元素分析:计算值:C,67.66;H,8.78;N,7.17。实测值:C,67.87;H,9.16;N,7.15。
实施例2在聚苯乙烯树脂上制备的N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-3-(N-吗啉代)
丙基酰胺
树脂的还原胺化
在一个大的摇动容器中,将(4-甲酰基-3,5-二甲氧基苯氧基)甲基聚苯乙烯树脂(产自Polymer Laboratories),1.82毫摩尔/克,10克)悬浮在N-甲基吡咯烷酮(100毫升)与乙酸(25毫升)的混合物中。加入N-3-氨丙基吗啉(0.1摩尔),把此混合物在室温摇动1小时。然后将在N-甲基吡咯烷(50毫升)中的三乙氧硼氢化钠(0.05摩尔)加入,并把此混合物在室温下摇动过夜。随后滤出树脂,用1∶1DMF/水洗涤(3次),用DMF洗涤(3次),用二氯甲烷洗涤(4次)。
Fmoc氨基酸的偶合
把已还原胺化的树脂(50毫克)悬浮在1毫升N-甲基吡咯烷酮中。往其中加入(S)-Fmoc苯丙氨酸(0.25毫摩尔),1-羟基-7-氮杂苯并三氮唑(0.25毫摩尔)及二异丙基碳二亚胺(0.25毫摩尔)。将此反应混合物在室温下摇动过夜,过滤,用DMF洗涤(4次),并把偶合重复一次。把树脂滤出,用DMF洗涤(4次),用二氯甲烷洗涤(4次)。
除去FMOC基
把由上步得到的产物用溶在DMF之中的20%哌啶(1.5毫升)处理并搅拌1小时。用DMF把此树脂洗涤(4次)。
R-2-壬基琥珀酸4-叔丁酯的偶合
把由上步得到的产物悬浮在N-甲基吡咯烷酮(1毫升)中。往其中加入R-2-壬基琥珀酸4-叔丁酯(0.25毫摩尔),1-羟基-7-氮杂苯并三唑(0.25毫摩尔)及二异丙基碳二亚胺(0.25毫摩尔。把此反应混合物在室温摇动16小时,过滤,将些树脂用DMF洗涤(4次),用甲醇洗涤(4次),及用二氯甲烷洗涤(4次)。
TFA裂解生成N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-3-(N-吗啉代)丙基酰胺(12)。
将从上面步骤获得的树脂用三氟乙酸(1.5毫升)处理并搅拌8小时,过滤,用二氯甲烷洗涤。把合并的滤液浓缩,并用自动制备型HPLC进行提纯和在真空离心中进行浓缩。当用LC/MS分析时,残留物的分子量为517。
加入本发明化合物的药用制剂可制成各种形式。
这类制剂的例子如下。
实施例3
吸入剂
将通式(I)或(II)的化合物(1毫克~100毫克)由计量剂量吸入器气溶胶化,为每次使用送上所需量的药物。
实施例4
片剂配方
片剂/成分 每片
1.活性成分(通式I或II的化合物) 40毫克
2.玉米淀粉 20毫克
3.藻酸 20毫克
4.藻酸钠 20毫克
5.硬脂酸镁 1.3毫克
片剂的制法
在合适的混合器/掺混器中,将组份1、2、3及4掺混。在加入每一组份后,在仔细混合下一份份地加入足量水,直到这些物质达到能转变为湿粒的稠度。使用8号目(2.38毫米)筛,让此湿物料通过振荡成粒机使它变为颗粒。然后将此湿颗粒在140°F(60℃)的炉子中烘烤直至干燥为止。用组份5使干颗粒润滑,并把此已润滑的颗粒在合适的压片机上进行挤压。
实施例5
胃肠外用制剂
在加热下将合适数量的通式(I)或(II)化合物溶于聚乙二醇中,制得胃肠外用的药物组合物。随后将此溶液用水稀释,制备ph Eur注射液(至100毫升)。然后把此溶液过滤通过0.22微米的膜滤器使之变成无菌的,并封入消毒容器中。
所有出版物,包括但不限于本说明书中所引用的专利和专利申请,在这里被引用作参考文献,就象前面特别和单独指出的那样将每一单独出版收作参考文献。
Claims (6)
2.根据权利要求1的化合物,它选自下列化合物:
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-2-(N-吗啉代)乙基酰胺;
N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-3-(N-吗啉代)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-缬氨酸-N-2-(N-吗啉代)乙基酰胺;
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-(4-甲氧基苯基)酰胺;
N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-(4-甲氧基苯基)酰胺;
N-[2(R)-壬基琥珀酸]-L-正缬氨酸-N-(4-甲氧基苯基)酰胺;
N-[2(R)-壬基琥珀酸]-L-精氨酸-N-(4-甲氧基苯基)酰胺;
N-[2(R)-壬基琥珀酸]-L-苯基甘氨酸-N-甲基酰胺;
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-环戊基酰胺;以及
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-3-二甲氨基丙基酰胺。
3.根据权利要求1的化合物,它选自下列化合物:
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-(2-吗啉磺酰氨基)乙基酰胺;
N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-(2-吗啉磺酰氨基)乙基酰胺;
N-[2(R)-壬基琥珀酸]-L-缬氨酸-N-(2-吗啉磺酰氨基)乙基酰胺;
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-(3-吗啉磺酰氨基)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-(3-吗啉磺酰氨基)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-缬氨酸-N-(3-吗啉磺酰氨基)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-苯甘氨酸-N-(3-吗啉磺酰氨基)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-苯甘氨酸-N-(2-吗啉磺酰氨基)乙基酰胺。
4.一种通过给药根据权利要求1的MMP-2/MMP-9抑制剂治疗疼痛的方法。
5.根据权利要求4的方法,其中此化合物选自下列化合物:
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-3-(N-吗啉代)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-苯甘氨酸-N-3-(N-吗啉代)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-亮氨酸-N-3-(N-吗啉代)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-蛋氨酸-N-3-(N-吗啉代)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-2-(N-吗啉代)乙基酰胺;
N-[2(R)-壬基琥珀酸]-L-苯丙氨酸-N-3-(N-吗啉代)丙基酰胺;
N-[2(R)-壬基琥珀酸]-L-缬氨酸-N-2-(N-吗啉代)乙基酰胺;
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-(4-甲氧基苯基)酰胺;
N-[2(R)-壬基琥珀酸]-L-苯基丙氨酸-N-(4-甲氧基苯基)酰胺;
N-[2(R)-壬基琥珀酸]-L-正缬氨酸-N-(4-甲氧基苯基)酰胺;
N-[2(R)-壬基琥珀酸]-L-精氨酸-N-(4-甲氧基苯基)酰胺;
N-[2(R)-壬基琥珀酸]-L-苯基甘氨酸-N-甲基酰胺;
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-环戊基酰胺;以及
N-[2(R)-壬基琥珀酸]-L-酪氨酸-N-3-二甲氨基丙基酰胺。
6.根据权利要求5的方法,其中所治疗的疾病选自下列疾病:中风;出血;再灌注损伤;脑局部缺血;脑梗塞;对疼痛的高的或超常敏感如痛觉过敏、灼痛和异常性疼痛;急性疼痛;灼烧痛;典型的面部痛;神经病痛;背痛;复杂的局部疼痛综合症I和II;关节炎痛;运动损伤痛;涉及病毒如HIV感染的疼痛、脊髓灰质炎后综合症及疱疹后神经痛;幻象肢痛;分娩痛;癌痛;化疗后痛;中风后痛;手术后痛;生理性痛;炎症痛;急性炎症/内脏痛例如咽痛、应激性肠综合症(IBS)及炎性肠疾病;神经病痛;神经痛;疼痛性糖尿病神经病;创伤神经痛;脊索损伤;以及对麻醉药的耐受性或从麻醉药的病理性退隐。
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CN102325768A (zh) * | 2008-12-23 | 2012-01-18 | 阿奎卢斯制药公司 | 治疗疼痛和其他疾病的化合物和方法 |
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US7354955B2 (en) * | 2004-01-07 | 2008-04-08 | Abbott Laboratories | (2S)-amino(phenyl)acetic acid and derivatives as α2δ voltage-gated calcium channel ligands |
EP1871420A4 (en) * | 2005-04-15 | 2010-09-22 | Univ North Carolina | PROCESS FOR ENABLING CELL SURVIVAL VIA NEUROTROPHINE MIMETICS |
US8147836B2 (en) | 2007-12-17 | 2012-04-03 | Dyax Corp. | Compositions and methods for treating osteolytic disorders comprising MMP-14 binding proteins |
JP2011517662A (ja) | 2008-03-03 | 2011-06-16 | ダイアックス コーポレーション | メタロプロテアーゼ9結合タンパク質 |
CA2717803A1 (en) * | 2008-03-03 | 2009-09-11 | Dyax Corp. | Metalloproteinase 9 and metalloproteinase 2 binding proteins |
AU2010319349B2 (en) | 2009-11-12 | 2015-07-16 | Pharmatrophix, Inc. | Crystalline forms of neurotrophin mimetic compounds and their salts |
US10273219B2 (en) | 2009-11-12 | 2019-04-30 | Pharmatrophix, Inc. | Crystalline forms of neurotrophin mimetic compounds and their salts |
EP2681209B1 (en) * | 2011-03-02 | 2018-05-09 | Aquilus Pharmaceuticals, Inc | Compounds and methods for the treatment of pain and other disorders |
US10314909B2 (en) | 2011-10-21 | 2019-06-11 | Dyax Corp. | Combination therapy comprising an MMP-14 binding protein |
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DE69529100T2 (de) * | 1994-01-22 | 2003-07-17 | British Biotech Pharm | Metalloproteinaseinhibitoren |
EP0763012B1 (en) * | 1994-05-28 | 1999-06-09 | British Biotech Pharmaceuticals Limited | Succinyl hydroxamic acid, n-formyl-n-hydroxy amino carboxylic acid and succinic acid amide derivatives as metalloprotease inhibitors |
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DE69632821T2 (de) * | 1995-04-25 | 2005-08-25 | Daiichi Fine Chemical Co., Ltd., Takaoka | In wasser hochlöslicher metalloproteinase-inhibitor |
ATE205184T1 (de) * | 1995-11-23 | 2001-09-15 | British Biotech Pharm | Metalloproteinase inhibitoren |
AUPO048296A0 (en) * | 1996-06-14 | 1996-07-11 | Fujisawa Pharmaceutical Co., Ltd. | New compound and its preparation |
WO2001026671A1 (en) * | 1999-10-12 | 2001-04-19 | Smithkline Beecham Corporation | Methods of treatment using dual matrix-metalloproteinase-2 and matrix metalloproteinase-9 inhibitors |
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HUP0302316A2 (hu) | 2003-11-28 |
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