CN1642973A - 治疗变态反应的方法 - Google Patents
治疗变态反应的方法 Download PDFInfo
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- CN1642973A CN1642973A CNA018183867A CN01818386A CN1642973A CN 1642973 A CN1642973 A CN 1642973A CN A018183867 A CNA018183867 A CN A018183867A CN 01818386 A CN01818386 A CN 01818386A CN 1642973 A CN1642973 A CN 1642973A
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Abstract
组织蛋白酶S抑制剂用于治疗变应性病症,特别是特异反应性变应性病症的用途,更具体地讲用于治疗枯草热、哮喘、特应性皮炎或食物变态反应。
Description
技术领域
本发明涉及组织蛋白酶S抑制剂用于治疗变应性病症,特别是特异反应性变应性病症的用途。
背景技术
在发达国家特应性变态反应使至少20%的人口遭受痛苦,其中包括了范围很广的IgE-介导的疾病枯草热,哮喘,特应性皮炎,及食物变态反应。过敏体质的患者接触相应的变应原,造成变应原特异性IgE结合肥大细胞,引发脱粒和促炎性介体如组胺和廿烷类的释放,其在皮试中引起条痕和潮红反应。其特征在于,此早期反应后产生长时间的晚期反应,其中炎性细胞,特别是噬酸性细胞和激活的TH-2 CD4 T细胞,募集到接触变应原的部位。TH-2细胞产生的炎性细胞因子如IL-4和IL-5,分别对B细胞产生IgE和嗜酸细胞增多发挥重要作用。已表明在降低IgE产生、促炎性细胞活化及炎性介体释放方面,靶向CD4 T细胞的免疫治疗是有效的。
目前,靶向CD4 T细胞的变态反应治疗在多方面获得了成功。用变应原提取物或疫苗脱敏对很多变应原来说是有效的,如膜翅目昆虫叮咬,其可能引起危及生命的变态反应。其机理可能是诱导T细胞耐受性或TH-2向TH-1的转变。但是,该治疗需要长期的治疗方案、频繁的医生随访及用其它药物治疗先稳定病情,并与某些发病率和罕见的死亡有关。或者,免疫抑制性药物如有效稳定进行性变态反应的甾类化合物,常常带来严重的副作用。
在变态反应的引发和维持中,CD4 T细胞的活化是主要的因素。特定的抗原呈递细胞(APC)如树状突细胞和B细胞吸收变应原。蛋白变应原通过核内体或溶酶体系统,在其中它们被不同的蛋白酶降解。这些肽片断被II类MHC结合,在该细胞表面其是由两种跨膜糖蛋白链(α和β)组成的杂三聚体,其形成第三种组分一11-20个氨基酸的肽的结合位点。抗原-II类MHC分子复合物被CD4 T细胞识别并导致T细胞活化。活化的T细胞依次激活免疫系统中若干其它组分,如B细胞和巨噬细胞,它们对机体对病原体的反应是至关重要的,但是它们同时也导致变态反应症状。
象其它跨膜蛋白一样,II类分子合成后易位到内质网(ER),在其中它们与第三种蛋白恒定链(li)结合。该恒定链分钟是II型跨膜蛋白,它作为II型特异性伴侣蛋白,促进从ER中脱出II类-li复合物,并防止II类分子结合ER和分泌路径中的肽和未折蛋白。li的细胞质尾部中靶向基元引导II类-li复合物从分泌路径进入核内体系统。
在II类MHC分钟可以呈递抗原前,li必须被破坏li的一系列蛋白酶除去。所得li肽片断,称为与II类相结合的恒定链肽(CLIP),占据II类分子的肽结合沟,且在大多数情况下不是自发地释放。在细胞内转运期间以及li在核内体系统中降解后,CLIP保护II类结合袋,防止其降解。结合产生自胞吞的蛋白的抗原性肽,需要空的、且仍开放的结合位点。因此,当稳定开放的结合位点以允许其它肽结合的同时,CLIP必须释放。人白细胞抗原-DM(“HLA-DM”)介导同时这些功能,于是促进抗原肽的结合。获得肽后,II类分子通过很大程度上未知的途经转运到细胞表面。
综上所述,恒定链蛋白水解作用的抑制会防止li从II类结合袋中除去,其随后特异性阻断抗原与II类MHC分子的结合。
组织蛋白酶S(“CatS”)是在淋巴组织中表达的半胱胺酸蛋白酶。CatS介导恒定链蛋白水解,其是肽负荷II类MHC分子的先决条件(Riese等,(1996)Immunity 4:357)。CatS与组织蛋白酶L和K具有50-60%的同源性,但是不同的是其具有延伸至碱性pH值的宽范围的pH最佳值。CatS调节动物模型中抗原呈递,而其抑制剂在哮喘模型中有效(Riese等,(1998)J.Clin.Invest.101:2351)。缺乏组织蛋白酶S小鼠的由专门抗原呈递细胞呈递外源性蛋白的能力受到损害(Nakagawa等,(1999)Immunity 10:207;Shi等,(1999)Immunity 10:197)。
预计抑制人组织蛋白酶S的蛋白水解活性的化合物可用于治疗慢性自身免疫性疾病,包括但不限于狼疮和类风湿先关节炎;并在调节对组织移植产生的免疫反应方面具有潜在的用途。用调节组织蛋白酶S活性(如将li链蛋白水解)的试剂调节自身免疫性的方法,以及治疗自身免疫性疾病患者的方法,评价某种疗法调节免疫反应的能力的方法描述于WO 99/58153。
发明概述
本发明涉及组织蛋白酶S抑制剂治疗变应性病症,包括但不限于特应性变态反应的用途。变应性病症的实例包括枯草热、哮喘、特应性皮炎和食物变态反应。变应原包括粉尘、花粉、霉菌及宠物皮屑或宠物毛发。
一方面,本发明提供了治疗变应性病症患者,特别是特异反应性变应性病症的方法,所述方法包括给所述患者使用治疗有效量的含有组织蛋白酶S抑制剂的药物组合物。
另一方面,本发明提供了治疗IgE-介导的变应性病症患者,特别是特异反应性变应性病症患者的方法,所述方法包括给所述患者使用治疗有效量的含有组织蛋白酶S抑制剂的药物组合物。
本发明的第三方面提供了制备组织蛋白酶抑制剂的药物的用途,该药物用于治疗变应性病症,更特别是治疗IgE-介导的变应性病症,尤其特别是治疗枯草热、哮喘、特应性皮炎或食物变态反应。
本发明还涉及抗变态反应的药物组合物,其中含有有效量的组织蛋白酶S抑制剂作为活性组分,以及药用载体。该活性组分可以以适于特定变应性病症的任何方式进行配制,包括气雾剂、口服和局部制剂以及时间释放制剂。
组织蛋白酶S抑制剂是本领域已知的;或者,它们可以用本领域已知方法进行鉴定,如下文实施例1描述的组织蛋白酶S抑制试验。
从以下发明详述及实施例,以及权利要求中,本发明的其它特征和优点是显而易见的。
附图简述
附图1显示了对两类尘螨Derp和Der f产生的人T细胞增殖反应的抑制。上图1A:得自变态反应供者的纯化PBMC与滴定剂量的由Derp和Der f制备的变应原提取物培养7天的稀释度曲线。通过在培养结束时检测18小时3H-胸苷的掺入进行T细胞增殖评分。下图1B:滴定剂量的LHVS对尘螨提取物的T细胞增殖反应的作用。
附图2显示了LHVS对豚草而不是ConA产生的人T细胞增殖反应的抑制。上图2A:得自变态反应供者的纯化PBMC与滴定剂量的由小豚草(Ragweed short)和大豚草(Ragweed giant)制备的变应原提取物培养7天的稀释度曲线。通过在培养结束时检测18小时3H-胸苷的掺入进行T细胞增殖评分。下图2B:滴定剂量的LHVS对豚草提取物的T细胞增殖反应的作用。
发明详述
本发明的目的是确定组织蛋白酶S的抑制是否会影响人系统中特定抗原的呈递。按照本发明,现已发现在人活体外试验中组织蛋白酶抑制剂阻断若干粗变应原提取物的呈递,于是支持了组织蛋白酶S抑制剂用于治疗此类变应性病症的用途。
阻断li降解将降低抗原向CD4 T细胞的呈递并中断正常的免疫反应。组织蛋白酶S抑制剂将特异性地影响CD4 T细胞的活化,因此限制伴发的免疫抑制(皮质类固醇治疗的不良副作用)的程度。
按照本发明方法通过使用组织蛋白酶S抑制剂,变态反应的免疫成分可以阻断到不同的程度,较目前的疗法具有选择性更强、副作用较少或减轻(或兼而有之)的优点。某种程度上讲,本发明是基于活体外试验中组织蛋白酶S抑制剂可以阻断粗变应原提取物的呈递这一发现。该活体外系统非常接近地模拟了人体中发生的过程:抗原进入血液,并由抗原呈递细胞呈递,其依次激活CD4 T细胞。在患者的治疗过程中,该抑制剂或其代谢物也会象活体外试验中那样存在于血液中。
A.术语
下列术语定义如下并在整个公开文本中使用。
“烷基”包括任选地被取代的直链或支链烃,其中除去至少一个氢原子以形成一个基团。烷基包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、1-甲基丙基、戊基、异戊基、仲戊基、己基、庚基、辛基等。烷基包括环烷基,如环丙基、环丁基、环戊基及环己基。
“链烯基”包括具有至少一个碳碳双键(sp2)的如上所述的任选地被取代的直链或支链烃基团。链烯基包括乙烯基(或乙烯基),丙-1-烯基,丙-2-烯基(或烯丙基),异丙烯基(或1-甲基乙烯基),丁-1-烯基,丁-2-烯基,丁间二烯基,2-戊烯基,己-2,4-二烯基等。同时具有双键和三键的烃基团如2-戊烯基-4-炔基,在本文中归类为链炔基。链烯基包括环链烯基。顺式和反式或者(E)和(Z)构型包括在本发明中。
“链炔基”包括具有至少一个碳碳三键(sp)的如上所述的任选地被取代的直链或支链烃基团。链炔基包括乙炔基、丙炔基、丁炔基及戊炔基。同时具有双键和三键的烃基团如2-戊烯基-4-炔基,在本文中归类为链炔基。链炔基不包括环链炔基。
“烷氧基”包括通过一个末端氧原子连接烷基和分子的其余部分的任选地被取代的直链或支链烷基。烷氧基包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基等。“氨基烷基”、“烷硫基”和“磺酰基烷基”类似于烷氧基,分别将烷氧基的末端氧原子替换为NH(或NR)、S及SO2。杂烷基包括烷氧基、氨基烷基、烷硫基等。
“芳基”包括苯基、萘基、联苯基、四氢萘基等,其中任何一个都可以任选地被取代。芳基还包括芳基烷基如苄基、苯乙基及苯基丙基。芳基包括含一个任选地被取代的6-员碳环芳环的环系,所述环系可以是双环、桥环和/或稠环。该环系可以包括芳香、或部分或完全不饱和的环。环系的实例包括茚基、戊搭烯基、1,4-二氢萘基、二氢茚基、苯并咪唑基、苯并噻吩基、吲哚基、苯并呋喃基、异喹啉基等。
“杂环基”包括任选地被取代的环内具有碳原子和至少一个杂原子(O、S、N)或杂原子部分(SO2、CO、CONH、COO)的芳环或非芳环。除非另行说明,杂环基团可以具有一个化合价通过碳原子连接它和该分子的其余部分,如3-呋喃基或2-咪唑基,或通过一个杂原子连接,如N-哌啶基或1-吡唑基。优选单环杂环基具有4至7个环原子,或5至6个环原子;在该环内可以含有1至5个杂原子或杂原子部分,并优选1至3个。杂环基可以是饱和的、不饱和的、芳族(例如,杂芳基)、非芳族的或稠合的。
杂环基还包括稠合的,例如,双环,如任选地与任选地被取代的碳环或杂环5或6员芳环稠合的环。例如,“杂芳基”包括含1、2或3个氮原子的,与一个任选地被取代的5或6员碳环或杂环芳环稠合的,任选地被取代的6员芳杂环。与所述5或6员芳环稠合的所述杂环5或6员芳环,当其是6员环时,可以含有1、2或3个氮原子,当其是5员环时,可以含有1、2或3个选自氧原子、氮原子和硫原子的杂原子。
杂环基的实例包括噻唑基、呋喃基、吡喃基、异苯并呋喃基、吡咯基、咪唑基、吡唑基、异噻唑基、异噁唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚嗪基、异吲哚基、吲哚基、吲唑基、嘌呤基、喹啉基、呋咱基、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、二氢吲哚基及吗啉基。例如,优选的杂环基或杂环基团包括吗啉基、哌嗪基、吡咯烷基、吡啶基、环己基亚氨基、环庚基亚氨基,并更优选哌啶基。
杂芳基的实例为噻吩基、呋喃基、吡咯基、咪唑基、噁唑基、噻唑基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并噻唑基。
“酰基”指连接氢原子的羰基(即甲酰基)或连接任选地被取代的烷基或链烯基链、或杂环基的羰基。
“卤素”或“卤原子”包括氟、氯、溴及碘,并优选氯或溴作为取代基。
“烷二基”或“亚烷基”表示直链或支链的任选地被取代的二价烷基,如亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或亚己基。
类似地,“链烯二基”表示直链或支链的任选地被取代的二价链烯基,例如,亚丙烯基、亚丁烯基、亚戊烯基或亚己烯基。在此类基团中,连接氮原子的碳原子优选不是不饱和的。
“芳酰基”指连接任选地被取代的芳基或杂芳基的羰基部分,其中芳基及杂芳基定义如上。具体地讲,苯甲酰基是苯基羰基。
如本文中所定义,两个基团与它们连接的原子(一个或多个)一起可以形成任选地被取代的4至7、5至7或5至6员碳环或杂环,该环可以是饱和的、不饱和的或芳香的。所述环可以如发明概述部分所定义。此类环的实例见下一部分。
“药用盐、酯和酰胺”包括羧酸盐(例如,C1-8烷基、环烷基、芳基、杂芳基或非芳族杂环)、氨基酸加成盐、酯和酰胺,它们效益/风险比、药学有效性在合理的范围内,并适于与患者的组织接触而不引起不适当的毒性、刺激性和变态反应。代表性盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、桔橼酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡萄庚糖酸盐、乳二酸盐(lactiobionate)及十二烷基磺酸盐。这些可以包括碱金属和碱土金属阳离子如钠离子、钾离子、钙离子和镁离子,以及无毒铵离子、季铵离子和胺阳离子如四甲基铵、甲胺、三甲基胺和乙胺。例如,见S.M.Berge等,“药用盐”,J.Pharm.Sci.,1977,66:1-19,将其引入本文作为参考。本发明的代表性药用酰胺包括得自氨、伯C1-6烷基胺和仲二(C1-6烷基)胺的。仲胺包括含有至少一个氮原子及任选地存在的1至2个其它杂原子的5或6员杂环或芳杂环部分。优选的酰胺得自氨、C1-3烷基伯胺及二(C1-2烷基)胺。本发明的代表性的药用酯包括C1-7烷基、C5-7环烷基、苯基及苯基(C1-6)烷基酯。优选的酯包括甲酯。
“患者”或“对象”包括需要观察、试验、治疗或预防相关疾病或病症的哺乳动物如人和动物(狗、猫、马、大鼠、兔、小鼠、非人类灵长类)。优选该患者或对象是人。
“组合物”包括含有特定量的特定组分的产品,以及特定量的特定组分联合后直接或间接得到的任何产品。
“治疗有效量”或“有效量”指得出研究者、兽医、医生或其它临床医师要得到的组织系统、动物或人中的生物或治疗反应的活性化合物或药剂的量,这些反应包括所治疗的变态反应疾病或紊乱的症状的减轻。
关于本说明书和权利要求书中不同基团,给出三个总的说明。第一个说明涉及化合价。对于所有烃基团,不论饱和的、不饱和的或芳香性的,不论环的、支链的或支链的,对于所有杂环基团情况类似,各基团包括该类基团的被取代的基团,以及单价、二价及多价基团,如权利要求书中所示。该文本中会指出取代基是至少两个氢原子被除去(二价)或者多个氢原子被除去(多价)的亚烷基或烃。连接该分子两个部分的二价基团的实例为式(I)中的G,其连接两个环。
其次,本文中定义的基团或结构片断理解为包括被取代的基团或结构片断。烃基包括含碳原子和氢原子的单价基团如烷基、链烯基、链炔基、环烷基及环链烯基(不论是芳香性的还是不饱和的),以及相应的二价基团如亚烷基、亚链烯基、亚苯基等。杂烃基包括含碳原子、氢原子及至少一个杂原子的单价和二价杂烃基。单价杂烃基的实例包括酰基、酰氧基、烷氧基酰基、杂环基、杂芳基、芳酰基、苯甲酰基、二烷基氨基、羟基烷基等。用“烷基”作为实例来说,“烷基”应理解为包括被取代的烷基,其具有一个或多个取代,如1至5个,1至3个,或2至4个取代基。取代基可以相同(二羟基,二甲基),相似(氯氟),或不同(氯苄基-或氨基甲基-取代)。被取代的烷基的实例包括卤素烷基(如氟甲基、氯甲基、二氟甲基、全氯甲基、2-溴乙基、全氟代甲基及3-碘环戊基),羟基烷基(如羟基甲基、羟基乙基、2-羟基丙基,氨基烷基(如氨基甲基、2-氨基乙基、3-氨基丙基及2-氨基丙基),硝基烷基,烷基烷基等。二(C1-6烷基)氨基包括独立地选择的烷基,以形成,例如,甲基丙基氨基和异丙基甲基氨基,还有带有相同烷基的二烷基氨基如二甲基氨基或二乙基氨基。
第三,只包括稳定的化合物。例如,存在NR′R″基团,且R是一链烯基时,双键与氮原子至少相隔一个碳原子以避免烯胺的形成。类似地,当虚线是一个任选的sp2键时,如果其不存在,则要加上适当的氢原子(一个或多个)。
在下部分中进一步描述本发明化合物。
B.化合物
本发明涉及用概述部分中描述的一种或多种组织蛋白酶S抑制剂治疗变应性病症。
用于本发明方法中的适宜的组织蛋白酶S抑制性化合物本领域已公开的化合物或者通过本领域已知方法(见下文中的实施例1)发现其可以作为CatS抑制剂的化合物。用于本发明方法中的适宜的化合物的实例包括(a)Altmann等在WO-99/24460中描述的二肽基腈类(Novartis);(b)Palmer等在US5976858(转让给Arris(现Axys))描述的二肽基乙烯基砜类,其作为半胱胺酸蛋白酶抑制剂,包括组织蛋白酶S抑制剂,并特别是吗啉脲-亮氨酸-高苯丙氨酸-乙烯基砜苯基(“LHVS”),也称为4-吗啉甲酰胺,N-[(1S)-3-甲基-1-[[[(1S,2E)-1-(2-苯基乙基)-3-(苯基磺酰基)-2-丙-烯基]氨基]羰基]丁基]-;(c)Palmer等在US5776718(也转让给Arris/Axys)描述的肽基磺酰胺类;(d)Klaus等在US6030946中描述的化合物,作为半胱胺酸蛋白酶抑制剂,包括组织蛋白酶S抑制剂。前者转让给Arris(现Axys),后者转让给Axys;及(e)WO 99/58153中描述的组织蛋白酶S抑制剂类。上述所有5篇专利或专利申请提供了如何制备公开的化合物,并公开如何检测它们的蛋白酶和/或CatS抑制活性。这些专利或专利申请整体引入本文作为参考。
相关化合物
本发明提供了公开的化合物以及与这些公开的化合物密切相关的药用形式,如其盐、酯、酰胺、酸、水合物或溶剂化物;经掩蔽或保护的形式;以及外消旋混合物,或对映体纯或光学纯的形式。相关化合物还包括为了检测而进行修饰的本发明化合物,例如,用18F同位素标记以用作正电子发射断层显象(PET)或单光子发射计算机化断层显象(SPECT)中的探针。
本发明还包括一个或多个官能基(如羟基、氨基或羧基)被保护基掩蔽的公开化合物。例如,见Greene and Wuts,Protective Groupsin Organic Synthesis,第3版,(1999)John Wiley & Sons,NY。这些被掩蔽或保护的化合物中的一些是可药用的;其它将用作中间体。本文中公开的中间体和方法及其较小的改进也包括在本发明的范围内。
羟基保护基
羟基保护基包括甲基醚,被取代的甲基醚,被取代的乙基醚,被取代的苄基醚及甲硅烷基醚。
被取代的甲基醚
被取代的甲基醚的实例包括甲氧基甲基、甲硫基甲基、叔丁硫基甲基,(苯基二甲基甲硅烷基)甲氧基甲基,苄氧基甲基,对甲氧基苄氧基甲基,(4-甲氧基苯氧基)甲基,甲基邻苯二酚基甲基,叔丁氧基甲基,4-戊烯基氧基甲基,甲硅烷氧基甲基,2-甲氧基乙氧基甲基,2,2,2-三氯乙氧基甲基,双(2-氯乙氧基)甲基,2-(三甲基甲硅烷基)乙氧基甲基,四氢吡喃基,3-溴四氢吡喃基,四氢噻喃基,1-甲氧基环己基,4-甲氧基四氢吡喃基,4-甲氧基四氢噻喃基,4-甲氧基四氢噻喃基S,S-二氧化物,1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基,1,4-二噁烷-2-基,四氢呋喃基,四氢噻吩基及2,3,3a,4,5,6,7,7a-八氢-7,8,8-三甲基-4,7-桥亚甲基苯并呋喃-2-基。
被取代的乙基醚
被取代的乙基醚的实例包括1-乙氧基乙基,1-(2-氯乙氧基)乙基,1-甲基-1-甲氧基乙基,1-甲基-1-苄氧基乙基,1-甲基-1-苄氧基-2-氟乙基,2,2,2-三氯乙基,2-三甲基甲硅烷基乙基,2-(苯基氢硒基)乙基,叔丁基,烯丙基,对氯苯基,对甲氧基苯基,2,4-二硝基苯基及苄基。
被取代的苄基醚
被取代的苄基醚的实例包括对甲氧基苄基,3,4-二甲氧基苄基,邻硝基苄基,对硝基苄基,对卤代苄基,2,6-二氯苄基,对氰基苄基,对苯基苄基,2-和4-甲基吡啶基,3-甲基-2-甲基吡啶基N-氧化物,二苯基甲基,p,p′-二硝基二苯甲基,5-二苯并环庚基,三苯基甲基,α-萘基二苯基甲基,对甲氧基苯基二苯基甲基,二(对甲氧基苯基)苯基甲基,三(对甲氧基苯基)甲基,4-(4′-溴苯酰氧基)苯基二苯基甲基,4,4′,4″-三(4,5-二氯苯二酰亚氨基苯基)甲基,4,4′,4″-三(乙酰丙酰氧基苯基)甲基,4,4′,4″-三(苯甲酰氧基苯基)甲基,3-(咪唑-1-基甲基)双(4′,4″-二甲氧基苯基)甲基,1,1-双(4-甲氧基苯基)-1′-芘基甲基,9-蒽基,9-(9-苯基)夹氧蒽基,9-(9-苯基-10-氧代基团)蒽基,1,3-苯并二硫杂环戊烷-2-基及苯并异噻唑基S,S-二氧化物。
甲硅烷基醚
甲硅烷基醚的实例包括三甲基甲硅烷基,三乙基甲硅烷基,三异丙基甲硅烷基,二甲基异丙基甲硅烷基,二乙基异丙基甲硅烷基,二甲基己基甲硅烷基,叔丁基二甲基甲硅烷基,叔丁基二苯基甲硅烷基,三苄基甲硅烷基,三对二甲苯基甲硅烷基,三苯基甲硅烷基,二苯基甲基甲硅烷基及叔丁基甲氧基苯基甲硅烷基。
酯
除了醚,羟基可以以酯的形式加以保护。
酯的实例包括甲酸酯,苯甲酰基甲酸酯,乙酸酯,氯乙酸酯,二氯乙酸酯,三氯乙酸酯,三氟乙酸酯,甲氧基乙酸酯,三苯基甲氧基乙酸酯,苯氧基乙酸酯,对氯苯氧基乙酸酯,对-P-苯基乙酸酯,3-苯基丙酸酯,4-氧代戊酸酯(乙酰丙酸酯),4,4-(亚乙基二硫)戊酸酯,新戊酸酯,金刚烷酸酯,巴豆酸酯,4-甲氧基巴豆酸酯,苯甲酸酯,对苯基苯甲酸酯,2,4,6-三甲基苯甲酸酯(间三甲基苯甲酸酯)
碳酸酯
碳酸酯保护基的实例包括甲基,9-芴基甲基,乙基,2,2,2-三氯乙基,2-(三甲基甲硅烷基)乙基,2-(苯基磺酰基)乙基,2-(三苯基磷翁基)乙基,异丁基,乙烯基,烯丙基,对硝基苯基,苄基,对甲氧基苄基,3,4-二甲氧基苄基,邻硝基苄基,对硝基苄基,S-苄硫基碳酸酯,4-乙氧基-1-萘基及甲基二硫碳酸酯。
协助裂解
协助裂解的实例包括2-碘苯甲酸酯,4-叠氮基丁酸酯,4-硝基-4-甲基戊酸酯,邻(二溴甲基)苯甲酸酯,2-甲酰基苯磺酸酯,2-(甲硫基甲氧基)乙基碳酸酯,4(甲硫基甲氧基)丁酸酯及2-(甲硫基甲氧基甲基)苯甲酸酯。
各种酯
各种酯的实例包括2,6-二氯-4-甲基苯氧基乙酸酯,2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯,2,4-双(1,1-二甲基丙基)苯氧基乙酸酯,氯二苯基乙酸酯,异丁酸酯,单琥珀酸酯,(E)-2-甲基-2-丁烯酸酯(惕各酸酯),邻(甲氧基羰基)苯甲酸酯,对苯甲酸酯,α-萘甲酸酯,硝酸酯,烷基N,N,N′,N′-四甲基二氨基磷酸酯,N-苯基氨基甲酸酯,硼酸酯,二甲基硫膦基及2,4-二硝基苯基次磺酸酯。
磺酸酯
磺酸酯的实例包括硫酸酯,甲磺酸酯(mesylate),苄基磺酸酯及甲苯磺酸酯。
氨基保护基
氨基基团的保护包括氨基甲酸酯、酰胺及特殊的-NH保护基。
氨基甲酸酯的实例包括甲基和乙基氨基甲酸酯,被取代的乙基氨基甲酸酯,协助裂解的氨基甲酸酯,光裂解的氨基甲酸酯,脲类衍生物及各种氨基甲酸酯。
氨基甲酸酯
甲基和乙基氨基甲酸酯的实例包括甲基和乙基,9-芴基甲基,9-(2-硫代)芴基甲基,9-(2,7-二溴)芴基甲基,2,7-二-叔丁基-[9-(10,10-二氧代-10,10,10,10-四氢噻噁烷基)]甲基及4-甲氧基苯酰基。
被取代的乙基
被取代的乙基氨基甲酸酯的实例包括2,2,2-三氯乙基,2-三甲基甲硅烷基乙基,2-苯基乙基,1-(1-金刚烷基)-1-甲基乙基,1,1-二甲基2-卤素乙基,1,1-二甲基-2,2-二溴乙基,1,1-二甲基-2,2,2-三氯乙基,1-甲基-1-(4-联苯基)乙基,1-(3,5-二-叔丁基苯基)-1-甲基乙基,2-(2′-和4′-吡啶基)乙基,2-(N,N-二环己基甲酰氨基)乙基,叔丁基,1-金刚烷基,乙烯基,烯丙基,1-异丙基烯丙基,肉桂基,4-硝基肉桂基,8-喹啉基,N-羟基哌啶基,烷基二硫,苄基,对甲氧基苄基,对硝基苄基,对溴苄基,对氯苄基,2,4-二氯苄基,4-甲基亚磺酰基苄基,9-蒽基甲基和二苯基甲基。
协助裂解
协助裂解的实例包括2-甲硫基乙基,2甲基磺酰基乙基,2-(对甲苯磺酰基)乙基,[2-(1,3-二噻烷基)]甲基,4-甲硫基苯基,2,4-二甲硫基苯基,2-磷鎓基乙基,2-三苯基磷鎓基异丙基,1,1-二甲基-2-氰基乙基,间-氯-对酰氧基苄基,对(二羟基硼烷基)苄基,5-苯并异噁唑基甲基及2-(三氟甲基)-6-色酮基甲基。
光裂解
光裂解的实例包括间硝基苯基,3,5-二甲氧基苄基,邻硝基苄基,3,4-二甲氧基-6-硝基苄基及苯基(邻硝基苯基)甲基。
脲类衍生物
脲类衍生物的实例包括吩噻嗪基-(10)-羰基衍生物,N′-对甲苯磺酰基氨基羰基及N′-苯基氨硫基羰基。
各种氨基甲酸酯
各种氨基甲酸酯的实例包括叔戊基,S-苄硫基氨基甲酸酯,对氰基苄基,环丁基,环己基,环戊基,环丙基甲基,对癸基氧基苄基,二异丙基甲基,2,2-二甲氧基羰基乙烯基,邻(N,N-二甲基甲酰氨基)苄基,1,1-二甲基-3-(N,N-二甲基甲酰氨基)丙基,1,1-二甲基丙炔基,二(2-吡啶基)甲基,2-呋喃基甲基,2-碘乙基,异冰片基,异丁基,异烟碱基,对(p′-甲氧基苯基偶氮基)苄基,1-甲基环丁基,1-甲基环己基,1-甲基-1-环丙基甲基,1-甲基-1-(3,5-二甲氧基苯基)乙基,1-甲基-1-(对苯基偶氮基苯基)乙基,1-甲基-1-苯基乙基,1-甲基-1-(4-吡啶基)乙基,苯基,对(苯基偶氮基)苄基,2,4,6-三-叔丁基苯基,4-(三甲基铵)苄基及2,4,6-三甲基苄基。
酰胺的实例包括:
酰胺
N-甲酰基,N-乙酰基,N-氯乙酰基,N-三氯乙酰基,N-三氟乙酰基,N-苯基乙酰基,N-3-苯基丙酰基,N-吡啶甲酰基,N-3-吡啶基甲酰胺,N苯甲酰基苯基丙氨酰基衍生物,N-苯甲酰基,N-对苯基苯甲酰基。
协助裂解
N-邻硝基苯基乙酰基,N-邻硝基苯氧基乙酰基,N-乙酰基乙酰基,(N′-二硫苄基氧羰基氨基)乙酰基,N-3-(对羟基苯基)丙酰基,N-3-(邻硝基苯基)丙酰基,N-2-甲基-2-(邻硝基苯氧基)丙酰基,N-2-甲基-2-(邻苯基偶氮基苯氧基)丙酰基,N-4-氯丁酰基,N-3-甲基-3-硝基丁酰基,N-邻硝基肉桂酰基,N-乙酰基蛋氨酸衍生物,N-邻硝基苯甲酰基,N-邻(苯甲酰氧基甲基)苯甲酰基及4,5-二苯基-3-噁唑啉基-2-酮。
环酰亚胺衍生物
N-邻苯二甲酰亚胺,N-二硫代琥珀酰基,N-2,3-二苯基马来酰基,N-2,5-二甲基吡咯基,N-1,1,4,4-四甲基二硅氮杂环戊烷加成物,5-取代的1,3-二甲基-1,3,5-三氮杂环己烷-2-酮,5-取代的1,3-二苄基-1,3,5-三氮杂环己烷-2-酮及1-取代的3,5-二硝基-4-吡啶酮基。
特殊的-NH保护基
特殊的NH保护基的实例包括
N-烷基和N-芳基胺
N-甲基,N-烯丙基,N-[2-(三甲基甲硅烷基)乙氧基]甲基,N-3-乙酰氧基丙基,N-(1-异丙基-4-硝基-2-氧代-3-吡咯啉-3-基),季铵盐,N-苄基,N-二(4-甲氧基苯基)甲基,N-5-二苯并环庚基,N-三苯基甲基,N-(4-甲氧基苯基)二苯基甲基,N-9-苯基芴基,N-2,7-二氯-9芴基亚甲基,N-二茂铁基甲基及N-2-甲基吡啶基胺N′-氧化物。
亚胺衍生物
N-1,1-二甲硫基亚甲基,N-亚苄基,N-对甲氧基亚苄基,N-二苯基亚甲基,N-[(2-吡啶基)米基]亚甲基及N-(N′,N′-二甲基氨基亚甲基)。
羰基的保护
非环缩醛和缩酮
环缩醛和缩酮的实例包括二甲基,双(2,2,2-三氯乙基),二苄基,双(2-硝基苄基)和二乙酰基。
环缩醛和缩酮
环缩醛和缩酮的实例包括1,3-二噁烷,5-亚甲基-1,3-二噁烷,5,5-二溴-1,3-二噁烷,5-(2-吡啶基)-1,3-二噁烷,1,3-二氧杂环戊烷,4-溴甲基-1,3-二氧杂环戊烷,4-(3-丁烯基)-1,3-二氧杂环戊烷,4-苯基-1,3-二氧杂环戊烷,4-(2-硝基苯基)-1,3-二氧杂环戊烷,4,5-二甲氧基甲基1,3-二氧杂环戊烷,O,O′-亚苯基二氧基和1,5-二氢-3H-2,4-苯并二氧杂环庚三烯。
非环二硫缩醛和缩酮
环二硫缩醛和缩酮的实例包括S,S′-二甲基,S,S′-二乙基,S,S′-二丙基,S,S′-二丁基,S,S′-二戊基,S,S′-二苯基,S,S′-二苄基及S,S′-二乙酰基。
环二硫缩醛和缩酮
环二硫缩醛和缩酮的实例包括1,3-二噻烷,1,3-二硫杂环戊烷和1,5-二氢-3H-2,4-苯并二硫杂环庚三烯。
非环单硫缩醛和缩酮
非环单硫缩醛和缩酮的实例包括O-三甲基甲硅烷基-S-烷基,O-甲基-S-烷基或-S-苯基及O-甲基-S-2-(甲硫基)乙基。
环单硫缩醛和缩酮
环单硫缩醛和缩酮的实例包括1,3-氧杂硫杂环戊烷。
各种衍生物
O-取代的氰醇
O-取代的氰基醇包括O-乙酰基,O-三甲基甲硅烷基,O-1-乙氧基乙基和O-四氢吡喃基。
被取代的腙
被取代的腙的实例包括N,N-二甲基和2,4-二硝基苯基。
肟衍生物
肟衍生物的实例包括O-甲基、O-苄基及O-苯硫基甲基。
亚胺
被取代的亚甲基衍生物,环衍生物
被取代的亚甲基及环衍生物的实例包括噁唑烷,1-甲基-2-(1′-羟基烷基)咪唑,N,N′-二甲基咪唑烷,2,3-二氢-1,3-苯并噻唑,二乙基胺加成物及甲基铝双(2,6-二-叔丁基-4-甲基苯氧化物)(MAD)复合物。
羧基的保护
酯
被取代的甲基酯
被取代的甲基酯的实例包括9-芴基甲基,甲氧基甲基,甲硫基甲基,四氢吡喃基,四氢呋喃基,甲氧基乙氧基甲基,2-(三甲基甲硅烷基)乙氧基甲基,苄氧基甲基,苯酰基,对溴苯酰基,α-甲基苯酰基,对甲氧基苯酰基,甲酰氨基甲基及N-苯二酰亚氨基甲基。
2-取代的乙酯
2-取代的乙酯的实例包括2,2,2-三氯乙基,2-卤素乙基,ω-氯烷基,2-(三甲基甲硅烷基)乙基,2-甲硫基乙基,1,3-二噻烷基-2-甲基,2-(对硝基苯基亚硫酰基)乙基,2-(对甲苯磺酰基)乙基,2-(2′-吡啶基)乙基,2-(二苯基磷)乙基,1-甲基-1-苯基乙基,叔丁基,环戊基,环己基,烯丙基,3-丁烯-1-基,4-(三甲基甲硅烷基)-2-丁烯-1-基,肉桂基,α-甲基肉桂基,苯基,对(甲基巯基)苯基及苄基。
被取代的苄基酯
被取代的苄基酯的实例包括三苯基甲基,二苯基甲基,双(邻硝基苯基)甲基,9-蒽基甲基,2-(9,10-二氧代基团)蒽基甲基,5-二苯并环庚基,1-芘基甲基,2-(三氟甲基)-6-铬酰基甲基,2,4,6-三甲基苄基,对溴苄基,邻硝基苄基,对硝基苄基,对甲氧基苄基,2,6-二甲氧基苄基,4-(甲基亚磺酰基)苄基,4-硫代苄基,胡椒基,4-甲基吡啶基和对-P-苄基。
甲硅烷基酯
甲硅烷基酯的实例包括三甲基甲硅烷基,三乙基甲硅烷基,叔丁基二甲基甲硅烷基,1-丙基二甲基甲硅烷基,苯基二甲基甲硅烷基和二叔丁基甲基甲硅烷基。
活化的酯
活化的酯的实例包括硫醇。
各种衍生物
各种衍生物的实例包括噁唑,2-烷基-1,3噁唑啉,4-烷基-5-氧代-1,3-噁唑烷,5-烷基-4-氧代-1,3-二氧杂环戊烷,邻位酸酯,苯基和五氨基钴(III)复合物。
甲锡烷基酯
甲锡烷基酯的实例包括三乙基甲锡烷基和三正丁基甲锡烷基。
酰胺和酰肼
酰胺
酰胺的实例包括N,N-二甲基,吡咯烷基,哌啶基,5,6-二氢菲啶基,邻硝基苯胺,N-7-硝基吲哚基,N-8-硝基-1,2,3,4-四氢喹啉基及对-P-苯磺酰胺。
酰肼
酰肼的实例包括N-苯基及N,N′-二异丙基酰肼。
C.制剂和给药
本发明化合物抑制人组织蛋白酶S的蛋白水解活性,并因此用作药物,特别是在治疗患有变态反应疾病或病症患者的方法中,这些疾病通过组织蛋白酶S活性来调整或调节。
本发明涉及治疗患有组织蛋白酶S介导的变应性病症的患者的方法,所述方法包括给该对象使用治疗有效量的、含有本发明化合物的药物组合物。本发明还提供了抑制某对象中组织蛋白酶S活性的方法,该方法包括给该对象使用治疗有效量的、含有本发明化合物的药物组合物。
基于对人组织蛋白酶S蛋白水解活性的抑制作用,为给药目的本发明化合物可以配制为多种药物剂型。为了制备这些药物组合物,碱或酸加成盐形式的、有效量的特定化合物,作为活性组分,紧密地与药用载体混合。
根据给药所需的剂型,可以使用多种形式的载体。人们一般希望这些药物组合物是单元剂型的形式,优选适于口服给药或非肠道注射。例如,在制备口服剂型的组合物时,可以使用任何常规药用介质。对于口服液体制剂如混悬剂、糖浆、酏剂和溶液剂的情况,它们包括水、乙二醇、油、乙醇等;或对于散剂、丸剂、胶囊和片剂的情况,包括固体载体如淀粉、糖、高岭土、润滑剂、粘合剂、崩解剂等。为了便于给药,片剂和胶囊代表了最有利的口服单位剂型,其中一般使用固体药用载体。对于非肠道给药组合物,载体一般包括灭菌水,虽然例如为了帮助溶解可以包括其它组分,但是至少大部分是水。例如,可以制备注射液,其中载体包括盐水溶液、葡萄糖溶液或盐水和葡萄糖溶液的混合物。也可以制备注射用混悬剂,其中可以使用适当的液体载体、助悬剂等。在适于经皮给药的组合物中,载体任选地包括透皮促进剂和/或适宜的湿润剂,任选地与占小部分的任何性质的适宜的添加剂混合,这些添加剂对皮肤不引起显著的有害作用。这些添加剂可以促进对皮肤的给药和/或可以有助于制备所需的组合物。这些组合物可以通过多种途经给药,例如,作为透皮贴剂,作为膏药(spot-on),作为软膏。式I化合物的酸加成盐,由于它们较相应的碱形式水溶性增加,故更适于制备含水组合物。
为了给药的便利以及剂量的均匀性,将上述药物组合物配制为单位剂型是特别有利的。在本文中使用的单位剂型指适于作为单元剂型的完全独立的单元,各单元含有按计算产生所需治疗作用的预定量的活性组分,以及与其混合的所需药用载体。此类单位剂型的实例为片剂(包括刻痕片或包衣片)、胶囊、烷基、袋装散剂、糯米纸囊剂、注射用溶液剂或混悬剂、可以用餐匙计量的制剂等,以及其被隔离的并联形式。
药用酸加成盐包括具有治疗活性的、无毒的、被公开的化合物能够形成的酸加成盐形式。该加成盐可以通过用适当的酸处理该碱便利地获得。适当的酸,例如,包括无机酸如氢卤酸,如氢氯酸或氢溴酸;硫酸;硝酸;磷酸等;或者有机酸如乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、桔橼酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己氨磺酸、水杨酸、对氨基水杨酸、双羟萘酸等酸。术语酸加成盐还包括所公开化合物及其盐能够形成的溶剂化物。这些溶剂化物例如是水合物、醇化物等。相反,盐形式通过用碱处理可以转变为游离碱形式。
立体异构形式限定为式(I)化合物可能具有的所有可能的异构形式。除非另行说明,化合物的化学命名指使用可能的立体化学异构形式的混合物,所述混合物包括基础分子结构的所有非对映异构体和对映异构体。更具体地讲,立体中心可以具有(R)-或(S)-构型;二价饱和环基团上的取代基可以具有顺式或反式构型。本发明包括立体活性异构形式,其包括所公开化合物的非对映异构体,以及其任何比例的混合物。所公开的化合物还可以以互变异构的形式存在。这些形式虽没有在上述或下述结构式中清楚地指出,但是都包括在本发明的范围内。
在治疗组织蛋白酶S介导的疾病或病症领域的技术人员,由下文中给出的试验结果或其它信息中,会容易地确定有效的日剂量。一般来说,所述治疗有效量为0.001mg/kg至5mg/kg体重,更优选0.01mg/kg至0.5mg/kg体重。将治疗有效量分两个、三个、四个或更多个次级剂量在一天中以适当间隔给药,是适当的。所述次级剂量可以配制为单位剂型,例如,每单位剂型含0.05mg至250mg,并特别是0.5至50mg的活性组分。实例包括2mg、4mg、7mg、10mg、15mg、25mg及35mg的剂型。本发明的化合物还可以制备为时间释放制剂,或皮下或透皮贴剂。所公开的化合物还可以配制为喷雾剂或者其它局部或吸入制剂。
确切的剂量和给药频率依赖于所用特定的式(I)化合物,所治疗的特定病症,所治疗病症的严重性,特定患者的年龄、体重及总的身体状况以及该患者可能使用的其它药物,这些是本领域技术人员熟知的。此外,根据所治疗患者的反应和/或根据使用本发明化合物的医生的评价,所述有效的日剂量可以降低或升高,这是很显然的。因此,本文中提及的有效日剂量范围至少指导性的。
下部分包括了使用所公开化合物的详细信息。
D.实施例
实施例1
组织蛋白酶S抑制试验。
重组人组织蛋白酶S(CatS)在杆状病毒系统中表达并用丙硫基-葡聚糖柱一步纯化。10L得到约700mg的CatS,且N-末端序列定性。该验在含1mM DTT和100mM NaCl的100mM钠乙酸酯pH 5.0中进行。试验的底物是
(Aedens)EKARVLAEAA(Dabcyl)K-酰胺
该底物Km的约5uM,但是底物抑制的存在造成动力学分析困难。对于20uM底物,该试验速度在100μl反应中对于1-8ng范围的CatS是线性的,并在20分钟后仅消耗20%的底物就得到了约7倍的信号。用0.1%SDS停止该反应后开始主试验并随后检测荧光。其他试验,每隔20分钟检测一次。由斜率的升高计算速率,并由此计算百分抑制。
实施例2
组织蛋白酶S抑制剂对变态反应的离体抑制
下列试验说明了组织蛋白酶S抑制剂阻断人T细胞对粗变应原提取物的反应。
材料和方法
试剂:室内粉尘螨的甘油化的粗变应原提取物(Dermataphagoides pteronyssinus,Dermataphagoides farinae)和豚草[Ambrosia trifida(大),Ambrosia artemisiifolia(小)]购自Hollister-Stier Laboratories(Minneapolis,MN)。Concanavalin A(ConA)购自Calbiochem(La Jolla,CA)。
供者:所有的变应反应供者用RAST试验筛选他们的特异变应原。这些供者的HLA II单倍型用PCR测定。
细胞培养:人外周血单核细胞(PBMC)由变应反应供者的血液Ficoll-Hypaque梯度纯化,接着用磷酸缓冲盐水(PBS)洗涤。PBMC以0.5-1.0×106细胞/孔的浓度与滴定量的变应原提取物一起培养,一式三份或一式两份,此培养在已知组织蛋白酶S抑制剂,LHVS(吗啉脲-亮氨酸-高-苯丙氨酸-乙烯基砜苯基)的存在或不存在下进行(Palmeretal.(1995),J.Med.Chem.38:3193和Riese等,(1996),Immunity 4:357)。先在100%DMSO中制备LHVS的系列稀释贮存液,然后在40%羟基丙炔基环糊精(HPCD)中进行1∶15稀释。将在HPCD中的三个滴度的LHVS加入到PBMC培养物(200μL/孔)中。培养6天后,加入1μCi/孔的3H-胸苷(TdR)。18小时后,用Filtermate收集器(Packard)收集细胞并用Topcount(Packard)计数掺入的3H-TdR。
对室内尘螨引起的T细胞增殖反应的抑制
大多数种群中约10%对Dermatophagoides属的尘螨(HDM)过敏,其中Dermatophagoides pteronyssinus(Der p)和D.farinae(Derf)是多数国家以不同比例存在的两种主要种类。主要的临床症状是哮喘和四季性鼻炎。
在离体人T细胞增殖试验中检测组织蛋白酶S对HDM变应原特异性CD4 T细胞激活的抑制。将PBMC与得自Der p或Der f的粗提物一起培养,产生强增殖(图1A)。此增殖主要由变应原特异性CD4 T细胞组成。当组织蛋白酶S活性被特异性组织蛋白酶S抑制剂,LHVS阻断时(参见Riese等,(1996)Immunity 4:357),该增殖被强烈抑制(图1B)。LHVS造成的抑制对于HDM提取物引起的反应是特异性的,因为由ConA(一种原T细胞有丝分裂原)引起的T细胞增殖反应未受影响。此外,在所有四个HDM变应反应被测供者中都观察到了此抑制,尽管他们HLA II型单倍型不同(DR4;DR7,15;DR11,15;和DR4,11)。
此系统与体内情况非常相似。变应反应对象接触变应原的粗混合物,该变应原会导致T细胞增殖和变应反应。对组织蛋白酶S抑制剂造成CD4 T细胞激活抑制的观察表明该类抑制剂可以有效地治疗对室内尘螨过敏患者的总群体。
对豚草引起的T细胞增殖反应的抑制
美国约10%的人对豚草花粉过敏,使其成为临床疾病中最重要变应原之一。花粉中的变应原是此类人群中鼻炎和哮喘的普通沉淀物。
在离体人T细胞增殖试验中检测组织蛋白酶S对豚草变应原特异性CD4 T细胞激活的抑制。将PBMC与得自小豚草和大豚草的粗提物一起培养,产生强增殖(图2A)。此增殖主要由变应原特异性CD4 T细胞组成。当组织蛋白酶S活性被特异性组织蛋白酶S抑制剂,LHVS阻断时(参见Riese等,(1996)Immunity 4:357),该增殖被强烈抑制(图2B)。LHVS造成的抑制对于豚草提取物引起的反应是特异性的,因为由ConA(一种原T细胞有丝分裂原)引起的T细胞增殖反应未受影响。此外,在两个豚草变应反应被测供者中都观察到了此抑制,尽管他们HLA II型单倍型不同(DR7,15和DR4,11)。
此系统与体内情况非常相似。变应反应对象接触变应原的粗混合物,该变应原会导致T细胞增殖和变应反应。对组织蛋白酶S抑制剂造成CD4 T细胞激活抑制的观察表明该类抑制剂可以有效地治疗对豚草过敏患者的总群体。
实施例3
在人血中监测组织蛋白酶S的抑制作用
临床试验试剂盒中的组织蛋白酶S抑制剂体内给药的作用,可以通过检测受药对象血液中恒定链(li)即p10li片段的快速降解产物蓄积来监控。组织蛋白酶抑制剂给药一定时间后,例如,0.01至50mg/kg/天,导致在16至30小时时血药浓度优选为1nM-10μM,采血并分离白细胞,例如通过裂解红细胞或者通过Ficoll-Hypaque梯度离心。然后制备WBC的全细胞裂解物,并通过Western印迹试验或ELISA试验分析。对于Western印迹试验,先在SDS-PAGE凝胶上重新溶解细胞裂解物。转移到硝基纤维素膜上后,li和中间降解产物,包括p10li,可以用针对li的小鼠mAb检测,例如Pin1.1,或用对p10li片段具有特异性或抗整个p10li片段的兔多克隆抗体或小鼠单克隆抗体检测。对于ELISA试验,可以使用一对抗li的抗体,包括Pin1.1及抗p10li的C末端的兔多克隆抗体。同样的试验还可以用于监控动物研究中体内的组织蛋白酶S抑制剂的作用,例如,在猴,狗,猪,兔,豚鼠及啮齿动物中。
在本实施例中,将人血PBMC于组织蛋白酶S抑制剂,LHVS(吗啉脲-亮氨酸-高-苯基丙氨酸乙烯基砜苯基,也称为4-吗啉甲酰胺,N-[(1S)-3-甲基-1-[[[(1S,2E)-1-(2-苯基乙基)-3-(苯基磺酰基)-2-丙烯基]氨基]羰基]丁基]-。此混合物描述于美国专利No.5,976,858和Palmer等,(1995)J.Med.Chem.38:3193以及Riese等,(1996)Immunity 4:357。孵育24小时后,用标准SDS-PAGE方法将样品转移到硝基纤维素膜上并用识别包括p10li片段的恒定链的抗体探察。在LHVS存在时,观察到了p10lI片段,这表明了由于组织蛋白酶S的抑制导致的li降解的阻断。
实施例4
组织蛋白酶S抑制剂引起的变态反应的体内抑制的监控
为了显示组织蛋白酶S抑制剂抑制体内变态反应的效果,给变态反应患者使用组织蛋白酶S抑制剂,其用量达到抑制恒定链降解的水平。变应原置于皮下,并在15分钟,6小时和24小时测定皮肤反应的面积。在24小时进行皮肤活组织检查。立即产生的伤斑反应不是T细胞反应介导的,不能预期其受组织蛋白酶S抑制剂的影响,而后期(在6小时时出现,在24小时更显著)是由CD4 T细胞(及嗜酸性细胞)激活和侵润,并应由组织蛋白酶S抑制剂的使用而受到抑制。用皮肤活组织检查来确定此期间细胞组织,而于接受安慰剂的对象相比,接受组织蛋白酶S的对象预计存在较少的活化CD4 T细胞。
这些方法的参考文献见Eberlein-Konig等,(1999)Clin.Exp.Allergy 29:1641-1647和Gaga等,(1991)J.Immunol.147:816-822。
作为该试验的对照,使用泼尼松和环孢菌素A。泼尼松将抑制即发反应和迟发反应,而环孢菌素A只抑制迟发反应。
E.其它实施方案
本发明的特征和优点对于本领域普通技术人员来说是显而易见的。基于此公开,包括发明概述,详述,背景,实施例和权利要求,本领域普通技术人员将能够进行适于不同条件和用途的多种改变。此类实施方案也在本发明的范围内。
Claims (18)
1.治疗变应性病症患者的方法,所述方法包括给所述患者使用治疗有效量的含有组织蛋白酶S抑制剂的药物组合物。
2.权利要求1所述的方法,其中所述变应性病症是特应性IgE-介导的变应性病症。
3.权利要求1所述的方法,其中所述变应性病症选自枯草热、哮喘、特应性皮炎和对食物的变应性反应。
4.权利要求1所述的方法,其中所述组织蛋白酶S抑制剂是下式的化合物;或其药用盐、异构体或其异构体的混合物:
其中:n是0至13;
A-B表示选自如下的连接基团:-C(O)NR3、-CH2NR3-、-C(O)CH2-和-NR3C(O)-,其中R3是氢原子或定义如下;
X表示价键、亚甲基或连接基团-CH2CH(R4)-,其中R4是氢、烷基或芳基烷基;
Y是-CH(R5)-或-N(R5)-,其中R5是氢或定义如下;
Z是-(CH2)2-、-C(R6)(R7)-或-N(R7)-,其中R6是氢或甲基,而R7定义如下;
Z1是-(CH2)2-、-C(R6)(R8)-或-N(R8)-,其中R6是氢原子或甲基且R8是定义如下;R1是氢原子、烷氧羰基烷酰基、烷氧羰基、烷醇(任选地被选自如下的取代基取代:羧基、烷氧羰基及杂环烷基烷酰基氨基)、环烷基羰基、杂环烷基羰基(任选地被选自如下的取代基取代:羟基、烷基、烷酰基、烷氧羰基、芳基烷氧羰基及杂环烷基羰基)、芳基烷氧羰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、芳基氨基甲酰基、芳基烷基氨基甲酰基、芳基烷酰基、芳酰基、烷基磺酰基、二烷基氨基磺酰基、芳基磺酰基或杂芳基磺酰基;
R7和R8独立地是氢原子、烷基(任选地被选自如下的取代基取代:羟基、氨基、烷基氨基、二烷基氨基、脲基、巯基、烷硫基、羧基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、烷基磺酰基及胍基、或其被保护的衍生物、环烷基、环烷基烷基、杂芳基、杂芳基烷基、选自芳基及芳基烷基的基团(该基团在其芳环上被1至3个选自如下的基团任选地取代:羟基、氨基、胍基、卤素、任选地卤代的烷基、烷氧基和芳基、或其被保护的衍生物)或与相邻的R3或R5一起形成选自如下的二价基团:(C3-C4)亚甲基及1,2-亚苯基二亚甲基(该基团任选地被如下基团取代:羟基、或其被保护的衍生物、或氧代基团);且
R2是氢、烷基(任选地被选自如下的一个或多个选自如下的基团取代:氨基、卤素、羟基、烷氧基、硝基、烷基磺酰基及芳基磺酰基、或其被保护的衍生物、环烷基、环烷基烷基或选自芳基或芳烷基的基团(该基团在其芳环上被1至2个选自如下的取代基任选地取代:氨基、胍基、卤素、羟基、任选地卤代的烷基、烷氧基、硝基、烷基磺酰基及芳基磺酰基、或其被保护的衍生物)。
5.权利要求4所述的方法,其中所述组织蛋白酶S抑制剂是如下化合物:其中Z是-C(R6)(R7)-;n是0;R3、R5和R8各是氢原子;R1是氢原子、叔丁氧基羰基、苄基氧羰基、生物素基氨基己酰基、苯甲酰基、1-哌嗪基-羰基、4-甲基-1-哌嗪基羰基或4-吗啉基羰基;R8是丁基、2-苯基乙基或2-甲基磺酰基乙基;R2是苯基、1-萘基或2-苯基乙基;而R7是(C1-C5)烷基、2-甲基磺酰基乙基、任选地被取代的苄基、1-萘基甲基、2-萘基甲基、3-吡啶基甲基或2-甲基磺酰基乙基。
6.权利要求5所述的方法,其中所述组织蛋白酶S抑制剂是如下化合物:其中R1是1-哌嗪基羰基、4-甲基-1-哌嗪基羰基或4-吗啉基羰基;R8是2-苯基乙基;R2是苯基或萘-2-基;而R7是任选地被取代的苄基、1-萘基甲基或2-萘基甲基。
7.权利要求1所述的方法,其中所述组织蛋白酶S抑制剂是下式的化合物;或其药用盐、异构体或异构体的混合物:
其中:n是0至13;
A-B表示选自如下的连接基团:-C(O)NR3、-CH2NR3、-C(O)CH2-和-NR3C(O)-,其中R3是氢原子或定义如下;
Y是-CH(R5)-或-N(R5)-,其中R5是氢或定义如下;
Z是-(CH2)2-、-C(R6)(R7)-或-N(R7)-,其中R6是氢或甲基,而R7定义如下;
Z1是-(CH2)2-、-C(R6)(R8)-或-N(R8)-,其中R6是氢或甲基,且R8是定义如下;
R1是氢原子、烷氧羰基烷酰基、烷氧羰基、烷醇(任选地被选自如下的取代基取代:羧基、烷氧羰基及杂环烷基烷酰基氨基)、环烷基羰基、杂环烷基羰基(任选地被选自如下的取代基取代:羟基、烷基、烷酰基、烷氧羰基、芳基烷氧羰基及杂环烷基羰基)、芳基烷氧羰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、芳基氨基甲酰基、芳基烷基氨基甲酰基、芳基烷酰基、芳酰基、烷基磺酰基、二烷基氨基磺酰基、芳基磺酰基或杂芳基磺酰基;
R7和R8独立地是氢原子、烷基(任选地被选自如下的取代基取代:羟基、氨基、烷基氨基、二烷基氨基、脲基、巯基、烷硫基、羧基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、烷基磺酰基及胍基、或其被保护的衍生物)、环烷基、环烷基烷基、杂芳基、杂芳基烷基、选自芳基或芳烷基的基团(该基团在其芳环上被1至3个选自如下的基团任选地取代:羟基、氨基、胍基、卤素、任选地卤代的烷基、烷氧基和芳基、或其被保护的衍生物)或与相邻的R3或R5一起形成选自如下的二价基团:(C3-C4)亚甲基及1,2-亚苯基二亚甲基(该基团任选地被如下基团取代:羟基、或其被保护的衍生物或氧代基团);且
R9是氰基、-C(O)OR10、-P(O)(OR10)2、-S(O)(NR10)R10、C(O)R11、-S(O)R11、-C(O)NR12R13、-S(O)2NR12R13、-C(O)NHR14或-S(O)2NHR14、其中每个R10独立地是氢原子、烷基(任选地被选自如下的一个或多个选自如下的基团取代:氨基、卤素、羟基、烷氧基、硝基、烷基磺酰基及芳基磺酰基、或其被保护的衍生物)、环烷基、环烷基烷基或选自芳基或芳烷基的基团(该基团在其芳环上被1至2个选自如下的取代基任选地取代:氨基、卤素、羟基、任选地卤代的烷基、烷氧基、硝基、烷基磺酰基及芳基磺酰基、或其被保护的衍生物),R11是氢原子、烷基、全氟代烷基、环烷基、环烷基烷基、全氟代芳基、全氟代芳基烷基或选自芳基或芳烷基的基团(该基团在其芳环上被1至2个选自如下的取代基任选地取代:氨基、卤素、羟基、任选地卤代的烷基、烷氧基、硝基、烷基磺酰基及芳基磺酰基、或其被保护的衍生物),R12和R13独立地是氢原子、烷基、环烷基、环烷基烷基、芳基或芳烷基,而R14是-C(O)OR10,其中R10定义如上、或选自式(a)和(b)的基团:
其中各个n、A、B、Y、Z、R1和R10定义如权利要求4所述。
8.权利要求7所述的方法,其中所述组织蛋白酶S抑制剂是如下化合物:其中各R1是1-哌嗪基羰基、4-甲基-1-哌嗪基羰基或4-吗啉基羰基;R8是2-苯基乙基;而R7是任选地被取代的苄基、1-萘基甲基或2-萘基甲基。
9.权利要求8所述的方法,其中所述组织蛋白酶S抑制剂是如下化合物:其中R1是4-吗啉基羰基,R1是2-苯基乙基,R7是苄基及R1是苄基氨基甲酰基,即N2-4-(吗啉基羰基)-N1-3-苯基-1S-(2-苄基氨基甲酰基乙基)丙基-1-苯基丙氨酸酰胺。
10.权利要求1所述的方法,其中所述组织蛋白酶S抑制剂是下式的化合物:
其中A和X是N-取代基,其选自酰基、酰基肽基、烷氧羰基、烷氧羰基肽基、磺酰基,肽基、氨磺酰基、氨磺酰基肽基、亚磺酰基、亚磺酰基肽基、氨基甲酰基及氨基甲酰基肽基;
R1是一个氨基酸侧链或(b)氢原子;
R2是一个氨基酸侧链或(b)氢原子,其中(1)R1和R2都是氢原子,或(2)R1或R2之一是一个氨基酸侧链而R1和R2中的另一个是氢;且R3和R4是氢原子,或一起键合为亚乙基或被取代的亚乙基;
其中所述亚乙基取代基是一个氨基酸侧链。
11.权利要求1所述的方法,其中所述组织蛋白酶S抑制剂是下式的化合物:
其中A是一个N-取代基,其选自酰基肽基、烷氧羰基肽基,肽基、氨磺酰基肽基、亚磺酰基肽基及氨基甲酰基肽基;X是一个N-取代基,其选自酰基、酰基肽基、烷氧羰基、烷氧羰基肽基、磺酰基、磺酰基肽基、肽基、氨磺酰基、氨磺酰基肽基、亚磺酰基、亚磺酰基肽基、氨基甲酰基及氨基甲酰基肽基;
R1是氢;而
R2是一个氨基酸侧链。
12.权利要求1所述的方法,其中所述组织蛋白酶S抑制剂是下式的化合物:
其中A和X是N-取代基,其选自C(O)R7(酰基)、酰基肽基、C(O)OR8(烷氧羰基)、烷氧羰基肽基、S(O)2R9(磺酰基)、肽基、S(O)2NR10R11、(氨磺酰基)、氨磺酰基肽基、S(O)R9(亚磺酰基)、亚磺酰基肽基、C(O)NR10R11(氨基甲酰基)及氨基甲酰基肽基;
R7选自(C1-5)烷基、(C3-7)环烷基、(C3-7)环烷基(C1-5)烷基、(C3-7)环烷基(C1-5)链烯基、杂(C3-7)环烷基、(C5-14)芳基、被取代的(C5-14)芳基、(C7-12)芳烷基及被取代的(C7-12)芳烷基;其中所述杂基团(取代基?)选自羟基、(C1-5)烷基、杂(C3-7)环烷基、(C1-5)烷酰基、(C1-5)烷氧基羰基、(C5-14)芳基(C1-5)烷氧基羰基和杂(C3-7)环烷基羰基;
R8选自(C1-5)烷基(任选地一些如下基团取代:羟基、(C1-5)烷氧基、氨基、及原子序数9-35的卤原子)、(C3-7)环烷基、(C3-7)环烷基(C1-5)烷基、(C3-7)环烷基(C1-5)链烯基、(C5-14)芳基、被取代的(C5-14)芳基、(C7-12)芳烷基、及被取代的(C7-12)芳烷基;
R9选自(C1-5)烷基(任选地一些如下基团取代:羟基、(C1-5)烷氧基、氨基、和原子序数9-35的卤原子)、(C3-7)环烷基、(C3-7)环烷基(C1-5)烷基、(C3-7)环烷基(C1-5)链烯基、(C5-14)芳基、被取代的(C5-14)芳基、(C7-12)芳烷基、和被取代的(C7-12)芳烷基;
R10和R11独立地选自氢原子、(C1-5)烷基、(C3-7)环烷基、(C3-7)环烷基(C1-5)烷基、(C5-14)芳基、被取代的(C5-14)芳基、(C7-12)芳烷基、被取代的(C7-12)芳烷基;二(C1-5)烷基、(C1-5)烷基(C7-12)芳烷基;或R10和R11键合形成一5或6员脂环族或杂脂环族环部分;
肽基是1-10个氨基酸;
所述被取代的芳基及被取代的芳烷基的所述取代基是选自如下的1或2个基团:(C1-5)烷基、(C1-5)烷氧基、原子序数9-35的卤原子、羟基、和氨基;
R1是一个氨基酸侧链或(b)氢原子;R2是一个氨基酸侧链或(b)氢原子,其中或者(1)R1和R2都是氢原子,或(2)R1或R2是一个氨基酸侧链,而R1和R2中的另一个是氢;且
R3和R4是氢原子,或一起键合为亚乙基或被取代的亚乙基,其中所述亚乙基取代基是一个氨基酸侧链。
13.权利要求1所述的方法,其中所述组织蛋白酶S抑制剂是下式的化合物;或其药用盐、异构体或其异构体的混合物:
其中A和X独立地是R13-X1-;
R13选自氢原子,共3-10个碳原子的烷氧羰基烷酰基、(C1-9)烷氧羰基、(C2-10)烷酰基(任选地被选自如下的取代基取代:羧基、(C1-9)烷氧羰基及杂(C4-8)环烷基(C2-10)烷酰基氨基)、(C4-8)环烷基羰基、杂(C4-8)环烷基羰基(任选地被选自如下的取代基取代:羟基、(C1-5)烷基、杂(C4-8)环烷基、(C1-5)烷酰基、(C1-5)烷氧羰基、(C6-10)-芳基(C1-5)烷氧羰基及杂(C4-8)环烷基羰基)、(C6-10)芳基(C1-5)烷氧羰基、氨基甲酰基、(C1-5)烷基氨基甲酰基、二(C1-5)烷基氨基甲酰基、(C6-10)芳基氨基甲酰基、(C6-10)芳基(C1-5)烷基氨基甲酰基、(C6-10)芳基(C1-5)烷酰基、(C7-11)芳酰基、(C1-10)烷基磺酰基、(C6-10)芳基磺酰基、(C6-10)芳基(C1-5)烷基磺酰基、(C1-5)烷基氨磺酰基、二(C1-5)烷基氨磺酰基、(C6-10)芳基氨磺酰基、(C1-5)烷基亚磺酰基、二(C1-6)烷基氨基亚磺酰基、及(C6-10)芳基亚磺酰基;
X1是价键或式(a)或(b)的二价基团:
n是0至9;X3-X4表示选自如下的连接基团:-C(O)NR14-、-CH2NR14-、C(O)CH2-及-NR14C(O)-;
Y是-CH(R14)-或-NR14;
Z是-(CH2)2、-C(R15)(R16)-或-N(R16)-;
R14是氢或定义如下;
R15是氢或甲基;
各个R16独立地是氢原子、(C1-5)烷基(任选地被选自如下的取代基取代:羟基、(C1-5)烷氧基、氨基、(C1-5)烷基氨基、二(C1-5)烷基氨基、脲基、(C1-5)烷基脲基、巯基、(C1-5)烷硫基、羧基、氨基甲酰基、(C1-5)烷基氨基甲酰基、二(C1-5)烷基氨基甲酰基、(C1-5)烷基亚磺酰基、(C1-5)烷基磺酰基、胍基、-P(O)(OR12)2、-OP(O)(OR12)2或-OP(O)(R12)2、(C3-7)环烷基、(C3-7)环烷基(C1-5)烷基、(C5-14)芳基、(C5-14)芳基(C1-5)烷基(该基团在其芳环上被1至3个选自如下的基团任选地取代:羟基、氨基、胍基、卤原子、任选地被卤代的(C1-5)烷基、(C1-5)烷氧基和(C5-14)芳基、或其被保护的衍生物)或与相邻的R14一起形成选自如下的二价基团:(C3-4)亚甲基及1,2-亚苯基二亚甲基(该基团任选地被如下基团取代:羟基,或其被保护的衍生物,或氧代基团),其条件是X和A不都是氢原子;
各个R12独立地是氢原子或(C1-5)烷基或其被保护的衍生物;
R1和R2都是氢原子,或R1和R2之一是氰基、羧基、(C1-5)烷氧羰基、(C1-5)烷酰基、氨基甲酰基、(C1-5)烷基氨基甲酰基、二(C1-5)烷基氨基甲酰基、(C1-5)烷氧基((C1-5)烷基)氨基甲酰基,氨基(C1-5)烷基氨基甲酰基,
R16定义如上,或R13-X2-,其中R13定义如上,而X2是定义如上的式(a)或(b)的二价基团;
R3和R4是氢原子或一起形成任选地被取代的亚乙基,其中所述亚乙基取代基是一个氨基酸侧链或独立地是如上所述的R14。
14.权利要求1所述的方法,其中所述CatS抑制剂是下式的化合物;或其生理可接受的并可裂解的酯或其盐:
其中:
R是任选地被取代的(芳基、低级烷基、低级链烯基、低级链炔基或杂环基);R2和R3独立地是氢原子、或任选地被取代的[低级烷基、环烷基、双环烷基、或(芳基、双芳基、环烷基或双环烷基)低级烷基];或R2和R3一起表示低级亚烷基,任选地被O、S或NR6间隔,以便与它们连接的碳原子形成环,
其中R6是氢、低级烷基或芳基-低级烷基;或R2或R3通过低级亚烷基与相邻的氮原子连接形成环;R4和R5独立地是H、或任选地被取代的(低级烷基、芳基低级烷基)、C(O)OR7、或-C(O)NR7R8,
其中R7是任选地被取代的(低级烷基、芳基、芳基-低级烷基、环烷基、双环烷基或杂环基),而
R8是H,或任选地被取代的(低级烷基、芳基、芳基-低级烷基、环烷基、双环烷基或杂环基),或R4和R5一起表示低级亚烷基,任选地被O、S或NR6间隔,以便与它们连接的碳原子形成环,
其中R6是氢、低级烷基或芳基-低级烷基,或R4是H或任选地被取代的低级烷基,而R5是式-X2(Y1)n-(Ar)p-Q-Z的取代基,
其中
Y1是O、S、SO、SO2、N(R6)SO2、N-R6、SO2NR6、CONR6或NR6CO;
n是0或1;
p是0或1;
X2是低级亚烷基;或当n是0时,X2也是C2-C7-亚烷基,其被O、S、SO、SO2NR6、SO2NR6、CONR6或NR6CO间隔;其中R6是氢,低级烷基或芳基-低级烷基;
Ar是亚芳基;
Z是羟基、酰氧基、羧基、酯化的羧基、酰胺化的羧基、氨基磺酰基、(低级烷基或芳基-低级烷基)氨基磺酰基、或(低级烷基或芳基-低级烷基)磺酰基氨基羰基;或Z是四唑基、三唑基或咪唑基;Q是价键、低级亚烷基、Y1-低级亚烷基或被Y1间隔的C2-C7-亚烷基;
X1是-C(O)-、-C(S)-、-S(O)-、-S(O)2-或-P(O)(OR6)-,其中R6定义如上;
Y是氧原子或硫原子;
L是任选地被取代的-Het-、-Het-CH2-或-CH2-Het-,其中Het是选自O、N或S的杂原子,而x是0或1;
且在上述定义中芳基表示碳环或杂环芳基。
15.权利要求14所述的方法,其条件是当R是没有被芳基取代的低级烷基时,R4或R5之一是式-X2-(Y1)n-(Ar)p-Q-Z的取代基;其条件是当x是1,L是-O-或-CH2-O-,而X1是-C(O)-时,
R4或R5之一是式-X2-(Y1)n-(Ar)p-Q-Z的取代基,或R不是未被取代的苯基;
其条件是当R2=R4=R5=H,x是0而X1是-C(O)-时,当R是未取代的苯基时,R3不是H、-CH3、-CH(CH3)2、-CH2-CH-(CH3)2、-CH2-COOH或-CH2-COO-CH2-CH3,
当R是4-氨基苯基或4-硝基苯基时,R3不是H、-CH(CH3)2或-CH2-CH-(CH3)2,
当R是3-氨基苯基、3-硝基苯基2-氯吡啶-4-基或乙烯基时,R3不是H,或
当R是吡啶-3-基或2-氯吡啶-4-基时,R3不是-CH2-CH2-S-CH3,
其条件是当R2=R3=R4=H,x是0而X1是-C(O)-且R是苯基时,R5不是-CH(CH3)2,
其条件是当R3=R4=H,R5是-CH2-CH2-COOH,x是0而X1是-C(O)-时,
R2不与相邻的氮原子形成杂环,且其条件是当R2=R3=R4=R5=H,x是0而X1是-SO2-时,R不是4-甲基苯基。
17.权利要求16所述的方法,其中所述CatS抑制剂如下化合物:
其中
(a)p是1;
(b)Y1是O、S、SO、SO2、N(R6)SO2或N-R6;及
(c)X2是低级亚烷基;或当n是0时,X2也是被O、S、SO、SO2或NR6间隔的C2-C7-亚烷基,
(d)R30是一个得自有机羧酸、氨基甲酸和磺酸的酰基,
(e)及其药用盐和酯。
18.权利要求14所述的方法,其中所述CatS抑制剂下式的化合物或其药用盐或酯:
其中
R40是被取代的苯基或杂环芳基,(单-和双-碳环或杂环芳基)-低级烷基或低级链烯基,或杂环基;
R42是氢或低级烷基;
R43是碳环或杂环芳基或低级烷基;
R44和R45独立地是氢原子或低级烷基;或者
R44和R45合起来表示低级亚烷基。
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2001
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- 2001-09-05 RU RU2003106192/15A patent/RU2003106192A/ru not_active Application Discontinuation
- 2001-09-05 MX MXPA03001960A patent/MXPA03001960A/es unknown
- 2001-09-05 US US09/946,713 patent/US6579896B2/en not_active Expired - Lifetime
- 2001-09-05 RU RU2003106193/15A patent/RU2290179C2/ru not_active IP Right Cessation
- 2001-09-05 JP JP2002524487A patent/JP2004523469A/ja active Pending
- 2001-09-05 EP EP01968469A patent/EP1315741A2/en not_active Withdrawn
- 2001-09-05 CA CA002421502A patent/CA2421502A1/en not_active Abandoned
- 2001-09-05 CN CNA018183867A patent/CN1642973A/zh active Pending
- 2001-09-05 AU AU2001288714A patent/AU2001288714A1/en not_active Abandoned
- 2001-09-05 US US09/946,214 patent/US6369032B1/en not_active Expired - Lifetime
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Cited By (1)
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CN106715472A (zh) * | 2014-09-18 | 2017-05-24 | 豪夫迈·罗氏有限公司 | 用于监测组织蛋白酶s抑制的方法 |
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US20020115656A1 (en) | 2002-08-22 |
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RU2290179C2 (ru) | 2006-12-27 |
WO2002020002A3 (en) | 2002-11-28 |
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JP2004523469A (ja) | 2004-08-05 |
US6369032B1 (en) | 2002-04-09 |
HK1053129A1 (zh) | 2003-10-10 |
EP1315741A2 (en) | 2003-06-04 |
ZA200302637B (en) | 2004-07-05 |
ZA200302634B (en) | 2005-08-15 |
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