CN1289340A - 20S蛋白酶体α-酮酰胺抑制剂 - Google Patents
20S蛋白酶体α-酮酰胺抑制剂 Download PDFInfo
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- CN1289340A CN1289340A CN99802421A CN99802421A CN1289340A CN 1289340 A CN1289340 A CN 1289340A CN 99802421 A CN99802421 A CN 99802421A CN 99802421 A CN99802421 A CN 99802421A CN 1289340 A CN1289340 A CN 1289340A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
用于治疗哺乳动物内由20S蛋白酶体介导的紊乱的具有结构式(Ⅰ)的α-酮酰胺化合物。
Description
发明背景:
多催化作用的蛋白酶或者蛋白酶体具有一种被高度保护的细胞结构,这种细胞结构是形成大多数细胞蛋白质ATP-依赖蛋白分解的原因[Coux,O.,Tanaka,K.和Goldberg,A.1996生物化学评述年报(Ann.Rev.Biochem.)65,801-847]。20S蛋白酶体含有复合催化核,并20S蛋白酶体已从原始细菌嗜酸热原体[Lowe,J.,Stock,D.,Jap,B.,Zwicki,P.,Bauminster,W.和Huber,R.1995科学(Scinece)268,533-539]和发面酵母[Groll,M.,Ditzel,L.,Lowe,J.,Stock,D.,Bochtler,M.,Bartunik,HD和Hulber,R.1997自然(Nature)386,463-471]中结晶出来。和最初显示胰凝乳蛋白酶样的解蛋白活度的原始细菌蛋白酶体不同,[Dahlmann,B.,Kopp,F.,Kuehn,L.,Niedel,B.,Pfeifer,G.1989 FEBSLett.251,125-131;Seemuller,E.,Lupas,A.,Zuw,F.,Zwickl,P和Baumeister,W.FEBS Lett.359,173,(1995)],真核蛋白酶体含有至少五种可识别的解蛋白活度。这些活度中的三种类似于胰凝乳蛋白酶、胰岛素和肽基谷氨酰肽酶。其它两种描述的活度显示优选分裂支链氨基酸羧基侧上的肽键(BrAAP)和偏向短链中性氨基酸(SnAAP)之间的肽键[Orlowski,M.1990生物化学(Biochemistry)29,10289-10297)]。
尽管20S蛋白酶体含有解蛋白核,但在体内它并不能降解蛋白质,除非它在其结构的任意一端与19S帽复合,这种帽本身具有多种ATP酶活性。已知的较大的结构是26S蛋白酶体,通过加入多分子的8,5-kDa多肽、泛素能够迅速地降解已经被定为降解目标的蛋白质[参见Coux,O.,Tanaka,K.和Goldberg,A.1996生物化学评述年报(Ann.Rev.Biochem.)65,801-847]。
大量的源于底物的功能已经被用于潜在的丝氨酸蛋白酶和硫醇蛋白酶抑制剂。这些基元中的几种已经被描述成为蛋白酶体抑制剂。这些包含肽醛[Vinitsky,A.,Michaud,C.,Powers,J.和Orlowski,M.1992生物化学(Biochemistry)31,9421-9428;Tsubuki,S.,Hiroshi,K.,Saito,Y.,Miyashita,N.,Inomata,M.,和Kawashima,S.1993生物化学生物物理研究通讯(Biochem.Biophys.Res.Commun.)196,1195-1201;Rock,K.,I.,Gramm,C.,Rothstein,L.,Clark,K.,Stein,R.,Dick,L.,Hwang,D.和Goldberg,A.L.(1994)细胞(Cell)78,761-771]N-乙酰基-L-亮氨酸-L-亮氨酸-L-正亮氨酸(ALLN)和N-乙酰基-L-亮氨酸-1-亮氨酸-蛋氨酸(LLM)以及该类型最有效的抑制剂N-下氧羰基-1-L-亮氨酸-L-亮氨酸-L-正缬氨酸(MG115)。其它的报告描述了一系列IC50值为10至100nM的二肽抑制剂[Iqbal,M.,Chatterjee S.,Kauer,J.C.,Das,M.,Messina,P.,Freed,B.,Biazzo,W和Siman,R.1995I-Med.Chem.38,2276-2277]。一系列的α-酮羰基和硼酯衍生的二肽[Iqbai,M.,Chatterjee,S.,Kauer,J.C.,Mallamo,J.P.,Messian,P.A.,Reiboldt,A.和Siman,R.1996Bioorg.Med-Chem.Lett6,287-290]和环氧酮[Spattenstein,A.,Leban,JJ.,Huang,J.J.,Reinhardt,K.R.,Viveros,O.H.,Sigafoos,J.和Crouch,R.1996Tet.lett.37,1434-1346]已经被描述成是有效的蛋白酶体抑制剂。
在抑制蛋白酶体活性上显示特性的一种不同的化合物是乳胱氨酸(lactacystin)[Fenteany,G.,Standaert,R.F.,Lane,W.S.,Choi,S.,Corey,E.J.和Schreiber,S.L.1995科学(Science)268,726-731],其是链霉菌的代谢物。最初发现这种分子是因为它在成神经细胞瘤细胞系中有诱使神经突生长的能力[Omura,S.,Matsuzaki,K.,Fujimoto,T.,Kosuge,K.,Furuya,T.,Fujita,S.和Nakagawa,A.1991抗菌杂志(J.Antibiot.)44,117-118],后来显示有抑制几种类型细胞增殖的作用[Fenteany,G.,Standaert,R.F.,Reichard,G.A.,Corey,E.J.和Schreiber,S.L.1994Proc.Nat’l.Acad.Sci.USA91,3358-3362]。
现在已经确认蛋白酶体是包含在蛋白分解方法中主要的特殊溶酶体解蛋白体系,这些蛋白分解方法对于细胞分裂功能例如细胞分裂、抗原呈递和如致癌基因产物、细胞周期蛋白以及转录因子的短龄调节蛋白的降解功能是必需的[Ciechanover,A.(1994)细胞(Cell)79,13-21;Palombell,V.J.,Rando,O.J.,Goldberg,A.L.和Maniatis,T.1994细胞(Cell)78,773-785)。举例说明,NF-κB活化形式是由p65和p50亚基组成的杂二聚体。后者作为失活前体(p105)位于细胞液中。p105导致产生p50的解蛋白过程通过泛素-蛋白酶体的方法发生。此外,经加工的p50和p65作为蛋白IκB抑制剂的失活复合体存在于细胞液中。炎性的刺激物例如LPS通过激活导致IκB降解的信号通道激活NF-κB。这些信号也刺激p105转变成p50的过程。因此,两种均由泛素-蛋白酶体法支配的解蛋白过程需要促使NF-κB活化的信号。
通过利用针对蛋白酶体的抑制剂,临床上可得出这种观察结果,泛素-介蛋白酶体的蛋白分解在激活NF-κB中起决定的作用。刺激合成细胞因子后,在多种炎性和传染性疾病中观察到NF-κB反常的激活作用。NF-κB的激活作用对于血管生成和粘着分子的表达是必需的(CAMs和选择性蛋白(selects)),因此蛋白酶体抑制剂在与血管系统有关的疾病治疗中也有效。
文献记载,泛素-蛋白酶体法对调节破坏细胞周期蛋白很关键,该周期蛋白控制有丝分裂的中止和使得细胞前进到细胞周期的下一阶段[Glotzer,M.,Murray,A.W.和Kirschner,M.W.(1991)自然(Nature)349,132-138]。从而,通过采用蛋白酶体抑制剂抑制细胞周期蛋白降解导致生长抑制。因此,另一种蛋白酶体抑制剂的潜在作用是用于治疗由细胞异常分裂引起的疾病。
近来文献报道了几种类别的20S蛋白酶体肽抑制剂。α-酮酰氨基已经用于适于许多指证的蛋白酶抑制剂。特别地,作为20S蛋白酶体功能的有效的抑制剂,已经报道了一系列α-酮羰基和硼酯衍生的二肽[Iqbal,M.,Chatterjee,S.,Kauer,J.C.,Mallamo,J.P.,Messina,P.A.,Reiboldt,A.和Siman,R.1996Bioorg.Med.Chem.Lett6,287-290)。有人宣称3-吲哚基丙酮酸的衍生物作为药物活性化合物,通过调节脑内犬尿喹啉酸水平的机理,适用于中枢神经系统[De Luca,et alWO88/09789)紊乱的治疗。
即使已经发现了种种在一定程度上抑制细胞增殖的化合物,还存在对以20S蛋白酶体抑制细胞增殖的更有效的化合物的需要。
发明概述
本发明的一个目的是提供一种采用有效治疗剂量的化合物抑制哺乳动物细胞增殖的方法,迄今为止未知该化合物的细胞增殖抑制性能;
本发明的另一个目的是提供一种疾病的治疗方法,这种疾病可通过蛋白酶体功能的抑制来治疗;
进一步地,本发明的一个目的是提供一种增殖性疾病的治疗方法,该疾病可通过蛋白酶体功能的抑制治疗;
本发明的又一个目的是采用这里描述的有效治疗剂量的化合物抑制人体细胞的无序增殖;
本发明的又一个目的是采用这里描述的有效治疗剂量的化合物抑制蛋白酶体功能。
在一个实施方案中,本发明是具有如下结构式的化合物。
其中X2为Ar或Ar-X3,这里X3为-C=O,或-CH2CO-,Ar为苯基、取代的苯基、吲哚基、取代的吲哚基、和任何其它的杂芳基;R1和R2分别独自选自已知的侧链天然α-氨基酸和非天然的氨基酸、氢原子、1-10个碳原子的直链和支链烷基、1-10个碳原子的直链和支链取代的烷基、芳基、取代的芳基、1-10个碳原子的直链和支链取代的芳基、烷氧基芳基、3-8个碳原子的环烷基、杂环、取代的杂环、杂芳基(heteroaryl)和取代的杂芳基;X1选自氢氧化物、单烷基氨基、二烷基氨基、醇盐、芳基醇盐(arylalkoxide)和
其中X4为氢氧化物、芳氨基、单烷基氨基、二烷基氨基、醇盐、或者芳基醇盐;R3选自已知的天然α-氨基酸、非天然的氨基酸、氢原子、1-10个碳原子的直链和支链烷基、1-10个碳原子的直链和支链取代的烷基、芳基、取代的芳基、1-10个碳原子的直链和支链取代的芳基、烷氧基芳基、3-8个碳原子的环烷基、杂环、取代的杂环、杂芳基和取代的杂芳基。
在另一实施方案中,本发明是一种抑制哺乳动物蛋白酶体的蛋白酶因子的方法,其包括给予哺乳动物以有效治疗剂量的上面公开的化合物。
在仍是另一实施方案中,本发明是一种包含权利要求1的组分和一种或多种药学赋形剂的药学上的组合物。
现行实施方案的描述
本发明是一种采用具有下列通式的组分,抑制哺乳动物,尤其是人体的细胞无序增殖、传染性疾病和免疫性疾病的方法。这里:
X2为Ar或Ar-X3,其中X3为-C=O、或-CH2CO-、或(CH2)n(n=0-2),Ar为苯基、取代的苯基、吲哚基、取代的吲哚基、和任何其它的杂芳基;
R1和R2分别独自选自已知的侧链天然α-氨基酸和非天然的氨基酸、氢原子、1-10个碳原子的直链和支链烷基、1-10个碳原子的直链和支链取代的烷基、芳基和取代的芳基、1-10个碳原子的直链和支链取代的芳基、烷氧基芳基、3-8个碳原子的环烷基、杂环和取代的杂环、或杂芳基和取代的杂芳基;R2优选为联芳基或联苯;R1优选为异丁基;X1选自-OH、单或二烷基氨基、醇盐,芳基醇盐和其中:
X4为-OH、芳氨基、单或二烷基氨基、醇盐、或者芳基醇盐;优选-OH。
R3选自已知的侧链的天然α-氨基酸和非天然的氨基酸、氢原子、1-10个碳原子的直链烷基和支链烷基取代基、1-10个碳原子的直链和支链取代的烷基、芳基和取代的芳基、1-10个碳原子的直链和支链取代的芳基、烷氧基芳基、3-8个碳原子的环烷基、杂环和取代的杂环、或杂芳基和取代的杂芳基。
R3优选CO2H、CH2CO2H、(CH2)2CO2H、Arg、Lys、Asn、Gln、Asp、Glu、Phe和Nle。
下列是这里使用的特定术语的定义。
“卤素”指氟、溴、氯和碘原子。
“羟基”指-OH基团。
“硫醇”或“巯基”指-SH基团。
“烷基”指1至10个碳原子的环状、支链或直链烷基基团。通过下述基团如甲基、乙基、n-丙基、i-丙基、n-丁基、t-丁基、i-丁基(或3-甲基丙基)、环丙基甲基、i-戊基、n-戊基,n-己基和类似基团,进一步例证该术语。
“取代的烷基”指刚刚描述的包括一种或多种基团的低级烷基,该一种或多种基团例如羟基、硫醇、烷基硫醇、卤素、烷氧基、氨基、酰氨基、羧基、环烷基、取代环烷基、杂环、环杂烷基、取代的环杂烷基(cycloheteroalkyl)、酰基、羧基、芳基、取代芳基、芳氧基、杂芳基(hetaryl),取代的杂芳基、芳烷基、杂芳烷基、烷基链烯基、烷基炔基、烷基环烷基、烷基环杂烷基(alkyl cycloheteroalkyl)、氰基。这些基团可以附着在低级烷基部分的任一一个碳原子上。
“芳氧基”指-OAr基团,其中Ar是芳基、取代芳基、杂芳基、或者下面定义的取代杂芳基。
“氨基”指NRR’基团,其中R和R’可分别是氢原子、低级烷基、取代低级烷基、芳基、取代芳基、杂芳基、或者下面定义的取代杂芳基或酰基。
“酰氨基”指-C(O)NRR’基团,其中R和R’可分别是氢原子、低级烷基、取代低级烷基、芳基、取代芳基、杂芳基、或下面定义的取代杂芳基。
“羧基”指-C(O)OR基团,其中R可分别是氢原子、低级烷基、取代低级烷基、芳基、取代芳基、杂芳基、取代杂芳基或类似定义的基团。
“芳基”或“Ar”指具有至少一个芳环(例如,苯基或联苯基)或至少有一个环是芳环的多个稠环的芳香族碳环基团(例如,1,2,3,4-四氢萘基、萘基、蒽基、或菲基)。
“取代芳基”指以一种或多种官能团任意取代的芳基,该一种或多种官能团是例如卤素、低级烷基、低级烷氧基、硫代烷基、乙炔基、氨基、酰氨基、羧基、羟基、芳基、芳氧基、杂环、杂芳基、取代杂芳基、硝基、氰基、硫醇、硫酰氨基和类似基团。
“杂环”指饱和、不饱和、或者芳香族碳环基团,其具有一个单独的环(例如,吗啉代、吡啶基或呋喃基)或多个稠环(例如,萘基吡啶基、喹喔啉基、喹啉基、中氮茚基或苯[b]噻嗯基)且在环上含有至少一个如N、O或者S的杂原子,该碳环基团可任意是不取代的或用例如卤素、低级烷基、低级烷氧基、硫代烷基、乙炔基、氨基、酰氨基、羧基、羟基、芳基、芳氧基、杂环、杂芳基、取代杂芳基、硝基、氰基、硫醇、硫酰氨基和类似基团取代。
“杂芳基”或“杂芳基(hetar)”指一种杂环,在该杂环中至少一个杂环环是芳香族的环。优选的杂芳基是苯基、取代苯基、吲哚基和取代吲哚基。
“取代杂芳基”指用一种或多种官能团任意地单或多取代的杂环,该一种或多种官能团是例如卤素、低级烷基、低级烷氧基、硫代烷基、乙炔基、氨基、酰氨基、羧基、羟基、芳基、芳氧基、杂环、杂芳基、取代杂芳基、硝基、氰基、硫醇、硫酰氨基和类似基团。
“环烷基”指含有3至15个碳原子的二价环或多环烷基基团。
“取代的环烷基”指包括一种或多种取代基的环烷基团,该一种或多种取代基是例如卤素、低级烷基、取代低级烷基、烷氧基、硫代烷基、乙炔基、芳基、芳氧基、杂环、杂芳基、取代杂芳基、硝基、氰基、硫醇、硫酰氨基和类似基团。
下表Ⅰ介绍了可用于本发明的治疗方法,尤其是用做蛋白酶体功能抑制剂的化合物的实例。
上述的化合物可用于治疗疾病和治疗由20S蛋白酶体介导的紊乱,例如抗增殖性疾病、癌症、炎症。本发明的化合物优选用于治疗抗增殖性紊乱和炎症。本发明的化合物最优选用于治疗炎症。
本发明的化合物用于治疗哺乳动物由20S蛋白酶体介导的紊乱。
本发明的化合物通过以能够提供本发明的至少一种化合物给20S蛋白酶体的任一种给药方式,对哺乳动物预防和治疗地给药。有效的给药方式的非限定的列子包括口服、肠道外给药、皮肤给药、透皮地给药、直肠给药、鼻给药或者任何其他在本领域熟练人员知识范围内的适于药物组合物给药的途径。
本发明的组合物可以合适的药剂剂型给药。药剂的剂型极大地取决于采用的给药方式。术语药剂剂型指的是如片剂、胶囊、液体制剂和粉剂,这些剂型中单独含有本发明的20S蛋白酶体抑制剂或者还含有一种或多种药学赋形剂。助剂的选择,例如赋形剂和辅料,又大大取决于给药方式的选择。制药技术领域熟练人员会认可适于本发明的化合物给药的许多种剂型和赋形剂。
为本发明的化合物而选择的给药方式,基本上决定最终的形态和含有本发明的20S蛋白酶体抑制剂的化合物的药剂剂型。例如,以可口服的粉剂、片剂、胶囊、糊剂、酒剂、颗粒剂,或者可口服给药的溶液、混悬液和乳剂的形式,或者大丸药的形式,用含药的食物、饮用水口服本发明的化合物体内给药是有效的。体内给药也可采用定时释放制剂完成,该制剂包括如表面活性剂的添加剂或涂上一层淀粉的胶囊,或者采用一种如冻干速溶片的快速释放制剂完成。皮肤给药是有效的,例如,以透皮片、喷射剂或倾涂(pouring-on)和点抹(spotting-on)的形式。肠道外给药是有效的,例如,以注射剂(肌肉注射、皮下注射、静脉注射、腹膜注射)或植入片的形式。
包含有本发明的20S蛋白酶体抑制剂的适合的药剂剂型,包括但并非限制于溶液,例如注射液、口服液、稀释后口服给药的浓缩液、用于皮肤或体腔的溶液、倾涂(pour-on)和点抹(spot-on)制剂、凝胶;口服或皮肤给药以及注射用的乳剂和混悬液;半固体制剂;其中的活性化合物以膏基或者水包油或油包水乳剂基结合的制剂;固体制剂,例如粉剂、预混合物或浓缩物、颗粒剂、丸剂、片剂、块剂(boli)、胶囊剂;气溶胶和吸入剂,以及含有活性化合物的成形颗粒。
溶液剂型的药剂可通过静脉、腹膜和皮下注射给药。通过在合适的溶剂中溶解活性化合物制备注射溶液,如果适当,可加入辅料,例如增溶剂、酸、碱、缓冲盐、抗氧化剂和防腐剂。无菌过滤并抽取制得溶液。
可选择地,含有本发明组分的溶液可口服给药。本发明的组分的浓缩物优选口服给药,只不过是在将该浓缩物稀释至给药浓度之后给药。口服液和浓缩物以上述的注射液的制备方法制备。将所用的溶液滴加、涂刷、擦拭、喷溅或喷射于皮肤上。这些溶液以上述的注射液的制备方法制备。
凝胶体适用于皮肤,或者被引入体腔。凝胶体通过用一定用量的增稠剂以形成一种膏状稠度澄明物,处理注射用溶液情况下描述的制备方法制备的溶液制备,或者通过任一其它的本领域熟练人员公知的方法制备。
将倾涂和点抹制剂倾泻或溅泼在皮肤的有限区域内,活性化合物渗透入皮肤并系统地起作用。通过在适合的、皮肤耐受的溶剂或溶剂混合物中,溶解、混悬或乳化活性化合物来制备倾涂和点抹制剂。如果合适,可加入其它的辅料例如着色剂、吸收促进剂、抗氧化剂、光稳定剂和增粘剂。
乳剂可口服、皮肤或注射液形式给药。乳剂或是油包水型或是水包油型。通过在或疏水或亲水相中溶解20S蛋白酶体抑制剂,在合适的辅料例如乳化剂、着色剂、吸收促进剂、防腐剂、抗氧化剂、光稳定剂和增粘物质的帮助下,并以对应相的溶剂使该相均匀,制得乳剂。
混悬液可口服、皮肤或注射液形式给药。其通过在液体中混悬活性化合物制备,如果适合,可进一步加入辅料例如润湿剂、着色剂、吸收促进剂、防腐剂、抗氧化剂和光稳定剂。
本发明的药物组合物可包含一种或多种制药学上可接受的助剂形式的助剂。有效的助剂包括溶剂、增溶剂、防腐剂、增稠剂、润湿剂、着色剂、吸收促进剂、抗氧化剂、光稳定剂、增粘剂、增粘物质、填充剂、调味料、润滑剂,以及其它的对本领域熟练技术人员公知的药物组合物助剂。
所述助剂可以是溶剂,例如水,醇类如乙醇、丁醇、苯甲醇、甘油、丙二醇、聚乙二醇、N-甲基-吡咯烷酮、链烷醇、甘油,芳香醇如苯甲醇、苯基乙醇、苯氧乙醇,酯类如乙酸乙酯、乙酸丁酯、苯甲酸苄酯,醚类例如亚烷基二醇烷基醚如二丙二醇一甲醚、二乙二醇一丁基醚,酮类例如丙酮、甲基乙基酮,芳香族和/或脂肪族烃,植物的或合成的油,DMF,二甲基乙酰胺,N-甲基-吡咯烷酮,2,2-二甲基-4-氧代-亚甲基-1,3-二氧戊烷。
下列助剂可用作本发明组合物的增溶剂:提高活性化合物在主要溶剂中溶解度或防止其沉淀的溶剂。实例是聚乙烯基吡咯烷酮、聚氧乙基化的蓖麻油、聚氧乙烯化的脱水山梨糖醇醇酐酯。
例如,有用的防腐剂是苯乙醇、三氯丁醇、p-羟基苯甲酸酯和n-丁醇。
有效的增稠剂包括无机增稠剂例如皂土、硅胶体、一硬脂酸铝,有机增稠剂如纤维素衍生物、聚乙烯醇和它们的共聚物、丙烯酸酯和甲基丙烯酸酯。
可用于本发明药剂剂型的其它液体是,例如,均匀的溶剂、溶剂混合物和典型为表面活性剂的润湿剂。
有效的着色剂是无毒的并且可溶解或混悬的所有着色剂。
有效的吸收促进剂是DMSO、扩散油(spreading oils),例如肉豆蔻酸异丙酯、壬酸二丙二醇酯、硅油、脂肪酸脂、三酸甘油酯、脂肪醇。
有效的抗氧化剂是亚硫酸盐或偏亚硫酸氢盐例如偏亚硫酸氢钾,维生素C、丁基羟基甲苯、丁基羟基苯甲醚、维生素E。
一种有效的光稳定剂是苯基苯并咪唑磺酸(novantisolic acid)。
有效的增粘剂包括纤维素衍生物、淀粉衍生物、聚丙烯酸酯、天然聚合物如海藻酸盐、明胶。
有效的乳化剂包括非离子表面活性剂例如聚氧乙基化的蓖麻油、聚氧乙烯化的单油酸脱水山梨糖醇酯、单硬脂酸脱水山梨糖醇酯、单硬脂酸甘油酯、聚乙氧基硬脂酸酯、烷基酚聚乙二醇醚;两性表面活性剂,例如N-月桂醇-β-亚氨基二丙酸二钠或卵磷脂;阴离子表面活性剂,例如月桂醇硫酸钠、脂肪醇醚硫酸酯(fatty alcohol ether sulphates)、单/二烷基聚二醇醚正磷酸酯的单乙醇胺盐;阳离子表面活性剂例如氯化鲸蜡基三甲基铵(cetyltrimethylammonium chloride)。
用于稳定治疗乳剂的有效的增粘物质包括羧甲基纤维素、甲基纤维素和其它的纤维素以及淀粉衍生物、聚丙烯酸酯、海藻酸盐、明胶、阿拉伯胶、聚乙烯基吡咯烷酮、聚乙烯醇、甲基乙烯基醚和马来酸酐的共聚物、聚乙二醇、蜡、硅胶体或者上述物质的混合物。
为了制备固体药物剂型,如果合适就加入辅料,活性化合物与适合的助剂一起混合,得到的混合物就是期望的制剂。生理学上可接受的固体惰性助剂的实例包括氯化钠,碳酸盐例如碳酸钙、碳酸氢盐,氧化铝,二氧化硅,粘土,沉淀的或胶状的二氧化硅,以及磷酸盐。固体有机助剂的实例包括糖,纤维素,食物如奶粉、动物料粉、谷粉和糙谷粉以及淀粉。其它适合物助剂包括润滑剂和助流剂,例如硬脂酸镁、硬脂酸、滑石粉、皂土;崩解剂例如淀粉或交联的聚乙烯吡咯烷酮;粘合剂,例如淀粉、明胶或线性聚乙烯吡咯烷酮;以及干燥剂(dry binder)例如微晶纤维素。
这里描述的药剂剂型中,活性化合物可以与至少一种其他20S蛋白酶体抑制剂的混合物的形式存在。可以选择地,或者另外,本发明的药剂剂型可以,除至少一种20S蛋白酶体抑制剂之外,还包括任何的药物化合物,这种药物化合物能够治疗任一已知的疾病或紊乱,它们一起给药并不会产生不能接受的副作用。
治疗20S蛋白酶体介导的疾病和紊乱的方法包括给予有效剂量的所选化合物或者它们的混合物,其优选分散在药剂剂型内。本发明的现成药剂剂型含有10ppm至20wt%浓度的活性化合物,且优选0.1wt%至10wt%。给药之前稀释的本发明的药剂剂型优选含有活性化合物的浓度是0.5wt%至90wt%,更优选的是5wt%至50wt%。一般地,业已证实以每天按每公斤体重给予大约0.01mg至约100mg的活性化合物,可取得有效的结果。
在其它的因素中,根据给药的路线、年龄和患者的状况,本技术领域熟练人员可轻而易举地决定含有本发明的20S蛋白酶体抑制剂的药剂剂型的给药量和给药频率。为治疗急性或慢性疾病,每天给予这些剂量单位的药物1至10次。本发明的化合物按照本发明给药时,不会产生不能接受的毒理学作用。
含有本发明的20S蛋白酶体抑制剂的药剂剂型可通过下列制药学上常规技术制备,该技术包括磨粉、混合、制粒,如果需要可压片制成片剂;或者磨粉、混合并填充到硬明胶胶囊中。采用液体助剂时,该制剂可以是糖浆剂、酏剂、乳剂或者含水或无水混悬液。这类液体制剂可以经口(p.o.)直接给药或者填充到软胶囊中。
这里描述的化合物以上述的方法给药时,优选通过这里描述的口服给药该化合物所得到的本发明的方法。选择口服给药路线时,为产生与少量的例如肠道外的给药同样的作用,需要大量的活性剂。根据良好的临床实践,优选按照该方法给予一定浓度水平的化合物,在这种浓度水平化合物会产生有效的治疗结果,但并不产生有害的副作用。
本发明的化合物同样具有非治疗用途。本发明的组合物可用作20S蛋白酶体抑制剂试验的分析标准。
实施例1
用于本发明的治疗方法中的化合物可通过常规的有机化学方法制备。描述合成这些化合物的技术的参考资料包括Bodansky的“肽合成的实践(The Practice of Peptide Synthesis)”,Springer-Verlag,第一版,1984;“有机合成中的保护基团(Protective Groups inOrganic Synthesis,)”,第二版,John Wiley和Sons,纽约,1991。在室温下温和及持续地搅拌以完成所有肽的偶合。以胺的Kaiser检测监控肽的偶合和脱保护(deprotection)。Xaa指任何商业上可得到的、购买时预先附着在MBHA树脂上的氨基酸。Yaa和Zaa指任何商业上可得到的氨基酸。
本发明的化合物可以通过下列的固相肽合成(SPPS)通用步骤制备:称取Xaa-MBHA-树脂并将其转入带有多孔过滤器的注射器内。该树脂在二甲基甲酰胺(DMF)中预溶胀,然后通过在DMF中用30%哌啶处理30分钟,去除N-端的保护基团。除去脱保护溶液。该脱保护树脂以DMF洗涤5次,以甲醇洗涤5次,然后以DMF洗涤5次。接着,采用Yaa的DMF溶液[该溶液含有三种等量物质,它们是Yaa、碳化二亚胺偶合试剂和HOBT(羟基苯并三唑)]来将氨基酸Yaa偶合到脱保护树脂上。与Yaa溶液的随后的偶合对达到能通过Kaiser检测的偶合效率是必需的。重复N-端的基团脱保护和Yaa偶合步骤以偶合一个第三氨基酸Zaa。最后的偶合步骤是在DMF中采用酮酸、碳化二亚胺和HOBT,并且重复该步骤直到偶合通过Kaiser检测。真空干燥所得的树脂上的肽序列至少六小时,然后以或95/5三氟醋酸/水或新制备的90%的三氟醋酸溶液、3%乙二硫醇、5%苯硫基甲烷和2%苯甲醚溶液处理2.5小时将其分解。分解的产物通过或从水中冷冻干燥或从乙醚中捣碎回收。产物的纯度经TLC估测。通过1H NMR检测选择的肽样品以确定产物的身份。
实施例2
按照实施例1的方法制备本实施例的(3’-吲哚基丙酮酸)-N-联苯丙胺酸-D-Leu-Asp-OH。
称量Fmoc-N-Asp(Ot-Bu)-MBHA-树脂(20mg)并将其转入带有多孔过滤器的注射器内。该树脂以1ml的DMF预溶胀30分钟。然后通过在DMF中以20%哌啶处理30分钟,去除Fmoc(芴基甲氧基羰基)保护基团。除去脱保护溶液。将脱保护树脂以DMF洗涤5次、甲醇洗涤5次,然后以DMF洗涤5次。接着,在1ml含有Fmoc-D-Leu-OH(3等份)的DMF溶液中将Fmoc-D-Leu-OH偶合到脱保护树脂(1等份)上,这种DMF溶液同时含有碳化二亚胺(3等份)和HOBT(羟基苯并三唑)(3等份)。与Fmoc-D-Leu-OH溶液的二次或三次偶合对达到通过Kaiser检测的偶合效率是必需的。重复Fmoc脱保护和氨基酸偶合步骤以偶合Fmoc-N-(4,4-联苯)丙胺酸。最后的偶合步骤是在DMF中使用吲哚基丙酮酸(5等份)、二异丙基碳化二亚胺(5等份)和HOBT(5等份),并且重复该步骤直到偶合通过Kaiser检测。真空干燥所得的树脂上的肽序列至少六小时,然后以或95/5三氟醋酸/水或新制备的90%三氟醋酸溶液、3%乙二硫醇、5%苯硫基甲烷和2%苯甲醚溶液处理2.5小时将其分解。分解的产物通过从水中冷冻干燥或从乙醚中捣碎回收。产物的纯度经TLC估测。
1H NMR(400MHz,d6-DMSO):δ6.5-7.7(m,14H),4.5(m,1H),4.1(m,2H),3.4(m,2H),3(m,H),2.7(m,1H),1.1-1.5(m,3H),0.5-0.9(m,6H)。
实施例3
采用克伦米摩特帕斯(Chiron Mimotopes)大头针技术制备本实施例的(3’-吲哚基丙酮酸)-N-联苯丙胺酸-D-Leu-Asp-OH。
通过在800μl的偶合溶液(100mM氨基酸、100mM DIC、10mMDMAP、1/4的DMF/CH2CI2)中偶合每个树脂针状物2小时,第一氨基酸残基Xaa附着在4-(羟基甲基)苯氧基乙酰氨基柄针状物树脂(resinpins)(5.7μmole/pin)上。然后以DMF漂洗5分钟、甲醇漂洗涤两个5分钟,并于空气中干燥15分钟。在DMF中以800μl 20%的哌啶进行Fmoc基团的脱保护。重复针状物的洗涤(5分钟DMF洗涤,两个5分钟甲醇洗涤,15分钟空气干燥)。偶合(100mM Yaa、100mM DIC、100mM HOBT、和DMF中的溴酚蓝指示剂)第二氨基酸残基Yaa直到蓝色不再附着在针状物表面为止。需要时可重复该偶合。同样,重复漂洗周期和Fmoc脱保护洗涤。下一个氨基酸、Zaa通过重复偶合Yaa的偶合和洗涤步骤偶合,如果需要可反复偶合。最后的残基、15等份100mM吲哚基丙酮酸与15等份DIC、15等份HOBT和DMF中的溴酚蓝指示剂偶合。如果需要可重复偶合。最后的洗涤之后,在单个2ml塑料离心试管中,以1.5ml新制备的90%三氟醋酸、3%乙二硫醇、5%苯硫基甲烷和2%苯甲醚溶液处理2.5小时,从其载体上清除和分解橙色的针状物。从试管中除去这些针状物并在氮气流下将混合物吹到接近干。以乙醚研碎并旋转每个试管。这个步骤每个试管重复3次。收集、冻干、称量和使用沉淀的肽。通过TLC估测产物的纯度。对初始产物进行点样(cospot),并与实施例1中得到的真正样品核对。
实施例4
如下列方法试验按照实施例1制备的本发明的化合物。按照公布的方法(Wilk S.和Orlowski,M1983,40842 J.Neurochem)纯化来自牛脑的20S催化亚基蛋白酶体(也称之为多催化作用的蛋白酶体复合物)至均一。通过随着底物肽琥珀酰-亮氨酸-亮氨酸-缬氨酸-酪氨酸-7-氨基-4-甲基香豆素裂解的荧光的增强,检测该复合物的胰凝乳蛋白酶活度。体内标准的定量分析由在200μl 50mM HEPES中的2μg 20S蛋白酶体、0.1-100μg/ml蛋白酶体抑制剂组成,HEPES中含有0.1%的十二烷基硫酸钠,pH7.5。通过加入50μM荧光团肽底物激活蛋白分解反应,并使反应在37℃下进行15分钟。通过加入100μl、pH4.0的100mM醋酸盐缓冲液终止该反应。蛋白分解的速度直接与游离的氨基甲基香豆素的量成正比,该物质的量通过荧光光谱(EX370nm,EM430nm)测量。
表Ⅱ表示的是20S蛋白酶体抑制剂的定量分析结果。
表Ⅱ抑制20S蛋白酶体的胰凝乳蛋白酶活度的IC50值
化合物 | IC50μg/mL | 化合物 | IC50μg/mL |
1234567891011 | 1010>1010>10>10>10>10>10>10>10 | 105106107108109110111113114115116 | >10>10>10>10>10>10>10>10101010 |
化合物 | IC50μg/mL | 化合物 | IC50μg/mL |
1213141516171819202122232425262728293031323334353637383940414243444546474849505152535455 | >10>10>101010>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10 | 117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146147148149150151152153154155156157158159160 | 1010>10>10>10>10>10>10>10>10>10>101010101010>10>10>10>10>10>10>10>10>10>10101010101010>10>10>10>10>10>10>10>10>10>10>10 |
化合物 | IC50μg/mL | 化合物 | IC50μg/mL |
5657585960616263646566676869707172737475767778798081828384858687888990919293949596979899 | >10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10>10 | 161162163164165166167168169170171172173174175176177178179180181182183184185186187188189190191192193194195196197198199200201202203204 | >10>10>10>10>10>10>10>10>10>10>10>10>105>10110>10>10510>1010>105>10>105>10333>10>10>10>1010>10>10>10>10>10>10>10 |
化合物 | IC50μg/mL | 化合物 | IC50μg/mL |
100101103104 | >10>10>10>10 | 205206207 | >10>1010 |
如下列方法试验按照实施例1制备的本发明的化合物。按照公布的方法[Wilk S.和Orlowski,M1983,40842神经化学杂志(J.Neurochem)]纯化来自牛脑的20S催化亚基蛋白酶体(也称之为多催化作用的蛋白酶体复合物)至均一。通过随着底物肽CBZ-D-Ala-Leu-Arg-(7-氨基-4-甲基香豆素)裂解的荧光的增强,检测该复合物的胰蛋白酶活度。体内标准的定量分析由在200ml 50mM HEPES中的2μg 20S蛋白酶体、0.1-100μg/ml蛋白酶体抑制剂组成,HEPES中含有0.1%的十二烷基硫酸钠,pH7.5。通过加入50mM荧光团肽底物激活蛋白分解反应,并使反应在37℃下进行15分钟。通过加入100ml、pH4.0的100mM醋酸盐缓冲液终止该反应。蛋白分解的速度直接与游离的氨基甲基香豆素的量成正比,该物质的量通过荧光光谱(EX370nm,EM430nm)测量。抑制剂在>10μg/ml时,检测化合物1-207的胰蛋白酶活度抑制和活性。
实施例5
也可以如下列方法试验按照实施例1制备的本发明的化合物。按照公布的方法[Wilk S.和Orlowski,M1983,40842神经化学杂志(J.Neurochem)]纯化来自牛脑的20S催化亚基蛋白酶体(也称之为多催化作用的蛋白酶体复合物)至均一。通过随着底物肽CBZ D-Ala-Leu-Arg-(7-氨基-4-甲基香豆素)裂解的荧光的增强,检测该复合物的胰蛋白酶活度。体内标准的定量分析由在200μl 50mM HEPES中的20μg 20S蛋白酶体、0.1-100μg/ml蛋白酶体抑制剂组成,HEPES中含有0.1%的十二烷基硫酸钠,pH7.5。通过加入50mM荧光团肽底物激活蛋白分解反应,并使反应在37℃下进行15分钟。通过加入100μl、pH4.0的100mM醋酸盐缓冲液终止该反应。蛋白酶解的速度直接与游离的氨基甲基香豆素的量成正比,该物质的量通过荧光光谱(EX370nm,EM430nm)测量。抑制剂在>10μg/ml时,检测化合物1-207的胰蛋白酶活度抑制,且化合物1-207仍有活性。
实施例6
也可以如下列方法试验按照实施例1制备的本发明的化合物。按照公布的方法[Wilk S.和Orlowski,Ml983,40842神经化学杂志(J.Neurochem)]纯化来自牛脑的20S催化亚基蛋白酶体(也称之为多催化作用的蛋白酶体复合物)至均一。通过随着底物肽CBZ D-Ala-Leu-Glu-(7-氨基-4-甲基香豆素)裂解的荧光的增强,检测该复合物的胰蛋白酶活度。体内标准的定量分析由在200ml 50mM HEPES中的2μg 20S蛋白酶体、0.1-100μg/ml蛋白酶体抑制剂组成,HEPES中含有0.1%的十二烷基硫酸钠,pH7.5。通过加入50mM荧光团肽底物激活蛋白酶解反应,并使反应在37℃下进行15分钟。通过加入pH4.0的100mM醋酸盐缓冲液终止该反应。蛋白分解的速度直接与游离的氨基甲基香豆素的量成正比,该物质的量通过荧光光谱(EX370nm,EM430nm)测量。抑制剂在>10μg/ml时,检测化合物1-207的肽基谷氨酰基活度抑制。抑制剂为5μg/ml时,化合物190仍有活性。
Claims (28)
1、一种具有下列结构式的化合物,
其中:
X2为Ar或Ar-X3,这里X3为-C=O、或-CH2CO-或(CH2)n(n=0-2),Ar为苯基、取代的苯基、吲哚基、取代的吲哚基、和任何其它的杂芳基;
R1和R2分别各自选自已知的侧链天然α-氨基酸和非天然的氨基酸、氢原子、1-10个碳原子的直链和支链烷基、1-10个碳原子的直链和支链取代的烷基、芳基、取代的芳基、1-10个碳原子的直链和支链取代的芳基、烷氧基芳基、3-8个碳原子的环烷基、杂环、取代的杂环、杂芳基和取代的杂芳基;
X1选自-OH、单烷基氨基、二烷基氨基、醇盐、芳基醇盐和
其中X4为氢氧化物、芳氨基、单烷基氨基、二烷基氨基、醇盐、或者芳基醇盐;
R3选自已知的侧链天然α-氨基酸、非天然的氨基酸、氢原子、1-10个碳原子的直链和支链烷基、1-10个碳原子的直链和支链取代的烷基、芳基、取代的芳基、1-10个碳原子的直链和支链取代的芳基、烷氧基芳基、3-8个碳原子的环烷基、杂环、取代的杂环、杂芳基和取代的杂芳基。
2、根据权利要求1的化合物,其中X1是
3、根据权利要求2的化合物,其中X4为-OH。
4、根据权利要求1的化合物,其中X4为-OH。
5、根据权利要求4的化合物,其中R1选自1-10个碳原子的支链烷基和1-10个碳原子的直链烷基取代基。
6、根据权利要求1的化合物,其中X4为-OH,R1和R2分别各自选自已知的侧链天然α-氨基酸、非天然的氨基酸、和1-10个碳原子的直链和支链烷基取代基。
7、根据权利要求6的化合物,其中X3选自-C=O、-CH2CO-和(-CH2)n,这里n=0-2。
8、根据权利要求7的化合物,其中R3选自CO2H、CH2CO2H、(CH2)2CO2H、Arg、Lys、Asn、Gln、Asp、Glu、Phe和Nle。
9、根据权利要求8的化合物,其中Ar选自吲哚基和取代的吲哚基。
10、根据权利要求8的化合物,其中Ar选自苯基和取代的苯基。
11、根据权利要求1的化合物,其中X2为CH2CO,R1为异丁基。
12、根据权利要求11的化合物,其中X2为-OH,R3为H,X3为H,Ar选自包括苯基和吲哚基的基团。
13、根据权利要求11的化合物,其中Ar是吲哚基、R1是D-Leu(异丁基),X1为-OH,X3为-OH。
14、根据权利要求13的化合物,其中R2是2-NAP,R3为Asp。
15、根据权利要求13的化合物,其中R2是4,4’-BPA,R3选自包括Nle、Asp、Asn、β-丙胺酸、His和Arg的基团。
16、根据权利要求1的化合物,其中Ar是吲哚基,X3选自-C=O、-CH2CO,R2选自联芳基和取代的联苯,R1是异丁烷,R3为CH2CO2H并且X4为-OH。
17、根据权利要求1的化合物,其中Ar选自苯基和取代的苯基,X3选自-C=O、-CH2CO,R2选自联芳基和取代的联苯,R1是异丁基,R3为CH2CO2H并且X4为-OH。
18、根据权利要求1的化合物,其中Ar是吲哚基,X3为-CH2CO,R2是4,4’-联苯,R1是异丁基,R3为CH2CO2H并且X4为-OH。
19、一种权利要求1的化合物的阳离子盐。
20、一种权利要求1的化合物的酸性盐。
21、一种哺乳动物体内抑制癌的方法,包括给予哺乳动物有效治疗剂量的权利要求1的化合物。
22、根据权利要求21的方法,其中的有效治疗剂量范围为每kg哺乳动物的体重大约0.001至大约100mg。
23、根据权利要求21的方法,其中将该化合物给予患有包括狼疮、MS、ARD和关节炎的自身免疫性紊乱疾病的哺乳动物服用。
24、根据权利要求23的方法,其中的紊乱疾病是RA。
25、根据权利要求21的方法,其中的哺乳动物是人类。
26、一种包括权利要求1和一种或多种药物赋形剂的药物组合物。
27、权利要求26的药物组合物,其中药物组合物的剂型是溶液。
28、权利要求26的药物组合物,其中药物组合物的剂型是片剂。
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US (2) | US6075150A (zh) |
EP (1) | EP1058689A1 (zh) |
JP (1) | JP3863370B2 (zh) |
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CN (1) | CN1289340A (zh) |
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BR (1) | BR9907256A (zh) |
CA (1) | CA2319150C (zh) |
GE (1) | GEP20032869B (zh) |
HU (1) | HUP0100901A3 (zh) |
IL (2) | IL137475A0 (zh) |
NO (1) | NO327049B1 (zh) |
NZ (1) | NZ505892A (zh) |
PL (1) | PL202504B1 (zh) |
RU (1) | RU2192429C2 (zh) |
TW (1) | TW593339B (zh) |
UA (1) | UA71559C2 (zh) |
WO (1) | WO1999037666A1 (zh) |
ZA (1) | ZA99161B (zh) |
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1999
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- 1999-01-19 EP EP99903185A patent/EP1058689A1/en not_active Ceased
- 1999-01-19 KR KR10-2000-7008135A patent/KR100417888B1/ko not_active IP Right Cessation
- 1999-01-19 RU RU2000122474/04A patent/RU2192429C2/ru not_active IP Right Cessation
- 1999-01-19 WO PCT/US1999/001097 patent/WO1999037666A1/en active IP Right Grant
- 1999-01-19 CN CN99802421A patent/CN1289340A/zh active Pending
- 1999-01-19 PL PL343269A patent/PL202504B1/pl not_active IP Right Cessation
- 1999-01-19 UA UA2000074508A patent/UA71559C2/uk unknown
- 1999-01-19 HU HU0100901A patent/HUP0100901A3/hu unknown
- 1999-01-19 NZ NZ505892A patent/NZ505892A/xx unknown
- 1999-01-19 JP JP2000528587A patent/JP3863370B2/ja not_active Expired - Fee Related
- 1999-01-19 CA CA002319150A patent/CA2319150C/en not_active Expired - Fee Related
- 1999-01-19 BR BR9907256-4A patent/BR9907256A/pt not_active Application Discontinuation
- 1999-01-19 GE GEAP19995526A patent/GEP20032869B/en unknown
- 1999-01-20 AR ARP990100205A patent/AR012781A1/es active IP Right Grant
- 1999-01-22 TW TW088101002A patent/TW593339B/zh not_active IP Right Cessation
- 1999-07-19 US US09/356,842 patent/US6781000B1/en not_active Expired - Fee Related
-
2000
- 2000-07-24 IL IL137475A patent/IL137475A/en not_active IP Right Cessation
- 2000-07-25 NO NO20003807A patent/NO327049B1/no not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8594771B2 (en) | 2005-12-28 | 2013-11-26 | General Electric Company | Devices and methods for self-administered ECG examinations |
CN104837858A (zh) * | 2012-10-11 | 2015-08-12 | 弗·哈夫曼-拉罗切有限公司 | 酮酰胺免疫蛋白酶体抑制剂 |
Also Published As
Publication number | Publication date |
---|---|
US6075150A (en) | 2000-06-13 |
KR100417888B1 (ko) | 2004-02-11 |
NZ505892A (en) | 2002-10-25 |
PL202504B1 (pl) | 2009-06-30 |
NO20003807D0 (no) | 2000-07-25 |
AU2326799A (en) | 1999-08-09 |
ZA99161B (en) | 1999-07-28 |
NO327049B1 (no) | 2009-04-14 |
UA71559C2 (en) | 2004-12-15 |
JP3863370B2 (ja) | 2006-12-27 |
WO1999037666A1 (en) | 1999-07-29 |
BR9907256A (pt) | 2001-10-09 |
CA2319150A1 (en) | 1999-07-29 |
PL343269A1 (en) | 2001-08-13 |
US6781000B1 (en) | 2004-08-24 |
GEP20032869B (en) | 2003-01-27 |
HUP0100901A3 (en) | 2001-11-28 |
HUP0100901A2 (hu) | 2001-08-28 |
TW593339B (en) | 2004-06-21 |
KR20010034381A (ko) | 2001-04-25 |
NO20003807L (no) | 2000-09-25 |
AR012781A1 (es) | 2000-11-08 |
RU2192429C2 (ru) | 2002-11-10 |
EP1058689A1 (en) | 2000-12-13 |
AU747835B2 (en) | 2002-05-23 |
IL137475A (en) | 2006-10-05 |
IL137475A0 (en) | 2001-07-24 |
JP2002501080A (ja) | 2002-01-15 |
CA2319150C (en) | 2004-08-31 |
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