CN1247543A - 环肽衍生物 - Google Patents
环肽衍生物 Download PDFInfo
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- CN1247543A CN1247543A CN97181862A CN97181862A CN1247543A CN 1247543 A CN1247543 A CN 1247543A CN 97181862 A CN97181862 A CN 97181862A CN 97181862 A CN97181862 A CN 97181862A CN 1247543 A CN1247543 A CN 1247543A
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- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
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Abstract
本发明涉及式Ⅰ即环-(Arg-X-Asp-R1)化合物和其盐,其中X是Gly、Ala或NH-NH-CO,R1是式Ⅱ的基团,和R2、R3、R4具有在权利要求1中给出的含义,其可以作为整联蛋白抑制剂来预防和治疗循环方面的疾病,特别是血栓形成、心肌梗塞、冠心病、动脉硬化,通过血管生成来维持或传播的病理性疾病,以及治疗肿瘤。
Description
本发明涉及式I化合物和其盐:
环-(Arg-X-Asp-R1) I其中X是Gly、Ala或NH-NH-CO,这里上述氨基酸也可以是氨基酸衍生物,并且这些氨基酸残基以肽方式通过α-氨基和α-羧基相互连接起来,R1是式II的基团R2、R3、R4在各种情况下均相互独立地是H、A、Ar、R5-Ar、Het或R5-Het,A是具有1至6个碳原子的烷基,Ar是未取代的或被R7、R8或R9单、二或三取代的苯基或未取代的萘基,R5是具有1至6个碳原子的亚烷基,R6、R6’在各种情况下相互独立地是H、A、苄基或苯基,R7、R8、R9在各种情况下相互独立地是R6、OR6、Hal、NO2、NR6R6’、NHCOR6、CN、NHSO2R6、COOR6或COR6,Hal是F、Cl、Br或I,和Het是含有1至4个N、O和/或S原子的单核或双核杂环,该杂环是未取代的,或可以被一个、两个或三个Hal、A、NR6R6’、CN或NO2取代。其中,该化合物不仅包括旋光性氨基酸和氨基酸衍生物,而且还包括D和L构型。
在例如DE43 10 643或EP 0 683 173中公开了类似的环肽化合物。
本发明的目的是发现具有有利特性的新化合物,尤其是那些可以用于制备药物的化合物。
现已发现,式I化合物及其盐在好的耐受性下具有非常有用的药理学特性。特别是,它们可以作为整联蛋白抑制剂,其中尤其对αv、β3或β5-整联蛋白受体与其配体的相互反应具有抑制作用,例如,血纤蛋白原与β3-整联蛋白受体之间的结合。这些化合物对整联蛋白αvβ1、αvβ3、αvβ5、αIIb β3以及αvβ6和αvβ8具有特别的活性。这种活性作用可以按照例如J.W.Smith等人在《生物化学杂志》(J.Biol.Chem.)265,12267-12271(1990)中描述的方法来证明。
P.C.Brooks,R.A.Clark和D.A.Cheresh在《科学》(Science)264 569-71(1994)中报导了有关依赖血管整联蛋白与胞外基质蛋白间相互反应的血管生成的研究。
P.C.Brooks,A.M.Montgomery,M.Rosenfeld,R.A.Reisfeld,T.-Hu,G.Kilier和D.A.Cheresh在《细胞》(Cell)79,1157-64(1994)中描述了利用环肽来抑制这类相互反应并促使生血管性血管发生凋亡(编程性细胞死亡)的可能性。
能够阻断整联蛋白受体与其配体之间的相互作用,例如血纤蛋白原与血纤蛋白受体(糖蛋白,IIb/IIIa)的相互作用的式I化合物可以作为GPIIb/IIIa拮抗剂来预防因肿瘤转移而造成的肿瘤细胞扩散,这点可以通过如下观察来证明:
肿瘤细胞从局部性肿瘤扩散到血管系统中是肿瘤细胞与血液的血小板相互作用,结果导致形成微凝聚体(微凝血物)来进行的。微凝聚体中的保护作用使肿瘤细胞被屏蔽起来,并且这种肿瘤细胞不被免疫系统细胞识别。微凝聚体沉淀于血管壁上,易使肿瘤细胞进一步穿透到组织中。由于血纤蛋白原结合到血纤蛋白原受体上从而促成在血液中已活化血小板上形成微凝血物,所以GPIIa/IIIb拮抗剂可作为有效的肿瘤转移抑制剂。
式I化合物在人用药物和兽药中都可用作药物活性成分,尤其是为了预防和/或治疗血栓形成、心肌梗塞、动脉硬化、炎症、中风、心绞痛、肿瘤疾病、溶骨疾病例如骨质疏松症、病理性血管生成疾病例如炎症、眼科疾病、糖尿病视网膜病、斑变性、近视、眼组织胞浆菌病、风湿性关节炎、骨关节炎、潮红青光眼、溃疡性结肠炎、节段性回肠炎、动脉粥样硬化、牛皮癣、血管成形术后再狭窄、病毒性感染、细菌性感染、真菌性感染,在急性肝功能衰弱以及在创伤愈合中对治疗过程发挥辅助作用。
式I化合物也可以作为具有抗微生物作用的物质在采用了生物材料、植人物、导管或心脏起博器的手术中使用。在这里,化合物发挥着防腐抗菌作用。化合物抗微生物活性的功效可以通过P.Valentin-Weigund等人在《感染和免疫》(Infection andImmunity),2851-2855(1988)中描述的方法来证明。
因为式I化合物抑制血纤蛋白原形成和因此在血液血小板上生成血纤蛋白原受体的配体,所以该化合物可作为体内诊断剂用于血管系统中血栓的发现和定位,只要该化合物被放射性或UV可探测的基团取代。
式I化合物可以作为血纤蛋白原形成的抑制剂,而且可以作为活性助剂,用于研究血小板在不同活化期的新陈代谢和血纤蛋白原受体的细胞间信号机理的代谢作用。置入的“标记物”的可探测单位,例如通过3H的同位素标记,在结合到受体上之后,可以探测上述机理。
在上下文中引用的氨基酸残基缩写代表下列氨基酸残基:Ala 丙氨酸AMP 氨基甲基苯基Asn 天冬酰胺Arp 天冬氨酸Arg 精氨酸Cys 半胱氨酸Gln 谷氨酞胺Glu 谷氨酸Gly 甘氨酸His 组氨酸Homo-Phe 高苯丙氨酸Ile 异亮氨酸Leu 亮氨酸Lys 赖氨酸Met 甲硫氨酸Nle 正亮氨酸Orn 鸟氨酸Phe 苯丙氨酸Phg 苯基甘氨酸4-Hal-Phe 4-卤代-苯丙氨酸Pro 脯氨酸Ser 丝氨酸Thr 苏氨酸Trp 色氨酸Tyr 酪氨酸Val 颉氨酸
另外,下列缩写代表的含义是:Ac 乙酰基BOC 叔丁氧基羰基CBZ或Z 苄氧基羰基DCCl 二环己基碳化二亚胺DMF 二甲基甲酰胺EDCI N-乙基-N,N’-(二甲氨基丙基)碳化二亚胺Et 乙基FCA 荧光素羧酸Fmoc 9-芴基甲氧基羰基HOBt 1-羟基苯并三唑Me 甲基MBHA 4-甲基二苯甲基胺Mtr 4-甲氧基-2,3,6-三甲基苯基磺酰基HONSu N-羟基琥珀酰亚胺OBzl 苄基酯OtBu 叔丁酯Oct 辛酰基OMe 甲酯OEt 乙酯POA 苯氧基乙酰基Sal 水杨酰基TFA 三氟乙酸Trt 三苯甲基
如果上述氨基酸存在数种不同的对映体,那么,在上下文中,例如作为式I化合物的组成部分,氨基酸包括了所有异构体及它们的混合物(例如DL构型)。另外氨基酸,例如作为式I化合物的组成部分,可以具有相应的本身已知的保护基团。
本发明的化合物还包括所谓的前药物衍生物,即那些被例如烷基或酰基基团、糖类或寡肽基团修饰的式I化合物,这些化合物在机体内可以迅速地分解为本发明所述的有效化合物。对此还包括本发明化合物的可被生物降解的聚合衍生物,例如在《药物学国际杂志》(Int.J.Pharm.)115,61-67(1995)中所述的。
其构型没有具体给出的氨基酸具有(S)或(L)构型。
此外,本发明还涉及制备权利要求1的式I化合物及其盐的方法,其特征在于(a)用环化剂处理式III化合物或者式II化合物可反应的衍生物
H-Z-OH III其中Z 是-Arg-X-Asp-R1-
-X-Asp-R1-Arg-
-Asp-R1-Arg-X-或
-R1-Arg-X-Asp-以及X和R1具有权利要求中给出的含义,或者(b)经溶剂分解试剂或氢解试剂处理,将式I化合物从它们的官能衍生物中释放出,和/或式I的碱性或酸性化合物经用酸或碱处理而获得其盐。
在上文及下文中,除非另有指明,基团X、R1、R2、R3和R4具有在式I、II和III中给出的含义。
在上述的结构式中,优选的烷基是:甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,以及还有戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基。
R2和R3在各种情况下相互独立地优选是例如H或A,以及Ar或R5-Ar。
R4优选是例如H、A、Ar或R5-Ar,以及是Het或R5-Het。
如果R4是烷基,那么在烷基链中存在的亚甲基可以被N、O或S替代。
优选的亚烷基是:亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或亚己基。
R5-Ar优选是苄基或苯乙基。
上述提及的氨基酸和氨基酸残基可以是它们的衍生物,其中优选那些N-甲基-、N-乙基-、N-丙基-、N-苄基-或Cα-甲基的衍生物。
还优选Asp和Glu的衍生物,尤其优选其侧链羧基与甲基、乙基、丙基、丁基、叔丁基、新戊基或苄基生成的酯;还优选Arg的衍生物,其-NH-C(=NH)-NH2-基团被乙酰基、苯甲酰基、甲氧基羰基或乙氧基羰基取代。
R6优选是例如甲基或乙基,以及苄基或苯基。
OR6优选是例如羟基或甲氧基。
COR6是烷酰基,优选是甲酰基、乙酰基、丙酰基、丁酰基、戊酰基或己酰基。
Ar是未取代的,优选如上所述单取代的苯基,优选的苯基是邻-、间-或对-甲苯基、邻-、间-或对-乙基苯基、邻-、间-或对-丙基苯基、邻-、间-或对-异丙基苯基、邻-、间-或对-叔丁基苯基、邻-、间-或对-三氟甲基苯基、邻-、间-或对-羟基苯基、邻-、间-或对-硝基苯基、邻-、间-或对-氨基苯基、邻-、间-或对-(N-甲基氨基)苯基、邻-、间-或对-乙酰氨基苯基、邻-、间-或对-三氟甲氧基苯基、邻-、间-或对-氰基苯基、邻-、间-或对-甲氧基苯基、邻-、间-或对-乙氧基苯基、邻-、间-或对-羧基苯基、邻-、间-或对-甲氧基羰基苯基、邻-、间-或对-乙氧基羰基苯基、邻-、间-或对-苄氧基羰基苯基、邻-、间-或对-(羧基甲氧基)苯基、邻-、间-或对-(甲氧基羰基甲氧基)苯基、邻-、间-或对-(甲氧基羰基乙氧基)苯基、邻-、间-或对-(N,N-二甲基氨基)苯基、邻-、间-或对-(N-乙基氨基)苯基、邻-、间-或对-(N,N-二乙基氨基)苯基、邻-、间-或对-氟苯基、邻-、间-或对-溴苯基、邻-、间-或对-氯苯基、邻-、间-或对-(二氟甲氧基)苯基、邻-、间-或对-(氟甲氧基)苯基、邻-、间-或对-甲酰基苯基、邻-、间-或对-乙酰基苯基、邻-、间-或对-丙酰基苯基、邻-、间-或对-丁酰基苯基、邻-、间-或对-戊酰基苯基、邻-、间-或对-(苯基磺酰氨基羰基)苯基、邻-、间-或对-苯氧基苯基、邻-、间-或对-甲硫基苯基、邻-、间-或对-甲基亚磺酰基苯基、邻-、间-或对-甲基磺酰基苯基或萘基。
Het优选是2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2-、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-噁唑基、3-、4-或5-异噁唑基、2-、4-或5-噻唑基、3-、4-或5-异噻唑基、2-、3-或4-吡啶基、2-、4-、5-或6-嘧啶基,还优选1,2,3-三唑-1-、-4-或-5-基、1,2,4-三唑-1-、-3-或-5-基、1-或5-四唑基、1,2,3-噁二唑-4-或-5-基、1,2,4-噁二唑-3-或-5-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、2-、3-、4-、5-或6-2H-噻喃基、2-、3-或4-4-H-噻喃基、3-或4-哒嗪基、吡嗪基、2-、3-、4-、5-、6-或7-苯并呋喃基、2-、3-、4-、5-、6-或7-苯并噻吩基、1-、2-、3-、4-、5-、6-或7-吲哚基、1-、2-、4-或5-苯并咪唑基、1-、3-、4-、5-、6-或7-苯并吡唑基、2-、4-、5-、6-或7-苯并噁唑基、3-、4-、5-、6-或7-苯并异噁唑基、2-、4-、5-、6-或7-苯并噻唑基、2-、4-、5-、6-或7-苯并异噻唑基、4-、5-、6-或7-苯并-2,1,3-噁二唑基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、3-、4-、5-、6-、7-或8-噌啉基或2-、4-、5-、6-、7-或8-喹唑啉基。杂环基团还可以被部分或全部氢化。
所以,Het还可以是,例如,2,3-二氢-2-、-3-、-4-或-5-呋喃基、2,5-二氢-2-、-3-、-4-或-5-呋喃基、四氢-2-或-3-呋喃基、1,3-二氧戊环-4-基-、四氢-2-或-3-噻吩基、2,3-二氢-1-、-2-、-3-、-4-或-5-吡咯基、2,5-二氢-1-、-2-、-3-、-4-或-5-吡咯基、1-、2-或3-吡咯烷基、四氢-1-、-2-或-4-咪唑基、2,3-二氢-1-、-2-、-3-、-4-或-5-吡唑基、四氢-1-、-3-或-4-吡唑基、1,4-二氢-1-、-2-、-3-或-4-吡啶基、1-,2-,3-或4-四氢-1-、-2-、-3-、-4-、-5-或-6-吡啶基、1-,2-,3-或4-哌啶基、2-,3-或4-吗啉基、四氢-2-、-3-或-4-吡喃基、1,4-二噁烷基、1,3-二噁烷-2-、-4-或-5-基、六氢-1-、-3-或-4-哒嗪基、六氢-1-、-2-、-4-或-5-嘧啶基、1-、2-或3-哌嗪基、1-,2-,3-,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基、1-,2-,3-,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-异喹啉基。
优选的氨基保护基团是乙酰基、丙酰基、丁酰基、苯乙酰基、苯甲酰基、甲苯甲酰基、POA、甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC、2-碘代乙氧基羰基、CBZ(“苄酯基”)、4-甲氧基苄基氧基羰基、FMOC、Mtr或苄基。
式I化合物可具有一个或更多的手性中心,因此存在不同的立体异构体。式I包括所有这些异构体。
因此,本发明特别涉及那些其中至少一个基团具有上述定义的优选含义的式I化合物。化合物中的一些优选基团可以用下列局部结构式Ia-Ih来表示,这些局部结构式是相对于式I而言,并且其中的基团如不特别指明就具有与式I中相同的定义,其中在a)中,R2、R3 在各种情况下相互独立地是H或A,
R4是 H、A、Ar、R5-Ar、Het或R5-Het和
R6、R6’ 是H或A;在b)中 R2、R3 在各种情况下相互独立地是H或A,
R4是 H、A、Ar、R5-Ar、Het或R5-Het
R6、R6’ 是H或A和
Ar 是未取代的或被R7单取代的苯基;在c)中 R2、R3 在各种情况下相互独立地是H或A,
R4 是H、A、Ar、R5-Ar、Het或R5-Het和
R6、R6’ 是H或A
Ar 是未取代的或被R7单取代的苯基和
Het 是单核芳族或饱和的具有1或2个N或O原
子的杂环,其是未取代的或被Hal、A、NR6R6’、
CN或NO2取代一或二次;在d)中 R2、R3 在各种情况下相互独立地是H或A,
R4 是H、A、Ar或R5-Ar
R6、R6’ 是H或A和
Ar 是未取代的或被R7单取代的苯基;在e)中 X 是Gly或Ala
R2、R3 在各种情况下相互独立地是H或A,
R4 是H、A、Ar或R5-Ar,
R6、R6’ 是H或A和
Ar 是未取代的或被R7单取代的苯基。
通常,式I化合物以及用于制备它们的起始反应物可以按照本身已知的方法来制备,这些在文献中都有具体描述(例如在《标准化手册》,如Houben-Weyl,Methoden der organischen Chmie,《有机化学方法》,Georg-Thieme-Verlag,Stuttgart),且反应是在适当的已知的条件下进行。在这里,实际中还可以对已知方法进行多种常规的改变,但在此不详细介绍。
若需要,起始反应物还可以现场制备,这样就不必将它们从反应混合物中分离出来,而是立刻直接用于下一步的反应以制得式I化合物。
优选通过在肽合成条件下环化式III化合物来制得式I化合物。对此按照常规的肽合成方法进行,如在Houben-Weyl,1.c.,第15/II卷,第1至806页(1974)中所述的。
该反应优选地在-10至40℃、优选0至30℃下,在惰性溶剂中,在脱水剂存在下例如在碳化二亚胺如DCCl或EDCl,丙烷磷酸酐(参见Angew.Chem.92,129(1980)),二苯基磷酰叠氮化物还2-乙氧基-N-乙氧基羰基-1,2-二氢喹啉存在下进行,其中所述的惰性溶剂是卤代烃如二氯甲烷,醚如四氢呋喃或二噁烷,酰胺如DMF或二甲基乙酰胺,腈如乙腈,二甲基亚砜或这些溶剂的混合物。为了在分子间形成肽之前促进分子内环化,在稀释的溶液中进行是适当的。
根据所采用的反应条件,反应时间为几分钟至14天。
同样也可以使用式III化合物的衍生物,优选预活化羧酸,或者酰卤,对称或混合的酸酐或活化酯来代替式III化合物。此类在常规酰化反应中可活化羧基的基团在文献中有报导(例如标准化手册,如Houben-Weyl,《有机化学方法》(Methoden der organischenChmle),Georg Thieme Verlag,Stuttgart;)。活化酯适合现场制备,例如加入HOBt或N-羟基琥珀酰亚胺。
通常,反应是在惰性溶剂中,在使用酰氯时在酸结合剂存在下进行,酸结合剂尤其是有机碱,例如三乙胺、二甲基苯胺、吡啶或喹啉。在反应中还适合于加入碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐,或是碱金属或碱土金属与弱酸生成的其它盐,优选的金属是钾、钠、钙或铯。
式III的起始化合物一般是新的。其可以按照已知的肽合成方法制备。
此外,式I化合物还可以通过溶剂解、尤其是水解或氢解方法从其官能衍生物中释放出来。
用于溶剂解或氢解的起始化合物优选是那些在一个或多个自由氨基和/或羟基上都带有相应的氨基和/或羟基保护基团的化合物,优选那些与N键合的H原子被氨基保护基团代替的起始化合物,例如,那些符合结构式I但NHR’-基团替代了NH2-基团(其中R’是一个氨基保护基,例如BOC或CBZ)的化合物。
另外,起始化合物还优选那些羟基上的H原子被羟基保护基团取替代的化合物,例如那些符合结构式I但其羟基苯基基团被R”O-苯基基团替代(其中R”是羟基保护基团)的化合物。
起始反应物分子中还可以含有几种相同或不同的氨基和/或羟基保护基团。如果含有的保护基团彼此各不相同,那么在多数情况下它们可以被选择性地脱除。
术语“氨基保护基团”是熟知用语,它是指那些适用于保护(阻断)氨基使其不发生化学反应,并且当分子的其他位置上所希望的化学反应进行完毕后很容易脱除的保护基团。这些氨基保护基团的实例特别是未取代或取代的酰基、芳基、芳烷氧基甲基或芳烷基。由于在所需化学反应(一系列反应)后这些氨基保护基团要被脱除掉,那么其种类和大小通常不是关键的;但是,优选含有1-20个碳原子,更优选含有1-8个碳原子的保护基团。本发明制备过程中,术语“酰基”可以在可行的最广范围内进行选择。该酰基包括了那些来源于脂族、芳脂族、芳族或杂环的羧酸或磺酸的酰基以及特别是烷氧基羰基、酰氧基羰基和更优选是芳烷氧基羰基。这类酰基例如是:烷酰基,如乙酰基、丙酰基和丁酰基;芳烷酰基,例如苯基乙酰基;芳酰基,例如苯甲酰基或甲苯甲酰基;芳氧基烷酰基,例如POA;烷氧基羰基,例如甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC或2-碘代乙氧基羰基;芳烷氧基羰基,例如CBZ(“苄氧基羰基”),4-甲氧基苄氧基羰基或FOMC;芳基磺酰基,如Mtr。在这些氨基保护基团中优选BOC和Mtr,还优选CBZ、Fmoc、苄基和乙酰基。
术语“羟基保护基团”也是公知用语,它是指那些适用于保护(阻断)羟基使其不发生化学反应,并且当分子的其他位置上所希望的化学反应进行完毕后很容易脱除的保护基团。上述未取代的或取代的芳基、芳烷基或酰基以及烷基都是这类常用的羟基保护基团。由于在所希望化学反应或系列反应后这些羟基保护基团要再被脱除掉,那么它们的性质和大小不是关键的。优选含有1-20个碳原子,更优选含有1-10个碳原子的保护基团。羟基保护基团的具体例子是,即苄基、对-硝基苯甲酰基、对-甲苯磺酰基、叔丁基和乙酰基,其中优选苄基和叔丁基。天冬氨酸和谷氨酸中的COOH基团优选以其叔丁基酯的形式来保护(例如Asp(OBut))。
根据所用保护基团的不同,例如,可利用例如强酸来将结构式I所示化合物从其官能衍生物中释放出来,常用的强酸有TFA和高氯酸,但还有其他无机强酸,例如盐酸或硫酸;有机强酸,例如三氯乙酸;或磺酸,如苯磺酸或对-甲基苯磺酸。如果可能的话,还可同时存在附加的惰性溶剂,但这并不总是必需的。优选的适宜溶剂是:有机溶剂,例如羧酸,如乙酸;醚,如四氢呋喃或二噁烷;酰胺,如DMF;卤代烃,如二氯甲烷;还有醇,例如甲醇、乙醇或异丙醇;及水。上述溶剂的混合物也适合作为溶剂。当反应中不加入其他任何溶剂时,所用TFA最好要过量;而高氯酸是以比例为9∶1的乙酸:70%高氯酸的混合物的形式来使用。脱除保护基团的反应温度通常约是在0至约50℃之间,优选的脱除温度范围是15-30℃(室温)。
BOC、OBut和Mtr基团可以被脱除掉,例如,优选在15-30℃条件下,利用TFA的二氯甲烷溶液或约3至5N盐酸的二噁烷溶液进行脱除;而采用约5至50%二甲胺、二乙胺或哌啶的DMF溶液,在15至30℃条件下脱除FMOC基团。
组氨酸、天冬酰胺、谷氨酰胺和半胱氨酸中采用三苯甲基作为氨基酸保护基团。根据所希望终产物的不同,利用TFA/10%苯硫酚时将会把各氨基酸上的所有三苯甲基脱除;而当采用TFA/苯甲醚或TFA/苯硫基甲烷时,仅将His、Asn和Gln上的三苯甲基脱除,但Cys侧链上的仍保留。
能被氢解脱除的保护基团(例如CBZ或苄基)可以例如采用氢在催化剂(例如责金属催化剂如钯催化剂,通常这类催化剂附着在载体例如碳上)存在下来进行处理。此时,适用溶剂可以是上述溶剂,尤其是,例如醇,如甲醇或乙醇;或酰胺,如DMF。通常,氢解反应温度是在0-100℃之间,同时压力为约1-200巴,优选的反应条件是20-30℃和1-10巴。在20-30℃时,采用在5-10%Pd/C的甲醇液中的氢或在Pd/C的甲醇/DMF液中的甲酸铵(代替氢)来脱除CBZ基团可以得到满意的效果。
将式I的碱用酸处理可以转化成相应的酸加成盐,例如,将碱与等量的惰性溶剂中的酸,如乙醇中反应,然后蒸发浓缩。此类反应中,优选那些合适的并且能得到生理无毒性盐的酸。固此,可以采用无机酸,例如硫酸、硝酸、氢卤酸如盐酸或氢溴酸、磷酸如正磷酸和氨基磺酸;另外还包括有机酸,尤其是脂肪族、脂环族、芳脂族、芳香族或杂环的一元或多元羧酸、磺酸或硫酸,例如,甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、乙磺酸、乙二磺酸:2-羟基乙磺酸、苯磺酸、对甲苯磺酸、萘单磺酸、萘二磺酸和十二烷基硫酸。含有生理毒性酸的盐,如苦味酸盐,可以用来分离和/或纯化式I化合物。
另一方面,式I的酸可以通过与碱反应转化成生理无毒性的金属盐或铵盐。此时,特别适用的盐是钠、钾、镁、钙和铵盐,还有取代铵盐,例如,二甲基、二乙基或二异丙基铵盐,单乙醇、二乙醇或二异丙醇铵盐,环己基和二环己基铵盐,和二苄基乙二胺盐;以及,还有精氨酸或赖氨酸的盐。
本发明还进一步涉及式I化合物和/或其生理无毒性盐在制备药物制剂中的应用,尤其是通过非化学途径制备药物。在这方面,它们可以与至少一种固体、液体和/或半固体的载体物质或辅料共同制成适当的制剂,如果需要,还可适当地结合一种或多种其它活性化合物。
本发明还涉及了含有至少一种式I化合物和/或它们的生理无毒性盐的药物制剂。
这些制剂可以作为人用药物和兽药。合适的载体物质是那些适于肠胃内(例如口服)、肠胃外、局部施用或吸入喷剂形式给药的有机或无机物质,并且这些载体物质不与本发明新化合物发生反应,例如水、植物油、苯甲醇、亚烷基二醇、聚乙二醇、三乙酸甘油酯、明胶、碳水化合物如乳糖或淀粉、硬脂酸镁、滑石或凡士林。为了口服给药,尤其是制成片剂、丸剂、包衣片剂、胶囊、粉剂、颗粒剂、糖浆剂、(果)汁剂或滴剂;经直肠给药时可制成栓剂;采用肠胃外给药时可制成溶液,优选油性溶液或含水溶液,及悬浮液、乳剂或植人物;局部施用时采用软膏剂、霜剂或粉剂。该新化合物还可以被冷冻干燥,所得冻干物用于,例如,制成注射制剂。所述的制剂可以被灭菌和/或含有辅助物质,如润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、渗透压调节用盐、缓冲剂、染料、矫味剂和/或一种或多种附加活性化合物,例如一种或多种维生素。吸入喷剂给药时,喷剂中的活性物质既可以溶解也可以悬浮在抛射气体或抛射气体混合物中(例如,CO2或氟氯烃)。此时,活性化合物通常是微粒化形式,可能的话还可以同时存在一种或多种附加的可生理用溶剂例如乙醇。吸入溶液可以通过常规吸入器来给药。
式I化合物及其可生理用盐可以作为整联蛋白抑制物来防治疾病,尤其是血栓形成、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松症、炎症和感染。
权利要求1的式I化合物及其可生理用盐也可在通过血管维持或传播的病理性过程中使用,特别是在肿瘤或类风湿性关节炎中使用。
在这里,本发明所述物质的通常给予方式与一些已知的市售肽产品相似,尤其与US-A-4 472 305描述的化合物相似,优选的给药剂量范围约是每剂量单位0.05至500毫克,更优选是0.5至100毫克。优选的日剂量约是0.01至2毫克/千克体重。而且,不同患者所用的具体剂量要依据很多可变因素来确定,例如,所用特定化合物的活性、患者的年龄、体重、健康状态、性别、饮食、给药时间和途径、排泄速度、联合用药及被治疗疾病的严重程度。优选经肠胃外给药。
此外,式I化合物还可以作为整联蛋白配体用于制备在亲和色谱中用来洗脱整联蛋白的色谱柱。因此,该配体即式I化合物经固定官能(Ankerfunktion)例如Asp的羧基以共价键键合在聚合物载体上。
聚合物载体是肽化学中本身已知的优选具有亲水性能的聚合物固体相,例如交联多糖如纤维素、交联葡萄糖或SephadexR、丙酰胺、基于聚乙二醇的聚合物或TentakelpolymereR。
用于纯化整联蛋白的亲和色谱的材料制备在氨基酸缩合的常规条件下和本身已知的条件下进行。
式I化合物具有一个或多个手性中心,因此可以外消旋混合物或旋光体的形式存在。外消旋体可以采用本身已知的方法机械或化学地分离成对映体。优选通过外消旋混合物与旋光分离剂反应形成非对映体。分离剂例如是旋光酸,如酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸或乳酸的D和L构型或各种不同的旋光樟脑磺酸如β-樟脑磺酸。有利地,对映体的拆分借助填充有旋光分离剂(如二硝基苯甲酰基苯基甘氨酸)进行;流动相例如是己烷/异丙醇/乙腈的混合物,其体积比例例如是82∶15∶3。
当然也可按照上述方法通过使用已经是旋光性的起始化合物来获得式I的旋光化合物。
上文和下文中所有的温度都是℃。在下列实施例中,“常规处理步骤”代表了:若需要首先加入水,再根据需要和终产物组成调节pH值至2至10,将混合物用乙酸乙酯或二氯甲烷萃取,分离各相,有机相用硫酸钠干燥并蒸除溶剂,残留物用硅胶色谱和/或结晶法纯化。测定在硅胶上的Rf值。流动相:乙酸乙酯/甲醇9∶1。
RT=在下列体系中的HPLC保留时间(分钟):[A]色谱柱:LichrosorbRP 18(250×4;5微米)洗脱剂A:0.1%TFA的水溶液洗脱剂B:0.1%TFA在90%乙腈和10%水中的溶液流速:1毫升/分钟梯度:20至95%B/50分钟在215纳米下检测。
非对映体的分离优选在上述条件下进行。质谱(MS):FAB(快原子轰击)(M+H)+实施例1
等摩尔的(R,S)-2-溴-2-苯基-乙酸甲酯和3-羟基甲基-苯胺反应获得N-(3-羟基甲基苯基)-氨基-苯基-乙酸甲酯。通过与亚硫酰氯反应获得N-(3-氯甲基苯基)-氨基-苯基-乙酸甲酯,接着与叠氮化钠反应获得N-(3-叠氮基甲基苯基)-氨基-苯基-乙酸甲酯(“A”)。在1克Pd/C(5%)的存在下氢化9.2克“A”于350毫升乙酸乙酯中的溶液。在除去催化剂和溶剂后获得油状物N-(3-氨基甲基苯基)-氨基-苯基-乙酸甲酯(“B”),RT 19.5;FAB 271。
“B”与二苄基酸酐反应获得N-(3-苄氧基羰基-氨基甲基苯基)-氨基-苯基-乙酸甲酯,接着在KOH/甲醇中氢化获得N-(3-苄氧基羰基-氨基甲基苯基)-氨基-苯基-乙酸(=N-(Z-3-AMP)-氨基-苯基乙酸)。通过分别与1当量的H-Arg(Mtr)-Gly-OtBu、DCCl和HOBt在二氯甲烷中反应获得Z-3-AMP-Phg-Arg(Mtr)-Gly-OtBu。如上所述通过催化氢化除去Z-保护基团;随后与BOC-Asp(OBzl)-OH进行肽键合获得BOC-Asp(OBzl)-3-AMP-Phg-Arg(Mtr)-Gly-OtBu。在HCl/二噁烷中脱除BOC-保护基团和叔丁基酯之后获得H-Asp(OBzl)-3-AMP-Phg-Arg(Mtr)-Gly-OH,并且在该化合物环化之后获得环-(Asp(OBzl)-3-AMP-Phg-Arg(Mtr)-Gly)。在该酯皂化,在98%三氟乙酸中脱除Mtr-保护基团,纯化并经HPLC分离之后获得
环-(Asp-3-AMP-L-Phg-Arg-Gly)和
环-(Asp-3-AMP-D-Phg-Arg-Gly)这二种化合物的特征在于:RT 15.5 FAB 567或RT 12.5 FAB 567,其中尚未确定这二个特征值分别对应这二个非对映体中的那一个。类似地,由2-溴-3-甲基-丁酸获得
环-(Asp-3-AMP-L-Val-Arg-Gly)和
环-(Asp-3-AMP-D-Val-Arg-Gly)由2-溴乙酸获得
环-(Asp-3-AMP-Gly-Arg-Gly)和由2-溴-3-苯基-丙酸获得
环-(Asp-3-AMP-L-Phe-Arg-Gly)和
环-(Asp-3-AMP-D-Phe-Arg-Gly)
下列实施例涉及药物制剂。制剂例A:瓶装注射剂
将100克式I活性化合物和5g磷酸氢二钠的3升双蒸水溶液用2N盐酸调至pH值为6.5,过滤灭菌并灌装到注射瓶中;将溶液冷冻干燥,随后将瓶在无菌条件下封口。每个注射瓶中含有5毫克活性化合物。制剂例B:栓剂
将20g的式I活性化合物与100g大豆卵磷脂和1400克可可脂的混合物熔融,倾入到模具内并冷却。各栓剂含有20mg活性化合物。制剂例C:溶液
将1g式I活性化合物、9.38克NaH2PO4·2H2O、28.48Na2HPO4·12H2O和0.1g苯扎氯铵与940毫升双蒸水制成溶液。将该溶液的pH值调至6.8,体积加至1升并且进行照射灭菌。该溶液可作为滴眼液。制剂例D:软膏剂
500mg式I活性化合物与99.5克凡士林在无菌条件下混合。制剂例E:片剂
1千克式I活性化合物、4千克乳糖、1.2千克马铃薯淀粉、0.2千克滑石和0.1千克硬脂酸镁采用常规方法压制成片剂,这种片剂中每片含有10毫克活性化合物。制剂例F:包衣片剂
采用与制剂例E类似的方法压制出片剂,然后用常规方法将片剂包衣,包衣由蔗糖、马铃薯淀粉、滑石、黄蓍胶和染料组成。制剂例G:胶囊
将2kg式I活性化合物采用常规方法填充到明胶硬胶囊中,各胶囊含有20毫克活性化合物。制剂例H:安瓿
将1kg式I活性化合物溶解在60升双蒸水中,该溶液经过滤灭菌,灌装到安瓿中;将溶液在灭菌条件下冷冻干燥,然后将安瓿在无菌条件下封口。每个安瓿中含有10毫克的活性化合物。制剂例I:吸入喷剂
将14g式I活性化合物溶解中10升的等渗NaCl溶液中。将溶液灌装到可从市场上买到的带有泵压装置的喷罐中。这种溶液可以喷入到口腔或鼻腔中。每喷(约0.1毫升)中相应地含有约0.14mg剂量的活性化合物。
Claims (10)
1.式I化合物和其盐:
环-(Arg-X-Asp-R1) I
其中
X是Gly、Ala或NH-NH-CO,
这里上述氨基酸也可以是氨基酸衍生物,并且这些氨基酸残基以肽方式通过α-氨基和α-羧基相互连接起来,
R2、R3、R4在各种情况下均相互独立地是H、A、Ar、R5-Ar、Het或R5-Het,
A是具有1至6个碳原子的烷基,
Ar是未取代的或被R7、R8或R9单、二或三取代的苯基或未取代的萘基,
R5是具有1至6个碳原子的亚烷基,
R6、R6’在各种情况下相互独立地是H、A、苄基或苯基,
R7、R8、R9在各种情况下相互独立地是R6、OR6、Hal、NO2、NR6R6’、NHCOR6、CN、NHSO2R6、COOR6或COR6,
Hal是F、Cl、Br或I和
Het是含有1至4个N、O和/或S原子的单核或双核杂环,该杂环是未取代的,或可以被一个、两个或三个Hal、A、NR6R6’、CN或NO2取代,
其中,该化合物可以是旋光性氨基酸和氨基酸衍生物,也包括D和L构型。
2.权利要求1的式I化合物的对映体或非对映体。
3.权利要求1的化合物
a)环-(Arg-Gly-Asp-3-AMP-L-Phg);
b)环-(Arg-Gly-Asp-3-AMP-D-Phg);
c)环-(Arg-Gly-Asp-3-AMP-L-Val);
d)环-(Arg-Gly-Asp-3-AMP-D-Val);
e)环-(Arg-Gly-Asp-3-AMP-Phe);
f)环-(Arg-Gly-Asp-3-AMP-D-Phe);
g)环-(Arg-Gly-Asp-3-AMP-Gly);
以及其盐。
4.制备权利要求1的式I化合物及其盐的方法,其特征在于
(a)用环化剂处理式III化合物或者式II化合物可反应的衍生物
H-Z-OH III
其中
Z 是-Arg-X-Asp-R1-
-X-Asp-R1-Arg-
-Asp-R1-Arg-X-或
-R1-Arg-X-Asp-
以及X和R1具有权利要求1中给出的含义,
或者
(b)经溶剂分解试剂或氢解试剂处理,式I化合物及其盐从它们的官能衍生物中释放出,
和/或式I的碱性或酸性化合物经用酸或碱处理而获得其盐。
5.制备药物制剂的方法,其特征在于式I化合物和/或其生理无毒性盐与至少一种固体、液体和/或半固体的载体物质或辅料共同制成适当的剂型。
6.药物制剂,其特征在于含有至少一种权利要求1的式I化合物和/或它们的生理无毒性盐。
7.权利要求1的式I化合物及其生理可用盐作为整联蛋白抑制剂来防治血栓形成、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松症、炎症和感染。
8.权利要求1的式I化合物及其可生理用盐用于通过血管生成来维持或传播的病理性疾病的应用。
9.权利要求1的式I化合物及其可生理用盐用于制备药物的应用。
10.权利要求1的式I化合物及其可生理用盐用于防治疾病的应用。
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AT (1) | ATE199256T1 (zh) |
AU (1) | AU722817B2 (zh) |
CA (1) | CA2280233A1 (zh) |
CZ (1) | CZ223299A3 (zh) |
DE (2) | DE19653036A1 (zh) |
DK (1) | DK0948525T3 (zh) |
ES (1) | ES2156011T3 (zh) |
GR (1) | GR3035848T3 (zh) |
HU (1) | HUP0000490A3 (zh) |
NO (1) | NO993010L (zh) |
PL (1) | PL334186A1 (zh) |
PT (1) | PT948525E (zh) |
RU (1) | RU2202557C2 (zh) |
SK (1) | SK82099A3 (zh) |
TW (1) | TW494105B (zh) |
UA (1) | UA55439C2 (zh) |
WO (1) | WO1998027112A1 (zh) |
ZA (1) | ZA9711392B (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19728524A1 (de) | 1997-07-04 | 1999-01-07 | Merck Patent Gmbh | Cyclische Azapeptide |
US6235877B1 (en) * | 1999-08-04 | 2001-05-22 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Peptido-mimetic compounds containing RGD sequence useful as integrin inhibitors |
DE10041402A1 (de) | 2000-08-23 | 2002-03-14 | Morphochem Ag | Neue Verbindungen, die Faktor Xa-Aktivität inhibieren |
DE60233420D1 (de) * | 2001-09-27 | 2009-10-01 | Equispharm Co Ltd | Fumagillolderivate und verfahren zu deren herstellung |
ITMI20031476A1 (it) * | 2003-07-18 | 2005-01-19 | Univ Degli Studi Milano | Composti peptido-mimetici a struttura azabicicloalcanica comprendenti la sequenza rgd |
WO2007042241A2 (en) * | 2005-10-12 | 2007-04-19 | Annarita Del Gatto | Selective alfavbeta3 receptor peptide antagonist for therapeutic and diagnostic applications |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0648224T3 (da) * | 1992-06-04 | 1998-10-26 | Merrell Pharma Inc | Konformationsbegrænsede peptidanaloger som aktivestoffer mod blodpladeaggregation |
GB9524630D0 (en) * | 1994-12-24 | 1996-01-31 | Zeneca Ltd | Chemical compounds |
JPH09278669A (ja) * | 1996-04-17 | 1997-10-28 | Asahi Glass Co Ltd | 腎炎治療薬 |
-
1996
- 1996-12-19 DE DE19653036A patent/DE19653036A1/de not_active Withdrawn
-
1997
- 1997-12-15 RU RU99115767/04A patent/RU2202557C2/ru not_active IP Right Cessation
- 1997-12-15 PT PT97953826T patent/PT948525E/pt unknown
- 1997-12-15 AT AT97953826T patent/ATE199256T1/de not_active IP Right Cessation
- 1997-12-15 PL PL97334186A patent/PL334186A1/xx unknown
- 1997-12-15 ES ES97953826T patent/ES2156011T3/es not_active Expired - Lifetime
- 1997-12-15 CZ CZ992232A patent/CZ223299A3/cs unknown
- 1997-12-15 WO PCT/EP1997/007048 patent/WO1998027112A1/de not_active Application Discontinuation
- 1997-12-15 CN CN97181862A patent/CN1247543A/zh active Pending
- 1997-12-15 EP EP97953826A patent/EP0948525B1/de not_active Expired - Lifetime
- 1997-12-15 SK SK820-99A patent/SK82099A3/sk unknown
- 1997-12-15 AU AU57584/98A patent/AU722817B2/en not_active Ceased
- 1997-12-15 CA CA002280233A patent/CA2280233A1/en not_active Abandoned
- 1997-12-15 HU HU0000490A patent/HUP0000490A3/hu unknown
- 1997-12-15 UA UA99074097A patent/UA55439C2/uk unknown
- 1997-12-15 DE DE59703023T patent/DE59703023D1/de not_active Expired - Fee Related
- 1997-12-15 DK DK97953826T patent/DK0948525T3/da active
- 1997-12-15 US US09/341,552 patent/US6333308B1/en not_active Expired - Fee Related
- 1997-12-18 TW TW086119172A patent/TW494105B/zh active
- 1997-12-18 ZA ZA9711392A patent/ZA9711392B/xx unknown
- 1997-12-19 AR ARP970106015A patent/AR008717A1/es not_active Application Discontinuation
-
1999
- 1999-06-18 NO NO993010A patent/NO993010L/no not_active Application Discontinuation
-
2001
- 2001-05-11 GR GR20010400698T patent/GR3035848T3/el not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NO993010D0 (no) | 1999-06-18 |
UA55439C2 (uk) | 2003-04-15 |
HUP0000490A2 (hu) | 2000-08-28 |
SK82099A3 (en) | 2000-06-12 |
HUP0000490A3 (en) | 2000-10-30 |
US6333308B1 (en) | 2001-12-25 |
PL334186A1 (en) | 2000-02-14 |
PT948525E (pt) | 2001-07-31 |
EP0948525A1 (de) | 1999-10-13 |
TW494105B (en) | 2002-07-11 |
AR008717A1 (es) | 2000-02-09 |
ZA9711392B (en) | 1999-06-18 |
DK0948525T3 (da) | 2001-06-11 |
WO1998027112A1 (de) | 1998-06-25 |
GR3035848T3 (en) | 2001-08-31 |
DE19653036A1 (de) | 1998-06-25 |
EP0948525B1 (de) | 2001-02-21 |
NO993010L (no) | 1999-08-18 |
AU722817B2 (en) | 2000-08-10 |
ATE199256T1 (de) | 2001-03-15 |
CA2280233A1 (en) | 1998-06-25 |
ES2156011T3 (es) | 2001-06-01 |
DE59703023D1 (en) | 2001-03-29 |
CZ223299A3 (cs) | 1999-09-15 |
RU2202557C2 (ru) | 2003-04-20 |
AU5758498A (en) | 1998-07-15 |
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