CN1206997C - 内皮缩血管肽拮抗剂 - Google Patents
内皮缩血管肽拮抗剂 Download PDFInfo
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- CN1206997C CN1206997C CNB988035863A CN98803586A CN1206997C CN 1206997 C CN1206997 C CN 1206997C CN B988035863 A CNB988035863 A CN B988035863A CN 98803586 A CN98803586 A CN 98803586A CN 1206997 C CN1206997 C CN 1206997C
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Abstract
本发明提供被认为与高血压、伯格(Buerger)氏病、哮喘、眼底病及类似病症有关的内皮缩血管肽拮抗剂。即15-酮基-前列腺素E类化合物内皮缩血管肽拮抗剂,特别是13,14-二氢-15-酮基-16-单或二卤素-前列腺素。
Description
技术领域
本发明涉及15-酮基-前列腺素E作为内皮缩血管肽拮抗剂的新用途。
技术背景
内皮缩血管肽是含21个氨基酸的生物活性肽,已知3种内皮缩血管肽,即内皮缩血管肽-1,内皮缩血管肽-2和内皮缩血管肽-3。
内皮缩血管肽是以直接或间接的方式(调节多种内源性物质释放)持续收缩血管或非血管平滑肌的生物活性物质,内皮损伤可致内皮缩血管肽生成增加。内皮缩血管肽的过量生成被认为是诸如高血压、肺动脉高血压、伯格氏病、雷诺氏病、气喘、眼底(视网膜、脉络膜等)疾病、糖尿病、动脉硬化、肾衰竭、心肌梗塞、心绞痛、脑血管挛缩和脑梗塞的病因。而且,已知内皮缩血管肽是多器官衰竭,及诸如内毒素休克所致的弥漫性血管内凝血等、环胞素所致的肾损伤等的重要介质。此外,还发现在肝移植等器官移植后血液中内皮缩血管肽的浓度上升。
前列腺素(下文以PG表示)是人及动物组织和器官中含有的、具有广泛生理活性的一类有机羧酸。天然的PGs含有前列腺烷酸构架,其通式表示为结构式(A):
另一方面,一些合成的类似物具有修饰了的结构。
根据五元环的结构特点,天然PG被分为PGA类、PGB类、PGC类、PGD类、PGE类、PGF类、PGG类、PGH类、PGI类和PGJ类;根据链上有无不饱和键和是否氧化进一步分类如下:
下标数1.. 13,14-不饱和的-15-OH
下标数2.. 5,6-和13,14-两不饱和的-15-OH
下标数3.. 5,6-、13,14-和17,18-三不饱和的-15-OH
而且,根据9-位羟基的构型将PGF分为α-(羟基为α-构型)和β-(羟基为β-构型)。
已知PGE1、PGE2及PGE3具有舒张血管、降血压、减少胃液、增加肠蠕动、子宫收缩、利尿、支气管扩张和抗溃疡的活性。亦知PGF1α、PGF2α及PGF3α具有升压、收缩血管、促进肠运动、收缩子宫、黄体萎缩和收缩气管的活性。
此外,代谢过程中,一些15-酮基-前列腺素(即15位羟基被氧取代的PGs)和13,14-二氢-15-酮基-前列腺素为通过酶的作用天然产生的化合物(斯堪的纳维亚生理学报,66卷,509页(1966))。据报道,15-酮基-PGF2α具有抗妊娠作用。而且,已知15-酮基-PGF化合物可以用于治疗多种疾病(欧洲专利申请0 284 180 A号)。
因为抗内皮缩血管肽的活性,已知PGE2可抑制内皮缩血管肽诱发的大鼠血管收缩。该发明者报道了烃构架的α-链延伸的前列腺烷酸化合物具有较强的拮抗内皮缩血管肽的活性(WO 97/47595),以及15-酮基-前列腺素F经眼给药具有内皮缩血管肽拮抗活性(日本专利申请KOKAI No.Hei.10-007574)。然而,未见报道15-酮基-前列腺素E类化合物(α-主链具有8个或8个以上碳原子的化合物除外)具有拮抗内皮缩血管肽的活性。
本发明的最佳实施方案
本发明的目的是为治疗内皮缩血管肽参与的各种疾病和病理提供有效的内皮缩血管肽拮抗剂。本发明还涉及治疗内皮缩血管肽过量生成所致的疾病方法,以及15-酮基-前列腺素E类化合物在生产内皮缩血管肽拮抗剂中的用途。
作为15-酮基-PGE化合物生物学活性的研究结果,已发现15-酮基-PGE化合物表现出极强的拮抗内皮缩血管肽的作用。也就是说,本发明提供了由15-酮基-PGE类化合物(前列腺烷酸的α-链含8个或8个以上碳原子者除外)组成的有效的内皮缩血管肽拮抗剂。
本发明作为内皮缩血管肽拮抗剂具有极强的内皮缩血管肽拮抗活性,能有效地治疗各种与内皮缩血管肽有关的病理和疾病。本说明书中的“处理”包括控制疾病的各种方法,如预防、治愈、减退、减轻症状、阻止病情发展等。
本发明中“15-酮基-前列腺素E类化合物”(以下称为15-酮基-PGE类化合物)包括前列腺烷酸构架的15-位羟基被氧取代基取代的所有取代产物及衍生物,无论双键数目以及α-链或ω-链有否取代或修饰(α-主链有8个或8个以上碳原子者除外)。
本发明中15-酮基-PGE的命名采用了前文中结构式(A)所示的前列腺烷酸的编号系统。
结构式(A)所示的基本构架含二十个碳原子,本发明中的碳原子数无此限制。也就是说,构成基本构架的碳原子是这样编号的:羧酸碳的编号为1,α-链上碳原子按到五元环的方向被编号为2至7,五元环中的碳原子编号为8至12,ω-链上的碳原子分别编号为13至20。而当α-链上碳原子减少时,其编号从2-位逐次删除。同样地,ω-链上碳原子减少时,碳原子编号从20-位逐次删除,而当ω-链上碳原子数目增加时,在命名中,21-位及其后各位上的碳原子均被视作取代基。此外,在空间构型方面,如无特别说明,均与前文所示的基本构架一致。
因此,ω-链上有十个碳原子的15-酮基-PGE类化合物被命名为15-酮基-20-乙基-PGE类化合物(本发明中不包括α-链上含8个或8个以上碳原子的化合物)。
前文结构式显示了最典型的特殊构型,本说明书中的任何化合物,如无特殊说明均与此构型一致。
PGEs一般是指含有9-位氧基和11-位羟基的前列腺烷酸,但在发明中的15-酮基-PGE类化合物包括11-位羟基被其它基团取代的化合物。这时化合物以“11-去羟基-11-取代基”的形式命名。以氢原子取代11-位羟基的化合物则被直接称为11-去羟基化合物。
本发明中的15-酮基-PGE类化合物包括任何下述PGE衍生物:15-位以氧基代替羟基,α-链上有7个或更少的碳原子,13-和14-位间可能有一个双键(15-酮基-PGE的1类化合物),此外5-和6-位间可能有一个双键(15-酮基-PGE的2类化合物),以及两个双键分别位于5-和6-间及17-和18-位间(15-酮基-PGE的3类化合物)的PGE衍生物。
此外,15-酮基-PGE类化合物还包括13-14位饱和的化合物,即,13,14-二氢-15-酮基-PGE类化合物。
本发明中可用的典型实施例有15-酮基-PGE 1类、15-酮基-PGE 2类、15-酮基-PGE 3类、它们的衍生物及其类似物。
取代物或衍生物的实施例为15-酮基-PGEs的α-链端羧基被酯化、生理学上可接受的盐、2-和3-位间有双键或5-和6-位间有三键的化合物;化合物的3-、5-、6-、16-、17-、18-、19-和/或20-位有取代基的化合物;以低级烷基、羟基低级烷基或氢原子取代11-位上羟基的化合物。
本发明中,取代基可以与3-、17-、18-和/或19-位碳原子成键,例如,C1-4烷基,尤其是甲基或乙基。16-位取代基的例子包括诸如甲基或乙基等的低级烷基、羟基、诸如氯原子、氟原子等的卤原子、诸如三氟甲基苯氧基的芳氧基。17-位取代基有诸如氯原子、氟原子等的卤原子。20-位上的取代基可以是如C1-4烷基的饱和或不饱和的低级烷基、如C1-4的烷氧基的低级烷氧基、如C1-4烷氧基-C1-4烷基的低级烷氧烷基。5-位取代基可包括诸如氯原子、氟原子等的卤原子。6-位取代基可包括氧代形成的羰基。当11-位碳原子带有一个羟基,低级烷基或低级(羟基)烷基作为取代基时,这些基团的空间构型可以是α、β或其混合物。
此外,上述衍生物可以是ω-链端带有烷氧基、苯氧基、苯基等的化合物,其ω-链短于天然PGs的ω-链。
优选的化合物是16-位含有诸如甲基、乙基等的低级烷基,诸如氯原子、氟原子等的卤原子的化合物;17-位含有诸如甲基、乙基等的低级烷基、和/或诸如氯原子、氟原子等的卤原子的化合物;18-位或19-位含有诸如甲基、乙基等的低级烷基的化合物;5-位含有诸如氯原子、氟原子等的卤原子的化合物;6-位含有氧代基的化合物;20-位含有诸如甲基、乙基等的低级烷基的化合物;在16-位或17-位及其后碳原子上具有取代烷基链的苯基或苯氧基的化合物,所述基团可以由卤原子或卤代烷基取代。
13-位和14-位间的碳键为单键的13-14-二氢-15-酮基-PGE类化合物,16-位具有一或二个诸如氯原子、氟原子等的卤原子(15-酮基-16-一或二卤代-PGE类化合物)的化合物是示例性的最优选化合物。
用于本发明中的优选化合物以下述结构式(I)表示:
式中R为氢原子、羟基、羟(低级)烷基或低级烷基,
A是-CH2OH、-COCH2OH、-COOH或它们的功能性衍生物,
B是-CH2-CH2-,-CH=CH-,-C≡C-,
Q1和Q2是氢原子、卤原子或低级烷基,
R1是未取代的或由卤素、氧代或芳基取代的双键饱和或不饱和的C2-C6烃基,
R2是未取代的或由卤素、氧代、羟基、低级烷氧基、低级链烷酰基氧基、低级环烷基、芳基或芳氧基取代的饱和或不饱和的低级至中级的脂肪烃基;低级环烷基、芳基或芳氧基
上述结构式的R1和R2的定义中,术语“不饱和”意指主链或侧链中有孤立存在的、相隔存在的或连续存在的一个或多个碳-碳双键和/或叁键。根据通常的命名,两个相邻位置间的不饱和键的位置以较小的数位表示,两个不相邻的不饱和键以两个数位表示。优选的不饱和键是一个2-位双键和一个5-位双键或叁键。
术语“低级至中级脂肪烃”意指主链或侧链上含有1至14个碳原子的烃(其中侧链最好含1至3碳原子),尤其是含2至10个碳原子的烃。
术语“卤素”包括氟、氯、溴和碘。
术语“低级”在没有特别说明时意指含1至6个碳原子的基团。
术语“低级烷基”意指含有1至6个碳原子的直链或支链饱和烃基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、和己基。
术语“低级烷氧基”意指低级烷基-O-,其中低级烷基同上所述。
术语“羟基(低级)烷基”意指上述之烷基至少有一个羟基取代,例如,羟甲基、1-羟基乙基、2-羟基乙基、及1-甲基-1-羟基乙基。
术语“低级链烷酰基氧基”意指以结构式RCO-O-表示的基团,其中RCO-是上述低级烷基氧化形成的酰基,例如,乙酰基。
术语“低级环烷基”意指含有3个或3个以上碳原子的上述低级烷基环化形成的基团,例如,环丙基、环丁基、环戊基、及环己基。
术语“芳基”包括可以由下列取代基取代的芳烃环或杂环的基团(优选单环基团),所述取代基为例如,苯基、甲苯基、二甲苯基、及噻酚基。在此情况下的取代基的实例包括卤素、及卤代低级烷基(其中卤原子和低级烷基同前所述)。
术语“芳氧基”是指以结构式ArO-表示的基团(Ar是上文所述的芳基)。
A所表示的羧基的“官能衍生物”包括盐(尤指药学上可接受的盐)、酯、及酰胺。
适合的“药学上可接受的盐”的实例包括常用的无毒盐,它们是与无机碱形成的盐,例如,碱金属盐(钠盐、钾盐等)、碱土盐(钙盐、镁盐等)、铵盐;与有机碱形成的盐,例如,胺盐(例如甲胺盐、二甲胺盐、环己胺盐、苯胺盐、哌啶盐、1,2-乙二胺盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、三(羟甲基氨基)乙烷盐、一甲基-一乙醇胺盐、赖氨酸盐、普鲁卡因盐、及咔啡因盐);碱性氨基酸盐(例如精氨酸盐、及赖氨酸盐);四烷基铵盐等。这些盐可通过,例如,按照通常方法由相应的酸和碱制成或通过盐交换形成。
酯类包括脂肪族酯,例如,低级烷基酯,诸如甲酯、乙酯、丙酯、异丙酯、丁酯、异丁酯、叔丁酯、戊酯、1-环丙基乙酯;低级链烯基酯,例如乙烯基酯、及烯丙基酯;低级链炔基酯,例如乙炔基酯、及丙炔基酯;羟基(低级)烷基酯,如羟乙基酯;低级烷氧基(低级)烷基酯,诸如甲氧基甲酯、1-甲氧基乙酯:以及选择性取代的芳基酯,诸如苯基酯、对甲苯磺酸酯、叔丁基苯基酯、水杨基酯、3-,4-二甲氧基苯基、苯酰胺苯基酯;芳基(低级)烷基酯,诸如苄基酯、三苯甲基酯、以及二苯甲基酯。酰胺的实施例包括单-或双-低级烷基酰胺,诸如甲酰胺、乙酰胺、以及二甲酰胺;芳基酰胺,诸如苯酰氨、甲苯酰胺:以及烷基或芳基磺酰胺,诸如甲磺酰胺、乙磺酰胺、以及甲苯磺酰胺。
R的优选实例是氢或羟基,最优选羟基。
A的优选实例是-COOH、生理学上可接受的盐、酯或酰胺。
B的优选实例是-CH2-CH2-,即,含有13-,14-二氢结构组成者。
Q1和Q2的优选实例是至少一个为卤原子,优选两个都是卤原子。最优选是氟原子,即,16-16-二氟类型。
R1的优选实例是C4-C6的烃,最优选者是C6烃。
R2的优选实例是一个C1-C10的烃,最优选者是C2-C8的烃,尤其是含一至两个C1的侧链者。
上述结构式(I)中,环的构型、α-链和/或
-链可与天然前列腺素相同或不同。而且,本发明还包括天然前列腺素构型的化合物和非天然构型前列腺素的化合物的混合物。
本发明的典型化合物的实例是13-,14-二氢-15-酮基-16--或二氟PGE类化合物及其衍生物。作为衍生物,其范例是6-氧代衍生物、Δ2-衍生物、3-甲基衍生物、6-酮衍生物、5-氟衍生物、5,5-二氟衍生物、17-甲基衍生物、18-甲基衍生物、19-甲基衍生物、20-甲基衍生物、20-乙基衍生物、19-去甲基衍生物以及17-安眠酮(torinor)-17-苯基衍生物。
本发明采用的15-酮基-PGE类化合物中,当13,-14-位饱和而且15-位有氧代(即在13,14-二氢-15-酮基-结构的情况下)时,由于11-位羟基与15-位酮基间形成半缩醛而有酮-半缩醛平衡存在。
当有这样的互变体存在时,两种互变体的存在的比率依赖于其他部分或取代基类型,并根据环境的情况,其中一种互变体占有优势。然而,本发明包含了这样两种互变体,不管有无出现其互变体化合物,均以某一酮式结构式表示或命名。换句话说,这仅仅为方便起见,而没有排除半缩醛-形式化合物的意思。
本发明中,任何单一互变体及其混合物、或旋光异构体及其混合物、外消旋变化物、以及诸如立体异构的其它异构体都可以用于同样的目的。
本发明中采用的一些化合物可通过欧洲专利公告0281239A(日本专利公开KOKAI No.52753/89)、欧洲专利公告0690049A(日本专利公开KOKAI No.48665/96)等阐述的方法获得。作为其它方法,这些化合物可以按照上述方法或已知方法制备。
上述15-酮基-PGE类化合物被用作内皮缩血管肽的拮抗剂。
本发明中的化合物可以用作人类或动物治疗药,它们通常可根据眼用、口服、静脉注射(包括滴注)、皮下注射、直肠给药及类似给药方式作局部或系统给药。尽管剂量随类型、年龄、体重、治疗症状、预期临床效果、给药途径、治疗时间、治疗对象是人或动物等等而变化,一般获得显效的常用剂量为:眼睛局部给药时为0.01至100μg/眼,或系统用药时根据每日分作两至四次给药或维持情况下使用0.0001至500mg/kg的剂量。
根据本发明,眼用制剂包括滴眼液或眼膏等。滴眼液在给药时用诸如生理盐水、缓冲液等灭菌水溶液或联合使用两者以溶解活性物的方法来制备。眼膏的制备是将活性成分与基质混合。
根据本发明,口服给药的固体制剂包括片剂、锭剂、舌下含片、胶囊剂、丸剂、粉剂、颗粒剂等。在固体制剂中,一种或多种活性组分与至少一种无活性的稀释剂混合、所述稀释剂有,例如乳糖、甘露糖、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、硅铝酸镁。根据传统工序,除无活性的稀释剂外,组合物还可含有添加剂,例如,润滑剂如硬脂酸镁、崩解剂如纤维素葡萄糖酸钙;以及稳定剂,例如,醚化了的环糊精α-,β-,γ-环糊精、或二甲基-α-,二甲基-β-,三甲基-β-,及羟丙基-β-环糊精、支链环糊精如糖基-,麦芽糖基-环糊精、甲酸环糊精、含硫环糊精、misoprotol(thonetic),以及磷酯。当使用上述任何一种环糊精时,包裹化合物的包衣由环糊精构成,以增加组合物的稳定性。此外,利用磷酯形成酯质体时,产品的稳定性增加。需要时,片剂和丸剂可以用一层或两层或多层薄膜覆盖或包裹,膜可由在胃或肠中可溶解的物质制成,例如,庶糖、明胶、羟丙基纤维素以及羟丙基甲基纤维素邻苯二甲酸酯。此外,还可采用可崩解的物质,如明胶,将组合物制成胶囊。希望快速起效时,可将组合物制成舌下含片。
可采用甘油、乳糖及其类似物作为基质。口服液体制剂的实例有乳剂、溶液、混悬液、糖浆、以及酏剂配方。其中可含有常用的无活性的稀释剂,例如纯水和乙醇。除无活性的稀释剂外,所有这些组合物可进一步含有添加剂,例如湿润剂、悬浮剂、甜剂、矫味剂、香料、芳香剂和防腐剂等。
喷雾剂作为口服给药的另一种组合物含有一种或多种活性成份,并且按照已知的方式配方。
根据本发明,非肠道吸收的溶液的实例包括无菌的水或非水溶液、混悬液、以及乳剂。水溶液和混悬液的溶媒的实例包括注射用蒸馏水、生理盐水、以及林格溶液。
非水溶液和混悬液的稀释剂的实例包括丙二醇、聚乙二醇、植物油,例如橄榄油、醇如乙醇、聚山梨醇酯等等。这些组合物中还可能含有辅料,例如防腐剂、湿润剂、乳化剂、及分散剂。他们通过诸如细菌遏留滤纸过滤、蒸汽蒸馏、或放射灭菌等方法灭菌。他们还可制成无菌固体组合物,临用时以灭菌水或注射用无菌溶液溶解。
该组合物的另一种形式是栓剂或阴道栓剂。这些制剂是以活性成份与可可油等在体温下软化的基质混合制成,在此情况下,可能加入具有适宜软化温度的非离子表面活性剂,以促进吸收。
实施例
尽管本发明将以下述合成实施例和实验进行详细解释,但对本发明并无限制。
合成实施例1
16-,16-二氟-13,14-二氢-15-酮基-PGE1甲酯(12)的合成:
1-1)(1S,5R,6R,7R)-6-羟甲基-7-四氢吡喃氧基-2-氧杂二环[3.3.0]辛-3-酮(2)的合成:
将氟化四丁基铵的四氢呋喃(THF)(1.0M,300ml)液加入商业获得的(-)Corey内酯(1)(以THP保护)(37.9g)的THF溶液,室温下搅拌混合物3小时。
减压浓缩反应液,所得残留物经柱层析获得标题化合物(2)。产量:21.70g(82.8%)。
1-2)合成(1S,5R,6R,7R)-6-{(E)-4,4-二氟-5-氧代-2-辛烯基}-7-四氢吡喃氧基-2-氧杂二环[3.3.0]辛-3-酮(4):
在-78℃、氩气中将草酰氯的二氯甲烷液(2.0M,45.5ml)溶于二氯甲烷中,滴入二甲亚砜(DMSO)(12.9ml)并搅拌10分钟。向所得溶液滴加(1S,5R,6R,7R)-6-羟甲基-7-四氢吡喃氧基-2-氧杂二环[3.3.0]辛-3-酮(2)(11.65g)的二氯甲烷溶液,搅拌30分钟,滴入三乙胺(56ml)并搅拌1小时。以常法处理反应产物获得粗产物醛(3)。
将二甲基3,3-二氟-2-氧代庚基磷酯(11.9g)加入乙醇铊的二氯甲烷溶液(3.26ml)中并在氩气中搅拌1小时。使混合物冷至0℃,滴入在二氯甲烷中的按上述制备的醛(3)溶液,于室温下搅拌14小时。向该反应液中加入乙酸、硅藻土和碘化钾饱和溶液并过滤。常法处理滤液,所获粗产物经柱层析获得标题化合物(4)。
产量:7.787g(44.3%)
1-3)(1S,5R,6R,7R)-6-(4,4-二氟-5-氧代辛基)-7-四氢吡喃氧基-2-氧杂二环[3.3.0]-辛-3-酮(5)的合成:
将5%钯-碳(催化量)加入(1S,5R,6R,7R)-6-{(E)-4,4-二氟-5-氧代-2-辛烯基}-7-四氢吡喃氧基-2-氧杂二环[3.3.0]辛-3-酮(4)(5.57g)的乙酸乙酯溶液中,室温下氢气中混合7小时。过滤反应液,滤液减压浓缩滤液得到标题化合物(5)的粗产物。
产量:5.48g(97.8%)
1-4)合成(1S,5R,6R,7R)-6-{4,4-二氟-5(RS)-羟辛基}-7-四氢吡喃氧基-2-氧杂二环[3.3.0]-辛-3-酮(6):
将硼氢化钠(0.800g)加入0℃的(1S,5R,6R,7R)-6-(4,4-二氟-5-氧代-辛基)-7-四氢吡喃氧基-2-氧杂二环[3.3.0]-辛-3-酮(5)(5.48g)的甲醇溶液中,搅拌10分钟。常法处理反应产物,获得的粗产物经柱层析得标题化合物(6)。
产量:5.46g(99.5%)
1-5)16-,16-二氟-13,14-二氢-11-四氢吡喃氧基-PGF2α甲酯(9)的合成:
将(1S,5R,6R,7R)-6-{4,4-二氟-5(RS)-羟辛基}-7-四氢吡喃氧基-2-氧杂二环[3.3.0]-辛-3-酮(6)(2.579g)的甲苯溶液在氩气中冷却至-78℃,加入氢化二异丁基铝的甲苯溶液(1.5M,9.6ml)并搅拌30分钟。向反应液加入甲醇和饱和的罗舍尔盐水液,常法处理获得乳醇(7)的粗产物。
在氩气中将氧化叔丁醇钾的THF溶液(1.0M,52.84ml)滴入溴化4-羧基丁基三苯基膦(11.72g)的THF悬液中并搅拌20分钟。使反应液冷却至0℃,加入上面制备的乳醇(7)并在室温下搅拌15小时。
常法处理反应液获得羧酸(8)的粗产物。
在氩气中将1,8-重氮二环[5.4.0]十一-7-烯(DBU)(4.0ml)和碘甲烷(1.7ml)加入羧酸(8)的乙腈溶液中,60℃下搅拌3小时。使常法获得的粗产品经柱层析得到标题化合物(9)。
产量:2.737g(84.5%)
1-6)16,16-二氟-13,14-二氢-15-酮基-11-四氢吡喃氧基-PGE2甲酯(10)的合成:
向以常法从吡啶(26.2ml)制备的柯林斯试剂的二氯甲烷溶液及铬酸酐(16.18g)于-20℃的氩气中加入16-,16-二氟-13,14-二氢-11-四氢吡喃氧基-PGF2α甲酯(9)(2.646g)的二氯甲烷溶液,搅拌2小时。-5℃下继续搅拌反应产物9小时。将硫酸氢钠和醚加入反应产物中,过滤。减压浓缩滤液,然后经柱层析得化合物(10)。
产量:1.890g(64.4%)
1-7)16,16-二氟-13,14-二氢-15-酮基-PGE2甲酯(11)的合成:
使16,16-二氟-13,14-二氢-15-酮基-11-四氢吡喃氧基-PGE2甲酯(10)(2.809g)溶于乙酸、水和THF混合液(3∶1∶1)中,60℃下搅拌混合物5小时。减压浓缩反应液,经柱层析得标题化合物(11)。
产量:1.755g(75.5%)
1-8)16,16-二氟-13,14-二氢-15-酮基-PGE1甲酯(12)的合成:
将5%钯-碳(催化量)加入16,16-二氟-13,14-二氢-15-酮基-PGE2甲酯(11)(1.755g)的乙酸乙酯溶液中,室温下氢气中搅拌6小时。过滤反应液,减压浓缩反应液。产物经柱层析得标题化合物(12)。
产量:1.655g(93.8%)
1H NMR(CDCl3)δ0.87(3H,t,J=7Hz),1.15-2.05(23H,m),2.11-2.30(3H,m),2.50(1H,dd,J=7.5和17Hz),3.10-3.20(1H,br),3.71(3H,s),4.05-4.20(1H,m).
Mass(D1-E1)m/z 404(M+),
355(M+-H2O-CH3O),297(M+-C5H9F2).
合成实施例2
16,16-二氟-13,14-二氢-15-酮基-PGE1(16)的合成
2-1)(15RS)-16,16-二氟-13,14-二氢-11-四氢吡喃氧基-PGF2a苄酯(13)的合成:
DBu(2.1ml)和苄基溴(2.2ml)加入羧酸(8)(2.33g)的二氯甲烷(300ml)溶液中并于室温下搅拌混合物1.5小时。常法获得的粗产品经硅胶柱纯化得到苄酯(13)。
产量:2.522g(96.1%)
2-2)16,16-二氟-13,14-二氢-15-酮基-11-四氢吡喃氧基-PGE2苄酯(14)的合成:
于二氯甲烷中用铬酸酐(13.5g)和吡啶(21.8ml)制备柯林斯试剂,加入硅藻土(40g),使上述苄酯(13)(2.550g)于-20℃下氧化。处理后以常法获得粗产品,经硅胶柱纯化得到标题化合物(14)。
产量:1.911g(78.6%)
2-3)16,16-二氟-13,14-二氢-15-酮基-PGE2苯酯(15)的合成:
使PGE2苄酯(14)(1.550g)溶于乙酸-THF-水(3-1-1,50ml)中,50℃下恒温4小时。使常法获得的粗产品经硅胶柱纯化得到PGE2苄酯(15)。
产量:1.255g(92.9%)
2-4)16,16-二氟-13,14-二氢-15-酮基-PGE1(16)的合成:
在乙酸乙酯中以5%钯-碳催化PGE2苄酯(15)(0.844g)的还原反应。产品经柱层析纯化得到16,16-二氟-13,14-二氢-15-酮基-PGE1(16)。
产量:0.404g
1H NMR(CDCl3)δ0.94(3H,t,J=7.5Hz),1.20-2.70(26H,m),4.19(1H,m),4.80(2H,br).
Mass(DI-EI)m/z 390(M+),
372(M+-H2O),354(M+-2H2O).
下文表示反应图式:
实验实施例1
方法
1 以内皮缩血管肽1诱发狗的外周血循环功能不全:
本实验使用Beagle狗(雌雄兼用,体重8.2-11.8kg)。静脉注射和皮下注射苯巴比妥麻醉动物后,于一后肢暴露股动脉。于一小的股动脉分支插入插管作内皮缩血管肽1(以下用ET-1表示)给药用和测量动脉血压,扎紧之。刮净一小块后肢背侧面,皮肤表面安放激光多普勒流量计探针以测量皮下组织血流量。以3pmol/kg/min的速度向股动脉持续滴注ET-1(Peptide Istitute Inc.),采用注射泵(1100型,KD,Scientific Inc.)通过插管向股动脉分支注入以造成外周循环功能不全。
2 实验分组
表1
实验组 | 剂量(μg/0.5ml/kg) | 给药途径 | 模型数(Modelnumbers)(n) |
对照(溶媒)实验化合物1实验化合物1 | -0.31.0 | 静脉注射静脉注射静脉注射 | 333 |
溶媒:含0.01%多聚溶剂化物80和0.5%乙醇的生理盐水
实验化合物1:13,14-二氢-15-酮基-16,16-二氟-18S-甲基-PGE1实验设计:
向股动脉一侧持续滴注ET-1 30-40分钟后,注入ET-1的后肢远端背侧处的皮下组织的血流量减少。在确认皮下组织血流量减少并达到稳定水平后,通过十二指肠插管给予溶媒或实验化合物2分钟。测量并记录给药后40分钟内的两后肢远端背侧处的皮下组织的血流量和平均血压。
结果
后肢远端背侧处的皮下组织的血流量(均值±标准差ml/100g/min)的测量结果如表2所示。时间(分钟)表示给予溶媒或实验化合物后的时间。前值1表示开始持续滴注ET-1之前的血流量值,前值2表示溶媒或实验化合物开始给药之前的血流量值。
表2
实验组 | 剂量(μg/kg,i.v) | 模型数(n) | 前值1 2 | 时间(min.)10 15 25 35 |
对照组(溶媒) | - | 3 | 5.8 3.5±1.0 ±0.1 | 3.6 3.5 3.5 3.6±0.1 ±0.2 ±0.3 ±0.2 |
实验化合物1 | 0.3 | 3 | 5.9 3.6±1.0 ±0.4 | 3.7 3.7 3.7 3.7±0.4 ±0.4 ±0.5 ±0.4 |
实验化合物1 | 1.0 | 3 | 5.9 3.6±1.0 ±0.3 | 4.2* 4.2* 4.1 3.9±0.1 ±0.1 ±0.1 ±0.1 |
Dunnett检验:与对照组比较,*p<0.05
表2清楚地表明,与ET-1给药前相比,自股动脉持续滴注ET-1后,给予ET-1的后肢远端背侧处的皮下组织的血流量减少了40%。实验化合物1剂量依赖性地逆转ET-1所致的皮下组织血流量的减少。尤其是1.0μg/kg给药组,给药10或15分钟后皮下组织的血流量较对照组有显著增加。
在没注射ET-1的后肢,没有发现ET-1给药对皮下组织的血流量的影响。而且,亦没发现静脉注射实验化合物的影响。
此外,没有发现ET-1和实验化合物给药对动脉血压的影响。
上述结果表明,本发明中的内皮缩血管肽拮抗剂对内皮缩血管肽所致的循环性疾病有显著的拮抗活性。
产业可利用性
本发明采用的化合物可用作内皮缩血管肽拮抗剂。因此,它们有望用于治疗或预防高血压、伯格(Buerger)氏病、哮喘、眼底病等。
Claims (9)
1.除α-主链中含有8个或8个以上碳原子的化合物以外的15-酮基-前列腺素E类化合物在内皮缩血管肽拮抗剂生产中的用途。
2.权利要求1的用途,其中15-酮基-前列腺素E类化合物是以下通式(I)表示的化合物:
式中R为氢原子、羟基、羟基低级烷基或低级烷基;
A为-CH2OH、-COCH2OH、-COOH或它们的官能衍生物;
B为-CH2-CH2-、-CH=CH-或-CH≡CH-;
Q1和Q2为氢原子、卤原子或低级烷基;
R1为未取代的或由卤素、氧代、或芳基取代的双键饱和或不饱和的C2-6烃基;
R2为未取代的或由卤素、氧代、羟基、低级烷氧基、低级链烷酰基氧基、低级环烷基、芳基或芳氧基取代的饱和或不饱和的低级至中级的脂肪烃基;低级环烷基、芳基或芳氧基。
3.权利要求1的用途,其中15-酮基-前列腺素E类化合物是15-酮基-16-一或二卤素-前列腺素E类化合物。
4.权利要求1的用途,其中15-酮基-前列腺素E类化合物是13,14-二氢-15-酮基-前列腺素E类化合物。
5.权利要求1的用途,其中15-酮基-前列腺素E类化合物是13,14-二氢-15-酮基-16-一或二卤素-前列腺素E类化合物。
6.权利要求1的用途,其中15-酮基-前列腺素E类化合物是15-酮基-16-一或二氟-前列腺素E化合物。
7.权利要求1的用途,其中15-酮基-前列腺素E类化合物是13,14-二氢-15-酮基-16-一或二氟-前列腺素E化合物。
8.权利要求1的用途,其中15-酮基-前列腺素E类化合物是13,14-二氢-15-酮基-16-一或二氟-18-甲基-前列腺素E化合物。
9.权利要求1的用途,其中15-酮基-前列腺素E类化合物是13,14-二氢-15-酮基-16-一或二氟-18-甲基-前列腺素E1化合物。
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US5362751A (en) | 1988-05-11 | 1994-11-08 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Tracheobronchodilator using 16-substituted PGEs |
JP2597649B2 (ja) * | 1988-05-11 | 1997-04-09 | 株式会社上野製薬応用研究所 | 気管・気管支拡張剤 |
EP0343904B1 (en) | 1988-05-23 | 1993-04-28 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Hypersphyxia causing composition |
JPH0232031A (ja) * | 1988-07-22 | 1990-02-01 | Nippon Steel Chem Co Ltd | イソプロピル化p‐ターフェニル類の製造法 |
CA2027814C (en) * | 1989-10-20 | 1996-07-30 | Ryuji Ueno | Treatment of hepatobiliary disease with 15-keto-prostaglandin compounds |
CA2030346C (en) * | 1989-11-22 | 2000-04-11 | Ryuji Ueno | Treatment of cardiac dysfunction with 15-keto-prostaglandin compounds |
CA2030344C (en) * | 1989-11-22 | 2000-04-18 | Ryuji Ueno | Treatment of pulmonary dysfunction with 15-keto-prostaglandin compounds |
CA2030345C (en) * | 1989-11-22 | 1998-12-08 | Ryuji Ueno | Use of 15-keto-prostaglandin compound for improvement of encephalic function |
TW224942B (zh) | 1990-04-04 | 1994-06-11 | Adka Ueno Kk | |
DE69130586T2 (de) * | 1990-05-01 | 1999-06-17 | R Tech Ueno Ltd | Behandlung von Pankreaskrankheit mit 15-keto-Prostaglandin E-Derivaten |
CA2046069C (en) | 1990-07-10 | 2002-04-09 | Ryuji Ueno | Treatment of inflammatory diseases with 15-keto-prostaglandin compounds |
EP0503887B1 (en) * | 1991-03-14 | 1996-08-28 | R-Tech Ueno Ltd. | Promotion of wound-healing with 15-keto-prostaglandin compounds |
KR19990036322A (ko) | 1996-06-10 | 1999-05-25 | 류지 우에노 | 엔도텔린길항제 |
JPH107574A (ja) | 1996-06-17 | 1998-01-13 | R Tec Ueno:Kk | エンドセリン拮抗剤 |
-
1998
- 1998-11-16 AT AT98953058T patent/ATE401894T1/de active
- 1998-11-16 NZ NZ336960A patent/NZ336960A/en not_active IP Right Cessation
- 1998-11-16 US US09/355,270 patent/US6197821B1/en not_active Expired - Lifetime
- 1998-11-16 JP JP53056099A patent/JP4319256B2/ja not_active Expired - Fee Related
- 1998-11-16 ES ES98953058T patent/ES2310013T3/es not_active Expired - Lifetime
- 1998-11-16 DE DE69839767T patent/DE69839767D1/de not_active Expired - Lifetime
- 1998-11-16 CA CA002279267A patent/CA2279267C/en not_active Expired - Fee Related
- 1998-11-16 KR KR1019997006752A patent/KR100648868B1/ko not_active IP Right Cessation
- 1998-11-16 CN CNB988035863A patent/CN1206997C/zh not_active Expired - Fee Related
- 1998-11-16 PT PT98953058T patent/PT978284E/pt unknown
- 1998-11-16 AU AU10537/99A patent/AU739343B2/en not_active Ceased
- 1998-11-16 WO PCT/JP1998/005143 patent/WO1999027934A1/ja active IP Right Grant
- 1998-11-16 EP EP98953058A patent/EP0978284B1/en not_active Expired - Lifetime
- 1998-11-16 DK DK98953058T patent/DK0978284T3/da active
- 1998-11-17 TW TW087118975A patent/TW592701B/zh not_active IP Right Cessation
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1999
- 1999-07-27 NO NO19993647A patent/NO328460B1/no not_active IP Right Cessation
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2000
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104557845A (zh) * | 2015-01-13 | 2015-04-29 | 齐鲁制药有限公司 | 一种鲁比前列酮化合物的制备方法 |
CN104557845B (zh) * | 2015-01-13 | 2020-12-22 | 齐鲁制药有限公司 | 一种鲁比前列酮化合物的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
TW592701B (en) | 2004-06-21 |
ES2310013T3 (es) | 2008-12-16 |
CN1251040A (zh) | 2000-04-19 |
NO993647L (no) | 1999-09-27 |
EP0978284A1 (en) | 2000-02-09 |
NO328460B1 (no) | 2010-02-22 |
ATE401894T1 (de) | 2008-08-15 |
DE69839767D1 (de) | 2008-09-04 |
NZ336960A (en) | 2001-02-23 |
US6197821B1 (en) | 2001-03-06 |
WO1999027934A1 (fr) | 1999-06-10 |
KR20000070508A (ko) | 2000-11-25 |
HK1025521A1 (en) | 2000-11-17 |
JP4319256B2 (ja) | 2009-08-26 |
AU1053799A (en) | 1999-06-16 |
DK0978284T3 (da) | 2008-10-27 |
EP0978284B1 (en) | 2008-07-23 |
CA2279267C (en) | 2010-01-12 |
PT978284E (pt) | 2008-10-07 |
NO993647D0 (no) | 1999-07-27 |
AU739343B2 (en) | 2001-10-11 |
CA2279267A1 (en) | 1999-06-10 |
KR100648868B1 (ko) | 2006-11-24 |
EP0978284A4 (en) | 2001-07-18 |
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