CN1610659A - 羧酸衍生物 - Google Patents

羧酸衍生物 Download PDF

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Publication number
CN1610659A
CN1610659A CNA028263839A CN02826383A CN1610659A CN 1610659 A CN1610659 A CN 1610659A CN A028263839 A CNA028263839 A CN A028263839A CN 02826383 A CN02826383 A CN 02826383A CN 1610659 A CN1610659 A CN 1610659A
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ring
phenyl
group
alkyl
representative
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Inventor
斋藤秀次
须贺洋一郎
佐藤正和
涩谷正史
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Publication of CN1610659A publication Critical patent/CN1610659A/zh
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    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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Abstract

一种用作VEGF受体拮抗剂并具有优良性能的化合物。该化合物是右式(1)代表的羧酸衍生物或其可药用盐，其中环A表示苯环、萘环等；W表示C1－5亚烷基；Z表示单键或亚苯基；R1与R2相同或不同，各自独立表示氢原子、卤原子、C1－5烷基或C1－10烷氧基；R3表示氢原子、卤原子、C1－12烷基、C2－5炔基、三氟甲基、乙炔基、氰基、硝基、－CH2－R6、－Y－R11等；R4是上式(2)代表的基团，R5表示氢原子或C1－5烷基。

Description

羧酸衍生物
技术领域
本发明涉及一种具有血管内皮细胞生长因子(下文简称为“VEGF”)受体拮抗作用的新羧酸衍生物或其可药用盐。
背景技术
VEGF(血管内皮细胞生长因子)是一种对血管内皮细胞表现出极高特异性的生长因子。VEGF及其受体在胎盘形成等生理性血管新生过程中具有重要作用。已经报道的VEGF受体有Flt-1(fms样酪氨酸激酶)和KDR(含激酶插入区的受体)(Advances in CancerResearch，vol.67，pp.281-316，1995)。据报道VEGF及其受体不仅在生理血管新生中有重要作用，而且在糖尿病性视网膜病、慢性风湿病和实性肿瘤等疾病中观察到的病理性血管新生中有重要作用(Advances in Cancer Research，vol.67，pp.281-316，1995)，且与这些疾病的发展密切相关。此外，已知VEGF及其受体不仅与血管新生有关还与血管通透性增高有关。据报道VEGF导致的血管通透性增高与癌性腹水潴留或缺血再灌注损伤后的脑水肿等病理症状密切相关(J.Clin.Invest，vol.104，pp.1613-1620，1999)。因此认为能抑制VEGF与其受体相结合的物质对于治疗各种与VEGF导致的病理性血管新生相关的疾病是有用的，并且能缓解与VEGF导致的高血管通透性相关的病理症状。有VEGF受体拮抗作用的低分子量化合物例如包括在JP-A-12-72653(WOO1/02344)中记载的氨基苯甲酸衍生物，如5-氨基-2-(4-羧基苯氧基)-N-[3-{4-(1-十八烷基氧基)-苯基}丙酰基]苯甲酸。
但是，上述氨基苯甲酸衍生物在水中的溶解度不够充分。
本发明的目的是提供一种用作VEGF受体拮抗剂并具有优良物理性能的化合物，用以治疗与VEGF导致血管新生相关的疾病以及改善VEGF导致的病理症状。
发明内容
为了解决上述问题，发明人经过不懈的研究之后发现下式(1)代表的羧酸衍生物及其可药用盐具有VEGF受体拮抗作用而且具有优良的水溶性，从而完成了本发明。
本发明提供了下式(1)代表的羧酸衍生物或其可药用盐：
          
其中环A表示苯环、萘环或包含1-4个从氮原子、氧原子和硫原子中任意选取的杂原子的杂环，
W表示C1-5亚烷基，
Z表示单键或亚苯基，
R1与R2相同或不同，各自独立表示氢原子、卤原子、C1-5烷基或C1-10烷氧基，
R3表示氢原子、卤原子、C1-12烷基、C2-5炔基、三氟甲基、乙炔基、氰基、硝基、-CH2-R6代表的基团[其中R6表示C1-5烷硫基，或下式代表的基团：
            
(其中m代表0或1，n表示0-3的整数)]，或下式代表的基团：
            
Figure A0282638300053
[其中环B表示苯环或含1-3个从氮原子、氧原子、硫原子中任意选取的杂原子的单环杂环，R7表示氢原子或C1-5烷基，R8表示氢原子、C1-5烷基或下式代表的基团：
         
Figure A0282638300061
(其中R9与R10相同或不同且各自独立表示氢原子、卤原子、C1-5烷基或C1-5烷氧基，p表示0-8的整数)]，或-Y-R11代表的基团(其中Y是-CO-、-O-、-S-或-SO2-代表的基团，R11表示C1-10烷基、被1-3个氟原子取代的甲基、苯基、被C1-5烷基取代的苯基、被C1-5烷氧基取代的苯基、C2-8二烷基氨基或环氨基)]，
R4是下式代表的基团：
(其中R12表示氢原子或被C1-5烷氧基取代的苯氧基，q表示1-5的整数，r表示10-24的整数)，且
R5表示氢原子或C1-5烷基。
本发明所用的术语定义如下。
本发明中“Cx-y”指其后的基团含x至y个碳原子。
A定义中的含1-4个从氮原子、氧原子和硫原子中任意选取的杂原子的杂环，指含1-4个从氮原子、氧原子和硫原子中任意选取的杂原子的单环或稠环杂环，例子包括呋喃环、噻吩环、吡咯环、噁唑环、异噁唑环、噻唑环、异噻唑环、咪唑环、吡唑环、噁二唑环、噻二唑环、四唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、呋喃并呋喃环、噻吩并呋喃环、咪唑并噻唑环、苯并呋喃、苯并噻吩环、吲哚环、中氮茚环、苯并噁唑环、苯并异噁唑环、苯并噻唑环、苯并异噻唑环、苯并咪唑、苯并吡唑环、苯并三唑环、嘌呤环、邻苯二甲酰亚胺环、喹啉环、异喹啉环、喹唑啉环、喹喔啉环、香豆素环、异香豆素环、二苯并呋喃环、萘并呋喃环、二苯并噻吩环、萘并噻吩环、吖啶环、菲啶环、吩噻嗪环。其中优选噻吩环、噻唑环、异噁唑环、苯并噻唑环、邻苯二甲酰亚胺环、香豆素环或二苯并呋喃环。
B定义中的含1-3个从氮原子、氧原子和硫原子中任意选取的杂原子的单环杂环，其例子包括呋喃环、噻吩环、吡咯环、噁唑环、异噁唑环、噻唑环、异噻唑环、咪唑环、吡唑环、噁二唑环、噻二唑环和四唑环。其中优选噁唑环和噁二唑环。
“C1-5亚烷基”指含1-5个碳原子的直链或支链亚烷基，其例子包括亚甲基、甲基亚甲基、亚乙基、三亚甲基、甲基亚乙基、四亚甲基、乙基亚乙基、二甲基亚乙基和五亚甲基。
“C1-5烷基”、“C1-10烷基”、“C1-12烷基”分别指含1-5个碳原子的直链或支链烷基、含1-10个碳原子的直链或支链烷基、含1-12个碳原子的直链或支链烷基。其例子包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、异己基、正辛基、正癸基。
卤原子指氟原子、氯原子、溴原子和碘原子。
“C1-5烷硫基”指含1-5个碳原子的直链或支链烷基硫基，其例子包括甲硫基、乙硫基、正丙基硫基、异丙基硫基、正丁基硫基、异丁基硫基、叔丁基硫基和正戊基硫基。
“C1-5烷氧基”指含1-5个碳原子的直链或支链烷氧基，其例子包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基和正戊氧基。“C1-10烷氧基”指含1-10个碳原子的直链或支链烷氧基，其例子除了包括上述之外，还包括正己氧基、正庚氧基和正癸氧基。
“被C1-5烷基取代的苯基”指被含1-5个碳原子的直链或支链烷基取代的苯基，其例子包括2-甲基苯基、3-乙基苯基、2-正丙基苯基、4-异丙基苯基、2-正丁基苯基、2-异丁基苯基、4-叔丁基苯基和3-正戊基苯基。
“被C1-5烷氧基取代的苯基”指被含1-5个碳原子的直链或支链烷氧基取代的苯基，其例子包括2-甲氧基苯基、4-乙氧基苯基、3-正丙氧基苯基、3-异丙氧基苯基、3-正丁氧基苯基、4-异丁氧基苯基、4-叔丁氧基苯基和2-正戊氧基苯基。
“被C1-5烷氧基取代的苯氧基”指被含1-5个碳原子的直链或支链烷氧基取代的苯氧基，其例子包括3-甲氧基苯氧基、4-乙氧基苯氧基、4-正丙氧基苯氧基、3-异丙氧基苯氧基、2-正丁氧基苯氧基、4-异丁氧基苯氧基、3-叔丁氧基苯氧基和4-正戊氧基苯氧基。
被1-3个氟原子取代的甲基指氟甲基、二氟甲基或三氟甲基。
C2-10二烷基氨基指被两个相同或不同且各含1-5个碳原子的直链或支链烷基取代的氨基，其例子包括二甲基氨基、N-乙基-N-甲基氨基、二乙基氨基、N-乙基-N-异丙基氨基、二丙基氨基、二异丙基氨基、二丁基氨基、二异丁基氨基和二戊基氨基。
环氨基的例子包括环丙啶基、氮杂环丁烷基、吡咯烷基、哌啶子基、奎宁环基和吗啉代。
本发明中可药用盐的例子包括，与硫酸、盐酸、磷酸等无机酸的盐，与乙酸、草酸、乳酸、酒石酸、富马酸、马来酸、甲磺酸或苯磺酸等有机酸的盐，与三乙胺或甲基胺等胺的盐，以及与钠离子、钾离子或钙离子等金属离子的盐。
本发明的有些化合物表现出多晶形现象，本发明包括其任一种晶形。
本发明的化合物(1)可以通过下述方法来制备。
1)其中R5表示C1-5烷基的本发明化合物被称为化合物(1a)，化合物(1a)可以通过下列反应式所示的方法来制备。
上述反应式中，A、W、Z、R1、R2、R3和R4与前文中定义的相同，R13表示C1-5烷基，X表示离去基团如卤原子、甲磺酰氧基、三氟甲磺酰氧基或对甲苯磺酰氧基。
可以利用氨基化合物(8)作为起始原料来制备本发明化合物(1a)。换言之，可以通过氨基化合物(8)与羧酸化合物(9)缩合来制备酰胺化合物(10)。
在该缩合反应中，优选使用缩合剂。缩合剂的例子包括亚硫酰卤如亚硫酰氯或亚硫酰溴，卤化磷如三氯化磷、三溴化磷或五氯化磷，卤化氢如氯化氢、溴化氢或碘化氢，卤甲酸烷基酯如氯甲酸甲酯、氯甲酸乙酯或溴甲酸乙酯，碳二亚胺化合物如二环己基碳二亚胺或1-乙基-3-(3-二甲基氨基)丙基碳二亚胺，磺酰氯如甲磺酰氯，磷化合物如磷酸二苯酯或二苯基磷酰氯，三苯基膦，偶氮二甲酸二乙酯和N，N-羰基二咪唑。
使用亚硫酰卤、卤化磷、卤代甲酸烷基酯等时，优选在碱存在下进行反应，碱的例子包括碱金属氢氧化物如氢氧化锂、氢氧化钠或氢氧化钾，碱金属碳酸盐如碳酸锂、碳酸钠或碳酸钾，碱金属碳酸氢盐如碳酸氢钠或碳酸氢钾，碱金属氢化物如氢化钠或氢化钾，碱金属如金属钠或金属钾，氨基碱金属如氨基钠，氨，氨水，有机碱如三乙胺、二异丙基乙基胺、三正丁基胺、1，5-二氮杂双环[4.3.0.]-5-壬烯、1，8-二氮杂双环[5.4.0]-7-十一碳烯、吡啶或N，N-二甲基氨基吡啶，碱金属烷氧化物如甲醇钠、乙醇钠或叔丁醇钾，有机金属化合物如甲基锂、正丁基锂、仲丁基锂、叔丁基锂、N，N-二异丙基氨基锂或双(三甲基甲硅烷基)氨基钠。
该反应可以在有溶剂或无溶剂下进行。所用溶剂的例子包括醇类如甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、2-甲氧基甲醇或乙二醇，醚类如二噁烷、四氢呋喃、二甲氧基乙烷、异丙醚或二乙醚，腈类如乙腈，酮类如丙酮或甲乙酮，脂肪烃如石油醚、正己烷或环己烷，芳香烃如苯、甲苯、二甲苯或氯苯，酯类如乙酸乙酯或丙酸乙酯，烷基卤化物如二氯甲烷、氯仿、四氯化碳或1，2-二氯乙烷，吡啶，N，N-二甲基甲酰胺、二甲亚砜和水。
溶剂和试剂的种类及其用量根据反应采用的反应条件和基质适当选择。
本发明化合物(1a)可以通过用酯化合物(11)将酰胺化合物(10)酰胺基团上的氮原子烷基化来制备。
该反应优选在碱存在下进行反应，碱的例子包括碱金属氢氧化物如氢氧化锂、氢氧化钠或氢氧化钾，碱金属碳酸盐如碳酸锂、碳酸钠或碳酸钾，碱金属碳酸氢盐如碳酸氢钠或碳酸氢钾，碱金属氢化物如氢化钠或氢化钾，碱金属如金属钠或金属钾，氨基碱金属如氨基钠，氨，氨水，有机碱如三乙胺、二异丙基乙基胺、三正丁基胺、1，5-二氮杂双环[4.3.0.]-5-壬烯、1，8-二氮杂双环[5.4.0]-7-十一碳烯、吡啶或N，N-二甲基氨基吡啶，碱金属烷氧化物如甲醇钠、乙醇钠或叔丁醇钾，有机金属化合物如甲基锂、正丁基锂、仲丁基锂、叔丁基锂、N，N-二异丙基氨基锂或双(三甲基甲硅烷基)氨基钠。
该反应可以在有溶剂或无溶剂下进行。所用溶剂的例子包括醇类如甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、2-甲氧基甲醇或乙二醇，醚类如二噁烷、四氢呋喃、二甲氧基乙烷、异丙醚或二乙醚，腈类如乙腈，酮类如丙酮或甲乙酮，脂肪烃如石油醚、正己烷或环己烷，芳香烃如苯、甲苯、二甲苯或氯苯，酯类如乙酸乙酯或丙酸乙酯，烷基卤化物如二氯甲烷、氯仿、四氯化碳或1，2-二氯乙烷，吡啶，N，N-二甲基甲酰胺、二甲亚砜和水。
溶剂和试剂的种类及其用量根据反应采用的反应条件和基质适当选择。
2)其中R5表示氢原子的本发明化合物被称为化合物(1b)，化合物(1b)可以由本发明的化合物(1a)来制备。
也就是说，本发明的化合物(1b)可以通过本发明化合物(1a)的酯部分水解来制备。
该反应是在酸性或碱性条件下进行的普通酯水解反应。酸性条件指盐酸、硫酸、乙酸、三氟乙酸、甲磺酸、三氟甲磺酸、磷酸、多聚磷酸等单独使用或任意组合使用的条件。碱性条件指使用碱金属氢氧化物如氢氧化锂、氢氧化钠、氢氧化钾，碱金属碳酸盐如碳酸锂、碳酸钠或碳酸钾，或氨。
该反应可以在有溶剂或无溶剂下进行。所用溶剂的例子包括醇类如甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、2-甲氧基甲醇或乙二醇，醚类如二噁烷、四氢呋喃、二甲氧基乙烷、异丙醚或二乙醚，腈类如乙腈，酮类如丙酮或甲乙酮，脂肪烃如石油醚、正己烷或环己烷，芳香烃如苯、甲苯、二甲苯或氯苯，酯类如乙酸乙酯或丙酸乙酯，烷基卤化物如二氯甲烷、氯仿、四氯化碳或1，2-二氯乙烷，吡啶，N，N-二甲基甲酰胺、二甲亚砜和水。
反应中，溶剂和试剂的种类及其用量根据反应采用的反应条件和基质适当选择。
式(1)代表的本发明羧酸化合物或其可药用盐用于治疗VEGF相关的疾病时，本发明的化合物可以口服或非肠道使用。其剂型为片剂、胶囊、颗粒剂、abstracts、粉剂、锭剂、膏、霜、乳液、悬浮液、栓剂、注射剂等，可以根据常规制剂技术来制备(例如，日本药典第十二版所述方法)。剂型可以根据患者年龄和治疗目的等条件适当选择。在制备各种剂型时，可以使用常规赋形剂(例如结晶纤维素、淀粉、乳糖、甘露醇等)、粘合剂(例如羟丙基纤维素、聚乙烯吡咯烷酮等)、润滑剂(例如硬脂酸镁、滑石等)、崩解剂(例如羧甲基纤维素钙等)等。用于治疗成年人时，本发明化合物的剂量为每天1-2000mg，一次或分次服用。该剂量可根据各个患者的年龄、体重和条件而不同。
本发明的最佳实施方式
接下来将提供实施例和试验实施例更详细地描述本发明。
实施例1：
N-[3-{4-(1-十八烷氧基)苯基}丙酰基]-N-苯基甘氨酸的制备
将3-{4-(1-十八烷氧基)苯基}丙酸(2.00g，4.78mmol)和亚硫酰氯(3.26g，274.00mmol)在苯(40ml)中的悬浮液加热回流1.5小时。向减压除去溶剂后的残留物中加入二氯甲烷(80ml)，并依次加入苯胺(0.60g，6.44mmol)和三乙胺(1.45g，14.3mmol)，之后在室温下搅拌2小时。反应液用氯仿稀释并依次用1M盐酸和饱和盐水洗。有机层经无水硫酸镁干燥后减压除去溶剂。向这样得到的残余物(1.0g，2.03mmol)中加入四氢呋喃/N，N-二甲基甲酰胺(5∶1)的混合液(30ml)以制成溶液，然后室温下加入60％氢化钠(0.12g，3.05mmol)，然后将所得混合物搅拌30分钟。之后，向反应液中滴加溴代乙酸叔丁酯(0.48g，2.44mmol)后在室温下搅拌14小时。向反应体系中加入饱和氯化铵水溶液，混合物用乙酸乙酯萃取。有机层依次用水、饱和盐水洗，经无水硫酸镁干燥后减压除去溶剂。向所得残余物中加入三氟乙酸(20ml)后搅拌1小时。减压除去三氟乙酸后，残余物在甲醇中重结晶得到N-[3-{4-(1-十八烷氧基)苯基}丙酰基]-N-苯基甘氨酸(0.91g)，为无色粉末。
1H-NMR(300MHz，δppm in CDCl3)
0.88 (3H，t，J＝7Hz)，1.25-1.79(32H，m)，2.40(2H，t，J＝8Hz)，
2.85(2H，t，J＝8Hz)，3.89(2H，t，J＝7Hz)，4.39(2H，s)，6.75-7.41
(9H，m)
实施例2-113
按照实施例1的相同方法，由相应的氨基化合物和相应的羧酸制备表1中的本发明化合物(实施例2-113)。
Figure A0282638300131
Figure A0282638300132
Figure A0282638300141
Figure A0282638300161
Figure A0282638300171
Figure A0282638300231
Figure A0282638300281
Figure A0282638300291
Figure A0282638300301
Figure A0282638300311
实施例114：
N-[3-{4-(1-十二烷氧基)苯基}丙酰基]-N-(2-苯氧基苯基)甘氨酸甲酯的制备
将3-{4-(1-十二烷氧基)苯基}丙酸(0.60g，1.79mmol)和亚硫酰氯(0.64g，5.38 mmol)在苯(7ml)中的悬浮液加热回流0.5小时。向减压除去溶剂后的残留物中加入二氯甲烷(14ml)，并依次加入2-苯氧基苯胺(0.30g，1.63mmol)和三乙胺(0.54g，5.38mmol)，将混合物在室温下搅拌5小时。从反应液中蒸除溶剂后，将所得残余物溶于乙酸乙酯，依次用1M盐酸和饱和氯化钠水溶液洗。有机层经无水硫酸镁干燥后减压除去溶剂。这样得到3-[4-(1-十二烷氧基)苯基]-N-(2-苯氧基苯基)丙酰胺的粗晶体(0.65g，79％)。向用正己烷洗过的60％氢化钠(0.036g，0.70mmol)中，加入0.30g(0.60mmol)如此获得的粗晶体在N，N-二甲基甲酰胺(4ml)中的溶液，之后室温搅拌20分钟，向其中加入溴乙酸甲酯(0.14g，0.90mmol)，之后室温搅拌48小时。反应液用乙酸乙酯稀释，依次用水和饱和氯化钠水溶液洗，经无水硫酸镁干燥后减压除去溶剂。这样得到的残余物经硅胶柱色谱(洗脱剂∶正己烷/乙酸乙酯＝5∶1)提纯得到N-[3-{4-(1-十二烷氧基)苯基}丙酰基]-N-(2-苯氧基苯基)甘氨酸甲酯(0.23g)，为无色油状物。
1H-NMR(300MHz，δppm in CDCl3)
0.88(3H，t，J＝7Hz)，1.20-1.45(20H，m)，1.74(2H，m)，2.43
(2H，m)，2.83(2H，m)，3.69(1H，d，J＝17Hz)，3.73(3H，s)，3.89
(2H，t，J＝7Hz)，4.87(1H，d，J＝17Hz)，6.72-7.50(13H，m)
实施例115-121
根据实施例114化合物的制备方法得到下列本发明化合物。
N-[2-(2-甲基苯氧基)苯基]-N-[3-{4-(1-十八烷氧基)-苯基}丙酰基]甘氨酸叔丁酯(实施例115)
1H-NMR(300MHz，δppm in CDCl3)：
0.88(3H，t，J＝7Hz)，1.20-1.43(30H，m)，1.74(2H，m)，2.19
(3H，s)，2.47(2H，m)，2.87(2H，m)，3.88(2H，t，J＝7Hz)，4.23
(2H，q，J＝17Hz)，6.70-7.52(12H，m)
N-[2-(5-苯基-1，3，4-噁二唑-2-基)苯基]-N-[3-{4-(1-十八烷氧基)-苯基}丙酰基]甘氨酸叔丁酯(实施例116)
1H-NMR(300MHz，δ ppm in CDCl3)：
0.88(3H，t，J＝7Hz)，1.20-1.40(30H，m)，1.45(9H，s)，1.67
(2H，m)，2.35(2H，m)，2.83(2H，m)，3.50(1H，d，J＝17Hz)，3.75
(2H，t，J＝7Hz)，5.01(1H，d，J＝17Hz)，6.59(2H，m)，6.88(2H，
m)，7.48-7.62(5H，m)，7.74(1H，m)，8.00-8.08(2H，m)，8.33
(1H，m)
N-[4-{1 2-(4-甲氧基苯氧基)十二烷氧基}苯基乙酰基]-N-[2-(5-苯基-1，3，4-噁二唑-2-基)苯基]甘氨酸叔丁酯(实施例117)
1H-NMR(300MHz，δppm in CDCl3)：
1.20-1.65(20H，m)，1.45(9H，s)，1.76(2H，m)，3.24(1H，m)，
3.55(1H，d，J＝17Hz)，3.62(1H，m)，3.77(3H，s)，3.90(2H，t，
J＝7Hz)，5.05(1H，d，J＝17Hz)，6.50(2H，m)，6.75(2H，m)，6.83
(4H，m)，7.48-7.68(3H，m)，7.80(1H，m)，7.95-8.03(2H，m)，
8.25(1H，m)
2-氨基-N-[2-(5-苯基-1，3，4-噁二唑-2-基)苯基]-N-[3-{4-(1-十八烷氧基)苯基}丙酰基丙酸叔丁酯(实施例118)
1H-NMR(300MHz，δppm in CDCl3)：
0.88 (3H，t，J＝7Hz)，0.94(3H，d，J＝7Hz)，1.20-1.40(30H，m)，
1.51(9H，s)，1.68(2H，m)，2.26(2H，m)，2.80(2H，m)，3.75
(2H，t，J＝7Hz)，5.00(1H，q，J＝7Hz)，6.60(2H，m)，6.85(2H，
m)，7.48-7.68(5H，m)，7.83(1H，m)，8.00-8.08(2H，m)，8.33
(1H，m)
4-氨基-N-[2-(5-苯基-1，3，4-噁二唑-2-基)苯基]-N-[3-{4-(1-十八烷氧基)苯基}丙酰基]丁酸乙酯(实施例119)
1H-NMR(300MHz，δppm in CDCl3)：
0.88(3H，t，J＝7Hz)，1.19(3H，t，J＝7Hz)，1.00-1.46(30H，m)，
1.63-1.96(4H，m)，2.28(4H，m)，2.80(2H，m)，3.04(1H，m)，
3.80(2H，t，J＝7Hz)，4.06(2H，q，J＝7Hz)，4.30(1H，m)，6.65
(2H，m)，6.90(2H，m)，7.08(1H，m)，7.56(5H，m)，8.08(2H，m)，
8.34(1H，m)
N-[3-{4-(1-十八烷氧基)苯基}丙酰基]-N-(2，4，6-三甲基苯基)甘氨酸甲酯(实施例1 20)
1H-NMR(300MHz，δppm in CDCl3)：
0.88(3H，t，J＝7Hz)，1.17-1.48(30H，m)，1.74(2H，m)，2.15
(3H，s)，2.23(2H，m)，2.27(3H，s)，2.85(2H，m)，3.76(3H，s)，
3.89(2H，t，J＝7Hz)，4.09(2H，s)，6.76(2H，m)，6.89(2H，s)，
6.99(2H，m)
N-(2-苯基)-N-[3-{4-(1-十八烷氧基)苯基}丙酰基]-甘氨酸叔丁酯
(实施例121)
1H-NMR(300MHz，δppm in CDCl3)：
0.88(3H，t，J＝7Hz)，1.20-1.46(39H，m)，1.78-1.69(2H，m)，
2.38(2H，t，J＝8Hz)，2.85(2H，t，J＝8Hz)，3.89(2H，t，J＝7Hz)，
4.23(2H，s)，6.75-7.22(9H，m)
实验实施例1[VEGF受体结合实验]
根据文献(Cell Growth&Differentiation，Vol.7，pp.213-221，1996)所述方法进行下列实验。
将其中Flt-1强制表达的NIH3T3细胞种入24孔胶原被覆板(7×104细胞/孔)，在含10％牛血清和200μg/ml Geneticin G418的Dulbecco’s modified Eagle’s medium(DMEM)中、在5％二氧化碳气体的气氛下、37℃培养24小时。细胞在缓冲液A[DMEM中含10mMHEPES(N-2-羟乙基哌嗪-N’-2-乙磺酸)和0.1％BSA(牛血清白蛋白)]中于4℃预培养30分钟。然后，将培养基替换为缓冲液B(DMEM中含10mM HEPES和0.5％BSA)。将表2所示的实验化合物分别溶于二甲亚砜中并用缓冲液B将其稀释至预定浓度，然后向其中加入[125I]-VEGF(最终浓度为25pM)。于4℃进行结合反应90分钟。反应完成后，细胞用冰冷的缓冲液A洗3次。向各个孔中分别加入0.5ml0.5M NaOH溶液，将细胞在室温下裂解30分钟。利用γ计数器测量各个孔中裂解细胞的放射活性，计算[125I]-VEGF的总结合量。[125I]-VEGF非特异性结合量通过10nM非标记VEGF存在下的竞争实验来测定。[125I]-VEGF的特异性结合量由[125I]-VEGF总结合量与[125I]-VEGF非特异性结合量的差值来计算。实验化合物的结合抑制率通过下列方程来计算。
Figure A0282638300351
表1
  实验化合物(实施例序号) 抑制率(％)   浓度(μg/ml)
    36     40     3
    57     61     1
    82     59     1
    91     55     3
    94     53     3
    95     55     3
    96     60     3
    a     65     1
a：5-氨基-2-(4-羧基苯氧基)-N-[3-{4-(1-十八烷氧基)苯基}丙酰基]苯甲酸；JP-A-12-072653(WO01/02344)中公开的一种氨基苯甲酸衍生物
实验实施例2[溶解度实验]
在螺口试管中称量1mg实验化合物，向其中加入1ml磷酸盐缓冲液(pH：6.8；20mM；离子强度＝0.15)，室温遮光条件下振荡2小时后，于25℃培养22小时。试管于25℃以3000rpm离心10分钟后得到的上清液进一步于25℃以11000rpm离心10分钟。这样得到的上清液用水/乙腈(1∶1)混合液以2-21倍稀释比进行稀释从而制得样品溶液(A)。0.5mg实验化合物溶于5ml乙腈，并用乙腈稀释两倍从而制得标准溶液(B)。将10μl样品溶液(A)和10μl标注溶液(B)根据HPLC方法测量确定各溶液中的实验化合物的峰面积。利用测量值根据下列方程计算实验化合物的溶解度(mg/ml)。
<HPLC操作条件>
柱子：shiseido capcell pak UG120(4.6×150mm)
流动相：乙腈/10mM乙酸铵的混合液(90∶10)
检测波长：230nm
流速：1ml/min
柱温：40℃
表2
  实验化合物(实施例序号) pH     溶解度(μg/ml)
    82     6.7     353.5
    91     6.8     168.2
    94     6.9     216.1
    96     6.7     381.9
    a     6.9     0.029
工业实用性
式(1)代表的本发明羧酸化合物或其可药用盐具有VEGF受体拮抗作用并且对于治疗VEGF相关疾病是有用的。本发明化合物通过抑制配体(VEGF)与VEGF受体相结合从而抑制了血管内皮细胞的VEGF依赖性增生并且抑制了血管新生。该化合物还能抑制VEGF导致的血管通透性增高。VEGF相关疾病和病理症状的例子包括糖尿病性视网膜病和其他视网膜病、慢性风湿病、实性肿瘤、与缺血再灌注损伤相关的脑水肿和伤害、银屑病、动脉粥样硬化、晶状体后纤维组织形成、新生血管性绿内障、老年性黄斑变性、甲状腺增生(包括格雷夫斯病(Graves’disease))、慢性炎症、肺炎、肾炎综合症、肿瘤征兆性免疫机能减退、腹水潴留、心内膜液渗出(与心内膜炎等有关)以及胸膜积水存留。

Claims (5)

1.一种下式代表的羧酸衍生物或其可药用盐：
其中环A表示苯环、萘环或包含1-4个从氮原子、氧原子和硫原子中任意选取的杂原子的杂环；
W表示C1-5亚烷基；
Z表示单键或亚苯基；
R1与R2相同或不同，各自独立表示氢原子、卤原子、C1-5烷基或C1-10烷氧基；
R3表示氢原子、卤原子、C1-12烷基、C2-5炔基、三氟甲基、乙炔基、氰基、硝基、-CH2-R6代表的基团[其中R6表示C1-5烷硫基或下式代表的基团：
(其中m代表0或1，n表示0-3的整数)]，或下式代表的基团：
Figure A028263830002C3
[其中环B表示苯环或含1-3个从氮原子、氧原子、硫原子中任意选取的杂原子的单环杂环，R7表示氢原子或C1-5烷基，R8表示氢原子、C1-5烷基或下式代表的基团：
(其中R9与R10相同或不同且各自独立表示氢原子、卤原子、C1-5烷基或C1-5烷氧基，p表示0-8的整数)]，或-Y-R11代表的基团
(其中Y是-CO-、-O-、-S-或-SO2-代表的基团，R11表示C1-10烷基、被1-3个氟原子取代的甲基、苯基、被C1-5烷基取代的苯基、被C1-5烷氧基取代的苯基、C2-8二烷基氨基或环氨基)]；
R4是下式表示的基团：
Figure A028263830003C1
(其中R12表示氢原子或被C1-5烷氧基取代的苯氧基，q表示1-5的整数，r表示10-24的整数)，且
R5表示氢原子或C1-5烷基。
2.根据权利要求1的羧酸衍生物或其可药用盐，其中环A是苯环、萘环、噻吩环、噻唑环、异噁唑环、苯并噻唑环、邻苯二甲酰亚胺环、香豆素环或二苯并呋喃环，环B是苯环、噁唑环或噁二唑环。
3.根据权利要求2的羧酸衍生物或其可药用盐，其中m是1，n是1-3的整数；当Y表示-CO-、-O-或-S-时，R11是C1-10烷基、被1-3个氟原子取代的甲基、苯基、被C1-5烷基取代的苯基或被C1-5烷氧基取代的苯基；当Y表示-SO2-时，R11是C2-8二烷基氨基或环氨基。
4.根据权利要求3的羧酸衍生物或其可药用盐，其中环A是苯环，R1与R2相同或不同且各自独立表示氢原子或C1-5烷基，R3是-Y-R11代表的基团或下式代表的基团：
环B是噁唑环或噁二唑环，Y是-CO-或O-，R11是苯基、被C1-5烷基取代的苯基或被C1-5烷氧基取代的苯基。
5.根据权利要求4的羧酸衍生物或其可药用盐，其中R3是下式代表的基团：
Figure A028263830003C3
环B是噁唑环或噁二唑环。
CNA028263839A 2001-12-27 2002-12-26 羧酸衍生物 Pending CN1610659A (zh)

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NO20042664L (no) 2004-09-27
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KR20040074102A (ko) 2004-08-21
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US20050222423A1 (en) 2005-10-06
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