CN101784278A - 用于治疗fab-相关的疾病的嘌呤衍生物 - Google Patents
用于治疗fab-相关的疾病的嘌呤衍生物 Download PDFInfo
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- CN101784278A CN101784278A CN200880103199A CN200880103199A CN101784278A CN 101784278 A CN101784278 A CN 101784278A CN 200880103199 A CN200880103199 A CN 200880103199A CN 200880103199 A CN200880103199 A CN 200880103199A CN 101784278 A CN101784278 A CN 101784278A
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Abstract
本发明公开了选择的嘌呤衍生物在治疗过度增生性疾病中的用途。
Description
本发明公开了具有对于治疗所有种类的病理状况的抑制能力的物质的用途。
成纤维细胞活化蛋白(Fibroblast Activation Protein，FAP)，也已知为seprase，属于丝氨酸蛋白酶家族。FAP，如酶DPP IV(二肽基肽酶IV)，例如属于从存在的蛋白或通式X-Pro-XAA的肽裂解二肽的酶。FAP为由760个氨基酸组成的跨膜蛋白。FAP表现出与DPP IV高度的同源性，且也与该蛋白形成异源二聚体。与DPP IV不同，FAP的表达和活性是非常有限的。因此，FAP在正常成年人组织中不表达。在组织创伤或损伤后，在活化的成纤维细胞中产生FAP。FAP也在所有种类的人上皮肿瘤的肿瘤间质组织中以及在多种骨和软组织肉瘤的恶性细胞中表达。这些尤其包括，多于90％的乳腺癌、非小细胞肺癌和结肠直肠癌。FAP优选存在于下述成纤维细胞中，该成纤维细胞在邻近新形成的或已经形成的血管中产生，并在肿瘤毛细血管内皮和真实恶性上皮细胞以及细胞簇之间形成特定的细胞腔隙。
FAP-阳性成纤维细胞存在于原发癌(primary carcinomas)和转移癌(metastasising carcinomas)中。FAP的表达状况表明FAP在肿瘤侵入健康组织以及在肿瘤形成和转移中起作用。
FAP抑制剂，即能够降低或抑制FAP的蛋白水解活性的物质，对于治疗所有种类的肿瘤疾病是有用的治疗试剂。FAP抑制剂优选用于治疗上皮源的肿瘤(tumours of epithelial origin)如乳腺肿瘤、非小细胞肺癌、结肠直肠癌和软组织癌。FAP抑制剂也用于所有种类的转移瘤(metastasising tumours)如黑素瘤(melanomas)。
此外，FAP抑制剂也用于其它过度增生性疾病(hyperproliferativediseases)。这些尤其包括，心脏肥大、肝硬化(cirrhoses)和纤维瘤病(fibromatoses)。
此外，FAP抑制剂也可以用作用于治疗风湿类疾病(rheumatic spectrumdiseases)如关节炎或骨关节炎和神经损伤性疾病(neurotraumatic disorders)的有价值的治疗剂。
FAP抑制剂也用于治疗伤口愈合病症(wound healing disorders)和痤疮和增生性皮肤病如牛皮癣。
此外，FAP抑制剂也用于治疗所有来源的疼痛和偏头痛。
根据本发明所选择的嘌呤衍生物可以为式(I)、式(II)、式(III)或式(IV)化合物，或其互变异构体、对映异构体及其盐，及其混合物
式(I)
式(II)
式(III)
式(IV)
其中
R1表示吡啶基甲基、嘧啶基甲基、喹啉基甲基、(2-氧代-1，2-二氢-喹啉基)甲基、异喹啉基甲基、喹唑啉基甲基、(4-氧代-3，4-二氢-喹唑啉基)甲基、喹喔啉基甲基、[1，5]二氮杂萘基甲基([1，5]naphthyridinylmethyl)、(1H-萘嵌间二氮杂苯基)甲基((1H-perimidinyl)methyl)、菲啶基甲基(phenanthridinylmethyl)、(11H-二苯并[b，e]氮杂
基)甲基、(二苯并[b，f][1，4]氧氮杂
基)甲基、(5H-二苯并[b，e][1，4]二氮杂基)甲基或(咪唑并[1，2-a]喹啉基)甲基，且上述基团的杂环基团可以被Ra单取代或二取代，且取代基可以相同或不同，且Ra表示氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、环丙基、苯基、甲氧基、乙氧基、氨基、甲基氨基、二甲基氨基、吡咯烷基(pyrrolidino)、哌啶子基、吗啉代、哌嗪基(piperazino)或N-甲基哌嗪基，
R2表示甲基、乙基、丙基、异丙基、环丙基或苯基，且所述甲基、乙基、丙基和异丙基可以被羧基、甲氧基羰基、乙氧基羰基、氨基羰基、甲基氨基羰基、二甲基氨基羰基、吡咯烷基羰基、哌啶子基羰基、吗啉代羰基、哌嗪基羰基或N-甲基哌嗪基羰基所取代，
R3表示2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、苄基、氟苄基、氯苄基、溴苄基或氰基苄基，且
R4表示哌嗪基、高哌嗪基(homopiperazino)、3-(R)-氨基-哌啶-1-基、3-(S)-氨基-哌啶-1-基、(2-氨基-乙基)-甲基氨基、(2-氨基-2-甲基-丙基)-甲基氨基、((R)-2-氨基-丙基)-甲基氨基或((S)-2-氨基-丙基)-甲基氨基。
式(I)至(IV)的嘌呤衍生物中，式(I)和(II)的那些化合物是尤其优选的。
R1的优选定义为吡啶-2-基甲基、吡啶-3-基甲基、吡啶-4-基甲基、嘧啶-2-基甲基、嘧啶-4-基甲基、喹啉-2-基甲基、喹啉-3-基甲基、喹啉-4-基甲基、喹啉-5-基甲基、喹啉-6-基甲基、喹啉-7-基甲基、喹啉-8-基甲基、(2-氧代-1，2-二氢-喹啉-6-基)甲基、异喹啉-1-基甲基、异喹啉-3-基甲基、异喹啉-4-基甲基、异喹啉-8-基甲基、喹唑啉-2-基甲基、喹唑啉-4-基甲基、喹唑啉-6-基甲基、喹唑啉-7-基甲基、(4-氧代-3，4-二氢-喹唑啉-2-基)甲基、喹喔啉-2-基甲基、喹喔啉-5-基甲基、喹喔啉-6-基甲基、[1，5]二氮杂萘-2-基甲基、[1，5]二氮杂萘-3-基甲基、[1，5]二氮杂萘-4-基甲基、(1H-萘嵌间二氮杂苯-2-基)甲基、菲啶-6-基甲基、(11H-二苯并[b，e]氮杂
-6-基)甲基、(二苯并[b，f][1，4]氧氮杂-11-基)甲基、(5H-二苯并[b，e][1，4]二氮杂
-11-基)甲基或(咪唑并[1，2-a]喹啉-2-基)甲基，且上述基团的杂环基团可以被氰基、乙基、环丙基、苯基或吗啉代单取代，或被甲基单取代或二取代，
优选为3-氰基-吡啶-2-基甲基、(4-苯基-嘧啶-2-基)甲基、(4，6-二甲基-嘧啶-2-基)甲基、3-氰基-喹啉-2-基甲基、3-甲基-异喹啉-1-基甲基、4-氰基-异喹啉-3-基甲基、喹唑啉-2-基甲基、(1-甲基-2-氧代-1，2-二氢-喹啉-6-基)甲基、(4-甲基-喹唑啉-2-基)甲基、(4，5-二甲基-喹唑啉-2-基)甲基、(4-乙基-喹唑啉-2-基)甲基、(4-环丙基-喹唑啉-2-基)甲基、(4-氰基-喹唑啉-2-基)甲基、(4-吗啉代-喹唑啉-2-基)甲基、(4-苯基-喹唑啉-2-基)甲基、(4-氧代-3，4-二氢-喹唑啉-2-基)甲基、喹喔啉-2-基甲基、喹喔啉-6-基甲基、[1，5]二氮杂萘-2-基甲基、(1H-萘嵌间二氮杂苯-2-基)甲基、菲啶-6-基甲基、(11H-二苯并[b，e]氮杂
-6-基)甲基、(二苯并[b，f][1，4]氧氮杂
-11-基)甲基、(5-甲基-5H-二苯并[b，e][1，4]二氮杂-11-基)甲基或(咪唑并[1，2-a]喹啉-2-基)甲基。
R2的优选定义为甲基、羧基甲基、甲氧基羰基甲基、乙氧基羰基甲基、环丙基和苯基，
尤其为甲基、羧基甲基和苯基。
R3的优选定义为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、苄基、2-氯苄基、2-溴苄基或2-氰基苄基，尤其为3-甲基-2-丁烯-1-基、2-丁炔-1-基或苄基。
R4的优选定义为哌嗪基、高哌嗪基、3-(R)-氨基-哌啶-1-基、3-(S)-氨基-哌啶-1-基、(2-氨基-乙基)-甲基氨基、((R)-2-氨基-丙基)-甲基氨基或((S)-2-氨基-丙基)-甲基氨基。
通式(I)至(IV)的嘌呤衍生物可利用文献中已知的方法制备。通式(I)的嘌呤衍生物可以按例如WO 2002/068420、WO 2004/018468、WO 2004/041820、WO 2005/051950、WO 2005/082906、WO 2005/085246、WO 2006/027204和WO 2006/029769中所述制备。
通式(II)的嘌呤衍生物可以利用例如WO 2004/050658、WO 2004/111051、WO 2005/058901、WO 2005/097798和WO 2005/110999中所述制备。
通式(III)和(IV)的嘌呤衍生物可以利用例如WO 2006/068163和WO2007/071738中所述制备。
本发明优选的嘌呤衍生物为下述化合物，其互变异构体、对映异构体及其治疗有效的盐：
·1-[(喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(80))：
·1-[(3-甲基-异喹啉-1-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(130))：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((S)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(141))：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(142))：
·1-[(4-苯基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(217))：
·2-((R)-3-氨基-哌啶-1-基)-3-(丁-2-炔基)-5-(4-甲基-喹唑啉-2-基甲基)-3，5-二氢-咪唑并[4，5-d]哒嗪-4-酮(参见WO 2004/050658，实施例136))：
·1-[([1，5]二氮杂萘-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(252))：
·1-[(1H-萘嵌间二氮杂苯-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/041820，实施例1(29))：
·1-[(4-乙基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(22))：
·1-[(4-环丙基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(23))：
·1-[(4-苯基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(31))：
·1-[(4-氰基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(37))：
·1-[(11H-二苯并[b，e]氮杂
-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/041820，实施例1(5))：
·1-[(菲啶-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/041820，实施例1(33))：
·1-[(二苯并[b，f][1，4]氧氮杂
-11-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/041820，实施例1(8))：
·1-[(5-甲基-5H-二苯并[b，e][1，4]二氮杂
-11-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/041820，实施例1(12))：
·1-[(4，5-二甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(28))：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(2-氨基-乙基)-甲基氨基]-黄嘌呤(参见WO 2006/029769，实施例1(1))：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-苯基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/082906，实施例1(8))：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(3-甲基-2-丁烯-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，类似于实施例2(20))：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-苄基-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，类似于实施例2(294))：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(哌嗪-1-基)-黄嘌呤(参见WO 2005/051950，实施例1)：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(高哌嗪-1-基)-黄嘌呤(参见WO 2005/051950，实施例1(3))：
·1-[(3-氰基-喹啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(30))：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-(2-氨基-丙基)-甲基氨基]-黄嘌呤(参见WO 2006/029769，实施例2(4))：
·1-[(咪唑并[1，2-a]喹啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/041820，实施例1(32))：
·1-[(4-氧代-3，4-二氢-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(71))：
·1-[(喹喔啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(169))：
·1-[(喹喔啉-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(83))：
·1-[(4-吗啉代-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(180))：
·1-[(1-甲基-2-氧代-1，2-二氢-喹啉-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(227))：
·1-[(4-氰基-异喹啉-3-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(88))：
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-羧基甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2006/027204，实施例2)：
·1-[(4，6-二甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(82))：
·1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(52))：
化合物的生物学性质如下研究：
FAP测试：
所用的FAP源为CD8huFAP细胞的均质化制品，且其用缓冲液以1∶100稀释。对于反应所用的底物为Bachem生产的H-Ala-Pro_7-氨基-4-三氟甲基香豆素(AlaPro-AFC)(Prod.No I-1680)。
测试物质在DMSO(二甲亚砜)和缓冲液中稀释，并移液至96-孔板中。在其中加入70uL酶和20uL底物。将该板在环境温度培养1小时，然后使用Wallac Victor 1420多标记计数器检测荧光，激发波长为405nm，且发射波长为535nm。
通过将有测试物质存在时的荧光与对照组的荧光进行比较来计算结果。扣除背景荧光。
本发明的化合物在100μM浓度的FAP抑制＞50％，例如。本发明的优选化合物在3μM浓度的FAP抑制＞50％。
对于药物用途而言，本发明的化合物通常用于温血脊椎动物，尤其是人，剂量为0.001-100mg/kg体重，优选0.1-15mg/kg，每天1-4次。出于该目的，所述化合物任选与其他活性物质组合，与下述物质一起配制：一种或多种常规惰性载体和/或稀释剂，如玉米淀粉、乳糖、葡萄糖、微晶纤维素、硬脂酸镁、聚乙烯吡咯烷酮、柠檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨醇、水/聚乙二醇、丙二醇、十六十八烷醇、羧甲基纤维素或脂肪物质如硬脂，或它们适宜的混合物，以形成常规的盖伦制剂，如素片或包衣片剂、胶囊、粉剂、悬浮剂或栓剂。
药物制剂根据所需的给药方法(口服、静脉、肠胃外等)来设计，优选的制剂为口服制剂。
因此本发明的药物组合物(含有上述嘌呤衍生物)由本领域技术人员使用允许的制剂赋形剂通过现有技术中描述的方法制备。这些赋形剂的实例为稀释剂、粘合剂、载体、填充剂、润滑剂、流动剂、结晶阻滞剂、崩解剂、溶解剂(solubilisers)、着色剂、pH调节剂、表面活性剂和乳化剂。
适宜的稀释剂的实例包括纤维素粉末、磷酸氢钙、赤藓醇、(低取代的)羟丙基纤维素、甘露醇、预凝胶淀粉或木糖醇。
适宜的粘合剂的实例包括乙烯基吡咯烷酮与其他乙烯基衍生物的共聚物(共聚维酮)、羟丙甲纤维素(HPMC)、羟丙基纤维素(HPC)、聚乙烯基吡咯烷酮(聚维酮)、预凝胶淀粉、或低取代的羟丙基纤维素。
适宜的润滑剂的实例包括滑石、聚乙二醇、山嵛酸钙、硬脂酸钙、氢化蓖麻油或硬脂酸镁。
适宜的崩解剂的实例包括玉米淀粉或交联聚维酮。
制备本发明的DPP IV抑制剂的药物制剂的适宜的方法为：
·将活性物质与适宜的压片赋形剂的粉末混合物直接压片；
·用适宜的赋形剂制粒，且随后与适宜的赋形剂混合，且随后压片以及膜包衣；或
·将粉末混合物或颗粒封装至胶囊中。
适宜的制粒方法为：
·在强力混合器中湿法制粒，然后流化床干燥；
·一锅制粒；
·流化床制粒；或
·与适宜的赋形剂一起干法制粒(如，通过滚压机压缩)，随后压片或封装至胶囊中。
由于不同的功能疾病通常同时发生，因此建议将许多不同的活性原理彼此组合。因此，根据所诊断的功能疾病，如果FAP抑制剂与通常用于所关注的疾病的(允许的)活性物质组合，可能获得改善的治疗结果，例如与具有抗-过度增殖性质的活性物质或用于治疗过度增生性疾病(如癌症)的活性物质组合。
该组合治疗可以以活性物质的自由组合给予，或以固定组合的形式给予，例如片剂或胶囊。对于此所需的组合物质的药物制剂可以作为市售药物组合物获得，或可以由技术人员利用常规方法配制。可以作为市售药物组合物获得的活性物质描述于现有技术中的许多地方，例如每年出版的药物列表，药物工业联合会(Federal Association of the Pharmaceutical Industry)的″Rote Liste″，或每年更新的对于已知作为″Physicians’Desk Reference″的处方药的制造商信息的汇编。
本文所定义的抗癌治疗可以作为单独治疗使用，或可以除本发明化合物外还包含常规手术、放疗或化疗。该化疗可以包括一种或多种下述类型的化学治疗的和/或靶向的抗肿瘤试剂：
可以提及下述类型和他们中的一些典型的代表，作为已知化学治疗抗肿瘤试剂的实例：
(i)烷化/氨甲酰化(alkylating/carbamylating)活性物质，如环磷酰胺(Endoxan)、异环磷酰胺(Holoxan)、塞替派、美法仑(Alkeran)或氯乙基亚硝基脲(CENU)；(ii)铂衍生物如顺铂(Platinex)、奥沙利铂、沙铂或卡铂(Carboplat)；(iii)抗有丝分裂活性物质/微管蛋白抑制剂如长春花生物碱类(VIncristin，Vinblastin，Vinorelbin)、紫杉烷类如紫杉醇(Taxol)、多西紫杉醇(Taxotere)或其类似物和轭合物、埃博霉素如埃博霉素B(Patupilone)、氮杂埃博霉素(azaepothilone)(Ixabepilone)或ZK-EPO；(iv)拓扑异构酶抑制剂，如蒽环类抗生素(如多柔比星/阿霉素)、表鬼臼毒素(如依托泊苷/Etopophos)和喜树碱和喜树碱类似物(如伊立替康/Camptosar或Topotecan/Hycamtin)；(v)嘧啶拮抗剂，如5-氟尿嘧啶(5-FU)、卡培他滨(Xeloda)、阿糖胞嘧啶/阿糖胞苷(Alexan)或吉西他滨(Gemzar)；(vi)嘌呤拮抗剂，如6-巯基嘌呤(Puri-Nethol)、6-硫鸟嘌呤或氟达拉滨(Fludara)，和(vii)叶酸拮抗剂如甲氨蝶呤(Farmitrexat)或Premetrexed(Alimta)。
可以提及下述类型和他们中的一些典型的代表，作为在实验或标准癌症治疗中使用的靶向抗肿瘤试剂的实例：
激酶(如Abl、EGFR、VEGFR、PDGFR等)抑制剂，如伊马替尼(Glivec)、ZD-1839/吉非替尼(Iressa)、Bay43-9006(Sorafenib、Nexavar)、SU11248/舒尼替尼(Sutent)或OSI-774/厄洛替尼(Tarceva)、达沙替尼(Sprycel)、拉帕替尼(Tykerb)、或瓦他拉尼、凡德他尼(Zactima)或帕唑帕尼；(ii)蛋白酶抑制剂，如PS-341/bortezumib(Velcade)；(iii)热休克蛋白90抑制剂，如17-烯丙基氨基格尔德霉素(17-AAG)；(iv)血管靶向试剂(VTAs)，如combretastin A4Phosphat或AVE8062/AC7700、以及抗血管生成活性物质，如VEGF抗体，如贝伐珠单抗(Avastin)、血管激酶抑制剂或KDR酪氨酸激酶抑制剂，如PTK787/ZK222584(Vatalanib)或凡德他尼(Zactima)或帕唑帕尼；(v)单克隆抗体，如曲妥珠单抗(Herceptin)、利妥昔单抗(MabThera/Rituxan)、阿仑珠单抗(Campath)、托西莫单抗(Bexxar)、C225/西妥昔单抗(Erbitux)、贝伐单抗或帕尼单抗、单克隆抗体的突变体和轭合物，如吉妥珠单抗奥唑米星(Mylotarg)或替伊莫单抗(Zevalin)、以及抗体片段；(vi)基于寡核苷酸的活性物质，如G-3139/oblimersen(Genasense)；(vii)toll-样受体/TLR9激动剂如ProMune、TLR7激动剂如咪喹莫特(Aldara)或艾沙托立宾及其类似物，或TLR7/8激动剂，如瑞喹莫德、以及免疫刺激的RNA，如TLR7/8激动剂；(viii)蛋白酶抑制剂(ix)激素活性物质，如抗雌激素(如他莫昔芬或雷洛昔芬)、抗雄激素(如氟他胺或康士得)、LHRH类似物(如亮丙瑞林、戈舍瑞林或曲普瑞林)，以及芳香酶抑制剂。
可以提及下述活性物质作为其他可以用于癌症治疗的靶向抗肿瘤试剂的实例：博来霉素、维甲酸类如全反式维甲酸(ATRA)、DNA甲基转移酶抑制剂如地西他滨(Docagen)或5-氮胞苷、阿拉诺新、细胞因子，如白介素-2、干扰素，如干扰素-α2或干扰素-γ、死亡受体激动剂，如TRAIL、DR4/5激动抗体、FasL和TNF-R激动剂(如TRAIL受体激动剂，如mapatumumab或lexatumumab)，以及HDAC抑制剂如SAHA。
Claims (11)
1.式(I)、式(II)、式(III)或式(IV)化合物，或其互变异构体、对映异构体或其盐之一，或其混合物在制备用于治疗响应于抑制FAP的疾病的药物组合物中的用途
式(I)
式(II)
式(III)
式(IV)
其中
R1表示吡啶基甲基、嘧啶基甲基、喹啉基甲基、(2-氧代-1，2-二氢-喹啉基)甲基、异喹啉基甲基、喹唑啉基甲基、(4-氧代-3，4-二氢-喹唑啉基)甲基、喹喔啉基甲基、[1，5]二氮杂萘基甲基、(1H-萘嵌间二氮杂苯基)甲基、菲啶基甲基、(11H-二苯并[b，e]氮杂
基)甲基、(二苯并[b，f][1，4]氧氮杂
基)甲基、(5H-二苯并[b，e][1，4]二氮杂
基)甲基或(咪唑并[1，2-a]喹啉基)甲基，且上述基团的杂环基团可以被Ra单取代或二取代，且取代基可以相同或不同，且Ra表示氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、环丙基、苯基、甲氧基、乙氧基、氨基、甲基氨基、二甲基氨基、吡咯烷基、哌啶子基、吗啉代、哌嗪基或N-甲基哌嗪基，
R2表示甲基、乙基、丙基、异丙基、环丙基或苯基，且所述甲基、乙基、丙基和异丙基可以被羧基、甲氧基羰基、乙氧基羰基、氨基羰基、甲基氨基羰基、二甲基氨基羰基、吡咯烷基羰基、哌啶子基羰基、吗啉代羰基、哌嗪基羰基或N-甲基哌嗪基羰基所取代，
R3表示2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、苄基、氟苄基、氯苄基、溴苄基或氰基苄基，且
R4表示哌嗪基、高哌嗪基、3-(R)-氨基-哌啶-1-基、3-(S)-氨基-哌啶-1-基、(2-氨基-乙基)-甲基氨基、(2-氨基-2-甲基-丙基)-甲基氨基、((R)-2-氨基-丙基)-甲基氨基或((S)-2-氨基-丙基)-甲基氨基。
2.权利要求1的用途，其中所述化合物为式I、II、III或IV化合物，或其互变异构体、对映异构体或其盐，或其混合物，其中
R1表示吡啶-2-基甲基、吡啶-3-基甲基、吡啶-4-基甲基、嘧啶-2-基甲基、嘧啶-4-基甲基、喹啉-2-基甲基、喹啉-3-基甲基、喹啉-4-基甲基、喹啉-5-基甲基、喹啉-6-基甲基、喹啉-7-基甲基、喹啉-8-基甲基、(2-氧代-1，2-二氢-喹啉-6-基)甲基、异喹啉-1-基甲基、异喹啉-3-基甲基、异喹啉-4-基甲基、异喹啉-8-基甲基、喹唑啉-2-基甲基、喹唑啉-4-基甲基、喹唑啉-6-基甲基、喹唑啉-7-基甲基、(4-氧代-3，4-二氢-喹唑啉-2-基)甲基、喹喔啉-2-基甲基、喹喔啉-5-基甲基、喹喔啉-6-基甲基、[1，5]二氮杂萘-2-基甲基、[1，5]二氮杂萘-3-基甲基、[1，5]二氮杂萘-4-基甲基、(1H-萘嵌间二氮杂苯-2-基)甲基、菲啶-6-基甲基、(11H-二苯并[b，e]氮杂
-6-基)甲基、(二苯并[b，f][1，4]氧氮杂
-11-基)甲基、(5H-二苯并[b，e][1，4]二氮杂
-11-基)甲基或(咪唑并[1，2-a]喹啉-2-基)甲基，且上述基团的杂环基团可以被氰基、乙基、环丙基、苯基或吗啉代单取代，或可以被甲基单取代或二取代。
3.权利要求1或2的用途，其中所述化合物为式I、II、III或IV化合物，或其互变异构体、对映异构体或其盐，或其混合物，其中
R2表示甲基、羧基甲基、甲氧基羰基甲基、乙氧基羰基甲基、环丙基或苯基。
4.权利要求1-3中任一项的用途，其中所述化合物为式I、II、III或IV化合物，或其互变异构体、对映异构体或其盐，或其混合物，其中
R3表示2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、苄基、2-氯苄基、2-溴苄基或2-氰基苄基。
5.权利要求1-4中任一项的用途，其中所述化合物为式I、II、III或IV化合物，或其互变异构体、对映异构体或其盐，或其混合物，其中
R4表示哌嗪基、高哌嗪基、3-(R)-氨基-哌啶-1-基、3-(S)-氨基-哌啶-1-基、(2-氨基-乙基)-甲基氨基、((R)-2-氨基-丙基)-甲基氨基或((S)-2-氨基-丙基)-甲基氨基。
6.权利要求1-5中任一项的用途，其中所述化合物为式I或II化合物。
7.权利要求1-6中任一项的用途，其中所述响应于抑制FAP的疾病为过度增生性疾病。
8.权利要求1-6中任一项的用途，其中所述响应于抑制FAP的疾病为癌症，例如上皮源的肿瘤疾病如乳腺肿瘤、非小细胞肺癌、结肠直肠癌或软组织癌，和转移瘤如黑素瘤。
9.权利要求1-6中任一项的用途，其中所述响应于抑制FAP的疾病为非癌症的过度增生性疾病，例如心脏肥大、肝硬化、纤维瘤病、类风湿性关节炎、骨关节炎、神经损伤性疾病、疼痛、偏头痛、伤口愈合病症、痤疮、增生性皮肤病如牛皮癣。
10.一种制备用于治疗权利要求1、7、8和9中任一项所述疾病的药物组合物的方法，其特征在于使用权利要求1-6中任一项所述的化合物。
11.权利要求1-6中任一项所述的化合物，其用于治疗权利要求1、7、8和9中任一项所述的疾病。
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| NZ573360A (en) * | 2006-05-04 | 2012-08-31 | Boehringer Ingelheim Int | Polymorphic forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine |
| PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
| WO2008017670A1 (en) * | 2006-08-08 | 2008-02-14 | Boehringer Ingelheim International Gmbh | Pyrrolo [3, 2 -d] pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus |
| EP2190434B1 (en) | 2007-08-17 | 2019-04-17 | Boehringer Ingelheim International GmbH | Purin derivatives for use in the treatment of fap-related diseases |
-
2008
- 2008-08-15 EP EP08787268.5A patent/EP2190434B1/en not_active Revoked
- 2008-08-15 KR KR1020107003508A patent/KR101610005B1/ko active IP Right Grant
- 2008-08-15 CA CA2696579A patent/CA2696579C/en active Active
- 2008-08-15 NZ NZ600126A patent/NZ600126A/en unknown
- 2008-08-15 US US12/673,176 patent/US20110112069A1/en not_active Abandoned
- 2008-08-15 BR BRPI0815405-8A2A patent/BRPI0815405A2/pt not_active Application Discontinuation
- 2008-08-15 RU RU2010109545/15A patent/RU2569749C2/ru active
- 2008-08-15 MX MX2010001821A patent/MX2010001821A/es active IP Right Grant
- 2008-08-15 WO PCT/EP2008/060740 patent/WO2009024542A2/en active Application Filing
- 2008-08-15 JP JP2010521404A patent/JP5769966B2/ja active Active
- 2008-08-15 EP EP19169300.1A patent/EP3542801A1/en not_active Withdrawn
- 2008-08-15 AU AU2008290582A patent/AU2008290582B2/en active Active
- 2008-08-15 ES ES08787268T patent/ES2733348T3/es active Active
- 2008-08-15 CN CN200880103199A patent/CN101784278A/zh active Pending
-
2010
- 2010-01-05 ZA ZA201000075A patent/ZA201000075B/xx unknown
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2016
- 2016-01-20 US US15/001,301 patent/US20160136180A1/en not_active Abandoned
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383893A (zh) * | 2011-08-30 | 2018-08-10 | 塔夫茨大学信托人 | 用于治疗实体瘤的fap-活化的蛋白酶体抑制剂 |
| CN103254193A (zh) * | 2012-02-15 | 2013-08-21 | 上海医药工业研究院 | 黄嘌呤类化合物中间体及其制备方法 |
| CN103254192A (zh) * | 2012-02-15 | 2013-08-21 | 上海医药工业研究院 | 黄嘌呤类化合物、其盐、中间体、制备方法及应用 |
| CN103254193B (zh) * | 2012-02-15 | 2015-04-22 | 上海医药工业研究院 | 黄嘌呤类化合物中间体及其制备方法 |
| CN103254192B (zh) * | 2012-02-15 | 2015-12-02 | 上海医药工业研究院 | 黄嘌呤类化合物、其盐、中间体、制备方法及应用 |
| CN103373999A (zh) * | 2012-04-28 | 2013-10-30 | 上海医药工业研究院 | 嘌呤类化合物、中间体、制备方法及其应用 |
| CN103373999B (zh) * | 2012-04-28 | 2016-01-13 | 上海医药工业研究院 | 嘌呤类化合物、中间体、制备方法及其应用 |
| CN112540176A (zh) * | 2020-07-08 | 2021-03-23 | 深圳罗兹曼国际转化医学研究院 | 用于诊断fap表达异常相关疾病的试剂盒、方法及计算机可读存储介质 |
| CN112540176B (zh) * | 2020-07-08 | 2021-09-28 | 深圳霁因生物医药转化研究院 | 用于诊断fap表达异常相关疾病的试剂盒、方法及计算机可读存储介质 |
| CN112522388A (zh) * | 2020-12-18 | 2021-03-19 | 上海市东方医院（同济大学附属东方医院） | 成纤维细胞激活蛋白作为药物靶点在治疗骨关节炎中的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5769966B2 (ja) | 2015-08-26 |
| MX2010001821A (es) | 2010-03-10 |
| EP2190434A2 (en) | 2010-06-02 |
| US20160136180A1 (en) | 2016-05-19 |
| AU2008290582B2 (en) | 2014-08-14 |
| RU2569749C2 (ru) | 2015-11-27 |
| RU2010109545A (ru) | 2011-09-27 |
| CA2696579A1 (en) | 2009-02-26 |
| ZA201000075B (en) | 2010-09-29 |
| ES2733348T3 (es) | 2019-11-28 |
| WO2009024542A3 (en) | 2009-05-22 |
| NZ600126A (en) | 2013-12-20 |
| AU2008290582A1 (en) | 2009-02-26 |
| BRPI0815405A2 (pt) | 2015-02-03 |
| US20110112069A1 (en) | 2011-05-12 |
| EP3542801A1 (en) | 2019-09-25 |
| KR101610005B1 (ko) | 2016-04-08 |
| EP2190434B1 (en) | 2019-04-17 |
| CA2696579C (en) | 2017-01-24 |
| JP2010536820A (ja) | 2010-12-02 |
| WO2009024542A2 (en) | 2009-02-26 |
| KR20100055423A (ko) | 2010-05-26 |
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