CN101686985A - 含有ep4激动剂的细胞毒性t细胞的活化剂 - Google Patents
含有ep4激动剂的细胞毒性t细胞的活化剂 Download PDFInfo
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- CN101686985A CN101686985A CN200880023882A CN200880023882A CN101686985A CN 101686985 A CN101686985 A CN 101686985A CN 200880023882 A CN200880023882 A CN 200880023882A CN 200880023882 A CN200880023882 A CN 200880023882A CN 101686985 A CN101686985 A CN 101686985A
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Abstract
本发明以提供分子量低、可以更简单地应用、且对于癌症和/或微生物介导的感染病具有免疫增强活性的药物为课题。EP4激动剂具有通过细胞毒性T细胞的活化作用而介导的免疫增强活性,因此对于预防和/或治疗癌症或微生物感染病有用。
Description
技术领域
本发明涉及细胞毒性T细胞的活化剂,其含有EP4激动剂。
更具体地,本发明涉及通过细胞毒性T细胞的活化作用而介导的免疫增强剂,其包含EP4激动剂,特别是涉及用于癌症和/或微生物感染病的免疫增强剂。
背景技术
癌症的常规治疗方法包括外科治疗,使用抗癌剂的化学治疗,放射治疗,和包含它们的组合的治疗方法。然而,已知这些方法会产生问题,例如不能通过手术应对癌细胞转移,作为手术补充的化学治疗和放射治疗不仅攻击癌细胞还攻击正常细胞,会引起严重的副作用或者对抗癌剂或放射线产生抗性。
面对这种情形,最近进行了关于消除癌细胞的治疗方法的研究,其通过增强活体中固有存在的免疫系统,作为治疗癌症的新方法。例如,进行了使用非特异性免疫活化剂(例如,Krestin,Bestatin等),细胞因子疗法(例如,干扰素,白介素等),抗体疗法(例如,Herceptin等),免疫细胞疗法(例如,树突细胞疫苗疗法,肽疫苗疗法等)等的临床研究。特别是,最近针对活化细胞毒性T细胞(细胞毒性T淋巴细胞:CTL)的免疫细胞疗法引起了注意。在该方法中,未成熟的T细胞识别由抗原呈递细胞(例如,树突细胞,巨噬细胞等)呈递的主要组织相容性复合体(MHC)分子和抗原肽(例如,碎裂的癌细胞抗原等)的复合物,同时来自共刺激分子的信号导入,由此该未成熟的T细胞被诱导成对该被呈递的复合物具有特异细胞毒性的成熟T细胞,即,CTL。树突细胞疫苗疗法是这样一种方法,其中通过给予呈递有抗原的树突细胞而有效诱导CTL,但在如使用含胎牛血清的培养液和给药的途径等方面还存在问题。肽疫苗疗法是这样一种方法,其中将源自灭活的癌细胞或微生物感染的细胞的抗原肽给药以促进特异性识别这些抗原的CTL的活化。此外,在使用灭活的病毒片段或微生物如原生动物的微生物肽作为抗原肽的情况下,免疫细胞疗法不仅用于癌症,而且用于微生物感染病(microbial infectiousdiseases,微生物感染症)。
迄今为止,已开发出包含它们的组合的更有效和更安全的免疫细胞治疗。例如,已开发出经皮免疫治疗方法,其中使用强粘合带去除角质层,从而活化表皮朗格汉斯细胞(一种树突细胞),且将抗原肽涂布于去除了角质层的皮肤,从而诱导活体中的CTL(参见专利文件1和非专利文件1和2)。
另一方面,已知特异结合至EP4受体(PGE2受体的亚型)的EP4激动剂,直接抑制胃癌细胞的增殖(参见非专利文件3),促进表皮朗格汉斯细胞(其为抗原呈递细胞)的成熟和迁移,与接触性皮炎的恶化相关(参见非专利文件4),用作自身免疫疾病如风湿病的治疗剂(参见专利文件2)。也已知EP4拮抗剂可用于预防和/或治疗癌症(癌形成,癌生长,癌内脏转移,癌骨转移,伴随癌骨转移的高血钙等)(参见专利文件3)。
然而,这些文件没有提及或暗示EP4激动剂通过活化细胞毒性T细胞而显示免疫增强作用,特别是单独的EP4激动剂基于该免疫增强作用可用于治疗癌症(特别是黑素瘤),病毒感染等。
[专利文献1]日本专利号3879785
[专利文献2]国际公开号2003/009872
[专利文献3]国际公开号01/062708
[非专利文献1]Proceedings of the natural academy sciences of USA,Vol.97,371-376,2000
[非专利文献2]Cancer research,Vol.66,10136-10144,2006
[非专利文献3]The journal of laboratory and clinical medicine,Vol.140,92-102,2002
[非专利文献4]Nature medicine,Vol.9,744-749,2003
发明内容
本发明要解决的问题
迄今为止,已尝试使用免疫细胞疗法作为癌症或感染病的治疗方法;,然而,还没有将该疗法建立为有效的治疗方法,因为其中例如关于所使用的抗原肽的有效性和给药方法存在问题,且使用的树突细胞的安全性方面有问题。因此,本发明的目的是提供一种药物,其通过活化细胞毒性T细胞而增强对癌症、病毒等的免疫,其也可用作佐剂,其为低分子量的,为更安全的且方便适用。
解决问题的方法
本发明人努力研究完成了上述目的,且出人意料地发现EP4激动剂(1)具有活化细胞毒性T细胞的作用,(2)通过活化细胞毒性T细胞显示免疫增强作用,且特别是(3)显示对癌症和/或微生物感染病的免疫增强作用,从而研发出本发明。
也就是说,本发明涉及
[1]细胞毒性T细胞的活化剂,其包含EP4激动剂,
[2]根据上述[1]的活化剂,其中该EP4激动剂为
式(I)表示的3,7-二硫前列腺酸衍生物、与作为其平衡化合物的8-表(epi)型化合物的混合物、其非毒性盐、或其环糊精包合物,
其中R1为羟基、C1-6烷基氧基或NR6R7,其中R6和R7各自独立地为氢原子或C1-6烷基;
R2为氢原子或羟基;
R3为单键或C1-6亚烷基;
R4为
(i)被1至3个选自C1-6烷基氧基和卤素原子的取代基取代的C1-8烷基、C2-8烯基或C2-8炔基,
(ii)苯基氧基或C3-7环烷基氧基,
(iii)呋喃基,呋喃基氧基,噻吩基,噻吩基氧基,萘基,萘基氧基,1,3-二氢异苯并呋喃基(phthalanyl)或1,3-二氢异苯并呋喃基氧基,
(iv)被1至3个选自以下的取代基取代的苯基、苯基氧基、C3-7环烷基或C3-7环烷基氧基:
(1)C1-6烷基,(2)C2-6烯基,(3)C2-6炔基,(4)C1-6烷基氧基,(5)C1-6烷基氧基-C1-6烷基,(6)C1-6烷基氧基-C1-6烷基氧基,(7)C2-6烯基氧基-C1-6烷基,(8)被1至3个羟基取代的C1-6烷基,(9)被1至3个卤素原子取代的C1-6烷基,(10)C1-6烷基硫基,(11)C1-6烷基硫基-C1-6烷基,(12)C1-6烷基硫基-C1-6烷基氧基,(13)C2-6烯基硫基-C1-6烷基,(14)C1-6烷基磺酰基,(15)卤素原子,(16)三卤代甲基,(17)氰基,(18)硝基,(19)氨基,(20)羟基,(21)C3-7环烷基,(22)C3-7环烷基氧基,(23)C3-7环烷基-C 1-6烷基,(24)C3-7环烷基氧基-C1-6烷基,(25)苯基,(26)苯基氧基,(27)苯基-C1-6烷基,(28)苯基-C2-6烯基,(29)苯基-C2-6炔基,(30)苯基氧基-C1-6烷基,(31)苯基氧基-C2-6烯基,(32)苯基氧基-C2-6炔基,(33)呋喃基,(34)呋喃基氧基,(35)呋喃基-C1-6烷基,(36)呋喃基氧基-C1-6烷基,(37)噻吩基,(38)噻吩基氧基,(39)噻吩基-C1-6烷基或(40)噻吩基氧基-C1-6烷基,其中上述苯基、呋喃基、噻吩基和环烷基任选被1至3个选自C1-6烷基、C1-6烷基氧基、C1-6烷基氧基-C1-6烷基、硝基、卤素、三卤代甲基、氨基和羟基的取代基取代;
或
(v)被1至3个选自以下的取代基取代的呋喃基、呋喃基氧基、噻吩基、噻吩基氧基、萘基、萘基氧基、1,3-二氢异苯并呋喃基或1,3-二氢异苯并呋喃基氧基:
(1)C1-6烷基,(2)C2-6烯基,(3)C2-6炔基,(4)C1-6烷基氧基,(5)C1-6烷基氧基-C1-6烷基,(6)C1-6烷基氧基-C1-6烷基氧基,(7)C2-6烯基氧基-C1-6烷基,(8)被1至3个羟基取代的C1-6烷基,(9)被1至3个卤素原子取代的C1-6烷基,(10)C1-6烷基硫基,(11)C1-6烷基硫基-C1-6烷基,(12)C1-6烷基硫基-C1-6烷基氧基,(13)C2-6烯基硫基-C1-6烷基,(14)C1-6烷基磺酰基,(15)卤素原子,(16)三卤代甲基,(17)氰基,(18)硝基,(19)氨基,(20)羟基,(21)C3-7环烷基,(22)C3-7环烷基氧基,(23)C3-7环烷基-C1-6烷基,(24)C3-7环烷基氧基-C1-6烷基,(25)苯基,(26)苯基氧基,(27)苯基-C1-6烷基,(28)苯基-C2-6烯基,(29)苯基-C2-6炔基,(30)苯基氧基-C1-6烷基,(31)苯基氧基-C2-6烯基,(32)苯基氧基-C2-6炔基,(33)呋喃基,(34)呋喃基氧基,(35)呋喃基-C1-6烷基,(36)呋喃基氧基-C1-6烷基,(37)噻吩基,(38)噻吩基氧基,(39)噻吩基-C1-6烷基或(40)噻吩基氧基-C1-6烷基,其中上述苯基、呋喃基、噻吩基和环烷基任选被1至3个选自C1-6烷基、C1-6烷基氧基、C1-6烷基氧基-C1-6烷基、硝基、卤素、三卤代甲基、氨基和羟基的取代基取代;
R5为氢原子或C1-6烷基;
条件是,R2为氢原子时,R3表示的C1-6亚烷基可被一个羟基取代,式(IL)表示的化合物、其盐,其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物,
其中
为(1)单键或(2)双键,R19L和R20L各自独立地为(1)氢原子,(2)C1-10烷基或(3)卤素原子,TL为(1)氧原子或(2)硫原子,XL为(1)-CH2-,(2)-O-或(3)-S-,AL为A1L或A2L,A1L为(1)任选被1至2个C1-4烷基取代的C2-8直链亚烷基,(2)任选被1至2个C1-4烷基取代的C2-8直链亚烯基或(3)任选被1至2个C1-4烷基取代的C2-8直链亚炔基,A2L为-G1L-G2L-G3L-,G1L为(1)任选被1至2个C1-4烷基取代的C1-4直链亚烷基,(2)任选被1至2个C1-4烷基取代的C2-4直链亚烯基或(3)任选被1至2个C1-4烷基取代的C2-4直链亚炔基,G2L为(1)-YL-、(2)-(环1L)-、(3)-YL-(环1L)-、(4)-(环1L)--或(5)-YL-(C1-4亚烷基)-(环1L)-,YL为(1)-S-、(2)-SO-、(3)-SO2-、(4)-O-或(5)-NR1L,R1L为(1)氢原子、(2)C1-10烷基或(3)C2-10酰基,G3L为(1)单键,(2)任选被1至2个C1-4烷基取代的C1-4直链亚烷基,(3)任选被1至2个C1-4烷基取代的C2-4直链亚烯基或(4)任选被1至2个C1-4烷基取代的C2-4直链亚炔基,DL为D1L或D2L,D1L为(1)-COOH、(2)-COOR2L、(3)四唑-5-基或(4)CONR3LSO2R4L,R2L为(1)C1-10烷基、(2)苯基、(3)被苯基取代的C1-10烷基或(4)联苯基,R3L为(1)氢原子或(2)C1-10烷基,R4L为(1)C1-10烷基或(2)苯基,D2L为(1)-CH2OH、(2)-CH2OR5L、(3)羟基、(4)-OR5L、(5)甲酰基、(6)-CONR6LR7L、(7)-CONR6LSO2R8L、(8)-CO-(NH-氨基酸残基-CO)mL-OH、(9)-O-(CO-氨基酸残基-NH)mL-H、(10)-COOR9L、(11)-OCO-R10L、(12)-COO-Z1L-Z2L-Z3L、(13)
R5L为C1-10烷基,R6L和R7L各自独立地为(1)氢原子或(2)C1-10烷基,R8L为被苯基取代的C1-10烷基,R9L为(1)被联苯基取代的C1-10烷基,该联苯基任选被1至3个C1-10烷基、C1-10烷氧基或卤素原子取代或(2)被1至3个C1-10烷基、C1-10烷氧基或卤素原子取代的联苯基,R10L为(1)苯基或(2)C1-10烷基,mL为1或2,Z1L为(1)C1-15亚烷基,(2)C2-15亚烯基或(3)C2-15亚炔基,Z2L为(1)-CO-,(2)-OCO-,(3)-COO-,(4)-CONR11L-,(5)-NR12LCO-,(6)-O-,(7)-S-,(8)-SO-,(9)-SO2-,(10)-NR13L-,(11)-NR14LCONR15L-,(12)-NR16LCOO-,(13)-OCONR17L-或(14)-OCOO-,Z3L为(1)氢原子,(2)C1-15烷基,(3)C2-15烯基,(4)C2-15炔基,(5)环2L或(6)被C1-10烷氧基、C1-10烷基硫基、C1-10烷基-NR18L-基或环2L取代的C1-10烷基,R11L,R12L,R13L,R14L,R15L,R16L,R17L和R18L各自独立地为(1)氢原子或(2)C1-15烷基,R11L和Z3L可与它们相连的氮原子一起形成5至7元饱和单-杂环,且该杂环可还包含一个选自氧原子、氮原子和硫原子的杂原子,EL为E1L或E2L,E1L为(1)C3-7环烷基或(2)环3L,E2L为(1)C3-7环烷基,(2)环4L或(3)环5L,环1L和环5L任选被1至3个R21L和/或R22L取代,环3L任选被1至2个R21L取代,E2L表示的C3-7环烷基被一个R21L或R22L取代,且该E2L表示的C3-7环烷基任选还进一步被1至2个R21L和/或R22L取代,环4L被一个R22L取代,且环4L任选还进一步被1至2个R21L和/或R22L取代,由R11L和Z3L与相连的氮原子形成的杂环或环2L可被R23L取代,R21L为(1)C1-10烷基,(2)C1-10烷氧基,(3)卤素原子,(4)硝基,(5)被1至3个卤素原子取代的C1-10烷基或(6)苯基,R22L为(1)C2-10烯基,(2)C2-10炔基,(3)C1-10烷基硫基,(4)羟基,(5)-NR24LR25L,(6)被C1-10烷氧基取代的C1-10烷基,(7)被C1-10烷氧基取代的C1-10烷基,该C1-10烷氧基被1至3个卤素原子取代,(8)被-NR24LR25L取代的C1-10烷基,(9)环6L,(10)-O-环7L,(11)被环7L取代的C1-10烷基,(12)被环7L取代的C2-10烯基,(13)被环7L取代的C2-10炔基,(14)被环7L取代的C1-10烷氧基,(15)被-O-环7L取代的C1-10烷基,(16)-COOR26L或(17)被1至3个卤素原子取代的C1-10烷氧基,R24L、R25L和R26L各自独立地为(1)氢原子或(2)C1-10烷基,R23L为(1)C1-15烷基,(2)C2-15烯基,(3)C2-15炔基或(4)被C1-10烷氧基、C1-10烷基硫基或C1-10烷基-NR27L-基取代的C1-10烷基,R27L为(1)氢原子或(2)C1-10烷基,环1L,环2L,环5L,环6L和环7L为(1)C3-15单-、二-或三-碳环芳基,其可为部分或完全饱和的或(2)包含1至4个选自氧、氮和硫原子的杂原子的3至15元单-、二-或三-杂环芳基,其可为部分或完全饱和的,环3L和环4L为(1)噻吩基,(2)苯基或(3)呋喃基,环6L和环7L可被1至3个R28L取代,R28L为(1)C1-10烷基,(2)C2-10烯基,(3)C2-10炔基,(4)C1-10烷氧基,(5)被C1-10烷氧基取代的C1-10烷基,(6)卤素原子,(7)羟基,(8)被1至3个卤素原子取代的C1-10烷基或(9)被C1-10烷氧基取代的C1-10烷基,该C1-10烷氧基被1至3个卤素原子取代,
或
式(IM)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物,
其中R1M为羟基、C1-6烷基氧基或NR6MR7M,其中R6M和R7B各自独立地为氢或C1-4烷基,R2M为氧原子、卤素原子或O-COR8M,其中R8M为C1-4烷基、苯基或苯基(C1-4烷基),R3M为氢原子或羟基,R4aM和R4bM各自独立地为氢原子或C1-4烷基,R5M为被以下取代基取代的苯基:
i)1至3个选自以下的取代基(a)C1-4烷基氧基-C1-4烷基,(b)C2-4烯基氧基-C1-4烷基,(c)C2-4炔基氧基-C1-4烷基,(d)C3-7环烷基氧基-C1-4烷基,(e)C3-7环烷基(C1-4烷基氧基)-C1-4烷基,(f)苯基氧基-C1-4烷基,(g)苯基-C1-4烷基氧基-C1-4烷基,(h)C1-4烷基硫基-C1-4烷基,(i)C2-4烯基硫基-C1-4烷基,(j)C2-4炔基硫基-C1-4烷基,(k)C3-7环烷基硫基-C1-4烷基,(l)C3-7环烷基(C1-4烷基硫基)-C1-4烷基,(m)苯基硫基-C1-4烷基和(n)苯基-C1-4烷基硫基-C1-4烷基,
ii)(a)C1-4烷基氧基-C1-4烷基和C1-4烷基,(b)C1-4烷基氧基-C1-4烷基和C1-4烷基氧基,(c)C1-4烷基氧基-C1-4烷基和羟基,(d)C1-4烷基氧基-C1-4烷基和卤素原子,(e)C1-4烷基硫基-C1-4烷基和C1-4烷基,(f)C1-4烷基硫基-C1-4烷基和C1-4烷基氧基,(g)C1-4烷基硫基-C1-4烷基和羟基或(h)C1-4烷基硫基-C1-4烷基和卤素原子,
iii)(a)卤代烷基或(b)羟基-C1-4烷基,或
iv)C1-4烷基和羟基;
为单键或双键,且其不为连续双键,条件是,当R2M为O-COR8M基时,8-9位表示双键。
[3]根据上述[1]的活化剂,其中所述细胞毒性T细胞的活化是对癌症和/或微生物感染病的免疫增强作用。
[4]根据上述[3]的活化剂,其中所述癌症为选自消化系统癌、皮肤癌、呼吸系统癌、泌尿系统癌、肝癌和胰腺癌的一种或多种,
[5]根据上述[4]的活化剂,其中是皮肤癌为黑素瘤,
[6]根据上述[3]的活化剂,其中所述微生物是选自病毒、细菌和真菌的一种或多种,
[7]根据上述[1]的活化剂,其中EP4激动剂为11α,15α,-二羟基-9-氧代-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲-3,7-二硫前列腺-13E-烯酸,4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸,4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸或4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯,
[8]根据上述[1]的活化剂,其中所述活化剂还包含抗原肽。
[9]根据上述[8]的活化剂,其中所述抗原肽为黑素瘤特异性抗原肽,
[10]一种药物,其给药于除去角质层后的皮肤并增强对癌症的免疫作用,并且副作用少,该药物包含4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸、4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸或4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯作为有效成分。
[11]根据上述[10]的药物,其中所述癌症为黑素瘤,
[12]根据上述[10]的药物,其中所述药物还包含抗原肽,
[13]根据上述[12]的药物,其中所述抗原肽为黑素瘤特异性抗原肽,且所述癌症为黑素瘤,
[14]在哺乳动物中活化细胞毒性T细胞的方法,该方法包括向哺乳动物给药有效量的EP4激动剂,
[15]EP4激动剂在制备细胞毒性T细胞的活化剂中的用途,和
[16]用于活化细胞毒性T细胞的EP4激动剂。
发明效果
单独的EP4激动剂通过活化细胞毒性T细胞显示免疫增强作用。因此,这些激动剂用于预防和/或治疗癌症、微生物感染病等。而且,通过将该激动剂与抗原肽组合使用,也可得到佐剂效果。
具体方式
在本发明中,如以下实施例所示,单独的EP4激动剂活化细胞毒性T细胞(细胞毒性T淋巴细胞:下文有时缩写为CTL),因此可单独用作细胞毒性T细胞的活化剂。
在本发明中,CTL也称为杀伤T细胞,指在表面表达CD8分子的T细胞。通常,通过抗原呈递细胞(例如,巨噬细胞,树突细胞(例如,滤泡树突样细胞,淋巴组织树突细胞,互连(interconnecting)细胞,朗格汉斯细胞,胸腺树突细胞等)等),未成熟的T细胞与呈递在主要组织相容性复合体(MHC)分子上的抗原(例如,癌细胞-特异的肽,病毒-特异的肽)强烈结合,结合后T细胞作为抗原特异性的CTL被活化。
在本发明中,细胞毒性T细胞的活化是指CTL本身量的增加和与细胞毒性相关的质的功能亢进。例如,这些包括促进CTL在淋巴结的分裂(division)和增殖,促进分化或成熟为CTL,促进通过血流的CTL的体循环,促进CTL迁移至异物进入的部分等;两种或多种这些作用可同时显示。优选地是,促进CTL在淋巴结的分裂(division)和增殖和促进分化或成熟为CTL。活化的CTL优选为对靶细胞(例如,癌细胞、病毒感染的细胞)的抗原特异的CTL,实例包括对黑素瘤抗原TRP-2特异的CTL和对单纯疱疹病毒抗原HSVgpB特异的CTL。
在本发明中,免疫增强作用是指基于CTL的活化,消除被敌人(例如,癌细胞、病原微生物等)感染的靶细胞的作用增强。可被该免疫增强作用预防和/或治疗的适应症的实例包括癌症、微生物感染病等,癌症是适合的。
在本发明中,可被免疫增强作用预防和/或治疗的的癌症包括通常称为恶性肿瘤的所有癌症,实例包括:涉及脑神经的癌症(例如,小儿脑瘤(例如,成神经细胞瘤,成神经管细胞瘤,星形细胞瘤(幼年毛细胞性星形细胞瘤),室管膜瘤,颅咽管瘤,生殖细胞瘤,视神经神经胶质瘤,脉络丛乳头状瘤,脑干神经胶质瘤),成人脑肿瘤(例如,成人星形细胞瘤,成人恶性星形细胞瘤,成人成胶质细胞瘤,成人脑室室管膜瘤,成人恶性脑室室管膜瘤,成人恶性少突胶质细胞瘤(oligodendrocytoma),成人成神经管细胞瘤,成人脑膜瘤,成人恶性脑膜瘤),神经胶质瘤(例如,星形细胞瘤,少突胶质细胞瘤,室管膜瘤,脑干神经胶质瘤),垂体腺瘤,听神经鞘瘤,成视网膜细胞瘤,葡萄膜恶性黑素瘤等),呼吸系统癌(例如,咽癌(例如,咽上部癌(epipharyngealcancer),咽中部癌,咽下部癌),喉癌,旁鼻窦癌,肺癌(例如,小细胞癌症,非小细胞癌症),胸腺瘤,间皮瘤等),消化系统癌(例如,食道癌,胃癌,十二指肠癌,结肠直肠癌(例如,结肠癌,直肠癌,肛门癌)等),口腔癌(例如,牙龈癌,舌癌,唾液腺癌等),泌尿系统癌症(例如,阴茎癌,肾盂-尿道癌,肾细胞癌,睾丸(睾丸)肿瘤,前列腺癌,膀胱癌等),雌性相关性癌症(外阴癌,子宫癌(例如,子宫颈癌,子宫体癌(子宫内膜癌)),子宫肉瘤,绒毛状疾病(例如,葡萄胎,绒毛膜癌,胎盘绒毛肿瘤,持久性滋养层疾病),阴道癌,乳腺癌,乳腺肉瘤,卵巢癌,卵巢胚组织瘤等),皮肤癌(例如,黑素瘤(恶性黑素瘤)(例如,恶性小痣黑素瘤,表面扩散性黑素瘤,结节性黑素瘤,肢端雀斑样痣性黑素瘤(acral lentigenous melanoma),侵蚀性黑素瘤),蕈样霉菌病,鳞状上皮细胞癌,基底细胞癌,皮肤癌前驱症状/表皮内癌(例如,光化性角化病,Bowen’s疾病,Paget’s疾病),淋巴瘤样丘疹病,真皮CD30-阳性间变性大细胞淋巴瘤,Sézary综合症,真皮B细胞淋巴瘤等),骨/肌肉癌症(例如,骨肉瘤,软部分(soft parts)的肉瘤,横纹肌肉瘤,滑膜性肉瘤,脂肉瘤等),甲状腺癌,类癌,肝癌(肝癌),肝胚细胞瘤,胆管瘤,胆囊癌,胰腺癌,胰腺内分泌肿瘤(例如,胰岛素瘤,胃泌素瘤,产生VIP的腺瘤等),未知起源的癌症,遗传性肿瘤/家族性肿瘤(例如,遗传性非-息肉病结肠直肠癌,家族性结肠直肠的息肉病,遗传性乳腺癌,卵巢癌综合症,Li-Fraumeni综合症,遗传性黑素瘤,Wilms’瘤,遗传性乳头状肾细胞癌,von Hippel-Lindau综合症,多发内分泌肿瘤等),白血病(例如,急性髓细胞性白血病,急性淋巴细胞性白血病,骨髓发育不良综合症,慢性髓细胞性白血病/慢性骨髓增生性疾病,成人T细胞白血病淋巴瘤,慢性淋巴细胞性白血病/小细胞淋巴瘤等),多发性骨髓瘤,原发性巨球蛋白血症,恶性淋巴瘤(例如,Hodgkin’s淋巴瘤,适度或高度恶性淋巴瘤,Burkitt’s淋巴瘤,成淋巴细胞性淋巴瘤,滤泡性淋巴瘤,套细胞淋巴瘤,MALT(粘膜-相关的淋巴样组织)淋巴瘤,NK(自然杀伤)细胞淋巴瘤等)等。可通过免疫增强作用预防和/或治疗的癌症适当地包括消化系统癌,皮肤癌,呼吸系统癌,泌尿系统癌,肝癌和胰腺癌,皮肤癌是更适合的,且黑素瘤是特别适合的。
在本发明中,可通过免疫增强作用预防和/或治疗的微生物感染病包括通常称为感染病的所有疾病,且具体由以下症状所表示:该症状由于一种或多种病原微生物、病毒、细菌、真菌等感染的体内正常细胞的增殖而发展。这些病原微生物也包括立克次氏体、衣原体、原虫、寄生虫等。
在本发明中,微生物感染病涉及的病毒的实例包括人肝炎病毒(例如,肝炎B,肝炎C,肝炎A,肝炎E等),人逆转录病毒,人免疫缺陷病毒(例如,HIV1,HIV2等),人T细胞白血病病毒或人T淋巴-定向的病毒(例如,HTLV1,HTLV2等),单纯疱疹病毒1型或2型,Epstein-Barr(EB)病毒,巨细胞病毒,水痘-带状疱疹病毒,人疱疹病毒(例如,人疱疹病毒6等),脊髓灰质炎病毒,麻疹病毒,风疹病毒,日本脑炎病毒,腮腺炎病毒,流感病毒,感冒病毒(例如,腺病毒,肠病毒,鼻病毒等),引起严重急性呼吸器官综合症(SARS)的病毒,埃博拉病毒,西尼罗病毒,黄病毒,埃可病毒,柯萨奇病毒,冠状病毒,呼吸多核体(respiratory coenocytic)(合胞体)病毒,轮状病毒,诺如病毒(norovirus),沙波病毒(Sapovirus),麻疹病毒,Parvo病毒,牛痘病毒,HTL病毒,登革病毒,乳头状瘤病毒,软疣病毒,狂犬病病毒,JC病毒,虫媒病毒,脑炎病毒,汉坦病毒等。微生物感染病涉及的病毒合适地为单纯疱疹病毒1型或2型。
在本发明中,微生物感染病涉及的细菌的实例包括霍乱弧菌,沙门氏菌细菌,大肠杆菌,军团杆菌,炭疽杆菌,幽门螺旋杆菌,单核细胞增多性李司忒氏菌,结核杆菌,非结核性耐酸细菌,葡萄球菌,链球菌,肺炎球菌,脑膜炎菌,肺炎杆菌,沙雷氏菌细菌,Coryne细菌白喉,布鲁氏杆菌,Bartonellahenselae,猪红斑丹毒丝菌,放线菌,莱姆疾病包柔氏螺旋体,产气荚膜梭状芽胞杆菌,痢疾杆菌,鼠疫耶氏菌,破伤风杆菌,肠道细菌等。
在本发明中,微生物感染病涉及的真菌的实例包括念珠菌属,曲霉属,隐球菌属,芽生菌属,球孢子菌属,组织胞浆菌属,副球孢子菌属,孢子丝菌属等。
在本发明中,微生物感染病中涉及的原虫的实例包括疟疾原生动物、toxoplasma原生动物等。
在本发明中,微生物感染病涉及的寄生虫的实例包括痢疾阿米巴,蛔虫,巴贝虫,隐孢子虫,兰氏贾第鞭毛虫,钩虫,蛲虫,血吸虫,条虫,旋毛虫,鞭虫等。
在本发明中,微生物感染病涉及的其它微生物的实例包括支原体(mycoplasmata),螺旋体等。
在本发明中,包含EP4激动剂的细胞毒性T细胞的活化剂(下文有时缩写为本发明的活化剂)也可作为其致敏物或佐剂与抗原肽组合使用。优选使用的抗原肽为使得CTL特异性识别癌症或微生物的抗原,该癌症或微生物为本发明的药物免疫增强作用的靶向。例如,TRP-2(酪氨酸酶-相关蛋白2),一种黑素瘤特异性的抗原肽,预期有对黑素瘤的免疫增强作用,可用作抗原肽。
其它抗原肽的实例包括癌症(肿瘤)抗原肽、病毒抗原肽等。癌症(肿瘤)抗原肽的实例包括MAGE-1,MAGE-2,MAGE-3,MAGE-A4,MAGE-6,MART1,TRP-1,酪氨酸酶,gp100,HER2/neu,CEA,β-联蛋白,CHP,CpG,MUC-1,NY-ESO-1,BAGE,GAGE-1,GAGE-2,SAGE,LAGE,WT-1,hTERT,CDK4,p15,p53,PSA,gp1001,MAGE-12,端粒酶,SART,SYT-SSX,存活蛋白,CTL前体-定向的肽,MN/CA9,OY-TES-1,SCP-1,GnT-V,PRAME等。病毒抗原肽的实例包括EB病毒抗原,巨细胞病毒抗原,疱疹病毒抗原(例如,HSV糖蛋白B),流感病毒抗原,HIV抗原等。其它抗原肽的实例包括沙门氏菌抗原,痢疾抗原,肠杆菌抗原,来自原虫或寄生虫的抗原等。
对本领域技术人员明显地是,上述癌症(肿瘤)抗原肽可根据作为治疗靶点的癌症和抗原肽结合的具体的主要组织相容性抗原(人白细胞抗原;HLA)而恰当使用。例如,当黑素瘤为靶点时,可使用结合至HLA-A0201或HLA-A2402的抗原肽;特别地,优选使用MART-1,gp-100,MAGE-2,MAGE-3,酪氨酸酶,或TRP-2。
同样,对于病毒抗原肽,当疱疹病毒感染为靶点时,优选使用HSV糖蛋白B。
同样,对本领域技术人员明显地是,上述抗原肽优选具有相应于CTL特异识别的表位的部分序列。例如,当使用TRP-2时,VYDFFVWL(SEQ ID NO.1)用作其部分序列。
本发明使用的EP4激动剂包括选择性结合至EP4且显示激动剂活性的化合物,该EP4为前列腺素E2(PGE2)受体的亚型。这种本发明的EP4激动剂不仅包括那些已发现的,而且包括以后会发现的那些。已发现的EP4激动剂包括,例如,描述于以下(A)-(H)和(J)-(N)的化合物和以下所列的其他EP4激动剂。
(A)在特开2000-001472的说明书中,描述了下式(I)表示的化合物具有EP4激动活性。式(I)表示的化合物的各基团的定义详细描述于特开2000-001472的说明书中。因此,本发明的活化剂中使用的EP4激动剂包括:式(I)表示的3,7-二硫前列腺酸衍生物、与作为其平衡化合物的8-表(epi)型化合物的混合物、其非毒性盐、或其环糊精包合物:
其中R1为羟基、C1-6烷基氧基或NR6R7,其中R6和R7各自独立地为氢原子或C1-6烷基;
R2为氢原子或羟基;
R3为单键或C1-6亚烷基;
R4为
(i)C1-8烷基、C2-8烯基或C2-8炔基,它们被1至3个选自C1-6烷基氧基和卤素原子的取代基取代,
(ii)苯基氧基或C3-7环烷基氧基,
(iii)呋喃基,呋喃基氧基,噻吩基,噻吩基氧基,萘基,萘基氧基,1,3-二氢异苯并呋喃基或1,3-二氢异苯并呋喃基氧基,
(iv)苯基、苯基氧基、C3-7环烷基或C3-7环烷基氧基,它们被1至3个选自以下的取代基取代:
(1)C1-6烷基,(2)C2-6烯基,(3)C2-6炔基,(4)C1-6烷基氧基,(5)C1-6烷基氧基-C1-6烷基,(6)C1-6烷基氧基-C1-6烷基氧基,(7)C2-6烯基氧基-C1-6烷基,(8)被1至3个羟基取代的C1-6烷基,(9)被1至3个卤素原子取代的C1-6烷基,(10)C1-6烷基硫基,(11)C1-6烷基硫基-C1-6烷基,(12)C1-6烷基硫基-C1-6烷基氧基,(13)C2-6烯基硫基-C1-6烷基,(14)C1-6烷基磺酰基,(15)卤素原子,(16)三卤代甲基,(17)氰基,(18)硝基,(19)氨基,(20)羟基,(21)C3-7环烷基,(22)C3-7环烷基氧基,(23)C3-7环烷基-C1-6烷基,(24)C3-7环烷基氧基-C1-6烷基,(25)苯基,(26)苯基氧基,(27)苯基-C1-6烷基,(28)苯基-C2-6烯基,(29)苯基-C2-6炔基,(30)苯基氧基-C1-6烷基,(31)苯基氧基-C2-6烯基,(32)苯基氧基-C2-6炔基,(33)呋喃基,(34)呋喃基氧基,(35)呋喃基-C1-6烷基,(36)呋喃基氧基-C1-6烷基,(37)噻吩基,(38)噻吩基氧基,(39)噻吩基-C1-6烷基或(40)噻吩基氧基-C1-6烷基,其中上述苯基、呋喃基、噻吩基和环烷基任选被1至3个选自C1-6烷基、C1-6烷基氧基、C1-6烷基氧基-C1-6烷基、硝基、卤素、三卤代甲基、氨基和羟基的取代基取代;
或
(v)呋喃基、呋喃基氧基、噻吩基、噻吩基氧基、萘基、萘基氧基、1,3-二氢异苯并呋喃基或1,3-二氢异苯并呋喃基氧基,它们被1至3个选自以下的取代基取代:
(1)C1-6烷基,(2)C2-6烯基,(3)C2-6炔基,(4)C1-6烷基氧基,(5)C1-6烷基氧基-C1-6烷基,(6)C1-6烷基氧基-C1-6烷基氧基,(7)C2-6烯基氧基-C1-6烷基,(8)被1至3个羟基取代的C1-6烷基,(9)被1至3个卤素原子取代的C1-6烷基,(10)C1-6烷基硫基,(11)C1-6烷基硫基-C1-6烷基,(12)C1-6烷基硫基-C1-6烷基氧基,(13)C2-6烯基硫基-C1-6烷基,(14)C1-6烷基磺酰基,(15)卤素原子,(16)三卤代甲基,(17)氰基,(18)硝基,(19)氨基,(20)羟基,(21)C3-7环烷基,(22)C3-7环烷基氧基,(23)C3-7环烷基-C1-6烷基,(24)C3-7环烷基氧基-C1-6烷基,(25)苯基,(26)苯基氧基,(27)苯基-C1-6烷基,(28)苯基-C2-6烯基,(29)苯基-C2-6炔基,(30)苯基氧基-C1-6烷基,(31)苯基氧基-C2-6烯基,(32)苯基氧基-C2-6炔基,(33)呋喃基,(34)呋喃基氧基,(35)呋喃基-C1-6烷基,(36)呋喃基氧基-C1-6烷基,(37)噻吩基,(38)噻吩基氧基,(39)噻吩基-C1-6烷基或(40)噻吩基氧基-C1-6烷基,其中上述苯基、呋喃基、噻吩基和环烷基任选被1至3个选自C1-6烷基、C1-6烷基氧基、C1-6烷基氧基-C1-6烷基、硝基、卤素、三卤代甲基、氨基和羟基的取代基取代;
R5为氢原子或C1-6烷基;
条件是R2为氢原子时,R3表示的C1-6亚烷基可被一个羟基取代。
此外,上述化合物中第8位的构型示为α-构型,但对本领域技术人员清楚地是,该8α-化合物与8β-化合物平衡,其为8-表型化合物。因此,式(I)的化合物包括8α-化合物和与其异构的8β-化合物的混合物。
(B)在WO02/042268描述了下式(IB)表示的化合物具有EP4激动活性。同样,式(IB)表示的化合物的各基团的定义详细描述于WO02/042268。因此,本发明使用的EP4激动剂包括式(IB)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中虚线为键或没有键,
XB为-CH2-或-O-,
ZB为-(CH2)3-、噻吩基、噻唑基或苯基,条件是XB为O时,ZB为苯基,
QB为羧基、C1-4烷氧基羰基或四唑基,
R2B为-ArB或-Ar1B-VB-Ar2B-,
VB为键、-O-、-OCH2-或-CH2O-,
ArB为任选具有1至4个任意选自氧原子、硫原子和氮原子的杂原子的部分饱和的、完全饱和的或完全不饱和的5至8元环,或由两个任选具有1至4个任意选自氧原子、硫原子和氮原子的杂原子的部分饱和的、完全饱和的或完全不饱和的5至6元环缩合而成的双环,此处所述部分或完全饱和的环或双环任选在碳上具有1或2个氧代基团,或任选在硫上具有1或2个氧代基团,
Ar1B和Ar2B各自独立地为部分饱和的、完全饱和的或完全不饱和的5至8元环,其任选具有1至4个随意选自氧原子、硫原子或氮原子的杂原子,所述部分或完全饱和的环任选在碳上具有1或2个氧代基团或任选在硫上具有1或2个氧代基团,
对于所述ArB,当其为单环时则在一个环上的碳或氮上、当其为双环时则在一个或两个环上的碳或氮上,任选具有选自以下(1)-(29)的最多三个取代基:(1)羟基,(2)卤素原子,(3)羧基,(4)C1-7烷氧基,(5)C1-4烷氧基C1-4烷基,(6)C1-7烷基,(7)C2-7烯基,(8)C3-7环烷基,(9)C3-7环烷基C1-4烷基,(10)C3-7环烷基C1-4烷酰基,(11)甲酰基,(12)C1-8烷酰基,(13)C1-6烷酰基C1-4烷基,(14)C1-4烷酰基氨基,(15)C1-4烷氧基羰基氨基,(16)羟基磺酰基,(17)氨基羰基氨基或被C1-4烷基取代的单-N-,二-N,N-,二-N,N′-,或三-N,N,N′-氨基羰基,(18)磺酰胺,(19)C1-4烷基磺酰胺,(20)氨基,(21)单-N-或二-N,N-C1-4烷基氨基,(22)氨基甲酰基,(23)单-N-或二-N,N-C1-4烷基氨基甲酰基,(24)氰基,(25)巯基,(26)C1-6烷基硫基,(27)C1-6烷基亚硫酰基,(28)C1-4烷基磺酰基,(29)单-N-或二-N,N-C1-4烷基氨基亚硫酰基,其中在ArB的定义中的烷基和烷氧基取代基任选被最多三个氟原子取代,
所述Ar1B和Ar2B任选在碳或氮上被至多三个选自以下(1)-(29)的取代基取代;(1)羟基,(2)卤素原子,(3)羧基,(4)C1-7烷氧基,(5)C1-4烷氧基C1-4烷基,(6)C1-7烷基,(7)C2-7烯基,(8)C3-7环烷基,(9)C3-7环烷基C1-4烷基,(10)C3-7环烷基C1-4烷酰基,(11)甲酰基,(12)C1-8烷酰基,(13)C1-6烷酰基C1-4烷基,(14)C1-4烷酰基氨基,(15)C1-4烷氧基羰基氨基,(16)羟基磺酰基,(17)氨基羰基氨基或被C1-4烷基取代的单-N-,二-N,N-,二-N,N′-,或三-N,N,N′-氨基羰基,(18)磺酰胺,(19)C1-4烷基磺酰胺,(20)氨基,(21)单-N-或二-N,N-C1-4烷基氨基,(22)氨基甲酰基,(23)单-N-或二-N,N-C1-4烷基氨基甲酰基,(24)氰基,(25)巯基,(26)C1-6烷基硫基,(27)C1-6烷基亚硫酰基,(28)C1-4烷基磺酰基,(29)单-N-或二-N,N-C1-4烷基氨基亚硫酰基,其中在Ar1B和Ar2B的定义中的烷基和烷氧基取代基任选被最多三个氟原子取代,
条件是
(a)当XB为-(CH2)-且ZB为-(CH2)3-时,则R2B不为噻吩基、苯基或被氯、氟、苯基、甲氧基、三氟甲氧基或C1-4烷基单取代的苯基,
(b)当XB为-(CH2)-,ZB为-(CH2)3-,且QB为羧基或C1-4烷氧基羰基时,则R2B不为下述(i)或(ii)所示的环:(i)C5-7环烷基或(ii)苯基、噻吩基或呋喃基,并且各环可任选被一个或两个选自以下的取代基单取代或二取代:(1)卤素原子或(2)可被一个或多个卤素原子或C1-4烷氧基取代的C1-3烷基。
(C)在WO03/008377描述了下式(IC)表示的化合物具有EP4激动活性。同样,式(IC)表示的化合物的各基团的定义详细描述于WO03/008377。因此,本发明的EP4激动剂包括式(IC)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物。
其中AC为-CH2-CH2-或-CH=CH-,
BC为单键、芳基或杂芳基,
ZC为-C(O)OR′C,-C(O)NR′LR″C,-C(O)NSO2R′C,-PR′C(O)(OR′C),-PO(OR′C)2或四唑-5-基(其中,R′C和R″C各自独立地为氢原子或C1-6烷基),
mC为1,2,3,4,5或6,
当BC为芳基或杂芳基且R3C、R4C、R5C和R6C不同时为氢原子时,R1C为烷基、烯基、炔基、环烷基烷基、杂环基烷基、芳基、芳基烷基、杂芳基,或当BC为单键且R3C、R4C、R5C和R6C同时为氢原子时,R1C为杂环基烷基、芳基、芳基烷基、杂芳基,
R2C为氢原子、C1-6烷基、C1-6烯基或C1-6炔基,
R3C、R4C、R5C和R6C各自独立地为氢原子或C1-6烷基,R3C和R4C、R5C和R6C、或R3C和R5C可与它们相连的原子一起形成C3-7烷基环。
(D)在WO03/035064,描述了下式(ID)表示的化合物结合至EP4。同样,式(ID)表示的化合物的各基团的定义详细描述于WO03/035064。因此,本发明使用的EP4激动剂包括式(ID)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中各R4D独立地为氢原子、任选取代的烷基、任选取代的碳环芳基或任选取代的杂芳环,
ED为氢原子、羟基、任选取代的烷氧基或任选取代的烷基硫基,
oD和pD各自独立地为0,1或2,oD和pD之和至少为1,
FD为-(CH2)nD(其中nD为1至6的整数),
GD为-C≡C-,-CH=CH-,-CH2-,任选取代的碳环芳基或任选取代的杂芳环,
LD为(CH2)n′D(其中n′D为0至3的整数),
MD为COXD、SO2XD(其中XD为OR′D或NHR′D,R′D为H或任选取代的烷基)、任选取代的四唑、NO2、NHSO2RD或NHC(O)RD(其中RD为H、任选取代的烷基),
DD为(CH2)n″D(其中n″D为0至2的整数),
QD为(CH2)n″′D(其中n″′D为0或1)、-CH=CH-或任选取代的碳环芳基,优选任选取代的苯基,
UD和VD各自独立地为任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的碳环芳基、或任选取代的杂芳环,
条件是,以下化合物除外:其中GD为CH2、n′D为3、ED为氢原子且pD为2、R4D为氢原子且oD为2、n″D为2、n″′D为0、VD为烷基。
(E)在WO03/053923,描述了下式(IE)表示的化合物结合至EP4。同样,式(IE)表示的化合物的各基团的定义详细描述于WO03/053923。因此,本发明使用的EP4激动剂包括式(IE)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中,R1E各自独立地为氢原子,任选取代的烷基,任选取代的烯基,任选取代的炔基,任选取代的杂烷基,任选取代的杂烯基,任选取代的杂炔基,任选取代的碳环芳基,任选取代的芳烷基,任选取代的杂脂环基,任选取代的杂芳基,任选取代的杂芳基烷基或任选取代的杂脂环基烷基,
GE为氧代,卤素原子,任选取代的烷基,任选取代的烷氧基,羟基,羧酸酯(carboxylate),任选取代的烷基羧酸酯(optionally substitutedalkylcarboxylate ester),
PE为0至4的整数,
YE为可包含0或1个C=C双键的(CR2ER3E)qE,其中qE为1至6的整数,R2E和R3E各自独立地为氢原子、任选取代的烷基、任选取代的烯基、任选取代的炔基、羟基、卤素原子或任选取代的烷氧基,
UE和U1E各自独立地为氢原子、羟基或任选取代的烷基,
AE为O,S,(CR2ER3E)q′E(其中,q′E为1至6的整数),
BE为(CR2ER3E)nE或单键,
AE和BE一起形成任选取代的1,2-亚乙烯基或亚乙炔基,
VE为(CR2ER3E)mE、任选取代的二价芳基或任选取代的二价杂芳基,
LE为C(O)ZE,
ZE为羟基,任选取代的烷基,任选取代的烯基,任选取代的炔基,任选取代的杂烷基,任选取代的杂烯基,任选取代的杂炔基,氨基,NR4ER5E,任选取代的环烷基,任选取代的杂环烷基,任选取代的碳环芳基,任选取代的杂芳基,任选取代的芳基烷基或任选取代的杂芳基烷基,
nE为0至3的整数,
mE为1至6的整数,
R4E和R5E各自独立地为氢原子,任选取代的烷基,任选取代的环烷基,任选取代的杂环烷基,任选取代的烯基,任选取代的炔基,任选取代的杂烷基,任选取代的杂烯基,任选取代的杂炔基,任选取代的碳环芳基,任选取代的杂芳基,任选取代的芳基烷基或任选取代的杂芳基烷基,或R4E和R5E一起形成杂环烷基。
(F)在WO03/103664,描述了下式(IF)表示的化合物具有EP4激动活性。同样,式(IF)表示的化合物的各基团的定义详细描述于WO03/103664。因此,本发明使用的EP4激动剂包括式(IF)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中XF为单键、氧原子或硫原子,
YF为=O或-OH,
R1F为羟基,CN,(CH2)pFCO2R6F,(CH2)nFSO3R6F,-CF2SO2NH2,-SO2NH2,-CHNHSO2R2F-,-SO2NHCOR6F,-PO(OH)2,CONHPO2R6F,CONHR8F,C1-4烷氧基,-(CH2)nFNR6FR7F,羟基甲基酮或-(CH2)nF杂环基,所述杂环基任选包含酸性氢原子,所述杂环基可以是未被取代的或被1至3个RaF取代,且,
R2F为氢原子,C6-10芳基或C1-4烷基,
R3F和R4F各自独立地为氢原子、卤素原子或C1-6烷基,
R5F为(CH2)mFC6-10芳基,(CH2)mFC5-10杂芳基,(CH2)mFC3-10杂环烷基或(CH2)mFC3-10环烷基,所述环烷基、杂环烷基、芳基或杂芳基未被取代或被1至3个RaF取代,
R6F和R7F为氢原子或C1-4烷基,
R8F为氢原子或磺酰基,
ZF为(C(RbF)2)nF,
各RbF独立地为氢原子,卤素原子,C1-6烷基或C3-6环烷基,
RaF为C1-6烷氧基,C1-6烷基,CF3,硝基,氨基,氰基,C1-6烷基氨基或卤素原子,
pF为1至3,
nF为0至4,
mF为0至8。
(G)在US2005/0049227中,描述了下式(IG)表示的化合物具有EP4激动活性。同样,式(IG)表示的化合物的各基团的定义详细描述于US2005/0049227。因此,本发明使用的EP4激动剂包括式(IG)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中RG为CO2R4G、CONR4G 2、CH2OR4G、CONR4GSO2R4G、P(O)(OR4G),
R4G为氢原子、苯基、C1-6烷基,
R1G和R2G各自独立地为氢原子、羟基、C1-6烷基氧基、C1-6酰基氧基,
R3G为氢原子、C1-6烷基、C1-6酰基,
YG为单键,或-CH2-、-O-、-S-、-N-,
ZG为C3-10烷基,C3-10环烷基,6至10元芳香碳环,包含一个选自氮原子、氧原子和硫原子的杂原子的4至10元芳香杂环。
(H)在WO2004/085430中,描述了下式(IH)表示的化合物具有EP4激动活性。同样,式(IH)表示的化合物的各基团的定义详细描述于WO2004/085430。因此,本发明使用的EP4激动剂包括式(IH)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中QH为(CH2)mH,(CH2)mH-C6-10芳基,(CH2)mH-C5-10杂环,(CH2)mH-C3-10杂环烷基,(CH2)mH-C3-8环烷基,被两个卤素原子取代的亚甲基,所述环烷基、杂环烷基、芳基、或杂环可被三个RaH取代,
XH和YH各自独立地为亚甲基、氧原子、被R9H取代的氮原子、硫原子,条件是,XH和YH不同时为氧原子、被R9H取代的氮原子、或硫原子,
UH为氢原子、C1-3烷基,但当WH为氧代时,不存在,
WH为羟基,氧代,条件是当WH为氧代时,UH不存在,
R1H为-(CH2)pH-羟基,-(CH2)pH-氰基,-(CH2)pH-CO2R10H,-(CH2)nH-SO3R6H,-(CH2)pH-CF2SO2NH2,-(CH2)pH-SO2NH2,-(CH2)pH-CONHSO2R2H,-(CH2)pH-SO2NHCOR2H,-(CH2)pH-PO(OH)2,(CH2)pH-CONHPO2R6H,-(CH2)pH-CONHR8H,-(CH2)pH-C1-4烷氧基,-(CH2)pH-环烷基,-(CH2)pH-羟基甲基酮,-(CH2)nH-杂环,所述杂环任选被1至3个RaH取代且任选包含酸性羟基,
R2H独立地为C1-10烷基,(CH2)mH-C6-10芳基,(CH2)mH-C5-10杂环,(CH2)mH-C3-10杂环烷基,(CH2)mH-C3-8环烷基,O-C1-10烷基,O-C6-10芳基,O-C3-10环烷基,O-C3-10杂环烷基,条件是当R2H为O-C1-10烷基,O-C6-10芳基,O-C3-10环烷基,O-C3-10杂环烷基时,则R3H和R4H不为卤素原子,所述烷基、环烷基、杂环烷基、芳基、或杂环任选被1至3个RaH取代,
R3H和R4H各自独立地为氢原子、卤素原子、C1-6烷基,R3H和R4H可一起形成3-7元碳环,该碳环任选包含1至2个选自氧原子、硫原子、SO、SO2和被R9H取代的氮原子的杂原子,
R6H和R7H各自独立地为氢原子、C1-4烷基,
R8H为氢原子、酰基、磺酰基,
R9H为氢原子、C1-6烷基,所述烷基任选被1至3个卤素原子、氰基、羟基、C1-6烷氧基、C1-6酰基氧基、氨基取代,
R10H为氢原子,C1-10烷基,C3-10环烷基,(CH2)pH-C6-10芳基,(CH2)pH-C5-10杂环,CR6HR7HOC(O)-C3-10环烷基,CR6HR7HOC(O)-C1-10烷基,
ZTH为三键、氧原子、硫原子、(C(RbH)2)nH、-CH=CH-,
RbH为氢原子、C1-6烷基、卤素原子,
RaH为C1-6烷氧基、C1-6烷基、CF3、硝基、氨基、氰基、C1-6烷基氨基、卤素原子,RaH进一步为芳基、杂环、S-C1-6烷基、S-C6-10芳基、S-C5-10杂环、CO2R6H、O-C6-10芳基、O-C5-10杂环、CH2O-C1-6烷基、CH2S-C1-6烷基、CH2O-芳基、CH2S-芳基,
pH为0至3,
nH为0至4,
mH为0至8。
(J)在WO2004/085431,描述了下式(IJ)表示的化合物具有EP4激动活性。同样,式(IJ)表示的化合物的各基团的定义详细描述于WO2004/085431。因此,本发明使用的EP4激动剂包括式(IJ)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中UJ为氢原子、C1-3烷基,但当WJ为时,不存在,
WJ为羟基、氧代,条件是,当WJ为氧代时,UJ不存在,
ZJ为(CH2)nJ、-CH=CH-,
R1J为(CH2)pJ-羟基、(CH2)pJ-CO2R10J、(CH2)nJ杂环,所述杂环任选被1至3个RaJ取代且任选包含酸性羟基,
R2J独立地为C1-10烷基、(CH2)mJ-C6-10芳基、(CH2)mJ-C5-10杂环、(CH2)mJ-C3-10杂环烷基、(CH2)mJ-C3-8环烷基,所述烷基、环烷基、杂环烷基、芳基、或杂环可被1至3个RaJ取代,
R3J和R4J各自独立地为氢原子、卤素原子、C1-6烷基,
R6J为氢原子、C1-4烷基,
R10J为氢原子、C1-10烷基、C3-10环烷基、(CH2)pJ-C6-10芳基、(CH2)pJ-C5-10杂环,
RaJ为C1-6烷氧基、C1-6烷基、CF3、硝基、氨基、氰基、C1-6烷基氨基、卤素原子,RaJ进一步为芳基、杂环、S-C1-6烷基、S-C6-10芳基、S-C5-10杂环、O-C6-10芳基、O-C5-10杂环、CO2R6J、CH2O-C1-6烷基、CH2S-C1-6烷基、CH2O-芳基、CH2S-芳基,
pJ为0至3,
nJ为0至4,
mJ为0至8。
(K)在WO2004/063158,描述了下式(IK)表示的化合物具有EP4激动活性。同样,式(IK)表示的化合物的各基团的定义详细描述于WO2004/063158。因此,本发明使用的EP4激动剂包括式(IK)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中mK为1至4,
nK为0至4,
AK为烷基、芳基、杂芳基、芳基烷基、芳基环烷基、环烷基烷基、芳基氧基烷基,
EK为-CHOH-、-C(O)-,
XK为-(CH2)2-、-CH=CH-,
YK为-CH2-、-CH=CH-、亚芳基、杂亚芳基、-O-、-S(O)pK-(其中pK为0至2)、-NRaK-(其中,RaK为氢原子、烷基),
ZK为-CH2OH-、-CHO、四唑-5-基、-COORbK(其中RbK为氢原子、烷基),
R1K、R2K、R3K、R4K、R5K、R6K、R7K、R8K、R9K和R10K各自独立地为氢原子或烷基。
(L)在WO03/009872,描述了下式(IL)表示的化合物具有EP4激动活性。同样,式(IL)表示的化合物的各基团的定义详细描述于WO03/009872。因此,本发明使用的EP4激动剂包括式(IL)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中为(1)单键或(2)双键,R19L和R20L各自独立地为,(1)氢原子,(2)C1-10烷基或(3)卤素原子,TL为(1)氧原子或(2)硫原子,XL为(1)-CH2-,(2)-O-或(3)-S-,AL为A1L或A2L,A1L为(1)任选被1至2个C1-4烷基取代的C2-8直链亚烷基,(2)任选被1至2个C1-4烷基取代的C2-8直链亚烯基或(3)任选被1至2个C1-4烷基取代的C2-8直链亚炔基,A2L为-G1L-G2L-G3L-,G1L为(1)任选被1至2个C1-4烷基取代的C1-4直链亚烷基,(2)任选被1至2个C1-4烷基取代的C2-4直链亚烯基或(3)任选被1至2个C1-4烷基取代的C2-4直链亚炔基,G2L为(1)-YL-,(2)-(环1L)-,(3)-YL-(环1L)-,(4)-(环1L)-YL-或(5)-YL-(C1-4亚烷基)-(环1L)-,YL为(1)-S-,(2)-SO-,(3)-SO2-,(4)-O-或(5)-NR1L,R1L为(1)氢原子,(2)C1-10烷基或(3)C2-10酰基,G3L为(1)单键,(2)任选被1至2个C1-4烷基取代的C1-4直链亚烷基,(3)任选被1至2个C1-4烷基取代的C2-4直链亚烯基或(4)任选被1至2个C1-4烷基取代的C2-4直链亚炔基,DL为D1L或D2L,D1L为(1)-COOH,(2)-COOR2L,(3)四唑-5-基或(4)CONR3LSO2R4L,R2L为(1)C1-10烷基,(2)苯基,(3)被苯基取代的C1-10烷基或(4)联苯基,R3L为(1)氢原子或(2)C1-10烷基,R4L为(1)C1-10烷基或(2)苯基,D2L为(1)-CH2OH,(2)-CH2OR5L,(3)羟基,(4)-OR5L,(5)甲酰基,(6)-CONR6LR7L,(7)-CONR6LSO2R8L,(8)-CO-(NH-氨基酸残基-CO)mL-OH,(9)-O-(CO-氨基酸残基-NH)mL-H,(10)-COOR9L,(11)-OCO-R10L,(12)-COO-Z1L-Z2L-Z3L,(13)
R5L为C1-10烷基,R6L和R7L各自独立地为,(1)氢原子或(2)C1-10烷基,R8L为被苯基取代的C1-10烷基,R9L为(1)被联苯基取代的C1-10烷基,该联苯基任选被1至3个C1-10烷基、C1-10烷氧基或卤素原子取代或(2)被1至3个C1-10烷基、C1-10烷氧基或卤素原子取代的联苯基,R10L为(1)苯基或(2)C1-10烷基,mL为1或2,Z1L为(1)C1-15亚烷基,(2)C2-15亚烯基或(3)C2-15亚炔基,Z2L为(1)-CO-,(2)-OCO-,(3)-COO-,(4)-CONR11L-,(5)-NR12LCO-,(6)-O-,(7)-S-,(8)-SO-,(9)-SO2-,(10)-NR13L-,(11)-NR14LCONR15L-,(12)-NR16LCOO-,(13)-OCONR17L-或(14)-OCOO-,Z3L为(1)氢原子,(2)C1-15烷基,(3)C2-15烯基,(4)C2-15炔基,(5)环2L或(6)被C1-10烷氧基、C1-10烷基硫基、C1-10烷基-NR18L-或环2L取代的C1-10烷基,
R11L、R12L、R13L、R14L、R15L、R16L、R17L和R18L各自独立地为(1)氢原子或(2)C1-15烷基,R11L和Z3L可与它们相连的氮原子一起形成5至7元饱和单-杂环,且该杂环可还进一步包含一个选自氧原子、氮原子和硫原子的杂原子,EL为E1L或E2L,E1L为(1)C3-7环烷基或(2)环3L,E2L为(1)C3-7环烷基,(2)环4L或(3)环5L、环1L和环5L任选被1至3个R21L和/或R22L取代,环3L任选被1至2个R21L取代,E2L表示的C3-7环烷基被1个R21L或R22L取代且还进一步任选被1至2个R21L和/或R22L取代,环4L被R22L之一取代,任选被其它1至2个R21L和/或R22L取代,由R11L和Z3L及相连的氮原子形成的杂环或环2L可被R23L取代,R21L为(1)C1-10烷基,(2)C1-10烷氧基,(3)卤素原子,(4)硝基,(5)被1至3个卤素原子取代的C1-10烷基或(6)苯基,R22L为(1)C2-10烯基,(2)C2-10炔基,(3)C1-10烷基硫基,(4)羟基,(5)-NR24LR25L,(6)被C1-10烷氧基取代的C1-10烷基,(7)被C1-10烷氧基取代的C1-10烷基,该C1-10烷氧基被1至3个卤素原子取代,(8)被-NR24LR25L取代的C1-10烷基,(9)环6L,(10)-O-环7L,(11)被环7L取代的C1-10烷基,(12)被环7L取代的C2-10烯基,(13)被环7L取代的C2-10炔基,(14)被环7L取代的C1-10烷氧基,(15)被-O-环7L取代的C1-10烷基,(16)-COOR26L或(17)被1至3个卤素原子取代的C1-10烷氧基,R24L、R25L和R26L各自独立地为,(1)氢原子或(2)C1-10烷基,R23L为(1)C1-15烷基,(2)C2-15烯基,(3)C2-15炔基或(4)被C1-10烷氧基,C1-10烷基硫基或C1-10烷基-NR27L-基取代的C1-10烷基,R27L为(1)氢原子或(2)C1-10烷基,环1L、环2L、环5L、环6L和环7L为(1)C3-15单-、二-或三-碳环芳基,其可为部分或完全饱和的或(2)包含1至4个选自氧、氮和硫原子的杂原子的3至15元单-、二-或三-杂环芳基,其可为部分或完全饱和的,环3L和环4L为(1)噻吩基,(2)苯基或(3)呋喃基,环6L和环7L可被1至3个R28L取代,R28L为(1)C1-10烷基,(2)C2-10烯基,(3)C2-10炔基,(4)C1-10烷氧基,(5)被C1-10烷氧基取代的C1-10烷基,(6)卤素原子,(7)羟基,(8)被1至3个卤素原子取代的C1-10烷基或(9)被C1-10烷氧基取代的C1-10烷基,该C1-10烷氧基被1至3个卤素原子取代,
环1L、环2L、环3L、环4L和环5L各自独立地为:
(1)C3-15单-、二-或三-碳环芳基,其可为部分或完全饱和的,或(2)3至15元单-、二-或三-杂环芳基,其可为部分或完全饱和的,且包含选自1至4个氮原子、1-2个氧原子氮和/或1-2个硫原子的杂原子,
条件是:
1)当EL为E2L,E2L为U1L-U2L-U3L,并且U1L为C2亚烷基或C2亚烯基时,U2L不表示-CHOH-,
2)当U3L表示至少被一个羟基取代的C1-8烷基时,U1L-U2L不表示C2亚烷基或C2亚烯基,
3)当AL表示A1L,并且DL表示D1L时,EL不表示E1L,
4)当TL表示氧原子,XL表示-CH2-,DL表示D1L,D1L表示COOH,AL表示A1L,A1L表示直链的C2-8亚烷基,EL表示E2L,E2L表示U1L-U2L-U3L,U1L表示C1-4亚烷基,并且U3L表示C1-8烷基时,U2L不表示单键、-CH2-、-NR12L-、或羰基,
5)当TL表示氧原子,XL表示-CH2-,DL表示D1L,D1L表示COOH,AL表示A2L,G1L表示C1-4亚烷基,G2L表示-O-或-NR1L-,G3L表示单键或C1-4亚烷基,EL表示E2L,E2L表示U1L-U2L-U3L,U1L表示C1-4亚烷基,并且U3L表示C1-8烷基时,U2L不表示单键、-CH2-、-NR12L-、或羰基,
6)当TL表示氧原子,XL表示-CH2-,DL表示D1L,EL表示E2L,E2L表示U1L-U2L-U3L,U1L表示C2亚烷基或C2亚烯基,并且U2L表示-CO-时,AL不表示A1L,
7)排除4-[(2-{(2R)-2-[(1E,3S)-3-羟基-辛-1-烯基]-5-氧代-吡咯烷-1-基}乙基)硫基]丁酸、和4-{2-[(R)-2-((E)-3-羟基-辛-1-烯基)-5-氧代-吡咯烷-1-基]乙基}-苯甲酸。
在式(IL)表示的化合物中,优选式(IL-1)表示的化合物
其中E1-1具有与EL相同的意思,RL-1为氢原子或C1-4烷基。
(M)在WO00/03980,描述了下式(IM)表示的化合物具有EP4激动活性。同样,式(IM)表示的化合物的各基团的定义详细描述于WO00/03980。因此,本发明使用的EP4激动剂包括式(IM)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中R1M为羟基、C1-6烷基氧基或NR6MR7M,其中R6M和R7B各自独立地为氢原子或C1-4烷基,R2M为氧原子、卤素原子或O-COR8M,其中R8M为C1-4烷基、苯基或苯基(C1-4烷基),R3M为氢原子或羟基,R4aM和R4bM各自独立地为氢原子或C1-4烷基,R5M为被以下取代基取代的苯基:
i)1至3个选自以下的基团(a)C1-4烷基氧基-C1-4烷基,(b)C2-4烯基氧基-C1-4烷基,(c)C2-4炔基氧基-C1-4烷基,(d)C3-7环烷基氧基-C1-4烷基,(e)C3-7环烷基(C1-4烷基氧基)-C1-4烷基,(f)苯基氧基-C1-4烷基,(g)苯基-C1-4烷基氧基-C1-4烷基,(h)C1-4烷基硫基-C1-4烷基,(i)C2-4烯基硫基-C1-4烷基,(j)C2-4炔基硫基-C1-4烷基,(k)C3-7环烷基硫基-C1-4烷基,(l)C3-7环烷基(C1-4烷基硫基)-C1-4烷基,(m)苯基硫基-C1-4烷基和(n)苯基-C1-4烷基硫基-C1-4烷基,
ii)(a)C1-4烷基氧基-C1-4烷基和C1-4烷基,(b)C1-4烷基氧基-C1-4烷基和C1-4烷基氧基,(c)C1-4烷基氧基-C1-4烷基和羟基,(d)C1-4烷基氧基-C1-4烷基和卤素原子,(e)C1-4烷基硫基-C1-4烷基和C1-4烷基,(f)C1-4烷基硫基-C1-4烷基和C1-4烷基氧基,(g)C1-4烷基硫基-C1-4烷基和羟基或(h)C1-4烷基硫基-C1-4烷基和卤素原子,
iii)(a)卤代烷基或(b)羟基-C1-4烷基,或
iv)C1-4烷基和羟基;
条件是当R2M为O-COR8M时,该8-9位置表示双键。
(N)在WO03/007941,描述了下式(IN)表示的化合物具有EP4激动活性。同样,式(IN)表示的化合物的各基团的定义详细描述于WO03/007941。因此,本发明使用的EP4激动剂包括式(IN)表示的化合物、其盐、其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中QN为CH2或氧原子,
BN为-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-CH=CH-、-CH2-CH=CH-、-CH=CH-CH2-或-CH2-CH=CH-CH2-,条件是当BN为-CH=CH-,或-CH=CH-CH2-时,QN为CH2,
XN为-NRaN-(其中RaN为氢原子、卤素原子、C1-6烷基、C1-6酰基)、-O-、-S-、-SO-、-SO2-或单键,条件是XN为单键时,QN为氧原子,
JN为-(CRbNRcN)nN-(其中nN为1至4的整数,RbN和RcN都为氢原子,或RbN和RcN中的一个或两个为低级烷基且剩余的为氢原子,或RbN和RcN如果连接至同一碳原子则形成C2-5多亚甲基)、或-CH2-CH=CH-,
AN为-CH2-CH2-、-CH=CH-或-C≡C-,
ZN为CH2OH、-C(O)OR’N、-C(O)NR’NR”N、-C(O)NSO2R’N、-P(C1-6烷基)(O)(OR’N)、-PO(OR’N)2或四唑-5-基,其中R’N和R”N各自独立地为氢原子或C1-6烷基,
nN为1,2,3或4,
R1N为-(CH2)pNR7N或-(CH2)qNOR8N(R7N和R8N各自独立地为C1-6烷基、卤代C1-6烷基、C3-6环烷基、杂环基、芳基或杂芳基,pN和qN各自独立地为0,1,2,3,4或5),
R2N为氢原子、C1-6烷基、C1-6烯基、C1-6炔基,
R3N、R4N、R5N和R6N各自独立地为氢原子或C1-6烷基。
作为其它EP4激动剂,包括描述于以下文献中的化合物:WO2005/012232,WO2005/023267,WO2005/100339,WO2005/116010,WO2006/014206,WO2006/014207,WO2006/058063,WO2006/055481,WO2006/052630,WO2006/52892,WO2006/080323,US2006/252742,WO2006/113571,WO2006/137472,WO2007/014454,WO2007/014462,WO2007/088190,WO2007/143825,WO2008/012344和WO2008/012347。
作为本发明的EP4激动剂,优选式(I)、(IL)、(IL-1)、(IM)或(IN)表示的化合物。更优选地,包括以下化合物:11α,15α,-二羟基-9-氧代-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲-3,7-二硫前列腺(dithiaprost)-13E-烯酸,4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸,4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸,4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯等。还优选地,包括以下化合物:4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸,4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸,4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯。
[异构体]
除非另有所述,所有异构体都包含在以上式(I)、(IB)至(IH)和(IJ)至(IN)表示的各化合物中(下文集中缩写为本发明使用的化合物)。例如,烷基、烯基、炔基、烷基氧基、烷氧基、烯基氧基、炔基氧基、烷基硫基、烷基亚硫酰基、烷基磺酰基、亚烷基、亚烯基、亚炔基、酰基和酰基氧基基团包含直链或支链的链。此外,关于双键、环、稠合的环的异构体(E-,Z-,顺-,反-异构体)、从不对称碳原子产生的异构体(R-,S-异构体,α-,β-构型,对映异构体,非对映异构体)、旋光异构体(D-,L-,d-,1-异构体)、色谱分离产生的极性化合物(高极性的化合物,低极性的化合物)、平衡化合物、旋转异构体、它们随意比例的混合物和外消旋混合物也包含在本发明中。而且,包括互变异构体。
[盐和溶剂合物]
本发明使用的化合物的盐包括药物可接受的盐。作为药物可接受的盐,优选无毒、水溶性盐。作为合适的盐,例如,包括碱金属(例如,钾,钠,锂等)的盐,碱土金属(例如,钙,镁等)的盐,铵盐(例如,四甲基铵盐,四丁基铵盐等),有机胺(例如,三乙胺,甲基胺,二甲基胺,环戊基胺,苄基胺,苯乙基胺,哌啶,单乙醇胺,二乙醇胺,三(羟基甲基)甲基胺,赖氨酸,精氨酸,N-甲基-D-葡糖胺等)的盐,酸加成盐(无机酸的盐(例如,盐酸盐,氢溴酸盐,氢碘酸盐,硫酸盐,磷酸盐,硝酸盐等),和有机酸的盐(例如,乙酸盐,三氟乙酸盐,乳酸盐,酒石酸盐,草酸盐,富马酸盐,马来酸盐,苯甲酸盐,柠檬酸盐,甲磺酸盐,乙磺酸盐,苯磺酸盐,甲苯磺酸盐,羟乙基磺酸盐,葡糖醛酸盐,葡糖酸盐等)。
而且,该盐包括季铵盐。所述季铵盐为以下化合物:其中本发明使用的化合物的氮被R0季铵化。R0为任选被苯基取代的C1-8烷基。
本发明使用的化合物的溶剂合物包括如,水、醇溶剂(例如,甲醇、乙醇等)等的溶剂合物。该溶剂合物优选为无毒和水溶性的。合适的溶剂合物包括,例如,水或醇(例如,乙醇等)的溶剂合物。而且,本发明使用的化合物的溶剂合物包括本发明使用的化合物的碱(碱土)金属盐、铵盐、有机胺盐和酸加成盐的溶剂合物。
本发明使用的化合物可通过已知方法转化为其盐和其溶剂合物。
[环糊精包合物化合物]
本发明使用的化合物可通过描述于JP-B-50-3362、52-31404或61-52146的说明书的方法使用α-,β-或γ-环糊精或其混合物转化为相应的环糊精包合物。转化为相应的环糊精包合物用来增加化合物的稳定性和在水中的溶解性,因此对药物使用是有用的。在环糊精包含物化合物中,优选转化为α-环糊精包合物化合物。
[前药]
本发明使用的化合物的前药是指以下化合物,其在生物体内通过与酶、胃酸等反应而转化为本发明使用的化合物。本发明使用的化合物的前药包括,当本发明使用的化合物具有氨基,该前药为以下化合物,其氨基被酰化,烷基化,或磷酰基化(例如,该化合物为以下本发明使用的化合物,其氨基被二十烷酸化,丙氨酰化,戊基氨基羰基化,(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲氧基羰基化,四氢呋喃化,吡咯烷基甲基化,新戊酰基氧基甲基化,乙酰氧基甲基化,叔丁基化,等);第本发明使用的化合物具有羟基时,该前药为以下化合物,其羟基酰基化,烷基化,磷酰基化或硼化(例如,该化合物为以下本发明使用的化合物,其羟基被乙酰基化,棕榈酰化,丙酰基化,新戊酰化,琥珀酰化,富马酰化,内氨酰化,二甲基氨基甲基羰基化等);当本发明使用的化合物具有羧基,该前药为以下化合物,其羧基被酯化或酰胺化(例如,该化合物为以下本发明使用的化合物,其羧基被乙基酯化,苯基酯化,羧基甲基酯化,二甲基氨基甲基酯化,新戊酰基氧基甲基酯化,1-{(乙氧基羰基)氧基}乙基酯化,酞基酯化,(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基酯化,1-{[(环己基氧基)羰基]氧基}乙基酯化,甲基酰胺化等);等。这些化合物可通过已知方法制备。此外,本发明使用的化合物的前药可为水合物或非水合物。此外,本发明使用的化合物的前药可在生理条件下转化为本发明的化合物,其描述于1991年Hirokawa shoten中163-198页公开的“molecular design”第7卷“the development of medicine”。而且,本发明使用的化合物可用同位素(例如3H,14C,35S,125I等)等标记。
[制备本发明化合物的方法]
本发明使用的EP4激动剂可通过已知方法制备,如,描述于以下的方法:JP2000-001472,WO02/042268,WO2003/008377,WO2003/035064,WO2003/053923,WO2003/103664,WO2003/007941,US2005/0049227,WO2004/085430,WO2004/085431,WO2004/063158,WO2003/009872,WO00/03980,WO2003/007941,WO2005/012232,WO2005/023267,WO2005/100339,WO2005/116010,WO2006/014206,WO2006/014207,WO2006/058063,WO2006/055481,WO2006/052630,WO2006/52892,WO2006/080323,US2006/252742,WO2006/113571,WO2006/137472,WO2007/014454,WO2007/014462,WO2007/088190,WO2007/143825,WO2008/012344,WO2008/012347等,或其类似方法。例如,11α,15α,-二羟基-9-氧代-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲-3,7-二硫前列腺-13E-烯酸,其作为优选EP4激动剂示例,可通过描述于JP2000-001472的方法制备。
4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸可通过描述于WO2003/009872的方法制备。
4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸和4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯可通过描述于WO00/03980的方法制备。
[毒性]
本发明使用的EP4激动剂的毒性非常低,且足够安全以用作药物试剂。
[药物产品的应用]
EP4激动剂通过活化细胞毒性T细胞而显示免疫增强活性,因此可用于预防和/或治疗哺乳动物如人或除人外的动物的癌症或微生物介导的感染病,该除人外的动物例如猴,羊,牛,马,狗,猫,兔,大鼠,小鼠等。当其与上述抗原肽一起使用时该EP4激动剂可用作致敏物或佐剂。
除了上述抗原肽,本发明使用的EP4激动剂还可与其它药物组合给药,作为并用药物疗法以实现以下目的:
1)补偿和/或增强细胞毒性T细胞的活化;
2)改善所述EP4激动剂的动力学/吸收和减少剂量;和/或
3)减轻所述EP4激动剂的副作用。
本发明使用的EP4激动剂和抗原肽和/或其它药物可以在单一制剂中加入这些成分的制剂形式给药,或可以分别的制剂给药。当这些药物以分别的制剂给药时,它们可同时或在不同时间给药。在后一情况下,EP4激动剂、抗原肽和其它药物可以任何顺序给药。
所述其它药物可为低分子化合物。此外,它们可为大分子蛋白质、多肽、多核苷酸(DNA、RNA和基因)、反义物(antisense)、诱杀剂(decoy)、抗体或疫苗等,条件是上述抗原肽除外。抗原肽和/或其它药物的剂量可相应地按临床剂量为基准进行选择。此外,在本发明中使用的EP4激动剂、抗原肽和/或其它药物的混合比例可通过给药对象的年龄和体重、给药方法、给药时间等相应地选择。例如,相对于1重量份本发明使用的EP4激动剂,使用的抗原肽和/或其它药物可从0.01至100重量份。该抗原肽和/或其它药物可以适当比例任意组合两种或更多种而给药。补偿和/或增强细胞毒性T细胞的活化效果的其它药物不仅包括已发现的药物,还包括基于以下机理以后将会发现的药物。
其它药物包括免疫刺激剂,抗癌药物如烷化剂、抗代谢物、抗癌性抗生素、植物药物、激素药物、铂化合物、组蛋白脱乙酰酶(HDAC)抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂等、抗病毒药物、抗生素、抗真菌药物、抗寄生虫药、抗原虫剂等。
该免疫刺激剂包括,例如,蘑菇多糖、溶链菌素、云星、西佐喃、乌苯美司、干扰素、氯苯扎利、TF、GM-CSF、M-CSF、G-CSF、IL-1、IL-2、IL-3、IL-12等。
该烷化剂包括,例如,氮芥N-氧化物盐酸盐、环磷酰胺、异环磷酰胺、美法仑、塞替派、卡波醌、白消安、尼莫司汀羟基氯化物、达卡巴嗪、雷莫司汀等。
该抗代谢物包括,例如,甲氨蝶呤、疏基嘌呤、6-疏基嘌呤核苷、氟尿嘧啶、替加氟、替加氟/尿嘧啶、卡莫氟、去氧氟尿苷、阿糖胞苷、依诺他滨、替加氟/gimestat/otastat、吉西他滨盐酸盐、阿糖胞苷酯、丙卡巴肼盐酸盐、羟基脲等。
该抗癌性抗生素包括,例如,放线菌素D、丝裂霉素C、柔红霉素盐酸盐、多柔比星盐酸盐、阿柔比星盐酸盐、新制癌菌素、吡柔比星盐酸盐、表柔比星(盐酸盐)、伊达比星盐酸盐、色霉素A3、博来霉素(盐酸盐)、培洛霉素硫酸盐、therarubicin、净司他丁斯酯等。
该植物药物包括,例如,长春碱硫酸盐、长春新碱硫酸盐、长春地辛硫酸盐、伊立替康盐酸盐、依托泊苷、氟他胺、长春瑞滨ditartrate、多西紫杉醇水合物、紫杉醇等。
该激素药物包括,例如,雌莫司汀磷酸酯钠(estramustine phosphatesodium),美雄烷,环硫雄醇,醋酸戈舍瑞林,磷雌酚(己烯雌酚二磷酸酯),柠檬酸他莫昔芬,柠檬酸托瑞米芬,盐酸法倔唑水合物,醋酸甲羟孕酮,比卡鲁胺,醋酸亮丙瑞林,阿那曲唑,依西美坦等。
该铂化合物包括,例如,卡铂、顺铂、奈达铂等。
该HDAC抑制剂包括,例如,伏林司他(vorinostat),AN-9,belinostat,MGCD-0103,MS-275,帕比司他(panobinostat),romidepsin,泰克地那林(tacedinaline),丙戊酸,VP-101,CRA-024781,ITF-2357,pyroxamide,CS-055,EHT-0205,FR-135313,NSC-3852,PXD-118490,SAHA类似物,LAQ-824等。
该PARP抑制剂包括,例如,GPI-15427,GPI-16539,GPI-18078,GPI-6000,GPI-6150,KU-0687,INO-1001,FK-866,4-(4-(N,N-二甲基氨基甲基)苯基)-5-羟基异喹啉铜(isoquinolinone),FR-255595,FR-257516,FR-261529,FR-247304,M-50916,ABT-472,ONO-1924H,DR-2313,CEP-8983,AG-014699,BGP-15,AAI-028,PD-141076,PD-141703,ONO-2231等。
该抗病毒药物包括,例如,抗HIV药物如CCR5抑制剂,CXCR4抑制剂,逆转录酶抑制剂,融合抑制剂等,抗流感病毒药物如磷酸奥塞米韦,扎那米韦水合物等,抗抗疱疹药物如阿昔洛韦等,干扰素-α或β,各种免疫球蛋白等。
该抗生素包括,例如,头孢烯(cefem)抗生素如头孢克洛等,青霉素抗生素如阿莫西林等,大环内酯抗生素如红霉素乙基琥珀酸酯等,头孢布烯,头孢呋辛钠,多柔比星,妥布霉素,美罗培南三水合物,盐酸头孢他美,硫酸阿司米星,硫酸西索米星,硫酸奈替米星等。
该抗真菌药物包括,例如,伊曲康唑,氟康唑,拉诺康唑,硝酸硫康唑,硝酸奥昔康唑,硝酸益康唑,硝酸伊曲康唑,氯康唑盐酸硝酸盐,克霉唑,特比萘芬盐酸盐,托萘酯,联苯苄唑,奈康唑盐酸盐,酮康唑,布替萘芬盐酸盐,硝酸咪康唑,伏立康唑,两性霉素B,氟胞嘧啶,灰黄霉素,micafungin等。
该抗寄生虫药包括,例如,山道年,噻嘧啶,supatonin,甲苯达唑,噻苯达唑,eskazole,吡喹酮,奎宁,防治疟,甲硝唑,haisigyn等。
该抗原虫剂包括,例如,甲硝唑、喷他脒等。
为出于上述目的使用本发明的EP4激动剂或本发明的EP4激动剂与抗原肽和/或其它药物的组合,这些通常经口或肠胃外给药于人体的全身或局部部分。
给药剂量分别根据例如,年龄、体重、症状、所需治疗效果、给药途径,和治疗持续时间等而确定。在成人中,通过口服给药每人的剂量通常为0.1ng至1000mg,且每天一至多次,且肠胃外给药为0.1ng至1000mg,每天一至多次,或每天静脉连续给药1至24小时或局部给药1天至三个月。
如上所述,该剂量根据不同条件而改变。因此,存在低于上述剂量的剂量是足够的情况,或需要比上述剂量范围更大的剂量。
本发明使用的EP4激动剂,或本发明使用的EP4激动剂与其它并用药物(concomitant medication)可以以下组合给药,例如,用于口服给药的固体组合物或液体组合物,或注射剂,外用剂,用于肠胃外给药的栓剂、滴眼剂或吸入剂等
用于口服给药体内使用的固体制剂的实例包括片剂、丸剂、胶囊、散剂、颗粒等。所述胶囊包括硬胶囊和软胶囊。该片剂包括舌下片剂、口腔贴片(intraoral patches),口腔速崩片剂等。
这种内用固体制剂通过通常使用的配制方法制备,其使用一种或多种活性物质的原样或使用与以下物质的混合物,所述试剂为赋形剂(乳糖,甘露醇,葡萄糖,微晶纤维素,淀粉等)、粘合剂(羟基丙基纤维素,聚乙烯吡咯烷酮,硅酸铝酸镁等)、崩解剂(纤维素乙醇酸钙等)、润滑剂(硬脂酸镁等)、稳定剂和溶出辅剂(dissolution aid)(谷氨酸,天冬氨酸等)。如果需要,其可用包衣剂(蔗糖,明胶,羟基丙基纤维素,羟基丙基甲基纤维素邻苯二甲酸酯等)包衣。其可包衣两层或更多层。而且,由可吸收材料如明胶制备的胶囊在其范围内。
该舌下片剂可根据众所周知的方法制备或调节。例如,舌下片剂通过通常使用的配制方法制备,其使用与以下物质混合的一种或多种活性物质,所述物质为赋形剂(乳糖,甘露醇,葡萄糖,微晶纤维素,胶体二氧化硅,淀粉,等)、粘合剂(羟基丙基纤维素,聚乙烯吡咯烷酮,硅酸铝镁(magnesiummetasilicate aluminate)等)、崩解剂(淀粉,L-羟基丙基纤维素,羧基甲基纤维素,交联羧甲基纤维素钠,纤维素乙醇酸钙,等)、润滑剂(硬脂酸镁等)、溶胀剂(羟基丙基纤维素,羟基丙基甲基纤维素,卡波普(carbopol),羧基甲基纤维素,聚乙烯醇,黄原胶,瓜尔胶等)、溶胀助剂(葡萄糖,果糖,甘露醇,木糖醇,赤藓醇,麦芽糖,海藻糖,磷酸盐,柠檬酸盐,硅酸盐,甘氨酸,谷氨酸,精氨酸,等)、稳定剂、溶出辅剂(聚乙二醇,丙二醇,谷氨酸,天冬氨酸等)、增味剂(橙,草莓,薄荷,柠檬,香草等)。如果需要,其可用包衣剂(蔗糖,明胶,羟基丙基纤维素,羟基丙基甲基纤维素邻苯二甲酸酯等)包衣。如果需要,其可包衣两层或更多层。而且,其也可进一步包含一些添加剂如防腐剂、抗氧化剂、着色剂、甜味剂等。
该口腔贴片可根据众所周知的方法制备或调节。例如,口腔贴片通过通常使用的配制方法制备,其使用与以下物质混合的一种或多种活性物质,所述物质为赋形剂(乳糖,甘露醇,葡萄糖,微晶纤维素,胶体二氧化硅,淀粉,等)、粘合剂(羟基丙基纤维素,聚乙烯吡咯烷酮,硅酸铝酸镁,等)、崩解剂(淀粉,L-羟基丙基纤维素,羧基甲基纤维素,交联羧甲基纤维素钠,纤维素乙醇酸钙,等)、润滑剂(硬脂酸镁等)、附着剂(attach agent)(羟基丙基纤维素,羟基丙基甲基纤维素,卡波普,羧基甲基纤维素,聚乙烯醇,黄原胶,瓜尔胶,等),附着助剂(attach aid agent)(葡萄糖,果糖,甘露醇,木糖醇,赤藓醇,麦芽糖,海藻糖,磷酸盐,柠檬酸盐,硅酸盐,甘氨酸,谷氨酸,精氨酸等)、稳定剂、溶出辅剂(聚乙二醇,丙二醇,谷氨酸,天冬氨酸等)、增味剂(橙,草莓,薄荷,柠檬,香草等)等。如果需要,其可用包衣剂(蔗糖,明胶,羟基丙基纤维素,羟基丙基甲基纤维素邻苯二甲酸酯等)包衣等。如果需要,其可包衣两层或更多层。而且,其也可进一步包含一些添加剂如防腐剂、抗氧化剂、着色剂、甜味剂等。
该口腔速崩片剂可根据众所周知的方法制备或调节。例如,口腔速崩片剂通过通常使用的配制方法制备,其直接使用一种或多种活性物质,或使用在活性物质的粒子或粒化颗粒上用适当的包衣剂(乙基纤维素,羟基丙基纤维素,羟基丙基甲基纤维素,丙烯酸和甲基丙烯酸共聚物等)覆盖的活性物质,且与以下物质混合:增塑剂(聚乙二醇,三乙基柠檬酸酯等),赋形剂(乳糖,甘露醇,葡萄糖,微晶纤维素,胶体二氧化硅,淀粉等)、粘合剂(羟基丙基纤维素,聚乙烯吡咯烷酮,硅酸铝酸镁,等)、崩解剂(淀粉,L-羟基丙基纤维素,羧基甲基纤维素,交联羧甲基纤维素钠,纤维素乙醇酸钙,等)、润滑剂(硬脂酸镁等)、分散助剂(葡萄糖,果糖,甘露醇,木糖醇,赤藓醇,麦芽糖,海藻糖,磷酸盐,柠檬酸盐,硅酸盐,grylcine,谷氨酸盐,精氨酸等)、稳定剂和溶出辅剂(聚乙二醇,丙二醇,谷氨酸,天冬氨酸等)、增味剂(橙,草莓,薄荷,柠檬,香草,等)等。如果需要,其可用包衣剂(蔗糖,明胶,羟基丙基纤维素,羟基丙基甲基纤维素邻苯二甲酸酯等)包衣等。如果需要,其可包衣两层或更多层。而且,其也可进一步包含一些添加剂如防腐剂、抗氧化剂、着色剂、甜味剂等。
口服给药的液体形式包括药物可接受的溶液、悬浮液、乳剂、糖浆和酏剂。在这些形式中,可将一种或多种活性化合物溶解、悬浮或乳化于现有技术通常使用的稀释剂(如纯化水,乙醇或其混合物)中。此外这些液体形式也可包含一些添加剂,如湿润剂、悬浮剂、乳化剂、甜味剂、增味剂、香料、防腐剂或缓冲剂。
在肠胃外给药中,外用制剂包括,例如,软膏、凝胶、乳膏、泥罨剂、贴片、搽剂、雾化剂、吸入剂、喷雾剂、滴眼剂、滴耳剂和鼻的喷雾剂等。它们包括一种或多种活性化合物且通过已知方法或常规方法制备或调节。
软膏通过已知方法或常规方法制备。例如,其通过研磨或融合一种或多种活性化合物和基质而制备或调节。软膏的基质选自已知或常用的。例如,高级脂肪酸或高级脂肪酸酯(己二酸、肉豆蔻酸、棕榈酸、硬脂酸、油酸、己二酸酯、肉豆蔻酸酯、棕榈酸酯、硬脂酸酯、油酸酯等)、蜡(黄蜂蜡、鲸蜡、地蜡等)、表面活性剂(聚氧乙烯烷基醚磷酸酯等)、高级醇(鲸蜡醇、硬脂醇、鲸蜡硬脂醇等)、硅油(二甲基聚硅氧烷等)、烃(亲水性矿脂、白矿脂、纯化的羊毛脂、液体石蜡等)、二醇(乙二醇、二甘醇、丙二醇、聚乙二醇、聚乙二醇等)、植物油(蓖麻油、橄榄油、芝麻油、松节油等)、动物油(貂油、卵黄油、角鲨烷、角鲨烯等)、水、吸收促进剂、皮肤适合抑制剂(skin fit inhibitor)等作为选自它们的单一物质或作为选自它们的两种或更多种的混合物而使用。而且,可添加润湿剂、防腐剂、稳定剂、抗氧化剂、香料等。
凝胶通过已知方法或常规方法制备。例如,其通过融合一种或多种活性化合物和基质而制备或调节。凝胶的基质选自已知或常用的。例如,低级醇(乙醇、异丙基醇等)、胶凝剂(羧基甲基纤维素、羟基乙基纤维素、羟基丙基纤维素、乙基纤维素等)、中和剂(三乙醇胺、二异丙醇胺等)、表面活性剂(聚乙二醇单硬脂酸酯等)、胶质、水、吸收促进剂、皮肤适合抑制剂等作为选自它们的单一物质或作为选自它们的两种或更多种的混合物而使用。而且,可添加防腐剂、抗氧化剂、香料等。
乳膏通过已知方法或常规方法制备。例如,其通过融合或乳化一种或多种活性化合物和基质而制备或调节。乳膏的基质选自已知或常用的。例如,高级脂肪酸酯,低级醇,烃,多醇(丙二醇,1,3-丁二醇等),高级醇(2-己基癸醇,鲸蜡醇,等),乳化剂(聚氧乙烯烷基醚,脂肪酸酯等),水,吸收促进剂,皮肤适合抑制剂等作为选自它们的单一物质或作为选自它们的两种或更多种的混合物而使用。而且,可添加防腐剂,抗氧化剂,香料等。
巴布剂(Poultice,湿布剤)通过已知方法或常规方法制备。例如,其通过融合一种或多种活性化合物和基质,然后将揉捏后的物质置于支持介质上而制备。巴布剂的基质选自已知或常用的。例如,增稠剂(聚丙烯酸,聚乙烯吡咯烷酮,阿拉伯胶,淀粉,明胶,甲基纤维素等)、润湿剂(脲,甘油,丙二醇等),填充剂(bulking agent)(高岭土,氧化锌,滑石,钙,镁等),水,增溶剂,增稠剂,皮肤适合抑制剂等作为选自它们的单一物质或作为选自它们的两种或更多种的混合物而使用。而且,可添加防腐剂、抗氧化剂、香料等。
贴剂(patch)通过已知方法或常规方法制备。例如,其通过融合其一种或多种活性化合物和基质,然后置于支持介质上而制备。用于贴剂的基质选自已知或常用的。例如,聚合物基质(苯乙烯-异戊二烯-苯乙烯嵌段共聚物,聚异丁烯橡胶,丙烯酸酯树脂,丙烯基体系共聚物树脂,硅橡胶等),脂肪,高级脂肪酸,透皮促进剂(percutaneous permeation accelerator)(油酸,异丙基肉豆蔻酸酯,D-薄荷醇,克罗米通等),增稠剂(松香衍生物,脂环族饱和烃树脂等),皮肤适合抑制剂(甘油,克罗米通等)等作为选自它们的单一物质或作为选自它们的两种或更多种的混合物而使用。而且,可添加防腐剂、抗氧化剂、香料等。该贴剂包括,例如,硬膏剂(plaster agent)如基质(粘性单层)型,贮器型(reservoir type)等,和巴布剂等。而且,在基质型中,包括药物分散性、药物溶出型等。该硬膏剂称为胶带剂(tape agent)。
搽剂通过已知方法或常规方法制备。例如,可将一种或多种活性化合物作为选自它们的单一物质或作为选自它们的两种或更多种的混合物而溶于、悬浮于或乳化于水、醇(乙醇,聚乙二醇等)、高级脂肪酸、甘油、皂、乳化剂、悬浮剂等。而且,可添加防腐剂、抗氧化剂、香料等。
雾化剂、吸入剂和喷雾剂除了稀释剂,可包含稳定剂如亚硫酸氢钠和等渗缓冲液如氯化钠、柠檬酸钠或柠檬酸。而且,包括气溶胶。
用于肠胃外给药的吸入剂的剂型包括气溶胶、吸入用粉末或吸入用液体。吸入用液体可按需要溶于或悬浮于水或其它合适的溶剂。
这些吸入剂按已知方法制备。
例如,如果需要,吸入用液体可通过从防腐剂(苯扎氯铵或对氨基苯甲酸(benzonic acid))、着色剂、缓冲剂(磷酸钠或乙酸钠)、等渗剂(氯化钠或浓缩甘油)、增稠剂(羧基乙烯基聚合物)、或吸收促进剂等选择合适的添加剂而制备。
如果需要,吸入用粉末可通过从润滑剂(如硬脂酸及其盐)、粘合剂(如淀粉,糊精)、稀释剂(如乳糖,纤维素)、着色剂、防腐剂(如苯扎氯铵或对氨基苯甲酸)、吸收促进剂等选择合适的添加剂而制备。
在给药吸入用液体的情况下,通常使用喷雾器(雾化器,喷雾器),且在给药吸入用粉末的情况下,通常使用用于粉末试剂的吸入给药装置。
用于肠胃外给药的注射剂包括无菌水溶液(sterile aqueous)、悬浮液、乳剂和固体形式,其在使用前立即溶解或悬浮于注射用溶剂中。在注射剂中,可将一种或多种活性化合物溶解、悬浮或乳化于溶剂中。该溶剂可包括注射用蒸馏水、生理盐溶液、植物油、丙二醇、聚乙二醇、醇、例如乙醇、或其混合物。注射剂可包括一些添加剂,如稳定剂、溶液佐剂(谷氨酸,天冬氨酸,聚山梨酯80(注册商标)等)、悬浮剂、乳化剂、安抚剂、缓冲剂、防腐剂。它们可在最终步骤灭菌,或可通过无菌操作制备或调节。它们也可以无菌固体形式,例如,冻干的产物制备,其可在使用前立即溶于无菌水或一些其它的注射用无菌稀释剂。
用于肠胃外给药的其它组合物包括用于直肠内给药的栓剂和用于阴道给药的阴道栓剂,其包括一种或多种活性物质且可通过本身已知的方法制备。
为增加本发明的药物的效果,特别是对抗癌症的免疫增强作用,其他治疗癌症的方法可与该药物组合使用。例如,可提及其它免疫治疗(例如,经皮免疫治疗(例如,胶带剥离方法(tape stripping method)),NK(自然杀伤)细胞治疗,CTL治疗(在此,CTL治疗是指使用外来的(extraneous)培养的癌症特异性CTL的免疫治疗),细胞因子治疗,CD3-LAK治疗,LAK治疗,树突细胞疫苗治疗等),使用上述抗癌剂的化学治疗,放射治疗,粒子射线(带电荷的重粒子射线)治疗,定位放射线照射,温热疗法,造血干细胞移植等。优选地,使用经皮免疫治疗,特别是胶带剥离方法。
该胶带剥离方法具体是指使用具有粘着性的胶带制剂(tape preparation)、丙酮等,将活化细胞毒性T细胞的物质(例如,本发明的药物中使用的EP4激动剂、抗原肽等)给药于(皮肤表皮)角质层已被物理或化学方法去除的部位的方法,如日本专利第3879785公报和其它地方所描述。其中,优选使用具有粘着性的胶带制剂;具体地,优选包含丙烯酸聚合物、橡胶-系列聚合物、亲水性聚合物等用作粘合剂,且塑料膜(例如,聚乙烯,聚对苯二甲酸乙酯,聚氨酯,聚乙烯,聚丙烯,聚酯,聚乙酸乙烯酯,乙烯-乙酸乙烯酯共聚物等)用作支持体的胶带制剂。作为使用具有粘着性的胶带制剂破坏角质层的方法,可使用以下方法,其中将胶带制剂粘附至表皮角质层表面然后剥离该制剂的操作重复一次至多次。
当本发明的药物与上述带剥离(tape stripping)方法组合使用时,本发明的药物中使用的EP4激动剂可以包含在胶带剥离方法中使用的带制剂的粘合层中的状态给药,或可给药于已通过胶带剥离方法剥离皮肤表皮角质层或角质层的部位,该给药通过任意选择的方法(例如,贴片,注射),或可给药于除所述部位以外的任何部位(例如,口服给药、静脉内给药、皮下给药)。而且,当与抗原肽组合使用时,该抗原肽可以包含在胶带制剂的粘合层中的状态给药,或可以与EP4激动剂一起包含在粘合层中的状态给药,或可通过任意选择的方法(例如,贴片)给药于上述剥离部位(deprival site),或可给药于除所述部位以外的任何部位(例如,静脉内给药)。
在给药抗原肽的方法中,角质层被破坏,然后将目标抗原肽溶液(二甲基亚砜(DMSO),磷酸盐缓冲溶液(PBS)等)吸收至任选大小的纱布垫上,且将纱布施加于除去角质层的1个至多个部位。在将抗原肽给药于多个部位时,该抗原肽可在臂、股、腹部和背部的不同部位给药。考虑到给药时间,可持续给药1至3个月,同时每24小时更换新的垫。
为保证能有效地显示本发明的药物的作用,特别是对抗癌症的免疫增强作用,尤其是对抗黑素瘤,优选该EP4激动剂、抗原肽、上述其它治疗癌症的方法等按以下所示进行组合。具体地,优选4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸、4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸和4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯中的任何一种作为EP4激动剂,和抗原肽组合使用;更优选地,将4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸、4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸和4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯中的任何一种、抗原肽、以及作为另一癌症治疗方法的经皮免疫治疗进行组合;还更优选地,将4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸、4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸和4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯中的任何一种、作为抗原肽的黑素瘤特异性抗原肽(TRP-2)、以及胶带剥离方法进行组合。
上述组合可以在使用胶带剥离方法对黑素瘤的免疫治疗中用作药物或药物组合物。在其优选实施方案中,例如,向通过胶带剥离方法剥离皮肤表皮角质层或角质层的部位,将EP4激动剂4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸、4-{[-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸和4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯中的任何一种作为活性成分包含在粘合层中,以贴剂的形式给药。而且,当使用贴剂时,优选一起组合使用抗原肽TRP-2;在该实施方案中,更优选TRP-2和EP4激动剂以分开的贴剂给药,或以其粘合层包含TRP-2和以下任一种EP4激动剂的单一贴剂给药:4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸、4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸和4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯。
在上述药物或药物组合物(特别是贴剂)中,可以通过局部给药于皮肤防止药物进入体循环,从而使由于口服给药、静脉内给药等进入体循环可能引起的副作用最小化。
本发明还包括被EP4激动剂活化了的细胞毒性T细胞。该细胞可通过用最佳量的EP4激动剂处理由众所周知的技术培养的未成熟的T细胞而制得。该细胞毒性T细胞是否被活化可通过通常使用的方法确定,例如,流式细胞仪分析等。如此获得的细胞可用于免疫治疗,例如,CTL疗法。
实施例
EP4激动剂具有本发明的效果,该事实通过以下实验证实。使用的实验步骤示于以下,然而,其不用来限制本发明的范围。例如,可按照相同的步骤,但使用以上所列的抗原肽代替以下实施例使用的肽抗原TRP-2和HSVgpB,也可评价对抗靶癌症和微生物感染病的增强免疫作用。
生物实施例
实施例1:颈部淋巴结中细胞毒性T细胞的活化
实施例1(1):通过使用粘着胶带重复剥离步骤10次,破坏C57BL/6(B6)小鼠耳廓(auricle)的角质层,且涂布作为受试物质的抗原肽或EP4激动剂。使用的抗原肽为黑素瘤特异性抗原肽(Accord K.K.Peptide BusinessDepartment;下文缩写为TRP-2)溶解在70%乙醇中的溶液;各耳廓的一侧涂布10μg。使用的EP4激动剂为11α,15α,-二羟基-9-氧代-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲-3,7-二硫前列腺-13E-烯酸(下文缩写为化合物A-(1))在丙酮∶橄榄油=10∶1的混合溶剂中的溶液;各耳廓的一侧涂布20μL的100μM的溶液。涂布受试物质一周后,颈部淋巴结被去除。通过流式细胞仪分析(FACScaliber;Becton,Dickinson and Company.)使用四聚体(tetramer)(Medical&Biological Laboratories Co.,Ltd.),测定当以颈部淋巴结中单核细胞的总数作为100时,TRP-2-特异的CTL的频率。建立四个实验组:(1)一组仅进行带剥离(下文缩写为TS),(2)一组进行TS然后涂布TRP-2,(3)一组进行TS然后涂布化合物A-(1),和(4)一组进行TS然后涂布TRP-2和化合物A-(1)。
该黑素瘤特异性的抗原肽TRP-2是基于描述于上述非专利文件1的部分序列(SEQ ID NO.1)合成的(Accord K.K.Peptide Business Department)。
TRP-2;酪氨酸酶-相关蛋白质2181-188
实施例1(2):进行与实施例1(1)相同的步骤,除了所使用的EP4激动剂为4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸(下文缩写为化合物L-(1))和4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸(下文缩写为化合物M-(1))来评价各化合物活化细胞毒性T细胞的作用。建立四个实验组:(1)一组仅进行TS,(2)一组进行TS然后涂布TRP-2,(3)一组进行TS然后涂布化合物TRP-2和化合物L-(1),和(4)一组进行TS然后涂布TRP-2和化合物M-(1)。
[结果]
实施例1(1)和实施例1(2)的结果分别示于下表1和表2。
表1
实验组 | (1) | (2) | (3) | (4) |
TRP-2特异性CTL的比例 | 0.11 | 0.35 | 0.55 | 0.63 |
表2
实验组 | (1) | (2) | (3) | (4) |
TRP-2特异性CTL的比例 | 1.19 | 1.28 | 1.92 | 1.66 |
这些结果显示在接受作为EP4激动剂涂布的化合物A-(1)的组中,与仅进行TS的组相比,颈部淋巴结中TRP-2特异性的CTL的比例增加。在化合物L-(1)和化合物M-(1)中观察到相似的作用,表明单独的EP4激动剂可显示活化TRP-2特异性的CTL的作用。表1所示的实验组(4)的结果和表2所示的实验组(3)和(4)的结果表明EP4激动剂当与抗原肽组合使用时可增强其作用。
实施例1(3):进行与实施例1(1)相同的步骤,除了使用的抗原肽为单纯疱疹病毒特异性抗原HSV糖蛋白B(下文缩写为HSVgpB),且进行使用五聚体(pentamer)(ProImmune Company)的流式细胞仪分析,评价各化合物活化细胞毒性T细胞的作用。建立五个实验组:(1)一组仅进行TS,(2)一组进行TS然后涂布HSVgpB,(3)一组进行TS然后涂布HSVgpB和化合物A-(1),(4)一组进行TS然后涂布HSVgpB和化合物L-(1),和(5)一组进行TS然后涂布HSVgpB和化合物M-(1)。
该单纯疱疹病毒特异性抗原肽HSVgpB是基于SEQ ID NO.2所示的部分序列(Virology,Vol.195,pp.62-70,(1993))合成的(ProImmune Company)。
HSVgpB;单纯疱疹病毒糖蛋白B 498-505
[结果]
实施例1(3)的结果示于以下表3。
表3
实验组 | (1) | (2) | (3) | (4) | (5) |
HSVgpB特异性CTL的比例 | 0.20 | 0.25 | 0.41 | 0.29 | 0.30 |
这些结果表明,EP4激动剂具有活化HSVgpB特异性CTL的作用,而且当与抗原肽组合使用时可增强其作用。
实施例2:在分离的朗格汉斯细胞中活化细胞毒性T细胞
从各C57BL/6(B6)小鼠的一个耳廓的角质层去除一定面积,得到耳廓表皮片,用胰蛋白酶处理以得到表皮细胞悬浮液。将得到的表皮细胞悬浮液使用对I-Ab抗原特异性的抗体,通过淘洗法(panning)分离表皮朗格汉斯细胞。将各受试物质(TRP-2(浓度;10μg/mL)和化合物A-(1)(1μM))添加至分离的朗格汉斯细胞(细胞密度;105个细胞/mL),然后将细胞用培养基(cRPMI1640培养基;Sigma-Aldrich Japan)培养。半天后,将细胞与从B6小鼠颈部淋巴结分离的脾细胞(splenocytic)淋巴细胞共培养7天。随后,使用四聚体(Medical&Biological Laboratories Co.,Ltd.)进行流式细胞仪分析(FACScaliber;Becton,Dickinson and Company.),以培养基中的单核细胞总数作为100,测定TRP-2-特异性CTL的频率。建立三个实验组:(1)一组没有处理,(2)一组添加TRP-2,和(3)一组添加TRP-2和化合物A-(1)。
[结果]
结果示于下表4。
表4
实验组 | (1) | (2) | (3) |
TRP-2特异性CTL的比例 | 2.1 | 3.2 | 6.6 |
在添加作为抗原肽的TRP-2的组中(实验组(2)),B6脾细胞淋巴细胞中TRP-2特异性CTL的比例增加,证明TRP-2特异性CTL被诱导。该作用等价于化合物A-(1)的作用。而且,同时添加化合物A-(1)的组(实验组(3))的结果表明不论是否进行TS,通过组合使用EP4激动剂和抗原肽可增强诱导TRP-2-特异性CTL的能力。
实施例3:黑素瘤生长抑制作用
按与实施例1相同的方式,通过TS从各B6小鼠的右耳廓将角质层去除,且将受试物质(TRP-2和化合物A-(1))涂布于其上;2周后,左耳廓以相同方式处理。涂布于两耳的受试物质以相同组合使用;TRP-2为以10μg涂布于各耳廓的一侧,且化合物A-(1)以20μL100μM溶液的涂布于各耳廓的一侧。上述处理四天后,各小鼠通过皮下移植接受2×105个B16黑素瘤细胞(理化学研究所细胞库,RIKEN’s CellBank),且观察肿瘤生长。实验组按实施例1(1)建立(每组5只动物)。
[结果]
作为肿瘤生长指标,在接种B16黑素瘤细胞后在不同天数对各组肿瘤直径(mm)进行测量;结果示于图1。
在接受作为EP4激动剂涂布的化合物A-(1)的组中(实验组(3)和(4)),与实验组(1)相比,肿瘤直径更小;观察到肿瘤生长速率降低。因此,其表明单独的EP4激动剂显示肿瘤生长抑制作用,且通过与实验组(2)比较,该作用等价于TRP-2的作用。而且,B16黑素瘤细胞没有在实验组(4)的任何动物中生长,表明实施例1和2中表明的EP4激动剂和抗原肽的组合效果产生对黑素瘤免疫的有效增强作用。
实施例4:接种黑素瘤的小鼠的寿命延长效果
将2×105个B16黑素瘤细胞按与实施例3相同的方式移植于B6小鼠。在移植后的第5天,各B6小鼠的右耳廓按与实施例3相同的方法用各受试物质(TRP-2(每个耳廓的一侧10μg)、化合物A-(1)(每个耳廓的一侧20μL的100μM溶液)处理。10天后,左耳廓以相同方式处理,且检测各实验组的小鼠的死亡率。建立三个实验组:(1)一组仅进行TS,(2)一组进行TS然后涂布化合物A-(1),和(3)一组进行TS然后涂布TRP-2和化合物A-(1)(每组10只动物)。
[结果]
各实验组中存活个体数(动物只数)随时间的变化示于表5。
表5
B16黑素瘤细胞接种后的天数 | 实验组(1) | 实验组(2) | 实验组(3) |
16 | 10 | 10 | 10 |
21 | 9 | 10 | 10 |
24 | 9 | 10 | 10 |
27 | 6 | 7 | 10 |
29 | 3 | 7 | 10 |
31 | 0 | 7 | 10 |
3335 | 00 | 72 | 1010 |
37 | 0 | 2 | 10 |
38 | 0 | 2 | 10 |
40 | 0 | 0 | 8 |
4244 | 00 | 00 | 85 |
46 | 0 | 0 | 4 |
48 | 0 | 0 | 2 |
50 | 0 | 0 | 2 |
52 | 0 | 0 | 2 |
55 | 0 | 0 | 2 |
57 | 0 | 0 | 1 |
实验组(1)中的所有动物在第31天前死亡,而在接受EP4激动剂的组中的许多动物在31天后存活;因此,证实了单独的EP4激动剂在黑素瘤-接种的小鼠中具有寿命延长效果。特别是,在实验组(3),即使在第38天所有动物也存活,证实了显著的寿命延长效果;其表明该寿命延长效果可通过组合使用EP4激动剂和抗原肽而增强。
[制剂例]
制剂例1:片剂
将4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸(250mg)在乙醇中的溶液(1000ml)、硬脂酸镁(10g)、二氧化硅(2000mg)、滑石(1000mg)和羧基甲基纤维素钙(20g)通过常规方法混合,干燥,然后将微晶纤维素(500g)添加至混合物中,且将总量调节至1000g。将它们充分混合直到它们均匀,然后通过常规方法冲压以得到10000个片剂,每片含30μg活性成分。
制剂例2:注射剂
将4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯(50mg)的α-环糊精包合物(600mg)溶于注射用蒸馏水(30L),将该溶液使用膜滤器无菌过滤,然后将每份3mL溶液填充至5mL容量注射用安瓿以得到每安瓿含5μg活性成分的注射剂(10000个安瓿)。
制剂例3:贴剂
通过将苯乙烯-异戊二烯-苯乙烯嵌段共聚物(300mg)、超浅色松香酯(ultra-hypochromic rosin ester)(300mg)和轻质液体石蜡(400mg)溶于乙酸乙酯(Kishida Chemical Co.,Ltd.)(1000mg)制备粘着液体。通过将4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯(40mg)溶于粘着液体制备涂覆液体。使用Baker型敷料器将涂覆液体铺展于背衬层(支持体)达到厚度为约60μm。将粘附面在减压在室温干燥18小时。将干燥的粘附面用剥离层(releaseliner)覆盖且适当切割以得到贴剂(主要成分含量:0.2mg/cm2)。
工业应用
EP4激动剂通过活化细胞毒性T细胞显示免疫增强活性,因此可用于预防和/或治疗癌症或微生物感染病。
附图简述
图1为显示实施例3的实验组(1)至(4)中黑素瘤生长的抑制效果的示图。
序列表
<110>国立大学法人浜松医科大学(NATIONAL UNIVERSITY CORPORATION,HAMAMATSU
UNIVERSITY SCHOOL OF MEDICINE)
小野药品工业株式会社(ONO Pharmaceutical Co.,Ltd.)
<120>含有EP4激动剂的细胞毒性T细胞的活化剂
<130>ONP-6823PCT
<150>JP 2007-123119
<151>2007-05-08
<160>2
<210>1
<211>8
<212>PRT
<213>人工序列
<220>
<223>酪氨酸酶-相关蛋白质2残基181-188
<400>1
Val Tyr Asp Phe Phe Val Trp Leu
1 5
<210>2
<211>8
<212>PRT
<213>人工序列
<220>
<223>单纯疱疹病毒糖蛋白B 498-505
<400>2
Ser Ser Ile Glu Phe Ala Arg Leu
1 5
Claims (16)
1.细胞毒性T细胞的活化剂,该活化剂包含EP4激动剂。
2.根据权利要求1的活化剂,其中所述EP4激动剂为通式(I)表示的3,7-二硫前列腺酸衍生物、与作为其平衡化合物的8-表型化合物的混合物、其非毒性盐、或其环糊精包合物,
其中R1为羟基、C1-6烷基氧基或NR6R7,其中R6和R7各自独立地为氢原子或C1-6烷基;
R2为氢原子或羟基;
R3为单键或C1-6亚烷基;
R4为
(i)C1-8烷基、C2-8烯基或C2-8炔基,它们被1至3个选自C1-6烷基氧基和卤素原子的取代基取代,
(ii)苯基氧基或C3-7环烷基氧基,
(iii)呋喃基、呋喃基氧基、噻吩基、噻吩基氧基、萘基、萘基氧基、1,3-二氢异苯并呋喃基或1,3-二氢异苯并呋喃基氧基,
(iv)苯基、苯基氧基、C3-7环烷基或C3-7环烷基氧基,它们被1至3个选自以下的取代基取代:
(1)C1-6烷基,(2)C2-6烯基,(3)C2-6炔基,(4)C1-6烷基氧基,(5)C1-6烷基氧基-C1-6烷基,(6)C1-6烷基氧基-C1-6烷基氧基,(7)C2-6烯基氧基-C1-6烷基,(8)被1至3个羟基取代的C1-6烷基,(9)被1至3个卤素原子取代的C1-6烷基,(10)C1-6烷基硫基,(11)C1-6烷基硫基-C1-6烷基,(12)C1-6烷基硫基-C1-6烷基氧基,(13)C2-6烯基硫基-C1-6烷基,(14)C1-6烷基磺酰基,(15)卤素原子,(16)三卤代甲基,(17)氰基,(18)硝基,(19)氨基,(20)羟基,(21)C3-7环烷基,(22)C3-7环烷基氧基,(23)C3-7环烷基-C1-6烷基,(24)C3-7环烷基氧基-C1-6烷基,(25)苯基,(26)苯基氧基,(27)苯基-C1-6烷基,(28)苯基-C2-6烯基,(29)苯基-C2-6炔基,(30)苯基氧基-C1-6烷基,(31)苯基氧基-C2-6烯基,(32)苯基氧基-C2-6炔基,(33)呋喃基,(34)呋喃基氧基,(35)呋喃基-C1-6烷基,(36)呋喃基氧基-C1-6烷基,(37)噻吩基,(38)噻吩基氧基,(39)噻吩基-C 1-6烷基或(40)噻吩基氧基-C 1-6烷基;其中上述苯基、呋喃基、噻吩基和环烷基任选被1至3个选自C1-6烷基、C1-6烷基氧基、C1-6烷基氧基-C1-6烷基、硝基、卤素、三卤代甲基、氨基和羟基的取代基取代;
或
(v)呋喃基、呋喃基氧基、噻吩基、噻吩基氧基、萘基、萘基氧基、1,3-二氢异苯并呋喃基或1,3-二氢异苯并呋喃基氧基,它们被1至3个选自以下的取代基取代:
(1)C1-6烷基,(2)C2-6烯基,(3)C2-6炔基,(4)C1-6烷基氧基,(5)C1-6烷基氧基-C1-6烷基,(6)C1-6烷基氧基-C1-6烷基氧基,(7)C2-6烯基氧基-C1-6烷基,(8)被1至3个羟基取代的C1-6烷基,(9)被1至3个卤素原子取代的C1-6烷基,(10)C1-6烷基硫基,(11)C1-6烷基硫基-C1-6烷基,(12)C1-6烷基硫基-C1-6烷基氧基,(13)C2-6烯基硫基-C1-6烷基,(14)C1-6烷基磺酰基,(15)卤素原子,(16)三卤代甲基,(17)氰基,(18)硝基,(19)氨基,(20)羟基,(21)C3-7环烷基,(22)C3-7环烷基氧基,(23)C3-7环烷基-C1-6烷基,(24)C3-7环烷基氧基-C1-6烷基,(25)苯基,(26)苯基氧基,(27)苯基-C1-6烷基,(28)苯基-C2-6烯基,(29)苯基-C2-6炔基,(30)苯基氧基-C1-6烷基,(31)苯基氧基-C2-6烯基,(32)苯基氧基-C2-6炔基,(33)呋喃基,(34)呋喃基氧基,(35)呋喃基-C1-6烷基,(36)呋喃基氧基-C1-6烷基,(37)噻吩基,(38)噻吩基氧基,(39)噻吩基-C1-6烷基或(40)噻吩基氧基-C1-6烷基,其中上述苯基、呋喃基、噻吩基和环烷基任选被1至3个选自C1-6烷基、C1-6烷基氧基、C1-6烷基氧基-C1-6烷基、硝基、卤素、三卤代甲基、氨基和羟基的取代基取代;
R5为氢原子或C1-6烷基;
条件是R2为氢原子时,R3表示的C1-6亚烷基可被一个羟基取代;
式(IL)表示的化合物、其盐,其N-氧化物或其溶剂合物,或者它们的前药或它们的环糊精包合物:
其中
R19L和R20L各自独立地为(1)氢原子,(2)C1-10烷基或(3)卤素原子,
TL为(1)氧原子或(2)硫原子,
XL为(1)-CH2-,(2)-O-或(3)-S-,
AL为A1L或A2L;A1L为(1)任选被1至2个C1-4烷基取代的C2-8直链亚烷基,(2)任选被1至2个C1-4烷基取代的C2-8直链亚烯基或(3)任选被1至2个C1-4烷基取代的C2-8直链亚炔基;A2L为-G1L-G2L-G3L-,G1L为(1)任选被1至2个C1-4烷基取代的C1-4直链亚烷基,(2)任选被1至2个C1-4烷基取代的C2-4直链亚烯基或(3)任选被1至2个C1-4烷基取代的C2-4直链亚炔基,G2L为(1)-YL-、(2)-(环1L)-、(3)-YL-(环1L)-、(4)-(环1L)-基-或(5)-YL-(C1-4亚烷基)-(环1L)-,YL为(1)-S-、(2)-SO-、(3)-SO2-、(4)-O-或(5)-NR1L-,R1L为(1)氢原子、(2)C1-10烷基或(3)C2-10酰基,G3L为(1)单键,(2)任选被1至2个C1-4烷基取代的C1-4直链亚烷基,(3)任选被1至2个C1-4烷基取代的C2-4直链亚烯基或(4)任选被1至2个C1-4烷基取代的C2-4直链亚炔基,DL为D1L或D2L,D1L为(1)-COOH、(2)-COOR2L、(3)四唑-5-基或(4)CONR3LSO2R4L,R2L为(1)C1-10烷基、(2)苯基、(3)被苯基取代的C1-10烷基或(4)联苯基,R3L为(1)氢原子或(2)C1-10烷基,R4L为(1)C1-10烷基或(2)苯基,D2L为(1)-CH2OH、(2)-CH2OR5L、(3)羟基、(4)-OR5L、(5)甲酰基、(6)-CONR6LR7L、(7)-CONR6LSO2R8L、(8)-CO-(NH-氨基酸残基-CO)mL-OH、(9)-O-(CO-氨基酸残基-NH)mL-H、(10)-COOR9L、(11)-OCO-R10L、(12)-COO-Z1L-Z2L-Z3L、(13)
R5L为C1-10烷基,R6L和R7L各自独立地为,(1)氢原子或(2)C1-10烷基,R8L为被苯基取代的C1-10烷基,R9L为(1)被联苯基取代的C1-10烷基,该联苯基任选被1至3个C1-10烷基、C1-10烷氧基或卤素原子取代,或(2)被1至3个C1-10烷基、C1-10烷氧基或卤素原子取代的联苯基,R10L为(1)苯基或(2)C1-10烷基,mL为1或2,Z1L为(1)C1-15亚烷基,(2)C2-15亚烯基或(3)C2-15亚炔基,Z2L为(1)-CO-,(2)-OCO-,(3)-COO-,(4)-CONR11L-,(5)-NR12LCO-,(6)-O-,(7)-S-,(8)-SO-,(9)-SO2-,(10)-NR13L-,(11)-NR14LCONR15L-,(12)-NR16LCOO-,(13)-OCONR17L-或(14)-OCOO-,Z3L为(1)氢原子,(2)C1-15烷基,(3)C2-15烯基,(4)C2-15炔基,(5)环2L或(6)被C1-10烷氧基、C1-10烷基硫基、C1-10烷基-NR18L-、或环2L取代的C1-10烷基,
R11L,R12L,R13L,R14L,R15L,R16L,R17L和R18L各自独立地为(1)氢原子或(2)C1-15烷基,R11L和Z3L可与它们相连的氮原子一起形成5至7元饱和单-杂环,且该杂环可还含有一个选自氧原子、氮原子和硫原子的杂原子,EL为E1L或E2L,E1L为(1)C3-7环烷基或(2)环3L,E2L为(1)C3-7环烷基,(2)环4L或(3)环5L,环1L和环5L任选被1至3个R21L和/或R22L取代,环3L任选被1至2个R21L取代,E2L表示的C3-7环烷基被一个R21L或R22L取代,且该E2L表示的C3-7环烷基任选还进一步被1至2个R21L和/或R22L取代,环4L被一个R22L取代,且该环4L任选还进一步被1至2个R21L和/或R22L取代,由R11L与Z3L以及相连的氮原子一起形成的杂环或者环2L可被R23L取代,R21L为(1)C1-10烷基,(2)C1-10烷氧基,(3)卤素原子,(4)硝基,(5)被1至3个卤素原子取代的C1-10烷基或(6)苯基,R22L为(1)C2-10烯基,(2)C2-10炔基,(3)C1-10烷基硫基,(4)羟基,(5)-NR24LR25L,(6)被C1-10烷氧基取代的C1-10烷基,(7)被C1-10烷氧基取代的C1-10烷基,该C1-10烷氧基被1至3个卤素原子取代,(8)被-NR24LR25L取代的C1-10烷基,(9)环6L,(10)-O-环7L,(11)被环7L取代的C1-10烷基,(12)被环7L取代的C2-10烯基,(13)被环7L取代的C2-10炔基,(14)被环7L取代的C1-10烷氧基,(15)被-O-环7L取代的C1-10烷基,(16)-COOR26L或(17)被1至3个卤素原子取代的C1-10烷氧基,R24L、R25L和R26L各自独立地为(1)氢原子或(2)C1-10烷基,R23L为(1)C1-15烷基,(2)C2-15烯基,(3)C2-15炔基或(4)被C1-10烷氧基、C1-10烷基硫基或C1-10烷基-NR27L-基取代的C1-10烷基,R27L为(1)氢原子或(2)C1-10烷基,环1L、环2L、环5L、环6L和环7L为(1)部分或完全饱和的C3-15单-、二-或三-碳环芳基,或(2)包含1至4个选自氧原子、氮原子和硫原子的杂原子的部分或完全饱和的3至15元单-、二-或三-杂环芳基,环3L和环4L为(1)噻吩基,(2)苯基或(3)呋喃基,环6L和环7L可被1至3个R28L取代,R28L为(1)C1-10烷基,(2)C2-10烯基,(3)C2-10炔基,(4)C1-10烷氧基,(5)被C1-10烷氧基取代的C1-10烷基,(6)卤素原子,(7)羟基,(8)被1至3个卤素原子取代的C1-10烷基或(9)被C1-10烷氧基取代的C1-10烷基,该C1-10烷氧基被1至3个卤素原子取代,
或
通式(IM)表示的化合物、其盐,其N-氧化物或其溶剂合物,或它们的前药或它们的环糊精包合物,
其中R1M为羟基、C1-6烷基氧基或NR6MR7M,其中R6M和R7B各自独立地为氢或C1-4烷基,R2M为氧原子、卤素原子或O-COR8M,其中R8M为C1-4烷基、苯基或苯基(C1-4烷基),R3M为氢原子或羟基,R4aM和R4bM各自独立地为氢原子或C1-4烷基,R5M为被以下取代基取代的苯基:
i)1至3个选自以下的取代基(a)C1-4烷基氧基-C1-4烷基,(b)C2-4烯基氧基-C1-4烷基,(c)C2-4炔基氧基-C1-4烷基,(d)C3-7环烷基氧基-C1-4烷基,(e)C3-7环烷基(C1-4烷基氧基)-C1-4烷基,(f)苯基氧基-C1-4烷基,(g)苯基-C1-4烷基氧基-C1-4烷基,(h)C1-4烷基硫基-C1-4烷基,(i)C2-4烯基硫基-C1-4烷基,(j)C2-4炔基硫基-C1-4烷基,(k)C3-7环烷基硫基-C1-4烷基,(l)C3-7环烷基(C1-4烷基硫基)-C1-4烷基,(m)苯基硫基-C1-4烷基和(n)苯基-C1-4烷基硫基-C1-4烷基,
ii)(a)C1-4烷基氧基-C1-4烷基和C1-4烷基,(b)C1-4烷基氧基-C1-4烷基和C1-4烷基氧基,(c)C1-4烷基氧基-C1-4烷基和羟基,(d)C1-4烷基氧基-C1-4烷基和卤素原子,(e)C1-4烷基硫基-C1-4烷基和C1-4烷基,(f)C1-4烷基硫基-C1-4烷基和C1-4烷基氧基,(g)C1-4烷基硫基-C1-4烷基和羟基或(h)C1-4烷基硫基-C1-4烷基和卤素原子,
iii)(a)卤代烷基或(b)羟基-C1-4烷基,或
iv)C1-4烷基和羟基;
3.根据权利要求1的活化剂,其中所述细胞毒性T细胞的活化是对癌症和/或微生物感染病的免疫增强作用。
4.根据权利要求3的活化剂,其中所述癌症为选自消化系统癌、皮肤癌、呼吸系统癌、泌尿系统癌、肝癌和胰腺癌的一种以上。
5.根据权利要求4的活化剂,其中是皮肤癌为黑素瘤。
6.根据权利要求3的活化剂,其中所述微生物是选自病毒、细菌和真菌的一种以上。
7.根据权利要求1的活化剂,其中EP4激动剂为11α,15α,-二羟基-9-氧代-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲-3,7-二硫前列腺-13E-烯酸,4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸,4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸或4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯。
8.根据权利要求1的活化剂,其中所述活化剂还包含抗原肽。
9.根据权利要求8的活化剂,其中所述抗原肽为黑素瘤特异性抗原肽。
10.一种药物,其给药于除去角质层后的皮肤,增强对癌症的免疫作用并且副作用少,该药物包含4-[(2-{(2R)-2-[(1E,3S)-4-(4-氟苯基)-3-羟基丁-1-烯基]-5-氧代吡咯烷-1-基}乙基)硫基]丁酸、4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸或4-{[2-((1R,2R,3R)-3-羟基-2-{(1E,3S)-3-羟基-4-[3-(甲氧基甲基)苯基]丁-1-烯基}-5-氧代环戊基)乙基]硫基}丁酸甲酯作为有效成分。
11.根据权利要求10的药物,其中所述癌症为黑素瘤。
12.根据权利要求10的药物,其中所述药物还包含抗原肽。
13.根据权利要求12的药物,其中所述抗原肽为黑素瘤特异性抗原肽,且所述癌症为黑素瘤。
14.在哺乳动物中活化细胞毒性T细胞的方法,该包括向哺乳动物给药有效量的EP4激动剂。
15.EP4激动剂在制备细胞毒性T细胞的活化剂中的用途。
16.用于活化细胞毒性T细胞的EP4激动剂。
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JP2007023028A (ja) | 2005-06-16 | 2007-02-01 | Ono Pharmaceut Co Ltd | 内耳疾患治療剤 |
WO2006137472A1 (ja) | 2005-06-24 | 2006-12-28 | Taisho Pharmaceutical Co., Ltd. | プロスタグランジン誘導体 |
EP1912957A4 (en) | 2005-08-03 | 2009-05-13 | Merck Frosst Canada Ltd | EP4 AGONIST RECEIVER, COMPOSITIONS AND METHODS RESULTING THEREFROM |
WO2007014454A1 (en) | 2005-08-03 | 2007-02-08 | Merck Frosst Canada Ltd. | Ep4 receptor agonist, compositions and methods thereof |
UY30121A1 (es) | 2006-02-03 | 2007-08-31 | Glaxo Group Ltd | Nuevos compuestos |
US7705035B2 (en) | 2006-06-12 | 2010-04-27 | Merck Frosst Canada Ltd. | Indoline amide derivatives as EP4 receptor ligands |
GB0615105D0 (en) | 2006-07-28 | 2006-09-06 | Glaxo Group Ltd | Novel compounds |
GB0615111D0 (en) | 2006-07-28 | 2006-09-06 | Glaxo Group Ltd | Novel compounds |
US8183286B2 (en) * | 2006-11-16 | 2012-05-22 | Gemmus Pharma Inc. | EP2 and EP4 agonists as agents for the treatment of influenza a viral infection |
-
2008
- 2008-05-07 WO PCT/JP2008/058464 patent/WO2008136519A1/ja active Application Filing
- 2008-05-07 CA CA 2684922 patent/CA2684922A1/en not_active Abandoned
- 2008-05-07 CN CN200880023882A patent/CN101686985A/zh active Pending
- 2008-05-07 EP EP20080764261 patent/EP2147672A4/en not_active Withdrawn
- 2008-05-07 AU AU2008246579A patent/AU2008246579A1/en not_active Abandoned
- 2008-05-07 MX MX2009012043A patent/MX2009012043A/es not_active Application Discontinuation
- 2008-05-07 US US12/599,194 patent/US8507545B2/en not_active Expired - Fee Related
- 2008-05-07 KR KR1020097023236A patent/KR20100016299A/ko not_active Application Discontinuation
- 2008-05-07 BR BRPI0811306 patent/BRPI0811306A2/pt not_active IP Right Cessation
- 2008-05-07 JP JP2009513028A patent/JP5479092B2/ja not_active Expired - Fee Related
- 2008-05-07 RU RU2009145280/15A patent/RU2009145280A/ru not_active Application Discontinuation
-
2009
- 2009-11-04 IL IL201918A patent/IL201918A0/en unknown
- 2009-11-04 ZA ZA200907760A patent/ZA200907760B/xx unknown
-
2013
- 2013-12-03 JP JP2013250375A patent/JP2014074042A/ja not_active Withdrawn
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103781482A (zh) * | 2011-04-19 | 2014-05-07 | 苏坎波公司 | 用于调节细胞因子活性的方法 |
Also Published As
Publication number | Publication date |
---|---|
WO2008136519A1 (ja) | 2008-11-13 |
US8507545B2 (en) | 2013-08-13 |
JP5479092B2 (ja) | 2014-04-23 |
KR20100016299A (ko) | 2010-02-12 |
ZA200907760B (en) | 2010-07-28 |
US20100216689A1 (en) | 2010-08-26 |
IL201918A0 (en) | 2010-06-16 |
EP2147672A1 (en) | 2010-01-27 |
BRPI0811306A2 (pt) | 2015-01-27 |
RU2009145280A (ru) | 2011-06-20 |
JP2014074042A (ja) | 2014-04-24 |
MX2009012043A (es) | 2010-02-18 |
JPWO2008136519A1 (ja) | 2010-07-29 |
CA2684922A1 (en) | 2008-11-13 |
EP2147672A4 (en) | 2011-11-02 |
AU2008246579A1 (en) | 2008-11-13 |
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