CN102007117B - 作为磷酸二酯酶-4抑制剂的叔胺衍生物 - Google Patents
作为磷酸二酯酶-4抑制剂的叔胺衍生物 Download PDFInfo
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- CN102007117B CN102007117B CN200980113261.1A CN200980113261A CN102007117B CN 102007117 B CN102007117 B CN 102007117B CN 200980113261 A CN200980113261 A CN 200980113261A CN 102007117 B CN102007117 B CN 102007117B
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- methyl
- phenyl
- chloro
- bis
- pyridin
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Abstract
本发明涉及磷酸二酯酶-4(PDE4)酶抑制剂(I)。更具体地,本发明涉及叔胺化合物,制备此类化合物的方法,含有它们的组合物以及其治疗用途。
Description
技术领域
本发明涉及磷酸二酯酶-4(PDE4)酶的抑制剂。更具体地,本发明涉及叔胺衍生物,制备此类化合物的方法,含有它们的组合物以及其治疗用途。
背景技术
环状核苷酸特异性磷酸二酯酶(PDEs)包含一个目前已知有十一个同工酶的家族,该家族催化多种环状单磷酸核苷(包括cAMP和cGMP)的水解。这些环状核苷酸充当细胞内的第二信使,并且作为信使,其传送来自细胞表面受体的脉冲(impulse),该细胞表面受体已经与多种激素和神经递质结合。PDEs通过降解此类环状单核苷酸来调节细胞内环状核苷酸的水平并维持环状核苷酸的稳态,从而造成其信使角色的终止。
可以根据同工酶对cAMP或cGMP水解的特异性,对钙、钙调蛋白或cGMP调节的敏感性,以及其被多种化合物的选择性抑制将同工酶分组。
PDE4是cAMP特异性的,其抑制引起气道舒张、抗炎,认知增强以及抗抑郁活性。
因此PDE4同工酶抑制剂是可用于治疗涉及炎症的疾病,例如哮喘或关节炎,或中枢神经疾病,例如认知减退或记忆丧失的治疗剂。
已知有多种PDE4抑制剂的化学分类。
特别地,WO2005/061458和WO2006/135828中已经公开了属于叔胺类的PDE4抑制剂。
然而,通常已知具有IC50值高于1000nM的化合物的治疗活性可能不令人满意。
因此,已知的PDE4抑制剂,特别是属于叔胺类的PDE4抑制剂的活性仍然需要改进。
因此本发明的一个目的是提供属于叔胺类的,具有较已知PDE4抑制剂具有改善活性的化合物。
发明内容
本发明涉及充当磷酸二酯酶4(PDE4)酶抑制剂的化合物,制备此类化合物的方法,含有它们的组合物以及其治疗用途。
特别地,本发明涉及具有通式(I)的叔胺衍生物
其中:
n=1或2,优选为1;
R1和R2不同或者相同,并且独立地选自下列组成的组:
-C1-C4烷氧基;
-C3-C7环烷氧基;和
-(C3-C7)环烷基-(C1-C3)烷氧基;
并且其中R1和R2的至少一个是C1-C4烷氧基;
A是芳基或杂芳基环系,具有5到10个环原子,其中至少一个环原子是杂原子(例如N,S或O),且其任选被一个或多个独立地选自下列组成的组的取代基取代:
-任选被一个或多个C3-C7环烷基取代的C1-C6烷基;
-任选被一个或多个C3-C7环烷基取代的C2-C6烯基;
-任选被一个或多个C3-C7环烷基取代的C2-C6炔基;
-C3-C7环烷基;
-C5-C7环烯基;
-C3-C7环烷氧基,
其中所述基团中的一个或多个氢原子可以被卤素原子代替;
-OR3,其中R3选自下列组成的组:
-H;
-任选被一个或多个C3-C7环烷基取代的C1-C6烷基;
-C3-C7环烷基;
其中所述基团中的一个或多个氢原子可以被卤素原子代替;
-苯基;
-苄基;和
-NR4R5-C1-C4烷基,其中R4和R5各自独立地为H或C1-C6烷基或它们与其连接的氮原子共同形成饱和的或部分饱和的环,优选为哌啶环;
-卤素原子;
-CN;
-NO2;
-NR6R7,其中R6和R7不同或相同,并且独立地选自下列组成的组:
-H;
-任选被苯基取代的C1-C6烷基;
-C1-C4烷基磺酰基;
-COC6H5;和
-COC1-C4烷基;
或它们与其连接的氮原子共同形成饱和的或部分饱和的环,优选为哌啶环;
-COR8,其中R8是OH,NH2,苯基或C1-C6烷基;
-氧代;
-HNSO2R9,其中R9是C1-C4烷基或苯基,其任选被卤素原子或C1-C4烷基取代;
-SO2R10,其中R10是C1-C4烷基,OH或NR6R7,其中R6和R7如上定义;
-SOR11,其中R11是苯基或C1-C4烷基;
-SR12,其中R12是H,苯基或C1-C4烷基;
-COOR13,其中R13是H,C1-C4烷基,苯基,苄基和
-(CH2)qOR14,其中q=1、2、3或4,且R14是H,C1-C4烷基或C1-C4环烷基;
及其药学上可接受的盐。
本发明还提供通式(I)化合物单独或与一种或多种药学上可接受的载体组合的组合物。
更进一步地,本发明提供通式(I)化合物在制备用于预防和/或治疗任何其中需要PDE4抑制的疾病的药物中的用途。
本发明还提供通式(I)化合物制备药物的用途。
更近一步地,本发明提供通式(I)化合物在制备用于预防和/或治疗炎性疾病、障碍或病症的药物中的用途,所述炎性疾病、障碍或病症以不期望的炎性免疫反应为特征或与不期望的炎性免疫反应有关,或由TNF-α和PDE4过度分泌诱导或与TNF-α和PDE4过度有关。
本发明还提供用于治疗神经和精神障碍(psychiatric disorder),例如阿尔茨海默病、多发性硬化症、肌萎缩性侧索硬化症(ALS)、多系统萎缩(MSA)、精神分裂症、帕金森病、亨廷顿氏病、皮克病、抑郁、中风、以及脊髓损伤的化合物。
此外本发明提供预防和/或治疗炎性疾病、障碍或病症的方法,包括给予有此需要的患者治疗有效量的通式(I)化合物,所述炎性疾病、障碍或病症以不期望的炎性免疫反应为特征或与不期望的炎性免疫反应有关,或由TNF-α和PDE4过度分泌诱导或与TNF-α和PDE4过度分泌有关。
定义
本文中使用的术语“卤素原子”包括氟、氯、溴、碘,优选氯。
本文中使用的表述“线性(linear)或分支(branched)C1-Cx烷基”,其中x是大于1的整数,是指直链或支链烷基基团,其中碳原子数目在1到x的范围内。特别优选的烷基基团是甲基、乙基、正-丙基、异丙基 或叔-丁基。
任选地所述基团中的一个或多个氢原子可以被卤素原子,优选氯或氟代替。
衍生的表述“C2-C6烯基”和“C2-C6炔基”以类似的方式解释。
本文中使用的表述“C3-Cx环烷基”,其中x是大于3的整数,是指含有3到x个环碳原子的非芳香族环烃基团。例子包括环丙基、环丁基、环戊基、环己基和环庚基。
任选地所述基团中的一个或多个氢原子可以被卤素原子,优选氯或氟代替。
衍生的表述“C5-Cx环烯基”,其中x是大于5的整数,以类似的方式解释。
本文中使用的表述“环系”是指可以为饱和、部分不饱和、或不饱和的单或双环系,例如芳基、C3-C8环烷基或具有5到10个环原子且其中至少一个环原子是杂原子(例如N,S或O)的杂芳基。
适合的单环系的例子包括噻吩、苯基和呋喃。适合的双环系的例子包括萘基和苯并噻吩。
发明详述
本发明涉及叔胺衍生物,其中取代基是被两个烷氧基基团、一个芳基甲基基团和一个吡啶基甲基基团取代的芳环。
更特别地,本发明涉及具有通式(I)的叔胺衍生物
药学上可接受的盐包括通过将化合物与无机或有机酸反应以形成盐来获得那些,例如盐酸盐、硫酸盐、磷酸盐、甲磺酸盐、樟脑磺酸盐、草酸盐、马来酸盐、琥珀酸盐和枸橼酸盐。
药学上可接受的盐还包括其中当存在酸性官能团(acidic function)时,其与适当的碱反应形成的那些,例如钠盐、钾盐、钙盐、镁盐、铵盐和盐酸盐。
已发现当A中的苯基被环烷基部分代替时,特别是在细胞测定中活性降低。
此外,对筛选结果的分析显示,A区域中苯环上的氢键供体或受体取代基似乎是优选的,事实上它们使化合物在无细胞的测定(cell-freeassay)中显示出改善的抑制活性。
还已在IC50 PBMCs测定中发现其中A直接与氨基氮连接的化合物显示出高于1000nM的活性。
在一个优选的实施方式中,R1和R2是C1-C4烷氧基。
在本发明的一个特别的实施方式中,A是杂芳基环,其选自由呋喃或苯并噻吩组成的组。
在本发明的另一个特别的实施方式中,A是萘基。
在本发明的一个优选的实施方式中,A是苯基。
在本发明的一个优选的实施方式中,环系A的任选取代基Rx选自下列组成的组:C1-C6烷基、卤素原子,优选氟;SO2R10,其中R10是C1-C4烷基,优选甲基或NH2;CN;OH;COR8,其中R8是优选OH;HNSO2R9,其中R9是C1-C4烷基,优选甲基。
在本发明的一个优选的实施方式中,Rx是选自由OR3组成的组的氢键供体或受体取代基,其中R3是C1-C6烷基,优选甲基或NR6R7。
根据一个优选的实施方式,本发明提供下列化合物:
化合物 | 化学名 |
C1 | (3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(4-氟-苄基)-胺 |
C2 | 3-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苄腈 |
C3 | (3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(3-甲氧基-苄基)-胺 |
C4 | (3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(4-甲磺酰工基-苄基)-胺 |
C5 | 苄基-(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-胺 |
C6 | (3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-苯乙基-胺 |
C7 | (3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苄基)-(3,4-二甲氧基-苯基)-胺 |
C8 | (3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(3-氟-4-甲氧基-苄基)-胺 |
C9 | (3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-呋喃-2-基甲基-胺 |
C10 | 4-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯磺酰胺 |
C11 | 4-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯甲酸甲酯 |
C12 | N-(3-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯基)-甲磺酰胺 |
C13 | (3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(4-甲氧基-苄基)-胺 |
C14 | (3,5-二氯-吡啶-4-基甲基)-(3-乙氧基-4-甲氧基-苯基)-(4-甲氧基-苄基)-胺 |
C15 | (3,5-二氯-吡啶-4-基甲基)-(3-异丙氧基-4-甲氧基-苯基)-(4-甲氧基-苄基)-胺 |
C16 | 4-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯甲酸 |
C17 | (3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-噻吩-2-基甲基-胺 |
C18 | 苯并[b]噻吩-2-基甲基-(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-胺 |
C19 | 3-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯酚(phenol) |
可以用传统方法制备通式(I)的化合物。可以使用的方法的实施例在下面描述并在方案中报道。
方案
如上述方案中报道的,按照包括下述步骤的方法制备通式(I)的化合物,其中制备式(A)的胺的操作是熟知的:
第1步:用适当的醛(PhCl2)-CHO进行还原氨化对式(A)的胺进行官能化(functionalization),生成通式(B)的仲胺。
例如可以用分子筛在甲苯中形成亚胺中间体进行反应,之后将溶剂 蒸发,在乙醇中用硼氢化钠(NaBH4)对亚胺衍生物进行后续还原。
第2步:通过还原氨化或使用初级(primary)烷化剂烷化对通式(B)的仲胺进一步官能化,生成通式(C)的最终化合物。
本发明还提供与一种或多种药学上可接受的载体混合的通式(I)化合物的组合物,所述载体例如在Remington′s Pharmaceutical Sciences Handbook,XVII Ed.,Mack Pub.,N.Y.,U.S.A.中描述的那些。
可以根据患者的需要完成本发明化合物的给药,例如经口、鼻腔、胃肠外(皮下、静脉内、肌内、胸骨内以及通过输注)、通过吸入、直肠、阴道、表面(topically)、局部、经皮、以及经眼给药。可以使用多种固体口服剂型给予本发明的化合物,包括片剂、软胶囊、胶囊、小胶囊、颗粒剂、锭剂和整装粉剂。可以单独给予本发明的化合物或与多种药学上可接受的载体,稀释剂(例如蔗糖、甘露醇、乳糖、淀粉)和已知赋形剂组合给予,所述赋形剂包括但不限于助悬剂、增溶剂、缓冲剂、粘合剂、崩解剂、防腐剂、着色剂、调味剂、润滑剂等等。延时释放(time release)胶囊、片剂和凝胶剂也是有利的。
可以使用多种液体口服剂型给予本发明的化合物,包括含水溶液和不含水溶液、乳剂、悬浮剂、糖浆剂和酏剂。此类剂型还可以含有本领域已知的适当的惰性稀释剂,例如水,以及本领域已知的适当的赋形剂,例如防腐剂、润湿剂、甜味剂、调味剂、以及用于乳化和/或悬浮本发明化合物的介质(agent)。本发明的化合物可以注射,例如以等渗无菌溶液的形式静脉内注射。其它制剂也是可以的。
可以通过将化合物与适当的赋形剂,例如可可脂、水杨酸酯(salicylate)和聚乙二醇混合制备用于本发明化合物直肠给药的栓剂。
用于阴道给药的剂型可以为乳膏剂、凝胶剂、糊剂、泡沫剂、或喷雾剂的形式,其除活性成分之外含有适当的已知载体。
用于局部给药时,药物组合物可以为适于皮肤、眼、耳或鼻给药的乳膏剂、软膏剂、搽剂、洗剂、乳剂、悬浮剂、凝胶剂、溶液剂、糊剂、粉剂、喷雾剂、以及滴剂的形式。局部给药还可以包括经由例如透皮贴剂的方式透皮给药。
本发明化合物的剂量取决于多种因素,包括待治疗的特定疾病、症状的严重程度、给药途径、给药间隔频率、使用的特定化合物、以及化合物的效力、毒理学特征、药物代谢动力学特征。
有利地,通式(I)的化合物可以以例如0.001-1000mg/天,优选0.1-500mg/天的剂量给药。
可以给予通式(I)的化合物用于预防和/或治疗任何其中需要PDE4抑制的疾病。所述疾病包括:涉及炎症的疾病,例如哮喘和COPD,变应性疾病状态,例如特应性皮炎、荨麻疹、变应性鼻炎、变应性结膜炎、春季结膜炎、嗜酸细胞肉芽肿、银屑病、炎性关节炎、类风湿性关节炎、脓毒性休克、溃疡性结肠炎、克罗恩病、心肌和脑再灌注损伤、慢性肾小球性肾炎、内毒素性休克、囊性纤维化、动脉再狭窄、动脉粥样硬化、角化病、类风湿性脊椎炎、骨关节炎、发热(pyresis)、糖尿病、尘肺、中毒和过敏性接触性湿疹、特应性湿疹、脂溢性湿疹、单纯性苔癣、晒伤、肛门生殖器区域瘙痒、斑秃、肥大性瘢痕、盘状红斑狼疮、系统性红斑狼疮、滤泡性和广泛性脓皮病(follicular and wide-area pyodermias)、内源性或外源性痤疮、红斑痤疮、Beghet’s病,过敏性紫癜肾炎(anaphylactoid purpura nephritis)、炎性肠病、白血病、多发性硬化、胃肠疾病、自身免疫病等等。
它们还包括神经和精神障碍,例如阿尔茨海默病,多发性硬化、肌萎缩性侧索硬化症(ALS)、多发性系统萎缩(MSA)、精神分裂症、帕金森病、亨廷顿氏病、皮克病、抑郁、中风、以及脊髓损伤。
将通过下述实施例进一步描述本发明。
实施例1
制备中间体(A)(方案)
制备(3-乙氧基-4-甲氧基-苯基)-胺(A2)
步骤1:制备2-乙氧基-1-甲氧基-4-硝基-苯
在氮气氛下将2-甲氧基-5-硝基-苯酚(508mg,3毫摩尔)溶解于DMF(20mL)。加入K2CO3(900mg,6.5毫摩尔),KI(490mg,2.95mmol)和溴乙烷(0.250mL,3.3毫摩尔),将悬浮液加热至40℃,保持28小 时。用AcOEt(60mL)稀释混合物,以1N NaOH(40mL)和水(40mL)提取。用Na2SO4干燥有机层,蒸发至干。不经纯化将粗制物(crude)用于下一步骤。
步骤2:制备3-乙氧基-4-甲氧基-苯胺
将第1步中得到的粗制物溶解在乙醇中(99%,20mL)。加入Pd/C(10%,60mg)和甲酸铵(1.71g),将所得混合物于室温搅拌1h。过滤除去催化剂,减压蒸发溶剂。通过快速色谱(SiO2,石油醚/AcOEt,从7/3到5/5)纯化粗制物。得到325mg量的标题化合物。用适当的试剂应用同样的操作合成(A2)(3-异丙氧基-4-甲氧基-苯基)-胺。
表1
实施例2
制备中间体(B)(方案)
制备(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-胺(B1)
在氮气氛下将市售的3,4-二甲氧基-苯基-胺(1.74g,11.3毫摩尔)和3,5-二氯-吡啶-4-羧醛(2.0g,11.3毫摩尔)溶解于甲苯(40mL)中。加入分子筛(4A,1g),将混合物加热至回流。用TLC分析(石油醚/AcOEt 7/3)进行反应监控:3小时后完成亚胺中间体的形成。通过过滤除去分子筛,蒸发溶剂。将残渣溶解于乙醇(99%,40mL)中。溶液冷却至0℃,加入NaBH4(559mg,14.7mmol)。将得到的混合物于室温搅拌18小时,然后加水(50mL),以AcOEt(3×60mL)提取混合物。用盐水洗涤有机层,用Na2SO4干燥,蒸发至干。用快速色谱(SiO2,石油醚/AcOEt,从9/1到7/3)纯化粗制物。得到黄色固体状的标题化合物(3.04g)。
按照同样合成操作使用适当的试剂制备下述化合物:
表2
实施例3
制备化合物(C)(方案)
制备(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(4-氟-苄基)-胺(C1)
将中间体B1(480mg,1.5毫摩尔)溶解于CH3CN中(7.5mL)。加入固体K2CO3(518mg,3.75毫摩尔),固体KI(250mg,1.5毫摩尔)和净(neat)4-氟-苄基-溴(bromide)(0.191mL,1.5毫摩尔),将混合物在密封的小瓶中于微波炉内120℃加热30+30分钟。用水(40mL)稀释反应混合物,用AcOEt提取(3×40mL)。用盐水洗涤有机层,用Na2SO4干燥,蒸发至干。用快速色谱(SiO2,石油醚/AcOEt,从9/1到7/3)纯化粗制物。得到407mg量的淡黄色固体状的标题化合物。
用中间体B1或B2、B3、B4和适当的烷化剂以同样的操作制备下表3中列出的和报道的最终化合物。
用适当的试剂以同样的合成操作制备下述化合物:
表3
用于合成上面列出的最终化合物而所采用的下述烷化剂(见表4)并非市售,并且按照下述的实施例4、5、6合成。
表4
实施例4
制备烷化剂(K)(方案)
制备4-溴甲基-苯-磺酰胺(K1)
步骤1:4-羟甲基-苯-磺酰胺
在氮气氛下将LiAlH4(235mg,6.2毫摩尔)悬浮在干燥的THF(10mL)中。将悬浮液冷却至0℃,加入4-氨磺酰基-苯甲酸(500mg,2.48毫摩尔,在10mL干THF中的悬浮液)。将得到的混合物回流18小时。于0℃通过加入3N HCl淬灭反应。用AcOEt提取淬灭的混合物,用Na2SO4干燥有机层,蒸发至干。用快速色谱(SiO2,石油醚/AcOEt,从9/1到1/1)纯化粗制物,得到105mg量的标题化合物。
步骤2:4-溴甲基-苯-磺酰胺
将4-羟甲基-苯-磺酰胺(0.105mg,0.56毫摩尔)溶解于DCM(5mL)中。加入聚合物负载(supported)三苯基膦(294mg,2.4毫摩尔/g,1.12毫摩尔),混合物用振荡器于室温搅拌10分钟。然后加入CBr4(557mg,1.68毫摩尔),持续搅拌3小时。通过过滤除去负载试剂,蒸发溶剂,用快速色谱(SiO2,石油醚/AcOEt,9/1)纯化粗制物,得到淡黄色固体状的标题化合物(70mg)。
从相应的市售醇衍生物开始,按照实施例4中步骤2合成烷化剂K3和K4。
实施例5
制备甲磺酸呋喃2-基甲基酯(K2)
将呋喃-2-基-甲醇(0.477mL,5.5毫摩尔)溶解在干燥的DCM(10mL)中。将溶液冷却至0℃,逐滴加入三乙胺(1.16mL,8.25毫摩尔)和甲磺酰氯(0.554mL,7.15毫摩尔)。得到的混合物室温搅拌3小时。通过过滤除去悬浮物(盐酸三乙胺),将滤液蒸发至干,不经纯化在下一步中使用粗制物。
步骤2:4-溴甲基-3,5-二氯-吡啶
将(3,5-二氯-吡啶-4-基)-甲醇(918mg,5.15毫摩尔)溶解在干燥的DCM(25mL)中。加入三苯基膦(2.70g,10.3毫摩尔)将混合物于室温搅拌10分钟。然后将溶液冷却至0℃,加入CBr4(5.12g,15.4 毫摩尔)。将混合物于室温搅拌30分钟,然后蒸发溶剂,用快速色谱(SiO2,石油醚/AcOEt,95/5)纯化粗制物,得到850mg标题化合物。
实施例6
制备N-(3-氯甲基-苯基)-甲烷-磺酰胺(K5)
步骤1:(3-氨基-苯基)-甲醇
在氮气氛下将3-氨基苯甲酸(1.05g,7.65毫摩尔)溶解在THF中(30mL)。加入硼烷(在THF中的1M BH3溶液,24mL,24毫摩尔),将得到的溶液室温搅拌20小时。然后将反应混合物倒入饱和NH4Cl溶液(100mL)中,用AcOEt提取(3×100mL)。用Na2SO4干燥有机层,蒸发至干,得到388mg标题化合物,其不经进一步纯化在下一步中使用。
步骤2:N-(3-氯甲基-苯基)-甲烷-磺酰胺
将(3-氨基-苯基)-甲醇(388mg,3.15毫摩尔),氯化锂(270mg,6.3毫摩尔)和2,6-二甲基吡啶(0.821mL,6.93毫摩尔)在DMF中的溶液(10mL)在氮气氛下冷却至0℃。逐滴加入甲磺酰氯(0.536mL,6.93毫摩尔),将混合物于室温搅拌3小时。然后加入水(30mL),用AcOEt(3×40mL)提取混合物。用盐水洗涤有机层,用Na2SO4干燥,蒸发至干。用快速色谱(SiO2,石油醚/AcOEt,从10/0到8/2)纯化粗制物,得到330mg标题化合物。
实施例7
4-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯甲酸(C16)
将化合物C11(350mg,0.75mmol)溶解在MeOH(14mL)中。加入1N KOH(3mL,3毫摩尔),将混合物回流1小时。蒸发溶剂,将残渣溶解在水(15mL)中,用3N HCl处理至pH=1。用AcOEt(3×40mL)提取溶液,用Na2SO4干燥有机层,蒸发至干。用快速色谱(SiO2,AcOEt/石油醚,从1/1到1/0)纯化粗制物,得到230mg量的标题化合物。
表5
实施例8
制备最终化合物(C)(方案)
合成(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-噻吩-3-基甲基-胺
将中间体B1(200mg,0.64毫摩尔)溶解在MeOH(10mL)中。加入分子筛(4A,200mg),然后加入噻吩-3-羧醛(0.056mL,0.64毫摩尔)。将混合物于室温搅拌2小时,然后加入NaBH3CN(121mg,1.9毫摩尔)。逐滴加入AcOH至pH=5。48小时后通过过滤除去分子筛,加入水(20mL)。用AcOEt(3×50mL)提取混合物,用盐水洗涤有机层,用Na2SO4干燥,蒸发至干。用快速色谱(SiO2,石油醚/AcOEt,从9/1到7/3)纯化粗制物,得到173mg量的标题化合物。
使用中间体B1和适当的醛,适当的试剂按照同样的合成操作制备化合物C17、C18和C19:
表6
图例
*NMR
s=单峰
d=二重峰
t=三重峰
q=四重峰
dd=双二重峰
m=多重峰
br=宽的
ESI=电喷雾
药理学活性
实施例9
在无细胞测定中体外测定PDE4抑制活性
用U937人单核细胞系作为PDE4酶的来源。基本上按照Torphy TJet al J.Pharmacol.Exp.Ther.1992;263:1195-1205的描述培养并收集细胞,制备上清液。
通过测定孵育混合物中cAMP的消失测定细胞上清液中的PDE4活性。将50μl细胞上清液于30℃孵育30分钟,终体积为200μl,含有1.6μMcAMP,其含有或不含有受试化合物(50μl)。
受试化合物的浓度范围为10-12M-10-6M。通过热灭活(100℃,2.5分钟)停止反应,用基于电化学发光的免疫测定法测定残留的cAMP。
结果以产生cAMP消失的50%抑制的受试化合物摩尔浓度(IC50)的平均值±95%置信限表示。对化合物C1-C14进行了实验,其在无细胞测定中的IC50值被证明是在27到807nM之间。
假定在不存在抑制剂时cAMP的消失为100%,而在热灭活的样品中cAMP的消失为0%,来计算PDE4活性的抑制百分比。
本发明代表性的受试化合物的所有IC50值均低于0.2μM。
实施例10
在外周血单核细胞(PBMCs)测定中体外测定PDE4抑制活性
基于PDE4抑制剂对脂多糖(LPS)诱导的肿瘤坏死因子α(TNF-α外周血单核细胞(PBMCs)中释放)所产生的已知抑制活性,按照Hatzelmann A et al J.Pharmacol.Exp.Ther.2001;297:267-279和通过Draheim R et al J.Pharmacol.Exp.Ther.2004;308:555-563描述的方法进行测定。
将冷藏保存的人PBMCs(100μl/孔)于96孔板中孵育30min(105细胞/孔),其中存在或不存在受试化合物(50μl),所述受试化合物的浓度范围为10-12M到10-6M。然后加入LPS(3ng/ml)。
在潮湿的含95%空气和5%CO2的气氛的孵箱中在37℃孵育18h后收集培养基,用ELISA测定TNF-α。
结果以产生LPS诱导的TNF-α释放的50%抑制的受试化合物摩尔浓度(IC50)的平均值±95%置信限表示。
假定在不存在抑制剂化合物时LPS诱导的TNF-α生成为100%,在不存在LPS时PBMCs中的基础TNF-α生成为0%,从而将受试化合物的作用计算为TNF-α的抑制百分比。
比较实施例
在WO2005/061458和WO2006/135828的教导下,我们已经合成了分别相应于本发明的化合物1的比较分子,其区别仅在于在氨基氮和芳基部分之间缺少亚甲基桥,以及类似于化合物5的比较分子,其区别在于在氨基氮和芳基部分之间缺少亚甲基桥,其是环丙基甲基部分。
两个化合物的IC50 PBMCs值都高于1000nM。
Claims (11)
1.通式(I)的化合物
其中:
n=1或2;
R1和R2不同或者相同,并且独立地选自:
-C1-C4烷氧基;
A是芳基或杂芳基环系,具有5到10个环原子,其中在所述杂芳基环系中的至少一个环原子是选自N,S或O的杂原子,且所述芳基或杂芳基环系任选被一个或多个独立地选自下列组成的组的取代基取代:
-OR3,其中R3选自:-C1-C6烷基;
-卤素原子;
-CN;
-NO2;
-C1-C4烷基磺酰基;
-COR8,其中R8是OH或C1-C6烷基;
-HNSO2R9,其中R9是C1-C4烷基;
-SO2R10,其中R10是NR6R7,其中R6和R7是H;
-COOR13,其中R13是H或C1-C4烷基;
及其药学上可接受的盐。
2.权利要求1的化合物,其中A是任选取代的苯基。
3.权利要求1的化合物,其中A是任选取代的杂芳基环,其选自由呋喃或苯并噻吩组成的组。
4.权利要求1的化合物,选自:
(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(4-氟-苄基)-胺;
3-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苄腈;
(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(3-甲氧基-苄基)-胺;
(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(4-甲磺酰基-苄基)-胺;
苄基-(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-胺;
(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-苯乙基-胺;
(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苄基)-(3,4-二甲氧基-苯基)-胺;
(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(3-氟-4-甲氧基-苄基)-胺;
(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-呋喃-2-基甲基-胺;
4-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯磺酰胺;
4-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯甲酸甲酯;
N-(3-{[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯基)-甲磺酰胺;
(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(4-甲氧基-苄基)-胺;
(3,5-二氯-吡啶-4-基甲基)-(3-乙氧基-4-甲氧基-苯基)-(4-甲氧基-苄基)-胺;
(3,5-二氯-吡啶-4-基甲基)-(3-异丙氧基-4-甲氧基-苯基)-(4-甲氧基-苄基)-胺;
44[(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-氨基]-甲基}-苯甲酸;
(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-噻吩-2-基甲基-胺;
苯并[b]噻吩-2-基甲基-(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-胺。
5.权利要求4的化合物,其为(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(4-氟-苄基)-胺。
6.权利要求4的化合物,其为(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-呋喃-2-基甲基-胺。
7.权利要求4的化合物,其为(3,5-二氯-吡啶-4-基甲基)-(3,4-二甲氧基-苯基)-(4-甲氧基-苄基)-胺。
8.药物组合物,含有与一种或多种药学上可接受的载体和/或赋形剂混合的前述权利要求任一项的化合物。
9.权利要求1到7的任一项的化合物在制备用于预防和/或治疗炎性疾病、障碍或病症的药物中的用途,所述炎性疾病、障碍或病症以不期望的炎性免疫反应为特征或与不期望的炎性免疫反应有关,或由TNF-α和PDE4过度分泌诱导。
10.权利要求1到7的任一项的化合物在制备用于预防和/或治疗炎性疾病、障碍或病症的药物中的用途,所述炎性疾病、障碍或病症与TNF-α和PDE4过度分泌有关。
11.权利要求1到7的任一项的化合物在制备用于治疗神经和精神障碍的药物中的用途,所述神经和精神障碍选自阿尔茨海默病、多发性硬化症、肌萎缩性侧索硬化症、多系统萎缩、精神分裂症、帕金森病、亨廷顿氏病、皮克病、抑郁、中风、以及脊髓损伤。
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PCT/EP2009/002242 WO2009127320A1 (en) | 2008-04-14 | 2009-03-27 | Tertiary amine derivatives as phosphodiesterase-4 inhibitors |
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EP2216327A1 (en) | 2009-02-06 | 2010-08-11 | CHIESI FARMACEUTICI S.p.A. | Benzoic acid (1-phenyl-2-pyridin-4-yl)ethyl esters as phosphodiesterase inhibitors |
RU2578975C2 (ru) | 2010-08-03 | 2016-03-27 | КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. | Фармацевтический препарат, содержащий ингибитор фосфодиэстеразы |
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CN104822671B (zh) | 2012-12-05 | 2017-10-31 | 奇斯药制品公司 | 作为pde4抑制剂的苯乙基吡啶衍生物 |
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US9427376B2 (en) | 2013-10-10 | 2016-08-30 | Chiesi Farmaceutici S.P.A. | Process for preparing pharmaceutical formulations for inhalation comprising a high-dosage strength active ingredient |
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HK1155450A1 (zh) | 2012-05-18 |
EA201001481A1 (ru) | 2011-06-30 |
CA2721240A1 (en) | 2009-10-22 |
AU2009238014B2 (en) | 2013-07-18 |
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US7820698B2 (en) | 2010-10-26 |
EP2110375A1 (en) | 2009-10-21 |
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