CN101796028B - 1-苯基-2-吡啶基烷醇的衍生物作为磷酸二酯酶抑制剂 - Google Patents
1-苯基-2-吡啶基烷醇的衍生物作为磷酸二酯酶抑制剂 Download PDFInfo
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- CN101796028B CN101796028B CN2008801023963A CN200880102396A CN101796028B CN 101796028 B CN101796028 B CN 101796028B CN 2008801023963 A CN2008801023963 A CN 2008801023963A CN 200880102396 A CN200880102396 A CN 200880102396A CN 101796028 B CN101796028 B CN 101796028B
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Classifications
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明涉及磷酸二酯酶4(PDE4)酶的抑制剂。更特别地,本发明涉及1-苯基-2-吡啶基烷醇衍生物化合物,这一化合物的制备方法,和包含它们的组合物及其治疗用途。
Description
发明领域
本发明涉及磷酸二酯酶4(PDE4)的酶抑制剂。更特别地,本发明涉及1-苯基-2-吡啶基烷醇衍生物的化合物,这种化合物的制备方法,包含它们的组合物及其治疗用途。
发明背景
气道阻塞表征了许多严重的呼吸疾病,其中包括哮喘和慢性阻塞性肺病(COPD)。导致气道阻塞的事件包括气道壁的水肿、增加的粘液产生和炎症。
目前通过吸入给药治疗呼吸疾病,例如哮喘和COPD的药物。与全身路径相比,吸入路径的优点之一是在作用位点处直接传输药物,避免了任何全身的副作用,从而导致更加快速的临床应答和更高的治疗比。
吸入的皮质甾类是当前哮喘以及急性症状缓解用支气管扩张药β 2-激动剂的维持治疗选择,它们形成了该疾病当前治疗的主流。当前COPD的治疗主要通过支气管扩张疗法,采用吸入的抗胆碱能药和吸入的β2-肾上腺素能受体激动剂进行对症治疗。然而,皮质甾类没有降低COPD的炎性应答,而它们在哮喘中产生炎性应答。
鉴于在治疗炎性呼吸疾病,例如哮喘和COPD中的消炎效果而被广泛研究的另一组治疗剂以磷酸二酯酶(PDEs),尤其磷酸二酯酶4型(下文称为PDE4)的酶抑制剂为代表。
现有技术中公开了充当PDE 4抑制剂的各种化合物。然而,第一代的数种PDE4抑制剂,例如环戊苯吡酮和吡拉米司特的有效性因其非所需的副作用导致受到局限。所述副作用包括因在中枢神经系统中在PDE4上的作用导致的恶心和呕吐以及由于在肠道内的肠壁细胞中在 PDE4上的作用导致的胃酸分泌。
人们广泛研究了所述副作用的原因。
已发现,PDE4以代表不同构型的两种不同的形式存在,它们表示为高亲和力的环戊苯吡酮结合位点或HPDE4,特别地存在于中枢神经系统和肠壁细胞内,和在免疫与炎性细胞中发现的低亲和力的环戊苯吡酮结合位点或LPDE4(Jacobitz,S等人Mol.Pharmacol,1996,50,891-899)。尽管这两种形式显示出催化活性,但它们对抑制剂的灵敏度不同。特别地,对LPDE4具有较高亲和力的化合物不那么容易诱导副作用,例如恶心、呕吐和增加的胃酸分泌。
靶向LPDE4的努力导致第二代PDE4抑制剂,例如西洛司特和罗氟司特的选择性的稍微改进。然而,即使这些化合物也没有提供对LDPE4良好的选择性。
现有技术中公开了充当PDE4抑制剂的其他组化合物。
例如,EP 1634606尤其公开了酮衍生物,例如苯并呋喃或1,3-苯并二噁唑衍生物。
WO 9402465尤其公开了下述通式的酮衍生物:
其中R1是低级烷基,和R2可以是烷基、链烯基、环烷基、环烷基、环烯基、环硫代烷基或环硫代烯基。
以Celltech Therapeutics名义申请的WO 9535281涉及三取代的苯基衍生物。
这两个申请均没有涉及与抑制HPDE4有关的副作用问题且没有报道关于对HPDE4和LPDE4的亲和性的数据。
因此,尽管迄今为止公开了数种PDE4抑制剂,但仍需要更加有效和更加耐受性的化合物。
特别地,高度有利的是提供例如相对于对HPDE4的亲和性,对 LPDE4赋予更高的亲和性的选择性更大的化合物,以便减弱或避免与其抑制有关的副作用。
本发明通过提供对LPDE4具有改进的选择性的PDE4抑制剂,解决了这些问题。
事实上,已发现,通过提供与PDE4的活性位点具有相互作用的额外部分的PDE抑制剂,将改进抑制剂对LPDE4的选择性。
本发明的PDE4抑制剂当吸入施用时将有效地起作用,且特征可在于在肺内具有良好的持久性和短的全身持续时间。
发明概述
本发明涉及作为磷酸二酯酶4(PDE4)的酶抑制剂的化合物,制备所述化合物的方法,包含它们的组合物及其治疗用途。
特别地,本发明涉及通式(I)的1-苯基-2-吡啶基烷醇衍生物:
其中:
Z选自:
(CH2)m,其中m=0、1或2;
(CH2)nO,其中n=1、2或3;
O(CH2)p,其中p=0、1、2或3;
CH2SO2;
CH2NR6;
NR6,其中R6是H或直链或支链的(C1-C4)烷基;和
OCOR4R5;和
CR4R5,其中
R4独立地选自H或直链或支链(C1-C4)烷基,优选甲基,其任选地被(C1-C4)环烷基取代,和
R5独立地选自:
-直链或支链(C1-C4)烷基,优选甲基;
-苯基;
-苄基;
-NH2;和
-HNCOOR′,其中R′是直链或支链(C1-C4)烷基,优选叔丁基。
R1和R2相同或不同且独立地选自:
-H;
-直链或支链(C1-C6)烷基,其任选地被选自(C3-C7)环烷基或(C5-C7)环烯基中的一个或更多个取代基取代;
-(C3-C7)环烷基;
-(C5-C7)环烯基;
-直链或支链(C2-C6)链烯基;和
-直链或支链(C2-C6)炔基。
R3是独立地选自H,CN,NO2,CF3和卤素原子中的一个或更多个取代基。
A是环体系,亦即单环或双环,所述环可以饱和、部分不饱和或不饱和,例如是芳基、(C3-C8)环烷基或杂芳基,所述环体系A具有5-10个环原子,其中至少一个环原子是杂原子(例如,N,S或O),其中在A环体系上的任选取代基Rx可以是一个或更多个,可以相同或不同,且独立地选自下述:
-被一个或更多个(C3-C7)环烷基任选取代的直链或支链(C1-C6)烷基;
-被一个或更多个(C3-C7)环烷基任选取代的直链或支链(C2-C6)链烯基;
-被一个或更多个(C3-C7)环烷基任选取代的直链或支链(C2-C6) 炔基;
-(C5-C7)环烯基;
-苯基;
-(C3-C7)杂环烷基;
-OR7,其中R7选自下述:
-H;
-被一个或更多个(C3-C7)环烷基任选取代的(C1-C10)烷基;
-(C3-C7)环烷基;
-(C1-C4)烷基-(C3-C7)杂环烷基;
-CO(C1-C6)烷基;
-COO(C1-C6)烷基;
-苯基;
-苄基;
-(C1-C10)烷基-NR8R9,其中R8和R9独立地选自H、直链或支链(C1-C6)烷基,它们和与之相连的氮原子一起形成饱和、部分饱和或不饱和的环,优选NR8R9与(C1-C10)烷基相连,从而形成例如饱和、部分饱和或不饱和的哌啶、噁嗪、咪唑环,其中这些环被(C1-C4)烷基任选取代;和
-卤素原子;
-CN;
-NO2;
-NR10R11,其中R10和R11相同或不同,且独立地选自:
-H;
-被苯基或(C3-C7)环烷基任选取代的直链或支链(C1-C6)烷基;
-COC6H5;
-CO-(C1-C4)烷基;
-COO-(C1-C4)烷基;
-CONH-(C1-C6)烷基-R12,其中R12选自:
-H;
-(C1-C4)烷基;和
-CONH(C1-C4)烷基-N(C1-C4)烷基;
或它们和与之相连的氮原子一起形成饱和或部分饱和的环,优选哌啶环;
-(C1-C4)烷基-NR10R11;
-COR12,其中R12是苯基或直链或支链(C1-C6)烷基;
-氧(oxo);
-HNSO2R13,其中R13是被卤素原子或(C1-C4)烷基任选取代的(C1-C4)烷基或苯基;
-SO2R14,其中R14是(C1-C4)烷基、OH或NR10R11,其中R10和R11如上所定义;
-SOR15,其中R15是苯基或(C1-C4)烷基;
-SR16,其中R16是H、苯基或(C1-C4)烷基;
-COOR17,其中R17是H、(C1-C4)烷基、苯基或苄基;和
-(CH2)qOR18,其中q=1、2、3或4,和R18是H或(C1-C4)环烷基。
及其药学上可接受的盐和在其吡啶环上的N-氧化物。
本发明还包括药学上可接受的盐和/或其溶剂化物。
本发明进一步涉及在吡啶环上的相应的N-氧化物。
本发明进一步包括制备通式(I)的化合物的方法。
本发明还提供单独或与一种或更多种药学上可接受的载体的混合物结合的通式(I)的化合物的药物组合物。
在进一步的方面中,本发明提供通式(I)的化合物作为药物的用途。
在进一步的方面中,本发明提供通式(I)的化合物制备药物的用途。
特别地,本发明提供通式(I)的化合物预防和/或治疗特征在于磷酸二酯酶4(PDE4)活性过大和/或其中希望抑制PDE4活性的任何疾病。
特别地,可单独或与其他活性成分结合施用通式(I)的化合物用于预防和/或治疗特征在于气道阻塞的呼吸道疾病,例如哮喘和COPD。
在进一步的方面中,本发明提供通式(I)的化合物的用途,其用于制备预防和/或治疗炎性疾病、特征在于与非所需的炎性免疫应答有关或因TNF-α和PDE4过度分泌诱导或与其有关的疾病或状况的药物。
而且,本发明提供预防和/或治疗其中要求抑制PDE4的任何疾病的方法,所述方法包括给需要这种治疗的患者施用治疗有效量的通式(I)的化合物。
定义
此处所使用的术语“卤素原子”包括氟、氯、溴和碘,优选氯。
此处所使用的措辞“直链或支链(C1-Cx)烷基”其中x是大于1的整数,是指直链和支链烷基,其中组成的碳原子数范围为1-x。特别的烷基是甲基、乙基、正丙基、异丙基和叔丁基。
任选地,在所述基团中,一个或更多个氢原子可被卤素原子,优选氯或氟取代。
衍生的措辞“(C2-C6)链烯基”和“(C2-C6)炔基”以类似的方式解释。
此处所使用的措辞“(C3-Cx)环烷基”,其中x是大于3的整数,是指含有3到x个环碳原子的环状非芳族烃基。实例包括环丙基、环丁基、环戊基、环己基和环庚基。
任选地,在所述基团中,一个或更多个氢原子可被卤素原子,优选氯或氟取代。
此处所使用的措辞“(C3-C7)杂环烷基”是指含有一个或更多个杂原子(例如,N、S或O)的环状非芳族烃基,它被一个或更多个(C1-C4)烷基任选取代。
衍生的措辞“(C1-Cx)环烷氧基”以类似的方式解释。
衍生的措辞“(C5-Cx)环烯基”,其中x是大于5的整数,以类似 的方式解释。
此处所使用的措辞“环体系”是指单环或双环的环体系,所述环体系可以是具有5-10个环原子(其中至少一个环原子是杂原子(例如,N、S或O))的饱和、部分不饱和或不饱和的环体系,例如是芳基、(C3-C8)环烷或杂芳基。
合适的单环体系的实例包括苯基、吡啶基、哌嗪基、哌啶基、吗啉基、环戊基、环己基、环己烯基、环庚基、二噁烷、咪唑和四氢咪唑烷。
合适的双环体系的实例包括萘基、喹啉基、异喹啉基、茚基、芴、苯并咪唑、苯并四氢咪唑、黄嘌呤及其部分或完全氢化的衍生物。
发明详述
本发明涉及充当磷酸二酯酶4(PDE4)酶抑制剂的一组化合物。
所述化合物组抑制环核苷酸,尤其环腺苷酸(cAMP)转化成它们的无活性的5`-单核苷酸形式。
在气道内,对环核苷酸,尤其cAMP较高的胞内水平的生理应答将导致抑制免疫和前炎性(pro-inflammatory)细胞,例如肥大细胞、巨噬细胞、T-淋巴细胞、噬酸性粒细胞和中性粒细胞的活性,从而导致含细胞因子,例如IL-1、IL-3和肿瘤坏死因子-α(TNF-α)的炎症介质的释放降低。
它还导致气道平滑肌松弛和水肿降低。
PDE4的催化位点已经得到确认:它主要包括其中存在两个亚囊(sub-pocket),例如S0和S1的疏水区域,和其中含金属离子Zn2+和Mg2+的亲水区域,所述亲水区域本身又包括在金属离子周围散布的亚囊S2和在疏水囊中间分叉约90°的亚囊S3。
现有技术的大多数化合物具有能与疏水区域的亚囊S0和S1相互作用的部分,例如取代的儿茶酚基并具有能与S2亚囊中的金属离子间接相互作用的另一部分,例如杂环,如吡啶或吡咯烷酮。
本发明涉及一种化合物,其中设计所述化合物,以便它们可通过 取代的儿茶酚基维持与亚囊S0和S1的相互作用和通过吡啶环维持与金属离子区域的相互作用,例如其他已知的PDE4抑制剂,但区别在于存在能与亚囊S3建立额外的相互作用的进一步的基团。
特别地,本发明涉及通式(I)的1-苯基-2-吡啶基烷醇衍生物:
药学上可接受的盐包括通过使充当碱(base)的主要化合物与无机或有机酸反应,形成盐,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、琥珀酸盐和柠檬酸盐而获得的那些。
对于本领域的技术人员来说,显而易见的是通式(I)的化合物可含有不对称中心。因此,本发明还包括其光学立体异构体和混合物。
在本发明的化合物具有至少一个不对称中心的情况下,它们因此可以对映体形式存在。在本发明的化合物具有两个或更多个不对称中心的情况下,它们可另外以非对映体形式存在。要理解,任何比例的所有这种异构体及其混合物包括在本发明的范围内。
发现通式(I)的化合物在nM范围内对PDE4酶显示出体外抑制活性,且证明当在COPD的动物模型内,当在气管内施用时,它们在肺内赋予良好的活性。
在一些情况下,它们在肺内还显示出持续的肺内水平,同时没有发现可检测的血浆水平,这是短的全身作用的指示。
与对HPDE4相比,这些化合物对LPDE4的出人意料的高的选择性的一种可能的解释是,它们的特征全部在于具有可通过A取代基,适配(fit)到PDE4酶的催化位点中的S3亚囊内的部分。
根据实施例13报道的结果,可理解,发现本发明的代表性化合物对LPDE4的选择性确实比对HPDE4大1319倍左右。
通式(I)的一组优选化合物是通式(II),其中2-吡啶环在3和5位被两个氯原子取代的化合物:
其中R1、R2、Z和A如上所定义。
有利地,当R1或R2是H时,在儿茶酚基上的另一个取代基不同于H。
优选地,R1和R2均不同于H。
通式(II)的第一组更优选的化合物是下述的那些,其中:
R1和R2如上所定义;
Z是(CH2)n,其中n为0;和
A如上所定义。
更优选的第二组化合物是下述的那些,其中:
R1和R2如上所定义;
Z是CHR5,其中R5是直链或支链(C1-C4)烷基,优选甲基;和
A如上所定义。
更优选的第三组化合物是下述的那些,其中:
R1和R2如上所定义;
Z是CR4R5,其中R4和R5都是直链或支链(C1-C4)烷基,且它们和与之相连的碳原子一起形成具有3、4、5、或6个碳原子,优选具有3个碳原子的环;和
A如上所定义。
在优选的实施方案之一中,A被取代,和Rx选自:直链或支链 (C1-C6)烷基、直链或支链(C2-C6)链烯基、直链或支链(C2-C6炔基,或OR7,其中R7如上所定义。
在另一优选的实施方案中,A被取代,和Rx是能改进整个分子的水溶解度的基团,例如NR10R11或HNSO2R13,其中R10、R11和R13如上所定义。
在本发明的特别的实施方案中,当A是杂芳基环时,该环优选选自吡咯、吡唑、呋喃、噻吩、咪唑、噁唑、异噁唑、噻唑、吡啶、嘧啶、吡嗪和吡喃、咪唑、四氢咪唑烷,和更优选吡啶。
根据优选的实施方案,本发明提供以下报道的化合物:
化合物 | 化学名 |
1 | 2-(4-异丁基-苯基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二 甲氧基-苯基)乙酯 |
2 | 苯基-乙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基) 乙酯 |
3 | 1-苯基-环丙烷羧酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧 基-苯基)乙酯 |
4 | 3,4-二甲氧基-苯甲酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲 氧基-苯基)-乙酯 |
5 | (S)-叔丁氧基羰基氨基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
6 | (R)-叔丁氧基羰基氨基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
7 | (S)-氨基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
8 | (R)-氨基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
9 | 2-(4-异丁基-苯基)-丙酸1-(3-环戊氧基-4-甲氧基-苯 |
[0157]
基)-2-(3,5-二氯-吡啶-4-基)乙酯 | |
11 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4- 二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
12 | 2-(4-异丁基-苯基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧基- 苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
13 | 2-(4-异丁基-苯基)-丙酸2-(3,5-二氯-1-氧基-吡啶-4- 基)-1-(3,4-二甲氧基-苯基)乙酯 |
14 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4- 二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
15 | 2-(4-异丁基-苯基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧基- 苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
16 | 2-(4-氨基-苯基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲 氧基-苯基)乙酯 |
17 | 2-(4-甲磺酰基氨基-苯基)-丙酸2-(3,5-二氯-吡啶-4- 基)-1-(3,4-二甲氧基-苯基)乙酯 |
25 | 4-(2-哌啶-1-基-乙氧基)-苯甲酸1-(3-环丙基-甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
26 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环戊氧基-4-甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
27 | 4-(2-哌啶-1-基-乙氧基)-苯甲酸2-(3,5-二氯-1-氧基-吡啶 -4-基)-1-(3,4-二甲氧基-苯基)乙酯 |
28 | 异烟酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯基)-2-(3,5-二氯 -1-氧基-吡啶-4-基)乙酯 |
29 | 烟酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1- 氧基-吡啶-4-基)乙酯 |
30 | 4-(2-咪唑-1-基-乙氧基)-苯甲酸1-环丙基-甲氧基-4-二氟甲 氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
[0158]
31 | 1-(2-{4-[1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二 氯-1-氧基-吡啶-4-基)-乙氧基羰基]-苯氧基}-乙基)-1-甲基- 哌啶鎓 |
32 | 4-(2-吗啉-4-基-乙氧基)-苯甲酸环丙基甲氧基-4-二氟甲氧基- 苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
33 | 4-二氟甲氧基-3-(2-哌啶-1-基-乙氧基)-苯甲酸2-(3,5-二氯 -1-氧基-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯 |
34 | 2-(6-甲氧基-萘-2-基)-丙酸1-(3-环丙基甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
35 | 4-(3,4,5-三乙酰氧基-6-乙酰氧基甲基-四氢-吡喃-2-基氧基)- 苯甲酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯基)-2-(3,5-二 氯-1-氧基-吡啶-4-基)乙酯 |
36 | 3-环丙基甲氧基-4-(2-哌啶-1-基-乙氧基)-苯甲酸1-(3-环丙基 甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基) 乙酯 |
37 | 2-(6-甲氧基-萘-2-基)-丙酸2-(3,5-二氯-1-氧基-吡啶-4- 基)-1-(3,4-二甲氧基-苯基)乙酯 |
38 | 2-(6-甲氧基-萘-2-基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4- 二甲氧基-苯基)乙酯 |
39 | 2-(6-甲氧基-萘-2-基)-丙酸1-(3-环丙基甲氧基-4-二氟甲氧基 -苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
40 | 4-氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
41 | 2-(4-氨基-苯基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
42 | 4-氨基-苯甲酸1-(3-环戊氧基-4-甲氧基-苯基)-2-(3,5-二氯 -1-氧基-吡啶-4-基)乙酯 |
43 | 4-二甲基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 |
[0159]
基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 | |
44 | 对苯二甲酸单-[1-(3-环丙基甲氧基-4-二氟-甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙基]酯 |
45 | 3-二甲基氨基-4-甲氧基-苯甲酸1-(3-环丙基-甲氧基-4-二氟甲 氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
46 | 4-咪唑-1-基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
47 | 4-二甲基氨基甲基-苯甲酸1-(3-环丙基-甲氧基-4-二氟甲氧基- 苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
48 | 1-甲基-1H-咪唑-4-羧酸1-(3-环丙基-甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
49 | 4-甲磺酰基氨基-苯甲酸1-(3-环丙基-甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
50 | 3-(环丙甲基-甲基-氨基)-4-甲氧基-苯甲酸1-(3-环丙基甲氧基 -4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
51 | 4-甲基-3,4-二氢-2H-苯并[1,4]噁嗪-7-羧酸1-(3-环丙基甲氧 基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
52 | 1,2-二甲基-1H-苯并咪唑-5-羧酸1-(3-环丙基甲氧基-4-二氟甲 氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
53 | 喹啉-3-羧酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5- 二氯-1-氧基-吡啶-4-基)乙酯 |
54 | (1,3-二甲基-2,6-二氧-1,2,3,6-四氢-嘌呤-7-基)-乙酸1-(3- 环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶 -4-基)乙酯 |
55 | 十六烷酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二 氯-1-氧基-吡啶-4-基)乙酯 |
56 57 | 戊酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1- 氧基-吡啶-4-基)乙酯 |
[0160]
58 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4- 二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
59 | 4-(3-环丙甲基-脲基)-苯甲酸1-(3-环丙基-甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
60 | 喹啉-8-羧酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5- 二氯-1-氧基-吡啶-4-基)乙酯 |
61 | 3-环丙基甲氧基-4-二甲基氨基-苯甲酸1-(3-环丙基甲氧基-4- 二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
62 | 4-[3-(2-甲氧基-乙基)-脲基]-苯甲酸1-(3-环丙基-甲氧基-4- 二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
63 | 1,3-二甲基-2-氧-2,3-二氢-1H-苯并咪唑-5-羧酸1-(3-环丙基 甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基) 乙酯 |
64 | 2-(2-氟-联苯基-4-基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
65 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4- 甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
66 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4- 甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
67 | 2-(6-二甲基氨基-萘-2-基)-丙酸1-(3-环丙基甲氧基-4-二氟甲 氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
68 | 2-(6-二甲基氨基-萘-2-基)-丙酸1-(3-环丙基甲氧基-4-二氟甲 氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
69 | 3-环丙基甲氧基-4-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基 -4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
70 | 4-(3,7,12-三羟基-10,13-二甲基-十六氢-环戊二烯并 (cyclopenta)[a]菲-17-基)-戊酸1-(3-环丙基甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
[0161]
71 | 4-(3,7,12-三羟基-10,13-二甲基-十六氢-环戊二烯并[a]菲 -17-基)-戊酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
72 | 乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡 啶-4-基)乙酯 |
73 | 苯基-乙酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯基)-2-(3,5- 二氯-吡啶-4-基)乙酯 |
74 | 丁酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡 啶-4-基)乙酯 |
75 | 4-苯基-丁酸1-(3-环丙基甲氧基二氟甲氧基-苯基)-2-(3,5-二 氯-吡啶-4-基)乙酯 |
76 | 4-[3-(2-二甲基氨基-乙基)-脲基]-苯甲酸1-(3-环丙基甲氧基 -4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
77 | 6-二甲基氨基-萘-2-羧酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
78 | 乙酰氧基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
79 | 1-(3-甲磺酰基氨基-4-甲氧基-苯基)-环丙烷-羧酸1-(3-环丙基 甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基) 乙酯 |
80 | 1-[3-(环丙甲基-甲基-氨基)-4-甲氧基-苯基]-环丙烷羧酸 1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基 -吡啶-4-基)乙酯 |
81 | 氧基-苯甲酸1-(3-环戊氧基-4-甲氧基-苯基)-2-(3,5-二氯-吡 啶-4-基)乙酯 |
82 | 2,3-二氢-苯并[1,4]二噁英-6-羧酸1-(3-环丙基甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
83 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸2-(3,5-二氯-吡啶-4- |
[0162]
基)-1-(2,2-二氟-苯并[1,3]二氧-5-基)乙酯 | |
84 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸2-(3,5-二氯-吡啶-4- 基)-1-(2,3-二氢-苯并[1,4]二噁英-6-基)乙酯 |
85 | 3,4,5-三乙氧基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
86 | 4-氟-3-甲氧基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
87 | 1-甲氧基-萘-2-羧酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
88 | 3,4,5-三氟-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
89 | 2-(2-氟-联苯基-4-基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
90 | 2-氧-噻唑烷-4-羧酸1-(3-环丙基-甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
91 | 4-甲基-3,4-二氢-2H-苯并[1,4]噁嗪-7-羧酸1-(3-环丙基甲氧 基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
92 | 1-环丙甲基-3-甲基-2-氧-2,3-二氢-1H-苯并咪唑-5-羧酸1-(3- 环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶 -4-基)乙酯 |
93 | 1-(3′,4′-二氯-2-氟-联苯基-4-基)-环丙烷-羧酸1-(3-环丙基 甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氟-1-氧基-吡啶-4-基) 乙酯 |
94 | 2,3-二氢-苯并[1,4]二噁英-6-羧酸1-(3-环丙基甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
95 | 6-二甲基氨基-萘-2-羧酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
96 | 1-环丙甲基-1H-吲哚-5-羧酸1-(3-环丙基甲氧基-4-二氟甲氧基 |
[0163]
-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 | |
97 | 4,7,7-三甲基-3-氧-2-氧杂-双环[2.2.1]庚烷-1-羧酸1-(3-环 丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶 -4-基)乙酯 |
98 | 2-苄氧基-丙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
99 | (3,4-二甲氧基-苯基磺胺基)-乙酸1-(3-环丙基-甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
100 | 4-甲磺酰基氨基-苯甲酸1-(3-环丙基-甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
101 | 4-[9-(4-乙基-苯氧基)-壬氧基]-苯甲酸1-(3-环丙基甲氧基-4- 二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
有利的是,本发明化合物的特征在于,对LPDE4的选择性高于HPDE4,这通过其IC50的测定来获得。
在LPDE4的情况下,IC50是50%抑制cAMP消失的试验化合物的摩尔浓度,这根据Cortijo J等人Br J Pharmacol 1993,108:562-568中所述来评估,而在HPDE4的情况下,IC50是产生50%[H3]环戊苯吡酮键合抑制的试验化合物的摩尔浓度,这根据Duplantier AJ等人JMed Chem 1996;39:120-125中所述来评估。
优选地,本发明化合物的HPDE4/LPDE4 IC50比高于5,优选高于10,更优选高于20,和甚至更优选高于100。
可方便地根据现有技术中公开的方法,制备通式(I)的化合物。以下在流程图中描述并报道了可使用的-些方法,且不应当视为限制制备本发明化合物可获得的合成方法的范围。
流程图
例如,根据本发明的特别的实施方案(流程图),可根据包括下述步骤的方法,制备通式(5)的化合物:
第一步-还原通式(I)的乙酮衍生物,得到通式(2)的醇衍生物(路径2)。
可通过在室温下,在氮气氛围中,在溶剂,例如甲醇中使用硼氢化钠(NaBH4),进行反应。
第二步-添加化学式AZCOOH的合适的酸到通式(2)的醇衍生物溶液中,得到通式(5)的化合物。
在合适的强碱,例如二异丙基酰胺锂(LDA)、NaH、二甲基氨基吡啶(DMAP)存在下,和在缩合剂,例如1-乙基-3-[3-二甲基氨基丙基]碳二酰亚胺盐酸盐(EDC)和N-羟基苯并三唑(HOBT)存在下,在溶剂,例如二氯甲烷中,在氮气氛围中进行反应。可使用其他溶剂,例如二甲基甲酰胺(DMF)、四氢呋喃(THF)、氯仿、二噁烷和本领域技术人员已知的任何其他非质子溶剂。在特别的实施方案中,反应也可在不存在溶剂的情况下进行。
在羧酸的情况下,A-Z-COOH带有反应性基团,例如羟基、羧基、硫醇基或氨基,它们可能需要通过保护基,例如叔丁氧基羰基、苄基、苄氧基羰基、甲基、三甲基甲硅烷基和类似基团保护,且在某些合成步骤中,去保护,再次获得游离的反应性基团;去保护的基团然后可与合适的试剂,例如烷化、酰化、磺酰化试剂或类似试剂反应。
在“Protective Groups in Organic Chemistry(有机化学中的保护基)”,第三版,T.W.Greene和P.G.M.Wuts,Wiley-Interscience(1999)和“Protecting Groups(保护基)”,P.J.Kocienski,GeorgThieme Verlag(1994)中描述了官能团的保护和去保护。
也可根据本领域技术人员已知的工序,通过添加通式为A-Z-COCl的合适酰氯或通式为A-Z-NCO的合适异氰酸酯到通式(2)的醇衍生物溶液中,采用化学计量或催化量的合适碱,制备通式(5)的化合物。
或者,可使用双-(三甲基甲硅烷基)-酰胺锂(LiHMDS)或类似的强碱和溶剂,例如四氢呋喃(THF)或其他非质子溶剂,通过使式(3)的苯甲醛衍生物与式(4)的甲基吡啶衍生物反应(路径2),制备通式(2)的醇衍生物。
通式(3)和(4)的中间体可商购或者可根据文献中获得且是本领域技术人员已知的。
可根据文献中可获得且本领域已知的方法,制备在通式(5)的化合物中的2-吡啶环上的N-氧化物。例如,可通过在CH2Cl2或CHCl3中溶解通式(5)的化合物,然后添加氧化剂,例如间氯过苯甲酸(mCPBA)到所得溶液中,制备N-氧化物。可使用的其他氧化剂是过氧化氢、过苯甲酸和过乙酸。
对于其中A是用对氧化敏感的官能团取代的环的那些化合物来说,相应的N-氧化物或者可通过在路径A的第二步之前进行氧化步骤来制备。
本发明还提供通式(I)的化合物与一种或更多种药学上可接受的载体,例如在Remington′s Pharmaceutical Sciences Handbook,XVIIEd.,Mack Pub.,N.Y.,U.S.A.中所述的那些载体混合的药物组合物。
可根据患者需求,例如口服、经鼻、肠胃外(皮下、静脉内、肌肉内、胸骨内和通过灌注)、通过吸入、直肠、阴道、局部、定位、经皮,和通过眼内施用,实现本发明化合物的施用。各种固体口服剂型可用于施用本发明的化合物,其中包括例如片剂、软胶囊、胶囊、小胶囊、颗粒、锭剂和大块粉末之类的固体剂型。可单独或与本领域已知的各种药学上可接受的载体、稀释剂(例如蔗糖、甘露糖、乳糖、淀粉)和赋形剂,其中包括,但不限于,悬浮剂、增溶剂、缓冲剂、粘合剂、崩解剂、防腐剂、着色剂、香料、润滑剂和类似物结合,施用本发明的化合物。在施用本发明的化合物中,同样有利的是定时释放的胶囊、片剂和凝胶。
也可使用各种液体口服剂型来施用本发明的化合物,其中包括含水和非水溶液、乳液、悬浮液、糖浆和酏剂。这种剂型也可含有本领域已知的合适的惰性稀释剂,例如水和本领域已知的合适的赋形剂,例如防腐剂、润湿剂、增甜剂、香料以及乳化和/或悬浮本发明化合物的试剂。可例如以等渗灭菌溶液形式静脉内注射本发明的化合物。其他制剂也是可能的。
可通过混合该化合物与合适的赋形剂,例如可可脂、水杨酸酯和聚乙二醇类,制备直肠施用本发明化合物的栓剂。
阴道施用的配方也可以是除了活性成分以外,还含有本领域已知的这种合适的载体的霜、凝胶、糊剂、泡沫体或喷洒配方形式。
对于局部施用来说,该药物组合物可以是适合于施用到皮肤、眼睛、耳朵或鼻子上的霜、药膏、擦剂、洗剂、乳液、悬浮液、凝胶、溶液、糊剂、粉末、喷雾剂和滴剂形式。局部施用也可牵涉借助例如经皮贴剂之类的方式的经皮施用。
为了治疗呼吸道疾病,优选通过吸入来施用本发明的化合物。
可吸入的制剂包括可吸入的粉末、含推进剂的计量气溶胶或不含推进剂的可吸入的配方。
为了以干燥粉末形式施用,可使用本领域已知的单一或多-剂量吸入器。在这一情况下,粉末可填充在明胶、塑料或其他胶囊、试剂盒 或泡罩包装内或者容器内。
通常无毒且对本发明化合物呈化学惰性的稀释剂或载体,例如乳糖或适合于改进可吸入部分的任何其他添加剂可加入到本发明的粉化化合物中。
含推进剂气体,例如氢氟烷烃的吸入气溶胶可含有溶液或分散形式的本发明化合物。推进剂驱动的配方也可含有其他成分,例如共溶剂、稳定剂和任选的其他赋形剂。
含本发明化合物的不含推进剂的可吸入配方可以是在水、醇或含水醇介质内的溶液或悬浮液形式,且通过根据现有技术已知的喷射或超声雾化器或者通过soft-mist雾化器,例如 传输它们。
可作为唯一的活性试剂或者结合其他药物活性成分,其中包括目前治疗呼吸疾病中使用的那些,例如β2-激动剂、皮质甾类和抗胆碱能药或抗毒蕈碱剂来施用本发明的化合物。
本发明化合物的剂量取决于各种因素,其中包括待治疗的特定疾病、症状的严重程度、施用路径、给药间隔时间的频率、所使用的特定化合物、效率、毒性曲线和该化合物的药物动力学曲线。
有利的是,可例如在包括0.001-1000mg/天,优选0.1-500mg/天的剂量下来施用通式(I)的化合物。
当通过吸入路径施用时,通式(I)的化合物的剂量有利地包括0.01-20mg/天,优选0.1-10mg/天。
优选地,可单独或与其他活性成分结合施用通式(I)的化合物,以供预防和/或治疗任何阻塞呼吸的疾病,例如哮喘、慢性支气管炎和慢阻肺病(COPD)。
然而,可施用通式(I)的化合物以供预防和/或治疗其中要求PDE4抑制的任何疾病。所述疾病包括过敏性疾病,例如特异反应性皮炎、寻麻疹(urticaria)、过敏性鼻炎、过敏性结膜炎、春季结膜炎、细胞肉芽肿病、银屑病、炎性关节炎、类风湿性关节炎、败血症性休克、溃疡性结肠炎、局限性回肠炎、心肌和大脑的再灌注损伤、慢性肾小球肾炎、内毒素性休克、膀胱纤维变性、动脉再硬化、动脉粥样硬化、 皮肤角化病、类风湿性脊椎炎、骨关节炎、pyresis,糖尿病,肺尘症,毒性和过敏性接触湿疹,特异反应性湿疹、脂溢性湿疹、单纯苔癣,晒斑,肛门与生殖器区域内的搔痒症、斑秃,肥大的伤疤,盘状红斑狼疮,系统性红斑狼疮,滤泡和大面积的pyodermias,内源性和外源性痤疮、酒糟鼻、Beghet′s病、过敏反应的紫癜性肾炎、炎性肠病,白血病、多发性硬化、肠胃病、自身免疫疾病和类似疾病。
它们还包括神经和生理疾病,例如阿尔兹海默氏症,多发性硬化、肌萎缩性侧索硬化症(ALS)、多器官功能萎缩(MSA),精神分裂症,帕金森症、亨廷顿病、皮克病、抑郁症、休克和脊髓损伤。
通过下述非限定性实施例,进一步描述本发明。
具体实施方案
实施例1
制备3,5-二氯-4-甲基吡啶(流程图的中间体(4))
将二异丙基胺(70mL,500mmol)溶解在干燥的四氢呋喃(THF)(500mL)中,冷却该溶液到-10℃,并在搅拌下逐滴加入丁基锂(在己烷内2.5N,210mL,525mmol)。30分钟之后,将该溶液冷却到-20℃,并逐滴加入在四氢呋喃(200mL)内的3,5-二氯吡啶(66.6g,450mmol)。在-10℃下搅拌该溶液30分钟,冷却到-70℃,并逐滴加入在四氢呋喃(100mL)内的碘代甲烷(50mL,1.6mol)。允许反应混合物温热到室温,用水(100mL)骤冷,并用二乙醚(3x100mL)提取;在硫酸钠(5g)上干燥结合的有机层,并蒸发至干。粗产物从含水乙醇,然后从己烷中结晶2次,得到白色固体形式的3,5-二氯-4-甲基吡啶(49.9g,306mmol,68%产率)。
MS/ESI+162-164-166m/z[MH]+。
实施例2
制备2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙酮(流程图的中间体(1))
冷却在干燥四氢呋喃(30ml)内的3,5-二氯-4-甲基-吡啶(2.06g,12.7mmol)溶液到-78℃,然后在搅拌下,逐滴加入1.8M在四氢呋喃(7.4ml,13.3mmol)内的二异丙基酰胺锂溶液,保持温度低于-70℃。搅拌所得溶液30分钟,然后逐滴加入在干燥四氢呋喃(20ml)内的3,4-二甲氧基-苯甲酰氯溶液(2.55g,12.7mmol),保持温度低于-70℃。在搅拌15分钟之后,添加冰(20g),接着进一步添加500ml水。用乙酸乙酯(2x50ml)提取该混合物,在硫酸钠上干燥结合的有机层,并减压蒸发,得到油状物,通过闪蒸色谱法,纯化所述油状物(洗脱剂:10/90-30/70v∶v的乙酸乙酯/石油醚)。
获得白色固体形式的2.1g(6.4mmol,52%产率)标题化合物。
MS/ESI+326-328-330m/z[MH]+;1H NMR(CDCl3,在7.26ppm下校正)3.91和3.95(2s,6H),4.62(s,2H),6.91-6.95(d,1H),7.53-7.54(d,1H),7.67-7.75(dd,1H),8.49(s,2H)。
使用所述路径与合适的溶剂,制备下述中间体。
表1
实施例3
制备2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙醇(流程图中的中间体(2))
路径A
在室温下,在氮气氛围中,将硼氢化钠NaBH4(45.2mg,2.5eq.)加入到2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙酮(150mg,1eq.)在CH3OH(5ml)内的悬浮液中。在室温下搅拌该混合物过夜,然后用水骤冷该反应,并用EtOAc提取。在硫酸钠上干燥有机层,并蒸发溶剂。通过闪蒸色谱法,在硅胶上用从石油醚/EtOAc 9/1 v/v到石油醚/EtOAc 7/3v/v,梯度洗脱,纯化粗产物,获得75mg标题化合物(50%产率)。
MS/ESI+328-330-332[MH]+
使用所述路径与合适的溶剂,制备下述中间体:
表2
实施例4
制备2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙醇(流程图中的中间体(2))
路径B
在-60℃下,在氮气氛围中,将3,5-二氯-4-甲基吡啶(500mg,1eq.)溶解在干燥THF(2mL)中。借助注射器,逐滴加入LiN(TMS)2(在THF内1.0M,3.38mL,1.1eq.),保持该温度低于-55℃。混合物变黄,并在-60℃下搅拌约30分钟。然后借助注射器逐滴加入在干燥THF(2mL)内的3,4-二甲氧基苯甲醛溶液(513mg,1eq.),保持该温度低于-55℃。在添加之后,缓慢地温热混合物到室温,并在室 温下搅拌约2小时。然后用水骤冷并用EtOAc提取。在硫酸钠上干燥有机层,并蒸发溶剂。用Et2O滴定粗产物,过滤,以白色固体形式获得741mg标题化合物(73%产率)。MS/ESI+328-330-332[MH]+
实施例5
制备(S)-2-(4-异丁基-苯基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物1)
在室温下,在氮气氛围中,将(1-乙基-3-[3-二甲基氨基丙基]碳二酰亚胺盐酸盐)(EDC.HCl)(345mg,3eq.)加入到2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙醇(200mg,1eq.)、(S)-2-(4-异丁基-苯基)-丙酸(148mg,1.2eq.)和4-二甲基氨基吡啶(DMAP)(37mg,0.5eq.)在干燥CH2Cl2(8mL)内的溶液中。在室温下搅拌混合物过夜,然后用NH4Cl(20ml)的饱和溶液处理,并用EtOAc(2x20ml)提取。在硫酸钠上干燥结合的有机层并蒸发溶剂。通过闪蒸色谱法,在硅胶上,梯度洗脱(从石油醚/EtOAc 9/1 v/v-石油醚/EtOAc 7/3 v/v)),纯化粗产物,得到259mg纯化合物。
使用所述路径与合适的试剂,制备下述化合物:
表3
实施例6
制备(S)-2-(4-异丁基-苯基)-丙酸2-(3,5-二氯-1-氧基-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物13)
将化合物1(51.5mg,0.1mmol)溶解在CH2CL2(1mL).中,添加间氯过苯甲酸(mCPBA,15mg,0.12mmol),并在室温下搅拌所得溶液2小时。然后用CH2Cl2(5mL)稀释该混合物并用1N NaOH(5ml)提取。在硫酸钠上干燥有机相并蒸发溶剂。通过制备型HPLC,纯化粗产物,得到37mg标题化合物。
使用相同的路径与合适的试剂,制备下述化合物:
表4
以与前面的实施例已经描述的方法类似的方式,在合适地选择试剂并根据前面所述的通用合成方法,制备化合物。
化合物 | 化学名 |
26 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环戊氧基-4-甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
27 | 4-(2-哌啶-1-基-乙氧基)-苯甲酸2-(3,5-二氯-1-氧基-吡啶-4- 基)-1-(3,4-二甲氧基-苯基)乙酯 |
28 | Iso烟酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯 -1-氧基-吡啶-4-基)乙酯 |
29 | 烟酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1- 氧基-吡啶-4-基)乙酯 |
30 | 4-(2-咪唑-1-基-乙氧基)-苯甲酸1-环丙基甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
[0246]
31 | 1-(2-{4-[1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二 氯-1-氧基-吡啶-4-基)-乙氧基羰基]-苯氧基}-乙基)-1-甲基-哌 啶鎓 |
32 | 4-(2-吗啉-4-基-乙氧基)-苯甲酸环丙基甲氧基-4-二氟甲氧基- 苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
33 | 4-二氟甲氧基-3-(2-哌啶-1-基-乙氧基)-苯甲酸2-(3,5-二氯 -1-氧基-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯 |
34 | 2-(6-甲氧基-萘-2-基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
35 | 4-(3,4,5-三乙酰氧基-6-乙酰氧基甲基-四氢-吡喃-2-基氧基)- 苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯 -1-氧基-吡啶-4-基)乙酯 |
36 | 3-环丙基甲氧基-4-(2-哌啶-1-基-乙氧基)-苯甲酸1-(3-环丙基 甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基) 乙酯 |
37 | 2-(6-甲氧基-萘-2-基)-丙酸2-(3,5-二氯-1-氧基-吡啶-4- 基)-1-(3,4-二甲氧基-苯基)乙酯 |
38 | 2-(6-甲氧基-萘-2-基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4- 二甲氧基-苯基)乙酯 |
39 | 2-(6-甲氧基-萘-2-基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
40 | 4-氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
41 | 2-(4-氨基-苯基)-丙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
42 | 4-氨基-苯甲酸1-(3-环戊氧基-4-甲氧基-苯基)-2-(3,5-二氯 -1-氧基-吡啶-4-基)乙酯 |
43 | 4-二甲基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 |
[0247]
基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 | |
44 | 对苯二甲酸单-[1-(3-环丙基甲氧基-4-二氟-甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙基]酯 |
45 | 3-二甲基氨基-4-甲氧基-苯甲酸1-(3-环丙基-甲氧基-4-二氟甲 氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
46 | 4-咪唑-1-基-苯甲酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
47 | 4-二甲基氨基甲基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基- 苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
48 | 1-甲基-1H-咪唑-4-羧酸1-(3-环丙基-甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
49 | 4-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
50 | 3-(环丙甲基-甲基-氨基)-4-甲氧基-苯甲酸1-(3-环丙基甲氧基 -4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
51 | 4-甲基-3,4-二氢-2H-苯并[1,4]噁嗪-7-羧酸1-(3-环丙基甲氧 基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
52 | 1,2-二甲基-1H-苯并咪唑-5-羧酸1-(3-环丙基甲氧基-4-二氟甲 氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
53 | 喹啉-3-羧酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯 基)-2-(3,5-二氟-1-氧基-吡啶-4-基)乙酯 |
54 | (1,3-二甲基-2,6-二氧-1,2,3,6-四氢-嘌呤-7-基)-乙酸1-(3- 环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶 -4-基)乙酯 |
55 | 十六烷酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯 -1-氧基-吡啶-4-基)乙酯 |
56 57 | 戊酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1- 氧基-吡啶-4-基)乙酯 |
[0248]
58 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4- 二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
59 | 4-(3-环丙甲基-脲基)-苯甲酸1-(3-环丙基-甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
60 | 喹啉-8-羧酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
61 | 3-环丙基甲氧基-4-二甲基氨基-苯甲酸1-(3-环丙基甲氧基-4- 二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
62 | 4-[3-(2-甲氧基-乙基)-脲基]-苯甲酸1-(3-环丙基-甲氧基-4- 二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
63 | 1,3-二甲基-2-氧-2,3-二氢-1H-苯并咪唑-5-羧酸1-(3-环丙基 甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基) 乙酯 |
64 | 2-(2-氟-联苯基-4-基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
65 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4- 甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
66 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4- 甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
67 | 2-(6-二甲基氨基-萘-2-基)-丙酸1-(3-环丙基甲氧基-4-二氟甲 氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
68 | 2-(6-二甲基氨基-萘-2-基)-丙酸1-(3-环丙基甲氧基-4-二氟甲 氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
69 | 3-环丙基甲氧基-4-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基 -4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
70 | 4-(3,7,12-三羟基-10,13-二甲基-十六氢-环戊二烯并-[a]菲 -17-基)-戊酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5- 二氯-吡啶-4-基)乙酯 |
[0249]
71 | 4-(3,7,12-三羟基-10,13-二甲基-十六氢-环戊二烯并-[a]菲 -17-基)-戊酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5- 二氯-1-氧基-吡啶-4-基)乙酯 |
72 | 乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡 啶-4-基)乙酯 |
73 | 苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二 氯-吡啶-4-基)乙酯 |
74 | 丁酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡 啶-4-基)乙酯 |
75 | 4-苯基-丁酸1-(3-环丙基甲氧基二氟甲氧基-苯基)-2-(3,5-二氯 -吡啶-4-基)乙酯 |
76 | 4-[3-(2-二甲基氨基-乙基)-脲基]-苯甲酸1-(3-环丙基-甲氧基 -4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
77 | 6-二甲基氨基-萘-2-羧酸1-(3-环丙基-甲氧基-4-二氟甲氧基- 苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
78 | 乙酰氧基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
79 | 1-(3-甲磺酰基氨基-4-甲氧基-苯基)-环丙烷-羧酸1-(3-环丙基 甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基) 乙酯 |
80 | 1-[3-(环丙甲基-甲基-氨基)-4-甲氧基-苯基]-环丙烷羧酸 1-(3-环丙基甲氧基-4-二氟-甲氧基-苯基)-2-(3,5-二氯-1-氧基 -吡啶-4-基)乙酯 |
81 | 氧基-苯甲酸1-(3-环戊氧基-4-甲氧基-苯基)-2-(3,5-二氯-吡 啶-4-基)乙酯 |
82 | 2,3-二氢-苯并[1,4]二噁英-6-羧酸1-(3-环丙基甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
83 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸2-(3,5-二氯-吡啶-4- |
[0250]
基)-1-(2,2-二氟-苯并[1,3]二氧-5-基)乙酯 | |
84 | 3-环丙基甲氧基-4-二氟甲氧基-苯甲酸2-(3,5-二氯-吡啶-4- 基)-1-(2,3-二氢-苯并[1,4]二噁英-6-基)乙酯 |
85 | 3,4,5-三乙氧基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
86 | 4-氟-3-甲氧基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
87 | 1-甲氧基-萘-2-羧酸1-(3-环丙基-甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
88 | 3,4,5-三氟-苯甲酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
89 | 2-(2-氟-联苯基-4-基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧 基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
90 | 2-氧-噻唑烷-4-羧酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
91 | 4-甲基-3,4-二氢-2H-苯并[1,4]噁嗪-7-羧酸1-(3-环丙基甲氧 基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
92 | 1-环丙甲基-3-甲基-2-氧-2,3-二氢-1H-苯并咪唑-5-羧酸1-(3- 环丙基甲氧基-4-二氟-甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶 -4-基)乙酯 |
93 | 1-(3′,4′-二氯-2-氟-联苯基-4-基)-环丙烷羧酸1-(3-环丙基甲 氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙 酯 |
94 | 2,3-二氢-苯并[1,4]二噁英-6-羧酸1-(3-环丙基甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
95 | 6-二甲基氨基-萘-2-羧酸1-(3-环丙基-甲氧基-4-二氟甲氧基- 苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
96 | 1-环丙甲基-1H-吲哚-5-羧酸1-(3-环丙基甲氧基-4-二氟甲氧基 |
[0251]
-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 | |
97 | 4,7,7-三甲基-3-氧-2-氧杂-双环[2.2.1]庚烷-1-羧酸1-(3-环 丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4- 基)乙酯 |
98 | 2-苄氧基-丙酸1-(3-环丙基甲氧基-4-二氟-甲氧基-苯 基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
99 | (3,4-二甲氧基-苯基磺胺基)-乙酸1-(3-环丙基-甲氧基-4-二氟 甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯 |
100 | 4-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
101 | 4-[9-(4-乙基-苯氧基)-壬氧基]-苯甲酸1-(3-环丙基-甲氧基 -4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯 |
实施例7
制备2-(4-氨基-苯基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物16)
将化合物10(50mg,0.1mmol)溶解在二甲基甲酰胺(DMF)(3mL)中。添加氯化锡(SnCl2x2H2O,113mg,0.5mmol),并在室温下搅拌所得混合物17小时。然后用水(15mL)稀释该混合物并用Et2O(2x30mL)提取。在硫酸钠上干燥有机相并蒸发溶剂。通过制备型HPLC纯化粗产物,得到10mg标题化合物。
表5
实施例8
制备2-(4-甲磺酰基氨基-苯基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物17)
在氮气氛围中,将化合物16(26mg,0.05mmol)溶解在干燥CH2Cl2(10mL)中。将该溶液冷却到0℃并添加三乙胺(0.009mL,0.066mmol)和甲磺酰氯(0.0052mL,0.06mmol)。然后允许该混合物在室温下反应17小时。然后用水(15mL)稀释该反应混合物并用AcOEt(2x30mL)提取。在硫酸钠上干燥有机相并蒸发溶剂。通过制备型HPLC纯化粗产物,以非对映异构体混合物形式得到10mg标题化合物。
表6
实施例9
制备1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙醇(化合物18)
将中间体2b(100mg,0.25mmol)溶解在CHCL3(3mL)中。添加间氯过苯甲酸(mCPBA,80mg,0.46mmol),并在0℃下保持所得溶液过夜。
然后用CHCl3(5mL)稀释混合物并用1N NaOH(5ml)洗涤。在硫酸钠上干燥有机相并蒸发溶剂。
通过用乙醇结晶,纯化粗产物。过滤该白色固体并用石油醚洗涤,得到70mg标题化合物。
按照相同的路径,使用合适的试剂,制备下述化合物:
表7
实施例10
制备4-(2-哌啶-1-基-乙氧基)-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯盐酸盐(化合物25)
在室温下,在氮气氛围中,将(1-乙基-3-[3-二甲基氨基丙基]碳二酰亚胺盐酸盐)(EDC.HCl)(55mg,eq.)加入到化合物18(60mg,0.14mmol)、4-(2-哌啶-1-基-乙氧基)-苯甲酸(81mg,0.28eq.)和4-二甲基氨基吡啶(DMAP)(37mg,0.5eq.)在干燥DMF(4mL)内的溶液中。在室温下搅拌该混合物过夜,然后用NH4Cl的饱和溶液(20ml)处理并用EtOAc(2x20ml)提取。在硫酸钠上干燥结合的有机层并蒸发溶剂。通过制备型HPLC,纯化粗产物。将油状残渣溶解在乙酸乙酯(2ml)内,并添加略过量的1M干燥HCl在乙酸乙酯内的溶液。在蒸发溶剂之后,从甲醇/二乙醚中结晶该残渣,得到14mg标题化合物。
表8
符号表
*NMR
s=单峰
d=双峰
t=三重峰
q=四重峰
dd=双峰的双峰(doublet of doublets)
m=多重峰
br=宽
ESI=电喷雾
本发明化合物的药物活性
实施例11
在不含细胞的分析中,体外测定DE4的抑制活性
U937人类单核细胞系用作PDE4酶源。基本上如Torphy TJ等人J.Pharmacol.Exp.Ther.1992;263:1195-1205中所述,培养、收获并制备上清液部分。
通过分析温育混合物中cAMP的消失,测定细胞上清液内的PDE4活性。在1.6μM cAMP存在下,在有或无试验化合物(50μl)的情况下,在30℃下,在200μl的最终体积内,温育50μl细胞上清液30分钟。
试验化合物的浓度范围为10-12M-10-6M。通过加热失活(在100℃下2.5分钟),终止反应,并使用电化学发光(ECL)-基免疫分析,测量残留的cAMP。
在实施例12中,表9报道了结果,结果以产生cAMP消失的50%抑制(IC50)的试验化合物摩尔浓度的平均值±95%置信度范围表达。
计算PDE4活性的抑制百分数,其中认为在不存在抑制剂的情况下,cAMP消失为100%,和在加热失活样品中cAMP消失为0%。
作为本发明代表的所有试验化合物的IC50值小于0.2microM。
实施例12
在外周血单核细胞(PBMCs)分析中体外测定PDE4抑制活性
根据前面所述的方法(Hatzelmann A等人J.Pharmacol.Exp.Ther.2001;297:267-279;Draheim R等人J.Pharmacol.Exp.Ther.2004;308:555-563),进行分析,该分析基于PDE4抑制剂在脂多糖(LPS) 诱导的肿瘤坏死因子-α(在外周血单核细胞(PBMCs)内的TNF-α释放)上产生的已知抑制活性。
在其浓度范围为10-12M-10-6M的试验化合物存在或不存在下(50微升),在96孔板内温育冷藏人类PBMCs(100μl/孔)30分钟。随后,添加LPS(3ng/ml)。
在加湿的孵育器内,在95%空气和5%二氧化碳氛围下,在37℃下温育18小时之后,收集培养介质并通过ELISA测量TNF-α。
表9中报道了结果,该结果以产生50%LPS-诱导的TNF-a释放抑制(IC50)的试验化合物摩尔浓度的平均值±95%置信度范围表达。
以TNF-a释放抑制的百分数形式计算所测试化合物的效果,其中认为在不存在抑制剂化合物情况下的LPS-诱导的TNF-a产生为100%,而在不存在LPS情况下PBMCs的基本TNF-a产生为0%。
表9-本发明的代表性化合物的体外PDE4抑制活性
化合物 | IC50不具有细胞 (nM) | IC50PBMCS (nM) |
1 | 118 | 69 |
2 | - | 89 |
3 | 118 | 52 |
4 | 3.4 | 34.2 |
6 | 9 | 95 |
7 | 7 | 99 |
8 | 22 | - |
9 | 22 | 85 |
11 | 12 | 51 |
12 | 12 | 456 |
13 | 1.5 | 13 |
14 | 0.2 | 2 |
15 | 8.6 | 15 |
16 | 6.3 | 36 |
[0303]
实施例13
相对于竞争高亲和性HPDE4的能力,评价抑制低亲和性LPDE4的能力
分别如前面的Cortijo J等人Br J Pharmacol 1993,108:562-568和Duplantier AJ等人J Med Chem 1996;39:120-125中所述,评估对LPDE4和HPDE4的亲和性。
试验化合物的浓度范围为10-12M和10-5M。
表10中报道了IC50结果。
在LPDE4情况下,IC50是产生cAMP消失的50%抑制的试验化合物的摩尔浓度,而在HPDE4情况下,IC50是产生50%抑制[H3]环戊苯吡酮结合的试验化合物的摩尔浓度。
结果表明本发明的化合物在纳摩尔以下,抑制LPDE4且对LPDE4的选择性显著大于HPDE4。
表10-本发明的代表性化合物的活性曲线
化合物 | HPDE4 IC50(nM) | LPDE4 IC50(nM) | HPDE4/LPDE4 |
14 | 13.9 | 0.0881 | 158 |
15 | 2.17 | 0.169 | 273 |
20 | 299 | 0.759 | 394 |
9 | 399 | 0.738 | 541 |
11 | 153 | 0.116 | 1319 |
Claims (18)
1.通式(I)的化合物和其药学上可接受的盐及其在吡啶环上的N-氧化物:
其中:
Z选自:
(CH2)m,其中m=0或1;和
CR4R5,其中
R4独立地选自H或直链或支链(C1-C4)烷基,和
R5是直链或支链(C1-C4)烷基;
R1和R2相同或不同且独立地选自:
-直链或支链(C1-C6)烷基,其中任选一个或更多个氢原子被卤素原子取代,并且其中直链或支链(C1-C6)烷基任选地被(C3-C7)环烷基取代;
-(C3-C7)环烷基;
R3是一个或多个卤素原子;
A是苯基,其中任选取代基Rx可以是一个或更多个,可以相同或不同,且独立地选自下述:
-OR7,其中R7选自直链或支链(C1-C10)烷基,其中任选一个或多个氢原子被卤素原子取代,且其中直链或支链(C1-C10)烷基被一个或更多个(C3-C7)环烷基任选取代;
-NR10R11,其中R10和R11是H;
-HNSO2R13,其中R13是(C1-C4)烷基。
2.权利要求1的化合物,其中R3是氯。
4.权利要求3的化合物,其中Z是(CH2)m,其中m等于0。
5.权利要求4的化合物,它是3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯。
6.权利要求4的化合物,它是3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯。
7.权利要求3的化合物,其中Z是CHR5,其中R5是直链或支链C1-C4烷基。
8.权利要求7的化合物,其中R5是甲基。
10.权利要求9的化合物,其中R4和R5均为直链或支链C1-C4烷基,或它们和与之相连的碳原子一起形成具有3个碳原子的环。
12.一种药物组合物,它包括权利要求1-10任何一项的化合物作为活性成分并与一种或更多种药学上可接受的载体混合。
13.权利要求12的药物组合物,其适合于吸入施用。
14.权利要求1-10任何一项的化合物用于制备预防和/或治疗特征在于磷酸二酯酶4活性过大和/或其中希望抑制磷酸二酯酶4活性的任何疾病的药物的用途。
15.权利要求14的用途,其中疾病是特征在于气道阻塞的呼吸道疾病。
16.权利要求15的用途,其中疾病选自:哮喘或慢性支气管炎或慢阻肺病。
17.权利要求1-10任何一项的化合物制备用于治疗特征在于非所需的炎性免疫应答或者与之有关或者由TNF-α和磷酸二酯酶4过度分泌诱导或者与之有关的炎性疾病、不适或状况的药物的用途。
18.2-(4-异丁基-苯基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物1);
苯基-乙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物2);
1-苯基-环丙烷羧酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物3);
3,4-二甲氧基-苯甲酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙酯(化合物4);
(R)-叔丁氧基羰基氨基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯(化合物6);
(S)-氨基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯(化合物7);
(R)-氨基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯(化合物8);
2-(4-异丁基-苯基)-丙酸1-(3-环戊氧基-4-甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯(化合物9);
3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯(化合物11);
2-(4-异丁基-苯基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)乙酯(化合物12);
2-(4-异丁基-苯基)-丙酸2-(3,5-二氯-1-氧基-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物13);
3-环丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯(化合物14);
2-(4-异丁基-苯基)-丙酸1-(3-环丙基-甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯(化合物15);
2-(4-氨基-苯基)-丙酸2-(3,5-氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物16);
如下通式的化合物:
其中R1是甲基,R2是环戊基(化合物20)。
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WO2024062005A1 (en) | 2022-09-22 | 2024-03-28 | Chiesi Farmaceutici S.P.A. | Capsule inhaler for the administration of a phosphodiesterase-4 inhibitor |
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