CN101478989A - 炎性肠病的处置剂 - Google Patents
炎性肠病的处置剂 Download PDFInfo
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- CN101478989A CN101478989A CNA2007800238253A CN200780023825A CN101478989A CN 101478989 A CN101478989 A CN 101478989A CN A2007800238253 A CNA2007800238253 A CN A2007800238253A CN 200780023825 A CN200780023825 A CN 200780023825A CN 101478989 A CN101478989 A CN 101478989A
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- Prior art keywords
- amino
- fluorophenyl
- pyridine radicals
- pyrazoles
- methyl
- Prior art date
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- -1 aromatic heterocyclic radical Chemical class 0.000 claims description 104
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
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- 229910052760 oxygen Inorganic materials 0.000 claims description 23
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Classifications
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Abstract
本发明公开了以具有作为前效药物的性质的p38MAP激酶抑制剂作为有效成分的炎性肠病的处置剂。
Description
技术领域
本发明涉及炎性肠病的处置剂,其特征在于:含有具有作为前效药物(antedrug)的性质的p38MAP激酶抑制剂作为有效成分。
背景技术
炎症是在对生物体组织施加了某些损伤性因素时可见的生物体的反应,与其说是对组织损伤的直接性反应,更可理解为对组织损伤而产生的炎症的化学介质的反应。已知这种化学介质有例如肿瘤坏死因子-α(以下称为“TNF-α”)、白细胞介素(以下称为“IL”)、环加氧酶(以下称为“COX”)、前列腺素、血栓烷、白三烯等。
另一方面,近年来已经明确了炎症反应中p38MAP激酶的作用。TNF-α、IL-1、IL-6、IL-8、COX-II等细胞因子或蛋白质通过NF-κB、AP-1、CREB等转录因子与编码这些细胞因子或蛋白质的DNA上的共通的序列结合而合成,p38MAP激酶具有活化这些转录因子的功能。转录因子被活化,则mRNA的转录得到促进,由此也促进了TNF-α等细胞因子或蛋白质的合成。这样,p38MAP激酶位于炎症反应途径的上游,促进TNF-α等细胞因子或蛋白质的合成。由此,如果抑制p38MAP激酶,则有望有效处置或预防炎性疾病,例如慢性类风湿性关节炎、变形性膝关节病、克罗恩氏病、溃疡性结肠炎(以下有时将克罗恩氏病和溃疡性结肠炎总称为“IBD”(炎性肠病))、支气管炎、支气管哮喘、变应性鼻炎、特应性皮炎等。
迄今为止,已知具有p38MAP激酶抑制作用的化合物有例如:咪唑衍生物(参照Bioorganic & Medicinal Chemistry,Vol.5,No.1,49-64(1997))和PCT国际公开WO93/14081小册子)、吡唑衍生物(参照PCT国际公开WO98/52940和WO00/39116小册子)、异噁唑衍生物(参照日本特开2000-86657号公报、以及PCT国际公开WO96/25405、WO2004/17968和WO2004/22555小册子)、噻唑衍生物(参照PCT国际公开WO00/64894小册子)、三唑并吡啶衍生物(参照PCT国际公开WO2004/72072小册子)、吡啶并嘧啶衍生物(参照PCT国际公开WO2004/14907小册子)、萘啶衍生物(参照PCT国际公开WO2004/73628小册子)、六元环稠合吡唑衍生物(参照PCT国际公开WO2005/73189和WO2005/85249小册子)、二环式杂芳环化合物(参照PCT国际公开WO2004/00846小册子)等。
这些化合物中,有过去已进行了临床研究的、或现在正进行临床研究的。例如,对于为咪唑衍生物的、被称为“开发编号SB-203580”的化合物,研究了其对于风湿病或哮喘等的适应性。对于为噻唑衍生物的、被称为“开发编号TAK-715”的化合物,目前正以风湿病作为适应症进行临床试验。但是,目前尚没有作为药物上市的p38MAP激酶抑制剂。
由于其作用基理,p38MAP激酶抑制剂主要以风湿病作为适应症进行开发。对于风湿病这样的全身性疾病,通常必须使药物全身性地持续作用一定时间,但目前已研究过的p38MAP激酶抑制剂会产生中枢转移性或肝毒性、肾毒性等问题,难以保持一定的血药浓度来达到药效,不得已只好放弃作为全身性炎性疾病的处置剂的开发。
最近有报道称,某种三嗪衍生物具有强p38MAP激酶抑制作用,且代谢迅速,因此有望减轻副作用,有可能作为抗风湿药物(参照J.Med.Chem.,Vol.47,6283-6291(2004))。
类固醇性抗炎药物由于其强烈的抗炎作用而对炎性疾病的治疗极为有用,但是内服时存在副作用,例如库欣综合征、白内障、青光眼、抑制垂体-肾上腺系统、诱发糖尿病、诱发高血压、使传染病恶化或诱发传染病等。不过,一部分化合物,例如戊酸乙酸泼尼松龙、布地奈德等在局部表现抗炎作用后向血液中转移并迅速被代谢,因此全身性的副作用少。这种在局部作用后向血液中转移并迅速灭活的药物被称为“前效药物”。
但是,目前作为前效药物已知的药物主要是外用的类固醇化合物,作为p38MAP激酶抑制剂的前效药物则完全未知。也没有将前效药物用于处置IBD的例子。
发明内容
本发明的目的在于提供炎性肠病的处置剂,该处置剂以p38MAP激酶抑制剂作为有效成分、药物分布于全身所伴随的副作用小。
本发明人发现:p38MAP激酶抑制剂中存在具有向血液中转移后迅速被代谢而消失的、即作为前效药物的性质的化合物群,这些化合物的副作用小,有望用于炎性肠病的处置,为此进行了各种研究,从而完成了本发明。
即,本发明提供炎性肠病的处置剂,其特征在于:含有具有作为前效药物的性质的p38MAP激酶抑制剂作为有效成分。
本说明书中,“具有作为前效药物的性质的p38MAP激酶抑制剂”是指具有p38MAP激酶抑制作用的化合物,该化合物在局部作用后向血液中转移,血液转移量多,例如一半以上迅速地被代谢/灭活为不显示p38MAP激酶抑制作用的化合物。这里,“迅速”是指在1小时以内、优选30分钟以内、进一步优选20分钟以内。
本发明的效果通过在本发明的处置剂中使用具有作为前效药物的性质的p38MAP激酶抑制剂来实现。因此,本发明的处置剂中使用的p38MAP激酶抑制剂只要具有作为前效药物的性质即可,对其种类没有特别限定。
迄今为止已经报道了很多具有p38MAP激酶抑制作用的化合物,但它们并非都具有作为前效药物的性质。具有作为前效药物的性质的p38MAP激酶抑制剂的筛选例如可通过后述的化合物代谢速度的测定实验容易地进行。
即,本发明的处置剂中,可用作具有作为前效药物的性质的p38MAP激酶抑制剂的化合物的具体例子例如有:
(A)式(I)所示的化合物或其盐:
式中,
R1表示取代或未取代的六元芳族杂环基,
R2表示取代或未取代的芳族碳环基或芳族杂环基,
R3表示具有链由选自碳原子、氧原子和氮原子的1-5个原子构成的直链状连接基团的取代或未取代的碳环基或杂环基,
A表示碳原子、氧原子、硫原子或氮原子。
(B)式(II)所示的化合物或其盐:
式中,
R4表示直接或者经由连接基团与三嗪环结合的杂环基,
R5表示取代或未取代的氨基,
R6表示取代或未取代的苯基。
(C)式(III)所示的化合物或其盐:
式中,
Ar1表示取代或未取代的芳族碳环基或芳族杂环基,
Ar2表示取代或未取代的芳族碳环或杂环,
X表示O或S,
L表示链由选自碳原子、氧原子和硫原子的1-3个原子构成的连接基团,
Q表示取代或未取代的杂环基。
不过,即使是通式(I)-(III)中包含的化合物,不具有作为前效药物的性质的也被排除在本发明中可使用的化合物之外。
本说明书中,“炎性肠病”是克罗恩氏病和溃疡性结肠炎的总称,通常简称为“IBD”。本发明在提供对目前不存在有用的治疗药物的克罗恩氏病和溃疡性结肠炎有用的处置剂方面具有重大意义。
本说明书中,称为“低级”的术语是指带该术语的基团的碳原子数为6个以下,优选4个以下。
本说明书中的“低级烷基”可以是直链状或支链状的,例如有甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。“低级烷氧基”是结合了该低级烷基的氧基(O),例如有甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基等。
本说明书中,“低级烷基氨基”是指氨基(-NH2)的一个氢原子被上述低级烷基取代所得的氨基,“二低级烷基氨基”是指氨基的两个氢原子被相同或互不相同的上述低级烷基取代所得的氨基。“低级芳烷基氨基”是指上述低级烷基氨基中低级烷基部分被芳基取代所得的基团,“酰基氨基”是指被甲酰基、乙酰基、丙酰基、丁酰基等低级烷酰基或苯甲酰基等芳酰基酰基化所得的氨基。
本说明书中,“低级烷硫基”和“低级烷基亚硫酰基”分别指结合了上述低级烷基的硫基(S)和亚硫酰基(SO)。
本说明书中,“卤素原子”包含氟、氯、溴和碘原子。
上式(I)的R1定义中的“取代或未取代的六元芳族杂环基”包括根据情况可被1-3个选自卤素原子、低级烷基、低级烷氧基、氨基、低级烷基氨基、二低级烷基氨基、低级芳烷基氨基、酰基氨基、低级烷硫基、低级烷基亚硫酰基、羧基、低级烷氧基羰基、氨基羰基、低级烷基氨基羰基、氰基和硝基的取代基取代的吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基,其中,优选根据情况可被1个选自上述取代基的取代基取代的吡啶基或嘧啶基。
上式(I)的R2定义中的“取代或未取代的芳族碳环基或芳族杂环基”包括根据情况可被1-3个选自与上述“取代或未取代的六元芳族杂环基”中说明的同样的取代基的基团取代的苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基或噻唑基,其中,优选根据情况可被1-3个与上述同样的取代基取代的苯基或吡啶基。
上式(I)的R3定义中的“链由选自碳原子、氧原子和氮原子的1-5个原子构成的直链状连接基团”例如有:-CH2-、-CO-、-O-、-NH-、-CH2CH2-、-COCH2-、-CH2O-、-OCH2-、-CONH-、-NHCH2-、-NHCO-、-CH2CH2CH2-、-CH2CH2CO-、-CH2CH2O-、-OCH2CH2-、-CH2OCH2-、-CH2CH2NH-、-NHCH2CH2-、-NHCOCH2-、-CONHCH2-、-CH2CH2CH2CH2-、-COCH2CH2CH2-、-CH2CH2CONH-、-NHCOCH2CH2-、-CH2CH2CH2CH2CH2-、-COCH2CH2CH2CH2-、-NHCOCH2CH2CH2-等,其中,优选构成链的原子数为2-4个的连接基团。另外,上式(I)的R3定义中的“取代或未取代的碳环基或杂环基”为根据情况可被1-3个选自与上述R1定义中的“取代或未取代的六元芳族杂环基”中说明的同样的取代基的基团取代的碳环基或杂环基,该碳环基例如有:苯基、萘基、环戊基、环己基、环庚基等,该杂环基例如有:呋喃基、吡啶基、吡咯烷基、哌啶基、氮杂基等,其中,优选为可被1或2个选自与上述R1定义中的“取代或未取代的六元芳族杂环基”中说明的同样的取代基的基团取代的苯基。
上式(I)中,A表示碳原子或氮原子时,该原子可具有一个取代基,该取代基例如有低级烷基、苯基等。本发明中,优选上式(I)中的A表示氧原子、硫原子或氮原子。
上式(II)的R4定义中的“连接基团”有与上述R3定义中的“链由选自碳原子、氧原子和氮原子的1-5个原子构成的直链状连接基团”中说明的同样的连接基团。这里,R4定义中的杂环基优选与三嗪环直接结合或者经由构成链的原子数为1个的连接基团与三嗪环结合。上式(II)的R4定义中的“杂环基”例如有:呋喃基、吡咯基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、苯并咪唑基、苯并噁唑基、苯并噻唑基、喹啉基、异喹啉基、喹唑啉基、吡咯烷基、哌啶基、哌嗪基、氮杂基、二氮杂基等。
上式(II)的R5定义中的“取代或未取代的氨基”具体有:氨基、低级烷基氨基、二低级烷基氨基或环烷基氨基,这里,该环烷基氨基中的环烷基例如有环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
上式(II)的R6定义中的“取代或未取代的苯基”的苯基上的取代基有与上式(I)的R1定义中的“取代或未取代的六元芳族杂环基”中说明的同样的取代基,该苯基可以被1-3个选自这些取代基的基团取代。
上式(III)的Ar1定义中的“取代或未取代的芳族碳环基或芳族杂环基”可以是与上式(I)的R2定义中的“取代或未取代的芳族碳环基或芳族杂环基”中说明的同样的基团,其中,优选被1-3个选自与上述“取代或未取代的六元芳族杂环基”中说明的同样的取代基的基团取代的苯基、萘基或吡啶基。
上式(III)的Ar2定义中的“取代或未取代的芳族碳环或杂环”包括根据情况可被1或2个选自与上式(I)的R1定义中的“取代或未取代的六元芳族杂环基”中说明的同样的取代基的基团取代的芳族碳环或杂环,该芳族碳环例如有:亚苯基、亚萘基等,该杂环有与上式(II)的R4定义中的“杂环基”中说明的同样的基团。
上式(III)的L定义中的“链由选自碳原子、氧原子和硫原子的1-3个原子构成的连接基团”例如有:-CH2-、-O-、-S—、-CH2CH2-、-CH2O-、-CH2S-、-OCH2-、-SCH2-、-CH2CH2CH2-、-CH2CH2O-、-CH2CH2S-、-OCH2CH2-、-SCH2CH2-、-CH2OCH2-、-CH2SCH2-等,其中,优选链由选自碳原子、氧原子和硫原子的1或2个原子构成的连接基团。
上式(III)的Q定义中的“取代或未取代的杂环基”是根据情况可被1-3个选自与上述式(I)的R1定义中的“取代或未取代的六元芳族杂环基”中说明的同样的取代基的基团取代的杂环基,这里,该杂环基有与上式(II)的R4定义中的“杂环基”中说明的同样的基团。
本发明的处置剂中可使用的具体的化合物例如有:
上式(I)的化合物有:
5-[(2-氯苯基)乙酰基氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯-6-氟苯基)乙酰基氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑、
3-(4-氯苯基)-5-[(2-氯苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(2,4-二氟苯基)-4-(4-嘧啶基)异噁唑、
3-(2,4-二氟苯基)-5-[(3-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(2-氟-4-甲氧基苯基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(2,3-亚甲二氧基苯基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑、
5-[(2-溴苯基)乙酰基氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑、
3-(3-甲基苯基)-5-[(2-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
3-(3-甲基苯基)-5-[(3-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
3-(2-氟-5-甲基苯基)-5-(苯基乙酰基氨基)-4-(4-嘧啶基)异噁唑、
5-[(3-甲氧基苯基)乙酰基氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑、
3-(3-甲基-4-氟苯基)-5-[(2-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
3-(3-甲基苯基)-5-(3-苯基丙酰基氨基)-4-(4-吡啶基)异噁唑、
3-(3-甲基苯基)-5-[(2-甲基苯基)丙酰基氨基]-4-(4-吡啶基)异噁唑、
5-[(3-氯苯基)丙酰基氨基]-3-(2-氟-5-甲基苯基)-4-(4-吡啶基)异噁唑、
3-(4-氟-3-甲基苯基)-5-苯基乙酰基氨基-4-(4-吡啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(4-氟-3-甲基苯基)-4-(4-吡啶基)异噁唑、
3-(4-氟-3-甲基苯基)-5-(3-苯基丙酰基氨基)-4-(4-吡啶基)异噁唑、
4-(4-氟苯基)-2-(4-羟基-3,5-二苯基)-5-(4-吡啶基)咪唑、
4-(4-氟苯基)-2-(4-甲磺酰基苯基)-5-(4-吡啶基)咪唑、
3-(4-氟苯基)-5-苯基乙酰基氨基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(4-甲氧基苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
5-(2-氯苯基乙酰基氨基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
5-(2,5-二氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2-氯-6-氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,6-二氯苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,4-二氯苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,6-二氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(3,5-二氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,3-二氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,5-二甲基苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,4-二甲氧基苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2-氯苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2-溴苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(2-氟苯基乙酰基氨基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-(2-甲基苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(2-甲氧基苯基乙酰基氨基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(2-硝基苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
1-乙基-3-(4-氟苯基)-5-苯基乙酰基氨基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-苯基乙酰基氨基-1-丙基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-(2-羟基乙基)-5-(2-甲氧基苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
5-(2-氯苯基乙酰基氨基)-3-(4-氟苯基)-1-(2-羟基乙基)-4-(4-吡啶基)吡唑、
1-甲基-3-(3,4-亚甲二氧基苯基)-5-苯基乙酰基氨基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-苯基乙酰基氨基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-(N-甲基-N-苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(N-甲酰基-N-苯乙基氨基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(1-羟基-4-苯基丁基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-[1-羟基-3-(3-甲苯基)丙基]-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(1-羟基-3-苯基丁基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(1-羟基-2-甲基-3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(1-羟基-3-苯基丙基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(2-吡啶基)-1-丙烯基]吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(3-吡啶基)-1-丙烯基]吡唑、
3-(4-氟苯基)-5-[2-甲基-3-(3-吡啶基)-1-丙烯基]-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(2-吡啶基)-1-丁烯基]吡唑、
3-(4-氟苯基)-1-甲基-4-(4-吡啶基)-5-[3-(3-吡啶基)-1-丙烯基]吡唑、
3-(4-氟苯基)-5-(3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(3-吡啶基)丁基]吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(2-吡啶基)丙基]吡唑、
3-(4-氟苯基)-5-[2-甲基-3-(3-吡啶基)丙基]-4-(4-吡啶基)-吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(2-吡啶基)丁基]吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(3-吡啶基)丙基]吡唑、
5-(3-苯基丙基)-3-(2-吡啶基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-[3-(4-硝基苯基)丙基]-4-(4-吡啶基)吡唑、
5-[3-(4-氨基苯基)丙基]-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-[3-(1-吡唑基)丙基]-4-(4-吡啶基)吡唑、
5-[3-(4-氨基苯基)丙基]-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-(3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-(2-羟基乙基)-5-(3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-(2-二甲基氨基乙基)-5-(3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(N-甲基-4-甲氧基苄基氨基羰基)-4-(4-吡啶基)吡唑、
5-(N-乙基苄基氨基羰基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
1-乙基-5-(N-甲基苄基氨基羰基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
1-乙基-5-(N-乙基苄基氨基羰基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-(N-甲基苄基氨基羰基)-4-(4-吡啶基)吡唑、
5-(苄基氧基甲基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
5-[1-(苄基氧基)乙基]-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(2-氧代-3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(3-羟基-3-苯基丙基)-4-(4-吡啶基)吡唑;
上式(II)的化合物有:
4-甲基-3-[4-[N-甲基-N-(2-苯基丙基)氨基]-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
4-甲基-3-[4-异丙基氨基-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
4-甲基-3-[4-(N-甲基-N-异丙基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-(4-甲基哌嗪-1-基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-(哌嗪-1-基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-(4-甲基-1,4-二氧杂环庚烷-1-基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-(1,4-二氧杂环庚烷-1-基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-乙基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-苄基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-羟基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-异丙基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
上式(III)的化合物有:
[4-(2-氰基吡啶-4-基甲基)-2-氟苯基]氨基-N-(2-萘基)甲酰胺、
[3-氯-4-(2-氰基吡啶-4-基甲基)苯基]氨基-N-(2,2-二氟苯并[d]-1,3-二噁烷-5-基)甲酰胺、
[3-氯-4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-(2,2-二氟苯并[d]-1,3-二噁烷-5-基)甲酰胺、
[3-氯-4-(2-氰基吡啶-4-基硫基)苯基]氨基-N-(2,2-二氟苯并[d]-1,3-二噁烷-5-基)甲酰胺、
[4-(2-氰基吡啶-4-基甲基)-3-甲基苯基]氨基-N-(2,2,3,3-四氟苯并[e]-1,4-二噁烷-6-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)-3-甲基苯基]氨基-N-(2,2,3,3-四氟苯并[e]-1,4-二噁烷-6-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)-2-氟苯基]氨基-N-(2-三氟甲基吡啶-4-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-(4-叔丁基吡啶-2-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)-3-氟苯基]氨基-N-(4-叔丁基吡啶-2-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-(4-乙基吡啶-2-基)甲酰胺、
[2-氯-4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-喹啉-6-基甲酰胺、
[3-氯-4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-异喹啉-3-基甲酰胺、
[4-(2-氰基吡啶-4-基氧基)-2-硝基苯基]氨基-N-苯并噻唑-5-基甲酰胺、
[4-(3-甲基氨基羰基吡啶-4-基氧基)-2-氟苯基]氨基-N-(3-三氟甲基-4-氯苯基)甲酰胺等。
本发明的处置剂中使用的化合物可以根据情况以盐的形式存在,该盐例如有:与盐酸、氢溴酸、硫酸、硝酸、磷酸等无机酸的盐;与乙酸、草酸、柠檬酸、乳酸、酒石酸、对甲苯磺酸等有机酸的盐;钠盐、钾盐、锂盐等碱金属盐;钙盐、镁盐等碱土金属盐;与三乙胺、二环己胺、吡咯烷、吗啉、吡啶等有机碱的盐;胺盐等,其中优选制药学上可接受的盐。
上式(I)的化合物可根据后述制备例所述方法或公知文献所述方法(例如PCT国际公开WO00/39116小册子、PCT国际公开WO00/75131小册子等中记载的方法)容易地制备。上式(II)的化合物例如可按照J.Med.Chem.,Vol.47,6283-6291(2004)等中所述的方法容易地制备。并且,上式(III)的化合物例如可按照PCT国际公开WO2004/078747小册子等中记载的方法容易地制备。
本发明的处置剂中使用的化合物所具有的p38MAP激酶抑制作用、TNF-α生成抑制作用和代谢消失速度可通过下述实验显示。
(1)p38MAP激酶结合抑制活性的测定:
将THP-1细胞悬浮于细胞溶胞缓冲液(20mM Tris盐酸缓冲液(pH7.4)、1mM氯化镁、1mM苯甲基磺酰氟、1mM胃蛋白酶抑制剂A、1mM亮抑蛋白酶肽和10mg/mL抑酶肽的混合液)中,然后在水中进行超声波处理。然后以100,000×g离心分离1小时,测定含有所得细胞溶胶组分的上清液的蛋白浓度,用细胞溶胞缓冲液稀释,使细胞溶胶组分的蛋白浓度为1mg/mL,然后分成小份分配,在-80℃下保存备用。
将THP-1细胞的细胞溶胶组分(100μg蛋白量)和被测化合物在15℃下温育30分钟,然后添加1.11KBq作为放射性配体的4-(4-氟苯基)-2-(4-羟基-3,5-二-3H-苯基)-5-(4-吡啶基)咪唑(925GBq/mmol,英国アマシャム制备),进一步在15℃下反应3小时,然后测定结合抑制活性。非特异性结合是添加20μM4-(4-氟苯基)-2-(4-甲磺酰基苯基)-5-(4-吡啶基)咪唑进行测定的。为了分离游离和结合型放射性配体,在加入活性炭溶液(1%活性炭和0.1%葡聚糖T-70)之后,冰冷却15分钟,离心分离(3,000rpm,10分钟,4℃)。所得上清中的放射活性使用液体闪烁计数仪测定。测定结果如下表A所示。
表A
(2)TNF-α生成抑制作用的测定:
将来自人的培养细胞THP-1(购自大日本制药)悬浮于RPMI 1640培养基(含10%胎牛血清、100单位/mL青霉素)中(1×105个细胞/mL)。向培养用24孔板中接种1.6mL THP-1细胞悬浮液,再加入0.2mL溶解于RPMI 1640培养基的被测物质和0.2mL 10μg/mL浓度的LPS(来自大肠杆菌055:B5,溶解于RPMI 1640培养基,Difco),然后在37℃、5%CO2的条件下培养2小时。离心分离(500×g,5分钟),将所得上清用ELISA(Amersham Biosiences,TNF-α Human,ELISA BiotrakSystem)测定,进行TNF-α的定量。如下求出各被测物质的50%抑制浓度(IC50)。首先,通过下式求出各种浓度下的TNF-α的生成抑制率(%)。
通过Prism 4 for Windows Ver 4.02(Graph Pad Software,Inc)计算由该式得到的TNF-α的生成抑制率(%)和此时的被测物质浓度,算出IC50值。该结果与下述(3)化合物的消失速度的测定结果一并表示在后述表B中。
(3)化合物的消失速度的测定:
向含有NADPH生成系统(含有3.3mmol/L MgCl2、3.3mmol/L葡萄糖6-磷酸、1.3mmol/L β·NADP+和0.4单位/mL葡萄糖6-磷酸脱氢酶)的磷酸钾缓冲液(50mmol/L,pH7.4)中添加化合物(此时,使终浓度为1μmol/L),在37℃下温育2分钟。温育后,添加人肝S9(将人肝细胞破碎液以9000×g离心分离所得的上清组分)的磷酸钾缓冲液悬浮液,使终浓度为0.5mg蛋白/mL。将该反应混合液在37℃下温育5分钟,然后添加反应混合液体积的4倍的乙腈,混合并冰冷却。冰冷却后离心分离(2000×g,10分钟),采集上清的一部分,通过LC/MS/MS进行分析,计算反应溶液中未变化体的残留率。该结果与上述(2)TNF-α生成抑制作用的测定结果一并表示在下述表B中。
表B
本发明的处置剂中使用的化合物对于病态模型的效果可由以下所述实验显示。
(4)小鼠的DSS诱发结肠炎模型
通过使BALB/c雌性小鼠在一周内自由饮水,饮入5%葡聚糖硫酸钠(DSS),制作结肠炎模型。
开始饮水的同时,以每天两次的比例经口给予被测物质一周。另外,以每天一次的比例经口给予作为对象物质的柳氮磺吡啶。开始饮水一周后摘除肠管,以结肠+直肠的长度作为指标评价被测物质的效果。将该结果与下述(5)大鼠的乙酸诱发结肠炎模型中的研究结果一并表示在后述表C中。
(5)大鼠的乙酸诱发结肠炎模型
将Wistar系雄性大鼠断食24小时,然后在戊巴比妥麻醉下开腹,使盲肠至大肠露出,用微量调节注射器由浆膜一侧向距盲肠5cm的肛门一侧的粘膜下组织中注入20μL 20%乙酸。然后将注入部位用生理盐水清洗,返回腹腔内缝合腹部,制作结肠炎模型。
从模型制作日起,以每天2次的比例直肠内给予被测物质。同样给予作为对象物质的5-氨基水杨酸。给予被测物质5天后,摘除肠管,以发生障碍的面积作为指标,评价被测物质的效果。将结果与上述(4)小鼠的DSS诱发结肠炎模型的研究结果一并表示在下述表C中。
表C
即,本发明的处置剂作为具有优异的p38MAP激酶抑制作用且血液转移后迅速消失的、副作用小的药物,可以经口给予或非经口给予(例如肌肉注射、静脉注射、直肠给予、透皮给予等)来处置人或人以外的哺乳动物的炎性肠病。
本发明的处置剂根据其用途,可以与无毒性的添加剂一起制成固体形态(例如片剂、硬胶囊剂、软胶囊剂、颗粒剂、散剂、细粒剂、丸剂、糖锭等)、半固体形态(例如栓剂、软膏等)或液体形态(例如注射剂、乳剂、混悬液、溶液、喷雾剂等)的任意制剂形态。另外,可在上述制剂中使用的无毒性的添加物例如有淀粉、明胶、葡萄糖、乳糖、果糖、麦芽糖、碳酸镁、滑石粉、硬脂酸镁、甲基纤维素、羧甲基纤维素或其盐、阿拉伯树胶、聚乙二醇、对羟基苯甲酸烷基酯、糖浆、乙醇、丙二醇、凡士林、碳蜡、甘油、氯化钠、亚硫酸钠、磷酸钠、柠檬酸等。该制剂还可以含有治疗学上有用的其它药物。
即,本发明提供用于处置炎性肠病的制药学组合物,该组合物是同时含有具有作为前效药物的性质的p38MAP激酶抑制剂与无毒性的添加物而成的。
本发明还提供炎性肠病的处置方法,其特征在于:将有效量的具有作为前效药物的性质的p38MAP激酶抑制剂给予需要处置的患者。
在所述制剂或组合物中,本发明的处置剂的含量根据其剂型而不同,通常,为固体和半固体形态时,希望以0.1-50%重量范围内的浓度含有,为液体形态时,希望以0.05-10%重量范围内的浓度含有。
本发明的处置剂的给予量可以根据作为对象的以人为代表的温血动物的种类、年龄、体重、给予途径、症状的轻重、医师的诊断等在较大范围内变化,通常可在每天0.02-20mg/kg,优选0.2-8mg/kg的范围内。当然也可以根据患者的症状轻重、医师的诊断等,给予比上述范围的下限还少的量或比上限还多的量。上述给予量可以每天一次或分数次给予。
实施例
以下通过实施例和制备例进一步具体说明本发明。
实施例1:片剂的制剂例
将活性成分粉碎为70μm以下的粒度,向其中加入淀粉、乳糖和羧甲基纤维素钙,充分混合。将10%淀粉浆加入到上述混合粉体中搅拌混合,制备颗粒。干燥后将粒径调整为1000μm左右,向其中混合滑石粉和硬脂酸镁,压片。
制备例1
3-(4-氟苯基)-5-(苯基乙酰基氨基)-4-(4-嘧啶基)异噁唑
a:二甲基-[(E)-2-(4-嘧啶基)乙烯基]胺的合成
将10g4-甲基嘧啶和38g N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)和46.6g DMF的混合物在密封管中、在140℃下搅拌24小时。将反应溶液冷却,然后减压馏去溶剂,得到15.08g为茶色晶体的标题化合物(收率95%)。
1H-NMR(CDCl3)δ:8.73(bs,1H),8.22(d,J=5.5Hz,1H),7.77(d,J=12.9Hz,1H),6.72(dd,J=5.5Hz,12.9Hz,1H),5.00(d,J=12.9Hz,1H),2.96(s,6H)
b:4-嘧啶基乙腈的合成
在5g二甲基-[(E)-2-(4-嘧啶基)乙烯基]胺的70mL水溶液中加入9.48g羟基胺-O-磺酸,在50℃下搅拌30分钟。在冰冷却下加入饱和碳酸氢钠水溶液,使反应溶液呈碱性,然后用乙酸乙酯萃取。乙酸乙酯萃取液用无水硫酸镁干燥,然后减压馏去溶剂,将所得残余物通过30g硅胶柱层析(洗脱溶剂为氯仿:甲醇=30:1)纯化,得到1.56g为淡黄色晶体的标题化合物(收率39%)。
1H-NMR(CDCl3)δ:9.21(d,J=1.2Hz,1H),8.80(d,J=5.2Hz,1H),7.51(dd,J=1.2Hz,5.2Hz,1H),3.93(s,2H)
c:5-氨基-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑的合成
将2.50g甲醇钠溶解于50mL甲醇中,滴加5g4-嘧啶基乙腈的50mL THF溶液,然后在室温下搅拌30分钟。接着滴加7.29g4-氟苯甲氯肟酸(4-fluorobenzohydroxymoyl chloride)的50mL甲醇溶液,然后在室温下搅拌7小时。反应溶液在减压下馏去溶剂,然后加入水滤取析出的残余物,水洗后减压干燥。将所得残余物用80g硅胶柱层析(洗脱溶剂为氯仿:甲醇=50:1-30:1)纯化,用醚洗涤,得到7.86g为浅灰色晶体的标题化合物(收率:73%)。
1H-NMR(CDCl3)δ:9.03(d,J=1.4Hz,1H),8.32(d,J=5.6Hz,1H),7.70~7.05(m,4H),6.88(bs,2H),6.70(dd,J=1.4Hz,5.6Hz,1H)
质谱,m/e:256(M+),111(基峰)
d:3-(4-氟苯基)-5-(苯基乙酰基氨基)-4-(4-嘧啶基)异噁唑的合成
将0.43g咪唑和1.9g DBU溶解于40mL THF中,冰冷却搅拌下滴加0.97g苯基乙酰氯,然后在室温下搅拌20分钟。接着滴加0.8g 5-氨基-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑的40mL THF溶液,然后在室温下搅拌6小时。减压馏去溶剂,加入水,用乙酸乙酯萃取反应液。用无水硫酸镁干燥有机层,然后减压馏去溶剂。将所得残余物用40g硅胶柱层析(洗脱溶剂为氯仿:甲醇=100:1)纯化,然后用醚洗涤,得到0.77g为无色晶体的标题化合物(收率:66%)。
1H-NMR(CDCl3)δ:11.39(s,1H),8.49(s,1H),8.36(d,J=5.6Hz,1H),7.50~7.38(m,7H),7.20(t,J=8.5Hz,2H),6.73(dd,J=1.3Hz,5.6Hz,1H),3.94(s,2H)
质谱,m/e:374(M+),240(基峰)
制备例2
5-[(2-氯苯基)乙酰基氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑(化合物编号:B-1)
使用2-氯苯基乙酰氯代替苯基乙酰氯,与制备例1-d同样,合成标题化合物。
1H-NMR(CDCl3)δ:11.45(bs,1H),8.54(s,1H),8.38(d,J=5.7Hz,1H),7.55~7.38(m,6H),7.20(t,J=8.7Hz,2H),6.75(dd,J=1.3Hz,5.7Hz,1H),4.06(s,2H)
质谱,m/e:408(M+),240(基峰)
制备例3
5-[(2-氯-6-氟苯基)乙酰基氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑(化合物编号:B-2)
与制备例2同样,合成标题化合物。
1H-NMR(CDCl3)δ:11.55(s,1H),8.64(s,1H),8.40(d,J=5.7Hz,1H),7.51~7.45(m,2H),7.43~7.34(m,2H),7.26~7.13(m,3H),6.78(dd,J=1.3Hz,5.7Hz,1H),4.14(s,2H)
质谱,m/e:426(M+),240(基峰)
制备例4
3-(4-氯苯基)-5-[(2-氯苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑(化合物编号:B-3)
使用4-氯苯甲氯肟酸(4-chlorobenzohydroxymoyl chloride)代替4-氟苯甲氯肟酸,与制备例1-c同样,合成5-氨基-3-(4-氯苯基)-4-(4-嘧啶基)异噁唑,然后与制备例2同样,合成标题化合物。
1H-NMR(CDCl3)δ:11.44(bs,1H),8.53(s,1H),8.39(d,J=5.6Hz,1H),7.54~7.39(m,8H),6.76(dd,J=1.5Hz,5.6Hz,1H),4.06(s,2H)
质谱,m/e:424(M+),256(基峰)
以下,与制备例4同样,合成制备例5-14的化合物。
制备例5
5-[(2-氯苯基)乙酰基氨基]-3-(2,4-二氟苯基)-4-(4-嘧啶基)异噁唑(化合物编号:B-4)
1H-NMR(CDCl3)δ:11.49(bs,1H),8.53(s,1H),8.41(d,J=5.4Hz,1H),7.54~7.40(m,5H),7.09~7.04(m,1H),6.98(dt,J=2.3Hz,8.5Hz,1H),6.67(td,J=1.5Hz,5.4Hz,1H),4.07(s,2H)
质谱,m/e:426(M+),258(基峰)
制备例6
3-(2,4-二氟苯基)-5-[(3-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑(化合物编号:B-5)
1H-NMR(CDCl3)δ:11.43(s,1H),8.48(s,1H),8.40(d,J=5.4Hz,1H),7.54~7.49(m,1H),7.40~7.36(m,1H),7.28~7.20(m,3H),7.09~7.04(m,1H),7.00~6.95(m,1H),6.76(dt,J=1.5Hz,5.4Hz,1H),3.89(s,2H),2.40(s,3H)
质谱,m/e:406(M+),258(基峰)
制备例7
5-[(2-氯苯基)乙酰基氨基]-3-(2-氟-4-甲氧基苯基)-4-(4-嘧啶基)异噁唑(化合物编号:B-6)
1H-NMR(CDCl3)δ:11.49(s,1H),8.52(s,1H),8.39(d,J=5.8Hz,1H),7.54~7.51(m,1H),7.48~7.46(m,1H),7.43~7.39(m,3H),6.84(dd,J=2.3Hz,8.5Hz,1H),6.76~6.72(m,2H),4.06(s,2H),3.87(s,3H)
质谱,m/e:438(M+),270(基峰)
制备例8
5-[(2-氯苯基)乙酰基氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑(化合物编号:B-7)
1H-NMR(CDCl3)δ:8.52(s,1H),8.34(d,J=5.4Hz,1H),7.54~7.20(m,8H),6.78(dd,J=1.5Hz,5.4Hz,1H),4.07(s,2H),2.39(s,3H)
质谱,m/e:404(M+),236(基峰)
制备例9
5-[(2-溴苯基)乙酰基氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑(化合物编号:B-8)
1H-NMR(CDCl3)δ:11.45(bs,1H),8.51(s,1H),8.34(d,J=5.5Hz,1H),7.41(d,J=8.1Hz,1H),7.49~7.31(m,5H),7.29(s,1H),7.23(d,J=7.3Hz,1H),6.77(dd,J=1.2Hz,5.5Hz,1H),4.09(s,2H),2.39(s,3H)
质谱,m/e:448(M+),236(基峰)
制备例10
3-(3-甲基苯基)-5-[(2-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑(化合物编号:B-9)
1H-NMR(CDCl3)δ:11.38(s,1H),8.40(d,J=1.4Hz,1H),8.31(d,J=5.6Hz,1H),7.41~7.31(m,6H),7.27(bs,1H),7.21(dd,J=7.7Hz,1H),6.74(dd,J=1.4Hz,5.6Hz,1H),3.92(s,2H),2.38(s,3H),2.36(s,3H)
质谱,m/e:384(M+),236(基峰)
制备例11
3-(3-甲基苯基)-5-[(3-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑(化合物编号:B-10)
1H-NMR(CDCl3)δ:11.49(s,1H),8.47(s,1H),8.33(d,J=5.4Hz,1H),7.39~7.32(m,3H),7.28~7.19(m,5H),6.76(dd,J=1.5Hz,5.4Hz,1H),3.89(s,2H),2.39(s,6H)
质谱,m/e:384(M+),236(基峰)
制备例12
3-(2-氟-5-甲基苯基)-5-(苯基乙酰基氨基)-4-(4-嘧啶基)异噁唑(化合物编号:B-11)
1H-NMR(CDCl3)δ:11.46(bs,1H),8.47(s,1H),8.37(d,J=5.4Hz,1H),7.51~7.40(m,5H),7.34~7.28(m,2H),7.07(t,J=9.3Hz,1H),6.70(td,J=1.9Hz,5.4Hz,1H),3.94(s,2H),2.37(s,3H)
质谱,m/e:388(M+),254(基峰)
制备例13
5-[(3-甲氧基苯基)乙酰基氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁 唑(化合物编号:B-12)
1H-NMR(CDCl3)δ:11.41(s,1H),8.59(s,1H),8.36(d,J=5.8Hz,1H),7.39(t,J=8.1Hz,1H),7.31(d,J=7.0Hz,1H),7.25~7.22(m,1H),7.11(t,J=9.3Hz,1H),6.98~6.94(m,3H),6.76(dd,J=1.2Hz,5.8Hz,1H),3.89(s,2H),3.83(s,3H),2.31(s,3H)
质谱,m/e:418(M+),254(基峰)
制备例14
3-(3-甲基-4-氟苯基)-5-[(2-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑(化合物编号:B-13)
1H-NMR(CDCl3)δ:11.35(bs,1H),8.41(d,J=1.4Hz,1H),8.34(d,J=5.4Hz,1H),7.41~7.30(m,5H),7.24~7.20(m,1H),7.11(t,J=9.3Hz,1H),6.74(dd,J=1.4Hz,5.4Hz,1H),3.92(s,2H),2.35(s,3H),2.30(d,J=1.9Hz,3H)
质谱,m/e:402(M+),254(基峰)
制备例15
3-(3-甲基苯基)-5-(3-苯基丙酰基氨基)-4-(4-吡啶基)异噁唑(化合物编号:B-14)
使用4-吡啶基乙腈代替4-嘧啶基乙腈,与制备例1-c同样,合成5-氨基-3-(3-甲基苯基)-4-(4-吡啶基)异噁唑,然后与制备例1-d同样,合成标题化合物。
1H-NMR(CDCl3)δ:8.39(dd,J=1.5Hz,4.6Hz,2H),8.34(bs,1H),7.30~7.16(m,8H),7.03(d,J=7.3Hz,1H),6.94(dd,J=1.5Hz,4.6Hz,2H),3.00(t,J=7.3Hz,2H),2.75(t,J=7.3Hz,2H),2.29(s,3H)质谱,m/e:383(M+),91(基峰)
以下,与制备例15同样,合成制备例16-20的化合物。
制备例16
3-(3-甲基苯基)-5-[(2-甲基苯基)丙酰基氨基]-4-(4-吡啶基)异噁唑(化合物编号:B-15)
1H-NMR(CDCl3)δ:8.44(d,J=6.0Hz,2H),8.03(bs,1H),7.24~7.18(m,3H),7.15~7.10(m,4H),7.05(d,J=7.03Hz,1H),6.97(d,J=6.0Hz,2H),2.99(t,J=7.6Hz,2H),2.71(t,J=7.6Hz,2H),2.30(s,3H),2.29(s,3H)
质谱,m/e:397(M+),105(基峰)
制备例17
5-[(3-氯苯基)丙酰基氨基]-3-(2-氟-5-甲基苯基)-4-(4-吡啶基)异噁唑(化合物编号:B-16)
1H-NMR(CDCl3)δ:8.41(d,J=5.8Hz,2H),8.07(bs,1H),7.28(dd,J=1.7Hz,6.2Hz,1H),7.23~7.19(m,4H),7.08~7.06(m,1H),6.92~6.88(m,3H),2.99(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,2H),2.33(s,3H)质谱,m/e:435(M+),269(基峰)
制备例18
3-(4-氟-3-甲基苯基)-5-(苯基乙酰基氨基)-4-(4-吡啶基)异噁唑(化合物编号:B-17)
1H-NMR(CDCl3)δ:8.45(dd,J=1.5Hz,4.6Hz,2H),7.60(bs,1H),7.42~7.33(m,3H),7.29~7.22(m,3H),7.08~7.03(m,1H),6.94(t,J=9.1Hz,1H),6.89(dd,J=1.5Hz,4.6Hz,2H),3.76(s,2H),2.22(d,J=1.9Hz,3H)
质谱,m/e;387(M+),91(基峰)
制备例19
5-[(2-氯苯基)乙酰基氨基]-3-(4-氟-3-甲基苯基)-4-(4-吡啶基)异噁唑(化合物编号:B-18)
1H-NMR(CDCl3)δ:8.49(dd,J=1.7Hz,4.4Hz,2H),7.63(bs,1H),7.45~7.42(m,1H),7.35~7.26(m,4H),7.09~7.05(m,1H),6.98(dd,J=1.7Hz,4.4Hz,2H),6.95(t,J=8.9Hz,1H),3.87(s,2H),2.22(d,J=1.9Hz,3H)
质谱,m/e:421(M+),125(基峰)
制备例20
3-(4-氟-3-甲基苯基)-5-(3-苯基丙酰基氨基)-4-(4-吡啶基)异噁唑(化合物编号:B-19)
1H—NMR(CDCl3)δ:8.49(d,J=5.8Hz,2H),7.69(s,1H),7.32~7.16(m,5H),7.09~7.04(m,1H),6.98~6.94(m,3H),3.01(t,J=7.4Hz,2H),2.77(t,J=7.4Hz,2H),2.23(s,3H)
质谱,m/e:401(M+),91(基峰)
Claims (5)
1.炎性肠病的处置剂,其特征在于:含有具有作为前效药物的性质的p38MAP激酶抑制剂作为有效成分。
2.权利要求1所述的处置剂,其中,具有作为前效药物的性质的p38MAP激酶抑制剂选自:
式(I)所示的化合物或其盐
式中,
R1表示取代或未取代的六元芳族杂环基,
R2表示取代或未取代的芳族碳环基或芳族杂环基,
R3表示具有链由选自碳原子、氧原子和氮原子的1-5个原子
构成的直链状连接基团的取代或未取代的碳环基或杂环基,
A表示碳原子、氧原子、硫原子或氮原子;
式(II)所示的化合物或其盐
式中,
R4表示直接或者经由连接基团与三嗪环结合的杂环基,
R5表示取代或未取代的氨基,
R6表示取代或未取代的苯基;
以及
式(III)所示的化合物或其盐,
式中,
Ar1表示取代或未取代的芳族碳环基或芳族杂环基,
Ar2表示取代或未取代的芳族碳环或杂环,
X表示O或S,
L表示链由选自碳原子、氧原子和硫原子的1-3个原子构成的
连接基团,
Q表示取代或未取代的杂环基。
3.权利要求1所述的处置剂,其中,具有作为前效药物的性质的p38MAP激酶抑制剂选自:
5-[(2-氯苯基)乙酰基氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯-6-氟苯基)乙酰基氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑、
3-(4-氯苯基)-5-[(2-氯苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(2,4-二氟苯基)-4-(4-嘧啶基)异噁唑、
3-(2,4-二氟苯基)-5-[(3-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(2-氟-4-甲氧基苯基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(2,3-亚甲二氧基苯基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑、
5-[(2-溴苯基)乙酰基氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑、
3-(3-甲基苯基)-5-[(2-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
3-(3-甲基苯基)-5-[(3-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
3-(2-氟-5-甲基苯基)-5-(苯基乙酰基氨基)-4-(4-嘧啶基)异噁唑、
5-[(3-甲氧基苯基)乙酰基氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑、
3-(3-甲基-4-氟苯基)-5-[(2-甲基苯基)乙酰基氨基]-4-(4-嘧啶基)异噁唑、
3-(3-甲基苯基)-5-(3-苯基丙酰基氨基)-4-(4-吡啶基)异噁唑、
3-(3-甲基苯基)-5-[(2-甲基苯基)丙酰基氨基]-4-(4-吡啶基)异噁唑、
5-[(3-氯苯基)丙酰基氨基]-3-(2-氟-5-甲基苯基)-4-(4-吡啶基)异噁唑、
3-(4-氟-3-甲基苯基)-5-苯基乙酰基氨基-4-(4-吡啶基)异噁唑、
5-[(2-氯苯基)乙酰基氨基]-3-(4-氟-3-甲基苯基)-4-(4-吡啶基)异噁唑、
3-(4-氟-3-甲基苯基)-5-(3-苯基丙酰基氨基)-4-(4-吡啶基)异噁唑、
4-(4-氟苯基)-2-(4-羟基-3,5-二苯基)-5-(4-吡啶基)咪唑、
4-(4-氟苯基)-2-(4-甲磺酰基苯基)-5-(4-吡啶基)咪唑、
3-(4-氟苯基)-5-苯基乙酰基氨基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(4-甲氧基苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
5-(2-氯苯基乙酰基氨基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
5-(2,5-二氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2-氯-6-氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,6-二氯苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,4-二氯苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,6-二氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(3,5-二氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,3-二氟苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,5-二甲基苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2,4-二甲氧基苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2-氯苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
5-(2-溴苯基乙酰基氨基)-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(2-氟苯基乙酰基氨基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-(2-甲基苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(2-甲氧基苯基乙酰基氨基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(2-硝基苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
1-乙基-3-(4-氟苯基)-5-苯基乙酰基氨基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-苯基乙酰基氨基-1-丙基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-(2-羟基乙基)-5-(2-甲氧基苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
5-(2-氯苯基乙酰基氨基)-3-(4-氟苯基)-1-(2-羟基乙基)-4-(4-吡啶基)吡唑、
1-甲基-3-(3,4-亚甲二氧基苯基)-5-苯基乙酰基氨基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-苯基乙酰基氨基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-(N-甲基-N-苯基乙酰基氨基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(N-甲酰基-N-苯乙基氨基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(1-羟基-4-苯基丁基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-[1-羟基-3-(3-甲苯基)丙基]-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(1-羟基-3-苯基丁基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(1-羟基-2-甲基-3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(1-羟基-3-苯基丙基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(2-吡啶基)-1-丙烯基]吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(3-吡啶基)-1-丙烯基]吡唑、
3-(4-氟苯基)-5-[2-甲基-3-(3-吡啶基)-1-丙烯基]-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(2-吡啶基)-1-丁烯基]吡唑、
3-(4-氟苯基)-1-甲基-4-(4-吡啶基)-5-[3-(3-吡啶基)-1-丙烯基]吡唑、
3-(4-氟苯基)-5-(3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(3-吡啶基)丁基]吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(2-吡啶基)丙基]吡唑、
3-(4-氟苯基)-5-[2-甲基-3-(3-吡啶基)丙基]-4-(4-吡啶基)-吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(2-吡啶基)丁基]吡唑、
3-(4-氟苯基)-4-(4-吡啶基)-5-[3-(3-吡啶基)丙基]吡唑、
5-(3-苯基丙基)-3-(2-吡啶基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-[3-(4-硝基苯基)丙基]-4-(4-吡啶基)吡唑、
5-[3-(4-氨基苯基)丙基]-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-[3-(1-吡唑基)丙基]-4-(4-吡啶基)吡唑、
5-[3-(4-氨基苯基)丙基]-3-(4-氟苯基)-1-甲基-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-(3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-(2-羟基乙基)-5-(3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-(2-二甲基氨基乙基)-5-(3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(N-甲基-4-甲氧基苄基氨基羰基)-4-(4-吡啶基)吡唑、
5-(N-乙基苄基氨基羰基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
1-乙基-5-(N-甲基苄基氨基羰基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
1-乙基-5-(N-乙基苄基氨基羰基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-1-甲基-5-(N-甲基苄基氨基羰基)-4-(4-吡啶基)吡唑、
5-(苄基氧基甲基)-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
5-[1-(苄基氧基)乙基]-3-(4-氟苯基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(2-氧代-3-苯基丙基)-4-(4-吡啶基)吡唑、
3-(4-氟苯基)-5-(3-羟基-3-苯基丙基)-4-(4-吡啶基)吡唑、
4-甲基-3-[4-[N-甲基-N-(2-苯基丙基)氨基]-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
4-甲基-3-[4-异丙基氨基-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
4-甲基-3-[4-(N-甲基-N-异丙基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-(4-甲基哌嗪-1-基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-(哌嗪-1-基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-(4-甲基-1,4-二氧杂环庚烷-1-基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-(1,4-二氧杂环庚烷-1-基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-乙基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-苄基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-甲氧基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-羟基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
N-异丙基-4-甲基-3-[4-(N-甲基-N-新戊基氨基)-6-((S)-吡咯烷-3-基氨基)-1,3,5-三嗪-2-基氨基]苯甲酰胺、
[4-(2-氰基吡啶-4-基甲基)-2-氟苯基]氨基-N-(2-萘基)甲酰胺、
[3-氯-4-(2-氰基吡啶-4-基甲基)苯基]氨基-N-(2,2-二氟苯并[d]-1,3-二噁烷-5-基)甲酰胺、
[3-氯-4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-(2,2-二氟苯并[d]-1,3-二噁烷-5-基)甲酰胺、
[3-氯-4-(2-氰基吡啶-4-基硫基)苯基]氨基-N-(2,2-二氟苯并[d]-1,3-二噁烷-5-基)甲酰胺、
[4-(2-氰基吡啶-4-基甲基)-3-甲基苯基]氨基-N-(2,2,3,3-四氟苯并[e]-1,4-二噁烷-6-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)-3-甲基苯基]氨基-N-(2,2,3,3-四氟苯并[e]-1,4-二噁烷-6-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)-2-氟苯基]氨基-N-(2-三氟甲基吡啶-4-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-(4-叔丁基吡啶-2-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)-3-氟苯基]氨基-N-(4-叔丁基吡啶-2-基)甲酰胺、
[4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-(4-乙基吡啶-2-基)甲酰胺、
[2-氯-4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-喹啉-6-基甲酰胺、
[3-氯-4-(2-氰基吡啶-4-基氧基)苯基]氨基-N-异喹啉-3-基甲酰胺、
[4-(2-氰基吡啶-4-基氧基)-2-硝基苯基]氨基-N-苯并噻唑-5-基甲酰胺、和
[4-(3-甲基氨基羰基吡啶-4-基氧基)-2-氟苯基]氨基-N-(3-三氟甲基-4-氯苯基)甲酰胺。
4.用于处置炎性肠病的制药学的组合物,该组合物是同时含有具有作为前效药物的性质的p38MAP激酶抑制剂与无毒性的添加物而成的。
5.炎性肠病的处置方法,其特征在于:将有效量的具有作为前效药物的性质的p38MAP激酶抑制剂给予需要处置的患者。
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KR100843526B1 (ko) | 2004-02-27 | 2008-07-03 | 에프. 호프만-라 로슈 아게 | 피라졸의 접합 유도체 |
US20050261762A1 (en) * | 2004-05-21 | 2005-11-24 | Medtronic Vascular, Inc. | Medical devices to prevent or inhibit restenosis |
US7939536B2 (en) * | 2004-12-28 | 2011-05-10 | Aska Pharmaceutical Co., Ltd. | Pyrimidinylisoxazole derivatives |
-
2007
- 2007-06-26 EP EP07745569A patent/EP2044957A4/en not_active Withdrawn
- 2007-06-26 KR KR1020097000255A patent/KR20090031721A/ko not_active Application Discontinuation
- 2007-06-26 CN CNA2007800238253A patent/CN101478989A/zh active Pending
- 2007-06-26 CA CA002655999A patent/CA2655999A1/en not_active Abandoned
- 2007-06-26 AU AU2007265964A patent/AU2007265964A1/en not_active Abandoned
- 2007-06-26 JP JP2008522671A patent/JPWO2008001929A1/ja active Pending
- 2007-06-26 WO PCT/JP2007/063206 patent/WO2008001929A1/ja active Application Filing
- 2007-06-26 US US12/308,750 patent/US20090192164A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
JPWO2008001929A1 (ja) | 2009-12-03 |
EP2044957A1 (en) | 2009-04-08 |
EP2044957A4 (en) | 2011-01-05 |
KR20090031721A (ko) | 2009-03-27 |
AU2007265964A1 (en) | 2008-01-03 |
WO2008001929A1 (fr) | 2008-01-03 |
US20090192164A1 (en) | 2009-07-30 |
CA2655999A1 (en) | 2008-01-03 |
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