CN1382122A - 作为磷酸二酯酶ⅶ抑制剂的吡咯衍生物 - Google Patents

作为磷酸二酯酶ⅶ抑制剂的吡咯衍生物 Download PDF

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CN1382122A
CN1382122A CN00814828A CN00814828A CN1382122A CN 1382122 A CN1382122 A CN 1382122A CN 00814828 A CN00814828 A CN 00814828A CN 00814828 A CN00814828 A CN 00814828A CN 1382122 A CN1382122 A CN 1382122A
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H·M·艾根维勒
R·卓那司
M·沃尔夫
M·伽森
T·维尔戈
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Abstract

作为磷酸二酯酶VII抑制剂的通式I的化合物,其中R1和R2,彼此单独地,各自表示H,A,OA,SA或Hal,R3表示H或A,R4表示A或NH2,R5表示H,NH2,NHA或NA2,A表示具有1－10个碳原子的烷基,链烯基,环烷基或烯化环烷基,Hal表示F,Cl,Br或I,及它们生理上可接受的盐和/或溶剂化物。

Description

作为磷酸二酯酶VII抑制剂的吡咯衍生物
本发明涉及作为磷酸二酯酶VII抑制剂的通式I的化合物
Figure A0081482800041
其中
R1和R2，彼此单独地，各自表示H，A，OA，SA或Hal，
R3表示H或A，
R4表示A或NH2，
R5表示H，NH2，NHA或NA2，
A表示具有1-10个碳原子的烷基，链烯基，环烷基或亚烷基环烷基，
Hal表示F，Cl，Br或I，
及它们生理上可接受的盐和/或溶剂化物。
本发明还涉及通式I的化合物用于制备抗变应性疾病，哮喘，慢性支气管炎，特异反应性皮炎，牛皮癣及其它皮肤病，炎性疾病，自身免疫性疾病，如类风湿性关节炎，(脑脊髓)多发性硬化，克罗恩氏病，糖尿病或溃疡性结膜炎，骨质疏松症，移植排斥反应，恶病质，肿瘤生长或肿瘤转移，脓毒症，记忆障碍，动脉粥样硬化及爱滋病的药物的用途。
通式I的吡咯衍生物已经由K.Gewald等在J.Prakt.Chem./Chem.-Ztg.(1992)，334(6)，491-496中描述过。
本发明的目的是要找到一些新的化合物，其具有有价值的性质，特别是可用于生产药物的那些化合物。
人们已经发现，通式I的化合物及它们的盐具有非常有价值的药理性质，且能被很好地耐受。特别是，它们显示出对“咯利普兰不敏感的”cAMP磷酸二酯酶(PDEVII)的特异性抑制。
通式I化合物的生物活性可用M.A.Giembycz等在Br.J.Pharmacol.(1996)，118，1945-1958中描述的方法来测定。
该化合物对cAMP磷酸二酯酶(PDEVII)的亲和力是通过测量它们的IC50值(获得50％酶活性的抑制所需的抑制剂浓度)确定的。为了进行测定，使用均化的SK-N-SH成神经细胞瘤细胞代替T-淋巴细胞，并使用C1-930进行PDEIII的抑制。这是一种选择性的PDEIII抑制剂(J.A.Bristol等，J.Med.Chem.1984，27(9)，1099-1101)。可供选择地，用HUT-78代替SK-N-SH，并用曲喹辛代替Cl-930进行抑制(D.Ruppert等，LifeSci.31：2037，1982)。
通式I的化合物可用于治疗哮喘病。
抗-哮喘作用可使用与T.Olsson，Actaallergologica26，438-447(1971)相似的方法测定。
因为cAMP可抑制破骨细胞并刺激成骨细胞(S.Kasugai等，M681，和K.Miyamoto，M682，Abstracts of the American Society for Boneand Mineral Research，18thAnnualMeeting，1996)，因此通式I的化合物可用于治疗骨质疏松症。
该化合物还显示出对TNFα(肿瘤坏死因子)产生的拮抗作用，因此适于治疗变应性和炎性疾病，自身免疫性疾病，如类风湿性关节炎，(脑脊髓)多发性硬化，克罗恩氏病，糖尿病或溃疡性结膜炎，移植排斥反应，恶病质及脓毒症。
通式I物质的抗-炎症作用及它们用于治疗自身免疫性疾病，如(脑脊髓)多发性硬化或类风湿性关节炎的有效性可使用与N.Sommer等，Nature Medicine 1，244-248(1995)，或L.Sekut等，Clin.Exp.Immunol.100.126-132(1995)相似的方法测定。
该化合物可用于治疗恶病质。抗-恶病质作用可在恶病质的TNF-依赖性模型中进行试验(P.Costelli等，J.Clin.Invest.95，2367ff.(1995)；J.M.Argiles等，Med.Res.Rev.17，477ff.1997))。
PDEVII抑制剂还可抑制肿瘤细胞的生长，因此适于肿瘤的治疗(D.Marko等，CellBiochem.Biophys.28，75ff.(1998)，与PDEIV抑制剂比较)。
它们还可用于治疗脓毒症和记忆障碍，动脉粥样硬化，特异反应性皮炎及爱滋病，并可用于治疗T-细胞依赖性疾病(L.Li等，Science，1999，283，848-851)。
通式I的化合物可被用作人类PDEVII抑制的药物活性成分和兽药。
A表示具有1-10个碳原子和具有1，2，3，4，5，6，7，8，9或10个碳原子的烷基，优选表示甲基，乙基或丙基，此外更优选异丙基，丁基，异丁基，仲-丁基或叔-丁基，和正-戊基，新戊基，异戊基或己基。在这些基团中，1-7个氢原子可被F和/或Cl取代。因此A也表示三氟甲基或五氟乙基。
A也可表示具有3-8个碳原子的环烷基，且优选表示，例如，环戊基或环己基。
A还可表示链烯基。链烯基具有2-10个碳原子，是线形的或支链的，并表示，例如，乙烯基，丙烯基或丁烯基。此外A还表示亚烷基环烷基。亚烷基环烷基具有4-10个碳原子，且优选表示，例如，亚甲基环戊基，亚乙基环戊基，亚甲基环己基或亚乙基环己基。
R1和R2优选各自表示，彼此单独的，H，甲基，乙基，丙基，丁基，异丙基，叔-丁基，甲氧基，乙氧基，丙氧基，异丙氧基，丁氧基，S-甲基，S-乙基，F或Cl。
R3优选表示H，甲基或乙基。
R4优选表示甲基，乙基，丙基，丁基或NH2。
R5优选表示H，氨基，甲氨基，乙氨基，二甲氨基或二乙氨基。
使用酸可将通式I的碱转换成相关的酸-加成盐，例如使当量的碱和酸在适宜的溶剂，如乙醇中反应，接着进行蒸发。用于此反应的适宜的酸是，特别是，提供生理上可接受的盐的那些酸。因此，可以使用无机酸，例如硫酸，硝酸，氢卤酸，如盐酸或氢溴酸，磷酸，如正-磷酸，氨基磺酸，还有有机酸，特别是脂肪酸，脂环酸，芳酯酸，芳香酸或杂环的一元或多元羧酸，磺酸或硫酸，例如甲酸，乙酸，丙酸，新戊酸，二乙基乙酸，丙二酸，丁二酸，庚二酸，富马酸，马来酸，乳酸，酒石酸，苹果酸，柠檬酸，葡萄糖酸，抗坏血酸，烟酸，异烟酸，甲磺酸或乙磺酸，乙烷二磺酸，2-羟乙磺酸，苯磺酸，对-甲苯磺酸，萘一-和二-磺酸，月桂基硫酸。具有生理上不可接受的酸的盐，例如苦味酸盐，可用于分离和/或纯化通式I的化合物。
本发明还涉及包含至少一种通式I的磷酸二酯酶VII抑制剂和/或至少一种其生理上可接受的盐和/或至少一种溶剂化物的药物组合物，其可用于抗变应性疾病，哮喘，慢性支气管炎，特异反应性皮炎，牛皮癣及其它皮肤病，炎性疾病，自身免疫性疾病，如类风湿性关节炎，(脑脊髓)多发性硬化，克罗恩氏病，糖尿病或溃疡性结膜炎，骨质疏松症，移植排斥反应，恶病质，肿瘤生长或肿瘤转移，脓毒症，记忆障碍，动脉粥样硬化及爱滋病。
这里的物质通常优选以大约1-500mg，特别是5-100mg/剂量单位的剂量给药。每日剂量优选约0.02-10mg/kg体重。然而，各患者的具体剂量取决于各种因素，例如所用具体化合物的效力，年龄，体重，一般的健康状况，性别，日常饮食，给药时间和方法，排泄的速率，药物的组合及所治疗的特殊疾病的严重程度。优选口服给药。
该药物制剂可被用作人类的药物或兽药。适宜的赋形剂是有机或无机的物质，其适于肠内(例如口服)，肠胃外或局部的给药，且其不与新的化合物反应，例如水，植物油，苯甲醇，亚烷基乙二醇，聚乙二醇，甘油三醋酸酯，明胶，碳水化合物如乳糖或淀粉，硬脂酸镁，滑石，凡士林。适于口服给药的是片剂，丸剂，包衣片剂，胶囊剂，散剂，颗粒剂，糖浆剂，糖汁或滴剂，适于直肠给药的是栓剂，适于肠胃外给药的是溶液，优选油性或水性溶液，还有悬浮液，乳液或植入物，适于局部施用的是软膏剂，乳膏或搽剂。还可以将新化合物冷冻干燥，并使用最终的冷冻干燥物，例如，用于制备注射制剂。该制剂还可以被灭菌和/或包含辅剂，如润滑剂，防腐剂，稳定剂和/或湿润剂，乳化剂，用于改善渗透压的盐，缓冲物质，染料，香料和/或大多数其它活性成分，例如一种或多种维生素。
本发明特别涉及下列实施例中所列的，作为PDEVII抑制剂的通式I化合物及其生理上可接受的盐和/或溶剂化物，和它们在制备用于抗变应性疾病，哮喘，慢性支气管炎，特异反应性皮炎，牛皮癣及其它皮肤病，炎性疾病，自身免疫性疾病，如类风湿性关节炎，(脑脊髓)多发性硬化，克罗恩氏病，糖尿病或溃疡性结膜炎，骨质疏松症，移植排斥反应，恶病质，肿瘤生长或肿瘤转移，脓毒症，记忆障碍，动脉粥样硬化及爱滋病的药物中的用途。
实施例1   R1   R2     R3   R4   R5
1   H   H     H   Me   H
2   4-Cl   H     Et   氨基   H
3   H   H     Et   Me   氨基
4   H   H     Et   氨基   H
5   H   H     Et   H   氨基
6   3-Cl   4-OMe     Et   氨基   H
7   3-Cl   4-OMe     Et   Me   氨基
8   4-OCF3   H     Et   氨基   H
Me＝甲基；Et＝乙基
下列实施例涉及药物制剂：
实施例A：注射瓶
使用2N盐酸调节100g通式I的磷酸二酯酶VII抑制剂和5g磷酸氢二钠的3升双蒸馏水溶液的pH至6.5，无菌过滤，转移到注射瓶中，在无菌条件下冷冻干燥，并在无菌条件下密封。每个注射瓶含5mg的活性成分。
实施例B：栓剂
用100g大豆卵磷脂和1400g椰子油溶解20g通式I的磷酸二酯酶VII抑制剂的混合物，注入模子中，冷却。每个栓剂含20mg的活性成分。
实施例C：溶液
在940ml双蒸馏水中，制备1g通式I的磷酸二酯酶VII抑制剂，9.38g的NaH2PO4·2H2O，28.48g的Na2HPO4和0.1g氯化苄烷铵的溶液。调节pH至6.8，将该溶液补至1升，辐照灭菌。此溶液可用于滴眼剂的形式。
实施例D：软膏剂
在无菌条件下，将500mg通式I的磷酸二酯酶VII抑制剂与99.5g的凡士林混合。
实施例E：片剂
用常规方法将1kg通式I的磷酸二酯酶VII抑制剂，4kg乳糖，1.2kg马铃薯淀粉，0.2kg滑石和0.1kg硬脂酸镁的混合物压制成片剂，以这种方法制成的每个片剂含10mg的活性成分。
实施例F：包衣片剂
按照与实施例E相似的方法压制片剂，随后以常规方法用蔗糖，马铃薯淀粉，滑石，西黄芪胶和染料的包衣层包衣。
实施例G：胶囊剂
用常规方法将2kg通式I的磷酸二酯酶VII抑制剂装到硬明胶胶囊中，以这种方法制成的每个胶囊含20mg活性成分。
实施例H：安瓿
无菌过滤1kg通式I的磷酸二酯酶VII抑制剂的60升双蒸馏水溶液，将其转移到安瓿中，在无菌条件下冷冻干燥，并在无菌条件下密封。每个安瓿含10mg活性成分。
实施例I：吸入喷雾剂
将14g通式I的磷酸二酯酶VII抑制剂溶解在10升等渗的NaCl溶液中，并将该溶液转移到商业可购得的具有泵机理的喷雾容器中。该溶液可被喷射到嘴或鼻中。喷射一次喷雾剂(约0.1ml)相当于约0.14mg的剂量。

Claims (3)

1.作为磷酸二酯酶VII抑制剂的通式I的化合物
Figure A0081482800021
其中
R1和R2，彼此单独地，各自表示H，A，OA，SA或Hal，
R3表示H或A，
R4表示A或NH2，
R5表示H，NH2，NHA或NA2，
A表示具有1-10个碳原子的烷基，链烯基，环烷基或亚烷基环烷基，
Hal表示F，Cl，Br或I，
及它们生理上可接受的盐和/或溶剂化物。
2.药物制剂，其特征在于它包含至少一种根据权利要求1所述的通式I的磷酸二酯酶VII抑制剂和/或至少一种其生理上可接受的盐和/或至少一种其溶剂化物。
3.根据权利要求1所述的通式I的化合物和/或它们生理上可接受的盐或溶剂化物在制备用于抗变应性疾病，哮喘，慢性支气管炎，特异反应性皮炎，牛皮癣及其它皮肤病，炎性疾病，自身免疫性疾病，如类风湿性关节炎，(脑脊髓)多发性硬化，克罗恩氏病，糖尿病或溃疡性结膜炎，骨质疏松症，移植排斥反应，恶病质，肿瘤生长或肿瘤转移，脓毒症，记忆障碍，动脉粥样硬化及爱滋病的药物中的用途。
CN00814828A 1999-11-04 2000-10-25 作为磷酸二酯酶ⅶ抑制剂的吡咯衍生物 Pending CN1382122A (zh)

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Families Citing this family (24)

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Publication number Priority date Publication date Assignee Title
US6946481B1 (en) * 1994-08-19 2005-09-20 Abbott Laboratories Endothelin antagonists
DE60222931T2 (de) 2001-12-13 2008-07-10 Asubio Pharma Co., Ltd. Pyrazolopyrimidinonderivate mit pde7-hemmender wirkung
DE10163991A1 (de) * 2001-12-24 2003-07-03 Merck Patent Gmbh Pyrrolo-pyrimidine
DE10226420A1 (de) * 2002-06-13 2004-01-15 Eucro European Contract Research Gmbh & Co Kg Verfahren zur Behandlung der Artherosklerose
JP2006219374A (ja) 2003-06-13 2006-08-24 Daiichi Asubio Pharma Co Ltd Ｐｄｅ７阻害作用を有するイミダゾトリアジノン誘導体
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DK2433943T3 (da) * 2004-07-01 2013-12-16 Daiichi Sankyo Co Ltd Mellemprodukter til thienopyrazol-derivater med PDE7-inhibitorisk aktivitet
EP1928437A2 (en) 2005-08-26 2008-06-11 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
EP2258359A3 (en) 2005-08-26 2011-04-06 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
CA2625153A1 (en) 2005-10-21 2007-04-26 Braincells, Inc. Modulation of neurogenesis by pde inhibition
AU2006308889A1 (en) 2005-10-31 2007-05-10 Braincells, Inc. GABA receptor mediated modulation of neurogenesis
US20100216734A1 (en) 2006-03-08 2010-08-26 Braincells, Inc. Modulation of neurogenesis by nootropic agents
EP2382975A3 (en) 2006-05-09 2012-02-29 Braincells, Inc. Neurogenesis by modulating angiotensin
WO2007134077A2 (en) 2006-05-09 2007-11-22 Braincells, Inc. 5 ht receptor mediated neurogenesis
MX2009002496A (es) 2006-09-08 2009-07-10 Braincells Inc Combinaciones que contienen un derivado de 4-acilaminopiridina.
US20100184806A1 (en) 2006-09-19 2010-07-22 Braincells, Inc. Modulation of neurogenesis by ppar agents
US8637528B2 (en) 2007-03-27 2014-01-28 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
WO2008119057A2 (en) 2007-03-27 2008-10-02 Omeros Corporation The use of pde7 inhibitors for the treatment of movement disorders
US20100216805A1 (en) 2009-02-25 2010-08-26 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
US9220715B2 (en) 2010-11-08 2015-12-29 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
CN103547267A (zh) 2010-11-08 2014-01-29 奥默罗斯公司 使用pde7抑制剂治疗成瘾和冲动控制障碍
EP2804603A1 (en) 2012-01-10 2014-11-26 President and Fellows of Harvard College Beta-cell replication promoting compounds and methods of their use
CA3069432A1 (en) 2017-07-12 2019-01-17 Dart Neuroscience, Llc Substituted benzoxazole and benzofuran compounds as pde7 inhibitors
WO2024038090A1 (en) 2022-08-18 2024-02-22 Mitodicure Gmbh Use of substituted benzoxazole and benzofuran compounds for the treatment and prevention of diseases associated with chronic fatigue, exhaustion and/or exertional intolerance

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