CN1387530A - 用作磷酸二酯酶vii抑制剂的咪唑并吡啶衍生物 - Google Patents
用作磷酸二酯酶vii抑制剂的咪唑并吡啶衍生物 Download PDFInfo
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Abstract
式I的化合物:其中R1表示CONR4R5,R2表示H或A,R4和R5各自独立表示H或A1,R3表示Hal,Hal表示F、Cl、Br或I,A表示具有1-4个碳原子的烷基,A1表示具有1-10个碳原子的烷基,X表示具有1-4个碳原子的亚烷基,其中亚乙基还可以用双键或三键来代替,和它们的生理可接受的盐和/或溶剂化物,作为磷酸二酯酶VII抑制剂,和它们用于制备药物的用途。
Description
其中
R1表示CONR4R5,
R2表示H或A,
R4和R5各自独立表示H或A1,
R3表示Hal,
Hal表示F、Cl、Br或I,
A表示具有1-4个碳原子的烷基,
A1表示具有1-10个碳原子的烷基
X表示具有1-4个碳原子的亚烷基,其中亚乙基还可以用双键或三键来代替,
和它们的生理可接受的盐和/或溶剂化物。
例如在EP 82369中公开了具有GABA兴奋作用的其它咪唑并吡啶衍生物。
本发明以发现具有有价值的性能的新型化合物为目的,尤其能够用于生产药剂的那些。
已经发现,式I的化合物和它们的盐具有很有价值的药理性能,并且很好地被耐受。
尤其,它们表现了“咯利普兰不敏感型”cAMP磷酸二酯酶(PDE VII)的特异抑制作用。
式I的化合物的生物活性能够通过例如由M.A.Giembycz等人在Br.J.Pharmacol.(1996),118,1945-1958中所述的方法来测定。
化合物对cAMP磷酸二酯酶(PDE VII)的亲合力通过检测它们的IC50值来测定(要求达到酶活性的50%抑制的抑制剂的浓度)。为了进行该检测,使用匀化SK-N-SH神经胚细胞瘤细胞代替T淋巴细胞,和使用CI-930进行PDE III抑制。这是选择性PDE III抑制剂(J.A.Bristol等人,J.Med.Chem.1984,27(9),1099-1101)。另外,SK-N-SH用HUT-78代替和用trequensin代替使用CI-930抑制(D.Ruppet等人,life Sci.31:2037,1982)。
式I的化合物能够用来治疗气喘疾病。抗气喘作用例如能够与T.Olsson,Acta allergologica 26,438-447(1971)的方法类似地来测定。
因为cAMP抑制破骨细胞和模拟成骨细胞的作用(S.Kasugai et al.,M681,and K.Miyamoto,M682,in Abstracts of American Society forBone and Mineral Research,18th,Annual Meeting,1996),式I的化合物能够用于治疗骨质疏松症。
这些化合物还表现了对TNFα(肿瘤坏死因子)产生的拮抗作用,并因此适合于治疗变应性和炎症性疾病,自体免疫性疾病,例如类风湿性关节炎,多发性硬化症,科劳恩氏(Crohn)病,糖尿病或溃疡性结肠炎,移植排斥反应,恶病质和败血症。
式I的物质的抗炎症作用和它们治疗例如自体免疫性疾病如多发性硬化症或类风湿性关节炎的效果能够类似于N.Sommer等人,NatureMedicine 1,244-248(1995),或L.Sekut等人,Clin.Exp.Immunol.100,126-132(1995)的方法来测定。
这些化合物能够用于治疗恶病质。抗恶病质作用能够在恶病质的TNF依赖性模型中测试(P.Costelli等人,J. Clin.Invest.95,2367ff.(1995);J.M.Argiles等人,Med.Res.Rev.17,477ff.(1997))。
PDE VII抑制剂还能够抑制肿瘤细胞的生长和因此适于肿瘤治疗(用作PDE IV抑制剂,参阅D.Marko等人,Cell Biochem.Biophys.28,75ff(1998))。
它们因此还能够用于治疗败血症和用于治疗记忆障碍,动脉粥样硬化,特应性皮炎和AIDS,此外用于治疗T细胞依赖性疾病(L.Li等人,Science,1999,283,848-851)。
式I的化合物能够用作人和兽医学中的药物活性成分。它们而且能够用作制备其它药物活性成分的中间体。尤其,式I的化合物能够用作人和兽医学中用于PDE VII抑制的药物活性成分。
本发明此外涉及式I的化合物用于制备抵抗变应性疾病,哮喘,慢性支气管炎,特应性皮炎,银屑病和其它皮肤疾病,炎症性疾病,自体免疫性疾病如类风湿性关节炎、多发性硬化症、科劳恩氏病,糖尿病或溃疡性结肠炎,骨质疏松症,移植排斥反应,恶病质,肿瘤生长或肿瘤转移,败血症,记忆障碍,动脉粥样硬化和AIDS的药物的用途。
A表示具有1-4个碳原子的烷基,和具有1、2、3或4个碳原子,优选表示甲基,乙基或丙基,此外优选异丙基,丁基,异丁基,仲丁基或叔丁基。在基团中的1-7H原子也可以被F和/或Cl取代。A因此还表示例如三氟甲基或五氟乙基。
A1表示具有1-10个碳原子的烷基,和具有1、2、3、4、5、6、7、8、9或10个碳原子,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,以及正戊基、新戊基、异戊基或己基。在这些基团中的1-7H原子还可以被F和/或Cl取代。A1因此还表示例如三氟甲基或五氟乙基。
X表示具有1-4个碳原子的亚烷基,优选亚甲基,亚乙基,亚丙基或亚丁基,其中一个亚乙基还可以被双键或三键所替代。X因此还表示例如-CH2-CH=CH-CH2-或-C≡C-。
因此,本发明尤其涉及其中所述基团的至少一个具有上述优选含义之一的式I的那些化合物。一些优选化合物族可以用以下从属式Ia-Ic来表示,它对应于式I,在这些从属式中,没有更详细地指定的基团具有在式I中所述的含义,但其中
在Ia中,R3表示Cl;
在Ib中,R3表示Cl,
X表示具有1-4个碳原子的亚烷基;
在Ic中,R3表示Cl,
X表示具有1、2、3或4个碳原子的亚烷基,
A1表示具有1、2、3或4个碳原子的烷基。
尤其可以如在EP 82369的第3页左手栏18行到第4页6栏16行,或者在实施例1中所述类似地制备式I的化合物和用于制备它们的起始原料。
式I的化合物和用于制备它们的起始原料另外通过本身已知的方法,如在文献中(例如在标准著作中,如Houben-Weyl,Methoden derorganischen Chemie[Methods of Organic Chemistry],Georg-Thieme-Verlag,Stuttgart)所述那样来制备,确切地说是在已知的和适合于所述反应的反应条件下。
能够使用酸将式I的碱转化成相关的酸加成盐,例如通过等量的碱和酸在适合的溶剂,如乙醇中反应,随后进行蒸发来完成。用于该反应的适合酸尤其是获得生理可接受的盐的那些。因此,可能使用无机酸,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,此外有机酸,尤其脂族、脂环族、芳脂族、芳族或杂环单或多元羧酸、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,葡糖酸,抗坏血酸,烟酸,异烟酸,甲烷或乙烷磺酸,乙烷二磺酸,2-羟基乙烷磺酸,苯磺酸,对甲苯磺酸,萘单和二磺酸,月桂基硫酸。具有生理不可接受的酸的盐,例如苦味酸盐,能够用于分离和/或纯化式I的化合物。
本发明还涉及作为磷酸二酯酶VII抑制剂的式I的药物和它们的生理可接受的盐。
本发明此外涉及包括至少一种式I的磷酸二酯酶VII抑制剂和/或它的生理可接受的盐和/或溶剂化物的一种的药物制剂,用于对抗变应性疾病,哮喘,慢性支气管炎,特应性皮炎,银屑病和其它皮肤疾病,炎症性疾病、自体免疫性疾病,例如类风湿性关节炎,多发性硬化症,科劳恩氏(Crohn)病,糖尿病或溃疡性结肠炎,骨质疏松症,移植排斥反应,恶病质,肿瘤生长或肿瘤转移,败血症,记忆障碍,动脉粥样硬化和AIDS。
这些物质通常优选以在约1和500mg之间,尤其在5和100mg之间/剂量单位的剂量给药。日剂量优选在大约0.02和10mg/kg体重之间。然而,各病人的具体剂量取决于各种因素,例如所使用的特定化合物的效力,年龄,体重,一般健康状况,性别,日常饮食,给药的时间和方法,排泄的速度,药物的结合和治疗所针对的特定疾病的严重性。口服给药是优选的。
这些药物制剂能够用作人或兽医学中的药剂。适合的赋型剂是适合于肠道(例如口服)、非肠道或局部给药和与该新型化合物不反应的有机或无机物质,例如水,植物油,苄基醇,亚烷基二醇,聚乙二醇,甘油三乙酸酯,明胶,糖类,如乳糖或淀粉,硬脂酸镁,滑石,凡士林。适合于口服给药的尤其是片剂、丸剂、包膜片剂、胶囊、粉剂、颗粒、糖浆、液汁或滴剂,适合于直肠给药的是栓剂,适合于非肠道给药的是溶液,优选油性或水性溶液,此外悬浮液,乳液或植入物,和适合于局部应用的是软膏、霜剂或粉剂。该新型化合物还可以进行冷冻干燥,和所得冻干物例如可用于制备注射制剂。所述制剂可以被灭菌和/或包括助剂,如润滑剂,防腐剂,稳定剂和/或润湿剂,乳化剂,用于改变渗透压的盐,缓冲物质,染料,香味剂和/或许多其它活性成分,例如一种或多种维生素。
本发明尤其涉及在以下实施例中列举的式I的化合物和它们的生理可接受的盐和/或溶剂化物作为PDE VII抑制剂和涉及它们用于制备对抗变应性疾病,哮喘,慢性支气管炎,特应性皮炎,银屑病和其它皮肤疾病,炎症性疾病,自体免疫性疾病,例如类风湿性关节炎,多发性硬化症,科劳恩氏病,糖尿病或溃疡性结肠炎,骨质疏松症,移植排斥反应,恶病质,肿瘤生长或肿瘤转移,败血症,记忆障碍,动脉粥样硬化和AIDS的药剂的用途。
实施例
2-(3-丁基-7-氯-3H-咪唑并[4,5-c]吡啶-4-基硫烷基)-N,N-二甲基-乙酰胺
2-(3-丁基-7-氯-3H-咪唑并[4,5-c]吡啶-4-基硫烷基)乙酰胺,
2-(3-丁基-7-氯-3H-咪唑并[4,5-c]吡啶-4-基硫烷基)丙酰胺,
2-(3-丁基-7-氯-3H-咪唑并[4,5-c]吡啶-4-基硫烷基)丁酰胺,
2-(3-丁基-7-氯-3H-咪唑并[4,5-c]吡啶-4-基硫烷基)-N-己基乙酰胺,
2-(3-丁基-7-氯-3H-咪唑并[4,5-c]吡啶-4-基硫烷基)-N-辛基乙酰胺,
4-(3-丁基-7-氯-3H-咪唑并[4,5-c]吡啶-4-基硫烷基)-丁-2-烯酸二甲酰胺。
以下实施例涉及药物制剂:
实施例A:注射瓶
100g式I的磷酸二酯酶VII抑制剂和5g磷酸氢二钠在3L双蒸水中的溶液使用2N盐酸调节至pH6.5,无菌过滤,转移至注射瓶,在无菌条件下冻干和在无菌条件下密封。各注射瓶含有5mg活性成分。
实施例B:栓剂
将20g的式I的磷酸二酯酶VII抑制剂的混合物在100g大豆卵磷脂和1400g可可脂内熔化,倒入模子中,使其冷却。各栓剂含有20mg活性成分。
实施例C:溶液
制备1g式I的磷酸二酯酶VII抑制剂,9.38g NaH2PO4·2H2O,28.48gNa2HPO4·12H2O和0.1g苯扎氯铵在940ml双蒸水中的溶液。将pH调节至6.8,和将溶液补充至1L并通过辐射灭菌。该溶液能够以眼滴剂的形式使用。
实施例D:软膏
500mg式I的磷酸二酯酶VII抑制剂与99.5g凡士林在无菌条件下混合。
实施例E:片剂
按照通常方法,以使得每片含有10mg活性成分的这样一种方式,将1kg式I的磷酸二酯酶VII抑制剂,4kg乳糖,1.2kg土豆淀粉,0.2kg滑石和0.1kg硬脂酸镁的混合物压制,以获得片剂。
实施例F:包膜片剂
类似于实施例E来压缩片剂,和随后按照通常方法用蔗糖、土豆淀粉、滑石、黄蓍胶和染料的包膜包覆。
实施例G:胶囊
按照通常方法,以使得每粒胶囊含有20mg活性成分的这样一种方式,将2kg式I的磷酸二酯酶VII抑制剂引入到硬明胶胶囊中。
实施例H:安瓿
1kg式I磷酸二酯酶VII抑制剂在60L双蒸水中的溶液进行无菌过滤,转移至安瓿中,在无菌条件下冻干和在无菌条件下密封。各安瓿含有10mg活性成分。
实施例I:吸入喷雾剂
将14g式I的磷酸二酯酶VII抑制剂溶解在10L等渗NaCl溶液中,以及用泵机械将溶液转移至商购喷雾容器中。该溶液能够喷雾至口或鼻中。一次喷雾量(大约0.1ml)对应于大约0.14mg的剂量。
Claims (6)
1、式I的化合物:
其中
R1表示CONR4R5,
R2表示H或A,
R4和R5各自独立表示H或A1,
R3表示Hal,
Hal表示F、Cl、Br或I,
A表示具有1-4个碳原子的烷基,
A1表示具有1-10个碳原子的烷基,
X表示具有1-4个碳原子的亚烷基,其中亚乙基还可以用双键或三键来代替,
和它们的生理可接受的盐和/或溶剂化物。
2、作为药物的根据权利要求1的式I的咪唑并吡啶衍生物和它们的生理可接受的盐和溶剂化物。
3、用于抑制磷酸二酯酶VII的根据权利要求2的药物。
4、用于对抗变应性疾病,哮喘,慢性支气管炎,特应性皮炎,银屑病和其它皮肤疾病,炎症性疾病,自体免疫性疾病,如类风湿性关节炎,多发性硬化症,科劳恩氏病,糖尿病或溃疡性结肠炎,骨质疏松症,移植排斥反应,恶病质,肿瘤生长或肿瘤转移,败血症,记忆障碍,动脉粥样硬化和AIDS的根据权利要求3的药物。
5、包括根据权利要求3和4之一的至少一种药剂和任选的赋型剂和/或助剂和任选的其它活性成分的药物制剂。
6、根据权利要求1的式I的化合物和/或它们的生理可接受的盐或溶剂化物用于制备对抗抗变应性疾病,哮喘,慢性支气管炎,特应性皮炎,银屑病和其它皮肤疾病,炎症性疾病,自体免疫性疾病,如类风湿性关节炎,多发性硬化症,科劳恩氏病,糖尿病或溃疡性结肠炎,骨质疏松症,移植排斥反应,恶病质,肿瘤生长或肿瘤转移,败血症,记忆障碍,动脉粥样硬化和AIDS的药物的用途。
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DE19953414A DE19953414A1 (de) | 1999-11-06 | 1999-11-06 | Imidazopyridinderivate als Phospodiesterase VII-Hemmer |
DE19953414.4 | 1999-11-06 |
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CN1264843C (zh) * | 2001-12-13 | 2006-07-19 | 第一阿斯比奥制药株式会社 | 具有pde7抑制作用的吡唑并嘧啶酮衍生物 |
DE10163991A1 (de) * | 2001-12-24 | 2003-07-03 | Merck Patent Gmbh | Pyrrolo-pyrimidine |
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 |
JP2006219373A (ja) * | 2003-06-13 | 2006-08-24 | Daiichi Asubio Pharma Co Ltd | Pde7阻害作用を有するピリジニルピラゾロピリミジノン誘導体 |
RU2376309C2 (ru) | 2004-07-01 | 2009-12-20 | Асубио Фарма Ко., Лтд. | Производное тиенопиразола, имеющее ингибирующую фосфодиэстеразу 7 (pde 7) активность |
CA2620333A1 (en) | 2005-08-26 | 2007-03-01 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
EP2377530A3 (en) | 2005-10-21 | 2012-06-20 | Braincells, Inc. | Modulation of neurogenesis by PDE inhibition |
WO2007053596A1 (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 |
JP2009536669A (ja) | 2006-05-09 | 2009-10-15 | ブレインセルス,インコーポレイティド | アンジオテンシン調節による神経新生 |
EP2026813A2 (en) | 2006-05-09 | 2009-02-25 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
KR20090064418A (ko) | 2006-09-08 | 2009-06-18 | 브레인셀즈 인코퍼레이션 | 4-아실아미노피리딘 유도체 포함 조합물 |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
CA2681650C (en) * | 2007-03-27 | 2016-11-22 | Omeros Corporation | The use of pde7 inhibitors for the treatment of movement disorders |
US8637528B2 (en) | 2007-03-27 | 2014-01-28 | Omeros Corporation | 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 |
US20150119399A1 (en) | 2012-01-10 | 2015-04-30 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
KR102640696B1 (ko) | 2017-07-12 | 2024-02-27 | 다트 뉴로사이언스, 엘엘씨 | Pde7 억제제로서 치환된 벤즈옥사졸 및 벤조푸란 화합물 |
WO2024038089A1 (en) | 2022-08-18 | 2024-02-22 | Mitodicure Gmbh | Use of a therapeutic agent with phosphodiesterase-7 inhibitory activity for the treatment and prevention of diseases associated with chronic fatigue, exhaustion and/or exertional intolerance |
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AU775993B2 (en) | 2004-08-19 |
US6613778B1 (en) | 2003-09-02 |
AR026352A1 (es) | 2003-02-05 |
EP1226143A2 (de) | 2002-07-31 |
WO2001034601A3 (de) | 2001-11-15 |
PT1226143E (pt) | 2003-08-29 |
CA2388729A1 (en) | 2001-05-17 |
ZA200204510B (en) | 2003-11-26 |
HUP0203245A3 (en) | 2003-12-29 |
DK1226143T3 (da) | 2003-06-30 |
AU1387201A (en) | 2001-06-06 |
EP1226143B1 (de) | 2003-04-02 |
NO20022124L (no) | 2002-05-03 |
ES2192183T3 (es) | 2003-10-01 |
MXPA02004448A (es) | 2004-09-10 |
CZ20021416A3 (cs) | 2002-08-14 |
JP2003513973A (ja) | 2003-04-15 |
WO2001034601A2 (de) | 2001-05-17 |
KR20020044591A (ko) | 2002-06-15 |
NO20022124D0 (no) | 2002-05-03 |
BR0015324A (pt) | 2002-07-09 |
HUP0203245A2 (hu) | 2003-01-28 |
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