CN1972907A - 磺酰胺化合物 - Google Patents
磺酰胺化合物 Download PDFInfo
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Abstract
本发明提供式(I)的化合物,其前药、药学上可接受的盐或溶剂化物(其中R1是被卤素任选取代的乙基、或被低级烷基任选取代的氨基,R2和R3各自独立地表示氢或低级烷基,X是亚环烷基、低级亚烷基或哌啶二基,Z是任选取代的苯基或任选取代的杂环基)。
Description
技术领域
本发明涉及具有NPYY5受体拮抗物活性的新的化合物或包含该化合物的药物组合物。更具体地,本发明涉及抗肥胖剂或食欲减退剂。
先有技术
神经肽Y(以下简称NPY)是一种于1982年从猪大脑中分离出来的、包含36个氨基酸残基的肽。NPY广泛地分布在人类和动物的中枢神经系统和周围组织中。
据报道NPY在中枢神经系统中具有促进摄入食物的活性、抗癫痫活性、促进学习的活性、抗焦虑活性、抗紧张活性等,并可能与中枢神经系统疾病(例如抑郁症、阿尔茨海默氏病和帕金森氏病)存在重要的关系。由于NPY能够在周围组织中引起平滑肌例如血管或心肌的收缩,因此认为NPY还与心血管疾病有关。此外,已知NPY还与新陈代谢疾病,例如肥胖、糖尿病和激素异常相关(非专利文献1)。因此,NPY受体拮抗物预计可作为药物用于预防或治疗象上述涉及NPY受体的多种疾病。
目前,作为NPY受体,已经确定了Y1、Y2、Y3、Y4、Y5和Y6亚型(非专利文献2)。已经表明,Y5受体至少与摄食行为相关,并且预计其拮抗物可作为抗肥胖剂(非专利文献3)。
专利文献1中描述了与本发明的化合物具有类似结构并具有NPY受体拮抗物活性的化合物。然而,该文件并没有具体公开乙基磺酰胺化合物或氨基被烷基取代的氨基磺酰胺化合物。
非专利文献1:Trends in Pharmacological Sciences,Vol.15,pp.153(1994)
非专利文献2:Trends in Pharmacological Sciences,Vol.18,pp.372(1997)
非专利文献3:Peptides,Vol.18,pp.445(1997)
专利文献1:WO01/37826
发明内容
本发明所要解决的问题
本发明的目的在于提供具有优异的NPYY5受体拮抗物活性的新化合物、以及包含该化合物的药物组合物。
解决该问题的办法
本发明提供
1)式(I)的化合物,其药学上可接受的盐或溶剂化物,
(其中R1是被卤素任选取代的乙基、或被低级烷基任选取代的氨基,
R2和R3各自独立地表示氢或低级烷基,
X是亚环烷基、低级亚烷基或哌啶二基,
Z是任选取代的苯基或任选取代的杂环基)。
2)如上述1)所述化合物,其药学上可接受的盐或溶剂化物,其中:
X是C2-C4亚烷基,
3)如上述1)或2)所述化合物,其药学上可接受的盐或溶剂化物,其中Z是
(i)被一个或多个取代基任选取代的苯基,所述取代基选自被低级烷基取代的吗啉代、卤代低级烷基、低级烷氧基、低级烷氧基羰基、低级亚烷基二氧基或卤代低级亚烷基二氧基,
(ii)被一个或多个选自卤代低级烷基或卤代低级烷氧基的取代基任选取代的吡啶基,
(iii)被低级烷基任选取代的咔唑基或被低级烷基任选取代的四氢咔唑基,
(iv)被一个或多个选自低级烷氧基、低级烷氧基羰基或低级烷基氨基甲酰基的取代基任选取代的苯并呋喃基,
(v)被氧任选取代的色烯基(chromenyl),或
(vi)环庚并苯并呋喃基。
4)如上述1)至3)任一项中所述的化合物,其药学上可接受的盐或溶剂化物,其中,R2和R3都是氢。
5)药物组合物,其包含上述1)至4)任一项中所述的化合物、其药学上可接受的盐或溶剂化物,
6)NPYY5受体拮抗物,其包含上述1)至4)任一项中所述的化合物、其药学上可接受的盐或溶剂化物。
发明效果
本发明的化合物具有NPYY5受体拮抗物活性。因此,本发明的化合物可作为非常有用的抗肥胖剂或食欲减退剂。
实施本发明的最佳方式
本说明书中,“卤素”包括氟、氯、溴和碘。特别优选氟。在“卤代低级烷基”、“卤代低级亚烷基二氧基”、“卤代低级烷氧基”、“卤代低级烷氧基羰基”或“卤代低级烷基氨基甲酰基”中的卤素同上。
术语“低级烷基”包括C1-C10直链或支链烷基。“低级烷基”的实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、己基、异己基、正庚基、异庚基、正辛基、异辛基和正壬基、正癸基。
“被低级烷基取代的吗啉代”、“卤代低级烷基”、“低级烷氧基”、“卤代低级烷氧基”、“低级烷氧基羰基”、“卤代低级烷氧基羰基”、“低级烷基氨基甲酰基”、“卤代低级烷基氨基甲酰基”、“被低级烷基取代的杂环基”或“低级烷基羰基”中的低级烷基部分的含义同上。
R2和R3中的“低级烷基”、或R1中“被低级烷基任选取代的氨基”中的低级烷基优选C1-C3烷基,更优选甲基。
术语“环烷基”包括C3-C8环状烷基,优选C5或C6环状烷基。实例为环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
“环烷基羰基”中环烷基部分的含义同上。
术语“亚环烷基”包括C3-C8环状亚烷基,优选C5或C6环状亚烷基。实例为亚环丙基、亚环丁基、亚环戊基、亚环己基、亚环庚基和亚环辛基,优选亚环己基,特别优选1,4-环己二基。
术语“低级亚烷基”包括含1~6个亚甲基、优选2~6个亚甲基、更优选3~6个亚甲基的二价基团。实例为亚甲基、亚乙基、亚丙基、亚丁基、亚戊基和亚己基,特别优选亚丁基。
“低级亚烷基二氧基”和“卤代低级亚烷基二氧基”中低级亚烷基部分的含义同上,优选亚甲基二氧基或亚乙基二氧基。
术语“低级烯基”包括在任何可能位置具有一个或多个双键的C2-C10、优选C2-C8、更优选C3-C6直链或支链烯基。实例为乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、异戊二烯基、丁二烯基、戊烯基、异戊烯、戊二烯基、己烯基、异己烯基、己二烯基、庚烯基、辛烯基、壬烯基和癸烯基。
“低级烯基羰基”中低级烯基部分的含义同上。
术语“芳基羰基”包括苯甲酰羰基和萘基羰基。
“任选取代的苯基”中取代基的实例是卤素、羟基、低级烷基、卤代低级烷基、低级烷氧基、卤代低级烷氧基、羧基、低级烷氧基羰基、卤代低级烷氧基羰基、酰基、酰氧基、氨基甲酰基、低级烷基氨基甲酰基、卤代低级烷基氨基甲酰基、被取代基α任选取代的苯基、被取代基α任选取代的杂环基(其中取代基α为卤素、羟基、低级烷基、卤代低级烷基、低级烷氧基、卤代低级烷氧基等)、低级亚烷基二氧基、卤代低级亚烷基二氧基、氧(oxo)等。该取代基可以被一个或多个选自上述的取代基取代。
优选被低级烷基取代的杂环基、低级烷基、卤代低级烷基、低级烷氧基、卤代低级烷氧基、羧基、低级烷氧基羰基、卤代低级烷氧基羰基、低级亚烷基二氧基或卤代低级亚烷基二氧基。
术语“杂环基”包括环上含一个或多个任选自O、S和N杂原子的杂环基。例如:5-或6-员杂芳基,例如吡咯基、咪唑基、吡唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三唑基、三嗪基、四唑基、异_唑基、_唑基、_二唑基、异噻唑基、噻唑基、噻二唑基、呋喃基和噻吩基;非芳香族杂环基,例如二氧六环基、硫杂环丙基(thiiranyl)、环氧乙基(oxiranyl)、氧硫杂环戊基(oxathiolanyl)、氮杂环丁基(azetidinyl)、thianyl、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、吗啉基、吗啉代、硫代吗啉基、硫代吗啉代、二氢吡啶基、四氢呋喃基、四氢吡喃基、四氢噻唑基和四氢异噻唑基;由两个环构成的稠合杂环基,例如吲哚基、异吲哚基、吲唑基、中氮茚基(indolizinyl)、二氢吲哚基、异二氢吲哚基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、萘啶基(naphthyridinyl)、喹喔啉基、嘌呤基、蝶啶基、色烯基(chromenyl)、苯并咪唑基、苯并异_唑基、苯并_唑基、苯并_二唑基、苯并异噻唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并三唑基、咪唑并吡啶基、三唑并吡啶基(triazoropyridyl)、咪唑并噻唑基、吡嗪并哒嗪基、喹唑啉基、喹啉基、异喹啉基、萘啶基、二氢吡啶基、四氢喹啉基和四氢苯并噻吩基;由三个环构成的稠合杂环基,例如咔唑基、四氢咔唑基、吖啶基、呫吨基、吩噻嗪基、phenoxathiinyl、吩_嗪基、二苯并呋喃基、环己并苯并呋喃基和环庚并苯并呋喃基(cycloheptabenzofuryl)。
优选吡啶基、咔唑、四氢咔唑基、苯并呋喃基或环庚并苯并呋喃基。
与杂环基以外的环缩合的稠合杂环基(例如苯并呋喃基)可以具有结合到任一环上的键。
“被低级烷基取代的杂环基”中的杂环基部分的含义同上,优选吗啉基。
“任选取代的杂环基”中的取代基与上述“任选取代的苯基”中的取代基相同,其被一个或多个选自它们的取代基任选取代。优选低级烷基、卤代低级烷基、卤代低级烷氧基、低级烷氧基、低级烷氧基羰基和低级烷基氨基甲酰基、氧等。
“被取代基α任选取代的杂环基”中的杂环基部分优选吗啉代、吗啡酚基(morpholyl)、硫代吗啉代、硫代吗啉基等。
术语“酰基”包括(1)C1-C10、优选C1-C6、更优选C1-C4直链或支链低级烷基羰基,或C2-C10、优选C2-C8、更优选C3-C6直链或支链低级烯基羰基,(2)C4-C9、优选C4-C7环烷基羰基,和(3)芳基羰基。实例为甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、特戊酰基、己酰基、丙烯酰基、丙炔酰基、异丁烯酰基、巴豆酰基、环丙基羰基、环己基羰基、环辛基羰基和苯甲酰基。
“酰氧基”中的“酰基”部分含义同上。
本发明的化合物包括它的任何可形成的且药学上可接受的盐。“药学上可接受的盐”的实例有与无机酸形成的盐类,例如与盐酸、硫酸、硝酸和磷酸形成的盐;与有机酸形成的盐类,所述有机酸有例如对甲苯磺酸、甲磺酸、草酸和柠檬酸;与有机碱形成的盐类,所述有机碱有例如氨、三甲胺和三乙胺;与碱金属形成的盐类,例如钠盐和钾盐;与碱土金属形成的盐类,例如钙盐和镁盐。
本发明的化合物包括其溶剂化物。优选水合物,且化合物(I)可用任意数量的溶剂分子配位。
当本发明的化合物(I)具有不对称的碳原子时,其包括外消旋物、所有对映异构体和所有立体异构体,例如其非对映异构体、差向异构体和对映异构体。另外,当本发明的化合物(I)具有双键形成E异构体或Z异构体时,化合物(I)包括这两种异构体。当X为亚环烷基时,化合物(I)包括顺式异构体和反式异构体两者。
可以通过例如专利文献1或下述方法合成本发明的化合物(I)。
(其中,Hal是卤素,其他符号定义同上)
步骤A
化合物(IV)与具有取代基R1(对应于目标化合物)的化合物(V)在适当的溶剂中,如果必要,在碱的存在下反应得到化合物(II)。
溶剂的实例为四氢呋喃、二甲基甲酰胺、乙醚、二氯甲烷、甲苯、苯、二甲苯、环己烷、己烷、氯仿、乙酸乙酯、醋酸丁酯、戊烷、庚烷、二氧杂环己烷、丙酮、乙腈、水及其混合物。优选二氧杂环己烷、二氯甲烷等。
碱的实例是氢氧化钠、氢氧化钾、氢氧化锂等。
反应温度为约0℃~50℃,优选约20℃~30℃。
反应时间约5分钟~30小时,优选约5~20小时。
对于化合物(IV)和(V),可以使用已知的化合物或者通过已知的化合物使用已有的方法合成。
步骤B
化合物(II)和具有对应于目标化合物的取代基Z和R3的化合物(III)在合适的溶剂中反应。
溶剂的实例为四氢呋喃、二甲基甲酰胺、乙醚、二氯甲烷、甲苯、苯、二甲苯、环己烷、己烷、氯仿、乙酸乙酯、醋酸丁酯、戊烷、庚烷、二氧杂环己烷、丙酮、乙腈、水及其混合物。优选二甲基甲酰胺、四氢呋喃、乙酸乙酯等。
如果必要,该反应可在缩合剂,例如1,3-二环己基碳二亚胺、1-乙基-3-(3-二甲氨基)碳二亚胺(WSCD;可溶于水的碳二亚胺),酸性赋形剂(acidic excipient),例如1-羟基苯并三唑、3,4-二氢-3-羟基-4-氧-1,2,3-苯并三嗪的存在下进行。
反应温度为约0℃~50℃,优选约20℃~30℃。
反应时间约5分钟~30小时,优选约5~20小时。
在适当的步骤,可使用适当的保护基采取常见的方式保护氨基。例如酞酰亚胺、低级烷氧基羰基、低级烯基氧基羰基、卤代烷氧基羰基、芳基低级烷氧基羰基、三烷基甲硅烷基、低级烷基磺酰基、卤代低级烷基磺酰基、芳基磺酰基、低级烷基羰基和芳基羰基可作为保护基。
该化合物经过保护以后进行上述反应,在适当的阶段,在适当的溶剂中用酸或碱对所得的化合物进行去保护处理。溶剂的实例为四氢呋喃、二甲基甲酰胺、乙醚、二氯甲烷、甲苯、苯、二甲苯、环己烷、己烷、氯仿、乙酸乙酯、醋酸丁酯、戊烷、庚烷、二氧杂环己烷、丙酮、乙腈及其混合物。碱的实例为肼、吡啶、氢氧化钠和氢氧化钾,酸的实例为盐酸、三氟乙酸和氢氟酸。
本发明的所有化合物都具有NPYY5受体拮抗物活性,并可采取下列试验方法验证其拮抗物活性。
在表达载体pME18S中对编码人类NPYY5受体的cDNA序列(WO96/16542)进行克隆(Takebe等,Mol.Cell.Biol.8,8957)。按照使用说明书的规定,使用Lipofect AMINE试剂(Trademark,GibcoBRL Co.,Ltd.),将所得的表达载体转染至宿主CHO细胞,得到NPYY5受体稳定表达的细胞。
从表达NPYY5受体的CHO细胞制备膜,于25℃在测定缓冲液(含0.1%牛血清清蛋白的20mM HEPES-Hanks缓冲剂,pH7.4)中将本发明的化合物和50000-70000cpm[125I]肽YY(最终浓度100-140pM:Amersham)培养2小时,然后用玻璃过滤器GF/B(用0.5%聚乙烯亚胺和0.25%牛血清清蛋白处理)过滤混合物。用测定缓冲液洗涤玻璃过滤器之后,用γ粒子计数器测量玻璃过滤器上的放射性。计算出本发明化合物对抗特异性肽YY结合的50%抑制浓度(IC50值)。膜制备物在1μM NPYY5激动剂([cPP1-7,NPY19-23,Ala31,Aib32,Gln34]-hPancreatic Polypeptide:Tocris Coockson)和50000-70000cpm[125I]肽YY的存在下培养之后,通过测量玻璃过滤器上的放射性,计算出本发明化合物对抗非特异性结合的50%抑制浓度。
在所有本发明的化合物中,特别优选以下化合物。
式(I)中,
(A1)其中R1是未取代的乙基的化合物(在下文中简称“R1为A1”),
(A2)其中R1是三氟乙基的化合物(在下文中简称“R1为A2”),
(A3)其中R1是二甲氨基的化合物(在下文中简称“R1为A3”),
(B1)其中R2和R3各自独立地表示氢或甲基的化合物(在下文中简称“R2和R3为B1”),
(B2)其中R2和R3都是氢的化合物(在下文中简称“R2和R3为B2”),
(C1)其中X是亚环己基的化合物(在下文中简称“X为C1”),
(C2)其中X是二亚甲基的化合物(在下文中简称“X为C2”),
(C3)其中X是四亚甲基的化合物(在下文中简称“X为C3”),
(C4)其中X是哌啶二基的化合物(在下文中简称“X为C4”),
(D1a)其中Z是被一个或多个选自被低级烷基取代的吗啉代、卤代低级烷基、低级烷氧基、低级烷氧基羰基、低级亚烷基二氧基或卤代低级亚烷基二氧基的取代基任选取代的苯基的化合物(在下文中简称该Z为D1a),
(D1b)其中Z是被一个或多个选自二甲基吗啉代、三氟甲基、甲氧基、甲氧羰基、亚甲基二氧基、二氟亚甲基二氧基或四氟亚乙基二氧基的取代基任选取代的苯基的化合物(在下文中简称该Z为D1b),
(D2a)其中Z是被一个或多个选自卤代低级烷基或卤代低级烷氧基的取代基任选取代的吡啶基的化合物(在下文中简称该Z为D2a),
(D2b)其中Z是被三氟甲基或三氟乙氧基任选取代的吡啶基的化合物(在下文中简称该Z为D2b),
(D3a)其中Z是被低级烷基任选取代的咔唑基或被低级烷基任选取代的四氢咔唑基的化合物(在下文中简称该Z为D3a),
(D3b)其中Z是被乙基或异丙基任选取代的咔唑基或被乙基或异丙基任选取代的四氢咔唑基的化合物(在下文中简称该Z为D3b),
(D4a)其中Z是被一个或多个选自低级烷氧基、低级烷氧基羰基或低级烷基氨基甲酰基的取代基任选取代的苯并呋喃基的化合物(在下文中简称该Z为D4a),
(D4b)其中Z是被一个或多个选自甲氧基、甲氧羰基或异丙基氨基甲酰基的取代基任选取代的苯并呋喃基的化合物(在下文中简称该Z为D4b),
(D5)其中Z是被氧任选取代的色烯基的化合物(在下文中简称该Z为D5),
(D6)其中Z是环庚并苯并呋喃基的化合物(在下文中简称该Z为D6),
(E)其中R1、R2和R3、X和Z(R1、R2和R3、X、Z)的组合是下列任一种组合的化合物,
(R1,R2和R3,X,Z)=(A1,B1,C1,D1a),(A1,B1,C1,D1b),(A1,B1,C1,D2a),(A1,B1,C1,D2b),(A1,B1,C1,D3a),(A1,B1,C1,D3b),(A1,B1,C1,D4a),(A1,B1,C1,D4b),(A1,B1,C1,D5),(A1,B1,C1,D6),(A1,B1,C2,D1a),(A1,B1,C2,D1b),(A1,B1,C2,D2a),(A1,B1,C2,D2b),(A1,B1,C2,D3a),(A1,B1,C2,D3b),(A1,B1,C2,D4a),(A1,B1,C2,D4b),(A1,B1,C2,D5),(A1,B1,C2,D6),(A1,B1,C3,D1a),(A1,B1,C3,D1b),(A1,B1,C3,D2a),(A1,B1,C3,D2b),(A1,B1,C3,D3a),(A1,B1,C3,D3b),(A1,B1,C3,D4a),(A1,B1,C3,D4b),(A1,B1,C3,D5),(A1,B1,C3,D6),(A1,B1,C4,D1a),(A1,B1,C4,D1b),(A1,B1,C4,D2a),(A1,B1,C4,D2b),(A1,B1,C4,D3a),(A1,B1,C4,D3b),(A1,B1,C4,D4a),(A1,B1,C4,D4b),(A1,B1,C4,D5),(A1,B1,C4,D6),(A1,B2,C1,D1a),(A1,B2,C1,D1b),(A1,B2,C1,D2a),(A1,B2,C1,D2b),(A1,B2,C1,D3a),(A1,B2,C1,D3b),(A1,B2,C1,D4a),(A1,B2,C1,D4b),(A1,B2,C1,D5),(A1,B2,C1,D6),(A1,B2,C2,D1a),(A1,B2,C2,D1b),(A1,B2,C2,D2a),(A1,B2,C2,D2b),(A1,B2,C2,D3a),(A1,B2,C2,D3b),(A1,B2,C2,D4a),(A1,B2,C2,D4b),(A1,B2,C2,D5),(A1,B2,C2,D6),(A1,B2,C3,D1a),(A1,B2,C3,D1b),(A1,B2,C3,D2a),(A1,B2,C3,D2b),(A1,B2,C3,D3a),(A1,B2,C3,D3b),(A1,B2,C3,D4a),(A1,B2,C3,D4b),(A1,B2,C3,D5),(A1,B2,C3,D6),(A1,B2,C4,D1a),(A1,B2,C4,D1b),(A1,B2,C4,D2a),(A1,B2,C4,D2b),(A1,B2,C4,D3a),(A1,B2,C4,D3b),(A1,B2,C4,D4a),(A1,B2,C4,D4b),(A1,B2,C4,D5),(A1,B2,C4,D6),(A2,B1,C1,D1a),(A2,B1,C1,D1b),(A2,B1,C1,D2a),(A2,B1,C1,D2b),(A2,B1,C1,D3a),(A2,B1,C1,D3b),(A2,B1,C1,D4a),(A2,B1,C1,D4b),(A2,B1,C1,D5),(A2,B1,C1,D6),(A2,B1,C2,D1a),(A2,B1,C2,D1b),(A2,B1,C2,D2a),(A2,B1,C2,D2b),(A2,B1,C2,D3a),(A2,B1,C2,D3b),(A2,B1,C2,D4a),(A2,B1,C2,D4b),(A2,B1,C2,D5),(A2,B1,C2,D6),(A2,B1,C3,D1a),(A2,B1,C3,D1b),(A2,B1,C3,D2a),(A2,B1,C3,D2b),(A2,B1,C3,D3a),(A2,B1,C3,D3b),(A2,B1,C3,D4a),(A2,B1,C3,D4b),(A2,B1,C3,D5),(A2,B1,C3,D6),(A2,B1,C4,D1a),(A2,B1,C4,D1b),(A2,B1,C4,D2a),(A2,B1,C4,D2b),(A2,B1,C4,D3a),(A2,B1,C4,D3b),(A2,B1,C4,D4a),(A2,B1,C4,D4b),(A2,B1,C4,D5),(A2,B1,C4,D6),(A2,B2,C1,D1a),(A2,B2,C1,D1b),(A2,B2,C1,D2a),(A2,B2,C1,D2b),(A2,B2,C1,D3a),(A2,B2,C1,D3b),(A2,B2,C1,D4a),(A2,B2,C1,D4b),(A2,B2,C1,D5),(A2,B2,C1,D6),(A2,B2,C2,D1a),(A2,B2,C2,D1b),(A2,B2,C2,D2a),(A2,B2,C2,D2b),(A2,B2,C2,D3a),(A2,B2,C2,D3b),(A2,B2,C2,D4a),(A2,B2,C2,D4b),(A2,B2,C2,D5),(A2,B2,C2,D6),(A2,B2,C3,D1a),(A2,B2,C3,D1b),(A2,B2,C3,D2a),(A2,B2,C3,D2b),(A2,B2,C3,D3a),(A2,B2,C3,D3b),(A2,B2,C3,D4a),(A2,B2,C3,D4b),(A2,B2,C3,D5),(A2,B2,C3,D6),(A2,B2,C4,D1a),(A2,B2,C4,D1b),(A2,B2,C4,D2a),(A2,B2,C4,D2b),(A2,B2,C4,D3a),(A2,B2,C4,D3b),(A2,B2,C4,D4a),(A2,B2,C4,D4b),(A2,B2,C4,D5),(A2,B2,C4,D6),(A3,B1,C1,D1a),(A3,B1,C1,D1b),(A3,B1,C1,D2a),(A3,B1,C1,D2b),(A3,B1,C1,D3a),(A3,B1,C1,D3b),(A3,B1,C1,D4a),(A3,B1,C1,D4b),(A3,B1,C1,D5),(A3,B1,C1,D6),(A3,B1,C2,D1a),(A3,B1,C2,D1b),(A3,B1,C2,D2a),(A3,B1,C2,D2b),(A3,B1,C2,D3a),(A3,B1,C2,D3b),(A3,B1,C2,D4a),(A3,B1,C2,D4b),(A3,B1,C2,D5),(A3,B1,C2,D6),(A3,B1,C3,D1a),(A3,B1,C3,D1b),(A3,B1,C3,D2a),(A3,B1,C3,D2b),(A3,B1,C3,D3a),(A3,B1,C3,D3b),(A3,B1,C3,D4a),(A3,B1,C3,D4b),(A3,B1,C3,D5),(A3,B1,C3,D6),(A3,B1,C4,D1a),(A3,B1,C4,D1b),(A3,B1,C4,D2a),(A3,B1,C4,D2b),(A3,B1,C4,D3a),(A3,B1,C4,D3b),(A3,B1,C4,D4a),(A3,B1,C4,D4b),(A3,B1,C4,D5),(A3,B1,C4,D6),(A3,B2,C1,D1a),(A3,B2,C1,D1b),(A3,B2,C1,D2a),(A3,B2,C1,D2b),(A3,B2,C1,D3a),(A3,B2,C1,D3b),(A3,B2,C1,D4a),(A3,B2,C1,D4b),(A3,B2,C1,D5),(A3,B2,C1,D6),(A3,B2,C2,D1a),(A3,B2,C2,D1b),(A3,B2,C2,D2a),(A3,B2,C2,D2b),(A3,B2,C2,D3a),(A3,B2,C2,D3b),(A3,B2,C2,D4a),(A3,B2,C2,D4b),(A3,B2,C2,D5),(A3,B2,C2,D6),(A3,B2,C3,D1a),(A3,B2,C3,D1b),(A3,B2,C3,D2a),(A3,B2,C3,D2b),(A3,B2,C3,D3a),(A3,B2,C3,D3b),(A3,B2,C3,D4a),(A3,B2,C3,D4b),(A3,B2,C3,D5),(A3,B2,C3,D6),(A3,B2,C4,D1a),(A3,B2,C4,D1b),(A3,B2,C4,D2a),(A3,B2,C4,D2b),(A3,B2,C4,D3a),(A3,B2,C4,D3b),(A3,B2,C4,D4a),(A3,B2,C4,D4b),(A3,B2,C4,D5)或(A3,B2,C4,D6),
及其药学上可接受的盐或溶剂化物。
本发明的化合物对于所有涉及NPY Y5的疾病是有效的,尤其可用于预防和/或治疗肥胖和厌食症。此外,化合物还可有效预防和/或治疗肥胖因素导致的疾病,例如糖尿病、高血压、高脂血症、动脉粥样硬化和急性冠状动脉综合症。
此外,本发明的化合物具有良好的特性,例如
a)CYP酶抑制作用弱
b)水溶性高
c)良好的药物分布性,例如生物利用度高
d)诱发贫血作用等的毒性低
e)新陈代谢稳定性高
f)Y5受体选择性高
本发明的化合物可以作为抗肥胖剂或食欲减退剂口服或非肠道形式施用。就口服而言、可以是任何常见的形式,例如片剂、颗粒、粉末、胶囊、丸剂、溶液、糖浆、颊含片和舌下片剂。当该化合物经非肠道给药时,优选任何常见的形式,例如注射(例如肌肉、静脉内)、栓剂、经皮肤药剂(endermic agents)和吸入剂(vapors)。特别优选口服,因为本发明的化合物显示出高口服可吸收性。
可以通过将有效量的本发明化合物与适合施用形式的多种药用添加剂混合来制备药物组合物,所述添加剂有例如赋形剂、粘结剂、湿润剂、崩解剂、润滑剂和稀释剂。当组合物用于注射时,可对活性成分连同适当的载体进行灭菌得到药物组合物。
赋形剂的实例包括乳糖、蔗糖、葡萄糖、淀粉、碳酸钙和结晶纤维素。粘结剂的实例包括甲基纤维素、羧甲基纤维素、羟基丙基纤维素、凝胶和聚乙烯基吡咯烷酮。崩解剂的实例包括羧甲基纤维素、羧甲基纤维素钠、淀粉、海藻酸钠、琼脂和十二烷基硫酸钠。润滑剂的实例包括滑石粉、硬脂酸镁和聚乙二醇(macrogol)。可可油、聚乙二醇、甲基纤维素等可用作栓剂的基体材料。当以溶液、乳化注射液或悬浮注射液制备该组合物时,可以加入溶解加速剂、悬浮剂、乳化剂、稳定剂、防腐剂、等张剂等。用于口服时可加入甜味剂、香料等。
尽管本发明的化合物作为抗肥胖剂或食欲减退剂的剂量应考虑患者的年龄和体重、疾病的类型和程度、给药途径等来确定,但对于成年人来说,常用的口服剂量为0.05~100mg/kg/天,优选0.1~10mg/kg/天。对于肠道外给药来说,尽管其剂量与给药途径有很大的关系,但常用的剂量为0.005~10mg/kg/天,优选0.01~1mg/kg/天。该剂量可以每天一次或分多次给药。
通过下列实施例对本发明进一步说明,其并非试图限制本发明的范围。
实施例中缩写的含义如下:
Me甲基
Et:乙基
iPr:异丙基
WSCD:1-乙基-3-(3-二甲氨基)碳二亚胺
DMF:N,N-二甲基甲酰胺
HOBt:1-羟基苯并三唑
实施例
实施例1
(步骤1)
在冰冷却下向搅拌着的5-氨基戊酸1 20.0g(171mmol)在二氧杂环己烷200ml的悬浮液中加入2mol/LNaOH溶液200ml(400mmol)。在冰冷却下用10分钟向搅拌着的该溶液中加入乙基磺酰氯33.0g(257mmol)。在室温下搅拌混合物15小时。将反应溶液浓缩至约一半体积,并向其中加入水(200ml)。向其中加入5mol/L-HCl酸化后,用乙酸乙酯萃取混合物两次。该有机层用盐水洗涤,并用无水硫酸镁干燥。在减压下蒸发溶剂。向残余物中加入乙醚和己烷。过滤沉淀的晶体得到19.6g磺酰胺化合物2(产率55%)。
1H-NMR(CDCl3);δ1.37(3H,t,J=7.5Hz),1.67(4H),2.41(2H,t,J=6.9Hz),3.05(2H,q,J=7.5Hz),3.14(2H,q,J=6.0Hz),4.81(1H,t,J=6.0Hz)ppm
(步骤2)
向羧酸2 209mg(1.00mmol)、3-氨基-N-乙基咔唑3 210mg(1.00mmol)和1-羟基苯并三唑163mg(1.21mmol)在N,N-二甲基甲酰胺5ml中形成的溶液中加入1-乙基-3-(3-二甲氨基)碳二亚胺盐酸盐231mg(1.21mmol)。在室温下搅拌混合物15小时。向反应溶液中加入水,将沉淀的晶体过滤,用水洗涤并干燥。使用柱色谱(SiO2 10g,CHCl3/MeOH=50)纯化所得的粗制晶体,并用乙醚结晶得到167mg本发明化合物Id-2(产率42%)。
用和上述相同的方法合成其它的化合物(I)。其结构和物理性能如下所示。
Ia-1
mp;232-234℃
1H-NMR(DMSO);1.19(3H,t,J=7.2Hz),1.26(2H),1.47(2H),1.90(4H),2.45(1H),3.00(2H,q,J=7.2Hz),3.03(1H),7.05(1H,d,J=8.1Hz),8.15(1H,d-d,J=8.7,2.1Hz),8.27(1H,d,J=8.7Hz),8.70(1H,d,J=2.1Hz),10.86(1H,s)ppm
Ia-2
mp;235-237℃
1H-NMR(DMSO);1.19(3H,t,J=7.2Hz),1.27(2H),1.48(2H),1.90(4H),2.23(1H),3.00(2H,q,J=7.2Hz),3.03(1H),4.93(2H,q,J=9.0Hz),6.94(1H,d,J=8.7Hz),7.04(1H,d,J=7.8Hz),7.97(1H,d-d,J=8.7,2.7Hz),8.39(1H,d,J=2.7Hz),9.95(1H,s)ppm
Ia-3
mp;122-123℃
1H-NMR(DMSO);1.18(3H,t,J=7.2Hz),1.49(2H),1.61(2H),2.32(2H),2.91(2H),2.97(2H,q,J=7.2Hz),4.93(2H,q,J=9.0Hz),6.95(1H,d,J=9.0Hz),7.01(1H),7.97(1H,d-d,J=9.0,2.7Hz),8.39(1H,d,J=2.7Hz),10.01(1H,s)ppm
Ib-1
mp;220-222℃
1H-NMR(DMSO);1.14(6H,d,J=6.0Hz),1.19(3H,t,J=7.2Hz),1.26(2H),1.47(2H),1.80(2H),1.93(2H),2.17(3H),2.98(2H,q,J=7.2Hz),3.02(1H),3.48(2H),3.68(2H),6.86(2H,d,J=9.0Hz),7.03(1H,d,J=7.2Hz),7.42(2H,d,J=9.0Hz),9.58(1H,s)ppm
Ib-2
mp;179-182℃
1H-NMR(DMSO);1.20(3H,t,J=7.2Hz),1.32(2H),1.49(2H),1.96(4H),2.24(1H),3.01(2H,q,J=7.2Hz),3.04(1H),3.76(3H,s),3.81(3H,s),3.86(3H,s),7.08(1H,d,J=7.2Hz),7.40(1H,s),8.21(1H,s),10.86(1H,s)ppm
Ib-3
mp;195-197℃
1H-NMR(DMSO);1.20(3H,t,J=7.2Hz),1.30(2H),1.47(2H),1.94(4H),2.22(1H),3.01(2H,q,J=7.2Hz),3.04(1H),3.77(3H,s),3.83(3H,s),7.06(1H,d,J=7.5Hz),7.19(1H,d-d,J=9.0,3.0Hz),7.35(1H,d,J=3.0Hz),8.04(1H,d,J=9.0Hz),10.26(1H,s)ppm
Ib-4
mp;104-105℃
1H-NMR(DMSO);1.14(6H,d,J=6.3Hz),1.17(3H,t,J=7.2Hz),1.48(2H),1.59(2H),2.21(4H),2.93(2H),2.97(2H,q,J=7.2Hz),3.48(2H),3.67(2H),6.86(2H,d,J=9.0Hz),7.00(1H),7.42(2H,d,J=9.0Hz),9.64(1H,s)ppm
Ic-1
mp;262-264℃
1H-NMR(DMSO);1.20(3H,t,J=7.2Hz),1.29(2H),1.50(2H),1.94(4H),2.29(1H),3.01(2H,q,J=7.2Hz),3.05(1H),3.82(3H,s),4.21(3H,s),7.04(1H,d,J=7.5Hz),7.39(1H,d-d,J=8.7,1.8Hz),7.90(1H,d,J=8.7Hz),8.05(1H,d,J=1.8Hz),10.19(1H,s)ppm
Ic-2
mp;264-266℃
1H-NMR(DMSO);1.18(6H,d,J=6.6Hz),1.20(3H,t,J=7.5Hz),1.29(2H),1.51(2H),1.90(4H),2.28(1H),3.00(2H,q,J=7.5Hz),3.04(1H),4.10(1H),4.16(3H,s),7.04(1H,d,J=7.8Hz),7.37(1H,d-d,J=8.7,1.5Hz),7.64(1H,d,J=8.1Hz),7.76(1H,d,J=8.7Hz),8.07(1H,d,J=1.5Hz),10.13(1H,s)ppm
Ic-3
mp;235-237℃
1H-NMR(DMSO);1.20(3H,t,J=7.2Hz),1.29(2H),1.49(2H),1.91(4H),2.26(1H),3.00(2H,q,J=7.2Hz),3.04(1H),3.85(3H,s),4.16(3H,s),7.04(1H,d,J=7.8Hz),7.57(2H,br.-s),8.33(1H,br.-s),10.00(1H,s)ppm
Ic-4
mp;265-267℃
1H-NMR(DMSO);1.18(6H,d,J=6.9Hz),1.20(3H,t,J=7.5Hz),1.29(2H),1.51(2H),1.90(4H),2.26(1H),3.00(2H,q,J=7.5Hz),3.04(1H),4.08(1H),4.12(3H,s),7.04(1H,d,J=7.2Hz),7.05(2H,br.-s),7.82(1H,d,J=8.1Hz),8.23(1H,br.-s),9.96(1H,s)ppm
Id-1
mp;239-240℃
1H-NMR(DMSO);1.21(3H,t,J=7.2Hz),1.29(3H,t,J=7.2Hz),1.30(2H),1.54(2H),1.93(4H),2.28(1H),3.01(2H,q,J=7.2Hz),3.05(1H),4.41(2H,q,J=7.2Hz),7.05(1H,d,J=7.5Hz),7.16(1H,t,J=7.5Hz),7.43(1H,t,J=7.5Hz),7.54(3H),8.04(1H,d,J=7.8Hz),8.43(1H,s),9.82(1H,s)ppm
Id-2
mp;117℃
1H-NMR(DMSO);1.19(3H,t,J=7.2Hz),1.30(3H,t,J=7.2Hz),1.54(2H),1.67(2H),2.35(2H,t,J=7.2Hz),2.96(2H),2.99(2H,q,J=7.2Hz),4.41(2H,q,J=7.2Hz),7.03(1H),7.17(1H,t,J=7.5Hz),7.43(1H,t,J=7.5Hz),7.56(3H),8.04(1H,d,J=7.5Hz),8.41(1H),9.89(1H,s)ppm
Id-3
mp;287-289℃
1H-NMR(DMSO);1.20(3H,t,J=7.2Hz),1.28(2H),1.47(6H,d,J=6.9Hz),1.50(2H),1.85(8H),2.23(1H),2.26(2H),2.72(2H),3.00(2H,q,J=7.2Hz),3.04(1H),4.57(1H),7.03(1H,d,J=7.5Hz),7.10(1H,d-d,J=8.7,2.1Hz),7.36(1H,d,J=8.7Hz),7.68(1H,d,J=2.1Hz),9.56(1H,s)ppm
Id-4
mp;120℃
1H-NMR(DMSO);1.18(3H,t,J=7.5Hz),1.47(6H,d,J=6.9Hz),1.50(2H),1.62(2H),1.81(4H),2.29(2H,t,J=7.2Hz),2.56(2H),2.72(2H),2.93(2H),2.97(2H,q,J=7.5Hz),4.58(1H),7.01(1H),7.12(1H,d-d,J=8.7,2.1Hz),7.37(1H,d,J=8.7Hz),7.66(1H,d,J=2.1Hz),9.63(1H,s)ppm
Ie-1
mp;256-258℃
1H-NMR(DMSO)δ;1.28(2H),1.49(2H),1.91(4H),2.24(1H),3.20(1H),4.40(2H,q,J=9.6Hz),4.93(2H,q,J=9.1Hz),6.95(1H,d,J=8.7Hz),7.78(1H,d,J=7.2Hz),7.97(1H,d-d,J=8.7,2.7Hz),8.39(1H,d,J=2.7Hz),9.96(1H,s)ppm
Ie-2
mp;234-236℃
1H-NMR(DMSO)δ;1.27(2H),1.48(2H),1.91(4H),2.46(1H),3.20(1H),4.40(2H,q,J=9.9Hz),7.79(1H,s),8.15(1H,d-d,J=8.7,2.1Hz),8.27(1H,d,J=8.7Hz),8.69(1H,d,J=2.1Hz),10.87(1H,s)ppm
Ie-3
mp;143-145℃
1H-NMR(DMSO)δ;1.56(4H),2.32(2H,t,J=7.2Hz),3.01(2H,t,J=6.6Hz),4.37(2H,q,J=10.2Hz),4.93(2H,q,J=9.3Hz),6.95(1H,d,J=8.7Hz),7.74(1H,s),7.97(2H,d-d,J=8.7,2.7Hz),8.39(1H,d,J=2.7Hz),10.01(1H,s)ppm
If-1
mp;239-241℃
1H-NMR(DMSO)δ;1.14(6H,d,J=6.0Hz),1.27(2H),1.48(2H),1.82(2H),1.95(2H),2.18(3H),3.20(1H),3.47(2H),3.67(2H),4.40(2H,q,J=9.9Hz),6.86(2H,d,J=9.0Hz),7.43(2H,d,J=9.0Hz),7.76(1H,d,J=7.5Hz),9.59(1H,s)ppm
If-2
mp;128-130℃
1H-NMR(DMSO)δ;1.14(6H,d,J=6.3Hz),1.55(4H),2.21(4H),3.00(2H,t,J=6.6Hz),3.48(2H),3.68(2H),4.37(2H,q,J=9.9Hz),6.86(2H,d,J=9.3Hz),7.42(2H,d,J=9.3Hz),7.34(1H,s),9.65(1H,s)ppm
Ig-1
mp;165-166℃
1H-NMR(DMSO)δ;1.30(3H,t,J=7.2Hz),2.61(2H,t,J=7.2Hz),3.39(2H),4.43(4H),7.18(1H,t,J=7.5Hz),7.44(1H,t,J=7.5Hz),7.55(3H),7.89(1H),8.04(1H,d,J=7.5Hz),8.41(1H,s),10.03(1H)ppm
Ih-1
mp;187-188℃
1H-NMR(DMSO);1.28(2H),1.47(2H),1.92(4H),2.25(1H),2.64(6H,s),2.98(1H),6.48(1H,d,J=9.9Hz),7.13(1H,d,J=7.8Hz),7.35(1H,d,J=9.0Hz),7.64(1H,d,J=9.3Hz),8.05(1H,d,J=9.0Hz),8.07(1H,s),10.04(1H,s)ppm
Ih-2
mp;219-220℃
1H-NMR(DMSO);1.26(2H),1.45(2H),1.92(4H),2.23(1H),2.64(6H,s),2.98(1H),4.93(2H,q,J=9.0Hz),6.95(1H,d,J=8.7Hz),7.13(1H,s),7.96(1H,d-d,J=2.9,9.0Hz),8.40(1H,d,J=2.4Hz),9.94(1H,s)ppm
Ih-3
mp;164.0-166.0℃
1H-NMR(DMSO);1.30-1.47(2H,m),1.79-1.90(2H,m),2.65(s,6H),2.89-3.02(2H,m),3.19-3.32(1H,m),3.99-4.09(2H,m),7.26(1H,d,J=7.8Hz),7.94(1H,d,J=9.0Hz),8.04(1H,d-d,J=9.0,1.8Hz),8.60(1H,s),9.77(1H,s)ppm
Ih-4
mp;154.0-156.0℃
1H-NMR(DMSO);1.29-1.45(2H,m),1.80-1.90(2H,m),2.65(s,6H),2.84-2.98(2H,m),3.16-3.32(1H,m),3.93-4.04(2H,m),4.92(2H,q,J=9.1Hz),6.89(1H,d,J=9.0Hz),7.26(1H,d,J=8.7Hz),7.84(1H,d-d,J=8.4,2.4Hz),8.21(1H,d,2.4Hz),8.59(1H,s)ppm
Ii-1
mp;220-222℃
1H-NMR(DMSO);1.28(2H),1.47(2H),1.93(4H),2.28(1H),2.65(6H,s),2.99(1H),7.14(1H,d,J=8.1Hz),7.65(2H,d,J=8.1Hz),7.80(2H,d,J=8.1Hz),10.18(1H,s)ppm
Ii-2
mp;220-221℃
1H-NMR(DMSO);1.25(2H),1.44(2H),1.88(4H),2.18(1H),2.64(6H,s),2.97(1H),5.96(2H,s),6.82(1H,d,J=8.1Hz),6.95(1H,d,J=8.1Hz),7.13(1H,d,J=7.8Hz),7.30(1H,s),9.71(1H,s)ppm
Ii-3
mp;168-178℃
1H-NMR(DMSO);1.20-1.50(m,4H),1.82-2.02(m,4H),2.22(dt,J=12Hz,1H),2.64(s,6H),2.98(m,1H),7.13(d,J=7.8Hz,1H),7.24(dd,J=8.7,2.0Hz,1H),7.33(d,J=8.4Hz,1H),7.77(d,J=1.8Hz,1H),10.04(s,1H)ppm
Ii-4
mp;218-220℃
1H-NMR(DMSO);1.20-1.50(m,4H),1.83-2.00(m,4H),2.23(dt,J=12Hz,1H),2.64(s,6H),3.00(m,1H),7.16(d,J=8.1Hz,1H),7.35-7.43(m,2H),7.82(d,J=1.8Hz,1H),10.18(s,1H)ppm
Ii-5
mp;230-231℃
1H-NMR(DMSO);1.30-1.47(2H,m),1.80-1.92(2H,m),2.66(s,6H),2.87-3.01(2H,m),3.18-3.34(1H,m),3.95-4.07(2H,m),7.26(1H,d,J=7.8Hz),7.57(2H,d,J=8.7Hz),7.67(2H,d,J=8.7Hz),8.90(1H,s)ppm
Ii-6
mp;155.0-157.0℃
1H-NMR(DMSO);1.27-1.44(2H,m),1.79-1.89(2H,m),2.65(s,6H),2.80-2.94(2H,m),3.16-3.30(1H,m),3.93-4.02(2H,m),5.93(2H,s),6.77(1H,d,J=8.4Hz),6.82(1H,d,J=8.7Hz),7.12(1H,s),7.25(1H,d,J=7.2Hz),8.38(1H,s)ppm
Ij-1
mp;216-218℃
1H-NMR(DMSO);1.25(2H),1.44(2H),1.86(4H),2.45(1H),2.64(6H,s),2.98(1H),7.14(1H,d,J=4.5Hz),8.15(1H,d-d,J=2.4,9.0Hz),8.27(1H,d,J=8.7Hz),8.70(1H,d,J=2.4Hz),10.86(1H,s)ppm
Ij-2
mp;201.0-203.0℃
1H-NMR(DMSO);1.30-1.46(2H,m),1.80-1.93(2H,m),2.66(s,6H),2.86-3.00(2H,m),3.18-3.36(1H,m),3.96-4.08(2H,m),6.45(1H,d,J=9.6Hz),7.26(1H,d,J=8.4Hz),7.30(1H,d,J=9.0Hz),7.60(1H,d,J=8.4Hz),7.84(1H,brs),8.02(1H,d,J=9.6Hz),8.73(1H,s)ppm
Ij-3
mp;219-221℃
1H-NMR(DMSO);1.22-1.52(m,4H),1.73-2.00(m,10H),2.24(dt,J=12Hz,1H),2.60(m,2H),2.64(s,6H),2.88(m,2H),2.99(m,1H),7.16(d,J=7.8Hz,1H),7.24(dd,J=8.7,2.0Hz,1H),7.33(d,J=8.7Hz,1H),7.83(s,1H),9.79(s,1H)ppm
实验1抗饲育活性
将一根导管植入7周龄自由进食饲养的大鼠(200-300g)的侧脑室中央部(ventriculus lateralis)。然后自由进食饲养大鼠约一周。
将本发明的化合物悬浮于0.5%HPMC溶液(羟基丙基甲基纤维素:60SH-50,Shin-Etsu Chemical Co.,Ltd.)中得到15mg/ml的最终浓度。
以2mL/kg的本发明化合物的悬浮液(化合物30mg/kg)对大鼠口服给药。同时,对照组中的大鼠经口给予相同量的0.5%HPMC。
将NPYY5激动剂([cPP1-7,NPY19-23,Ala31,Aib32,Gln34]-hPancreatic Polypeptide:Tocris Coockson)溶解在生理盐水中至浓度达到0.1nmol/10μL。在给予本发明的化合物后1小时,经由大鼠头中的导管注入0.1nmol上述溶液。注入后立即测量剩余食物的量。
注入激动剂后1、2或4小时测量出剩余食物的量,并计算出该时间内摄入的食物。对比对照组中大鼠的食物摄入,计算出本发明化合物的抗饲育率。结果显示如下。
表1
化合物No. | 抗饲育活性(%) | ||
1小时 | 2小时 | 4小时 | |
Ia-2 | 98** | 77** | 56** |
Ia-3 | 85** | 78** | 74** |
Ib-1 | 90** | 95** | 92** |
Id-1 | 5 | 37 | 49** |
Id-2 | 100** | 100** | 100** |
Id-4 | 100** | 94** | 95** |
Ie-3 | 56 | 62* | 21 |
Ig-1 | 67 | 44 | 48** |
Ii-1 | 42 | 38* | 31 |
*:p<0.05,**:p<0.01
上述结果表明本发明的化合物显著地抑制大鼠的食物摄入。
制剂实施例1 片剂
化合物(Ia-1) 15mg
淀粉 15mg
乳糖 15mg
结晶纤维素 19mg
聚乙烯醇 3mg
蒸馏水 30ml
硬脂酸钙 3mg
在将除硬脂酸钙之外的上述全部成分混合均匀之后,将该混合物研碎、制粒并干燥,得到合适尺寸的颗粒。向颗粒中加入硬脂酸钙,然后通过压模成型制成片剂。
制剂实施例2 胶囊
化合物(Ib-1) 10mg
硬脂酸镁 10mg
乳糖 80mg
将上述成分混合,制备成粉末或颗粒,然后填入胶囊。
制剂实施例3 颗粒剂
化合物(Ic-1) 30g
乳糖 265g
硬脂酸镁 5g
将上述成分均匀混合,压模成型,然后研碎、制粒并筛分,制备合适大小的颗粒。
工业实用性
如上述实验所示,本发明的化合物具有NPY Y5受体拮抗活性。因此,本发明的化合物作为抗肥胖剂或食欲减退剂是非常有效的。
Claims (6)
1、式(I)的化合物,其药学上可接受的盐或溶剂化物:
(其中R1是被卤素任选取代的乙基、或被低级烷基任选取代的氨基,
R2和R3各自独立地表示氢或低级烷基,
X是亚环烷基、低级亚烷基或哌啶二基,
Z是任选取代的苯基或任选取代的杂环基)。
3、根据权利要求1或2所述的化合物,其药学上可接受的盐或溶剂化物,其中Z是
(i)被一个或多个取代基任选取代的苯基,所述取代基选自被低级烷基取代的吗啉代、卤代低级烷基、低级烷氧基、低级烷氧基羰基、低级亚烷基二氧基或卤代低级亚烷基二氧基,
(ii)被一个或多个选自卤代低级烷基或卤代低级烷氧基的取代基任选取代的吡啶基,
(iii)被低级烷基任选取代的咔唑基或被低级烷基任选取代的四氢咔唑基,
(iv)被一个或多个选自低级烷氧基、低级烷氧基羰基或低级烷基氨基甲酰基的取代基任选取代的苯并呋喃基,
(v)被氧任选取代的色烯基,或
(vi)环庚并苯并呋喃基。
4、根据权利要求1~3任一项所述的化合物,其药学上可接受的盐或溶剂化物,其中R2和R3都是氢。
5、药物组合物,其包含上述权利要求1~4任一项所述的化合物、其药学上可接受的盐或溶剂化物。
6、NPYY5受体拮抗物,其包含上述权利要求1~4任一项所述的化合物、其药学上可接受的盐或溶剂化物。
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WO2007118854A1 (en) * | 2006-04-13 | 2007-10-25 | Euro-Celtique S.A. | Benzenesulfonamide compounds and the use thereof |
WO2007118853A1 (en) * | 2006-04-13 | 2007-10-25 | Euro-Celtique S.A. | Benzenesulfonamide compounds and their use as blockers of calcium channels |
CA2650683A1 (en) | 2006-04-28 | 2007-11-08 | Shionogi & Co., Ltd. | Amine derivative having npy y5 receptor antagonist activity |
CA2666193A1 (en) | 2006-08-08 | 2008-02-14 | Sanofi-Aventis | Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, process for preparing them, medicaments comprising these compounds, and their use |
EP2058305A4 (en) | 2006-08-30 | 2010-09-22 | Shionogi & Co | UREA DERIVATIVE |
WO2008026563A1 (fr) | 2006-08-30 | 2008-03-06 | Shionogi & Co., Ltd. | Dérivé d'hydrazine amide |
WO2008038640A1 (fr) * | 2006-09-28 | 2008-04-03 | Shionogi & Co., Ltd. | Procédé de production d'un sel de l'acide 4-sulfinylamino-1-cyclohexanecarboxylique |
WO2008047769A1 (fr) | 2006-10-18 | 2008-04-24 | Shionogi & Co., Ltd. | Agent améliorant le métabolisme du glucose |
US8399486B2 (en) | 2007-04-09 | 2013-03-19 | Purdue Pharma L.P. | Benzenesulfonyl compounds and the use thereof |
EP2025674A1 (de) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
US8765736B2 (en) * | 2007-09-28 | 2014-07-01 | Purdue Pharma L.P. | Benzenesulfonamide compounds and the use thereof |
SA08290668B1 (ar) | 2007-10-25 | 2012-02-12 | شيونوجي آند كو.، ليمتد | مشتقات أمين لها نشاط مضاد لمستقبل npy y5 واستخداماتها |
CL2009000904A1 (es) * | 2008-04-21 | 2010-04-30 | Shionogi & Co | Compuestos derivados de ciclohexil sulfonamidas que tienen actividad antagonista en el receptor npy y5, composicion farmaceutica y formulacion farmaceutica que los comprende. |
UY31968A (es) | 2008-07-09 | 2010-01-29 | Sanofi Aventis | Nuevos derivados heterocíclicos, sus procesos para su preparación, y sus usos terapéuticos |
WO2010068601A1 (en) | 2008-12-08 | 2010-06-17 | Sanofi-Aventis | A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof |
US8653125B2 (en) | 2009-03-05 | 2014-02-18 | Shionogi Co., Ltd. | Cyclohexane derivative having NPY Y5 receptor antagonism |
JP5642661B2 (ja) | 2009-03-05 | 2014-12-17 | 塩野義製薬株式会社 | Npyy5受容体拮抗作用を有するピペリジンおよびピロリジン誘導体 |
US8227618B2 (en) * | 2009-04-23 | 2012-07-24 | Shionogi & Co., Ltd. | Amine-derivatives having NPY Y5 receptor antagonistic activity and the uses thereof |
EP2470552B1 (en) | 2009-08-26 | 2013-11-13 | Sanofi | Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use |
JPWO2011058943A1 (ja) * | 2009-11-11 | 2013-03-28 | 塩野義製薬株式会社 | Mchr1アンタゴニスト活性を有する化合物とnpyy5受容体アンタゴニスト活性を有する化合物を組み合わせてなる医薬組成物 |
US8933024B2 (en) | 2010-06-18 | 2015-01-13 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
US8828994B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
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WO2012120056A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Tetrasubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
US8809324B2 (en) | 2011-03-08 | 2014-08-19 | Sanofi | Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof |
US8901114B2 (en) | 2011-03-08 | 2014-12-02 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
US8809325B2 (en) | 2011-03-08 | 2014-08-19 | Sanofi | Benzyl-oxathiazine derivatives substituted with adamantane and noradamantane, medicaments containing said compounds and use thereof |
EP2683699B1 (de) | 2011-03-08 | 2015-06-24 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
US8828995B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
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