CN1555260A - 氨基烷基取代的芳族二环化合物、它们的制备方法和它们作为药物的用途 - Google Patents
氨基烷基取代的芳族二环化合物、它们的制备方法和它们作为药物的用途 Download PDFInfo
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- CN1555260A CN1555260A CNA02818162XA CN02818162A CN1555260A CN 1555260 A CN1555260 A CN 1555260A CN A02818162X A CNA02818162X A CN A02818162XA CN 02818162 A CN02818162 A CN 02818162A CN 1555260 A CN1555260 A CN 1555260A
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
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- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明涉及氨基烷基取代的芳族二环化合物及其生理学上可接受的盐和生理学上的功能衍生物,其中各原子团具有所规定的含义,和它们的生理学上可接受的盐和它们的制备方法。这些化合物适合于预防和治疗肥胖。
Description
本发明涉及氨基烷基取代的芳族二环化合物及其生理学上可接受的盐和生理学上的功能衍生物。
具有药理作用的结构上相似的非芳族二环化合物已经在现有技术中有所描述(例如WO 01/21577)。
本发明的目的是提供这样的化合物,它们导致哺乳动物减重,适合于预防和治疗肥胖。
本发明因此涉及式I化合物,
其中
A是(C1-C8)烷基、(C0-C8)亚烷基芳基;
3至12元单环或二环的环,它可以含有一个或多个选自N、O和S的杂原子,该3至12元环可以携带另外的取代基,例如F、Cl、Br、NO2、CF3、OCF3、CN、(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、OH、O-(C1-C6)烷基、S-(C1-C6)烷基或NHCO(C1-C6)烷基;
X是一条键、C(R8)(R9)、C(OR10)(R11)、O、N(R12)、S、SO、SO2、CO;
R8、R9、R10、R11、R12彼此独立地是H、(C1-C6)烷基;
D是N、C(R41);
E是N、C(R42);
G是N、C(R43);
L是N、C(R44);
R1、R2、R3、R41、R42、R43、R44彼此独立地是H、F、Cl、Br、I、OH、CF3、NO2、CN、OCF3、O-(C1-C6)烷基、(C1-C4)烷氧基烷基、S-(C1-C6)烷基、(C1-C6)烷基、(C2-C6)烯基、(C3-C8)环烷基、O-(C3-C8)环烷基、(C3-C8)环烯基、O-(C3-C8)环烯基、(C2-C6)炔基、(C0-C8)亚烷基芳基、-O-(C0-C8)亚烷基芳基、S-芳基、N(R13)(R14)、SO2-CH3、COOH、COO-(C1-C6)烷基、CON(R15)(R16)、N(R17)CO(R18)、N(R19)SO2(R20)、CO(R21)、具有1-4个杂原子的5至7元杂环;
R13、R14彼此独立地是H、(C1-C6)烷基,
或者R13和R14与它们所键合的氮原子一起构成5至6元环,其中在6元环的情况下,一个CH2基团可以被O或S代替;
R15、R16彼此独立地是H、(C1-C6)烷基,
或者R15和R16与它们所键合的氮原子一起构成5至6元环,其中在6元环的情况下,一个CH2基团可以被O或S代替;
R17、R19彼此独立地是H、(C1-C6)烷基;
R18、R20、R21彼此独立地是(C1-C6)烷基、芳基;
B是N(R24)、O;
R24是H、(C1-C6)烷基;
R5是H、(C1-C6)烷基;
W是N、C(R25);
R25是H、(C1-C6)烷基、芳基、与Y连接的键;
T是N、C(R26);
R26是H、(C1-C6)烷基、芳基、(C0-C8)亚烷基芳基、与Y连接的键;
U是O、S、N(R27)、-C(R30)=N-、-N=C(R31)-;
R27、R30、R31彼此独立地是H、(C1-C6)烷基、与Y连接的键;
Y是(C1-C8)亚烷基,其中一个或多个碳原子可以被O、S、SO、SO2、C(R32)(R33)、CO、C(R34)(OR35)或N(R36)代替;
R32、R33、R34、R35、R36彼此独立地是H、(C1-C6)烷基、芳基;
R6、R7彼此独立地是H、(C1-C6)烷基、(C3-C7)环烷基,
或者R6和Y或R6和R7与它们所键合的氮原子一起构成3至8元环,其中一个或多个碳原子可以被O、N或S代替,该3至8元环可以携带另外的取代基,例如(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、OH、O-(C1-C6)烷基或NHCO(C1-C6)烷基;
R37、R38、R39、R40彼此独立地是H、(C1-C6)烷基;
及其生理学上可接受的盐。
优选这样的式I化合物,其中一个或多个原子团具有下列含义:
A是(C2-C7)烷基、(C0-C3)亚烷基芳基;
4至10元单环或二环的环,它可以含有一个或多个选自N、O和S的杂原子,该4至10元环可以携带另外的取代基,例如F、Cl、Br、NO2、CF3、(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、O-(C1-C6)烷基或NHCO(C1-C6)烷基;
X是一条键、C(R8)(R9)、O、N(R12)、S、SO2;
R8、R9、R12彼此独立地是H、(C1-C6)烷基;
D是N、C(R41);
E是N、C(R42);
G是N、C(R43);
L是N、C(R44);
其中由D、E、G和L所定义的氮原子的总数是0、1或2;
R1、R2、R3、R41、R42、R43、R44彼此独立地是H、F、Cl、Br、CF3、NO2、O-(C1-C6)烷基、(C1-C6)烷基、(C3-C8)环烷基、O-(C3-C8)环烷基、(C2-C6)炔基、(C0-C8)亚烷基芳基、-O-(C0-C3)亚烷基芳基、S-芳基、N(R13)(R14)、SO2-CH3、COO-(C1-C6)烷基、CON(R15)(R16)、N(R17)CO(R18)、N(R19)SO2(R20)、CO(R21);
R13、R14彼此独立地是H、(C1-C6)烷基,
或者R13和R14与它们所键合的氮原子一起构成5至6元环,其中在6元环的情况下,一个CH2基团可以被O或S代替;
R15、R16彼此独立地是H、(C1-C6)烷基,
或者R15和R16与它们所键合的氮原子一起构成5至6元环,其中在6元环的情况下,CH2基团可以被O或S代替;
R17、R19彼此独立地是H、(C1-C6)烷基;
R18、R20、R21彼此独立地是(C1-C6)烷基、芳基;
B是N(R24)、O;
R24是H、(C1-C6)烷基;
R5是H、(C1-C6)烷基;
W是N、C(R25);
R25是H、(C1-C6)烷基、芳基;
T是C(R26);
R26是H、(C1-C6)烷基、芳基、与Y连接的键;
U是O、S、N(R27)、-N=C(R31)-;
R27、R31彼此独立地是H、(C1-C6)烷基、与Y连接的键;
Y是(C1-C4)亚烷基,其中一个碳原子可以被SO2、C(R32)(R33)、CO或N(R36)代替;
R32、R33、R36彼此独立地是H、(C1-C6)烷基、芳基;
R6、R7彼此独立地是H、(C1-C6)烷基、(C3-C7)环烷基,
或者R6和Y或R6和R7与它们所键合的氮原子一起构成4至7元环,其中一个或多个碳原子可以被O、N或S代替,该4至7元环可以携带另外的取代基,例如(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、OH或NHCO(C1-C6)烷基;
R37、R38、R39、R40彼此独立地是H、(C1-C6)烷基;
及其生理学上可接受的盐。
特别优选这样的式I化合物,其中一个或多个原子团具有下列含义:
A是(C3-C7)烷基、(C0-C2)亚烷基芳基;
5至10元单环或二环的环,它可以含有0、1或2个选自N、O和S的杂原子,该5至10元环可以携带另外的取代基,例如F、Cl、Br、NO2、CF3、(C1-C6)烷基、芳基、O-(C1-C6)烷基或NHCO(C1-C6)烷基;
X是一条键、C(R8)(R9)、O、N(R12);
R8、R9、R12彼此独立地是H、(C1-C6)烷基;
D是N、C(R41);
E是N、C(R42);
G是N、C(R43);
L是N、C(R44);
其中由D、E、G和L所定义的氮原子的总数是0或1;
R1、R2、R3、R41、R42、R43、R44彼此独立地是H、F、Cl、CF3、NO2、O-(C1-C6)烷基、(C1-C6)烷基、O-(C3-C8)环烷基、(C0-C2)亚烷基芳基、-O-(C0-C3)亚烷基芳基、N(R13)(R14)、COO-(C1-C6)烷基、CON(R15)(R16)、N(R17)CO(R18)、N(R19)SO2(R20)、CO(R21);
R13、R14彼此独立地是H、(C1-C6)烷基;
R15、R16彼此独立地是H、(C1-C6)烷基;
R17、R19彼此独立地是H、(C1-C6)烷基;
R18、R20、R21彼此独立地是(C1-C6)烷基、芳基;
B是N(R24);
R24是H、(C1-C6)烷基;
R5是H、(C1-C6)烷基;
W是N、C(R25);
R25是H、(C1-C6)烷基;
T是C(R26);
R26是H、(C1-C6)烷基、与Y连接的键;
U是O、S、N(R27);
R27是H、(C1-C6)烷基、与Y连接的键;
Y是(C1-C3)亚烷基,其中一个碳原子可以被SO2、C(R32)(R33)或CO代替;
R32、R33彼此独立地是H、(C1-C6)烷基、芳基;
R6、R7彼此独立地是H、(C1-C6)烷基、(C3-C7)环烷基,
或者R6和Y或R6和R7与它们所键合的氮原子一起构成5或6元环,其中一个或多个碳原子可以被O或N代替,该5或6元环可以携带另外的取代基,例如(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、OH或NHCO(C1-C6)烷基;
R37、R38、R39、R40彼此独立地是H、(C1-C6)烷基;
及其生理学上可接受的盐。
本发明涉及式I化合物的外消旋物、富集对映体的混合物和纯对映体,和它们的非对映体及其混合物。
取代基R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R25、R26、R27、R30、R31、R32、R33、R34、R35、R36、R37、R38、R39、R40、R41、R42、R43和R44中的烷基、亚烷基、烯基和炔基原子团可以是直链的、支链的或任选卤代的。
术语“芳基”表示苯基或萘基。术语“环”表示环状结构,它可以是芳族的、部分饱和的或完全饱和的。
实施例6和16阐述了R6、Y与它们所键合的氮的任选的环生成,但不限制上述一般性说明。
药学上可接受的盐特别适合于医药应用,因为与起始或基本化合物相比,它们在水中的溶解度更大。所述盐必须具有药学上可接受的阴离子或阳离子。本发明化合物的适合的药学上可接受的酸加成盐是无机酸的盐和有机酸的盐,无机酸例如盐酸、氢溴酸、磷酸、偏磷酸、硝酸、磺酸和硫酸,有机酸例如乙酸、苯磺酸、苯甲酸、枸橼酸、乙磺酸、富马酸、葡糖酸、乙醇酸、羟乙磺酸、乳酸、乳糖酸、马来酸、苹果酸、甲磺酸、琥珀酸、对-甲苯磺酸、酒石酸和三氟乙酸。就医药目的而言,特别优选地使用氯盐。适合的药学上可接受的碱式盐是铵盐、碱金属盐(例如钠盐和钾盐)和碱土金属盐(例如镁盐和钙盐)。
具有药学上不可接受的阴离子的盐同样包括在本发明的范围内,作为中间体可用于制备或纯化药学上可接受的盐和/或用在非治疗应用中,例如体外应用。
本文所用的术语“生理学上的功能衍生物”涉及本发明式I化合物的任何生理学上可接受的衍生物,例如酯,它们在对哺乳动物、例如人给药后,能够(直接或间接)生成式I化合物或其活性代谢产物。
生理学上的功能衍生物还包括本发明化合物的前体药物。这类前体药物可以在体内被代谢为本发明化合物。这些前体药物本身可以是有或无活性的。
本发明化合物还可以存在各种多晶型,例如无定形形式和结晶性多晶型。本发明化合物的所有多晶型都包括在本发明的范围内,是本发明的另一方面。
所有对“根据式(I)的化合物”的称谓以下表示如上所述的式(I)化合物以及如本文所述的它们的盐、溶剂化物和生理学上的功能衍生物。
为了达到所需生物学效果所需要的根据式(I)的化合物的量依赖于多种因素,例如所选择的特定化合物、预期用途、给药的类型和患者的临床状态。一般而言,每日剂量在0.3mg至100mg范围内(通常3mg至50mg)每天每千克体重,例如3-10mg/kg/天。静脉内剂量例如可以在0.3mg至1.0mg/kg范围内,可以按适合的方式输注给药,剂量为10ng至100ng每千克每分钟。适合于这些目的的输注溶液例如可以含有0.1ng至10mg、通常1ng至10mg每毫升。单一剂量例如可以含有1mg至10g活性化合物。因而,注射用安瓿例如可以含有1mg至100mg,可口服给药的单一剂量制剂——例如片剂或胶囊剂——例如可以含有1.0至1000mg,通常10至600mg。在药学上可接受的盐的情况下,上述质量涉及作为盐基础的游离化合物的质量。用于上述病症预防或治疗的化合物可以是根据式(I)的化合物本身,但是它们优选地与可接受的载体一起呈现药物组合物的形式。当然载体必须是相容的,也就是说它与所述组合物的其他成分是相容的,并且对患者的健康是无害的。载体可以是固体或液体或者二者皆是,优选地与化合物配制成单一剂量,例如片剂,其中可以含有0.05至95重量%活性化合物。还可以存在另外的药学活性物质,包括另外的根据式(I)的化合物。本发明的药物组合物可以按照任何已知药学方法加以制备,这些方法在本质上包含将各成分与药理学上可接受的载体和/或助剂混合。
本发明的药物组合物是适合于口服、直肠、局部、经口(例如舌下)和肠胃外(例如皮下、肌内、真皮内或静脉内)给药的那些,不过最适合的给药方式在每个单一病例中依赖于所要治疗的病症的类型与严重性和在每一病例中所用根据式(I)的化合物的类型。糖衣制剂和糖衣缓释制剂也包括在本发明的范围内。优选耐酸和耐胃液制剂。适合的耐胃液涂层包括乙酸邻苯二甲酸纤维素、聚乙酸邻苯二甲酸乙烯酯、羟丙基甲基纤维素邻苯二甲酸酯和异丁烯酸与异丁烯酸甲酯的阴离子型聚合物。
适合于口服给药的药用化合物可以呈现独立的单元,例如胶囊剂、扁囊剂、锭剂或片剂,在每种情况下含有某一量的根据式(I)的化合物;粉剂或颗粒剂;在水性或非水性液体中的溶液或悬液;或者水包油型或油包水型乳剂。正如已经提到的,所述组合物可以按照任何适合的药学方法加以制备,包括使活性化合物与载体(可以包含一种或多种另外的组分)接触的步骤。一般而言,组合物是这样制备的,将活性化合物与液体和/或微细分散的固体载体均匀一致地混合,然后如果必要的话,使产物成型。因而例如,片剂可以这样制备,压制化合物——酌情与一种或多种另外的组分——的粉末或颗粒或者使之成型。压制片可以这样制备,在适合的机器中压制化合物——酌情混合有粘合剂、脱模剂、惰性稀释剂和/或一种或多种表面活性剂/分散剂——的自由流动形式——例如粉末或颗粒。成型片可以这样制备,在适合的机器中使用惰性液体稀释剂湿润的粉状化合物成型。
适合于经口(舌下)给药的药物组合物包括锭剂,它含有根据式(I)的化合物和矫味剂,通常为蔗糖和阿拉伯胶或黄蓍胶,和软锭剂,它在惰性基质中包括化合物,基质例如为明胶和甘油或蔗糖和阿拉伯胶。
适合于肠胃外给药的药物组合物优选地包含根据式(I)的化合物的无菌水性制剂,它们优选地与预期受药者的血液是等渗的。这些制剂优选地是静脉内给药的,不过它们也可以作为注射剂皮下、肌内或真皮内给药。所述制剂可以优选地这样制备,将化合物与水混合,使所得溶液无菌和与血液等渗。本发明的可注射组合物一般含有0.1至5重量%活性化合物。
适合于直肠给药的药物组合物优选地呈现单一剂量栓剂。它们可以这样制备,将根据式(I)的化合物与一种或多种常规的固体载体例如可可脂,混合,使所得混合物成型。
适合于皮肤局部用药的药物组合物优选地呈现软膏剂、霜剂、洗剂、糊剂、喷雾剂、气雾剂或油剂。可以使用的载体是凡士林、羊毛脂、聚乙二醇、醇类和两种或多种这些物质的组合。一般而言,活性化合物的浓度占组合物重量的0.1至15%,例如0.5至2%。
透皮给药也是可能的。适合于透皮给药的药物组合物可以呈现单一的贴剂,它们适合与患者的表皮长期紧密接触。这类贴剂适合含有活性化合物的任选被缓冲的水溶液,化合物溶解和/或分散在粘合剂中或者分散在聚合物中。适合的活性化合物浓度是约1%至35%,优选约3%至15%。特别可能的是,活性化合物可以通过电子转运或离子电渗而被释放,例如Pharmaceutical Research,2(6):318(1986)所述。
式I化合物因对脂质代谢的有益作用而卓著,它们特别适合于哺乳动物减重和减重后维持减少了的重量,和用作减食欲剂。化合物因它们的低毒性和较少副作用而卓著。可以采用单独的化合物或者与其他减重或减食欲活性化合物的组合。
这种类型另外的减食欲活性化合物例如在Roten Liste第01章减重剂/食欲抑制剂中有述,还可以包括这样的活性化合物,它们增加生物的能量转换,从而引起重量减少,或者这样的化合物,它们影响所述生物的一般代谢,以致所增加的热量摄取不会导致所述生物脂肪积存的扩大,正常的热量摄取导致脂肪积存的减少。该化合物适合于超重或肥胖的预防,特别是治疗。该化合物此外适合于II型糖尿病、动脉硬化的预防,特别是治疗,适合于脂质代谢的正常化和高血压的治疗。化合物充当MCH拮抗剂,还适合于感觉障碍和其他精神病指征的治疗,例如抑郁、焦虑、焦虑性神经机能病、精神分裂症,以及与昼夜节律有关的障碍的治疗和药物滥用的治疗。
在本发明的进一方面,式I化合物可以与一种或多种另外的药理活性物质联合给药,后者例如可以选自由抗糖尿病剂、抗脂肪剂、血压降低活性化合物、降脂剂和由糖尿病所导致或与糖尿病有关的并发症的治疗和/或预防活性化合物组成的组。
适合的抗糖尿病剂包括胰岛素、淀粉不溶素、GLP-1与GLP-2衍生物,例如由Novo Nordisk A/S公开在WO 98/08871中的那些,以及口服降血糖活性化合物。
所述口服降血糖活性化合物优选地包括磺酰脲、双胍、氯茴苯酸、噁二唑烷二酮、噻唑烷二酮、葡糖苷酶抑制剂、高血糖素受体拮抗剂、GLP-1激动剂、钾通道开放剂(例如由Novo Nordisk A/S公开在WO97/26265和WO 99/03861中的那些)、胰岛素致敏剂、胰岛素受体激酶活化剂、参与糖异生和/或糖原分解刺激的肝酶的抑制剂(例如糖原磷酸酶抑制剂)、葡萄糖摄取与葡萄糖排泄的调制剂、改变脂质代谢的化合物(例如抗高脂血活性化合物和抗脂血活性化合物,例如HMGCoA还原酶抑制剂)、胆固醇转运/胆固醇摄取抑制剂、胆酸重吸收抑制剂或微粒体甘油三酯转移蛋白(MTP)抑制剂、减少营养剂摄取的化合物、PPAR与RXR激动剂和作用于β细胞ATP依赖性钾通道的活性化合物。
在本发明的一种实施方式中,本发明化合物是与胰岛素联合给药的。
在另一种实施方式中,本发明化合物是与磺酰脲联合给药的,例如甲苯磺丁脲、格列本脲、格列美脲、格列吡嗪、格列喹酮、格列派特、格列波脲或格列齐特。
在另一种实施方式中,本发明化合物是与双胍联合给药的,例如二甲双胍。
在另一种实施方式中,本发明化合物是与氯茴苯酸联合给药的,例如瑞格列奈。
在另一种实施方式中,本发明化合物是与噻唑烷二酮联合给药的,例如曲格列酮、环格列酮、吡格列酮、罗格列酮(rosiglitazone)或由Dr.Reddy’s Research Foundation公开在WO 97/41097中的化合物,特别是5-[[4-[(3,4-二氢-3-甲基-4-氧代-2-喹唑啉基甲氧基]苯基]甲基]-2,4-噻唑烷二酮。
在另一种实施方式中,本发明化合物是与α-葡糖苷酶抑制剂联合给药的,例如米格列醇或阿卡波糖。
在另一种实施方式中,本发明化合物是与作用于β细胞ATP依赖性钾通道的活性化合物联合给药的,例如甲苯磺丁脲、格列本脲、格列美脲、格列吡嗪、格列齐特或瑞格列奈。
在另一种实施方式中,本发明化合物是与抗高脂血活性化合物或抗脂血活性化合物联合给药的,例如考来烯胺、考来替泊、氯贝特、非诺贝特、吉非贝齐、洛伐他汀、普伐他汀、辛伐他汀、托伐他汀(atorvastatin)、西伐他汀(cerivastatin)、氟伐他汀、普罗布考、ezetimibe或右旋甲状腺素。
在另一种实施方式中,本发明化合物是与一种以上上述化合物联合给药的,例如磺酰脲与二甲双胍、磺酰脲与阿卡波糖、瑞格列奈与二甲双胍、胰岛素与磺酰脲、胰岛素与二甲双胍、胰岛素与曲格列酮、胰岛素与洛伐他汀等。
此外,本发明化合物可以与一种或多种抗脂肪剂或食欲控制活性化合物联合给药。
这类活性化合物可以选自由CART激动剂、NPY拮抗剂、MC4激动剂、阿立新(Oxexin)拮抗剂、H3激动剂、TNF激动剂、CRF激动剂、CRF BP拮抗剂、尿皮质激素(urocortin)激动剂、β3激动剂、MSH(黑素细胞刺激激素)激动剂、CCK激动剂、血清素再摄取抑制剂、混合型血清素与去甲肾上腺素再摄取抑制剂、5HT调制剂、MAO抑制剂、韩蛙皮素激动剂、galanin拮抗剂、生长激素、生长激素释放化合物、TRH激动剂、解偶联蛋白2或3调制剂、苗条蛋白(leptin)激动剂、多巴胺激动剂(溴隐亭、Doprexin)、脂酶/淀粉酶抑制剂、大麻素受体1拮抗剂、酰化刺激蛋白(ASP)调制剂、PPAR调制剂、RXR调制剂、hCNTF模拟物或TR-β激动剂组成的组。
在本发明的一种实施方式中,抗脂肪剂是苗条蛋白或改性苗条蛋白。
在另一种实施方式中,抗脂肪剂是右旋苯丙胺或苯丙胺。
在另一种实施方式中,抗脂肪剂是芬氟拉明或右旋芬氟拉明。
在另一种实施方式中,抗脂肪剂是西布曲明或西布曲明的单-与二-去甲基化活性代谢产物。
在另一种实施方式中,抗脂肪剂是奥利司他。
在另一种实施方式中,抗脂肪剂是马吲哚、安非拉酮或芬特明。
此外,本发明化合物可以与一种或多种抗高血压活性化合物联合给药。抗高血压活性化合物的实例有β阻滞剂,例如阿普洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、普萘洛尔和美托洛尔,ACE(血管紧张素转化酶)抑制剂,例如贝那普利、卡托普利、依那普利、福辛普利、赖诺普利、喹那普利和雷米普利,钙通道阻滞剂,例如硝苯地平、非洛地平、尼卡地平、伊拉地平、尼莫地平、地尔硫和维拉帕米,以及α阻滞剂,例如多沙唑嗪、乌拉地尔、哌唑嗪和特拉唑嗪。此外,可以参照Remington:The Science and Practice of Pharmacy,19thedition,Gennaro,editor,Mack Publishing Co.,Easton,PA,1995。
不言而喻,本发明化合物与一种或多种上述化合物和任选的一种或多种其他药理活性物质的每种适合的组合都被视为被本发明保护范围所覆盖。
化合物的活性是如下测定的:
生物试验模型:
测试对雌性NMRI小鼠的减食欲作用。禁食17小时后,借助管饲法给以供试制备物。动物是单独笼养的,可自由饮水,在制备物给药后30分钟提供蒸发乳。每半小时测定蒸发乳的消耗量,持续7小时,监测动物的一般行为。将所测量的乳消耗量与载体处理的对照动物相比。
表1:减食欲作用,以受处理动物与对照动物相比的累积乳消耗量减少计
实施例 | 口服剂量(mg/kg) | 动物数/受处理动物的累积乳消耗量N/(ml) | 动物数/对照动物的累积乳消耗量N/(ml) | 累积乳消耗量的减少,为对照的% |
实施例1 | 30 | 5/2.28 | 5/3.26 | 30 |
实施例4 | 10 | 5/2.74 | 5/4.44 | 38 |
表格表明式I化合物表现非常良好的减食欲作用。
在《自然》中两篇同时发表的文章中(Nature 400,261-264,1999;Nature 400,265-269,1999,见附件),两个工作小组独立地描述了黑素浓集激素(MCH)的高特异性受体。MCH在营养摄取的控制上发挥重要的功能。作用于MCH受体的化合物因此具有减食欲作用,适合于肥胖的治疗。本发明式I化合物的减食欲作用试验因此是如下进行的。
关于IC50测定的功能测量
人MCH受体cDNA的克隆、表达人MCH受体的重组HEK293细胞系的制备和利用所述重组细胞系的功能测量是按照Audinot等的说明进行的(J.Biol.Chem.276,13554-13562,2001)。不过与参考文献不同,使用来自EDGE Biosystems(USA)的质粒pEAK8构建表达载体。名为“PEAK稳定性细胞”的转化HEK细胞系(同样来自EDGEBiosystems)充当转染的宿主。在激动剂(MCH)的加入之后,利用仪器厂商的方案,借助来自Molecular Devices(USA)的FLIPR仪器,在本发明配体的存在下进行细胞钙流的功能测量。
表2显示细胞测定结果。
表2:
实施例 | IC50/μM |
1 | 0,15 |
2 | 0,15 |
3 | 0,29 |
4 | 0,13 |
5 | 0,50 |
6 | 2,34 |
7 | 0,45 |
8 | 1,90 |
9 | 0,10 |
10 | 0,11 |
11 | 0,14 |
13 | 2,50 |
14 | 0,30 |
15 | 0,18 |
16 | 0,33 |
17 | 2,14 |
18 | 1,04 |
19 | 0,70 |
22 | 4,42 |
24 | 0,86 |
26 | 0,92 |
29 | 2,91 |
33 | 1,24 |
63 | 0,57 |
65 | 0,50 |
71 | 2,65 |
72 | 0,32 |
73 | 0,14 |
76 | 4,25 |
77 | 0,70 |
78 | 2,75 |
79 | 2,13 |
80 | 3,36 |
81 | 2,69 |
84 | 0,40 |
86 | 2,78 |
105 | 1,0 |
106 | 0,20 |
107 | 1,0 |
108 | 0,43 |
109 | 1,29 |
下列实施例和制备方法起到阐述发明的作用,但不限制之。
实施例1
1-[1-(2-二甲氨基乙基)-1H-吲哚-5-基]-3-(4-苯氧基苯基)脲
向冷却至0℃的1-二甲氨基乙基-5-氨基吲哚(6.30g)的二甲基甲酰胺(50ml)溶液加入羰基二咪唑(5.12g)。10分钟后,加入4-氨基二苯醚(5.84g),将反应混合物加热至80℃达2小时。冷却后,将反应物用乙酸乙酯稀释,用水洗涤。将有机相经硫酸镁干燥,过滤,浓缩。残余物经过硅胶色谱纯化(洗脱剂:二氯甲烷/甲醇9∶1)。从而得到产物,分子量为414.15(C25H26N4O2);MS(ESI):415(M+H+)。
实施例2
1-(4-丁氧基苯基)-3-[1-(2-二甲氨基乙基)-1H-吲哚-5-基]脲
如实施例1所述,从4-丁氧基苯胺和1-二甲氨基乙基-5-氨基吲哚制备该化合物。从而得到产物,分子量为394.52(C23H30N4O2);MS(ESI):395(M+H+)。
实施例3
1-(1-甲基-2-吡咯烷-1-基甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲
如实施例1所述,从4-氨基二苯醚和1-甲基-2-吡咯烷-1-基甲基-1H-吲哚-5-基胺制备该化合物。从而得到产物,分子量为440.55(C27H28N4O2);MS(ESI):441(M+H+)。
1-甲基-2-吡咯烷-1-基甲基-1H-吲哚-5-基胺
向1-甲基-5-硝基-2-吡咯烷-1-基甲基-1H-吲哚(150mg)、乙醇(2ml)与披氢氧化钯(II)碳(20%,30mg)的悬液加入甲酸(0.11ml),将悬液加热至60℃达5分钟。气体产生停止后,将悬液搅拌另外20分钟,滤出催化剂。浓缩滤液,在饱和碳酸钠溶液与甲基叔丁基醚之间分配。除去有机相,经硫酸镁干燥,浓缩。从而得到产物,分子量为229.33(C14H19N3);MS(ESI):230(M+H+)。
1-甲基-5-硝基-2-吡咯烷-1-基甲基-1H-吲哚
向冷却至0℃的(1-甲基-5-硝基-1H-吲哚-2-基)甲醇(121mg)在二氯甲烷(10ml)与三乙胺(0.17ml)中的溶液滴加甲磺酰氯(92mg)。15分钟后,加入吡咯烷(142mg),然后将溶液在室温下搅拌1小时。将反应溶液用饱和碳酸钠溶液洗涤,经硫酸镁干燥,浓缩。残余物经由硅胶色谱纯化(洗脱剂:乙酸乙酯/三乙胺99∶1)。从而得到产物,分子量为259.31(C14H17N3O2);MS(ESI):260(M+H+)。
(1-甲基-5-硝基-1H-吲哚-2-基)甲醇
在20分钟内向冷却至0℃的氢化铝锂的四氢呋喃悬液(50ml)滴加硫酸(96%,0.64ml)。20分钟后,滴加1-甲基-5-硝基-1H-吲哚-2-羧酸乙酯(1.85g)的四氢呋喃(40ml)溶液。30分钟后,加入水(2ml)。30分钟后,滤出所得沉淀,浓缩滤液。粗产物经由硅胶色谱纯化(洗脱剂:正庚烷/乙酸乙酯3∶2)。从而得到产物,分子量为206.20(C10H10N2O3);MS(ESI):207(M+H+)。
1-甲基-5-硝基-1H-吲哚-2-羧酸乙酯
将5-硝基-1H-吲哚-2-羧酸乙酯(2.34g)、碳酸钾(3.45g)、甲基碘(2.13g)与乙腈(30ml)的悬液在60℃下保持6小时。冷却至室温后,加入水,过滤分离所沉淀的产物。从而得到产物,分子量为248.24(C12H12N2O4);MS(ESI):249(M+H+)。
实施例4
1-[1-(2-二甲氨基乙基)-1H-苯并咪唑-5-基]-3-(4-苯氧基苯基)脲
向1-[4-(2-二甲氨基乙氨基)-3-硝基苯基]-3-(4-苯氧基苯基)脲(50mg)在二氯甲烷(10ml)与冰乙酸(1ml)中的溶液加入锌粉(250mg)。10分钟后,经由硅藻土滤出无机物。将滤液用碳酸钠溶液(10%)洗涤,经硫酸镁干燥,浓缩。将残余物溶于二氯甲烷(5ml)和乙醇(5ml),与二甲基甲酰胺缩二甲醇(0.3ml)和甲酸(0.3ml)混合。借助热空气枪加热混合物,驱出二氯甲烷。浓缩剩余混合物,在二氯甲烷与碳酸钠溶液(10%)之间分配。除去有机相,干燥,浓缩。残余物经过制备型HPLC纯化。从而得到产物,分子量为415.50(C24H25N5O2);MS(ESI):416(M+H+)。盐酸盐的熔点:213-215℃。
1-[4-(2-二甲氨基乙氨基)-3-硝基苯基]-3-(4-苯氧基苯基)脲
将2-二甲氨基乙胺的二甲基甲酰胺溶液(1M,2ml)和1-(4-氟-3-硝基苯基)-3-(4-苯氧基苯基)脲(200mg)搅拌48小时。使混合物在二氯甲烷与碳酸钠溶液(10%)之间分配。将有机相干燥,浓缩。使残余物从甲苯中重结晶。熔点:178-180℃。
1-(4-氟-3-硝基苯基)-3-(4-苯氧基苯基)脲
向4-苯氧基苯胺(2mmol)的二甲基甲酰胺(20ml)溶液加入4-氟-3-硝基苯基异氰酸酯(2.2mmol)。2天后,使反应混合物在二氯甲烷与饱和碳酸钠溶液之间分配。将有机相干燥,浓缩。残余物经由硅胶色谱纯化(洗脱剂:乙酸乙酯/二氯甲烷95∶5),随后从乙酸乙酯/己烷中重结晶。熔点:174-176℃。
实施例5
1-[1-(2-二甲氨基乙基)-2-甲基-1H-苯并咪唑-5-基]-3-(4-异丙氧基苯基)脲
如实施例4所述,使用锌粉还原1-[4-(2-二甲氨基乙氨基)-3-硝基苯基]-3-(4-异丙氧基苯基)脲(75mg)。将反应产物溶于甲醇,与原乙酸三乙酯(0.5ml)和冰乙酸(0.2ml)混合。将混合物在回流下加热5分钟。除去挥发性组分。使残余物在二氯甲烷与碳酸钠溶液之间分配。将有机相干燥,浓缩。残余物经过制备型HPLC纯化。从而得到产物,分子量为395.51(C22H29N5O2);MS(ESI):396(M+H+)。
1-[4-(2-二甲氨基乙氨基)-3-硝基苯基]-3-(4-异丙氧基苯基)脲
如实施例4所述,从1-(4-氟-3-硝基苯基)-3-(4-异丙氧基苯基)脲和2-二甲氨基乙胺得到该化合物。在进一步反应时无需纯化。
1-(4-氟-3-硝基苯基)-3-(4-异丙氧基苯基)脲
如实施例4所述,从4-氟-3-硝基苯基异氰酸酯和4-异丙氧基苯胺得到该化合物。熔点:170-172℃。
实施例6
1-[1-(1-乙基吡咯烷-2-基甲基)-2-甲基-1H-苯并咪唑-5-基]-3-(4-异丙氧基苯基)脲
如实施例5所述,从1-{4-[(1-乙基吡咯烷-2-基甲基)氨基]-3-硝基苯基}-3-(4-异丙氧基苯基)脲制备该化合物。从而得到产物,分子量为435.57(C25H33N5O2);MS(ESI):436(M+H+)。熔点(乙酸乙酯/己烷):185-187℃。
1-{4-[(1-乙基吡咯烷-2-基甲基)氨基]-3-硝基苯基}-3-(4-异丙氧基苯基)脲
如实施例4所述,从1-(4-氟-3-硝基苯基)-3-(4-异丙氧基苯基)脲和1-乙基吡咯烷-2-基甲基胺制备该化合物,在进一步反应时无需任何进一步纯化。
实施例7
1-(4-异丙氧基苯基)-3-[2-甲基-1-(2-哌啶-1-基乙基)-1H-苯并咪唑-5-基]脲
如实施例5所述,从1-(4-异丙氧基苯基)-3-[3-硝基-4-(2-哌啶-1-基乙氨基)苯基]脲制备该化合物。从而得到产物,分子量为435.57(C25H33N5O2);MS(ESI):436(M+H+)。
1-(4-异丙氧基苯基)-3-[3-硝基-4-(2-哌啶-1-基乙氨基)苯基]脲
如实施例4所述,从1-(4-氟-3-硝基苯基)-3-(4-异丙氧基苯基)脲和1-(2-氨基乙基)哌啶(60℃,4h)制备该化合物。熔点(乙酸乙酯):157-159℃。
实施例8
1-(4-异丙氧基苯基)-3-[2-甲基-1-(2-吗啉-4-基乙基)-1H-苯并咪唑-5-基]脲
如实施例5所述,从1-(4-异丙氧基苯基)-3-[4-(2-吗啉-4-基乙氨基)-3-硝基苯基]脲制备该化合物。从而得到产物,分子量为437.55(C24H31N5O3);MS(ESI):438(M+H+)。
1-(4-异丙氧基苯基)-3-[4-(2-吗啉-4-基乙氨基)-3-硝基苯基]脲
如实施例4所述,从1-(4-氟-3-硝基苯基)-3-(4-异丙氧基苯基)脲和1-(2-氨基乙基)吗啉(60℃,4h)制备该化合物。熔点(乙酸乙酯):191-193℃。
实施例9
1-(4-异丙氧基苯基)-3-[2-甲基-1-(2-吡咯烷-1-基乙基)-1H-苯并咪唑-5-基]脲
如实施例5所述,从1-[3-硝基-4-(2-吡咯烷-1-基乙氨基)苯基]-3-(4-苯氧基苯基)脲制备该化合物。从而得到产物,分子量为455.56(C27H29N5O2);MS(ESI):456(M+H+)。
1-[3-硝基-4-(2-吡咯烷-1-基乙氨基)苯基]-3-(4-苯氧基苯基)脲
如实施例4所述,从1-(4-氟-3-硝基苯基)-3-(4-苯氧基苯基)脲和1-(2-氨基乙基)吡咯烷(60℃,5h)制备该化合物。熔点(乙酸乙酯/己烷):179-181℃。
实施例10
1-[2-甲基-1-(2-二甲氨基乙基)-1H-苯并咪唑-5-基]-3-(4-苯氧基苯基)脲
如实施例5所述,从1-[4-(2-二甲氨基乙氨基)-3-硝基苯基]-3-(4-苯氧基苯基)脲制备该化合物。从而得到产物,分子量为429.53(C25H27N5O2);MS(ESI):430(M+H+)。
实施例11
1-(4-苯氧基苯基)-3-[1-(2-吡咯烷-1-基乙基)-1H-苯并咪唑-5-基]脲
如实施例4所述,从1-[3-硝基-4-(2-吡咯烷-1-基乙氨基)苯基]-3-(4-苯氧基苯基)脲制备该化合物。从而得到产物,分子量为441.54(C26H27N5O2);MS(ESI):442(M+H+)。
实施例12
1-[2-苄基-1-(2-二甲氨基乙基)-1H-苯并咪唑-5-基]-3-(4-苯氧基苯基)脲
如实施例4所述还原1-[4-(2-二甲氨基乙氨基)-3-硝基苯基]-3-(4-苯氧基苯基)脲(75mg)。将粗产物用苯基乙酸(0.33mmol),用HATU(0.33mmol)活化,以及二异丙胺(0.7mmol)的二甲基甲酰胺(1.5ml)溶液处理3小时。使反应混合物在二氯甲烷与碳酸钠溶液(10%)之间分配。将有机相干燥,浓缩。将残余物在三氟乙酸(1ml)、水(1ml)与乙腈(0.5ml)中回流加热5分钟。蒸发挥发性组分,残余物经过制备型HPLC纯化。从而得到产物,分子量为505.63(C31H31N5O2);MS(ESI):506(M+H+)。
实施例13
1-[1-(2-二甲氨基乙基)-2-苯基-1H-苯并咪唑-5-基]-3-(4-苯氧基苯基)脲
如实施例4所述还原1-[4-(2-二甲氨基乙氨基)-3-硝基苯基]-3-(4-苯氧基苯基)脲(50mg)。经由硅藻土过滤后,向滤液加入苯甲醛(0.2ml)。将反应混合物用碳酸钠溶液(10%)洗涤,干燥,与二氧化锰(0.5g)混合。15分钟后,滤出无机物,浓缩滤液。粗产物经过制备型HPLC纯化。从而得到产物,分子量为491.60(C30H29N5O2);MS(ESI):492(M+H+)。
实施例14
1-[2-乙基-1-(2-吡咯烷-1-基乙基)-1H-苯并咪唑-5-基]-3-(4-苯氧基苯基)脲
如实施例4所述还原1-[4-(2-吡咯烷子基乙氨基)-3-硝基苯基]-3-(4-苯氧基苯基)脲。使粗产物按照实施例5与原丙酸三乙酯反应。粗产物经过制备型HPLC纯化。从而得到产物,分子量为469.59(C28H31N5O2);MS(ESI):470(M+H+)。
实施例15
1-[2-甲基-1-(2-哌啶-1-基乙基)-1H-苯并咪唑-5-基]-3-(4-苯氧基苯基)脲
如实施例4所述还原1-[2-甲基-1-(2-哌啶-1-基乙基)-1H-苯并咪唑-5-基]-3-(4-苯氧基苯基)脲。如实施例5所述使粗产物与原乙酸三乙酯反应。粗产物经过制备型HPLC纯化。从而得到产物,分子量为469.59(C28H31N5O2);MS(ESI):470(M+H+)。
1-[2-甲基-1-(2-哌啶-1-基乙基)-1H-苯并咪唑-5-基]-3-(4-苯氧基苯基)脲
如实施例4所述,从1-(4-氟-3-硝基苯基)-3-(4-苯氧基苯基)脲和1-(2-氨基乙基)哌啶制备该化合物(60℃,4h)。熔点(乙酸乙酯/己烷):163-165℃。
实施例16
1-[1-(1-乙基吡咯烷-2-基甲基)-2-甲基-1H-苯并咪唑-5-基]-3-(4-苯氧基苯基)脲
如实施例4所述还原1-{4-[(1-乙基吡咯烷-2-基甲基)氨基]-3-硝基苯基}-3-(4-苯氧基苯基)脲。如实施例5所述使粗产物与原乙酸三乙酯反应。粗产物经过制备型HPLC纯化。从而得到产物,分子量为469.59(C28H31N5O2);MS(ESI):470(M+H+)。
1-{4-[(1-乙基吡咯烷-2-基甲基)氨基]-3-硝基苯基}-3-(4-苯氧基苯基)脲
如实施例4所述,从1-(4-氟-3-硝基苯基)-3-(4-苯氧基苯基)脲和C-(1-乙基吡咯烷-2-基)甲基胺制备该化合物(60℃,4h)。熔点(乙酸乙酯/己烷):129-132℃。
实施例17
1-(2-二甲氨基甲基-1H-苯并咪唑-5-基)-3-(4-苯氧基苯基)脲
如实施例4所述还原1-[4-(2,4-二甲氧基苄氨基)-3-硝基苯基]-3-(4-苯氧基苯基)脲(75mg)。使还原产物与二甲氨基乙酸(1mmol)、HATU(1mmol)和二异丙胺(2mmol)在二甲基甲酰胺(3ml)中反应。3小时后,使混合物在乙酸乙酯与碳酸钠溶液之间分配。将有机相干燥,浓缩。粗产物经过制备型HPLC纯化。从而得到中间体(N-{2-氨基-5-[3-(4-苯氧基苯基)脲基]苯基}-2-二甲氨基乙酰胺),分子量为419.49(C23H25N5O3);MS(ESI):420(M+H+)。
将该产物与新戊酸在回流下加热,然后在高真空下除去挥发性组分。粗产物经过制备型HPLC。从而得到产物,分子量为401.47(C23H23N5O2);MS(ESI):402(M+H+)。
1-[4-(2,4-二甲氧基苄氨基)-3-硝基苯基]-3-(4-苯氧基苯基)脲
如实施例4所述,从1-(4-氟-3-硝基苯基)-3-(4-苯氧基苯基)脲和2,4-二甲氧基苄胺制备该化合物(60℃,12h)。熔点(乙酸乙酯):214-216℃。
实施例18
1-[1-(2-二甲氨基乙基)-2,3-二甲基-1H-吲哚-5-基]-3-(4-苯氧基苯基)脲
如实施例1所述,从1-(2-二甲氨基乙基)-2,3-二甲基-1H-吲哚-5-基胺和4-苯氧基苯胺制备该化合物。粗产物经过制备型HPLC纯化。从而得到产物,分子量为442.57(C27H30N4O3);MS(ESI):443(M+H+)。
1-(2-二甲氨基乙基)-2,3-二甲基-1H-吲哚-5-基胺
如实施例3所述,借助[2-(2,3-二甲基-5-硝基吲哚-1-基)乙基]二甲基胺的氢化作用得到该化合物。从而得到产物,分子量为231.34(C14H21N3);MS(ESI):232(M+H+)。
[2-(2,3-二甲基-5-硝基吲哚-1-基)乙基]二甲基胺
在0℃下,向2,3-二甲基-5-硝基-1H-吲哚(1g)的四氢呋喃(10ml)溶液加入氢化钠(50%油中;0.8g)。在室温下30分钟后,加入二甲氨基乙基氯(盐酸盐;1.1g),然后将混合物在65℃下加热2小时。冷却反应溶液,用二氯甲烷萃取。将有机相干燥,浓缩。粗产物经由硅胶色谱纯化(洗脱剂:二氯甲烷/甲醇9∶1)。从而得到产物,分子量为261.33(C14H19N3O2);MS(ESI):262(M+H+)。
实施例19
1-[1-(2-二甲氨基乙基)-2-甲基-1H-吲哚-5-基]-3-(4-苯氧基苯基)脲
如实施例1所述,从1-(2-二甲氨基乙基)-2-甲基-1H-吲哚-5-基胺和4-苯氧基苯胺制备该化合物。粗产物经过制备型HPLC纯化。从而得到产物,分子量为428.54(C26H28N4O3);MS(ESI):428(M+H+)。
1-(2-二甲氨基乙基)-2-甲基-1H-吲哚-5-基胺
如实施例3所述,借助[2-(2-甲基-5-硝基吲哚-1-基)乙基]二甲基胺的氢化作用得到该化合物。从而得到产物,分子量为217.32(C13H19N3);MS(ESI):218(M+H+)。
[2-(2-甲基-5-硝基吲哚-1-基)乙基]二甲基胺
如实施例18所述,从2-甲基-5-硝基-1H-吲哚和二甲氨基乙基氯(盐酸盐)制备该化合物。从而得到产物,分子量为247.30(C13H17N3O2);MS(ESI):248(M+H+)。
表3:
式I的实例
其中部分x1是
x2是
且x2列在下表“苯胺”栏中。
分子离子峰([M+H]+)来自ESI质谱。
实施例20-51和71-109是按照实施例1制备的。
实施例52-70的合成
在0℃下,向1-(2-二甲氨基乙基)-1H-吲哚-5-基胺(0.25mmol)的二甲基甲酰胺(1ml)溶液加入羰基二咪唑(0.25mmol)。在室温下1小时后,将反应溶液再次冷却至0℃,加入适当的氨基酚(0.25mmol)。在室温下15小时后,加入碳酸铯(0.5mmol)和异丁基碘(0.5mmol),将溶液在80℃下加热2小时。过滤反应溶液,将滤液用碳酸氢钠溶液(5%)和氯化钠溶液(5%)洗涤。将有机相干燥,浓缩。粗产物经过制备型HPLC纯化。从而得到产物,分子量如表3所示,质谱的分子离子峰同样如表3所示。
实施例20-51的前体
将4-氟硝基苯(0.35mmol)、碳酸钾(0.7mmol)、适当的胺与二甲基甲酰胺(1ml)的混合物加热至100℃达3小时。过滤反应溶液,用氯化钠溶液(5%)洗涤。将有机相干燥,浓缩。将所得粗产物4-硝基苯胺溶于冰乙酸(1ml),加入锌粉(0.25g)。反应3小时后,将反应溶液用乙酸乙酯(10ml)稀释,过滤,将滤液用氯化钠溶液(5%)洗涤。将滤液干燥,浓缩。所得粗产物4-取代的苯胺在进一步反应时无需任何进一步纯化。
制备了下列4-硝基苯胺:
1-(4-硝基苯基)-azocan
环己基甲基-(4-硝基苯基)胺
1-(4-硝基苯基)吡咯烷
2,5-二甲基-1-(4-硝基苯基)吡咯烷
1-(4-硝基苯基)-1,2,3,6-四氢吡啶
2,6-二甲基-4-(4-硝基苯基)吗啉
4-(4-硝基苯基)硫代吗啉
2-甲基-1-(4-硝基苯基)哌啶
2-乙基-1-(4-硝基苯基)哌啶
3-甲基-1-(4-硝基苯基)哌啶
3,3-二甲基-1-(4-硝基苯基)哌啶
3,5-二甲基-1-(4-硝基苯基)哌啶
1-(4-硝基苯基)-4-苯基哌啶
4-甲基-1-(4-硝基苯基)哌啶
2-(4-硝基苯基)-1,2,3,4-四氢异喹啉
1-(4-硝基苯基)氮杂环庚烷
苄基甲基-(4-硝基苯基)胺
甲基-(4-硝基苯基)苯乙胺
丁基甲基-(4-硝基苯基)胺
苄基丁基-(4-硝基苯基)胺
二丁基-(4-硝基苯基)胺
(4aR,8aS)-2-(4-硝基苯基)十氢异喹啉
2-甲基-1-(4-硝基苯基)吡咯烷
5-乙基-2-甲基-1-(4-硝基苯基)哌啶
甲基-(4-硝基苯基)吡啶-3-基甲基胺
3-(4-硝基苯基)-3-氮杂二环[3.2.2]壬烷
2-异丙基-1-(4-硝基苯基)吡咯烷
2-异丁基-1-(4-硝基苯基)吡咯烷
1-(4-硝基苯基)-3-苯基吡咯烷
1-(4-硝基苯基)-3-三氟甲基哌啶
(4aR,8aR)-2-(4-硝基苯基)十氢异喹啉
(1S,5R)-1,3,3-三甲基-6-(4-硝基苯基)-6-氮杂二环[3.2.1]辛烷
所有上面列举的4-硝基苯胺都在ESI质谱中显示出预期的分子离子峰。
制备了下列4-取代的苯胺:
4-azocan-1-基苯基胺
N-环己基-N-甲基苯-1,4-二胺
4-吡咯烷-1-基苯基胺
4-(2,5-二甲基吡咯烷-1-基)苯基胺
4-(3,6-二氢-2H-吡啶-1-基)苯基胺
4-(2,6-二甲基吗啉-4-基)苯基胺
4-硫代吗啉-4-基苯基胺
4-(2-甲基哌啶-1-基)苯基胺
4-(2-乙基哌啶-1-基)苯基胺
4-(3-甲基哌啶-1-基)苯基胺
4-(3,3-二甲基哌啶-1-基)苯基胺
4-(3,5-二甲基哌啶-1-基)苯基胺
4-(4-苯基哌啶-1-基)苯基胺
4-(4-甲基哌啶-1-基)苯基胺
4-(3,4-二氢-1H-异喹啉-2-基)苯基胺
4-氮杂环庚烷-1-基苯基胺
N-苄基-N-甲基苯-1,4-二胺
N-甲基-N-苯乙基苯-1,4-二胺
N-丁基-N-甲基苯-1,4-二胺
N-苄基-N-丁基苯-1,4-二胺
N,N-二丁基苯-1,4-二胺
(4aR,8aS)-4-(八氢异喹啉-2-基)苯基胺
4-(2-甲基吡咯烷-1-基)苯基胺
4-(5-乙基-2-甲基哌啶-1-基)苯基胺
N-甲基-N-吡啶-3-基甲基苯-1,4-二胺
4-((1S,5R)-1,3,3-三甲基-6-氮杂二环[3.2.1]辛-6-基)苯基胺
4-(3-氮杂二环[3.2.2]壬-3-基)苯基胺
4-(2-异丙基吡咯烷-1-基)苯基胺
4-(2-异丁基吡咯烷-1-基)苯基胺
4-(3-苯基吡咯烷-1-基)苯基胺
4-(3-三氟甲基哌啶-1-基)苯基胺
(4aR,8aR)-4-(八氢异喹啉-2-基)苯基胺
所有上面列举的4-取代的苯胺都在ESI质谱中显示出预期的分子离子峰。
实施例110
[1-(2-二甲氨基乙基)-1H-吲哚-5-基]氨甲酸4-苯氧基苯基酯
按照实施例1,使羰基二咪唑活化的吲哚胺与去质子化的4-苯氧基苯酚反应,制备该化合物。从而得到产物,分子量为415.50(C25H25N3O3);MS(ESI):416(M+H+)。
实施例111
1-(2-咪唑-1-基甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲
在0℃下,向1-(2-羟甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲(0.2g)与三乙胺(0.16ml)的二氯甲烷(4ml)溶液加入甲磺酰氯(47μl)。10分钟后,加入咪唑(185mg)。12小时后,将反应溶液用氯化钠溶液洗涤,干燥,浓缩。粗产物经过制备型HPLC纯化。从而得到产物,分子量为437.51(C26H23N5O2);MS(ESI):438(M+H+)。
1-(2-羟甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲
如实施例1所述,使(5-氨基-1-甲基-1H-吲哚-2-基)甲醇与4-苯氧基苯胺和羰基二咪唑反应。从而得到产物,分子量为387.44(C23H21N3O3);MS(ESI):388(M+H+)。
(5-氨基-1-甲基-1H-吲哚-2-基)甲醇
如实施例3所述氢化(1-甲基-5-硝基-1H-吲哚-2-基)甲醇。从而得到产物,分子量为176.22(C10H12N2O);MS(ESI):177(M+H+)。
实施例112
1-[1-甲基-2-(2-甲基-4,5-二氢咪唑-1-基甲基)-1H-吲哚-5-基]-3-(4-苯氧基苯基)脲
如实施例111所述,从1-(2-羟甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲和2-甲基-4,5-二氢咪唑制备该化合物。从而得到产物,分子量为453.55(C27H27N5O2);MS(ESI):454(M+H+)。
实施例113
1-(2-环己氨基甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲
如实施例111所述,从1-(2-羟甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲和环己胺制备该化合物。从而得到产物,分子量为468.60(C29H32N4O2);MS(ESI):469(M+H+)。
实施例114
1-[2-(3-二甲氨基吡咯烷-1-基甲基)-1-甲基-1H-吲哚-5-基]-3-(4-苯氧基苯基)脲
如实施例111所述,从1-(2-羟甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲和3-二甲氨基吡咯烷制备该化合物。从而得到产物,分子量为483.62(C29H33N5O2);MS(ESI):484(M+H+)。
实施例115
1-[2-(4-羟基哌啶-1-基甲基)-1-甲基-1H-吲哚-5-基]-3-(4-苯氧基苯基)脲
如实施例111所述,从1-(2-羟甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲和4-羟基哌啶制备该化合物。从而得到产物,分子量为470.58(C28H30N4O3);MS(ESI):471(M+H+)。
实施例116
1-[1-甲基-2-(4-苯基哌啶-1-基甲基)-1H-吲哚-5-基]-3-(4-苯氧基苯基)脲
如实施例111所述,从1-(2-羟甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲和4-苯基哌啶制备该化合物。从而得到产物,分子量为530.68(C34H34N4O2);MS(ESI):531(M+H+)。
实施例117
N-(1-{1-甲基-5-[3-(4-苯氧基苯基)脲基]-1H-吲哚-2-基甲基}吡咯烷-3-基)乙酰胺
如实施例111所述,从1-(2-羟甲基-1-甲基-1H-吲哚-5-基)-3-(4-苯氧基苯基)脲和吡咯烷-3-基乙酰胺制备该化合物。从而得到产物,分子量为497.60(C29H31N5O3);MS(ESI):498(M+H+)。
实施例118
1-(4-苯氧基苯基)-3-(2-吡咯烷-1-基甲基苯并呋喃-5-基)脲
如实施例1所述,从2-吡咯烷-1-基甲基苯并呋喃-5-基胺和4-苯氧基苯胺制备该化合物。从而得到产物,分子量为427.51(C26H25N3O3);MS(ESI):428(M+H+)。
2-吡咯烷-1-基甲基苯并呋喃-5-基胺
如实施例3所述,借助1-(5-硝基苯并呋喃-2-基甲基)吡咯烷的氢化作用制备该化合物。从而得到产物,分子量为216.29(C13H16N2O);MS(ESI):217(M+H+)。
1-(5-硝基苯并呋喃-2-基甲基)吡咯烷
如实施例3所述,从(5-硝基苯并呋喃-2-基)甲醇制备该化合物。从而得到产物,分子量为246.27(C13H14N2O3);MS(ESI):247(M+H+)。
(5-硝基苯并呋喃-2-基)甲醇
如实施例3所述,借助5-硝基苯并呋喃-2-甲酸甲酯的还原作用制备该化合物。从而得到产物,分子量为193.16(C9H7NO4);MS(ESI):194(M+H+)。
实施例119
1-(4-苯氧基苯基)-3-(2-吡咯烷-1-基甲基苯并[b]噻吩-5-基)脲
如实施例1所述,从2-吡咯烷-1-基甲基苯并[b]噻吩-5-基胺和4-苯氧基苯胺制备该化合物。从而得到产物,分子量为44(C26H25N3O2S);MS(ESI):444(M+H+)。
2-吡咯烷-1-基甲基苯并[b]噻吩-5-基胺
如实施例3所述,借助1-(5-硝基苯并[b]噻吩-2-基甲基)吡咯烷的氢化作用制备该化合物。从而得到产物,分子量为232.35(C13H16N2S),MS(ESI):233(M+H+)。
1-(5-硝基苯并[b]噻吩-2-基甲基)吡咯烷
如实施例3所述,从(5-硝基苯并[b]噻吩-2-基)甲醇制备该化合物。从而得到产物,分子量为262.33(C13H14N2O2S);MS(ESI):263(M+H+)。
(5-硝基苯并[b]噻吩-2-基)甲醇
如实施例3所述,借助5-硝基苯并[b]噻吩-2-甲酸甲酯的还原作用制备该化合物。分子量为209.23(C9H7NO3S);MS(ESI):210(M+H+)。
一般而言,得到所有所述碱性化合物的游离碱或下列酸之一的盐形式:甲酸、三氟乙酸或盐酸。
Claims (10)
1、式I化合物,
其中
A是(C1-C8)烷基、(C0-C8)亚烷基芳基;
3至12元单环或二环的环,它可以含有一个或多个选自N、O和S的杂原子,该3至12元环可以携带另外的取代基,例如F、Cl、Br、NO2、CF3、OCF3、CN、(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、OH、O-(C1-C6)烷基、S-(C1-C6)烷基或NHCO(C1-C6)烷基;
X是一条键、C(R8)(R9)、C(OR10)(R11)、O、N(R12)、S、SO、SO2、CO;
R8、R9、R10、R11、R12彼此独立地是H、(C1-C6)烷基;
D是N、C(R41);
E是N、C(R42);
G是N、C(R43);
L是N、C(R44);
R1、R2、R3、R41、R42、R43、R44彼此独立地是H、F、Cl、Br、I、OH、CF3、NO2、CN、OCF3、O-(C1-C6)烷基、(C1-C4)烷氧基烷基、S-(C1-C6)烷基、(C1-C6)烷基、(C2-C6)烯基、(C3-C8)环烷基、O-(C3-C8)环烷基、(C3-C8)环烯基、O-(C3-C8)环烯基、(C2-C6)炔基、(C0-C8)亚烷基芳基、-O-(C0-C8)亚烷基芳基、S-芳基、N(R13)(R14)、SO2-CH3、COOH、COO-(C1-C6)烷基、CON(R15)(R16)、N(R17)CO(R18)、N(R19)SO2(R20)、CO(R21)、具有1-4个杂原子的5至7元杂环;
R13、R14彼此独立地是H、(C1-C6)烷基,
或者R13和R14与它们所键合的氮原子一起构成5至6元环,其中在6元环的情况下,一个CH2基团可以被O或S代替;
R15、R16彼此独立地是H、(C1-C6)烷基,
或者R15和R16与它们所键合的氮原子一起构成5至6元环,其中在6元环的情况下,一个CH2基团可以被O或S代替;
R17、R19彼此独立地是H、(C1-C6)烷基;
R18、R20、R21彼此独立地是(C1-C6)烷基、芳基;
B是N(R24)、O;
R24是H、(C1-C6)烷基;
R5是H、(C1-C6)烷基;
W是N、C(R25);
R25是H、(C1-C6)烷基、芳基、与Y连接的键;
T是N、C(R26);
R26是H、(C1-C6)烷基、芳基、(C0-C8)亚烷基芳基、与Y连接的键;
U是O、S、N(R27)、-C(R30)=N-、-N=C(R31)-;
R27、R30、R31彼此独立地是H、(C1-C6)烷基、与Y连接的键;
Y是(C1-C8)亚烷基,其中一个或多个碳原子可以被O、S、SO、SO2、C(R32)(R33)、CO、C(R34)(OR35)或N(R36)代替;
R32、R33、R34、R35、R36彼此独立地是H、(C1-C6)烷基、芳基;
R6、R7彼此独立地是H、(C1-C6)烷基、(C3-C7)环烷基,
或者R6和Y或R6和R7与它们所键合的氮原子一起构成3至8元环,其中一个或多个碳原子可以被O、N或S代替,该3至8元环可以携带另外的取代基,例如(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、OH、O-(C1-C6)烷基或NHCO(C1-C6)烷基;
R37、R38、R39、R40彼此独立地是H、(C1-C6)烷基;
及其生理学上可接受的盐。
2、如权利要求1所要求保护的式I化合物,其中
A是(C2-C7)烷基、(C0-C3)亚烷基芳基;4至10元单环或二环的环,它可以含有一个或多个选自N、O和S的杂原子,该4至10元环可以携带另外的取代基,例如F、Cl、Br、NO2、CF3、(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、O-(C1-C6)烷基或NHCO(C1-C6)烷基;
X是一条键、C(R8)(R9)、O、N(R12)、S、SO2;
R8、R9、R12彼此独立地是H、(C1-C6)烷基;
D是N、C(R41);
E是N、C(R42);
G是N、C(R43);
L是N、C(R44);
其中由D、E、G和L所定义的氮原子的总数是0、1或2;
R1、R2、R3、R41、R42、R43、R44彼此独立地是H、F、Cl、Br、CF3、NO2、O-(C1-C6)烷基、(C1-C6)烷基、(C3-C8)环烷基、O-(C3-C8)环烷基、(C2-C6)炔基、(C0-C8)亚烷基芳基、-O-(C0-C3)亚烷基芳基、S-芳基、N(R13)(R14)、SO2-CH3、COO-(C1-C6)烷基、CON(R15)(R16)、N(R17)CO(R18)、N(R19)SO2(R20)、CO(R21);
R13、R14彼此独立地是H、(C1-C6)烷基,
或者R13和R14与它们所键合的氮原子一起构成5至6元环,其中在6元环的情况下,一个CH2基团可以被O或S代替;
R15、R16彼此独立地是H、(C1-C6)烷基,
或者R15和R16与它们所键合的氮原子一起构成5至6元环,其中在6元环的情况下,CH2基团可以被O或S代替;
R17、R19彼此独立地是H、(C1-C6)烷基;
R18、R20、R21彼此独立地是(C1-C6)烷基、芳基;
B是N(R24)、O;
R24是H、(C1-C6)烷基;
R5是H、(C1-C6)烷基;
W是N、C(R25);
R25是H、(C1-C6)烷基、芳基;
T是C(R26);
R26是H、(C1-C6)烷基、芳基、与Y连接的键;
U是O、S、N(R27)、-N=C(R31)-;
R27、R31彼此独立地是H、(C1-C6)烷基、与Y连接的键;
Y是(C1-C4)亚烷基,其中一个碳原子可以被SO2、C(R32)(R33)、CO或N(R36)代替;
R32、R33、R36彼此独立地是H、(C1-C6)烷基、芳基;
R6、R7彼此独立地是H、(C1-C6)烷基、(C3-C7)环烷基,
或者R6和Y或R6和R7与它们所键合的氮原子一起构成4至7元环,其中一个或多个碳原子可以被O、N或S代替,该4至7元环可以携带另外的取代基,例如(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、OH或NHCO(C1-C6)烷基;
R37、R38、R39、R40彼此独立地是H、(C1-C6)烷基;
及其生理学上可接受的盐。
3、如权利要求1或2之一所要求保护的式I化合物,其中
A是(C3-C7)烷基、(C0-C2)亚烷基芳基;5至10元单环或二环的环,它可以含有0、1或2个选自N、O和S的杂原子,该5至10元环可以携带另外的取代基,例如F、Cl、Br、NO2、CF3、(C1-C6)烷基、芳基、O-(C1-C6)烷基或NHCO(C1-C6)烷基;
X是一条键、C(R8)(R9)、O、N(R12);
R8、R9、R12彼此独立地是H、(C1-C6)烷基;
D是N、C(R41);
E是N、C(R42);
G是N、C(R43);
L是N、C(R44);
其中由D、E、G和L所定义的氮原子的总数是0或1;
R1、R2、R3、R41、R42、R43、R44彼此独立地是H、F、Cl、CF3、NO2、O-(C1-C6)烷基、(C1-C6)烷基、O-(C3-C8)环烷基、(C0-C2)亚烷基芳基、-O-(C0-C3)亚烷基芳基、N(R13)(R14)、COO-(C1-C6)烷基、CON(R15)(R16)、N(R17)CO(R18)、N(R19)SO2(R20)、CO(R21);
R13、R14彼此独立地是H、(C1-C6)烷基;
R15、R16彼此独立地是H、(C1-C6)烷基;
R17、R19彼此独立地是H、(C1-C6)烷基;
R18、R20、R21彼此独立地是(C1-C6)烷基、芳基;
B是N(R24);
R24是H、(C1-C6)烷基;
R5是H、(C1-C6)烷基;
W是N、C(R25);
R25是H、(C1-C6)烷基;
T是C(R26);
R26是H、(C1-C6)烷基、与Y连接的键;
U是O、S、N(R27);
R27是H、(C1-C6)烷基、与Y连接的键;
Y是(C1-C3)亚烷基,其中一个碳原子可以被SO2、C(R32)(R33)或CO代替;
R32、R33彼此独立地是H、(C1-C6)烷基、芳基;
R6、R7彼此独立地是H、(C1-C6)烷基、(C3-C7)环烷基,
或者R6和Y或R6和R7与它们所键合的氮原子一起构成5或6元环,其中一个或多个碳原子可以被O或N代替,该5或6元环可以携带另外的取代基,例如(C1-C6)烷基、芳基、CON(R37)(R38)、N(R39)(R40)、OH或NHCO(C1-C6)烷基;
R37、R38、R39、R40彼此独立地是H、(C1-C6)烷基;
及其生理学上可接受的盐。
4、药物,包含一种或多种如权利要求1至3之一项或多项所要求保护的化合物。
5、药物,包含一种或多种如权利要求1至3之一项或多项所要求保护的化合物和一种或多种减食欲活性物质。
6、如权利要求1至3之一项或多项所要求保护的化合物用于制备药物的用途,该药物用于肥胖的预防或治疗。
7、如权利要求1至3之一项或多项所要求保护的化合物用于制备药物的用途,该药物用于II型糖尿病的预防或治疗。
8、用作药物的如权利要求1至3之一项或多项所要求保护的化合物与至少一种另外的减食欲活性物质的组合,该药物用于肥胖的预防或治疗。
9、用作药物的如权利要求1至3之一项或多项所要求保护的化合物与至少一种另外的减食欲活性物质的组合,该药物用于II型糖尿病的预防或治疗。
10、制备药物的方法,该药物包含如权利要求1至3之一项或多项所要求保护的化合物,该方法包含将活性物质与药学上适合的载体混合,再将所述混合物制成适合于给药的剂型。
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- 2002-08-03 WO PCT/EP2002/008686 patent/WO2003015769A1/de not_active Application Discontinuation
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- 2002-08-14 US US10/218,034 patent/US20030212070A1/en not_active Abandoned
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- 2004-04-09 US US10/820,736 patent/US20040198732A1/en not_active Abandoned
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102781914A (zh) * | 2010-01-06 | 2012-11-14 | 武田药品工业株式会社 | 吲哚衍生物 |
CN102781914B (zh) * | 2010-01-06 | 2014-09-17 | 武田药品工业株式会社 | 吲哚衍生物 |
CN103864753A (zh) * | 2014-02-27 | 2014-06-18 | 华东师范大学 | 含有五元芳杂环结构的抗丙肝化合物及制备方法和用途 |
CN103864753B (zh) * | 2014-02-27 | 2016-01-20 | 华东师范大学 | 含有五元芳杂环结构的抗丙肝化合物及制备方法和用途 |
CN106661005A (zh) * | 2014-07-16 | 2017-05-10 | 诺沃根公司 | 作为抗癌药物的功能化的和取代的吲哚 |
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US20040192693A1 (en) | 2004-09-30 |
JP2005505530A (ja) | 2005-02-24 |
GT200200165A (es) | 2003-05-22 |
AR043477A1 (es) | 2005-08-03 |
US20040198732A1 (en) | 2004-10-07 |
UY27417A1 (es) | 2002-11-29 |
EP1418906A1 (de) | 2004-05-19 |
PE20030333A1 (es) | 2003-04-24 |
HUP0401329A2 (hu) | 2004-12-28 |
IL160424A0 (en) | 2004-07-25 |
DE10139416A1 (de) | 2003-03-06 |
BR0211989A (pt) | 2004-09-28 |
PA8553001A1 (es) | 2003-02-28 |
CA2457037A1 (en) | 2003-02-27 |
ZA200401221B (en) | 2004-10-27 |
PL366794A1 (en) | 2005-02-07 |
MXPA04001307A (es) | 2004-05-20 |
US20040198731A1 (en) | 2004-10-07 |
US20040198733A1 (en) | 2004-10-07 |
NO20040678L (no) | 2004-05-13 |
RU2004107654A (ru) | 2005-09-10 |
US20030212070A1 (en) | 2003-11-13 |
EE200400055A (et) | 2004-04-15 |
HRP20040149A2 (en) | 2004-08-31 |
KR20040043197A (ko) | 2004-05-22 |
WO2003015769A1 (de) | 2003-02-27 |
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