CN1135223C - 芳基取代的丙醇胺衍生物、包含它们的药物和它们的用途 - Google Patents
芳基取代的丙醇胺衍生物、包含它们的药物和它们的用途 Download PDFInfo
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- CN1135223C CN1135223C CNB99811619XA CN99811619A CN1135223C CN 1135223 C CN1135223 C CN 1135223C CN B99811619X A CNB99811619X A CN B99811619XA CN 99811619 A CN99811619 A CN 99811619A CN 1135223 C CN1135223 C CN 1135223C
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及取代的丙醇胺衍生物和它们的药学上可接受的盐与功能衍生物。本发明涉及式(I)化合物，其中各基团具有所定义的含义，以及它们的生理学上可接受的盐、生理学上的功能衍生物及其制备方法。该化合物例如适合作为降血脂剂。
Description
技术领域
本发明涉及取代的丙醇胺衍生物及其酸加成盐。
背景技术
有几类活性物质已被描述可用于肥胖和脂质代谢障碍的治疗：
-聚合吸附剂，例如考来烯胺(Cholestyramin)
-苯并硫氮杂(WO 93/16055)
-胆汁酸二聚物和轭合物(EP 0489423)
-4-氨基-2-脲基嘧啶-5-羧酸酰胺(EP 0557879)
发明内容
为了提供更进一步的具有治疗学上可利用的降血脂作用的化合物，在此基础上完成了本发明。
本发明因此涉及式I化合物
其中
R1是苯基、杂芳基，它们是未取代的或者任选被一至三个相互独立的基团取代，其中芳环或杂芳环有可能被下列基团一至三取代：氟、氯、溴、碘、OH、CF3、-NO2、CN、(C1-C8)-烷氧基、(C1-C8)-烷基、NH2、-NH-R9、-N(R9)R10、CHO、-COOH、-COOR11、-(C＝O)-R12、(C1-C6)-烷基-OH、(C1-C6)-烷基(-OH)-苯基、(C1-C6)-烷基-CF3、(C1-C6)-烷基-NO2、(C1-C6)-烷基-CN、(C1-C6)-烷基-NH2、(C1-C6)-烷基-NH-R9、(C1-C6)-烷基-N(R9)R10、(C1-C6)-烷基-CHO、(C1-C6)-烷基-COOH、(C1-C6)-烷基-COOR11、(C1-C6)-烷基-(C＝O)-R12、-O-(C1-C6)-烷基-OH、-O-(C1-C6)-烷基-CF3、-O-(C1-C6)-烷基-NO2、-O-(C1-C6)-烷基-CN、-O-(C1-C6)-烷基-NH2、-O-(C1-C6)-烷基-NH-R9、-O-(C1-C6)-烷基-N(R9)R10、-O-(C1-C6)-烷基-CHO、-O-(C1-C6)-烷基-COOH、-O-(C1-C6)-烷基-COOR11、-O-(C1-C6)-烷基-(C＝O)-R12、-N-SO3H、-SO2-CH3、-O-(C1-C6)-烷基-O-(C1-C6)-烷基苯基、(C1-C6)-烷硫基、吡啶基，其中烷基基团中的一个或多个氢有可能被氟取代，苯基和吡啶基本身有可能被甲基、甲氧基或卤素一取代；
R2是H、OH、CH2OH、OMe、CHO、NH2；
R3是糖残基、二糖残基、三糖残基、四糖残基、HO-SO2-、(HO)2-PO-，其中糖残基、二糖残基、三糖残基或四糖残基任选地被糖保护基团一或多取代；
R4是H、甲基、F、OMe；
R9至R12彼此独立地是H、(C1-C8)-烷基；
Z是-NH-C0-C16-烷基-C＝O-、-O-C0-C16-烷基-C＝O-、-(C＝O)m-C1-C16-烷基-(C＝O)n、氨基酸残基、二氨基酸残基、共价键，该氨基酸残基或二氨基酸残基任选地被氨基酸保护基团一或多取代；
n是0或1；
m是0或1；
和它们的药学上可耐受的盐与生理学上的功能衍生物。
优选的式I化合物是其中一个或多个基团具有下列含义的那些：
R1是苯基、吡啶基、噻吩基、呋喃基、嘧啶基、吲哚基、噻唑基、咪唑基、香豆素基、邻苯二甲酰亚胺基、喹啉基、哌嗪基、四唑基、三唑基、噁唑基、异噁唑基、异噻唑基或它们的苯并-稠合衍生物，其中芳环或杂芳环有可能被下列基团一至三取代：氟、氯、溴、碘、OH、CF3、-NO2、CN、(C1-C8)-烷氧基、(C1-C8)-烷基、NH2、-NH-R9、-N(R9)R10、CHO、-COOH、-COOR11、-(C＝O)-R12、(C1-C6)-烷基-OH、(C1-C6)-烷基(-OH)-苯基、(C1-C6)-烷基-CF3、(C1-C6)-烷基-NO2、(C1-C6)-烷基-CN、(C1-C6)-烷基-NH2、(C1--C6)-烷基-NH-R9、(C1-C6)-烷基-N(R9)R10、(C1-C6)-烷基-CHO、(C1-C6)-烷基-COOH、(C1-C6)-烷基-COOR11、(C1-C6)-烷基-(C＝O)-R12、-O-(C1-C6)-烷基-OH、-O-(C1-C6)-烷基-CF3、-O-(C1-C6)-烷基-NO2、-O-(C1-C6)-烷基-CN、-O-(C1-C6)-烷基-NH2、-O-(C1-C6)-烷基-NH-R9、-O-(C1-C6)-烷基-N(R9)R10、-O-(C1-C6)-烷基-CHO、-O-(C1-C6)-烷基-COOH、-O-(C1-C6)-烷基-COOR11、-O-(C1-C6)-烷基-(C＝O)-R12、-N-SO3H、-SO2-CH3、-O-(C1-C6)-烷基-O-(C1-C6)-烷基苯基、(C1-C6)-烷硫基、吡啶基，其中烷基基团中的一个或多个氢有可能被氟取代，苯基和吡啶基本身有可能被甲基、甲氧基或卤素一取代；
R2是H、OH、CH2OH、OMe、CHO、NH2；
R3是糖残基、二糖残基、三糖残基、四糖残基、HO-SO2-、(HO)2-PO-，其中糖残基、二糖残基、三糖残基或四糖残基任选地被糖保护基团一或多取代；
R4是H、甲基、F、OMe；
R9至R12彼此独立地是H、(C1-C8)-烷基；
Z是-NH-C0-C16-烷基-C＝O-、-O-C0-C16-烷基-C＝O-、-(C＝O)m-C1-C16烷基-(C＝O)n、氨基酸残基、二氨基酸残基、共价键，该氨基酸残基或二氨基酸残基任选地被氨基酸保护基团一或多取代；
n是0或1；
m是0或1；
和它们的药学上可耐受的盐与生理学上的功能衍生物。
尤其优选的式I化合物是其中一个或多个基团具有下列含义的那些：
R1是苯基、吡啶基、噻吩基、呋喃基、嘧啶基、吲哚基、噻唑基、咪唑基、香豆素基、邻苯二甲酰亚胺基、喹啉基、哌嗪基、四唑基、三唑基、噁唑基、异噁唑基、异噻唑基，其中芳环或杂芳环有可能被下列基团一或二取代：氟、氯、溴、碘、OH、CF3、-NO2、CN、(C1-C8)-烷氧基、(C1-C8)-烷基、(C3-C6)环烷基、NH2、CHO、-COOH、OCF3；
R2是H、OH、CH2OH、OMe、CHO、NH2；
R3是糖残基、二糖残基、HO-SO2-、(HO)2-PO-，其中糖残基或二糖残基任选地被糖保护基团一或多取代；
R4是H、甲基、F、OMe；
Z是-NH-C0-C16-烷基-C＝O-、-O-C0-C16-烷基-C＝O-、-(C＝O)m-C1-C16-烷基-(C＝O)n、共价键；
n是0或1；
m是0或1；
和它们的生理上可耐受的酸加成盐。
非常优选的式I化合物是其中一个或多个基团具有下列含义的那些：
R1是苯基、噻唑基、噁唑基、异噁唑基，其中芳环或杂芳环有可能被下列基团一至二取代：氟、氯、溴、(C1-C8)-烷基；
R2是H、OH、CH2OH、OMe、CHO、NH2；
R3是
HO-SO2-，其中糖残基任选地被糖保护基团一或多取代；
R4是H、甲基、F、OMe；
Z是-NH-C6-C12-烷基-C＝O-、-O-C6-C12-烷基-C＝O-、-(C＝O)m-C6-C12-烷基-(C＝O)n；
n是0或1；
m是0或1；
和它们的生理上可耐受的酸加成盐。
上述杂芳基中，适合的杂原子的例子尤其是O、S和N。除非另有定义，杂芳环具有1-15个碳原子和1-6个杂原子，优选为1-5个碳原子和1-2个杂原子。上述定义中提到的杂芳基的例子是噻吩、呋喃、吡啶、嘧啶、吲哚、喹啉、噁唑、异噁唑、噻唑或异噻唑。
所列举的术语烷基指直链或支链烃。
所列举的糖残基指从可以属于D或L系列的、具有3至7个碳原子的醛糖和酮糖衍生的化合物；它们也包括氨基糖、糖醇或糖酸。可以提到的例子是葡萄糖、甘露糖、果糖、半乳糖、核糖、赤藓糖、甘油醛、景天庚酮糖、氨基葡糖、半乳糖胺、葡糖醛酸、半乳糖醛酸、葡糖酸、半乳糖酸、甘露糖酸、葡糖胺、3-氨基-1，2-丙二醇、葡糖二酸和半乳糖二酸。
二糖被理解为由两个糖单元组成的糖类。二、三或四糖是两个或多个糖的缩醛样连接的结果。连接可以按α-或β-方式发生。可以提到的例子是乳糖、麦芽糖和纤维素二糖。
如果糖被取代，那么取代位置优选在糖OH基的氢原子上。
下列保护基团基本上适用于糖的羟基：苄基、乙酰基、苯甲酰基、新戊酰基、三苯甲基、叔丁基二甲基甲硅烷基、亚苄基、亚环己基或亚异丙基保护基团。
术语氨基酸或氨基酸残基被理解为下列化合物的立体异构形式，即D或L型：丙氨酸 甘氨酸 脯氨酸半胱氨酸 组氨酸 谷氨酰胺天冬氨酸 异亮氨酸 精氨酸谷氨酸 赖氨酸 丝氨酸苯丙氨酸 亮氨酸 苏氨酸色氨酸 甲硫氨酸 缬氨酸酪氨酸 天冬酰胺2-氨基己二酸 2-氨基异丁酸3-氨基己二酸 3-氨基异丁酸β-丙氨酸 2-氨基庚二酸2-氨基丁酸 2，4-二氨基丁酸4-氨基丁酸 锁链素γ-氨基丁酸(piperidinic acid) 2，2-二氨基庚二酸6-氨基己酸 2，3-二氨基丙酸2-氨基庚酸 N-乙基甘氨酸2-(2-噻吩基)甘氨酸 3-(2-噻吩基)丙氨酸青霉胺 N-甲基甘氨酸N-乙基天冬酰胺 N-甲基异亮氨酸羟基赖氨酸 6-N-甲基赖氨酸别羟基赖氨酸 N-甲基缬氨酸3-羟基脯氨酸 正缬氨酸4-羟基脯氨酸 正亮氨酸异锁链素 鸟氨酸别异亮氨酸 11-氨基十一酸
术语氨基保护基团被理解为适用于保护氨基酸残基侧链官能团的基团(例如参见T.W.Greene，P.G.M.Wuts《有机合成中的保护基团》第2版，John Wiley and Sons，New York 1991)。主要采用下列保护基团：叔丁氧基-羰基(BOC)、9-芴基甲氧基-羰基(Fmoc)、苄氧基-羰基(Z)、2-(3，5-二甲氧基苯基)丙-2-基氧基羰基(Ddz)、甲基、叔丁基、三苯甲基、S-叔丁基。
由于水溶性优于原始化合物或基本化合物，药学上可耐受的盐尤其适合于药用。这些盐必须具有药学上可耐受的阴离子或阳离子。根据本发明的化合物的适合的药学上可耐受的酸加成盐是无机酸的盐，酸例如盐酸、氢溴酸、磷酸、偏磷酸、硝酸、磺酸和硫酸，和有机酸的盐，酸例如乙酸、苯磺酸、苯甲酸、柠檬酸、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。出于药用目的，尤其优选地使用氯化物盐。适合的药学上可耐受的碱式盐是铵盐、碱金属盐(例如钠和钾盐)和碱土金属盐(例如镁和钙盐)。
与非药学上可耐受的阴离子所形成的盐同样包括在本发明范围内，因为它们是药学上可耐受的盐的制备或纯化的有用中间体，和/或用在非治疗应用、例如体外应用中的有用中间体。
这里所用的术语“生理学上的功能衍生物”指代根据本发明的式I化合物的任意生理学上可耐受的衍生物，例如酯，它们一旦对哺乳动物、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也包括根据本发明的化合物的前体药物。这类前体药物能够在体内代谢成为根据本发明的化合物。这些前体药物本身可以是活性或无活性的。
根据本发明的化合物也可以以各种多晶型形式存在，例如无定形和结晶的多晶型形式。根据本发明的化合物的全部多晶型形式都包括在本发明范围内，是本发明的进一步内容。
下文中，全部关于“根据式(I)的化合物”的称谓都涉及如上所述的式(I)化合物和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作用所必需的式(I)化合物的量取决于一系列因素，例如所选择的具体化合物、所需用途、给药途径和患者的临床状况。一般来说，每日剂量为0.1mg至100mg(通常从0.1mg至50mg)每天每千克体重，例如0.1-10mg/kg/天。片剂或胶囊剂例如可以含有0.01至100mg，通常为0.02至50mg。在药学上可耐受的盐的情况下，上述重量涉及从该盐衍生的氨基丙醇离子的重量。式(I)化合物本身可以以化合物的形式用于上述疾病的预防或治疗，但是它们优选地与可耐受的赋形剂一起以药物组合物的形式存在。当然，该赋形剂必须是可耐受的，也就是说它与组合物的其它组分是相容的，并且对患者无害。赋形剂可以是固体或液体，或二者皆是，优选地与化合物配制成单一剂量，例如可以含有0.05至95重量％活性物质的片剂。还可以存在其它药学上的活性物质，包括其它式(I)化合物。根据本发明的药物组合物可以通过一种已知的药学方法加以制备，制备方法的本质在于将各组分与药理学上可耐受的赋形剂和/或助剂混合。
根据本发明的药物组合物是适合于口服和经口(例如舌下)给药的那些，不过在每种具体情况下，最适合的给药途径取决于所治疗疾病的性质与严重性和在每种情况下所用式(I)化合物的性质。糖衣制剂和糖衣缓释制剂也属于本发明范围。耐酸和胃液制剂是优选的。适合的耐胃液包衣包括乙酸邻苯二甲酸纤维素、聚乙酸邻苯二甲酸乙烯酯、羟丙基甲基纤维素的邻苯二甲酸酯和异丁烯酸与异丁烯酸甲酯的阴离子聚合物。
适合于口服给药的药物化合物可以存在于独立的单元内，例如是胶囊剂、糯米纸囊剂、锭剂或片剂，它们均含有一定量的式(I)化合物；例如是粉末或颗粒；例如是在水性或非水性流体中的溶液或悬浮液；或者例如是水包油或油包水型乳剂。已如上述，这些制剂可以通过任意适合的药学方法加以制备，制备方法包括使活性物质与赋形剂(它可以由一种或多种另外的组分组成)彼此接触的步骤。一般来说，组合物是这样制备的，将活性物质与液体和/或细分的固体赋形剂均匀一致地混合，然后如果需要的话，使产物成型。例如，片剂可以这样制备，压制化合物与酌情的一种或多种另外的组分的粉末或颗粒，或者使其成型。压制片可以这样制备，在适合的机械中，将自由流动形式、例如粉末或颗粒形式的化合物压片，酌情地化合物已与粘合剂、润滑剂、惰性稀释剂和/或一种(或多种)表面活性剂/分散剂混合成混合物。成型片可以这样制备，在适合的机械中，使粉状的用惰性液体稀释剂润湿的化合物成型。
适合于经口(舌下)给药的药物组合物包括锭剂，其中包含式(I)化合物与矫味剂、通常是蔗糖和阿拉伯胶或黄芪胶，以及软锭剂，其中在惰性基质内包含该化合物，惰性基质例如是明胶和甘油或蔗糖和阿拉伯胶。
本发明进而也涉及式I的异构体混合物和式I的纯的非对映异构体。
本发明进而涉及式I丙醇胺衍生物的制备方法。
制备式I化合物方法的特征在于，其中R4取代的亚胺是从II型的胺和III型的醛制备的，其中的R4具有式I给出的含义。为此，例如在20℃-150℃的温度下，加入或不加入一种酸，例如对甲苯磺酸，使胺II与醛III本身反应，或者在适合的溶剂中反应，溶剂例如为乙醇、甲苯或乙酸(a)。
被基团R1和R2取代的式VII酮化合物(其中R1和R2具有式I给出的含义)通过文献已知方法或其相似方法加以制备。例如，在-80℃与20℃之间的温度下，甲基吡啶衍生物V用适合的碱、例如正丁基锂金属化，并在四氢呋喃或另一种适合的溶剂中与相应的羧酸衍生物VI反应，例如羧酸二烷基酰胺或羧酸酯(基团X)(b)。
使IV型亚胺与VII型酮反应，得到VIII型化合物，它们均被基团R1、R2和R4取代，其中R1、R2和R4具有式I给出的含义。该反应例如可以这样进行，在20℃至150℃的温度下，将这两种化合物本身(没有溶剂)混合，随后加热，或者在适合的溶剂中，例如二氯甲烷、乙醇、甲苯、二甘醇二甲醚或十四烷中进行(c)。
借助于手性酸通过结晶法或色谱法，将VIII型外消旋化合物拆分为IX和X型纯的非对映异构体(手性酸例如是莰烷酸、五乙酰基葡糖酸、樟脑-10-磺酸、O-甲基扁桃酸或乳酸)(d)。
在-30℃与+40℃的温度下，在适合的溶剂中，例如甲醇、THF或THF/水，将IX或X型酮化合物用NaBH4或另一种适合的还原剂还原，得到XI型羟基化合物，这些化合物有可能被基团R1、R2和R4取代，其中R1、R2和R4具有式I给出的含义(e)。
在碱性或酸性条件下，例如使用KOH、NaOH或HCl，使手性酸在适合的溶剂中裂解，溶剂例如是甲醇、乙醇、THF或THF/水。随后通过文献已知的方法使硝基还原为胺，得到具有基团R1、R2和R4的XII型化合物(f)。
利用文献已知的方法，使XII型氨基化合物与烷基或酰基基团R3-Z-Y反应，其中Y代表离去基团，得到式I化合物(g)。如果采用X-Z-Y作为该烷基或酰基基团，其中X是保护基团，那么得到的是中间体，该中间体能够进一步与烷基或酰基基团R3-Y反应，得到式I化合物(h)。
式I化合物和它们的药学上可接受的盐与生理学上的功能衍生物是理想的药物，用于脂质代谢障碍、特别是高脂血症的治疗。式I化合物也适合于影响血清胆固醇水平，用于动脉硬化现象的预防和治疗。如果适当的话，该化合物也可以与他汀类药物联合给药，例如辛伐他汀、氟伐他汀、普伐他汀、cerivastatin、洛伐他汀或atorvastin。下列发现证实了根据本发明的化合物的药理学功效。
在测定对兔回肠刷状缘膜囊(Buerstensaummembranvesikeln)中[3H]-牛磺胆酸盐摄取的抑制作用的生物试验中测试根据本发明的化合物。如下进行抑制性试验：
1、兔回肠刷状缘膜囊的制备
通过所谓的Mg2+沉淀法，从小肠细胞制备刷状缘膜囊。通过静脉内注射0.5ml T61处死雄性新西兰兔(体重2至2.5kg)，T61是2.5mg丁卡因HCl、100mg乙甲丁酰胺和25mg碘环三甲铵的水溶液。摘除回肠，用冰冷却的生理盐水洗涤。回肠的末端7/10(按口-直肠方向测量，即末端回肠，含有活性Na+-依赖性胆汁酸转运系统)用于制备刷状缘膜囊。在-80℃氮下，将小肠在聚合物袋内冷冻。为了制备膜囊，将冷冻后的小肠在30℃水浴中解冻。刮掉粘膜，将其悬浮在60ml冰冷却的12mM Tris-HCl缓冲液(pH7.1)/300mM甘露糖醇、5mM EGTA/10mg/l苯甲基磺酰氟/1mg/l大豆胰蛋白酶抑制剂(32U/mg)/0.5mg/l牛肺胰蛋白酶抑制剂(193U/mg)/5mg/l杆菌肽中。混合物用冰冷却的蒸馏水稀释至300ml后，在Ultraturrax(18-杆，IKA Werk Staufen，Germany)中在75％最大功率下匀化3分钟，同时用冰冷却。加入3ml 1MMgCl2溶液后(最终浓度10mM)，混合物在0℃下放置1分钟整。Mg2+的加入导致细胞膜聚集，并沉淀，而刷状缘膜除外。在3000xg(5000rpm，SS-34转子)下离心15分钟后，弃去沉淀，将含有刷状缘膜的上清液在48000xg(20000rpm，SS-34转子)下离心30分钟。弃去上清液，沉淀再用Potter Elvejhem匀化器(Braun，Melsungen，900rpm，10-冲程)在60ml 12mM Tris/HCl缓冲液(pH7.1)/60mM甘露糖醇、5mMEGTA中匀化。加入0.1ml 1M MgCl2溶液，在0℃下培养15分钟后，混合物再在3000xg下离心15分钟。上清液随后在48000xg(20000rpm，SS-34转子)下离心30分钟。将沉淀溶于30ml 10mMTris/Hepes缓冲液(pH7.4)/300mM甘露糖醇，在1000rpm下用20冲程Potter Elveihem匀化器再悬浮。在48000xg(20000rpm，SS-34转子)下离心30分钟后，将沉淀溶于0.5至2ml Tris/Hepes缓冲液(pH7.4)/280mM甘露糖醇(最终浓度20mg/ml)，借助于27-量针结核菌素注射器再悬浮。膜囊在制备后立即用于转运试验，或者每份4mg贮存在-196℃液氮中。
2、对回肠刷状缘膜囊中Na+-依赖性[3H]-牛磺胆酸盐摄取的抑制作用
凭借所谓的膜过滤技术，测定上述刷状缘膜囊对底物的摄取作用。将10μl膜囊悬浮液滴(100μg蛋白质)吸移到聚苯乙烯培养管(11×70mm)壁上，培养管含有培养基以及有关的配体(90μl)。培养基含有0.75μl＝0.75μCi[3H(G)]牛磺胆酸盐(比活度：2.1Ci/mMol)/0.5μl10mM牛磺胆酸盐/8.75μl钠转运缓冲液(10mM Tris/Hepes，(pH7.4)/100mM甘露糖醇/100mM NaCl)(Na-T-P)或8.75μl钾转运缓冲液(10mM Tris/Hepes，(pH7.4)/100mM甘露糖醇/100mM KCl)(K-T-P)和80μl所研究抑制剂在Na/T缓冲液或K/T缓冲液中的溶液，这因实验而异。将培养基通过聚偏二氟乙烯膜滤器(SYHV LO 4NS，0.45μm，4mmΦ，Millipore，Eschborn，Germany)过滤。将膜囊与培养基混合，开始测量转运作用。每批培养的牛磺胆酸盐浓度为50μM。经过所需的培养时间(通常为1分钟)后，加入1ml冰冷却的猝灭溶液(10mMTris/Hepes，(pH7.4)/150mM KCl)以终止转运。立即在25至35毫巴真空下，通过硝酸纤维素膜滤器(ME 25，0.45μm，直径25mm，Schleicher & Schuell，Dassell，Germany)吸取所得混合物。滤器用5ml冰冷却的猝灭溶液清洗。
为了测量对放射性标记的牛磺胆酸盐的摄取作用，将膜滤器溶于4ml闪烁体Quickszint 361(Zinsser Analytik GmbH，Frankfurt，Germany)，通过液体闪烁测量法，在TriCarb 2500装置(CanberraPackard GmbH，Frankfurt，Germany)中测量放射性。装置已经借助于标准样本加以校准，并且任何可能存在的化学荧光已经加以校正后，得到测量值，以dpm(每分钟的分解量)表示。
分别在Na-T-P和K-T-P中测定对照值。Na-T-P和K-T-P之间摄取作用的差异代表Na+-依赖性转运。术语IC50Na+用于表示相对于对照水平，抑制50％Na+-依赖性转运的抑制剂浓度。
药理学数据包括一系列试验，这些试验研究了根据本发明的化合物与末端回肠中的肠内胆汁酸转运系统之间的相互作用。结果显示在表1中。
表1显示对兔回肠刷状缘膜囊中[3H]-牛磺胆酸盐摄取的抑制作用测量值(生物学试验)。所给出的数据是参照物质、即牛磺脱氧胆酸(TCDC)与所研究的供试物质的IC50Na值的商。
表1
表2
| 实施例(Bsp.) | R3 | Z | R4 | R3-Z-NH- | 经验式(分子量) | MS | 生物试验 |
| 1 | 葡糖酸 | - | H | 邻位 | C31H34N4O7(574,63) | 575,3 M+H+ | 1,09 |
| 2 | 葡糖酸 | -NH-CH2-CH2-CH2- | H | 邻位 | C34H41N5O7(631,73) | 632,4 M+H+ | 0,24 |
| 3 | 葡糖酸 | -(L)-Pro- | H | 邻位 | C36H41N5O8(671,75) | 672,4 M+H+ | 0,15 |
| Bsp. | R3 | Z | R4 | R3-Z-NH- | 经验式(分子量) | MS | 生物试验 |
| 4 | 葡糖酸 | -(L)-Phe-(L)-Pro- | H | 邻位 | C45H50N6O9(818,92) | 819,5 M+H+ | 1,69 |
| 5 | 葡糖酸 | -NH-CH2-(反式-1，4-环己基)-CO- | H | 邻位 | C39H47N5O8(713,83) | 714,4 M+H+ | 1,56 |
| 6 | 葡糖酸 | -NH-(反式-1，4-环己基)-CO- | H | 邻位 | C38H45N5O8(699,80) | 700,4 M+H+ | 1,19 |
| 7 | 五-O-乙酰基葡糖酸 | - | H | 邻位 | C41H44N4O12(784,81) | 785,4 M+H+ | 0,44 |
| 8 | 五-O-乙酰基葡糖酸 | -NH-(CH2)10-CO- | H | 邻位 | C52H65N5O13(968,11) | 968,6 M+H+ | 0,83 |
| 9 | 葡糖酸 | -NH-(CH2)10-CO- | H | 邻位 | C42H55N5O8(757,92) | 758,5 M+H+ | 1,78 |
| 10 | 葡糖酸 | -NH-(CH2)11-CO- | H | 邻位 | C43H57N5O8(771,95) | 772,5 M+H+ | 1,53 |
| 11 | 葡糖酸 | -NH-(CH2)7-CO- | H | 邻位 | C39H49N5O8(715,84) | 716,4 M+H+ | 1,59 |
| 12 | 葡糖酸 | -NH-(CH2)6-CO- | H | 邻位 | C38H47N5O8(701,82) | 702,4 M+H+ | 0,29 |
| 13 | 葡糖酸 | -NH-(CH2)5-CO- | H | 邻位 | C37H45N5O8(687,79) | 688,4 M+H+ | 0,28 |
| Bsp. | R3 | Z | R4 | R3-Z-NH- | 经验式(分子量) | MS | 生物试验 |
| 14 | 葡糖酸 | -NH-(CH2)4-CO- | H | 邻位 | C36H43N5O8(673,76) | 674,4 M+H+ | 0,23 |
| 15 | 葡糖胺 | -CO-(CH2)2-CO- | H | 邻位 | C35H41N5O8(659,74) | 660,4 M+H+ | 0,19 |
| 16 | 葡糖胺 | -CO-(CH2)8-CO- | H | 邻位 | C41H53N5O8(743,90) | 744,5 M+H+ | 0,86 |
| 17 | 葡糖胺 | -CO-(CH2)9-CO- | H | 邻位 | C42H55N5O8(757,92) | 758,5 M+H+ | |
| 18 | 葡糖胺 | -CO-(CH2)10-CO- | H | 邻位 | C43H57N5O8(771,95) | 772,5 M+H+ | 1,21 |
| 19 | 葡糖胺 | -CO-(CH2)12-CO- | H | 邻位 | C45H61N5O8(800,00) | 800,6 M+H+ | 2,73 |
| 20 | 葡糖胺 | -CO-(CH2)14-CO- | H | 邻位 | C47H65N5O8(828,06) | 828,7 M+H+ | 0,32 |
| 21 | 氨基葡糖 | -CO-(CH2)2-CO- | H | 邻位 | C35H39N5O8(657,72) | 658,4 M+H+ | 0,26 |
| 22 | 葡糖胺 | -(CH2)11-CO- | H | 邻位 | C43H59N5O7(757,97) | 758,5 M+H+ | |
| 23 | 葡糖胺 | -(CH2)10-CO- | H | 邻位 | C42H57N5O7(743,94) | 744,5 M+H+ | |
| 24 | 甘油胺 | -(CH2)10-CO- | H | 邻位 | C39H51N5O4(653,86) | 654,4 M+H+ |
| Bsp. | R3 | Z | R4 | R3-Z-NH- | 经验式(分子量) | MS | 生物试验 |
| 25 | HO-SO2- | - | H | 邻位 | C25H24N4O4S(476,55) | 477,3 M+H+ | |
| 26 | HO-SO2- | -NH-(CH2)11-CO- | H | 邻位 | C37H47N5O5S(673,87) | 674,4 M+H+ | 1,72 |
| 27 | HO-SO2- | -NH-(CH2)10-CO- | H | 邻位 | C36H45N5O5S(659,85) | 660,4 M+H+ | |
| 28 | HO-SO2- | -(L)-Phe-(L)-Pro- | H | 邻位 | C39H40N6O6S(720,85) | 721,5 M+H+ | 1,56 |
| 29 | 葡糖酸 | -O-CH2-CO- | H | 邻位 | C33H34N4O9(630,65) | 631,3 M+H+ | |
| 30 | 葡糖酸 | -O-CH2(CH3)2-CO- | H | 邻位 | C35H38N4O9(658,70) | 659,3 M+H+ | 0,42 |
| 31 | 葡糖酸 | -O-(CH2)11-CO- | H | 邻位 | C43H54N4O9(770,92) | 771,5 M+H+ | |
| 32 | 葡糖醛酸甲酯 | -O-(CH2)11-CO- | H | 邻位 | C44H56N4O9(784,94) | 785,5 M+H+ | |
| 33 | 葡萄糖 | -O-CH2-CO- | H | 邻位 | C33H36N4O8(616,67) | 617,3 M+H+ | 0,09 |
| 34 | 葡糖酸 | -NH-(CH2)10-CO- | 5-F | 邻位 | C42H54FN5O8(775,91) | 776,5 M+H+ | |
| 35 | 五-O-乙酰基葡糖酸 | -NH-(CH2)10-CO- | 5-F | 邻位 | C52H64FN5O13(986,10) | 986,7 M+H+ |
| Bsp. | R3 | Z | R4 | R3-Z-NH- | 经验式(分子量) | MS | 生物试验 |
| 36 | 葡糖酸 | -NH-(CH2)10-CO- | H | 间位 | C42H55N5O8(757,92) | 758,5 M+H+ | |
| 37 | 葡糖酸 | -NH-(CH2)10-CO- | H | 对位 | C42H55N5O8(757,92) | 758,5 M+H+ | |
| 38 | 五-O-乙酰基葡糖酸 | -NH-(CH2)10-CO- | H | 间位 | C52H65N5O13(968,11) | 968,6 M+H+ | |
| 39 | 五-O-乙酰基葡糖酸 | -NH-(CH2)10-CO- | H | 对位 | C52H65N5O13(968,11) | 968,6 M+H+ | |
| 40 | D-甘油基-D-古洛(gulo)-庚糖 | - | H | 邻位 | 632H36N4O7(604,66) | 604,3 M+H+ | |
| 41 | D-甘油基-D-古洛(gulo)-庚糖 | -NH-(CH2)10-CO- | H | 邻位 | C43H57N5O9(787,95) | 788,5 M+H+ | |
| 42 | (HO)2-PO-O- | -CH2-CO- | H | 邻位 | C27H27N4O6P(534,51) | 535,3 M+H+ |
| 实施例 | R1 | R3 | Z | 异构体 | 经验式(分子量) | MS | 生物试验 |
| 43 | 3，5-二甲基-异噁唑-4-基 | 葡糖酸 | NH-(CH2)10-CO | I | C41H56N6O9(776,9) | 777,4 M+H+ | 0,45 |
| 44 | 3，5-二甲基-异噁唑-4-基 | 葡糖酸 | NH-(CH2)10-CO | IA1 | C41H56N6O9(776,9) | 777,4 M+H+ | 0,49 |
| 45 | 3，5-二甲基-异噁唑-4-基 | 葡糖酸 | NH-(CH2)10-CO | IB1 | C41H56N6O9(776,9) | 777,4 M+H+ | |
| 46 | 3，5-二甲基-异噁唑-4-基 | 葡糖酸 | NH-(CH2)10-CO | II | C41H56N6O9(776,9) | 777,4 M+H+ | |
| 47 | 3，5-二甲基-异噁唑-4-基 | 葡糖酸 | NH-(CH2)10-CO | III | C41H56N6O9(776,9) | 777,4 M+H+ | |
| 48 | 3，5-二甲基-异噁唑-4-基 | 葡糖酸 | NH-(CH2)10-CO | IV | C41H56N6O9(776,9) | 777,4 M+H+ | |
| 49 | 2，4-二甲基-噻唑-5-基 | 葡糖酸 | NH-(CH2)10-CO | I | C41H56N6O8S(793,0) | 793,4 M+H+ | 0,24 |
| 50 | 2，4-二甲基-噻唑-5-基 | 葡糖酸 | NH-(CH2)10-CO | II | C41H56N6O8S(793,0) | 793,4 M+H+ | |
| 51 | 2，4-二甲基-噻唑-5-基 | 葡糖酸 | NH-(CH2)10-CO | III | C41H56N6O8S(793,0) | 793,4 M+H+ | |
| 52 | 2，4-二甲基-噁唑-4-基 | 葡糖酸 | NH-(CH2)10-CO | I | C41H56N6O9(776,9) | 777,4 M+H+ | 0,31 |
| 53 | 5-戊基-异噁唑-3-基 | 葡糖酸 | NH-(CH2)10-CO | I2 | C44H62N6O9(819,0) | 819,6 M+H+ | |
| 54 | 5-戊基-异噁唑-3-基 | 葡糖酸 | NH-(CH2)10-CO | II2 | C44H62N6O9(819,0) | 819,6 M+H+ | |
| 55 | 3，5-二甲基-异噁唑-4-基 | 五-O-乙酰基葡糖酸 | - | I | C40H45N5O13(803,8) | 804,1 M+H+ | 0,24 |
| 56 | 3，5-二甲基-异噁唑-4-基 | 五-O-乙酰基葡糖酸 | - | II | C40H45N5O13(803,8) | 804,1 M+H+ | |
| 57 | 3，5-二甲基-异噁唑-4-基 | 葡糖酸 | - | II | C30H35N5O8(593,6) | 594,4 M+H+ | |
| 58 | 3，5-二甲基-异噁唑-4-基 | 葡糖酸 | - | I | C30H35N5O8(593,6) | 594,4 M+H+ | |
| 59 | 5-甲基-异噁唑-3-基 | 葡糖酸 | NH-(CH2)10-CO | 3- | C40H54N6O9(762,9) | 763,4 M+H+ | |
| 60 | 2，5-二甲基-噁唑-4-基 | 葡糖酸 | - | 3- | C31H36N4O8(592,6) | 594,2 M+H+ | |
| 61 | 5-甲基-异噁唑-3-基 | 葡糖酸 | - | I | C29H33N5O8(579,6) | 580,2 M+H+ | |
| 62 | 2，4-二甲基-噻唑-5-基 | 五-O-乙酰基葡糖酸 | - | I | C40H45N5O12S(819,9) | 820,1 M+H+ | |
| 63 | 2，4-二甲基-噻唑-5-基 | 五-O-乙酰基葡糖酸 | - | II | C40H45N5O12S(819,9) | 820,1 M+H+ | |
| 64 | 2，4-二甲基-噻唑-5-基 | 葡糖酸 | - | I | C30H35N5O7S(609,7) | 610,2 M+H+ | |
| 65 | 2，4-二甲基-噻唑-5-基 | 葡糖酸 | - | II | C30H35N5O7S(609,7) | 610,2 M+H+ |
| 66 | 3-(3-氯苯基)-5-甲基-异噁唑-4-基 | 葡糖酸 | - | 3- | C35H36ClN5O8(690,2) | 690,2 M+H+ | |
| 67 | 3-(3-氯苯基)-5-甲基-异噁唑-4-基 | 葡糖酸 | NH-(CH2)10-CO | 3- | C46H57ClN6O9(873,4) | 873,3 M+H+ | |
| 68 | 4-甲基-2-(吡啶-4-基)-噻唑-5-基 | 五-O-乙酰基葡糖酸 | - | 3- | C44H46N6O12S(882,9) | 883,2 M+H+ |
1 对映异构体
2 非对映异构体对I或II
3 非对映异构体混合物
胆石形成试验
1.供试物质、剂量和用药
mg/kg/d表1实施例9(＝A1) 100 0.1％，添加在饲料中
2.目的
该试验研究胆石敏感性小鼠胆固醇胆石的形成。
3.材料和方法
3.1 动物和饲养环境
所用实验动物是雄性C57L小鼠(Jackson Laboratories)，在开始适应时的平均体重为25-30g。
将动物随机分为4组(n＝10，第2和第3组的n＝15)。从开始治疗时开始，通过Altromin给动物饲喂标准啮齿动物饲料(第1组)或成石性饮食(第2-4组)；该饮食的组成如下：
15％奶油、1％胆固醇、50％糖、20％酪蛋白、0.5％胆酸、5％矿质混合物、2.5％维生素混合物、2％玉米油、玉米淀粉至100％。
对动物每周进行称重，通过在饲喂前后连续称重来测定食物消耗量，由此计算剂量。
3.2 最后的检查
分别在11和13周后，将每组动物处死，随后准备胆囊。
记录胆囊内的胆石。切开胆囊，测定重量，分析胆汁和胆石的组成。
4.结果组/饲料 剂量 治疗时间[周] 胆石频率
[mg/kg/d] [n/n]1正常饲料 - 13 0/102成石性饮食 - 11 5/153成石性饮食 - 13 5/154成石性饮食+实施例9 100 13 0/10
测量值揭示了根据本发明的化合物有效预防胆石的形成。它们因此适合于胆石的预防和治疗。
所选择的表1实施例和完整结构 
实施例24 
实施例29 实施例33
实施例41
具体实施方案
下列实施例意在详细阐述发明，并不将后者限于实施例中所描述的产物和实施方式。
实施例A1(＝表1的实施例9)1a.
将0.7g对甲苯磺酸加入到25g(266mmol)2-氨基吡啶与40g(265mmol)2-硝基苯甲醛的300ml甲苯溶液中，混合物回流6小时。冷却后，在真空中除去一半溶剂，放置过夜。用吸滤法滤出所得沉淀，用冷甲苯洗涤，在真空中干燥。随后从正庚烷/乙酸乙酯2∶1重结晶，得到48.8g(81％)亚胺。
C12H9N3O2(227.2)MS(FAB)228.2 M+H+1b.
在-55℃下将250ml正丁基锂(15％己烷溶液)滴加到50g(0.54mol)2-甲基吡啶的770ml四氢呋喃溶液中，混合物搅拌10分钟。混合物随后加热至0℃，30分钟后，冷却至-55℃。随后缓慢滴加77g(0.52mol)N，N-二甲基苯甲酰胺的570ml四氢呋喃溶液。加入后，混合物加热至室温，搅拌1小时。加入500ml水和35ml浓HCl后，分离出有机相，含水相用乙酸乙酯萃取两次。经MgSO4干燥后，在真空中浓缩，将残余物在高真空中蒸馏。沸点134-136℃/0.3毫巴。收率：47.5g(47％)酮。
C13H11NO(197.2)MS(FAB)198.1 M+H+
1c 1d
在回流下，将200g(0.89mol)实施例1a亚胺和171g(0.88mol)实施例1b酮溶于二氯甲烷。原料已经溶解后，混合物冷却至室温。反应溶液用600ml乙酸乙酯和300ml正庚烷稀释。该溶液借助于充满500ml快速硅胶的玻璃料(1升)过滤，用500ml正庚烷/乙酸乙酯(1∶2)洗涤。滤液浓缩，得到370g粗产物。粗产物是全部四种可能的立体异构体混合物。通过从乙醇中结晶，得到两种所需的顺式产物1c/d。为此，将粗产物溶于600ml乙醇，在室温下放置两天；得到190g产物1c/d。五天后进一步从母液中分离到106g产物1c/d。立体异构体在溶液中处于平衡状态。对映异构体对1c/1d微溶于乙醇，并可结晶，而反式对映异构体对可溶于乙醇。得到296g(79％)1c/1d，为淡黄色晶体。
C25H20N4O3(424.2)MS(FAB)425.1 M+H+1e 1f
将33g(153mmol)(-)-莰烷酰氯CAMCl(Fluka)溶于500ml二氯甲烷，溶液冷却至10℃。向该溶液中加入50ml三乙胺。然后，缓慢加入52.3g(123mmol)实施例1c/d的结晶性酮，使反应温度不超过20℃。用薄层色谱法监测反应终点(大约30分钟)。反应溶液用500ml乙酸乙酯稀释，用水洗涤，经MgSO4干燥，过滤并浓缩。浓缩有机相至1f开始结晶。然后过滤，得到32.5g(44％)1f，为白色固体。母液用500ml正庚烷/乙酸乙酯(4∶1)稀释，再浓缩至产物1e又开始结晶。得到32g(44％)1e，为无色晶体。
C35H32N4O6(604.7)MS(FAB)605.3 M+H+
1g 1h
将8.5g(14.1mmol)实施例1e酮化合物溶于150ml THF/水10∶1，溶液用2.0g(53mmol)硼氢化钠处理，全部混合物在室温下搅拌10小时。用2N HCl酸化至pH为1，混合物在50℃下搅拌30分钟。冷却后，反应混合物用2N NaOH赋予碱性，用乙酸乙酯萃取两次。有机相经MgSO4干燥，浓缩至1g开始结晶。收率：3.6g白色晶体。母液进一步浓缩，可以分离到第二部分1g(2.45g)。总收率为6.05g(71％)1g。1f能够按照相似程序反应，得到1h，为无色晶体。用X-射线结构分析测定1h的立体化学(附录1)。
C35H34N4O6(606.7)MS(FAB)607.3 M+H+1i
将50g KOH溶于500ml乙醇。在室温下向该溶液中加入57g(94mmol)莰烷酸衍生物1g的500ml二氯甲烷溶液。2小时后，混合物进行含水处理，得到44.3g粗产物。将该粗产物溶于750ml二氯甲烷，加入7.5g炭上的钯(10％)。氢化10小时后，完成氢的摄取(大约6.5l)。反应溶液通过硅胶过滤，用400ml甲醇洗涤。在旋转蒸发器上蒸发溶剂后，得到40g粗产物。在乙酸乙酯/正庚烷中重结晶，得到25.2g 1i，为无色晶体(2步收率68％)。而且，从母液也得到10g 1i的无定形部分，纯度为80-90％。
C25H24N4O(396.49)MS(FAB)397.2 M+H+
旋光度(α)D 20＝+59°(C＝1，CH2Cl2)1j
将8.0g(18.8mmol)五-O-乙酰基-D-葡糖酰氯(《有机合成》(Org.Synth.)卷5，887)加入到8.0g(40mmol)11-氨基十一酸(Fluka)的150ml无水DMF悬浮液中。该悬浮液在室温下剧烈搅拌20小时。然后加入500ml乙酸乙酯和200ml水。含水相再用250ml乙酸乙酯萃取。合并后的有机相用氯化钠溶液洗涤三次，经MgSO4干燥，过滤并浓缩。得到9.5g(86％)1j，为无色的油。TLC(二氯甲烷/甲醇/浓氨水30/10/3)Rf＝0.8
C27H43NO13(589.6)MS(FAB)590.4 M+H+
1k
将27g(45.8mmol)1j和16g(40.3mmol)1i溶于300ml DMF(二甲基甲酰胺)。先后加入20g(61mmol)TOTU(Fluka)、7g(50mmol)肟(羟基亚氨基氰基乙酸乙酯；Fluka)和17ml(150mmol)NEM(4-乙基吗啉)。在室温下一小时后，混合物用1000ml乙酸乙酯稀释，用水洗涤三次。有机相经MgSO4干燥，过滤并浓缩。残余物通过快速色谱法纯化(乙酸乙酯/正庚烷1∶1)，得到37.1g(95％)1k，为无定形固体。
C52H65N5O13(968.1)MS(FAB)968.7 M+H+
A1(＝表1的实施例9)
将37.1g(38.3mmol)1k溶于300ml甲醇。加入3ml 1M甲醇钠的甲醇溶液后，混合物在室温下放置一小时。然后用HCl甲醇溶液中和，浓缩。残余物用快速色谱法纯化(二氯甲烷/甲醇/浓氨水30/5/1)，得到24.5g(84％)A1(＝表1的实施例9)，为无定形固体。
C42H55N5O8(757.9)MS(FAB)758.4 M+H+
实施例A2(＝表1的实施例23)
2a
将10.0g(25.0mmol)li和13.5g(50.0mmo1)11-溴十一酸(Fluka)溶于100ml DMF(二甲基甲酰胺)。在0℃下先后加入15g(45.7mmol)TOTU(Fluka)和17ml(150mmol)NEM(4-乙基吗啉)。在0℃下一小时后，混合物用500ml乙酸乙酯稀释，用水洗涤三次。有机相经MgSO4干燥，过滤并浓缩。残余物用快速色谱法纯化(乙酸乙酯/正庚烷2∶1)，得到9.9g(62％)2a，为无定形固体。
C36H43BrN4O2(643.7)MS(FAB)643.3 M+H+
A2(＝表1的实施例23)
将9.87g(15.3mmol)2a溶于200ml DMF。加入14g(77mmol)葡糖胺(Fluka)后，溶液在80℃下加热两小时。然后用500ml乙酸乙酯稀释，用水洗涤三次。有机相经MgSO4干燥，过滤并浓缩。残余物用快速色谱法纯化(二氯甲烷/甲醇/浓氨水30/5/1)，得到7.3g(65％)A2，为无定形固体。
C42H57N5O7(743.9)MS(FAB)744.4 M+H+
实施例A3
3a
将92g(0.43mol)1-(3，5-二甲基异噁唑-4-基)-2-吡啶-2-基-乙酮(如实施例1b所述加以制备，但是用3，5-二甲基异噁唑羧酸乙酯代替N，N-二甲基苯甲酰胺)溶于1200ml热乙醇。在室温下加入96.7g实施例1a的亚胺，反应混合物在室温下搅拌三天。数小时后，有淡黄色固体开始沉淀。为了分离反应产物，滤出已经沉淀出来的固体。得到118.9g(63％)淡黄色晶体，熔点为139-140℃。
C24H21N5O4(443.5)MS(FAB)444.4 M+H+
3b(强非极性非对映异构体)
按照实施例1g/h所述程序，将117g(0.264mol)实施例3a酮用硼氢化钠还原。所得粗产物用硅胶色谱法纯化，使用乙酸乙酯/正庚烷的2∶1混合物作为移动相。得到76g(65％)强非极性非对映异构体，熔点95℃；另外，也分离到少量其它三种可能的非对映异构体。
C24H23N5O4(445.5)MS(FAB)446.3 M+H+
3c(强非极性非对映异构体)
将44.5g(0.1mol)实施例3b的氨基丙醇溶于1500ml乙醇，在20℃下用570ml 15％ TiCl3水溶液处理。加入结束后，混合物在室温下搅拌2.5小时。反应混合物在减压下浓缩，剩余残余物用二氯甲烷/水萃取，加入NaHCO3中和，滤出不溶性氢氧化钛。有机相干燥并在减压下浓缩后，剩余残余物通过短硅胶柱过滤(移动相为乙酸乙酯)。除去洗脱剂后剩余的残余物用二乙醚搅拌、结晶，为无色晶体。得到33.2g(80％)无色晶体，熔点为115℃。
C24H25N5O2(415.5)MS(FAB)416.4 M+H+
3d(＝表2的实施例55)
将6.2g(0.015mol)实施例3c的氨基化合物(强非极性非对映异构体，它重新以对映异构体对的形式存在)溶于100ml无水DMF，在搅拌下用6.1g(0.015mol)五乙酰基-D-葡糖酸(《有机合成》卷5，887)、5.9g TOTU(Fluka)、2.1g羟基亚氨基氰基乙酸乙酯和5.9ml N-乙基吗啉处理。反应混合物在室温下搅拌20小时。在减压下除去溶剂，所得粗产物用水/二氯甲烷并使用饱和碳酸氢钠水溶液萃取。有机相用Na2SO4干燥，并在旋转蒸发器上除去萃取剂后，混合物用硅胶色谱法纯化(移动相为乙酸乙酯/正庚烷＝3∶1)。得到两种可能的非对映异构体，为无色晶体：
非极性非对映异构体：3.9g(31％)，熔点140℃
C40H45N5O13(803.8)MS(FAB)804.1 M+H+
极性非对映异构体：4.3g(35％)，熔点204℃
C40H45N5O13(803.8)MS(FAB)804.1 M+H+
3e(+对映异构体)
使实施例3d中合成的3.5g(4.4mmol)非极性非对映异构体如实施例A1所述进行反应(反应时间1小时；反应产物如表2所示，即实施例58)。将浓缩后所得粗产物溶于80ml 0.5M HCl的甲醇溶液，溶液在室温下搅拌六小时。随后在减压下浓缩，用CH2Cl2/水萃取。有机相用Na2SO4干燥，在减压下浓缩。得到1.8g(98％)无色晶体；化合物以对映异构纯的形式存在(柱子CSP-Chiralpak AD，250×4.6；移动相正己烷/乙醇＝10/1；纯度99.7％；(+)-对映异构体)，这可通过与由极性非对映异构体(实施例3d)的相似反应所得到的对映异构体比较而加以证实。
C24H25N5O2(415.5)MS(FAB)416.2 M+H+
3f
使来自实施例3e的1.8g(4.3mmol)对映异构纯化合物与实施例1j化合物进行类似于实施例1k的反应。得到3.7g(86％)淡黄色油。
C51H66N6O14(987.1)MS(FAB)987.5 M+H+
3g(＝表2的实施例44)
将3.7g(3.8mmol)实施例3f的乙酰基化合物如实施例A1所述进行脱酰作用(反应时间2小时)及处理。硅胶色谱法(移动相CH2Cl2/甲醇/NH3[33％]＝30/10/3)纯化后，得到1.78g(60％)无色晶体，熔点为60℃。
C41H56N6O9(776.9)MS(FAB)777.4 M+H+
Claims (10)
1、式I化合物
其中
R1是苯基、噻唑基、噁唑基、异噁唑基，其中上述基团有可能被下列基团一至二取代：氟、氯、溴、(C1-C8)-烷基；
R2是H；
R3是
HO-SO2-，其中糖残基任选地被糖保护基团一或多取代；
R4是H、甲基、F、OMe；
Z是-NH-C6-C12-烷基-C＝O-、-O-C6-C12-烷基-C＝O-、-(C＝O)m-C6-C12-烷基-(C＝O)n；
n是0或1；
m是0或1；
或其生理上可耐受的酸加成盐。
2、药物，包含一种或多种如权利要求1所要求保护的化合物。
3、如权利要求2的药物，包含一种或多种如权利要求1所要求保护的化合物和一种或多种其它具有降低脂质活性的物质。
4、如权利要求1所要求保护的化合物在制备药物中的应用，所述药物用于动脉硬化现象的预防或治疗。
5、如权利要求1所要求保护的化合物在药物制备中的应用，该药物用于脂质代谢障碍的预防或治疗。
6、如权利要求5的应用，该药物用于高脂血症的治疗。
7、如权利要求1所要求保护的化合物与至少一种其它具有降低脂质活性的物质结合在制备药物中的应用，所述药物用于脂质代谢障碍的预防或治疗。
8、如权利要求7的应用，所述药物用于高脂血症的治疗。
9、如权利要求1所要求保护的化合物与至少一种其它具有降低脂质活性的物质结合在制备药物中的应用，所述药物用于动脉硬化现象的预防或治疗。
10、药物的制备方法，该药物包含一种或多种如权利要求1所要求保护的化合物，该方法包括将该活性物质与药学上适合的赋形剂混合，并将该混合物制成适合于给药的剂型。
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| EP1345895B1 (de) * | 2000-12-21 | 2006-12-27 | Sanofi-Aventis Deutschland GmbH | Neue diphenzylazetidinone, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung zur behandlung von lipidstoffwechselstörungen |
| AU2002333373B2 (en) * | 2001-08-22 | 2006-12-14 | Sanofi-Aventis Deutschland Gmbh | Combined preparations, containing 1,4-benzothiepine-1,1-dioxide derivatives and other active substances, and the use thereof |
| JP2005505538A (ja) * | 2001-08-22 | 2005-02-24 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | アリール置換プロパノールアミン誘導体と他の活性成分との組み合わせ物およびその使用 |
| MXPA04001850A (es) | 2001-08-31 | 2004-06-15 | Aventis Pharma Gmbh | Derivados de diarilcicloalquilo, procedimientos para su preparacion y su utilizacion como agentes activadores de ppar. |
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| US7223796B2 (en) * | 2002-04-11 | 2007-05-29 | Sanofi-Aventis Deutschland Gmbh | Acyl-4-carboxyphenylurea derivatives, processes for preparing them and their use |
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| FI892341A (fi) * | 1988-06-10 | 1989-12-11 | Hoffmann La Roche | Propanolaminderivat. |
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| AUPO565997A0 (en) * | 1997-03-17 | 1997-04-10 | Fujisawa Pharmaceutical Co., Ltd. | Propanolamine derivatives |
| PT869121E (pt) | 1997-04-04 | 2004-10-29 | Aventis Pharma Gmbh | Derivados de propanolamina hipolipidemicos |
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