CN1031564C - 制备4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸及其衍生物的方法 - Google Patents
制备4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸及其衍生物的方法 Download PDFInfo
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- CN1031564C CN1031564C CN92103977A CN92103977A CN1031564C CN 1031564 C CN1031564 C CN 1031564C CN 92103977 A CN92103977 A CN 92103977A CN 92103977 A CN92103977 A CN 92103977A CN 1031564 C CN1031564 C CN 1031564C
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/06—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
- C07C251/08—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton being acyclic
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
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Abstract
描述了式(I)化合物及其生物前体及其可药用的盐,作为β3-肾上腺素能受体激动剂,它们具有抗肥胖症,降血糖及相关的治疗用途。同时还描述了它们的制备方法及含有它们的药物组合物。
Description
本发明涉及4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸及其生物前体。本发明还涉及此类化合物的制备方法和制备中间体,它们在治疗方法中的应用以及含有它们的药物组合物。本发明的化合物属β3-肾上腺素能受体激动剂,它们对于由这类肾上腺素能受体介导的疾病是有价值的。将本发明化合物给予温血动物能产生一种生热效应,即生热作用被激发,并且服用该化合物后,对肥胖及有关疾病如与肥胖有联系的成年人初起的糖尿病具有治疗效用。此外,本发明化合物在温血动物身上能改善对葡萄糖的耐受性,它们可用于治疗其中这种活性是有利的某些疾病,例如它们有降低血糖的活性。本发明化合物也可用于治疗非胰岛素依赖型糖尿病(NIDDM)和其中抗胰岛素性具有重要性的某些疾病如高血压,血脂过高和纤维蛋白溶解减少(Reaven氏综合症或综合征X)。
本发明申请人已经对β3-肾上腺素能受体激动剂进行了大量的研究,特别是对其生热效应。属本申请人的美国专利4,772,631公开了通式(A)化合物:其中Ra为氢或氟;Rb和Rc独立地选自氢和C1-3烷基;Z为羟甲基或式-CORd基团,其中Rd为羟基,C1-6烷氧基或氨基。
本申请人的美国专利4,940,168公开了通式(B)化合物其中Ra为氢或氟,Re和Rf独立地为氢或各种形成二级和三级酰胺的基团。人们认为,其中Rd为烷氧基或氨基的式(A)化合物及式(B)化合物最初就是生物前体,它们经相应的氧乙酸,即其中Rd为羟基的式(A)化合物而起作用。
本发明申请人发现其中Ra-Rc为氢,Rd为羟基的式(A)化合物具有重大意义。然而该化合物在溶解度和吸收特性方面并不理想。因此,本发明申请人发展了该化合物的二级酰胺生物前体。这种二级酰胺已引入到志愿受试病人身上试用。令人失望的是临床代谢速率不佳,这实际上指出β3-肾上腺素能受体处游离羧酸的功效不佳。
进一步调查研究发现,该化合物出入意料地产生了值得注意的生热效应,在有效剂量下,副作用较少。可以理解,生热作用的选择性(例如无心脏副作用)对于一种有效的,用于治疗例如肥胖和与其有关病症的治疗剂来说是一项重要的要求。
本发明提供的化合物是羧酸,它比前述的二级酰胺和游离羧酸显示出明显的优势。特别是,它已充分显示出在β3-肾上腺素能受体中的功效,而先前那些化合物给人服用后发现功效较低。此外,这类化合物还出入意料地显示出极好的溶解度和吸收特性。
因此,本发明提供了通式(I)化合物或其生物前体或其可药用的盐。
有利的是,式(I)化合物为羧酸或其可药用盐的形式。4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸和某些生物前体是两性化合物,并可以两性离子形式利用之,或以可药用的酸加成盐形式,或以与能提供药学上可接受的阳离子的碱形成的盐形式。可药用的酸加成盐的具体实例包括:例如,无机酸盐类,如氢卤酸盐,尤其是盐酸盐或溴氢酸盐,硫酸盐和磷酸盐,以及有机酸盐类,如琥珀酸盐,柠檬酸盐,乳酸盐,酒石酸盐以及衍生自酸性水溶性聚合物的盐。与能提供药学上可接受的阳离子的碱形成的盐的具体实例包括,例如,碱金属和碱土金属盐类,如钠,钾,钙和镁盐以及铵盐,还有与合适的有机碱,如三乙醇胺形成的盐类。
生物前体是那些可药用的化合物,它们在动物体内降解而产生母体酸。这些化合物可通过例如口服途径将被试化合物给予试验动物,而后通过检查试验动物的体液加以鉴定。
一类生物前体是4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸羧基的相应酯类生物前体,合适的酯类包括C1-5烷基酯,例如甲酯和乙酯。
另一类生物前体是羟基(-CH(OH)-)的相应酯生物前体,作为它们的酰基部分,这类酯包括如乙酰基,丙酰基,新戊酰基,C1-4烷氧羰基如乙氧羰基和苯乙酰基。
还有一类生物前体是4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸羧基的相应的酰胺生物前体。合适的酰胺包括,例如式-CONR1R2的酰胺,其中R1和R2独立地为氢,C1-6烷基,羟基C2-6烷基(其中羟基取代基不在α-碳原子上),C1-4烷氧基C1-6烷基,苯基烷基,烯丙基,环丙基或环戊基,或者-NR1R2基为吗啉代、哌啶子基或吡咯烷子基。大体上说,酰胺,特别是其中R1和R2独立为氢,原来就被看作为制备相应羧酸或酯的中间体。
4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸的生物前体本身具有生热效应,这是发明的另一方面。
特别优选的本发明的化合物是:(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸;(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺;(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸甲酯;4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸;4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺;及4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸甲酯;以及它们的可药用的盐。
应该理解,4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸及其生物前体含有一个或多个不对称碳原子,并能以光学活性的对映体或非光学活性的外消旋体存在。本发明包括任何对映体,外消旋体和/或非对映体(当两个或多个不对称碳原子存在时)。当这些化合物以治疗剂量给予温血动物时,可提供生热效应,有关如何制备单一的对映体,在化学工艺技术中是熟知的,例如拆分外消旋体或立体有择合成,另外,如何应用如下文中将描述的标准测试方法来测定生热性质也是本领域中熟知的技术。优选的是,本发明化合物在-CH(OH)-基团位置呈(R)绝对构型(遵循Cahn-Pnelog-lngold规则)。
为了将本发明化合物或其可药用的盐用于温血哺乳类(包括人)的治疗,通常按照标准制药技术,将其配制成为药物组合物。
因此,另一方面,本发明提供了包含4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体或其可药用的盐以及药学上可接受的载体的药物组合物。
本发明药物组合物可按标准方法给药,例如通过口服或非肠道给药。为此目的,可用熟知的工艺方法配制成例如片剂,胶囊,丸剂,粉剂,水或油溶液或悬浮液,乳状液,以及元菌的可供注射的水或油溶液或悬浮液。
一般来说,供口服给药的组合物是优选的。
应用标准的赋形剂及熟知的工艺方法,可获得组合物单位剂量形式如片剂或胶囊通常含有例如0.1-500mg活性成分,更合适地为10~250mg,最好为50-100mg本发明化合物。
组合物也可含有用于治疗所述疾病的其它已知的活性成分,例如食欲抑制剂,维生素,抗高血压药及降血糖药,如磺酰脲类,双胍类和噻唑烷二酮类。可以理解这样的组合物具有包含了两种或多种活性成分的共同配方,并且它们具有一致和持续的疗效。
在本发明的一个方面,4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体可配制成供口服的缓释组合物,例如,包含不溶性或可膨胀的聚合填料的基体片剂配方,或包核球状体配方。
当用于使包括人在内的温血动物产生生热效应时,则适当地给予4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体或其可药用的盐,每日给予一般范围的剂量0.002~20mg/kg,合适地为0.02~10mg/kg,最好为0.5~5mg/kg,按需要以单一剂量或分为几次剂量给药,典型的是一天1~3次。然而,熟悉技术的医务人员将会意识到,剂量必需适当地加以变化,这由所治病情的严重性及病人的年龄,性别而决定,并且要按照已知的医疗原则。
此外,本发明化合物可降低甘出三酯和胆固醇水平,并提高高密度脂蛋白(HDL)的水平,所以可用于治疗其中这种降低(和升高)被认为是有益的疾病。因此,除了用来治疗动脉粥样硬化疾病(如冠状动脉、脑血管动脉及外周动脉),心血管及有关疾病外,它们还可用来治疗血甘油三酯过多,血胆固醇过多以及低水平HDL的疾病。
因此,另一方面,本发明提供了一种降低甘油三酯和/或胆固醇水平和/或增加HDL水平的方法,其中包括给予需要这种作用的动物治疗有效量的4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体或其可药用的盐。再一方面,本发明提供一种治疗动脉粥样硬化的方法,其中包括给予需要这种作用的动物治疗有效量的4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体或其可药用的盐。该组合物以与上述对产生生热效应所述的同样的通用方法配制和给药。它们也可以含有已知的用于治疗动脉粥样硬化及有关疾病的其他活性成份,例如,降血胆甾醇药如安妥明,降脂苯酰和二甲苯氧庚酸;胆固醇生物合成抑制剂,如HMC-CoA还原酶抑制剂,例如lovasta-tin,simvastatin和pravastatin;胆固醇吸收抑制剂,如β-谷甾醇和(酰基CoA:胆固醇酰基转移酶)抑制剂如亚油甲苄胺;阴离子交换树脂,例如降脂一号树脂,降脂二号树脂或交联葡聚糖的二烃胺烷基衍生物;烟醇,烟酸或其盐;维生素E;以及拟甲状腺素。
再一方面,本发明化合物刺激胃肠道“非典型性”β-肾上腺素能受体,所以抑制了胃肠能动性。它们可用于治疗这样的疾病,在这些疾病中,对胃肠道“非典型的”β-肾上腺素能受体的刺激被认为是有益的,例如可用于治疗其中对胃肠能动性抑制被认为是有益的疾病。因此它们可用于例如治疗炎性肠病(IBD)(如节段性回肠炎,溃疡性结肠炎),过敏性肠综合征(IBS),非特异性腹泻和倾倒综合症。
因此,本发明提供了刺激胃肠道“非典型性”β-肾上腺素能受体的方法,其中包括给需要该刺激的动物治疗有效量的本发明化合物。
再一方面,本发明提供了抑制胃肠能动性,治疗IBD、治疗IBS,治疗非特异性腹泻以及治疗倾倒综合症中胃排空的方法,其中包括给需要该治疗的动物治疗有效量的本发明化合物。
再一方面,本发明提供了制备4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体或其可药用的盐的方法,该方法包括:a)使式(III)或(IV)化合物与式(V)化合物反应,其中-COR4为羧基或其生物前体,L为可置换基团;或者b)水解式(VI)化合物,其中COR4的定义同上文;或c)水解式(VII)化合物,用来制备4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸,其中R5为可水解基团;d)使式(VIII)化合物与式(IX)化合物反应,其中-COR4的定义同上文,L′为可置换基团;e)使式(X)化合物脱保护,其中R6为-COR4基团的保护衍生物;f)将4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸转变成生物前体,反之亦然,或将4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸的一种生物前体转变成4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸的另一种生物前体;g)将式(XI)化合物还原,其中-COR4的定义同上文;h)将式(XII)化合物还原,其中-COR4的定义同上文;i)将式(XIII)化合物还原,其中-COR4的定义同上文;并且其中任何一个官能团可被壬意地保护起来,然后;如有必要,
(i)除去任何保护基;
(ii)形成可药用的盐。
通常,保护基可选自文献上所描述的或为熟练的化学家所知晓的适于保护需要保护的基团的任何基团,保护基可用常规方法引入。
保护基可通过文献所描述的或为熟练的化学家所知的任何便利的,适合于脱去要脱去的保护基的方法除去,所选用的方法应使对分子中别处基团的干扰降到最低限度,同时又达到了除去保护基的目的。
特殊保护基是存在于-CH(OH)CH2NCH2CH2O-的氮原子上可氢解的基团。合适的保护基为苄基或取代苄基。这样的保护基的去除,按常规做法,应用催化氢化,例如用Pd/C催化剂在常压下氢化进行。合适的条件包括在室温常压或升温、升压条件下,于溶剂例如C2-6链烷醇,如乙醇或异丙醇中进行反应。在氮原子上用可氢解基团保护的,对应于式(I)的化合物,可采用相似于上述对式(I)化合物所述的方法制备。
式(III)或式(IV)化合物与式(V)化合物之间的反应可在合适的溶剂例如醇如乙醇或异丙醇中进行,反应温度范围为例如10-110℃,最方便是在反应混合物的沸点或接近沸点时。在式(IV)化合物中,L可以是例如卤素,如氯或溴,或芳磺酰氧基,如甲苯磺酰氧基,或烷磺酰氧基,如甲磺酰氧基。
式(V)化合物可采用技术熟练人员所知的任何便利的方法制备,例如,可方便地使式(XIV)化合物与式(XV)化合物反应制得:
NH2CH2CH2OH (XIV)
例如,该反应可利用Mitsunobu反应进行,反应物为偶氮二羧酸二乙酯和三苯膦。理想地,氨基官能团(以及羧基功能团,如果存在的话)在此反应中被保护起来,而后按常规做法脱保护。合适的氨基官能团保护基实例包括邻苯二甲酰基和叔丁氧羰基。式(XV)化合物可按照技术上已知的方法制备。
式(VI)化合物在β-肾上腺素能阻断剂技术中已知的条件下可被水解成4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体;例如在适合的溶剂中经由碱性水解。
式(VI)化合物可通过式(XV)与式(XVI)化合物反应制得:其中R7为-CH2CH2OH基团。该反应可按任何常规方法进行,例如采用相似于式(XIV)和(XV)反应的方法,另外,式(VI)化合物还可通过其中R7为氢的式(XVI)化合物与上文所述的式(IX)化合物反应制得。还有一种方法是,式(VI)化合物可通过式(III)化合物与式(XVII)化合物反应制得:其中COR4的定义同上文,且R8O-为离去基团,例如R8O-为C1-4烷氧基。
其中R7为-CH2CH2OH的式(XIV)化合物可通过例如式(III)化合物与其中羟基被任意保护的式(XIV)化合物的N-烷氧羰基衍生物例如叔丁氧羰基氨基乙醇的四氢吡喃醚反应制得。其中R7为氢的式(XVI)化合物可按照常规方法制得。式(IX)和(XVII)化合物可按照常规方法,通过式(XV)化合物的烷基化制得。
式(VIII)和(IX)之间的反应可便利地进行,其反应条件相似于(IV)与(V)之间的反应,L′的定义同上文中对L的定义相似。
在式(VII)化合物中,可水解基团R5的实例包括C1-6烷氧基和-NR1R2,因此-COR5代表C1-6烷基酯或酰胺官能团。这样的基团在常规条件下可水解(酸性,碱性,酶促)成-CO2H。其中R5为体内可水解部分的转化也代表4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸生物前体相互转化成4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸的实例。合适的酸性条件是例如有强无机酸例如盐酸、硫酸或磷酸的存在,反应于例如20°-110℃并在极性溶剂中,如水,C1-4链烷醇(例如甲醇或乙醇)或乙酸中便利地进行。在这种情况下,4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸的相应无机酸盐可被方便地分离出来,另外,反应也可采用碱性条件,例如,氢氢化锂、钠或钾,在合适的溶剂或稀释剂中,(如含水C1-4链烷醇中),于例如10-110℃进行;或者用碱金属卤化物如氯化锂于极性溶剂例如二甲基甲酰胺中进行反应。当-COR5为叔丁氧羰基时,分解反应还可,例如通过在例如100-220℃温度范围内单独或有合适稀释剂如二苯醚存在下热分解进行。
式(VII)化合物可通过相似于上文所述的制备4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体的方法制备,氨基官能团可任意加以保护,例如用苄基。
4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸及其酰胺生物前体可被转化成它的酯前体。合适的条件是,例如,在酸性条件下,例如加入浓硫酸作为催化剂,于相应的链烷醇中回流。
式(XI),(XII)和(XIII)化合物可通过常规化学方法或催化法进行还原反应,如用硼氢化钠化学还原或用催化剂如钯/碳,或铂催化氢化。
用硼氢化钠的还原可在醇(如甲醇)中方便地进行,反应温度通常在0-20℃。
催化氢化可在常规氢化溶剂例如醇如乙醇中进行。氢化反应通常在大约1-10个大气压的氢压及常温或升温条件下进行。
式(XI)化合物可通过式(V)和式(XVIII)化合物反应制得:其中L″为可置换基团。
式(XVIII)化合物和式(V)化合物之间的反应可在合适的溶剂如醇或醚(例如甲醇或乙醚)中进行,反应温度范围为例如-10~110℃,最方便在室温下。在式(XVIII)中,L″可以是例如卤素,如氯或溴。
生成的式(XI)化合物可被就地转化成4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体。
式(XVIII)化合物可用技术上已知的方法制得。
式(XIX)化合物与式(V)化合物之间的反应,可在合适的溶剂,如醇(例如乙醇)中进行,反应温度为例如0-80℃,最方便是在室温下。生成的式(XII)化合物可被就地转化成4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体。
式(XX)化合物和式(VIII)化合物之间的反应可在合适的溶剂如醇(例如乙醇)中进行,反应温度范围为例如0-80℃,最方便是在室温下。生成的式(XII)化合物可就地被转化成4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体。
式(XX)化合物可通过式(XXI)化合物的水解制得:其中COR4的定义同上文,R9和R10独立地为氢或C1-4烷基,合适的水解条件是例如用强无机酸,如盐酸或硫酸;反应于例如20-110℃温度范围内方便地进行,合适的溶剂有四氢呋喃;二氯甲烷或乙醚。
合适的条件包括:在合适的溶剂,如二氯甲烷中,在有温和碱(如Na2CO3)存在的条件下加热。在式(XXII)化合物中,L″′可以是例如卤素,如溴。
式(VI),(VII),(X),(XI),(XII)和(XIII)化合物是新的,且形成本发明的另一方面。
羟基的生物前体酯可以按照常规方法,例如通过羟基与酸的活化衍生物反应制得,反应条件系在β-肾上腺素能阻断剂技术中已知的。
可药用的盐类可通过常规方法,使4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸或其生物前体与合适的酸或碱反应制得。可选择地,当要求制备氢卤酸盐时,其可方便地通过游离碱与化学计量的,相应的卤化苄一起进行氢化反应制得。
下列生物试验方法、数据和实例用来说明本发明。
生热效应
式(I)化合物及其生物前体的生热效应,可应用下列一种或多种标准测试方法加以证明。(a)让大鼠在4℃寒冷环境中适应5天,以增加其生热的能力。然后转移到25℃温暖环境中2天。次目将被试化合物通过皮下或口服途径给予动物。1小时后杀死,将肩胛间的棕色脂肪组织(BAT)垫取出。通过差示离心法制得BAT线粒体,测定GDP结合作为生热激活的计量(Hol loway et al.,International Journal of Obesity,1984,8,295)。每个试验包括对照(只给予溶液/悬浮液载体)和阳性对照(给予异丙肾上腺素硫酸盐1mg·kg-1)。被试化合物例行地给予0.1,0.3,1.0,3.0和10mg·kg-1,根据由阳性对照产生的GDP结合效应表示测试结果。从这些结果,通过曲线拟合法计算产生50%异丙肾上腺素作用所需的剂量(ED50)。与对照相比,如果被试化合物显著地升高GDP结合,则认为在该试验中化合物有效。(b)让大鼠在热中性环境(29℃)中适应2周,以便降低动物对BAT介导的非颤抖生热的能力。在最后5天里,使用测量心率的仪器训练动物,该仪器非侵害性地经由连接心电图积分仪的脚垫电极,产生可连续读数的心率。通过皮下或口服途径给被试化合物(剂量按试验(a)中测得的ED50),在给药后15-30分钟测量心率。在以后的试验中重复该步骤,利用在试验(a)中测得的ED50值的递增倍数,直到心率达到或超过每分钟500次,或直到剂量达到在试验(a)中测得的ED50值的100倍。估计达到每分钟心率500次所需的剂量(D500剂量)。
D500对试验(a)中ED50的比率定义为选择性指数(SI),提供了化合物对BAT(对抗心血管系统)选择性的一种量度。化合物的SI大于1,则可认为有显著的选择性。非选择性化合物的SI小于1,例如异丙肾上腺素=0.06。(c)将大鼠维持在23℃环境下至少2天,然后禁食过夜。次日用闭路氧消耗仪器(型号见文献Arundel et al.,1984,J.Appl.Physiol.Respirat,Environ。Exercise Physiol.,1984,57(5)1591-1593描述)测定动物基础代谢率。然后以口服途径给予大鼠被试化合物,剂量约为1mg·kg-1,以0.025%w/v吐温80的溶液或悬浮液(0.5ml/100g)给予。然后,在给药后至少测定代谢率1小时。与对照动物(只给予溶液或悬浮液载体)(学生l检验:p<0.05)相比,如果化合物引起代谢率显著增加,则可认为在该试验中化合物有活性。
通常,在上述试验中,式(I)化合物产生如下等级的效应而不产生明显的毒性:-
试验(a):皮下或口服途径,BAT线粒体中GDP
结合ED500.01-10mg·kg-1;
试验(b):SI显示>50;以及
试验(c):口服剂量1mg·kg-1时,显示出2-9ml O2min-1
(kg0.75)-1。
作为说明,在所附实施例1中所描述的化合物在上述试验中产生如下效应:
(a)口服ED500.55mg·kg-1;
(b)SI>50(口服)
(c)剂量1mg·kg-1(口服)时,6.53ml O2min-1(kg0.75)-1。
口服葡萄糖耐量试验
雄性大鼠(125-150g)禁食24小时。禁食以后使一组6只大鼠麻醉,取出心脏血样。然后给予其它组大鼠实施例1化合物(5.0mg/kg口服),该化合物溶于0.025%吐温水溶液。对照组大鼠单独给予吐温溶液,给予溶液的体积为0.5 ml/100g体重。6只对照动物给予后60分钟,使6只给药治疗的大鼠麻醉,取出心脏样品。剩余大鼠口服葡萄糖负载(1g/kg),20%D-葡萄糖溶液剂量为0.5ml/100g。然后使每对照组和治疗组的6只大鼠的各个组麻醉,在葡萄糖负载后20,60和120分钟时放血,用标准方法测定血浆葡萄糖和胰岛素。结果 血浆葡萄糖(mM)与葡萄糖负载 对照 实施例1相关的时间(mins) 5mg/kg(口服)
-30 6.35±0.26
0 6.13±0.21 3.52±0.07
(P<0.001)
20 9.05±0.50 5.72±0.24
(P<0.001)
60 6.374±0.39 5.32±0.24
(P<0.05)
120 6.5±0.23 5.43±0.31
(P<0.05)
其结果为在每组中对6只大鼠观察的平均值±S.E.M.(平均数标准误差)。学生t检验用来测试对照组和治疗组之间差别的显著性。实施例1化合物具有明显的抗高血糖活性。在抗胰岛素的db/db小鼠体上对血液葡萄糖水平的影响
将C57BL/KsJ(db/db)小鼠分为两组,让其自由接近对照饮食或含实施例1化合物的饮食(浓度为50mg/kg饮食)。一组(+/+)小鼠对照组也包括在实验内。经过16天治疗,从小鼠体内取出血样,测定血液葡萄糖水平。结果
组别 血液葡萄糖(mM)
对照 4.94±0.1
(+/+)
未经治疗 14.53±0.66
(db/db) (P<0.001)
实施例1化合物 5.3±0.46
(db/db)
结果以每15只小鼠分组,观察得到的平均值±S.E.M.表示。学生t检验用来测试对照组(+/+)及治疗组(db/db)之间差别的显著性。实施例1化合物在抗胰岛素性动物模型上使血液葡萄糖水平正常化。
大鼠脂肪组织细胞脂解试验
切除雄性大鼠附睾脂肪组织,通过用胶原酶消化制备脂肪组织细胞。细胞用浮选法分离,用Krebs Ringer碳酸氢盐缓冲液(KRB)洗涤4次,最后在含有2%牛血清白蛋白的KRB缓冲液(KRB/BSA)中洗涤。细胞悬浮液的等分试样在一定浓度范围内的被试化合物存在下进行培养,条件为:化合物在总体积1ml KRB/2%BSA(内含0.1mg/ml抗坏血酸盐)中,在95%O2,5%CO2气氛下进行。培养也在一定浓度(3×10-6M)异丙肾上腺素存在下进行,已知后者对脂解有最大的作用。对照培养在KRB/2%BSA(内含抗坏血酸盐)中进行。在90分钟后将管子置于冰上终止培养,移出处于下层的等分试样,作游离脂肪酸的测定,仪器为WAKONEFA-C测定箱(Al pha Laboratories)。通过测定与对照组相比被试化合物引起的游离脂肪酸浓度增加,测得化合物脂解活性。测定化合物的最大作用(功效),并以异丙肾上腺素的最大作用的百分数表示。
被试化合物 功效
实施例1化合物 100%
4-[2-(2-羟基-2-苯氧丙 26%
氨基)-乙氧基]苯氧乙酸
(游离羧酸,自USP4772831)
功效是指被试化合物对脂解的最大作用,以异丙肾上腺素的最大作用的百分数表示。GDP效力的比较测试
在另外的比较测试中,实施例1化合物的效力(在上述试验(a)中)与参考化合物作出较。化合物 ED50(口服)
mg·kg-1实施例1 0.554-[2-(2-羟基-2-苯乙基氨基)乙氧基]苯氧乙酸 >3.00(在欧洲专利EP-A23385范围内)
本发明将通过以下实施例说明,除非另有说明,否则其中:(a)色谱分析在硅胶上进行,硅胶型号Art 9385;230-400目,得自E.merck,Darmstadt,联邦德国。(b)蒸发在减压下进行,利用旋转蒸发器。(c)熔点未经校正。
实施例1(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸
将(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺盐酸盐(3.5g)的2N HCl(100ml)溶液在蒸汽浴上加热2小时。过滤反应混合物,冷却,滤集固体。固体用水重结晶得(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸的盐酸盐(2.5g),mp207-209℃;微量元素分析:实测值C,61.5,H,6.5;N,3.8;Cl,10.1%;理论值(C18H22ClNO4):C,61.5;H,6.3;N,4.0;Cl,10.1%;[α]D 25=273°(c=0.99,甲醇)
室温下,将上述的盐酸盐产物(1g)溶于蒸馏水(50ml)中,加入2N NaOH小心地调其pH至6.7。析出的固体即为(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸(0.8g),m.p.209-211℃;微量元素分析:实测值C,68.4 ;H,6.8;N,4.5%;理论值(C18H21NO4):C,68.6;H,6.7;N,4.5%;[α]D 25=-30.1°(c,1.0,乙酸)。
此外,该产物还可采取与上述相似的方式,通过(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺进行酸水解得到,然后用水重结晶。
实施例2(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺
将(R)-4-[2-(N-苄基-N-(2-羟基-2-苯乙基)氨基)乙氧基]苯乙酰胺(12.9g)溶于乙醇(150ml)和冰醋酸(50ml)中。在约20bar、60℃下,将所得的溶液以10%w/wPd/C为催化剂(1.0g)氢化24小时。混合物冷却后,过滤,减压蒸发滤液。将所得的油状残留物(9.8g)中的1.2g溶于乙酸乙酯中,用氯化氢饱和的乙醚溶液对其进行处理。沉淀出来的固体经甲醇结晶,得(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺盐酸盐(0.8g),m.p.255-257℃;微量元素分析:实测值C,61.3;H,6.3;N,8.0;Cl,10.2%;理论值(C18H23ClN2O3):C,61.6;H6.6;N,8.0;Cl,10.1%;[α]D 25=-19.5°(c=1.0,DMSO)。此反应亦可在常温常压下于含有冰醋酸(1当量)的异丙醇水溶液中进行。
起始原料按下法制备
将4-[2-(苄基氨基)乙氧基]苯乙酰胺(OLS2135678)(14.0g)与(R)-氧化苯乙烯(5.92g)及异丙醇(200ml)组成的混合物加热回流72小时。混合物冷却后,减压蒸除溶剂。残余物通过闪式干柱层析纯化,以10%的甲醇/二氯甲烷溶液作洗脱剂,得(R)-4-[2-(N-苄基-N-(2-羟基-2-苯乙基)氨基)乙氧基]苯乙酰胺,为油状(12.9g)。此反应亦可在叔戊醇中回流来进行。
实施例3(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸甲酯
将(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺盐酸盐(0.45g)置于含有浓硫酸(0.5ml)的甲醇(20ml)中回流18小时。混合物冷却后减压蒸除溶剂。将残余物溶于二氯甲烷(30ml)中,依次用水(20ml),5%NaHCO3溶液(50ml)及水(20ml)洗涤, MgSO4干燥,然后减压蒸除溶剂。将残余物溶于乙酸甲酯(20ml)中,用被氯化氢饱和的乙醚处理之。用甲醇和乙酸甲酯的混合物对析出的沉淀进行结晶,得(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸甲酯盐酸盐(0.25g),m.p.181-183℃;微量元素分析:实测值:C,62.6;H,6.6;N,3.8;Cl,9.9%;理论值(C19H24ClNO4):C,62.4;H,6.6;N,3.8;Cl,9.7%;[α]D 25=-25.3°(c=0.99,甲醇)。
实施例44-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸
将4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺盐酸盐(2.8g)置于4N HCl(60ml)中于蒸汽浴上加热4小时。过滤反应混合物,冷却,滤集固体,得4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸的盐酸盐(1.4g),m.p.183-184℃(约178℃开始软化),微量元素分析:实测值C,61.4;H,6.3;H,4.1;Cl,10.3%;理论值(C18H22ClNO4):C,61.5;H,6.3;N,4.0;Cl,10.1%。
实施例54-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺
在压力约20巴及60℃下,对溶于异丙醇及冰醋酸(见下)中的4-[2-(N-苄基-N-(2-羟基-2-苯乙基)氨基)乙氧基]苯乙酰胺以10%w/w的Pd/C(1.0g)作催化剂氢化12小时。混合物冷却后,过滤,减压蒸发滤液。将所得的油状残留物溶于乙酸乙酯中,用被氯化氢饱和的乙醚对其进行处理。沉析出来的固体用甲醇结晶,得4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺盐酸盐(6.8g),m.p.250-251℃(约248℃开始软化);微量元素分析:实测值C,61.2;H,6.5;N,8.3;Cl,10.3%;理论值(C18H23ClN2O3):C,61.6;H,6.6;N,8.0;Cl,10.1%。
起始原料如下制备:
将4-(2-N-苄基氨基乙氧基)苯乙酰胺(OLS2135678)(5.68g),氧化苯乙烯(2.4g)及异丙醇(100ml)组成的混合物加热回流7 2小时。形成的4-[2-(N-苄基-N-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺冷却后,用异丙醇(30ml)及冰醋酸(20ml)稀释。
制备标题化合物的另-种方法:
将2-羟基-2-苯乙胺(1.91g),4-(2-溴乙氧基)苯乙酰胺(3.59g)及三乙胺(1.41g)白乙醇(450ml)溶液回流24小时。溶液冷却后,过滤除去少量不溶物质(0.2g)。减压蒸除溶剂,残余固体用少量水研制后过滤分离出来并干燥。将固体(3.1g)溶于甲醇(100ml)中,用被氯化氢饱和的乙醚溶液处理之,析出的沉淀用甲醇结晶,得4-[2-(2-羟基-2-苯乙氢基)乙氧基]苯乙酰胺盐酸盐,m.p.及混合m.p.250-251℃。
用于制备标题化合物的另外一种方法为:
将苯甲酰甲基溴(0.49g),4-(2-氨基乙氧基)苯乙酰胺(0.49g),K2CO3(0.35g)及甲醇(20ml)一起加热回流2小时,冷却至室温后,于1小时内搅拌下分小批加硼氢化钠(1.0g)。继续搅拌18小时,减压蒸除溶剂。残余物在二氯甲烷(20ml)和水(10ml)之间进行分配。分出水层,用二氯甲烷(20ml)提取。用水洗涤合并的二氯甲烷提取液,MgSO4干燥,蒸发。将残余胶状物溶于乙酸乙酯中,用被氯化氢饱和的乙醚处理之。析出的沉淀固体用甲醇和乙酸乙酯的混合物进行结晶,得4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺盐酸盐,m.p.及混合m.p.248-250℃。
制备标题化合物还有一种方法为
将水合苯甲酰甲醛(0.57g)与4-(2-氨基乙氧基)苯乙酰胺(0.49g)的甲醇(15ml)溶液在蒸汽浴上加热得到透明溶液,将其用冰浴冷却后,于1小时内,搅拌下,分小批加入硼氢化钠(1g)。在约100mg硼氢化钠加入后,开始有白色固体析出,再加入甲醇(35ml),使之溶解。混合物于室温下搅拌18小时后,减压蒸除溶剂。固体残余物用二氯甲烷(20ml)和水(20ml)处理,未溶解的固体经过滤分离。将此固体溶于甲醇(20ml)中,用被氯化氢饱和的乙醚处理之。蒸除大部分溶剂后,向其中加入乙酸乙酯(20ml),得标题化合物的盐酸盐,m.p.和混合m.p.250-251℃。
实施例64-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸甲酯
将4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺盐酸盐(2.5g)置于含有浓硫酸(1.5ml)的甲醇(50ml)中加热回流24小时。混合物冷却后,减压蒸除溶剂。残余物在二氯甲烷(150ml)和5%NaHCO3(150ml)溶液之间分配。分出有机层,依次用5%NaHCO3溶液(20ml)和水(20ml)洗涤,MgSO4干燥,减压蒸除溶剂。将残余物溶于乙酸甲酯(40ml)中,然后用被氯化氢饱和的乙醚溶液处理之。用甲醇和乙酸甲酯的混合物对沉淀出的固体进行结晶,得4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸甲酯的盐酸盐(1.8g),m.p.169-171℃;微量元素分析:实测值:C,62.5;H,6.6;N,2.8Cl,9.7%;理论值(C10H24ClNO4):C,62.4;H,6.6;N,3.8;Cl,9.7%。
实施例7(R)-4-[2-(2-乙酰氧基-2-苯乙氨基)乙氧基]苯乙酸
20℃下,使置于二氯甲烷(5ml)和三氟乙酸(5ml)混合溶液中的N-叔丁氧羰基-(R)-4-[2-(2-乙酰氧基-2-苯乙氨基)乙氧基]苯乙酸(500mg )放置90分钟。减压蒸除溶剂,然后将残余物溶于乙醇(5ml)中。将溶液冷却至-20℃,加入氯化氢乙醚溶液,得标题化合物的盐酸盐(300mg),其为白色结晶状;m.p.158-160℃;[α]D 25=-35.4°(c=1.0,甲醇);微量元素分析:实测值:C,60.2;H,6.5;N,3.4;H2O0.0.9%;理论值(C20H24ClNO5.0.25H2O):C,60.3;H,6.2;N,3.5;H2O1.1%。
起始原料如下制备:a)搅拌下,将二碳酸二叔丁酯(1.25g)的叔丁醇(15ml)溶液加到(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸盐酸盐(2.0g)在1N氢氧化钠水溶液(30ml)中的溶液中,混合物在20℃下搅拌90分钟。减压蒸除溶剂,向残余物中加水(20ml),用2N柠檬酸水溶液进行酸化。用合5%甲醇的二氯甲烷溶液(5×20ml)对产物进行提取。提取物经干燥后,减压蒸除溶剂,得N-叔丁氧羰基-(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸,其为玻璃样物质(1.3g);[α]D 25=+6.2°(c=1.0,甲醇)。b)将来自a)的产物的吡啶(2.5ml)和乙酸酐(2.5ml)溶液在20℃下放置16小时。减压蒸除溶剂混合物。将残余物溶于二氯甲烷(20ml)中。用水(3×100ml)洗涤后,干燥,减压蒸除溶剂,得一粘稠的油状物(1.3g)。将此油状物(1.3g)的二噁烷(1.0ml)和水(6ml)的混合溶液在回流下搅拌2小时,减压蒸除溶剂,残余物进行层析纯化,以含10%甲醇的二氯甲烷作洗脱剂。合并合适的级分,得N-叔丁氧羰基-(R)-4-[2-(2-乙氧基-2-苯乙氨基)乙氧基]苯乙酸,其为粘性油状物(500mg);[α]D 25=-16.8°(c=1.0,二氯甲烷)。
实施例8
如前所述,含有式(I)化合物合适的药物组合物可通过标准的配制技术来获得。
适合对温血动物进行口服给药的典型的片剂配方包含作为活性成份的前述的式(I)化合物或其可药用的盐(例如前述实例之一所述的),该片剂的生产可通过水性制粒,也可直接与含有标准崩解剂和/或润滑剂的磨碎的乳糖一起压片。当需要含有少量活性成份(例如0.5~10mg)的片剂时,可采用直接压片方法,其中活性成份是与乳糖按1∶10(重量比)的比例和/或与含有0.5%(重量)润滑剂(如硬脂酸镁)和5%(重量)的崩解剂(如交链羧甲基纤维素钠或淀粉甘醇酸钠)的微晶纤维素进行混合。通过水性制粒制得的片剂的例子为:含有活性成份(50~100mg),乳糖(230mg),玉米淀粉(80mg),明胶(2.2mg),硬脂酸镁(4mg)及交链羧甲基纤维素钠(7mg)的片剂。
Claims (6)
1.制备式(I)的化合物或其可药用的盐或其羧基的酯或酰胺或其羟基的酯的方法,
所述方法包括
其中,-COR4为羧基或它的酯或酰胺,
L为可置换的基团;或
b).水解式(VI)化合物:
其中COR4的定义同上文;或
其中R5为可水解基团;
其中-COR4的定义同上文,L′为可置换基团;
e).使式(X)化合物脱保护:
其中R6为基团-COR4的保护衍生物;
f).将4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸转化为其羧基的酯或酰胺或其羟基的酯,或者将所述羧基的酯或酰胺或羟基的酯转化成酸或醇形式,或将4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸的羧基的一种酯或酰胺或羟基的一种酯转化为4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸的羧基的另一种酯或酰胺或羟基的另一种酯;
其中-COR4的定义同上文,
h).还原式(XII)化合物:
其中-COR4的定义同上文;
其中-COR4的定义同上文;
其中任何官能团可任意加以保护,然后,如果需要的话,
(i)除去任何保护基;
(ii)形成可药用的盐。
2.权利要求1的方法,其中所述化合物为羧酸或其可药用的盐形式。
3.权利要求2的方法,其中所述化合物为与盐酸形成的盐。
5.权利要求4的方法,其中所述化合物中R4为甲氧基。
6.权利要求1的方法,其中制备的是
(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸;
(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰
胺;
(R)-4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸
甲酯;
4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸;
4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酰胺;或
4-[2-(2-羟基-2-苯乙氨基)乙氧基]苯乙酸甲酯;
或它们可药用的盐。
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- 1991-05-28 GB GB919111426A patent/GB9111426D0/en active Pending
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1992
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1994
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1995
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