CN1630636A - 二氢吲哚衍生物及其作为5-ht2受体配体的用途 - Google Patents
二氢吲哚衍生物及其作为5-ht2受体配体的用途 Download PDFInfo
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- CN1630636A CN1630636A CNA018174434A CN01817443A CN1630636A CN 1630636 A CN1630636 A CN 1630636A CN A018174434 A CNA018174434 A CN A018174434A CN 01817443 A CN01817443 A CN 01817443A CN 1630636 A CN1630636 A CN 1630636A
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- compound
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- hydrogen
- alkyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- 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
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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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
- A61P3/04—Anorexiants; Antiobesity agents
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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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
本发明涉及式(I)的化合物,其中R1至R7和环A具有说明书和权利要求书中给出的意义。这些化合物尤其有用于预防和治疗中枢神经***疾病,中枢神经***损伤,心血管疾病,胃肠道疾病,糖尿病,睡眠呼吸暂停以及特别是肥胖症。
Description
本发明涉及二氢吲哚衍生物,其制备方法和用于其制备的中间体,也涉及含有它们的药物组合物和其医药用途。本发明的活性化合物可用于治疗肥胖症,糖尿病和其它疾病。
已经认识到,肥胖症是一种受环境因素影响的疾病过程,其中传统的节食和锻炼减重法需要治疗产品的补充(S.Parker,″Obesity:Trends and Treatments″,Scrip Reports,P J B Publications Ltd,1996)。
一个人是否属于超重或肥胖一般以其由体重(kg)除以身高的平方(m2)所计算的体质指数(BMI)为基础确定。这样,BMI的单位是kg/m2,并可以计算在每十年的最小死亡率相关的BMI范围。超重被定义在25-30kg/m2的范围,而肥胖症为BMI大于30kg/m2。这种定义的问题是它没有考虑体重中肌肉与脂肪(脂肪组织)的比例。考虑到这一点,肥胖也可以以身体脂肪含量为基础定义:对于男性和女性分别为大于25%和30%。
随着BMI的增加,排除其它危险因素,死亡的危险也增加。伴随肥胖最常见的疾病是心血管病(尤其是高血压),糖尿病(肥胖会加速糖尿病的发展),胆囊病(尤其是癌症)和再生疾病。研究已经显示,即使是体重的有限减少也可能引起冠心病发展的明显降低。
已经上市的减肥剂包括Orlistat(XENICAL)和Sibutr胺。Orlistat(一种脂肪酶抑制剂)抑制脂肪的直接吸收,并产生很不愉快(虽然相对无害)的副作用如腹泻。Sibutr胺(一种混合的5-HT/去甲肾上腺素再摄取抑制剂)对一些患者会增加血压和心率。血清紧张素释放剂/再摄取抑制剂fenfluramine(Pondimin)和dexfenfluramine(ReduxTM)已经被报道在很长的周期(多于6个月)减少食物吸收和体重。但是,在报道了与其使用有关的心脏瓣膜异常的初步证据之后,两个产品都被撤销。因此需要开发更安全的减肥剂。
非选择性5-HT2C受体激动剂/部分激动剂m-氯苯基哌嗪(mCPP)和三氟甲基苯基哌嗪(TFMPP)已经对大鼠显示降低食物吸收(G.A.Kennett和G.Curzon,Psychopharmacol.,1988,96,93-100;G.A.Kennett,C T.Dourish和G.Curzon,Eur.J.Pharmacol.,1987,141,429-435)并加速行为饱感后果的出现(S.J.Kitchener和C T.Dourish,Psychopharmacol.,1994,113,369-377)。最近对正常的自愿者和肥胖者用mCPP研究发现都对食物吸收显示出降低。单剂量的mCPP对于女性自愿者降低食物吸收(A.E.S.Walsh et al.,Psychopharmacol.,1994,116,120-122),而对于肥胖的男性和女性在14天疗程的亚慢性治疗都降低食欲和体重(P.A.Sargeant et al.,Psychopharmacol.,1997,133,309-312)。mCPP的厌食作用对于5-HT2C受体剔除的突变小鼠不存在(L.H.Tecott et al.,Nature,1995,374,542-546),并在大鼠体内被5-HT2C受体拮抗剂SB-242084所拮抗(G.A.Kennett et al.,Neuropharmacol.,1997,36,609-620)。因此,似乎mCPP经对5-HT2C受体的激动作用降低食物吸收。
其他已经被推荐为5-HT2C受体激动剂用于治疗肥胖的化合物包括在EP-A-0655440中公开的取代的1-氨基乙基吲哚。CA-2132887和CA-2153937中公开了与5-HT2C受体结合并可用于治疗肥胖症的三环1-氨基乙基吡咯衍生物和三环1-氨基乙基吡唑衍生物。WO-A-98/30548公开了作为5-HT2C激动剂,用于治疗CNS疾病和食欲调节疾病的氨基烷基吲唑化合物。J.Med.Chem.,1970,13,327和J.Med.Chem.,1973,16,1411报道了取代的1,2,3,4-四氢咔唑作为人工的杀锥虫药。美国专利2,687,414和2,541,211公开了9-(2-二烷基氨基丙基)-1,2,3,4-四氢咔唑。DE 930,988公开了7-取代的-9-(2-二烷基氨基乙基)-1,2,3,4-四氢咔唑。J.Med.Chem.,1964,69,2910报道了2,3-聚亚甲基吲哚类的药理作用。J.Med.Chem.,1964,7,625报道了多环吲哚类作为抗抑郁剂。美国专利No.3,142,678公开了具有药理特性的氨基-取代的penthieno吲哚。FR 2,242,983和DE 2,438,413公开了1,2,3,4-四氢环戊二烯并[b]吲哚(环戊二烯并[b]吲哚)。Khim.Geterotskikl.Soedin,1970,6,371报道了4-(3-氨基丁基)-1,2,3,4-四氢环戊二烯并[b]吲哚(环戊二烯并[b]吲哚)。
本发明的一个目的是提供用于治疗,尤其是用作抗肥胖剂的选择性、直接作用的5-HT2受体配体。本发明的进一步目的是提供用于治疗,尤其是用作抗肥胖剂的直接作用的5-HT2B和/或5-HT2C受体选择性的配体。本发明的进一步目的是提供用于治疗,尤其是用作抗肥胖剂的选择性、直接作用的5HT2C受体配体,优选5HT2C受体激动剂。
本发明的进一步目的是提供用于治疗和/或预防与升高的血糖有关的疾病,特别是糖尿病,II型或者非胰岛素依赖性糖尿病(NIDDM),I型或者胰岛素依赖性糖尿病(IDDM),和III型或者营养不良-相关的糖尿病的式(I)化合物。该糖尿病可以是胰腺疾病继发性的糖尿病,或者与使用类固醇相关的糖尿病。本发明的式(I)化合物还可以用于治疗和/或预防高血糖症的后遗症,治疗和/或预防糖尿病并发症,以及治疗胰岛素依赖性。
本发明的一个方面涉及式(I)化合物:
其中
R1和R2独立地选自氢,烷基,烯基,炔基,和环烷基;
R3是烷基,烯基,炔基,或者环烷基;
R4,R5,R6和R7独立地选自氢,烷基,烯基,炔基,环烷基,卤素,卤代烷基,羟基,芳基,氨基,单-和二烷基氨基,烷氧基,环烷氧基,芳氧基,杂芳氧基,烷硫基,烷基亚硫酰基(alkylsulfoxyl),烷基磺酰基,硝基,氰基,烷氧基羰基,芳氧基羰基,杂芳氧基羰基,杂芳基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基,和羧基;
环A代表5或者6元部分不饱和的或者饱和的碳环,或者饱和的或者部分不饱和的杂环环,其中环A稠合的二氢吲哚环的两个原子形成饱和的C-C单键;和
其药用盐,酯和/或者加合化合物。
在本说明书中,术语″烷基″,单独或组合使用,表示具有1至8个碳原子的直链或支链烷基,优选具有1至4个碳原子的直链或支链烷基。直链或支链的C1-C8烷基的例子有甲基,乙基,丙基,异丙基,丁基,异丁基,叔-丁基,异戊基,异己基,异庚基和异辛基,优选甲基,乙基,丙基和异丙基。特别优选的是甲基和乙基。
术语″烯基″指定义烷基的烃链具有至少一个烯属双键(包括例如,乙烯基,烯丙基和丁烯基)。
术语″炔基″指定义烷基的烃链,具有至少一个不饱和三键(包括例如丙炔基,丁炔-(1)-基,等)。
术语″环烷基″,单独或组合使用,表示具有3至8个碳原子的环烷基环,优选具有3至6个碳原子的环烷基环。C3-C8环烷基的例子有环丙基,甲基-环丙基,二甲基环丙基,环丁基,甲基-环丁基,环戊基,甲基-环戊基,环己基,甲基环己基,二甲基-环己基,环庚基和环辛基,优选环丙基并且特别是环戊基。
术语“卤素”是指氟、溴、氯和碘。
术语″卤代烷基″,单独或组合使用,是指上文定义的烷基,其中的一个或几个氢原子,优选地一个氢原子已经被卤素取代。卤代烷基的实例有三氟甲基,五氟甲基和三氯甲基。优选的实例有三氟甲基和二氟甲基。
术语″羟基″指基团-OH,术语″氰基″指基团-CN。
术语″氨基″指基团-NH2。
术语″烷氧基″,单独或组合,指烷基醚基,其中术语“烷基″含义如前所述,例如甲氧基,乙氧基,n-丙氧基,异丙氧基,n-丁氧基,异丁氧基,仲丁氧基,叔丁氧基等。
术语″氧基″,单独或组合,指基团-O-。
术语″硫基″,单独或组合,指基团-S-。
术语″磺酰基″表示基团-S(O2)-,术语″亚硫酰基(sulfoxyl)″表示基团-S(O)-。″羟基″指-OH,和″硝基″-NO2。
术语″羧基″指基团-C(O)OH。
术语″羰基″指基团-C(O)-,术语″羰基氨基″指基团-C(O)-NH-。
术语″烷氧基羰基″指式-C(O)RC基团,其中RC是如上所定义的烷氧基。
术语″碳环环″是指其中所有的成环原子都是碳原子的环。
R4,R5,R6,和R7的术语″芳基″,单独或组合,指芳香碳环基,即6或10元芳香或部分芳香环,例如苯基,萘基,四氢萘基,优选苯基。芳基部分任选地被独立地选自以下基团的一个或多个,优选地一个至三个基团取代:卤素优选氟,烷氧基羰基,例如甲基羰基,羧基,氰基,烷基,烷氧基,苯基,苯氧基,三氟甲基,三氟甲氧基,1,3-间二氧杂环戊烯基,或者1,4-间二氧杂环戊烯基,烷硫基,烷基亚硫酰基和烷基磺酰基。最优选的基团是烷氧基和/或烷基磺酰基。
R4,R5,R6,和R7的术语″杂芳基″,单独或组合,指具有5-10,优选5-6个环原子的芳香单-或双环基,其含有一到三个杂原子,优选一个杂原子,例如独立地选自氮,氧或硫。杂芳基的例子有吡啶基,吡咯基,喹啉基,呋喃基,噻吩基,噁二唑基,噻二唑基,噻唑基,噁唑基,异噁唑基,吡唑基,***基,咪唑基和嘧啶基。优选的杂芳基有噻吩基,呋喃基和吡啶基。任选地,杂芳基可以独立地被选自以下基团的一个或者多个基团:卤素,优选氟,烷氧基羰基,例如甲基羰基,羧基,氰基,烷基,烷氧基,苯基,苯氧基,三氟甲基,三氟甲氧基,1,3-间二氧杂环戊烯基,或1,4-间二氧杂环戊烯基,烷硫基,烷基亚硫酰基和烷基磺酰基。最优选的基团是烷氧基和/或者烷基磺酰基。
术语″杂环基″单独或组合,指具有5-10,优选5-6个环原子的非芳香单-或双环基,其含有一到三个杂原子,优选一个杂原子,例如,独立地选自氮,氧或硫。任选地,杂环可以被独立地选自以下基团的一个基团取代:卤素,烷基,烷氧基,氧羧基(oxocarboxy),烷氧基羰基等,和/或在仲氮原子(即-NH-)上被烷基,芳基烷氧基羰基,烷基羰基取代,或在叔氮原子(即=N-)上被氧桥(oxido)取代。杂环基的例子是吗啉基,吡咯烷基,哌啶基,四氢呋喃基和六氢吡喃基等。
术语″药用盐″指式(I)化合物的任何药用盐。这些盐可以从药用的非毒性的酸和碱,包括无机和有机酸和碱制备。这些酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、ethenesulfonic,二氯乙酸,甲酸,富马酸、葡糖酸、谷氨酸,苯甲酰氨基乙酸,氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸,硝酸、草酸,pamoic,泛酸,磷酸,琥珀酸、硫酸、酒石酸、草酸,p-甲苯磺酸等。尤其优选的是富马酸、盐酸、氢溴酸、磷酸、琥珀酸、硫酸、和甲磺酸,特别是富马酸。可接受的碱盐包括碱金属(例如钠,钾),碱土金属(例如,钙,镁)和铝盐。
″药用酯″指通式(I)的化合物可以在功能基团上被衍生,得到能够在体内转化恢复成为原化合物的衍生物。这些化合物的例子包括生理可接受和代谢不稳定的酯衍生物,例如甲氧基甲基酯,甲硫基甲基酯和新戊酰氧基甲基酯。另外,类似于代谢不稳定酯、在体内能够产生通式(I)原化合物的通式(I)化合物的任何生理可接受的等价物都在本发明的范围内。
术语″加合化合物″指通式(I)的化合物的任何的药用加合化合物。其它的化合物包括那些不改变化合价而形成于通式(I)的化合物与一个或者多个其它分子的连接的化合物,特别是溶剂化物,水合物,和包合复合物(例如环糊精复合物)。
本发明明显地包括式(I)化合物的药用衍生物。在这个意义上,术语“衍生物”指式(I)化合物的任何药用衍生物,其在体内代谢成原化合物的衍生物(前药)。例如,R4至R7中的COOH可以被酯化。烷基和芳烷基酯是合适的酯的例子。甲酯,乙酯,丙酯,丁酯和苄酯是优选的酯。甲酯和乙酯是特别优选的。
式I的化合物也可被溶剂化,如水化。溶剂化作用在制造过程中进行,或可例如作为最初的无水的式I化合物的吸湿性(水合)的结果发生。
式I化合物可以含有几个不对称中心,并可以以旋光纯对映体,对映体的混合物,例如外消旋体,旋光纯的非对映体,非对映体混合物,非对映体外消旋体,或非对映体外消旋体的混合物的形式存在。旋光的形式可以例如通过拆分外消旋体,通过不对称合成或不对称色谱(用手性吸附剂或洗脱剂的色谱)获得。
优选的是式(I)化合物选自其中R1和R2独立地选自氢或者烷基的那些化合物。在一个实施方案中,式(I)化合物选自其中R1和R2相同的化合物。优选地,其中R1和R2是氢。
式(I)化合物优选地选自其中R3是烷基或者环烷基,优选烷基,和更优选甲基的化合物。
优选地,R4,R6和R7独立地选自氢,卤素,烷基和烷氧基。更优选,R4是氢。R6优选是氢,卤素或者烷氧基,更优选氢或者氟。R7优选是氢,卤素或者烷氧基,更优选氢,氯或者甲氧基。
在另一个优选的实施方案中,R5是氢,卤素,烷氧基,或者杂芳基羰基氨基,优选氢,氯,甲氧基,吡啶基羰基氨基或者噻吩基羰基氨基。
如上所述,环A代表5或者6元部分不饱和的或者饱和的碳环或者杂环环,其中环A稠合的二氢吲哚环的两个原子形成饱和的C-C单键。在本发明的优选的实施方案中,环A是5-元环,例如饱和的或者部分不饱和的环,例如环戊基,环戊烯基,四氢呋喃基和二氢呋喃基,优选饱和的碳环环,例如环戊基。
在本发明的另一个优选的实施方案中,环A可以选自吗啉基,哌啶基,四氢吡喃基,二氢吡喃基,四氢呋喃基和二氢呋喃基,任选地被烷基或者氧代基取代。
环A可以是取代的或者未取代的。如是取代的,则一般会有1-3个取代基,优选1个取代基。取代基可以包括:
a)含碳的基团,例如烷基,烯基,炔基,芳基(例如取代的和未取代的苯基,芳基烷基(例如取代的和未取代的苄基);
b)卤素原子和含卤素的基团,例如卤代烷基(例如三氟甲基),卤代芳基(例如氯苯基);
c)含氧的基团,例如氧代基,醇类(例如羟基,羟基烷基,羟基芳基,(芳基)(羟基)烷基),醚类(例如烷氧基,芳氧基,烷氧基烷基,芳氧基烷基,烷氧基芳基,芳氧基芳基),醛类(例如甲醛),酮类(例如烷基羰基,芳基羰基,烷基羰基烷基,烷基羰基芳基,芳基羰基烷基,芳基羰基芳基,芳基烷基羰基,芳基烷基羰基烷基,芳基烷基羰基芳基);
d)酸类(例如羧基,羧基烷基,羧基芳基),酸衍生物类,例如酯类(例如烷氧基羰基,芳氧基羰基,烷氧基羰基烷基,芳氧基羰基烷基,烷氧基羰基芳基,芳氧基羰基芳基,烷基羰基氧,烷基羰基氧烷基);
e)酰胺类(例如氨基羰基,单-或者二烷基氨基羰基,氨基羰基烷基,单-或者二烷基氨基羰基烷基,芳基氨基羰基,或者芳基烷基氨基羰基,烷基羰基氨基,芳基羰基氨基或者芳基烷基羰基氨基),
f)氨基甲酸酯类(例如烷氧基羰基氨基,芳氧基羰基氨基,芳基烷氧基羰基氨基,氨基羰基氧,单-或者二烷基氨基羰基氧,芳基氨基羰基氧,或者芳基烷基氨基羰基氧);
g)脲类(例如单-或者二-烷基氨基羰基氨基,芳基氨基羰基氨基,或者芳基烷基氨基羰基氨基);
h)含氮的基团,例如胺类(例如氨基,单-或者二烷基氨基,芳基氨基,氨基烷基,单-或者二烷基氨基烷基),叠氮化物类,腈类(例如氰基,氰基烷基),硝基;
i)含硫的基团,例如硫醇类,硫醚类,亚砜类,和砜类(例如烷硫基,烷基亚磺酰基,烷基磺酰基,烷硫基烷基,烷基亚磺酰基烷基,烷基磺酰基烷基,芳硫基,芳基亚磺酰基,芳基磺酰基,芳硫基烷基,芳基亚磺酰基烷基,芳基磺酰基烷基;和
j)含有一个或者多个,优选一个杂原子的杂环基,(例如噻吩基,呋喃基,吡咯基,咪唑基,吡唑基,噻唑基,异噻唑基,噁唑基,噁二唑基,噻二唑基,氮杂环丙烯基,氮杂环丁烷基,吡咯烷基,吡咯啉基,咪唑烷基,咪唑啉基,吡唑烷基,四氢呋喃基,吡喃基,吡喃酮基,吡啶基,吡嗪基,哒嗪基,哌啶基,六氢丫庚因基,哌嗪基,吗啉基,thianaphthyl,苯并呋喃基,异苯并呋喃基,吲哚基,氧吲哚基,异吲哚基,吲唑基,二氢吲哚基,7-氮杂吲哚基,苯并吡喃基,香豆素基,异香豆素基,喹啉基,异喹啉基,naphthridinyl,噌啉基,喹唑啉基,吡啶并吡啶基,苯并噁嗪基,喹喔啉基,苯并吡喃基,苯并二氢吡喃基,异苯并二氢吡喃基,2,3-二氮杂萘基和咔啉基)。
优选的取代基可以选自氢或者烷基。
本发明特别优选的化合物是
(2′S,3aS,8bS)-1-[4-(6-氯-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基]-2-丙基胺,
(2′S)-1-[4-(7-氟-6-1,2,3,3a,4,8b-六氢-6-甲氧基环戊二烯并[b]吲哚基)]-2-丙基胺,和
(2′S)-1-[4-(7-氟-1,2,3,3a,4,8b-六氢环-8-甲氧基戊二烯并[b]吲哚基)]-2-丙基胺。
本发明还涉及一种包括上述定义的化合物与药用赋形剂的药物组合物。本发明还涉及制造这种药物组合物的方法,包括上述定义的式(I)化合物与药用载体或赋形剂组合。本发明还涉及用于治疗的上述定义的式(I)化合物。
另外,本发明涉及上述定义的式I化合物在制备用于治疗中枢神经******疾病,中枢神经***损伤,心血管疾病,胃肠道疾病,尿崩症,和睡眠呼吸暂停的药物中的用途。在上述的用途中,中枢神经***疾病选自抑郁,非典型抑郁,双相型障碍(bipolar disorder),焦虑病,强迫观念与行为疾病,社会恐怖症或恐慌状态,睡眠失调,性机能障碍,精神病,精神***症,偏头痛和其他与头痛或其他疼痛有关的病症,升高的颅内压力,癫痫,人格障碍,与年龄有关的行为疾病,与痴呆有关的行为疾病,器质性精神障碍,儿童期精神障碍,攻击力,与年龄有关的记忆障碍,慢性疲乏综合症,药物和酒精上瘾,肥胖,易饿病,神经性厌食或经前期紧张。在本发明优选的实施方案中,上述的中枢神经***损伤是外伤,中风,神经变性疾病或毒性或传染性CNS疾病。在上述的用途中,毒性或传染性CNS疾病是脑炎或髓膜炎,而心血管疾病是血栓形成。在上述的用途中,胃肠道病症是胃肠道运动机能障碍。本发明的一个特别优选的实施方案是其中所述的药物用于治疗肥胖症的上述用途。另一个优选的实施方案是式I化合物在制备用于治疗糖尿病,I型糖尿病,II型糖尿病,胰腺疾病继发性的糖尿病,与使用类固醇相关的糖尿病,III型糖尿病,高血糖症,糖尿病并发症,和胰岛素抗性的药物中的用途。特别优选的是用于治疗II型糖尿病的式I化合物的上述的用途。本发明还涉及该化合物用作5HT2C受体激动剂的用途。
本发明还涉及治疗上述任意一种疾病的方法,包括对需要这种治疗的患者施用有效量的上述定义的式(I)化合物。治疗上述任意一种疾病的方法可以是预防性治疗。在一个优选的实施方案中,上述治疗方法中的疾病可以是肥胖症。在另一个优选的实施方案中,上述治疗方法中的疾病选自糖尿病,I型糖尿病,II型糖尿病,胰腺疾病继发性的糖尿病,与使用类固醇相关的糖尿病,III型糖尿病,高血糖症,糖尿病并发症,和胰岛素抗性的药物中的用途。特别优选的是上述治疗方法,其中所述的疾病是II型糖尿病。上述治疗方法可以是预防性治疗。
本发明还包括制备如上所定义的式(I)化合物的方法,包括下列步骤:
a)将式(IV)化合物
其中A,R3-R7如上所述并且PG是NH-保护基,例如叔-丁氧羰基,苄氧基羰基,乙氧羰基和9-芴基甲氧基羰基,与适于除去保护基的试剂反应制备式(I)化合物,其中R1和R2是氢,例如叔-丁氧羰基可以使用酸,例如盐酸,三氟乙酸或者甲磺酸除去,苄氧基羰基可以使用催化剂例如披钯碳或者氢氧化钯的催化氢解,或者在碱例如氢氧化钠的存在下水解,或者通过用在乙酸中的氢溴酸处理,或者通过用路易斯酸例如三溴化硼或者三甲基甲硅烷碘化物处理而除去,乙氧羰基通过在碱例如氢氧化钠的存在下水解,或者通过用在乙酸中的氢溴酸处理,或者通过用路易斯酸例如三溴化硼或者三甲基甲硅烷碘化物处理而除去并且9-芴基甲氧基羰基可以通过用碱例如吗啉或者氢氧化钠处理而除去,或者
b)为了制备式(I)化合物,其中R1和R2是如上定义的,但不是氢或者仅仅一个R1和R2是氢,可以通过还原性烷基化步骤a)所制备的化合物。
而且,本发明涉及上述的方法所制备的化合物。
本发明的化合物可以根据反应路线方便地制备(下文;R1-R7和A如上所述,并且PG是保护基,例如叔-丁氧羰基,苄氧基羰基,和乙氧羰基。吲哚(II)与烷基化剂例如叔-丁基[2-[(1-甲磺酰基)氧]丙基]氨基甲酸酯在碱例如氢氧化钾存在下在溶剂例如甲基亚砜中反应给出吲哚-氨基甲酸酯(III)。在溶剂例如乙酸中用还原剂例如氰基硼氢化钠还原(III)产生二氢吲哚-氨基甲酸酯(IV)。然后,可以使用,例如柱色谱,HPLC,或者重结晶分离(IV)的各个非对应异构体。其中R1=R2=H的式(I)化合物可以通过在合适的溶剂,例如甲醇中,用酸,例如盐酸处理而制得。其中R1和/或者R2=烷基的式(I)的化合物可以通过在还原剂例如甲酸、氰基硼氢化钠或三乙酰氧基硼氢化钠的存在下,使用醛或酮还原性烷基化而从其中R1=R2=H的式(I)化合物制得。
反应路线:
式(II)的吲哚可以通过在合适的溶剂,例如乙醇或者水中在酸性条件下,必要时,加热,用酮处理苯基肼而获得。合适时,该苯基肼可以根据本领域普通技术人员已知的方法从相应的苯胺制备,例如采用在溶剂例如水中,在酸例如盐酸的存在下依次与亚硝酸钠和氯化锡(II)反应。
在本文提及的任何其它方法中,如果R4,R5,R6或者R7不是所需要的,则该取代基可以通过已知的方法转化成所需的取代基。取代基R4,R5,R6或者R7也可能需要抵御进行反应的条件的保护。在此情况下,保护基可以在反应已经完成后除去。
检测程序
1.与5-羟色胺受体结合
式(I)化合物与5-羟色胺受体的结合在体外通过标准方法测定。该制剂根据后面给出的试验进行研究。
方法(a):用于与5-HT2C受体结合,5-HT2C受体用[3H]-5-HT放射标记。化合物与在CHO细胞系中的5-HT2C受体的亲和力根据D.Hoyer,G.Engel和H.O.Kalkman,European J.Pharmacol.,1985,118,13-23的程序测定。
方法(b):用于与5-HT2B受体结合,5-HT2B受体用[3H]-5-HT放射标记。化合物与在CHO细胞系中人5-HT2B受体的亲和力根据K.Schmuck,C.Ullmer,P.Engels和H.Lubbert,FEBS Lett.,1994,342,85-90的程序测定。
方法(c):用于与5-HT2A受体结合,5-HT2A受体用[125I]-DOI放射标记。化合物与在CHO细胞系中5-HT2A受体的亲和力根据D.J.McKenna和S.J.Peroutka,J.Neurosci.,1989,9,3482-90的程序测定。
所测定的实施例的化合物的活性示于表1中。
表1:放射性配体结合数据
化合物 | Ki(2C) | Ki(2B) | Ki(2A) |
实施例2 | 133nM | 302nM | 726nM |
实施例10 | 164nM | 109nM | 983nM |
实施例19 | 88nM | 513nM | 1156nM |
实施例20 | 318nM | 367nM | 481nM |
2.功能活性
式(I)化合物的功能活性用荧光计成像板计数器(FLIPR)分析。
表达人5-HT2C或5-HT2A受体的CHO细胞系被计数并在试验的前一天平铺到标准的96孔微滴板上给出一铺满的单层。次日,该细胞用钙敏染料Fluo-3-AM进行染料加载,其是通过与含有pluronic酸和溶解在DMSO中的Fluo 3-AM的无血清的维持培养基在CO2培养箱中于37℃和95%湿度的条件下孵育大约90分钟而进行的。未掺入的染料用自动细胞洗涤器通过用含有20mM Hepes和2.5mMprobenecid的Hanks平衡盐溶液(试验缓冲液)洗涤除去,留下总体积100μl/孔。
在荧光测量期间,药物(溶于50μl试验缓冲液)以70μl/秒的速率被加入FLIPR 96孔板的各孔。以1秒的间隔进行测量,测出最大荧光信号(在药物加入后大约10-15秒)并与由10μM 5-HT(定义为100%)产生的响应对比,被表示为响应百分数(相对效力)。剂量响应曲线用Graphpad Prism(Graph Software Inc.)构成。
如此测定的实施例的化合物的活性示于表2中。
表2:功能数据
化合物 | h5-HT2A | h5-HT2C | ||
EC50(nM) | 相对效力(%) | EC50(nM) | 相对效力(%) | |
实施例2 | 10000 | 7 | 585 | 90 |
实施例10 | 10000 | 20 | 737 | 84 |
实施例19 | 10000 | 0 | 391 | 84 |
实施例20 | 5490 | 17 | 464 | 62 |
按照本发明的另一个方面,提供了一种在需要这种治疗人中治疗肥胖的方法,该方法包含对人给药治疗有效量的按照式I的化合物和治疗有效量的脂酶抑制剂,特别优选地,其中所述脂酶抑制剂是orlistat。按照本发明的另一个方面,提供了一种在需要这种治疗人中治疗糖尿病,I型糖尿病,II型糖尿病,胰腺疾病继发性的糖尿病,与使用类固醇相关的糖尿病,III型糖尿病,高血糖症,糖尿病并发症,和胰岛素抗性的方法,该方法包含对人给药治疗有效量的按照式I的化合物和治疗有效量的脂酶抑制剂,特别优选地,其中所述脂酶抑制剂是orlistat。特别优选的是上述治疗方法,用于在需要这种治疗人中治疗II型糖尿病,该方法包含对人给药治疗有效量的按照式I的化合物和治疗有效量的脂酶抑制剂,特别优选地,其中所述脂酶抑制剂是orlistat。本发明的另一个主题是所提及的方法,其中所述给药是同时,分开或连续地给药。上述治疗方法中所述的治疗可以是预防性治疗。
本发明的另一个优选的实施方案是式I的化合物在制备用于治疗和预防患者肥胖的药物中的应用,所述患者也接受脂酶抑制剂的治疗,特别优选地,其中所述脂酶抑制剂是orlistat。本发明的另一个实施方案是式I的化合物在制备用于治疗和预防患者糖尿病,I型糖尿病,II型糖尿病,胰腺疾病继发性的糖尿病,与使用类固醇相关的糖尿病,III型糖尿病,高血糖症,糖尿病并发症,和胰岛素抗性的药物中的应用,所述患者也接受脂酶抑制剂的治疗,特别优选地,其中所述脂酶抑制剂是orlistat。特别优选的是上述的式I的化合物的用途,用于治疗和预防患者II型糖尿病,所述患者也接受脂酶抑制剂的治疗,特别优选地,其中所述脂酶抑制剂是orlistat。上述治疗方法中所述的治疗可以是预防性治疗。
术语″脂肪酶抑制剂″指能够抑制脂肪酶作用的化合物,例如胃和胰腺脂肪酶。例如在美国专利US-4,598,089中所述的orlistat和lipstatin是脂肪酶的强力抑制剂。Lipstatin是从微生物获得的天然产物,而orlistat是lipstatin的氢化产物。其他脂肪酶抑制剂包括通称为panclicins的一类化合物。Panclicins是orlistat的同系物(Mutoh等,1994)。术语″脂肪酶抑制剂″也指例如在国际专利申请WO99/34786(Geltex Pharmaceuticals Inc.)中所述的结合了聚合物的脂肪酶抑制剂。这些聚合物的特征在于它们已经被一个或多个抑制脂肪酶的基团取代。术语″脂肪酶抑制剂″也包含这些化合物的药用盐。术语″脂肪酶抑制剂″优选地指orlistat。
Orlistat是已知用于控制或预防肥胖症和高血脂的化合物。参见1986年7月1日颁发的美国专利4,598,089,该专利披露了制造orlistat的方法,而美国专利6,004,996公开了合适的药物组合物。更合适的药物组合物例如在国际专利申请WO 00/09122和WO 00/09123中描述。其他制备orlistat的方法在欧洲专利申请公开号No.185,359,189,577,443,449和524,495中公开。Orlistat优选地以分开的剂量每天2至3次,每天60-720mg口服给药。优选的是每天180至360mg,最优选360mg脂肪酶抑制剂对受治者给药,优选地以每天分为2或者特别是3次给药。该受治者优选地是肥胖或超重的人,即体重指数为25或更大的人。通常在食入含脂肪的膳食约1或2小时内施用脂肪酶抑制剂是优选的。一般说来,对于如上定义的脂肪酶抑制剂给药,优选的是对具有很强家族肥胖史的并且体重指数已经为25或更大的人施用治疗剂。Orlistat可以由常规的口服组合物,如,片剂,包衣片剂,硬和软胶囊,乳剂或悬浮液对人给药。可用于片剂,包衣片剂,糖丸和硬胶囊的载体的例子有乳糖,其他糖类和如山梨糖醇,甘露糖醇,麦芽糊精的糖醇,或其他填料;如月桂基硫酸钠,Brij 96,或Tween 80的表面活性剂;如淀粉乙醇酸钠,玉米淀粉或其衍生物的崩解剂;如聚乙烯吡咯烷酮,聚乙烯聚吡咯烷酮的聚合物;滑石;硬脂酸或其盐等。软胶囊的合适的载体有例如,植物油,蜡,脂肪,半固体和液体多醇等。而且,药物制剂可以含有防腐剂,增溶剂,稳定剂,润湿剂,乳化剂,甜味剂,着色剂,调味剂,改变渗透压的盐,缓冲剂,包衣剂和抗氧化剂。它们也可以含有其他有治疗价值的物质。该制剂可以以单位剂量形式存在,并可以通过在制药领域已知的方法制备。优选地,orlistat根据分别在实施例和美国专利6,004,996中所示的制剂给药。
如上文所述,含有本发明化合物以及相容的药用载体材料的药物也是本发明的一个目的,以及同样地,还有制备该药物的方法,其包括将一种或多种这些化合物或其盐以及,必要时,一种或者多种其它的治疗上有价值的物质,与相容的药用载体制成盖仑(galenical)给药剂型。
本发明的药物组合物可以口服给药,例如以片剂,包衣的片剂,糖锭剂,硬或者软明胶胶囊,溶液剂,乳剂或者混悬剂的形式。给药也可以通过直肠进行,例如使用栓剂;局部给药或者经皮肤给药,例如使用软膏剂,霜剂,凝胶剂或者溶液剂;或者胃肠外给药,例如使用注射溶液。
为了制备片剂,包衣的片剂,糖锭剂,硬明胶胶囊,本发明的化合物可以与药学惰性的,有机或无机赋形剂一起混合。合适的片剂,包衣的片剂,糖锭剂,硬明胶胶囊的赋形剂的实例包括乳糖,玉米淀粉或者其衍生物,滑石,或者硬脂酸或者其盐。
软明胶胶囊的合适的赋形剂包括例如植物油,蜡,脂肪,半固体或者液体多元醇等;但是,根据该活性成分的性质,可能有软明胶胶囊根本不需要任何赋形剂的情况。
为了制备溶液剂和糖浆剂,可以使用的赋形剂包括例如水,多元醇,糖类,转化糖和葡萄糖。
为了制备注射溶液,可以使用的赋形剂包括例如水,醇,多元醇,甘油,和植物油。
为了制备栓剂,和局部给药或者经皮肤给药用剂,可以使用的赋形剂包括例如天然或者硬化油,蜡,脂肪,半固体或者液体多元醇。
该药物组合物还可以含有防腐剂,增溶剂,稳定剂,润湿剂,乳化剂,甜味剂,着色剂,调味剂,改变渗透压的盐,缓冲剂,包衣剂或者抗氧化剂。正如上文中所述的,它们也可以含有其它的治疗上有价值的活性剂。
给药式(I)的化合物的有效量的剂量根据具体的活性成分,患者的年龄以及具体的要求以及给药方式的不同而变化。一般地,考虑每天每公斤体重0.1mg-100mg的日剂量,尽管在显示需要时,上述提供的上限可被超越。
提供下面的实施例作为帮助实施本发明的指南,而不是为了限制本发明的范围。
实施例
实施例I:
(3aR,8bR)和(3aS,8bS)2-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚-4-基)-乙基胺富马酸盐
A)2-(1,2,3,4-四氢环戊二烯并[b]吲哚-4-基)-乙基胺盐酸盐
在乙腈(60mL)中搅拌1,2,3,4-四氢环戊二烯并[b]吲哚(2.0g,13mmol),粉状氢氧化钠(2.0g,50mmol)和四丁基硫酸氢铵(0.17g,0.5mmol)的混合物10分钟。向该混合物中加入氯乙基胺盐酸盐(2.2g,19mmol)并且加热该混合物至回流,搅拌90分钟,然后冷却至室温。将该混合物注入水(100mL)中并且用醚(100mL)萃取两次。洗涤(水,盐水)合并的有机相,干燥(硫酸钠)并真空浓缩给出黄色油(2.65g)。将该油溶解在醚(50mL)中,并且滴加到在加入的醚(35mL)中的醚盐酸(1.0M,13mL,13mmol)的搅拌的溶液中。将该混合物冷却至0℃,搅拌15分钟,然后过滤。用醚洗涤滤饼并且真空干燥给出灰白色固体产物(2.66g,88%);m.p.276-277℃;实测值:C,65.37;H,7.22;N,11.66%.C13H17N2Cl.0.125H2O理论值:C,65.33;H,7.28;N,11.72%。
B)叔丁基-2-[4-(1,2,3,4-四氢环戊二烯并[b]吲哚基)]乙基氨基甲酸酯
向2-(1,2,3,4-四氢环戊二烯并[b]吲哚-4-基)乙基胺盐酸盐(1.0g,4.2mmol)在2-丙醇(15mL)和水(15mL)中的搅拌的溶液中滴加入氢氧化钠(0.34g,8.5mmol)的水(5mL)溶液。搅拌该混合物5分钟,然后加入二-叔-丁基二碳酸酯(1.0g,4.6mmol),并且再搅拌该混合物1小时。过滤沉淀,用水洗涤和真空干燥给出粗产物,白色固体(1.32g,>100%),其直接使用而无需进一步纯化;NMR(400MHz,CDCl3)δH7.42(1H,dd,J 1.5,7Hz),7.25(1H,d,J 7Hz),7.08(2H,m),4.53(1H,m,NH),4.16(2H,t,J 6Hz),3.44(2H,q,J 6Hz),2.84(4H,t,J 7Hz),2.53(2H,quint,J 7Hz)和1.43(9H,s);HPLC:[Xterra;2.0ml/分钟,梯度洗脱,甲醇-10mM乙酸铵水溶液(50∶50)-(80∶20),在4分钟内,然后(80∶20)]97%(6.72分钟)。
C)叔丁基-2-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]乙基氨基甲酸酯
向叔丁基-2-[4-(1,2,3,4-四氢环戊二烯并[b]吲哚基)]乙基氨基甲酸酯(0.20g,0.66mmol)在乙酸(5mL)中的搅拌的溶液加入氰基硼氢化钠(0.13g,2.0mmol)。搅拌该混合物2小时,然后注入氢氧化钠水溶液(2N,30mL),并且用两份醚(20mL)萃取。将合并的有机萃取相洗涤(水,盐水),干燥(硫酸钠)和真空浓缩给出粗产物,其为粘性油(0.216g,>100%),其直接使用而无需进一步纯化。NMR(400MHz,CDCl3)δH 6.99(2H,dt,J 1.5,7Hz),6.64(1H,dt,J 1,7Hz),6.34(1H,d,J 7Hz),4.77(1H,m,NH),4.13(1H,m),3.72(1H,dt,J 3,9Hz),3.30(2H,m),3.26(2H,m),1.99(1H,m),1.79(2H,m),1.62(2H,m),1.51(1H,m)和1.42(9H,s);HPLC:[Xterra;2.0ml/分钟,梯度洗脱,甲醇-10mM乙酸铵水溶液(50∶50)-(80∶20),在4分钟内,然后(80∶20)]95%(6.64分钟)。
D)(3aR,8bR)和(3aS,8bS)2-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚-4-基)-乙基胺富马酸盐
将叔丁基-2-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]乙基氨基甲酸酯(0.15g,0.5mmol)和浓盐酸(0.2mL)在甲醇(5mL)中的搅拌的溶液加热至回流,搅拌4小时,冷却至室温并且注入水(30mL)中。将该混合物用醚(10mL)洗涤;弃去醚洗液。用氢氧化钠水溶液(2N,5mL)碱化该含水层,然后用醚(2×20mL)萃取。将合并的醚萃取液洗涤(水,盐水),干燥(硫酸钠)和真空浓缩给出黄色油(0.067g)。将该油溶解于热2-丙醇(1mL)中,并且滴加入富马酸(0.06g)在热的2-丙醇(1mL)中的搅拌的溶液中。将该溶液冷却至0℃,用醚(5mL)稀释并且过滤。将该滤饼洗涤(醚),并真空干燥给出产物白色固体(0.081g,51%);m.p.172℃(dec.);NMR(400MHz,DMSO-d6)δH 6.96(2H,t,J 7.5Hz),6.53(1H,t,J 7.5Hz),6.46(2H,s),6.41(1H,d,J 7.5Hz),4.18(1H,m),3.69(1H,dt,J 3,9Hz),3.34(2H,m),2.92(2H,m),1.97(1H,m),1.74(1H,m),1.62(2H,m)和1.40(1H,m)。
实施例II
制备起始化合物
式A化合物
其中R代表取代类型,该取代类型由式(I)中定义的R4,R5,R6和R7组成,可以根据Fischer吲哚合成法(参见例如Catal.Lett.,1999,61(1,2),93-97)制备。苯基肼类化合物可以用作为起始化合物。苯基肼类化合物可以商购或者可以如下文中4-氟-3-甲氧基苯基肼盐酸盐所述制备。
A)制备苯基肼:4-氟-3-甲氧基苯基肼盐酸盐
向0℃下的搅拌的盐酸(100mL)中加入3-甲氧基-4-氟苯胺(10g,71mmol),随后是水(10mL)和更多的盐酸(10mL)。将该混合物温至室温,搅拌20分钟,然后冷却至-5℃。将亚硝酸钠(5.14g,75mmol)的水(25mL)溶液滴加入,使得内部温度维持在低于0℃。将该混合物温至室温和搅拌2小时。冷却该混合物至-5℃并且滴加入氯化锡(II)二水合物(64g,284mmol)在盐酸(200mL)中的溶液,使得内部温度维持在低于0℃。将该混合物温至室温和搅拌3小时,然后过滤。将滤饼用盐酸洗涤并且真空干燥给出粉红色固体(7.4g)。过滤从该合并的滤液中出现的沉淀,用盐酸洗涤,给出另一批产物(1.8g,合并收率9.2g,67%);m.p.250+℃(dec.);NMR:(400MHz,DMSO-d6)δH 10.17(3H,s,NH3),8.14(1H,s,MH),7.15(1H,dd,J 11.6,8.6Hz),6.95(1H,dd,J 7.6,3.0Hz),6.54(1H,dt,J 8.6,3.0Hz),3.83(3H,s,MeO)。
B-1)合成环A:1,2,3,4-四氢环戊二烯并[b]吲哚(实施例1a和4a-7a):
将苯基肼(32.44g,300mmol)的2-丙醇(300mL)溶液用环戊酮(27mL,25.7g,305mmol)处理。在20℃搅拌该溶液1小时并且注入冰(900g)和水(300mL)混合物中。搅拌该冷却了的混合物直至冰被融化,然后过滤。用水(2×300mL)洗涤该滤饼。将所得到的潮湿的固体加入到水(540mL)中。用浓硫酸(33mL,61g,600mmol)处理该搅拌的悬浮液,然后回流下加热30分钟,冷却至0℃,并且搅拌15分钟。过滤该暗红色的固体,用水(2×60mL)洗涤,并且空气-干燥18小时。将该粗产物加入二氯甲烷(300mL)中,搅拌30分钟,然后过滤,用二氯甲烷(100mL)洗涤。用二氧化硅(48g)处理该滤液,搅拌1小时,过滤并且用二氯甲烷(400mL)洗涤。浓缩该滤液给出固体,其用己烷研制给出1,2,3,4-四氢环戊二烯并[b]吲哚(30g,65%),其为粉红色固体。1,2,3,4-四氢环戊二烯并[b]吲哚的分析数据参见下表3。
如果中间体腙以油的形式获得,则使用以下方法:
将芳基肼(100mmol)的苯(100mL)溶液用环戊酮(9mL,8.6g,102mmol)处理。回流下加热该溶液共沸除去水30-60分钟。让该溶液冷却并且真空浓缩给出芳基腙,其为油状物,其直接用于如上文所述的环化步骤。
B-2)合成环A:1,2,3,4-四氢-6-甲氧基环戊二烯并[b]吲哚(实施例21a和22a):
在避光和室温下的氩气氛中,向搅拌、脱气的乙醇(20mL)加入3-甲氧基苯基肼盐酸盐(1.0g,5.6mmol)和环戊酮(0.5mL,5.7mmol)。回流下加热该混合物24小时,冷却至室温,然后注入300mL冰-水中,并且用饱和的碳酸氢钠水溶液碱化(至pH8)。过滤该悬浮液,用水洗涤该所得的固体并干燥得到粗产物暗褐色固体(0.95g,89%)。快速柱色谱[SiO2;异-己烷-二氯甲烷(3∶2->1∶1)]纯化给出分离的异构的的吲哚产物。
备选地,通过溶解在二氯甲烷,然后二氧化硅塞过滤和真空浓缩,随后是甲苯研制,过滤,和用冰-冷的甲苯-庚烷(1∶1)洗涤得到的固体而专门地得到6-异构体而实现粗产物的纯化。1,2,3,4-四氢-6-甲氧基环戊二烯并[b]吲哚的数据列在下表3中。
对于合适的实施例,产生自使用不对称的芳基肼的pentindole区域异构体通过自甲苯,环己烷,异己烷或乙醇中重结晶或者通过甲苯或庚烷研制而分离。
表3:起始化合物
实施例(方法) | 起始化合物:苯基肼类 | 式A化合物 | R | 数据 |
2a,3a(i) | 3-氯-苯基肼 | 6-氯-1,2,3,4-四氢环戊二烯并[b]-吲哚 | 6-Cl | m.p.188-191℃(EtOH);实测C,69.21;H,5.18;N,7.31%C11H10CIN理论C,68.94;H,5.26;N,7.30%. |
4a-7a(i) | 苯基肼 | 1,2,3,4-四氢环戊二烯并[b]-吲哚 | H | m.p.107-108℃(乙烷);实测:C,83.04;H,7.12;N,8.78%.C11H11N.0.1H2O理论C,83.09;H,7.10;N,8.81%. |
8a,9a,18a,19a(ii) | 4-氟-3-甲氧基苯基-肼 | 7-氟-6-甲氧基-1,2,3,4-四氢环戊二烯并[b]-吲哚 | 7-F,6-OMe | 甲苯中搅拌粗产物10分钟,过滤并在真空下干燥滤饼。不需进一步纯化而使用;NMR(400MHz,DMSO-d6)δH10.69(1H,s,NH),7.08 (1H,d,J12.0Hz),6.98(1H,d,J7.6Hz),3.83(3H,s,MeO),2.79(2H,m),2.69(2H,t,J7.0Hz),2.50(2H,m). |
10a,11a,16a,17a(i) | 3-氯-4-氟苯基肼 | 6-氯-7-氟-1,2,3,4-四氢环戊二烯并[b]-吲哚 | 6-Cl,7-F | m.p.139.5-140℃(环己烷);实测:C,62.87;H,4.35;N,6.69%.C11H9ClFN理论C,63.02;H,4.33;N,6.68%. |
12a,13a(i) | 3-氯-4-甲基苯基肼 | 8-氯-7-甲基-1,2,3,4-四氢环戊二烯并[b]-吲哚 | 8-Cl,7-Me | 低熔点的固体;NMR(400MHz,CDCl3)δH7.61(1H,m,NH),6.97(1H,d,J8Hz),6.87(1H,d,J8Hz),3.01(2H,tt,J1.5,7Hz),2.75(2H,tt,J1.5,7Hz),2.47(2H,m)和2.41(3H,s).HPLC:[Supelcosil ABZ+;1.0ml/min,甲醇-10mM乙酸铵水溶液(80∶20)]90%(8.90min)[和6-氯-7-甲基10%(8.54min)]. |
14a,15a(i) | 3-氯-4-氟苯基肼 | 8-氯-7-氟-1,2,3,4-四氢环戊二烯并[b]-吲哚 | 8-Cl,7-F | 低熔点的固体NMR(400MHz,CDCl3)δH 7.86(1H,m,NH),7.07(1H,dd,J3.5,9Hz),6.86(1H,t,J9Hz),3.03(2H,tt,J1.5,7Hz),2.84(2H,t,J7Hz)和2.53(2H,五重峰,J7Hz);HPLC:[Xterra;2.0ml/min,甲醇10mM乙酸铵水溶液(80∶20)]99.5%(8.29min). |
20a(ii) | 4-氟-3-甲氧基-苯基肼 | 7-氟-8-甲氧基-1,2,3,4-四氢环戊二烯并[b]-吲哚 | 7-F,8-OMe | 来自实施例8a,9a,18a和19a的母液的柱色谱。无需进一步纯化或分析而立即使用 |
21a,22a(ii) | 3-甲氧苯基肼 | 6-甲氧基-1,2,3,4-四氢环戊二烯并[b]-吲哚 | 6-OMe | m.p.136-137.5℃;NMR(400MHz,CDCl3)δH 7.68(1H,m,NH),7.29(1H,d,J8.5Hz),6.81(1H,d,J2Hz),6.74(1H,dd,J2,8.5Hz),3.83(3H,s),2.85-2.76(4H,m),2.55-2.47(2H,m). |
实施例III:吲哚烷基化
式B化合物
其中R代表取代类型,该取代类型由式(I)中定义的R4,R5,R6和R7组成,可以根据下文实施例的吲哚烷基化而获得:
制备(R)-叔-丁基-[2-[1-[4-(1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯(实施例4b和5b):
将甲基亚砜(40mL)升温至40℃15分钟,和用粉状氢氧化钾(85%,2.64g,40mmol)处理。搅拌该悬浮液5-10分钟和然后,加入1,2,3,4-四氢环戊二烯并[b]吲哚(1.57g,10mmol)。在40℃下搅拌该悬浮液60分钟,和在90分钟内每10分钟分批滴加入(R)-叔-丁基[2-[(1-甲磺酰基)氧]丙基]氨基甲酸酯(6.33g,25mmol)的甲基亚砜(13mL)溶液。在40℃下搅拌该悬浮液18小时,然后冷却至室温。加入二-叔-丁基二碳酸酯(2.3mL,2.2g,10mmol),并且在20℃下搅拌该悬浮液另外2小时,并且注入冰(165g)和水(55mL)混合物。搅拌该悬浮液1小时,并且通过过滤收集粗产物,用水(2×25mL)洗涤,并且空气-干燥5分钟[或者备选地,使用乙酸乙酯萃取反应混合物,然后柱色谱(SiO2;乙酸乙酯-二氯甲烷(0∶1->1∶19)的工艺操作]。将该粗产物溶解在乙酸乙酯中,干燥(硫酸镁),并且浓缩给出固体(用己烷(2.34g,74%)研制)。(R)4-[2-(叔-丁氧羰基氨基)-1-丙基]-1,2,3,4-四氢环戊二烯并[b]吲哚的数据列在下表4中,其中还有根据上述方法合成的其它产物的数据。
表4:用一般方法B合成的吲哚氨基甲酸酯
实施例 | 式B化合物 | R | 数据 |
2b,3b | (2′S)-叔-丁基[2-[1-[4-(6-氯-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 6-Cl(S) | m.p.172-174℃;NMR(400MHz,CDCl3)δH 7.29(1H,m)7.29(1H,d,J8Hz),7.01(1H,dd,J1.5,8Hz),4.42(1H,m,NH),4.12-3.89(3H,m),2.85(2H,t.,J7Hz),2.81(2H,t,J7Hz),2.52(2H,quint.,J7Hz),1.42(9H,s),1.11(3H,d,J6.5Hz). |
4b,5b | (2′R)-叔-丁基[2-[1-[4-(1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | H(R) | m.p.170-172℃(己烷);实测:C,71.08;H,8.27;N,8.71%.C19H26N2O2.0.67H2O理论C,71.22;H,8.39;N,8.74%. |
6b,7b | (2′S)-叔丁基[2-[1-[4-(1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | H(S) | m.p.172-173℃(异丙醚);实测:C,71.46;H,8.22;N,8.78%.C19H26N2O2.0.25H2O理论C,71.55;H,8.38;N,8.78%. |
8b,9b | (2′R)-叔-丁基[2-[1-[4-7-氟-6-甲氧基-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 7-F,6-OMe(R) | 自EtOH/水(5∶1)中结晶;NMR(400MHz,CDCl3)δH 7.05(2H,d,J12.2Hz),4.48-4.34(1H,m),4.2-3.98(2H,m),3.92(3H,s,MeO),3.84(1H,dd,J14.0,7.1Hz),2.80(2H,t,J7.0Hz),2.76(2H,t,J7.2Hz),2.48(2H,m),1.40(9H,br s),1.09(3H,d,J6.5Hz);).HPLC:[Supelcosil ABZ+;1.0ml/min,甲醇-10mM乙酸铵水溶液(70∶30)]99%(8.82min)和[Xterra;2.0mL/min,甲醇-10mM乙酸铵水溶液,在头4分钟内梯度洗脱50%至80%甲醇,然后80∶20]96%(6.89min). |
10b,11b | (2′S)-叔-丁基[2-[1-[4-(6-氯-7-氟-1,2,3,4-四氢 | 6-Cl,7-F(S) | m.p.173.5-176℃(己烷);实测:C,61.45;H,6.54;N,7.49%.C19H24ClFN2O2.0.25H2O理论C,61.45;H,6.65;N,7.54%. |
12b | (2′S)-叔-丁基[2-[1-[4-(8-氯-7-甲基-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基酸酯 | 8-Cl,7-Me(S) | NMR(400MHz,CDCl3)δH 7.12(1H,d,J8Hz),6.92(1H,d,J8Hz),4.40(1H,m,NH),4.14(1H,m),4.02(1H,dt,J6.5,12Hz),3.90(1H,q,J7Hz),3.06(2H,t,J7Hz),2.83(2H,t,J7Hz),2.50(2H,五重峰,J7 Hz),2.42(3H,s),1.43(9H,s)and 1.08(3H,d,J6.5Hz);HPLC:[Supelcosil ABZ+;1.0mL/min,甲醇-10mM乙酸铵水溶液(80∶20)]98%(8.70min). |
13b | (2′R)-叔-丁基[2-[1-[4-(8-氯-7-甲基-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 8-Cl,7-Me(R) | NMR(400MHz,CDCl3)δH 7.12(1H,d,J8Hz),6.91(1H,d,J8Hz),4.41(1H,m,NH),4.12(1H,m),4.02(1H,m),3.98(1H,q,J7Hz),3.06(2H,t,J7Hz),2.82(2H,t,J7Hz),2.50(2H,五重峰,J7Hz),2.42(3H,s),1.43(9H,s)and 1.08(3H,d,J6.5Hz);HPLC:[Supelcosil ABZ+;1.0ml/min,甲醇-10mM乙酸铵水溶液(80∶20)]98%(8.62min). |
14b | (2′R)-叔-丁基[2-[1-[4-(8-氯-7-氟-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 8-Cl,7-F(R) | m.p.160-161℃(己烷);实测:C,62.00;H,6.61;N,7.56%.C19H24ClFN2O2理论C,62.21;H,6.59;N,7.63%. |
15b | (2′S)-叔-丁基[2-[1-[4-(6-氯-7-氟-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 6-Cl,7-F(S) | NMR(400MHz,CDCl3)δH 7.17(1H,m),6.88(1H,t,J9Hz),4.40(1H,m),4.17(1H,m),4.01(1H,dt,J7,12.5Hz),3.89(1H,q,J7Hz),3.05(2H,t,J7Hz),2.84(2H,t,J7Hz),2.52(2H,五重峰,J7Hz),1.42(9H,s)and 1.10(3H,d,J6.5Hz);HPLC:[Supelcosil ABZ+;1.0ml/min,甲醇-10mM乙酸铵水溶液(80∶20)]99%(7.63min). |
16b,17b | (2′S)-叔-丁基[2-[1-[4-(6-氯-7-氟-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 6-Cl,7-F(R) | m.p.176-176.5℃(己烷);实测:C,61.71;H,6.59;N,7.49%.C19H24ClFN2O2.0.25H2O理论C,61.45;H,6.65;N,7.54%. |
18b,19b | (2′S)-叔-丁基[2-[1-[4-(7-氟-6-甲基-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 7-F,6-OMe(S) | NMR(400MHz,CDCl3)δH 7.08(1H,br.s),7.07(1H,d,J12Hz),4.41(1H,m,NH),4.16(1H,m),4.12(1H,m),3.94(3H,s),4.04(1H,dt,J6.5,12Hz),3.84(1H,q,J7Hz),2.80(4H,m),2.50(2H,五重峰,J7Hz),1.42(9H,s),1.11(3H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,梯度洗脱在,4分钟内甲醇-10mM乙酸铵水溶液(50∶50)到(80∶20)然后(80∶20)]97%(6.33min). |
20b | (2′S)-叔-丁基[2-[1-[4-(7-氟-8-甲氧基-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 7-F,8-OMe(S) | NMR(400MHz,CDCl3)δH 6.99-6.94(1H,m),6,84(1H,dd,J11.3,9.4Hz),4.44-4.37(1H,m,NH),4.16-4.00(2H,m),4.00(3H,s),3.87(1H,dd,J14.0,7.2Hz),2.96(2H,obs t,J6.6Hz),2.83(2H,obs t,J7.3Hz),2.51(2H,五重峰,J7.0Hz),1.42(9H,br s),1.11(3H,d,J6.8Hz);HPLC:[Xterra;2.0mL/min,甲醇-10mM乙酸铵水溶液,在头4分钟内梯度洗脱50%-80%,然后80∶20]99.7%(6.55min). |
21b | (2′S)-叔-丁基[2-[1-[4-[(6-甲氧基-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 6-OMe(S) | NMR(400MHz,CDCl3)δH 7.28(1H,d,J8.5Hz),6.94(1H,m),6.73(1H,dd,J2.5,8.5Hz),4.48(1H,m,NH),4.12(1H,m),4.05(1H,m),3.88(1H,dd,J6.5,14Hz),3.87(3H,s),2.86-2.78(4H,m),2.55-2.46(2H,m),1.43(9H,s),1.11(3H,d,J7Hz);HPLC:[Supelcosil ABZ+;1.0mL/min,甲醇-10mM乙酸铵水溶液(80∶20)]96%(3.87min). |
22b | (2′R)-叔-丁基[2-[1-[4-[(6-甲氧基-1,2,3,4-四氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 6-OMe(R) | NMR(400MHz,CDCl3)δH 7.28(1H,d,J8.5Hz),6.92(1H,m),6.73(1H,dd,J2,8.5Hz),4.44(1H,m,NH),4.15-4.01(2H,m),3.87(1H,dd,J6.5,14Hz),3.86(3H,s),2.86-2.77(4H,m),2.49(2H,quint.,J7Hz),1.42(9H,s),1.11(3H,d,J6.5Hz);HPLC:[Xterra;2.0mL/min,甲醇-10mM乙酸铵水溶液,在头4分钟内梯度洗脱50%-80%,然后80∶20]92%(6.00min). |
实施例IV
还原吲哚到二氢吲哚
使用上述在实施例I的合成中的方法将表4中的上述吲哚还原成式C化合物
其中R代表取代类型,该取代类型由式(I)中定义的R4,R5,R6和R7组成。如果可分离,用快速柱色谱分离二氢吲哚非对应异构体。下表5中描述了合适的色谱***和所获得的数据。
表5:用一般方法C合成的二氢吲哚氨基甲酸酯
实施例 | 式C化合物 | R | 数据 |
2c | (2′S,3aS,8bS)-叔-丁基[2-[1-[4-[6-氯-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基-氨基甲酸酯 | 6-Cl(3aS,8bS)(2’S) | 柱色谱分离的异构体1[SiO2;乙酸乙酯-庚烷(1∶10)];NMR(400MHz,CDCl3)δH 6.82(1H,dd,J1,7.5Hz),6.48(1H,dd,J2,7.5Hz),6.25(1H,d,J2Hz),4.28(2H,m),3.96(1H,m),3.67(1H,dt,J3,9Hz),3.18(1H,q,J7.5Hz),3.01(1H,dd,J6.5,14.5Hz),1.95(1H,m),1.80(1H,m),1.74-1.56(3H,m),1.46(1H,m),1.37(9H,s),1.18(3H,d,J 6.5Hz);HPLC:[Supelcosil ABZ+;1.0ml/min,甲醇-10mM乙酸铵水溶液(80∶20)]96%(6.24min);X射线晶体学显示实施例2c具有立体化学(3aS,8bS). |
3c | (2’S,3aR,8bR)-叔-丁基[2-[1-[4-[6-氯-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基-氨基甲酸酯 | 6-Cl(3aR,8bR)(2’S) | 柱色谱分离的异构体2[SiO2;乙酸乙酯-庚烷(1∶10)];NMR(400MHz,CDCl3)δH 6.84(1H,dd,J1,8Hz),6.50(1H,dd,J,2,8Hz),6.26(1H,d,J2Hz),4.43(1H,m,NH),4.21(1H,m),3.91(1H,ddd,J6.5,13,20Hz),3.66(1H,dt J3,9Hz),3.19(1H,dd,J6,14.5Hz),3.04(1H,dd,J1,14.5Hz),1.97(1H,m),1.84(1H,m),1.70(2H,m),1.62(1H,m),1.49(1H,m),1.43(9H,s),1.17(3H,d,J6.5Hz);HPLC:[OD;1.0ml/min,己烷-2-丙醇(95∶5)]96%(7.03min) |
4c | (2′R)-叔-丁基[2-[1-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体I | H(2’R) | 异构体1.Rf0.225 [SiO2,异丙醚-庚烷(2∶3)].NMR(400MHz,CDCl3)δH 6.98(2H,q,J7Hz),6.56(1H,t,J7Hz),6.34(1H,d,J7Hz),4.38(1H,m,NH),4.19(1H,m),3.94(1H,m),3.72(1H,d,J3,9Hz),3.21(1H,q,J7Hz),3.02(1H,q,J7Hz),1.97(1H,m),1.80(1H,m),1.70(2H,m),1.60(1H,m),1.50(1H,m),1.40(9H,s),1.18(3H,d,J7Hz). |
5c | (2′R)-叔-丁基[2-[1-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体II | H(2’R) | 异构体2.Rf0.175[SiO2,异丙醚-庚烷(2∶3)].NMR(400MHz,CDCl3)δH 6.99(2H,q,J7Hz),6.58(1H,t,J7Hz),6.37(1H,d,J8Hz),4.49(1H,m,NH),4.13(1H,sept,J3Hz),3.92(1H,sept.,J7Hz),3.71(1H,dt,J3.5,9Hz),3.22(1H,dd,J6,14Hz),3.01(1H,q,J7Hz),2.00(1H,m),1.83(1H,m),1.72(1H,m),1.60(1H,m),1.52(1H,m),1.43(9H,s),1.18(3H,d,J7Hz). |
6c | (2′S)-叔-丁基[2-[1-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体I | H(2’S) | 异构体1.m.p.130-133℃:实测:C,71.94;H,8.86;N,8.79%.C19H28N2O2理论C,72.12;H,8.92;N,8.85% |
7c | (2′S)-叔-丁基[2-[1-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体II | H(2’S) | 异构体2.m.p.92-96℃.NMR(400MHz,CDCl3)δH 6.98(2H,q,J7Hz),6.56(1H,t,J7Hz),6.34(1H,d,J7Hz),4.36(1H, m,NH),4.20(1H,m),3.94(1H,m),3.72(1H,dt,J3,9Hz),3.22(1H,q,J,7Hz),3.02(1H,q,J7Hz),1.98(1H,m),1.81(1H,m),1.72(2H,m),1.60(1H,m),1.49(1H,m),1.40(1H,m),1.19(3H,d,J6.5Hz). |
8c | (2′R)-叔-丁基[2-[1-[4-(7-氟-1,2,3,3a,4,8b-六氢-6-甲氧基-环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体I | 7-F,6-OMe(2’R) | 异构体1,柱色谱[SiO2:异丙醚-庚烷(2∶3至11∶9)];NMR(400MHz,CDCl3)δH 6.70(1H,d,J11.5Hz),6.17(1H,br s),4.44(1H,br s),4.10-4.06(1H,m),3.88(1H,obs dd,J13.6,7.1Hz),3.84(3H,s,MeO),3.60(1H,dt,J9.1,3.0),3.17(1H,dd,J13.8,6.0Hz),2.90(1H,dd,J13.8,7.5Hz),1.96-1.87(1H,m).1.82-1.78(1H,m),1.69-1.46(5H,m),1.41(9H,s,tBu),1.17(3H,d,J6.5Hz). |
9c | (2′R)-叔-丁基[2-[1-[4-(7-氟-1,2,3,3a,4,8b-六氢-6-甲氧基-环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体II | 7-F,6-OMe(2’R) | 异构体2;NMR(400MHz,CDCl3)δH 6.68(1H,d,J11.2Hz),6.07(1H,d,J6.0),4.33(1H,m),4.17-4.13(1H,m),3.92-3.85(1H,m),3.83(3H,s,MeO),3.62(1H,dt,J8.8,2.4Hz),3.15(1H,dd,J14.4,6.4Hz),2.95(1H,dd,J14.4,7.0Hz),1.95-1.86(1H,m),1.75(1H,m),1.69(5H,m),1.38(9H,s,tBu),1.17(3H,d,J6.6). |
10c | (2′S)-叔-丁基[2-[1-[4-(6-氯-7-氟-1,2,3,-3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体I | 6-Cl,7-F(2’S) | 异构体1.m.p.139-143℃;Rf 0.375(SiO2,异丙醚).NMR(400MHz,CDCl3)δH 6.74(1H,dd,J1,9Hz),6.23(1H,d,J5.5Hz),4.27(2H,m),3.94(1H,m),3.66(1H,dt,J3,9Hz),3.14(1H,q,J7Hz),2.97(1H,dd,J6.5,14.5Hz),1.98(1H,m),1.80(1H,m),1.67(2H,m),1.62(1H,m),1.48(1H,m),1.37(9H,s),1.17(3H,d,J6.5Hz). |
11c | (2′S)-叔-丁基[2-[1-[4-(6-氯-7-氟-1,2,3,-3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体II | 6-Cl,7-F(2’S) | 异构体2.Rf0.325(SiO2,异丙醚).NMR(400MHz,CDCl3)δH6.75(1H,dd,J1,8Hz),6.25(1H,d,J6Hz),4.40(1H,m,NH),4.17(1H,m),3.89(1H,sept.,J7Hz),3.64(1H,dt,J3.9Hz),3.15(1H,dd,J6,14Hz),2.98(1H,dd,J6.5,14.5Hz),1.97(1H,m),1.82(1H,m),1.65(3H,m),1.50(1H,m),1.42(9H,s),1.16(3H,d,J6.5Hz). |
12c | (2′R)-叔-丁基[2-[1-[4-(8-氯-1,2,3,3a,4,8b-六氢-7-甲基环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 8-Cl,7-Me(2’S) | 非对映异构体的混合物NMR(400MHz,CDCl3)δH 6.83(1H,t,J7.5Hz),6.23(0.5H,d,J7.5Hz),6.15(0.5H,d,J7.5Hz),4.43(0.5H,m),4.30(0.5H,m),4.22(0.5H,m),4.14(0.5H,m),3.94(0.5H,m),3.89(0.5H,六重峰J7Hz),3.75(1H,m),3.18(1H,m),2.96(1H,m),2.23(1.5H,s),2.22(1.5H,s),2.04(1H,m),1.84(1H,m),1.72(1H,m),1.62(1H,m),1.54(1H,m),1.42(4.5H,s),1.37(4.5H,s),1.17(1.5H,d,J6.5Hz)和1.16(1.5H,d,J6.5Hz);HPLC:[Supelcosil ABZ+;1.0ml/min,甲醇-10mM乙酸铵水溶液(80∶20)]47%(7.86min)和41%(8.54min). |
13c | (2′R)-叔-丁基[2-[1-[4-(8-氯-1,2,3,3a,4,8b-六氢-7-甲基环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 8-Cl,7-Me(2’R) | 非对映异构体的混合物 NMR(400MHz,CDCl3)δH 6.83(1H,t,J7.5Hz),6.23(0.5H,d,J7.5Hz),6.15(0.5H,d,J7.5Hz),4.43(0.5H,m),4.30(0.5H,m),4.22(0.5H,m),4.14(0.5H,m),3.94(0.5H,m),3.89(0.5H,六重峰,J7Hz),3.75(1H,m),3.18(1H,m),2.96(1H,m),2.23(1.5H,s),2.22(1.5H,s),2.04(1H,m),1.84(1H,m),1.72(1H,m),1.62(1H,m),1.54(1H,m),1.42(4.5H,s),1.37(4.5H,s),1.17(1.5H,d,J6.5Hz)和1.16(1.5H,d,J6.5Hz);HPLC:[Supelcosil ABZ+;1.0ml/min,甲醇-10mM乙酸铵水溶液(80∶20)]52%(7.97min)和41%(8.68min). |
14c | (2′R)-叔-丁基[2-[1-[4-(8-氯-7-氟-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 8-Cl,7-F(2’R) | 非对映异构体的混合物m.p。106-114℃;NMR(400MHz,CDCl3)δH 6.78(0.5H,t,J8Hz),6.76(0.5H,t,J8Hz),6.20(0.5H,dd,J3,8.5Hz),6.11(0.5H,dd,J3.5,8Hz),4.40(0.5H,m),4.28(1H,m),4.18(0.5H,m),3.94(0.5H,m),3.89(0.5H,sept.,J7Hz),3.75(1H,app.dq,J3.5,9Hz),3.21(0.5H,dd,J6,14.5Hz),3.16(0.5H,q,J7Hz),2.03(1H,m),1.84(2H,m),1.72(1H,m),1.64(1H,m),1.53(1H,m),1.43(4.5H,s),1.38(4.5H,s),1.16(3H,d,J7Hz). |
15c | (2′S)-叔-丁基[2-[1-4-(8-氯-7-氟-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 8-Cl,7-F(2’S) | 非对映异构体的混合物 NMR(400MHz,CDCl3)δH 6.78(0.5H,t,J8Hz),6.75(0.5H,t,J8.5Hz),6.20(0.5H,dd,J3,8.5Hz),6.10(0.5H,dd,J3.5,8.5Hz),4.40(0.5H,m),4.28(1H,m),4.17(0.5H,m),3.94(0.5H,m),3.89(0.5H,sept.,J7Hz),3.78(0.5H,dd,J3.5,9.5Hz),3.73(0.5H,dd,J4,9Hz),3.20(0.5,dd,J5.5,14Hz),3.16(0.5H,q,J7Hz),2.97(0.5H,q,J 7Hz),2.91(0.5H,q,J 7Hz),2.03(1H,m),1.84(2H,m),1.73(1H,m),1.64(1H,m),1.54(1H,m),1.43(4.5H,s),1.37(4.5H,s),1.16(3H,d,J6.5Hz);HPLC:[Xterra 2.0ml/min,在4分钟内梯度洗脱,甲醇-10mM乙酸铵水溶液(50∶50)到(80∶20),然后(80∶20)]51%(7.79min)和48%(7.95min). |
16c | (2’R)-叔-丁基[2-[1-[4-(6-氯-7-氟-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体I | 6-Cl,7-F(2’R) | 异构体1.Rf0.15[SiO2,异丙醚-庚烷(2∶3)].NMR(400MHz,CDCl3)δH 6.74(1H,dd,J1,8.5Hz),6.23(1H,d,J5.5Hz),4.26(2H,m),3.94(1H,m),3.36(1H,dt,J3,6Hz),3.14(1H,q,J7Hz),2.98(1H,dd,J6,14Hz),1.96(1H,m),1.78(1H,m),1.68(2H,m),1.62(1H,m),1.48(1H,m),1.37(1H,m),1.17(3H,d,J6.5Hz). |
17c | (2′R)-叔-丁基[2-[1-[4-(6-氯-7-氟-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体II | 6-Cl,7-F(2’R) | 异构体2.Rf0.10[SiO2,异丙醚-庚烷(2∶3)]。NMR(400MHz,CDCl3)δH 6.76(1H,dd,J1,8.5Hz),6.25(1H,d,J6Hz),4.41(1H,m,NH),4.17(1H,dt,J2.5,6.5Hz),3.89(1H,sept.,J7Hz),3.65(1H,dt,J3,9Hz),3.16(1H,dd,J6,14.5Hz),2.98(1H,q,J7Hz),1.97(1H,m),1.82(1H,m),1.68(1H,m),1.61(1H,m),1.43(9H,s),1.17(3H,d,J6.5Hz). |
18c | (2′S)-叔-丁基[2-[1-[4-(7-氟-1,2,3,3a,4,8b-六氢-6-甲氧基环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体I | 7-F,6-OMe(2’S) | 通过柱色谱部分分离异构体[SiO2:异丙醚-庚烷(1∶3)-(2∶5)]并无需进一步纯化或分析而用于下一步 |
19c | (2′S)-叔-丁基[2-[1-[4-(7-氟-1,2,3,3a,4,8b-六氢-6-甲氧基-环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯异构体II | 7-F,6-OMe(2’S) | 异构体2,如实施例18 |
20c | (2′S)-叔-丁基[2-[1-[4-(7-氟--1,2,3,3a,4,8b-六氢-8-甲氧基-环戊二烯并[b]吲哚基)]]丙基氨基甲酸酯 | 7-F,8-OMe(2’S) | 非对映异构体的混合物;NMR(400MHz,CDCl3)δH 6.77-6.70(1H,m),6.00(0.5H,dd,J 8.5,3.1Hz),5.92(0.5H,dd,J 8.5,3.0Hz),4.44-4.40(0.5H,m),4.38-4.28(0.5H,m),4.22-4.19(0.5H,m),4.16-4.09(0.5H,m),3.94(1.5H,s,MeO),3.93(1.5H,s,MeO),3.89-3.84(1H,m),3.80-3.72(1H,dq,J8.7,3.6Hz),3.18(0.5H,dd,J 14.1,6.7Hz),3.13(0.5H,dd,J14.7,7.0Hz),2.97(0.5H,dd,J14.4,7.0Hz),2.90(0.5H,dd,J14.1,7.2),2.06-1.95(1H,m),1.82-1.52(5H,m),1.44(9H,s,tBu),1.17(3H,d,J6.5);HPLC:[Xterra 2.0ml/min,在4分钟内梯度洗脱,甲醇-10-mM乙酸铵水溶液(50∶50)到(80∶20),然后(80∶20)]52%(6.90min)和46%(7.06min). |
21c | (2′S)-叔-丁基[2-[1-[4-(1,2,3,3a,4,8b-六氢-6-甲氧基-环戊二烯并[b]吲哚基)]]丙基氨基甲酸酯 | 6-OMe(2’S) | 非对映异构体的混合物m.p.128-144℃;NMR(400MHz,CDCl3)δH 6.86(0.5H,dd,J1,8Hz),6.84(0.5H,dd,J1,8Hz),6.11(0.5H,dd,J2.5,8Hz),6.09(0.5H,dd,J2.5,8Hz),5.97(0.5H,m),5.94(0.5H,d,J2.5Hz),4.45(0.5H,m,NH),4.35(0.5H,m,NH),4.22(0.5H,ddd,J2.5,6.5,8.5Hz),4.17(0.5H,ddd,J2.5,6,8.5Hz),3.92(1H,m),3.75(3H,s),3.65(1H,m),3.21(0.5H,dd,J6,14Hz),3.18(0.5H,dd,J6.5,14Hz),3.01(0.5H,dd,J7.5,14Hz),3.005(0.5H,q,J7Hz),1.93(1H,m),1.81(1H,m),1.69(2H,m),1.59(1H,m),1.50(1H,m),1.43(4.5H,s),1.40(4.5H,s),1.18(1.5H,d,J6.5Hz),1.17(1.5H,d,J6.5Hz). |
22c | (2’R)-叔-丁基[2-[1-[4-(1,2,3,3a,4,8b-六氢-6-甲氧基环戊二烯并[b]吲哚基)]]丙基]氨基甲酸酯 | 6-OMe(2’R) | 非对映异构体的混合物Rf0.45(SiO2,异丙醚);NMR(400MHz,CDCl3)δH 6.86(0.5H,dd,J1,8Hz),6.84(0.5H,dd,J1.5,8Hz),6.11(0.5H,dd,J2.5,8HZ),6.09(0.5H,dd,J2.5,8Hz),5.97(0.5H,m),5.94(0.5H,d,J2.5Hz),4.45(0.5H,m,NH),4.35(0.5H,m,NH),4.22(0.5H,m),4.17(0.5H,m),4.00-3.85(1H,m),3.75(3H,s),3.65(1H,app.tt,J3,9Hz),3.21(0.5H,dd,J6.5,14Hz),3.18(0.5H,q,J7Hz),3.01(0.5H,q,J7Hz),3.00(0.5H,q,J7Hz),1.94(1H,m),1.81(1H,m),1.69(2H,m),1.59(1H,m),1.50(1H,m),1.43(4.5H,s),1.40(4.5H,s),1.18(1.5H,d,J6.5Hz),1.17(1.5H,d,J6.5Hz). |
实施例V
Boc-二氢吲哚的脱保护
使用上述在实施例1的合成中的方法将二氢吲哚脱保护。表6中列出了式D的产物所获得的数据,
其中R代表取代类型,该取代类型由式(I)中定义的R4,R5,R6和R7组成。
表6:一般方法D合成的二氢吲哚类化合物
实施例 | 式D的产物 | R | 收率 | 数据 |
2 | (2’S,3aS,8bS)-[1-[4-(6-氯-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺盐酸盐 | 6-Cl(3aS,8bS)(2’S) | 83% | HCl.NMR 400MHz(DMSO-d6)δH 8.11(3H,m,-NH3 +),6.95(1H,d,J7.5Hz),6.52(1H,dd,J1.5,7.5Hz),6.49(1H,d,J1.5Hz),4.27(1H,ddd,J2.5,5.5,8.5Hz),3.69(1H,dt,J2.5,9Hz),3.45(1H,t,J7.5Hz),3.42(1H,dd,J7.5,17Hz),3.21(dt,J4.5,17Hz),1.97(1H,m),1.78-1.54(4H,m),1.35(1H,m),1.27(3H,d,J6.5Hz);HPLC:[SupelcosilABZ+;1.0ml/min,甲醇-10mM乙酸铵水溶液(80∶20)]96%(3.41min). |
3 | (2’S,3aR,8bR)-1-[4-(6-氯-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺盐酸盐 | 6-Cl(3aR,8bR)(2’S) | 100% | HCl.C14H19ClN2理论MH+251,253.实测m/z 251,253;HPLC:[Supelcosil ABZ+;1.0ml/min,甲醇-10mM乙酸铵水溶液(80∶20)]97%(3.49min). |
4 | (2’R)-1-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺异构体I富马酸盐 | H(2’R) | 70% | 异构体1;富马酸盐;NMR 400MHz(DMSO-d6)δH 6.97(1H,d,J7.5Hz),6.95(1H,t,J8Hz),6.54(1H,t,J7Hz),6.46(2H,s),6.42(1H,d,J8Hz),4.17(1H,sept,J3Hz),3.70(1H,dt,J2.5,8.5Hz),3.40(1H,六重峰,J6.5Hz),3.30(1H,q,J7Hz),3.15(1H,q,J7Hz),2.00(1H,m),1.78-1.54(4H,m),1.40(1H,m),1.22(3H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20),然后(80∶20)]94%(1.25min). |
5 | (2’R)-1-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺异构体II 富马酸盐 | H(2’R) | 91% | 异构体2;富马酸盐;NMR 400MHz(DMSO-d6)δH 6.97(1H,d,J7Hz),6.95(1H,t,J8Hz),6.54(1H,dt,J1,7Hz),6.46(2H,s),6.43(1H,t,J8Hz),4.16(1H,sept,J3Hz),3.70(1H,dt,J 3,9Hz),3.40(1H,六重峰J7Hz),3.27(1H,q,J7Hz),3.17(1H,q,J7Hz),1.98(1H,m),1.79-1.54(4H,m),1.40(1H,m),1.19(3H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20),然后(80∶20)] 98%(1.36min). |
6 | (2’S)-1-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺异构体I富马酸盐 | H(2’S) | 58% | 异构体1;富马酸盐;NMR 400MHz(DMSO-d6)δH 6.97(1H,d,J7Hz),6.94(1H,d,J8Hz),6.54(1H,t,J7Hz),6.46(2H,s),6.42(1H,t,J8Hz),4.17(1H,sept.,J3Hz),3.70(1H,dt,J2.5,8.5Hz),3.39(1H,六重峰J6.5Hz),3.31(1H,dd,J7,14Hz),3.15(1H,q,J7Hz),1.99(1H,m),1.78-1.54(4H,m),1.40(1H,m),1.22(3H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20),然后(80∶20)]97%(1.18min). |
7 | (2’S)-1-[4-(1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺异构体II富马酸盐 | H(2’S) | 60% | 异构体2;富马酸盐;NMR 400MHz(DMSO-d6)δH 6.97(1H,d,J7Hz),6.95(1H,t,J8Hz),6.54(1H,t,J7.5Hz),6.46(2H,s),6.43(1H,t,J8Hz),4.16(1H,sept.,J3Hz),3.70(1H,dt,J2.5,9Hz),3.40(1H,app.六重峰,J6.5Hz),3.27(1H,q,J7Hz),3.17(1H,q,J7Hz),1.99(1H,m),1.80-1.54(4H,m),1.41(1H,m),1.19(3H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20),然后(80∶20)]98%(0.92min). |
8 | (2’R)-1-[4-(7-氟-1,2,3,3a,4,8b-六氢-6-甲氧基环戊二烯并[b]吲哚基)]-2-丙基胺异构体I富马酸盐 | 7-F,6-OMe(2’R) | 67% | 异构体1;富马酸盐;NMR 400MHz(DMSO-d6)δH 6.84(1H,d,J9.1Hz),6.46(2H,s),6.37(1H,d,J7.7Hz),4.12(1H,ddd,J8.8,6.1,2.7Hz),3.78(3H,s,MeO),3.65(1H,dt,J8.6,2.6Hz),3.41-3.36(1H,m),3.30(1H,dd,J13.9,8.1),3.16(1H,dd,J13.9,6.0Hz),1.94-1.89(1H,m),1.75-1.43(4H,m),1.20(3H,d,J6.4Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]100%(1.13min). |
9 | (2’R)-1-[4-(7-氟-1,2,3,3a,4,8b-六氢-6-甲氧基环戊二烯并[b]吲哚基)]-2-丙基胺异构体II半富马酸盐 | 7-F,6-OMe(2’R) | 57% | 异构体2;半富马酸盐;NMR 400MHz(DMSO-d6)δH 6.82(1H,d,J11.5Hz),6.41(1H,s),6.22-(1H,d,J7.1Hz),4.17(1H,obs dt,J6.1,2.5Hz),3.78(3H,s,MeO),3.64(1H,dt,J8.5,2.5Hz),3.30-3.25(1H,m),3.18(1H,dd,J14.0,7.5Hz),3.05(1H,dd,J14.0,6.4Hz),1.94-1.89(1H,m),1.75-1.73(1H,m),1.67-1.55(3H,m),1.40-1.36(1H,m),1.16(3H,d,J6.1Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]97%(1.27min). |
10 | (2’S)-1-[4-(6-氯-7-氟-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺异构体I富马酸盐 | 6-Cl,7-F(2’S) | 47% | 异构体1;富马酸盐;NMR 400MHz(DMSO-d6)δH 7.04(1H,dd,J1,9Hz),6.58(1H,d,J6Hz),6.46(2H,s),4.21(1H,ddd,J2.5,6,9Hz),3.69(1H,dt,J3,9Hz),3.57(1H,sept,J7Hz),3.23(1H,dd,J8,14.5Hz),3.17(1H,dd,J6.5,14.5Hz),1.96(1H,m),1.74(1H,m),1.66(2H,m),1.57(1H,m),1.41(1H,m),1.18(3H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]97%(2.70min). |
11 | (2’S)-1-[4-(6-氯-7-氟1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺异构体II半富马酸盐 | 6-Cl,7-F(2’S) | 59% | 异构体2;半富马酸盐;NMR 400MHz(DMSO-d6)δH 7.02(1H,dd,J1,8.5Hz),6.46(1H,d,J6Hz),6.42(1H,s),4.24(1H,m),3.69(1H,dd,J2,8.5Hz),3.26(1H,sextet,J6.5Hz),3.17(1H,q,J7Hz),3.03(1H,dd,J6.5,14Hz),1.96(1H,m),1.77(1H,m),1.70-1.55(3H,m),1.36(1H,m),1.13(3H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]96%(2.45min). |
12 | (2’S)-[1-[4-(8-氯-1,2,3,3a,4,8b-六氢-7-甲基环戊二烯并[b]-2-丙基胺富马酸盐 | 8-Cl,7-Me(2’S) | 43% | 非对映异构体的混合物;富马酸盐;m.p.167-170℃(dec.);NMR400MHz(DMSO-d6)δH 6.93(1H,d,J8Hz),6.47(2H,s),6.36(0.5H,d,J8Hz),6.32(0.5H,d,J8Hz),4.21(1H,m),3.71(1H,dt,J3.5,9Hz),3.39(1H,m),3.31(0.5H,q,J,3.5Hz),3.27(0.5H,q,J3.5Hz),3.18(0.5H,dd,J3,7.5Hz),3.14(0.5H,dd,J3,7.5Hz),2.18(3H,s),2.12(1H,m),1.74(3H,m),1.60(1H,m),1.46(1H,m),1.21(1.5H,d,J6.5Hz)和1.17(1.5H,d,J6.5Hz). |
13 | (2’R)-[1-[4-(8-氯-1,2,3,3a,4,8b-六氢-7-甲基环戊二烯并[b]-2-丙基胺富马酸盐 | 8-Cl,7-Me(2’R) | 10% | 非对映异构体的混合物;富马酸盐;m.p.160-165℃(dec.);NMR400MHz(DMSO-d6)δH6.93(1H,d,J8Hz),6.47(2H,s),6.36(0.5H,d,J8Hz),6.32(0.5H,d,J8Hz),4.21(1H,m),3.71(1H,dt,J3.5,9Hz),3.39(1H,m),3.31(0.5H,q,J,3.5Hz),3.27(0.5H,q,J3.5Hz),3.18(0.5H,dd,J3,7.5Hz),3.14(0.5H,dd,J3,7.5Hz),2.18(3H,s),2.12(1H,m),1.74(3H,m),1.60(1H,m),1.46(1H,m),1.21(1.5H,d,J6.5Hz)和1.17(1.5H,d,J6.5Hz). |
14 | (2’R)-[1-[4-(8-氯-7-氟-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺富马酸盐 | 8-Cl,7-F(2’R) | 50% | 非对映异构体的混合物;富马酸盐;NMR 400MHz(DMSO-d6);δH6.99(0.5H,t,J9Hz),6.98(0.5H,t,J9Hz),6.46(2H,s),6.40(0.5H,dd,J3.5,8.5Hz),6.36(0.5H,J3.5,8.5Hz),4.26(1H,m),3.76(1H,dt,J4,9Hz),3.38(1H,sextet,J6.5Hz),3.29(1H,q,J7Hz),3.16(0.5H,dd,J6.5,14.5Hz),3.15(0.5H,dd,J,6.5,14Hz),2.04(1H,m),1.83-1.67(3H,m),1.61(1H,m),1.48(1H,m),1.21(1.5H,d,J6.5Hz),1.17(1.5H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]95%(3.03min). |
15 | (2’S)-[1-[4-(8-氯-7-氟-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺富马酸盐 | 8-Cl,7-F(2’S) | 61% | 非对映异构体的混合物;富马酸盐;NMR 400MHz(DMSO-d6);δH6.982(0.5H,t,J 9Hz),6.978(0.5H,t,J9Hz),6.47(2H,s),6.41(0.5H,dd,J4,9Hz),6.36(0.5H,dd,J3.5,9Hz),4.26(1H,dt,J5,9 Hz),3.76(1H,dt,J4,9Hz),3.39(1H,q,J6.5Hz),3.29(1H,q,J7.5Hz),3.17(1H,q,J7.5Hz),2.04(1H,app.tdd,J 3,6.5,9Hz),1.74(3H,m),1.61(1H,sept.,J5.5Hz),1.47(1H,m),1.22(1.5H,d,J6.5Hz),1.18(1.5H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]98%(3.76min). |
16 | (2’R)-1-[4-(6-氯-7-氟-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺异构体I富马酸盐 | 6-Cl,7-F(2’R) | 46% | 异构体1;富马酸盐;NMR 400MHz(DMSO-d6);δH 7.03(1H,dd,J,1,8.5Hz),6.52(1H,d,J6Hz),6.47(2H,s),4.25(1H,sept.,J3Hz),3.69(1H,dt,J2.5,9Hz),3.38(1H,sextet,J6.5Hz),3.31(1H,q,J7Hz),3.13(1H,dd,J6.5,14.5Hz),1.97(1H,m),1.80-1.54(4H,m),1.38(1H,m),1.21(3H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]99%(2.75min). |
17 | (2’R)-1-[4-(6-氯-7-氟-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基)]-2-丙基胺异构体II富马酸盐 | 6-Cl,7-F(2’R) | 44% | 异构体2;富马酸盐;NMR 400MHz(DMSO-d6);δH 7.04(1H,dd,J1,9Hz),6.59(1H,d,J6Hz),6.47(2H,s),4.21(ddd,J2.5,6,8.5Hz),3.70(1H,dt,J2.5,8.5Hz),3.38(1H,ddd,J7,13,19Hz),3.25(1H,dd,J7.5,14Hz),3.18(dd,J6.5,14Hz),1.96(1H,m),1.74(1H,m),1.67(2H,m),1.58(1H,m),1.42(1H,m),1.18(3H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]99%(2.91min). |
18 | (2’S)-1-[4-(7-氟-1,2,3,3a,4,8b-六氢-6-甲氧基-环戊二烯并[b]吲哚基)]-2-丙基胺异构体II 0.7富马酸盐 | 7-F,6-OMe(2’S) | 50% | 异构体1;0.7富马酸盐;NMR 400MHz(DMSO-d6)δH 6.81(1H,d,J10.0Hz),6.41(1.4H,s),6.32(1H,d,J7.0Hz),4.10(1H,ddd,J9.1,6.0,2.5Hz),3.76(3H,s,MeO),3.63(1H,dt,J9.1,2.7Hz),3.32-3.29(1H,m),3.22(1H,dd,J14.0,7.0Hz),3.10(1H,dd,J14.0,6.0Hz),1.94-1.85(1H,m),1.75-1.52(3H,m),1.48-1.38(1H,m),1.15(3H,d,J6.4Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]100%(1.22min). |
19 | (2’S)-1-[4-(7-氟-1,2,3,3a,4,8b-六氢-6-甲氧基-环戊二烯并[b]吲哚基)]-2-丙基胺异构体II0.7富马酸盐 | 7-F,6-OMe(2’S) | 68% | 异构体2;0.7富马酸盐;NMR 400MHz(DMSO-d6)δH 6.83(1H,d,J11.0Hz),6.43(1.4H,s),6.28(1H,d,J7.0Hz),4.18(1H,ddd,J8.7,6.1,2.8Hz),3.78(3H,s,MeO),3.64(1H,dt,J8.8,2.8Hz),3.38-3.23(2H,m),3.12(1H,dd,J13.5,6.6Hz),1.97-1.88(1H,m),1.75-1.54(3H,m),1.43-1.33(1H,m),1.21(3H,d,J6.6Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]98%(1.51min). |
20 | (2’S)-[1-[4-(7-氟-1,2,3,3a,4,8b-六氢-8-甲氧基-环戊二烯并[b]吲哚基)]-2-丙基胺富马酸盐 | 7-F,8-OMe(2’S) | 48% | 非对映异构体的混合物;富马酸盐:NMR 400MHz(DMSO-d6)δH6.87-6.82(1H,m),6.45(2H,s),6.14(0.5H,dd,J8.8,3.1Hz),6.08(0.5H,dd,J8.5,3.6Hz),4.20-4.14(1H,m),3.85(3H,s,MeO),3.79-3.73(1H,m),3.41-3.33(1H,m),3.28-3.21(1H,m),3.14-3.06(1H,m),2.04-1.94(1H,m),1.77-1.54(3H,m),1.52-1.42(1H,m),1.20(1.5H,d,J6.5Hz),1.17(1.5H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]98%(1.60min). |
21 | (2’R)-[1-[4-(1,2,3,3a,4,8b-六氢-6-甲氧基-环戊二烯并[b]吲哚基)]-2-丙基胺富马酸盐 | 6-OMe(2’R) | 32% | 非对映异构体的混合物富马酸盐:NMR 400MHz(DMSO-d6)δH6.83(1H,dd,J2.5,7.5Hz),6.46(2H,s),6.11-6.06(1.5H,m),6.04(0.5H,d,J2Hz),4.19(1H,m),3.68(3H,s),3.63(1H,dt,J2.5,9Hz),3.44-3.11(4H,m),1.93(1H,m),1.73(1H,m),1.63-1.52(3H,m),1.40(1H,m),1.22(1.5H,d,J6.5Hz),1.19(1.5H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20)然后(80∶20)]97%(1.08min). |
22 | (2’S)-[1-[4-(1,2,3,3a,4,8b-六氢-6-甲氧基环戊二烯并[b]吲哚基)]-2-丙基胺富马酸盐 | 6-OMe(2’S) | 32% | 非对映异构体的混合物;富马酸盐:NMR 400MHz(DMSO-d6)δH6.83(1H,dd,J2.5,7.5Hz),6.46(2H,s),6.11-6.06(1.5H,m),6.04(0.5H,d,J2.5Hz),4.20(1H,m),3.68(3H,s),3.63(1H,dt,J1.5,8Hz),3.44-3.11(4H,m),1.93(1H,m),1.72(1H,m),1.68-1.53(3H,m),1.40(1H,m),1.22(1.5H,d,J6.5Hz),1.19(1.5H,d,J6.5Hz);HPLC:[Xterra;2.0ml/min,在4分钟内甲醇-10mM乙酸铵水溶液(50∶50)至(80∶20),然后(80∶20)]98%(1.05min). |
实施例VI:药物组合物
含有下列成分的片剂可以由常规方式生产:
成分 | 每片 |
式I化合物 | 10.0-100.0mg |
乳糖 | 125.0mg |
玉米淀粉 | 75.0mg |
滑石 | 4.0mg |
硬脂酸镁 | 1.0mg |
Claims (48)
1.式I化合物和其药用盐,酯和/或加合化合物:
其中
R1和R2独立地选自氢,烷基,烯基,炔基,和环烷基;
R3是烷基,烯基,炔基,或者环烷基;
R4,R5,R6和R7独立地选自氢,烷基,烯基,炔基,环烷基,卤素,卤代烷基,羟基,芳基,氨基,单-和二烷基氨基,烷氧基,环烷氧基,芳氧基,杂芳氧基,烷硫基,烷基亚硫酰基,烷基磺酰基,硝基,氰基,烷氧基羰基,芳氧基羰基,杂芳氧基羰基,杂芳基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基,和羧基;
环A代表5或者6元部分不饱和的或者饱和的碳环,或者饱和的或者部分不饱和的杂环环,其中环A稠合的二氢吲哚环的两个原子形成饱和的C-C单键。
2.根据权利要求1的化合物,其中R1和R2独立地选自氢,或者烷基。
3.根据权利要求1或2的化合物,其中R1和R2是氢。
4.根据权利要求1至3中任意一项的化合物,其中R3是烷基或者环烷基。
5.根据权利要求1至4中任意一项的化合物,其中R3是烷基。
6.根据权利要求1至5中任意一项的化合物,其中R3是甲基。
7.根据权利要求1至6中任意一项的化合物,其中R4、R6和R7独立地选自氢,卤素,烷基,烷氧基。
8. 根据权利要求1至7中任意一项的化合物,其中R4是氢。
9.根据权利要求1至8中任意一项的化合物,其中R5是氢,卤素,烷氧基,或者杂芳基羰基氨基。
10.根据权利要求1至9中任意一项的化合物,其中R5是氢,氯,甲氧基,吡啶基羰基氨基,或者噻吩基羰基氨基。
11.根据权利要求1至10中任意一项的化合物,其中R6是氢,卤素或者烷氧基。
12.根据权利要求1至11中任意一项的化合物,其中R6是氢或者氟。
13.根据权利要求1至12中任意一项的化合物,其中R7是氢,卤素或者烷氧基。
14.根据权利要求1至13中任意一项的化合物,其中R7是氢,氯或者甲氧基。
15.根据权利要求1至14中任意一项的化合物,其中环A是5-元环。
16.根据权利要求1至15中任意一项的化合物,其中环A是饱和的碳环。
17.根据权利要求16的化合物,其中环A是环戊基。
18.根据权利要求1至15中任意一项的化合物,其中环A是含有选自N,O,和S的杂原子的杂环环。
19.根据权利要求16的化合物,其中环A选自吗啉基,哌啶基,四氢吡喃基,二氢吡喃基,四氢呋喃基和二氢呋喃基,其任选地被烷基或者氧代基取代。
20.根据权利要求1至19中任意一项的化合物,选自:
a)(2′S,3aS,8bS)-1-[4-(6-氯-1,2,3,3a,4,8b-六氢环戊二烯并[b]吲哚基]-2-丙基胺,
b)(2′S)-1-[4-(7-氟-6-1,2,3,3 a,4,8b-六氢-6-甲氧基环戊二烯并[b]吲哚基)]-2-丙基胺,和
c)(2′S)-1-[4-(7-氟-1,2,3,3a,4,8b-六氢环-8-甲氧基戊二烯并[b]吲哚基)]-2-丙基胺。
21.药物组合物,包含如权利要求1至20中任意一项定义的化合物和药用赋形剂。
22.用于治疗的根据权利要求1至20中任意一项的式(I)化合物。
23.权利要求1至20的式(I)化合物在制备用于治疗中枢神经***疾病;中枢神经***损伤;心血管疾病;胃肠道疾病;尿崩症,和睡眠呼吸暂停的药物中的用途。
24.根据权利要求23的用途,其中中枢神经***疾病选自抑郁,非典型抑郁,双相型障碍,焦虑病,强迫观念与行为疾病,社会恐怖症或恐慌症,睡眠失调,性机能障碍,精神病,精神***症,偏头痛和其他与头痛或其他疼痛有关的病症,升高的颅内压力,癫痫,人格障碍,与年龄有关的行为疾病,与痴呆有关的行为疾病,器质性精神障碍,儿童期精神障碍,攻击力,与年龄有关的记忆障碍,慢性疲乏综合症,药物和酒精上癮,肥胖,易饿病,神经性厌食或经前期紧张。
25.根据权利要求24的用途,其中中枢神经***损伤是外伤,中风,神经变性疾病或毒性或传染性CNS疾病。
26.根据权利要求25的用途,其中毒性或传染性CNS疾病是脑炎或髓膜炎。
27.根据权利要求24的用途,其中心血管疾病是血栓形成。
28.根据权利要求24的用途,其中胃肠道病症是胃肠道运动机能障碍。
29.权利要求1至20中任意一项的式I化合物在制备用于治疗肥胖症的药物中的用途。
30.权利要求1至20中任意一项的式I化合物在制备用于治疗糖尿病,I型糖尿病,II型糖尿病,胰腺疾病继发性的糖尿病,与使用类固醇相关的糖尿病,III型糖尿病,高血糖症,糖尿病并发症,和胰岛素抗性的药物中的用途。
31.权利要求1至20中任意一项的式I化合物在制备用于治疗II型糖尿病的药物中的用途。
32.根据权利要求24-31中任意一项的用途,其中所述治疗是预防性治疗。
33.治疗权利要求23至31所给出的任意疾病的方法,包括对需要这种治疗的患者施用有效量的如权利要求1至20中任意一项定义的式(I)化合物。
34.权利要求33的治疗方法,其中所述的疾病是肥胖症。
35.权利要求33的治疗方法,其中所述的疾病是糖尿病,I型糖尿病,II型糖尿病,胰腺疾病继发性的糖尿病,与使用类固醇相关的糖尿病,III型糖尿病,高血糖症,糖尿病并发症,和胰岛素抗性。
36.权利要求33的治疗方法,其中所述的疾病是II型糖尿病。
37.权利要求33的治疗方法,其中所述的治疗方法是预防性治疗。
38.对需要这种治疗的人治疗肥胖症的方法,包括对人施用治疗有效量的权利要求1至20中任意一项的化合物和治疗有效量的脂肪酶抑制剂。
39.权利要求38的治疗方法,其中所述的脂肪酶抑制剂是orlistat。
40.根据权利要求33至39中任意一项的方法,用于同时,分开或顺序给药。
41.根据权利要求1至20中任意一项的化合物在制备用于治疗或预防肥胖症的药物中的用途,该患者也接受脂肪酶抑制剂的治疗。
42.根据权利要求1至20中任意一项的化合物在制备用于治疗或预防糖尿病,I型糖尿病,II型糖尿病,胰腺疾病继发性的糖尿病,与使用类固醇相关的糖尿病,III型糖尿病,高血糖症,糖尿病并发症,和胰岛素抗性的药物中的用途,该患者也接受脂肪酶抑制剂的治疗。
43.根据权利要求1至20中任意一项的化合物在制备用于治疗或预防II型糖尿病的药物中的用途,该患者也接受脂肪酶抑制剂的治疗。
44.根据权利要求41至43中任意一项的用途,其中脂肪酶抑制剂是orlistat。
46.权利要求45的方法所制备的化合物。
47.制备权利要求21的组合物的方法,包括如权利要求1至20中任意一项定义的式(I)化合物与药用载体或赋形剂混合。
48.如上文所述的本发明。
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