CN1681806A - 酰氧基吡咯烷衍生物,其制备及其在治疗学上的应用 - Google Patents
酰氧基吡咯烷衍生物,其制备及其在治疗学上的应用 Download PDFInfo
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- CN1681806A CN1681806A CNA038218178A CN03821817A CN1681806A CN 1681806 A CN1681806 A CN 1681806A CN A038218178 A CNA038218178 A CN A038218178A CN 03821817 A CN03821817 A CN 03821817A CN 1681806 A CN1681806 A CN 1681806A
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- phenyl
- indol
- dimethoxyphenyl
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Abstract
本发明涉及通式(I)的酰氧基吡咯烷衍生物:式中:-R1是氢原子、(C1-C6)烷基、(C3-C6)环烷基、-CH2CH2COOH基团或-NR2R3基团;-R2和R3分别是氢原子或(C1-C6)烷基。本发明还涉及所述衍生物的制备方法及其治疗学上的应用。
Description
技术领域
本发明涉及酰氧基吡咯烷衍生物、其制备及其在治疗学上的应用。
本发明化合物对精氨酸加压素(AVP)V1b受体,或V1b和V1a两受体,均具有亲和力和选择性。
背景技术
AVP是一种激素,已知具有抑制尿分泌和动脉压调节作用。它刺激几种类型的受体:V1(V1a,V1b)和V2。这些受体位于肝脏、血管(冠状、肾、脑)、血小板、肾脏、子宫、肾上腺、胰腺、中枢神经系统和垂体。这样AVP作用于心血管、肝、胰以及起到抗利尿和抗血小板凝集的作用,并且作用于中枢神经和周围神经系统及子宫体。
各种受体的部位在下列文献中已有描述:S.JARD et al.,Vasopressin andoxytocin receptors:an overview,in Progress in Endocrinology.H.IMURA and K.SHIZURNE ed.,Experta Medica Amsterdam,1988,1183-1188,在以下文献也有报道:J.Lab.Clin.Med.,1989,
114(6),617-632 and Pharmacol.Rev.,1991,
43(1),73-108。
更特别的是,AVP的V1a受体位于许多周围器官和脑中。特别在大鼠和人,这些受体已被克隆,它们调节AVP的多数已知的作用:血小板凝集;子宫收缩;血管收缩;醛固酮分泌、皮质醇分泌、CRF(促肾上腺皮质激素释放因子)分泌和促肾上腺皮质激素(ACTH)分泌;肝糖原分解、细胞增殖和AVP的主要中枢作用(降低体温、记忆等)。
V1b受体最初是在多种动物(大鼠、猪、牛、羊等)包括人的腺垂体中发现的(S.JARD et al.,Mol.Pharmacol.,1986,
30,171-177;Y.ARSENIJEVIC etal.,J.Endocrinol.,1994,
141,383-391;J.SCHWARTZ et al.,Endocrinology,1991,
129(2),1107-1109;Y.DE KEYSER et al.,FEBS Letters,1994,
356,215-220),在腺垂体中,这些受体藉AVP刺激促肾上腺皮质激素的释放并增强了CRF对释放ACTH的作用(G.E.GILLIES et al.,Nature,1982,
299,355)。在下丘脑,V1b受体还诱导直接释放CRF(Neuroendocrinology,1994,
60,503-508)并在这些方面与各种紧张状况有关。
这些V1b受体已在大鼠、人和小鼠进行了克隆(Y.DE KEYSER,FEBS,Letters,1994,
356,215-220;T.SUGIMOTO et al.,J.Biol.Chem.,1994,
269(43),27088-27092;M.SAITO et al.,Biochem.Biophys.Res.Commun.,1995,
212(3),751-757;S.J.LOLAIT et al.,Neurobiology,1996,
92,6783-6787;M.A.VENTURE et al.,Journal of Molecular Endocrinology,1999,
22,251-260),并且各种研究(原位杂交、PCR(聚合酶链反应)等)表明这些受体普遍分布在不同的中枢组织(特别是脑、下丘脑、垂体前叶)和周围组织(肾脏、胰腺、肾上腺、心脏、肺、肠、胃、肝脏、肠系膜、膀胱、胸腺、脾、子宫、视网膜、甲状腺等)以及一些肿瘤(垂体、肺等肿瘤)中,这提示这些受体具有广泛的生物和/或病理作用并与许多疾病有潜在的关联性。
举例,对于大鼠研究显示,AVP经由V1b受体来调节内分泌胰腺,它通过刺激胰岛素和胰高血糖素的分泌(B.LEE et al.,Am.J.Physiol.269(Endocrinal.Metab.32):E1095-E1100,1995)或在肾上腺髓质产生儿茶酚胺来进行,而肾上腺髓质是局部合成AVP的部位(E.GRAZZINI et al.,Endocrinology,1996,
137(a),3906-3914)。因而,在肾上腺髓质中,AVP经由这些受体,在某些类型的肾上腺嗜铬细胞瘤中会起重要的作用。肾上腺嗜铬细胞瘤分泌AVP,结果导致儿茶酚胺大量产生,引起耐受抗血管紧张素II受体拮抗剂和血管紧张素转换酶抑制剂的高血压。肾上腺皮质也富含涉及产生糖皮质激素和盐皮质激素(醛固酮和皮质醇)的V1a受体。AVP(循环的或局部合成的)经由这些受体,可诱导产生醛固酮,其效率与血管紧张素II相当(G.GUILLON et al.,Endocrinology,1995,
136(3),1285-1295)。皮质醇是产生应激激素ACTH的强效调节剂。
最近研究也显示,肾上腺通过激活髓质细胞携带的V1b受体和/或V1a受体,能够直接释放CRF和/或ACTH(G.MAZZOCCHI et al.,Peptide,1997,18(2),191-195;E.GRAZZINI et al.,J.Clin.Endocrinal.Metab.,1999,
84(6),2195-2203)。
V1b受体也被认为是肿瘤的标志物。例如,分泌ACTH的肿瘤,即某些垂体肿瘤、某些支气管癌(小细胞肺癌,SCLC)、胰腺癌、肾上腺癌和甲状腺癌,一些病例中诱发库欣氏综合征(J.BERTHERAT et al.,Eur.J.Endocnnol.,1996,
135,173;G.A.WITTERT et al.,Lancet,1990,
335,991-994;G.DICKSTEIN et al.,J.Clin.Endocrinol.Metab.,1996,
81(8),2934-2941),均过度表达了V1b受体。至于V1a受体,它们是小细胞肺癌更为特异的标志物(P.J.WOLL et al.,Biochem.Biophys.Res.Commun.,1989,
164(1),66-73)。这样,本发明化合物在这些肿瘤的增殖和检测方面很明显可作为诊断工具并提供了一种新颖的治疗方法,甚至在早期(放射标记;SPECT,单光子发射计算机断层扫描;PET扫描,正电子发射计算机断层扫描)也可应用。
胃和肠有丰富的V1b受体信使,提示AVP经由这些受体参与胃肠激素如缩胆囊素、胃泌激素或分泌素的释放(T.SUGIMOTO et al.,Molecular cloningand functional expression of V1b receptor gene,in Neurohypophysis:RecentProgress of Vasopressin and Oxytocin Research;T.SAITO,K.KUROKAWA andS.YOSHIDA ed.,Elvesier Science,1995,409-413)。
国际专利申请书WO 01/55130描述了一族化合物。它们对精氨酸加压素V1b受体,或V1b和V1a两受体,均显示亲和力和选择性。
更特别的是,已报道了(WO 01/55130;J.Pharmacol.Exp.Ther,2002,300(3),1122-1130)一种选择性V1b受体拮抗剂,(2S,4R)-1-[5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-4-羟基-N,N-二甲基-2-吡咯烷甲酰胺,左旋异构体(下文称作化合物A)。
现在已发现新的化合物酰氧基吡咯烷衍生物,对精氨酸加压素V1b受体,或V1b和V1a两受体,均显示亲和性和选择性。
发明内容
本发明的主题是通式(I)化合物:
式中:
-R1是氢原子、(C1-C6)烷基、(C3-C6)环烷基、-CH2CH2COOH基团或-NR2R3基团;
-R2和R3分别是氢原子或(C1-C6)烷基。
通式(I)化合物包含三个不对称碳原子;带有-CON(CH3)2取代基的碳原子具有(S)构型,带有-OCOR1取代基的碳原子具有(R)构型,在吲哚-2-酮3位的碳原子具有(R)构型。
通式(I)化合物可以碱的形式存在,或与有机碱或无机碱的加成盐形式存在,比如碱金属或碱土金属的盐,或有机胺或无机胺的盐。这样的加成盐是本发明的一部分。
这些盐可用药用碱来很好地制备,但用来例如纯化或分离通式(I)化合物的其他碱生成的盐,也是本发明的组成部分。
通式(I)化合物可以水合物或溶剂化物形式存在,即该化合物与一个或多个水分子或一个溶剂分子缔合或结合。这些水合物和溶剂化物也是本发明的组成部分。
术语“烷基”是指有一至六个碳原子的直链或支链的烷基,如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基或异己基。
术语“环烷基”是指有三至六个碳原子组成的环烷基,如环丙基、环丁基、环戊基或环己基。
作为本发明主题的通式(I)化合物中,优选提到的化合物,其定义如下:
-R1是氢原子、甲基、乙基、异丙基、环己基、-CH2CH2COOH基团、氨基或二甲氨基;
以碱的形式或与有机碱或无机碱的加成盐形式,也可以是水合物和溶剂化物形式。
在本发明主题的通式(I)化合物中,特别提到下列化合物:
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基乙酸酯;
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基丙酸酯;
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基甲酸酯;
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基环己烷羧酸酯;
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基2-甲基丙酸酯;
4-[[(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基]氧]-4-氧代丁酸;
(2S,4R)-4-[(氨基羰基)氧]-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-N,N-二甲基-2-吡咯烷甲酰胺;
(2S,4R)-4-[[(二甲氨基)羰基]氧]-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-N,N-二甲基-2-吡咯烷甲酰胺;
以碱的形式或与有机碱或无机碱的加成盐形式,也可以是水合物和溶剂化物形式。
另一方面,本发明的主题是一种通式(I)化合物的制备方法,其特征在于:
(2S,4R)-1-[5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-4-羟基-N,N-二甲基-2-吡咯烷甲酰胺,左旋异构体,
分子式为:
与下列通式(II)的酸的官能团衍生物反应:
式中R1同通式(I)化合物中所定义的。
通式(I)化合物可用碱任选转化成其加成盐中的一种。
酰基氯、酸酐或游离酸本身可用作为通式(II)的酸的官能团衍生物。
当用酰基氯时,反应在某种溶剂中进行,比如氯化溶剂,像二氯甲烷、二氯乙烷或氯仿,比如醚,像四氢呋喃、二氧杂环己烷,或酰胺,像N,N-二甲基甲酰胺,反应在碱如三乙胺、N-甲基吗啉、吡啶、4-二甲氨基吡啶或N,N-二异丙基乙胺存在时进行,温度控制在-60℃至室温。
当用酸酐时,反应可在有碱或无碱存在情况下进行,此碱如吡啶或4-(二甲氨基)吡啶,使用或不使用有机溶剂,温度介于室温和反应介质回流温度之间。当使用溶剂时,该溶剂可选自氯化溶剂如二氯甲烷,和选自芳香溶剂如甲苯。
R1是-CH2CH2COOH基团的通式(I)化合物也能由化合物A与丁二酸酐反应制得,反应是在碱如吡啶存在下,使用溶剂或不使用溶剂,温度在室温和反应介质回流温度之间进行。
当用游离酸时,反应需使用缩合剂比如碳化二亚胺,例如1,3-二环己基碳化二亚胺或1,3-二异丙基碳化二亚胺,或者使用缩合剂比如咪唑,例如1,1’草酰二咪唑或N,N’-羰基-二咪唑。反应在存在或不存在碱比如三乙胺、N,N-二异丙基乙胺、吡啶、4-二甲氨基-吡啶、N-甲基吗啉的情况下进行,需要的溶剂比如氯化溶剂,例如二氯甲烷、二氯乙烷或氯仿,又比如酯,例如乙酸乙酯,还比如醚,例如二乙醚、二异丙醚、四氢呋喃或二氧杂环己烷,还比如腈,例如乙腈,还比如酰胺,例如N,N-二甲基甲酰胺,或芳香化合物,例如甲苯或二甲苯,温度在-20~80℃之间。
当用游离酸时,反应也可以在以下条件进行,存在酸催化剂比如无机酸,例如盐酸、氢溴酸、硫酸,比如有机酸,例如乙酸、甲酸、草酸或对甲苯磺酸,或比如路易斯酸,例如三氯化硼、三氟化硼或三溴化硼。该反应需在溶剂中进行,比如氯化溶剂,例如二氯甲烷、二氯乙烷或氯仿,比如醚,例如二乙醚、二异丙醚、四氢呋喃或二氧杂环己烷,比如酮,例如丙酮、甲乙酮或甲基异丁基酮,比如腈,例如乙腈,或比如酰胺,例如N,N-二甲基甲酰胺,温度在0℃至溶剂的回流温度之间。
R1是氢原子的通式(I)化合物也能由化合物A与甲酸反应制得,在乙酸酐和碱比如吡啶存在下,温度在0℃至室温之间。
依照另一种方法,当R1是-NR2R3基团时:
a)化合物A在碱存在下与氯甲酸苯酯反应得到化合物B,其分子式为:
b)化合物B与通式(III)化合物反应,通式(III)为:
HNR2R3 (III)
式中R2和R3定义同通式(I)化合物,结果得到R1=NR2R3的通式(I)化合物。
在a)步,化合物A与氯甲酸苯酯反应,反应在碱比如吡啶或三乙胺存在下,溶剂比如二氯甲烷或没有溶剂存在下进行,反应温度在0℃至100℃之间。
在b)步,化合物B与通式(III)化合物的反应,在二氯甲烷或四氢呋喃或这些溶剂的混合溶剂中进行,温度在-60℃至溶剂的回流温度之间。
这样得到的通式(I)化合物随后用常规方法,例如结晶或层析法,从反应介质中分离和纯化。
化合物A是根据专利申请书WO 01/55130描述的方法来制备的。
通式(II)的酸的官能团衍生物可通过商业途径获得,或可用已知方法制备。
另一方面,本发明的主题是化合物B。该化合物用作R1=NR2R3的通式(I)化合物的合成中间体。
下面实施例叙述了本发明一些化合物的制备。这些实施例仅用来说明本发明,而本发明不受这些实施例的限制。实施例中的化合物编号指的就是下表指出的号,该表说明本发明一些化合物的化学结构和物理性质。
具体实施方式
在实施例中,用到以下缩写:
EtOAc:乙酸乙酯
ether:二乙醚
iso ether:二异丙醚
DCM:二氯甲烷
M.p.:熔点
AT:环境温度,室温
B.p.:沸点
HPLC:高效液相色谱。
质子核磁共振(1H NMR)谱是以二甲亚砜-d6(DMSO-d6)的峰为对照,在二甲亚砜-d6中记录频率为200MHz的谱。化学位移δ表达为百万分之几(ppm)。观察到的信号表示:s为单峰;bs为宽单峰;d为双峰;dd为双二峰;t为三峰;q为四重峰;up为未解析峰;mt为多重峰。
NMR谱验证化合物的结构。
实施例1:化合物1号
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基乙酸酯。
(I):R1=-CH3。
将30g(2S,4R)-1-[5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-4-羟基-N,N-二甲基-2-吡咯烷基甲酰胺,左旋异构体(化合物A),1.45g 4-(二甲氨基)吡啶和300ml乙酸酐混和,回流2小时30分钟。反应混合物冷至室温后,加入170ml无水乙醇。混合物减压浓缩,残留物用1000ml EtOAc提取,有机相用670ml饱和NH4Cl水溶液洗涤,再用NaHCO3水溶液洗二次,减压蒸去溶剂。残留物置于190ml 2-丙醇中,混合物回流,然后冷至室温。混合物减压浓缩,残留物置于二异丙醚中,然后放置析出结晶。结晶产物离心滤出,用二异丙醚洗涤,然后干燥。得到30.28g预期产物,M.p.=194-195℃,α25 D=-133.9°(c=0.5;乙腈)。
1H NMR:d6-DMSO:δ(ppm):1.7~2.8:up:13H;3.3:bs:3H;3.7:s:3H;3.9:s:3H;4.6:mt:1H;5.2:mt:1H;6.6~8.2:up:10H。
实施例2:化合物2号
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基丙酸酯。
(I):R1=-CH2CH3。
5g化合物A,0.24ml 4-(二甲氨基)吡啶和50ml丙酸酐混和,回流2小时30分钟。反应混合物冷至室温后,加入28ml无水乙醇。混合物减压浓缩,残留物用60ml EtOAc提取,有机相用100ml饱和NaCl水溶液洗涤,再用110ml 10%NaHCO3水溶液洗三次,减压蒸去溶剂。残留物置于二异丙醚中,然后将生成的沉淀物离心滤出。得到4.31g预期产物,α25 D=-107°(c=0.5;乙腈)。
1H NMR:d6-DMSO:δ(ppm):0.95:t:2H;1.6~2.7:up:12H;3.3:bs:3H;3.6:s:3H;3.8:s:3H;4.5:mt:1H;5.15 mt:1H;6.6~8.2:up:11H。
实施例3:化合物3号
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基甲酸酯
(I):R1=H。
将4ml甲酸冷至0℃,滴加1.6ml乙酸酐,混合物在低于20℃下搅拌4小时。反应混合物在冰浴中冷却,将0.63g化合物A溶于7ml吡啶的溶液在5分钟内加入上述反应混合物中,混合物先行干燥,再在冰浴中冷却,然后在室温中搅拌48小时。加水至反应混合物中,用EtOAc提取,有机相用水再用饱和NaCl溶液洗涤,然后用Na2SO4干燥,减压蒸去溶剂。残留物用硅胶进行层析,用DCM/EtOAc混合物(70/30;v/v)洗脱。得到0.27g预期产物。在DCM/二异丙醚(80/20;v/v)中结晶,得到预期产物为含0.5mol二异丙醚的粉末,M.p.=127℃。α25 D=-173°(c=0.11;氯仿)
实施例4:化合物4号
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基环己胺羧酸酯
将1.5g化合物A,0.630ml环己烷碳酰氯,0.62g N,N-二异丙基乙胺和少量4-(二甲氨基)吡啶晶体,置于20ml DCM中,在室温搅拌8天。混合物减压浓缩,残留物置于EtOAc/水混合物中,加固体NaHCO3碱化,并使其沉降分离,有机相用饱和K2CO3溶液洗二次再用饱和NaCl溶液洗涤,然后用Na2SO4干燥,减压蒸去溶剂。残留物用硅胶进行层析,用EtOAc/DCM混合液(80/20;v/v)洗脱。得到的产物置于5ml二异丙醚中,室温搅拌48小时,生成的沉淀物经离心滤出,得到1.0g预期产物,M.p.=197-198℃。离心液减压浓缩,得到的固体用DCM/二异丙醚混合液进行结晶。进而得到0.9g结晶形的预期产物,M.p.=197-200℃。α25 D=-144°(c=0.18;氯仿)。
实施例5:化合物5号
(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基2-甲基丙酸酯。
(I):R1=-CH(CH3)2。
将1.5g化合物A,0.75ml异丁酰氯和1.22g N,N-二异丙基乙胺,置于20mlDCM中,室温搅拌36小时。混合物减压浓缩,残留物置于水中,加固体NaHCO3碱化,用EtOAc提取,有机相用水洗涤,然后用Na2SO4干燥,减压蒸去溶剂。残留物用硅胶进行层析,用DCM/EtOAc混合液(70/30;v/v)洗脱。用EtOAc/二异丙醚混合液结晶,得到1.17g预期产物,M.p.=183-185℃。α25 D=-172°(c=0.15;氯仿)。
实施例6:化合物6号
4-[[(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基]氧]-4-氧代丁酸。
(I):R1=-CH2CH2COOH。
将0.2g化合物A,0.2g丁二酸酐和3ml吡啶混和,于50℃加热5分钟至溶解,在25℃搅拌20小时。混合物减压浓缩,残留物置于2N HCl溶液中,用二乙醚提取并使其沉降分离。有机相中析出的沉淀用离心滤出,并用二乙醚洗涤。得到0.2g预期的结晶形产物,M.p.=225-228℃。α25 D=-252°(c=0.25;氯仿)。
1H NMR:d6-DMSO:δ(ppm):1.6~1.9:up:2H;2.2~2.6:up:12H;3.0~3.4:bs:3H;3.5~3.7:bs:3H;3.7~3.9:bs:3H;4.4~4.6:up:1H;5.1~5.3:up:1H;6.6~7.0:up:5H;7.26:t:1H;7.39:dd:1H;7.6~7.8:up:2H;7.94:d:1H;12.0:bs:1H。
实施例7:化合物7号
(2S,4R)-4-[(氨基羰基)氧]-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-N,N-二甲基-2-吡咯烷甲酰胺
(I):R1=-NH2。
(A)(2S,4R)-4-[(苯氧基羰基)氧]-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-N,N-二甲基-2-吡咯烷甲酰胺
在25℃,将4ml苯氯甲酸苯酯加至1.6g化合物A溶解于20ml吡啶的溶液中,混合物在25℃搅拌20小时。反应混合物减压浓缩,残留物置于1N HCl溶液中,用EtOAc提取,有机相用Na2SO4干燥,减压蒸去溶剂。滴入二异丙醚,得到1.23g预期产物,M.p.=115-125℃。
(B)(2S,4R)-4-[(氨基羰基)氧]-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-N,N-二甲基-2-吡咯烷甲酰胺
将上步得到的产物0.7g溶于15mlTHF中,冷至-60℃,喷射通入4gNH3气,混合物搅拌5小时,让温度回复并保持在0℃。反应混和物减压浓缩,残留物用硅胶进行层析,先用DCM、再用EtOAc洗脱。滴入二异丙醚,得到0.37g预期产物,M.p.=155-165℃。α25 D=-184°(c=0.25;氯仿)
实施例8:化合物8号
(2S,4R)-4-[[(二甲氨基)羰基]氧]-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-N,N-二甲基-2-吡咯烷甲酰胺。
(I):R1=-N(CH3)2。
将0.35g实施例7中的A步产物与10ml 2M二甲胺THF溶液混和,在25℃搅拌20小时。反应混和物减压浓缩,残留物与二异丙醚在热状态下研磨,生成的沉淀物用离心滤出。得到0.18g预期产物,M.p.=138-140℃。α25 D=-152°(c=0.25;氯仿)
下表I说明本发明一些实施例化合物的化学结构与物理性质
表I
6 | -CH2CH2COOH | 225-228二乙醚-252°(c=0.25) |
7 | -NH2 | 155-165二异丙醚-184°(c=0.25) |
8 | -N(CH3)2 | 138~140二异丙醚-152°(c=0.25) |
本发明化合物是生化研究的对象。
本发明的通式(I)化合物对精氨酸加压素的V1b受体亲和力,可用Y.DEKEYSER et al.,Febs Letters,1994,
356,215-220报道的方法进行体外测定。这个方法是在体外,研究用氚化的精氨酸加压素([3H]-AVP)置换携带大鼠或人V1b受体的细胞或腺垂体膜制剂中的V1b受体。本发明化合物对氚化的精氨酸加压素的结合的50%抑制浓度(IC50)一般小于5.0×10-9M。例如实施例1,化合物对人的V1b受体IC50为3.4×10-9M。
本发明通式(I)化合物对精氨酸加压素的V1a受体的亲和力,可用M.THIBONNIER et al.,J.Biol.Chem.,1994,
269,3304-3310报道的方法进行体外测定。这个方法是在体外,用氚化的精氨酸加压素([3H]-AVP)置换携带大鼠或人V1a受体的细胞或腺垂体膜制剂中的V1a受体。通式(I)的一些化合物也显示对精氨酸加压素V1a受体的亲和力,IC50在10-8M级,实施例1化合物对人V1a受体的IC50为8.4×10-8M。
前述化合物A对人的V1b受体IC50为1.0×10-8M,对人的V1a受体的IC50为3.1×10-7M。
也研究了本发明的通式(I)化合物对加压素的V2受体的亲和力(根据M.Birnbaumer et al.,Nature(Lond),1992,357,333-335描述的方法)。所研究的化合物对V2受体很少有或完全没有亲和力。
本发明化合物也因此可用来制备医药产品,特别是那些打算用来预防或治疗与精氨酸加压素和/或其V1b受体,或其V1b和V1a两受体有关的任何病症的医药产品。
这样,从另一方面来说,本发明的主题是医药产品,该产品含有通式(I)化合物,或其与药用碱的加成盐,或其他通式(I)化合物的溶剂化物或水合物。
这样,本发明化合物可供人用或动物用,用来治疗或预防各种加压素依赖性疾病,比如高血压、肺动脉高血压、心功能不全、心肌梗塞形成或冠状血管痉挛,特别在吸烟者中的雷诺病和不稳定绞痛与经皮冠状动脉内成形术(PTCA)、心肌缺血或止血障碍的心血管疾病;中枢神经系统疾病,比如偏头痛、脑血管痉挛、脑出血、脑水肿、抑郁症、焦虑、紧张、情绪紊乱、强迫症、急性焦虑发作、精神病或记忆障碍;肾脏系统疾病,比如肾脏血管痉挛、肾皮质坏死或肾性尿崩症;胃系统疾病,比如胃痉挛、肝硬化、溃疡或呕吐症状,例如,恶心包括由化疗或晕动症引起的恶心;或糖尿病肾病。本发明化合物也可用于性行为障碍的治疗;对于女性,本发明化合物可用于治疗月经紊乱(dismenorrhoea)或早产。本发明化合物也可用于治疗小细胞肺癌、血钠过少的脑病、肺综合症、Menière’s病;青光眼、白内障;肥胖;II型糖尿病;动脉硬化;库欣氏综合症(Cushing′s syndrome);抗胰岛素;或血甘油三酯过多;或术后治疗,特别腹部手术后的治疗。
本发明化合物也用于治疗或预防任何由紧张引起的病理状况,比如疲劳及其综合症、ACTH-依赖失调、心脏疾病、疼痛、在胃排空、粪便排泄(结肠炎、肠道易激综合征或克隆氏症(Crohn′s Disease))或酸分泌方面有改变、高血糖症、免疫抑制、炎症反应(类风湿性关节炎和骨关节炎)、多重感染、癌症、哮喘、牛皮癣、过敏症和各种神经精神异常,比如神经性厌食症、暴食症、情感性疾病、抑郁症、焦虑症、睡眠紊乱症、恐慌症、恐惧症、强迫症、痛觉障碍(纤维肌痛)、神经退化性疾病(阿耳茨海默氏病、帕金森氏症或亨廷顿舞蹈症),毒瘾,出血性应激,肌肉痉挛或低血糖症。本发明化合物还可用于治疗或预防慢性紧张性症状,比如免疫抑制、生育力问题或下丘脑-垂体-肾上腺轴功能障碍。
本发明化合物也用作中枢神经兴奋剂,可增加对环境的机敏性或情感反应性,以及更好的适应力。
另一方面,本发明涉及药物组合物,他们含有本发明化合物作为活性成份。这些药物组合物包含有效剂量的至少一种本发明化合物,或其可药用盐、溶剂化物或水合物,且包含至少一种药用赋形剂。
根据药物的形式和给药方法,赋形剂从已知的常用赋形剂中进行选择。
在供口服,舌下,皮下,肌内,静脉,表面,局部,气管内,鼻腔内,经皮或直肠途径给药的本发明药物组合物中,上述通式(I),或其可能的盐、溶剂物或水合物的活性成份,可以与常规药用赋形剂一起,以单剂量给药形式供兽用和人用,用于预防或治疗上述的失调或疾病。
适宜的单剂量给药形式包括口服给药形式,比如片剂、软或硬胶囊、粉剂、颗粒剂和口服溶液或混悬剂,舌下、口腔、气管内、眼内或鼻腔内给药形式,吸入给药形式,局部表面、经皮、皮下、肌内或静脉给药形式,直肠和植入给药形式。对于局部表面给药,本发明化合物可以用其霜剂、凝胶剂、软膏剂或洗剂。
举例说明,本发明化合物的单剂量给药形式,以片剂为例,可能含有以下组分:
本发明化合物 50.0mg
甘露醇 223.75mg
交联羧甲基纤维素钠 6.0mg
玉米淀粉 15.0mg
羟丙甲基纤维素 2.25mg
硬脂酸镁 3.0mg
口服给药,活性成份日剂量可达0.01~100mg/kg,分一次或几次服用,日剂量0.02~50mg/kg更好。
可以有适宜使用更高或更低剂量的特殊情况;这样的剂量没有脱离本发明的范围。常规的做法是,每个病人的合适剂量由医生根据给药方式、病人体重和用药后反应来决定。
另一方面,本发明也涉及治疗上述病症的方法,包含将本发明化合物、或其可药用的盐或水合物或溶剂化物中的一种的有效剂量给予病人。
Claims (9)
2.根据权利要求1所述的通式(I)化合物,其特征在于,R1是氢原子、甲基、乙基、异丙基、环己基、-CH2CH2COOH基团、氨基或二甲氨基;
以碱的形式或有机碱或无机碱的加成盐的形式,也可以是水合物或溶剂化物的形式。
3.一种化合物选自:
-(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基乙酸酯;
-(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基丙酸酯;
-(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基甲酸酯;
-(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基环己烷羧酸酯;
-(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基2-甲基丙酸酯;
-4-[[(3R,5S)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-5-[(二甲氨基)羰基]-3-吡咯烷基]氧]-4-氧代丁酸;
-(2S,4R)-4-[(氨基羰基)氧]-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-N,N-二甲基-2-吡咯烷甲酰胺;
-(2S,4R)-4-[[(二甲氨基)羰基]氧]-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-N,N-二甲基-2-吡咯烷甲酰胺;
以碱的形式或与有机碱或无机碱的加成盐的形式,也可以是水合物或溶剂化物的形式。
5.根据权利要求1所述的R1为-NR2R3的通式(I)化合物的制备方法,其特征在于:
a)权利要求4所述的化合物A在碱存在下,与氯甲酸苯酯反应,得到化合物B,其分子式为:
b)化合物B与下列通式(III)化合物反应:
HNR2R3 (III)
式中,R2和R3定义同权利要求1所述通式(I)化合物相同,得到R1=NR2R3的通式(I)化合物。
6.下式通式化合物:
7.医药产品,其特征在于,它含有权利要求1到3任何一项所述的通式(1)化合物,或该化合物与药用碱生成的加成盐,或通式(I)化合物的水合物或溶剂化物。
8.药物组合物,其特征在于,它含有权利要求1到3中任何一项所述的通式(1)化合物,或该化合物的可药用盐、水合物或溶剂化物,并且还含有至少一种药用赋形剂。
9.根据权利要求1至3中任一项所述的通式(I)化合物的应用,其特征在于,用来制备用于治疗心血管疾病、紧张、焦虑、抑郁、强迫症、惊恐症发作、肾脏系统疾病、胃系统疾病、小细胞肺癌、肥胖症、I型和II型糖尿病、胰岛素抗性、高甘油三酯血症、动脉硬化、库欣氏综合症、月经紊乱(dismenorrhoea)和早产的医药产品。
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FR0209242A FR2842527B1 (fr) | 2002-07-19 | 2002-07-19 | Derives d'acyloxypyrolidine, leur preparation et leur application en therapeutique |
FR02/09242 | 2002-07-19 |
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US7528124B2 (en) | 2003-08-28 | 2009-05-05 | Taisho Pharmaceutical Co., Ltd. | 1,3-dihydro-2H-indol-2-one derivative |
TW200643015A (en) | 2005-03-11 | 2006-12-16 | Akzo Nobel Nv | 2-(4-oxo-4H-quinazolin-3-yl)acetamide derivatives |
DE102005015957A1 (de) * | 2005-03-31 | 2006-10-05 | Abbott Gmbh & Co. Kg | Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung |
MX2007015427A (es) | 2005-06-07 | 2008-04-16 | Pharmacopeia Inc | Inhibidores de azinona y diazinona v3 para depresion y trastornos de estres. |
JP5256202B2 (ja) | 2006-09-11 | 2013-08-07 | エム・エス・ディー・オス・ベー・フェー | キナゾリノンおよびイソキノリノンアセトアミド誘導体 |
CN103864658B (zh) * | 2014-03-06 | 2016-06-15 | 南京工业大学 | 氮杂环丁酮衍生物及其制备方法与应用 |
CN104447489B (zh) * | 2014-12-29 | 2017-01-11 | 南京工业大学 | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 |
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