CN1299348A - 用于治疗疾病的sPLA2抑制剂化合物 - Google Patents
用于治疗疾病的sPLA2抑制剂化合物 Download PDFInfo
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- CN1299348A CN1299348A CN99805675A CN99805675A CN1299348A CN 1299348 A CN1299348 A CN 1299348A CN 99805675 A CN99805675 A CN 99805675A CN 99805675 A CN99805675 A CN 99805675A CN 1299348 A CN1299348 A CN 1299348A
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
本发明公开了治疗炎症性肠疾病的方法,该方法包括,向需要所述治疗的患者施用治疗有效量的sPLA2抑制剂,例如1H-吲哚-3-乙醛酰胺sPLA2抑制剂。
Description
发明领域
本发明涉及用于治疗炎症性肠疾病的化合物。更具体地讲,本发明涉及作为用于治疗炎症性肠疾病的sPLA2抑制剂的1H-吲哚-3-乙醛酰胺化合物。
发明背景
炎症性肠疾病(IBD)是指一种涉及胃肠道的慢性炎症性疾病。虽然这些疾病的确切原因尚不清楚,但它们所表现出的特点使得在大多数情况下均可以进行诊断。炎症性肠疾病包括两种主要的疾病状态:溃疡性结肠炎(UC)和节段性回肠炎(DC)。许多文献均描述了sPLA2抑制剂化合物对溃疡性结肠炎和节段性回肠炎的可能的治疗效果(参见,Peterson等,肠(Gut),39(5):698-704(1996),Murthy等,炎症(Inflammation)16(3):259-71(1992),Hastings等,美国家庭医生(Am.Famil.Physician)47(3):598-608(1993))。
在以下专利文献中要求了对sPLA2抑制剂用途的保护:WO98/18464;WO96/20959;WO95/02588A;WO93/24492A;WO92/21644A;欧洲专利申请公开号0675110。
已经提出的IBD的可能病因包括遗传学、感染、免疫学和心理学的原因。尽管该疾病的确切病因学尚不清楚,但据信这些疾病的表现是结肠内的上皮和/或内皮细胞对外界刺激的免疫反应的结果。
溃疡性结肠炎涉及影响结肠的炎症反应。结肠表现出溃疡和出血。炎症通常是均匀的和连续性的并且通常涉及直肠。溃疡性结肠炎的主要症状包括出血性腹泻或便秘、腹部疼痛、脱水的迹象、贫血、发烧和体重降低。结肠外的表现可以包括关节炎,肝病、皮肤病和肺病的迹象。
节段性回肠炎的特征是炎症在肠壁所有的层上蔓延,通常还包括肠系膜淋巴结。炎症可能会穿透粘膜并连合形成通道,称为瘘管和裂。在节段性回肠炎中,肠的炎症通常是不连续的并且通常是肉芽肿性的(参见Harrison’s Principles of Internal Medicine,第13版,1994,McGraw-Hill,Inc.,ISBN 0-07-032370-4,1403-1416页)。
治疗的选择包括手术去除受影响的组织,通常同时进行再建手术以使废物能够排出。手术的方法昂贵、不方便并且通常不能治愈,因为可能会复发并出现新的感染部位。药物治疗包括但不仅限于,施用皮质类固醇、柳氮磺胺吡啶、5-氨基水杨酸(5-ASA)、硫唑嘌呤、6-巯基嘌呤(6-MP)。这些治疗集中在炎症反应的改善上。
非常需要对IBD的特异性和有效的治疗方法(Sutherland CMAJ137;799-802,1987)。
本发明的目的是提供一种新的有效治疗炎症性肠疾病的方法。
发明概述
本发明涉及通过施用治疗有效量的1H-吲哚-3-乙醛酰胺sPLA2抑制剂在哺乳动物、包括人中治疗炎症性肠疾病。
本发明还涉及通过施用治疗有效量的1H-吲哚-3-乙醛酰胺sPLA2抑制剂在哺乳动物、包括人中预防炎症性肠疾病的方法。
本发明还涉及1H-吲哚-3-乙醛酰胺sPLA2抑制剂在患有属于炎症性肠疾病的胃和十二指肠溃疡的患者中减少急性或慢性肠感染并发症的用途。
本发明还涉及用1H-吲哚-3-乙醛酰胺sPLA2抑制剂与其它IBD治疗化合物联合对患有炎症性肠疾病的哺乳动物、包括人进行治疗的方法。
本发明还涉及1H-吲哚-3-乙醛酰胺sPLA2抑制剂化合物在生产用于治疗炎症性肠疾病的药物中的用途。
本发明还涉及用于治疗IBD的制剂,该制剂含有:(ⅰ)1H-吲哚-3-乙醛酰胺sPLA2抑制剂;(ⅱ)一种或多种其它IBD治疗化合物;(ⅲ)载体和稀释剂。
发明详述
定义:
一般定义:
术语“炎症性肠疾病”(缩写IBD)包括如下疾病状态:(ⅰ)溃疡性结肠炎、(ⅱ)节段性回肠炎和(ⅲ)IBD的症状,包括相关的炎症、溃疡和感染。
术语“治疗有效量”是足以明显缓解哺乳动物炎症性肠疾病的症状的1H-吲哚-3-乙醛酰胺sPLA2抑制剂的量。
术语“胃肠外”是指不通过消化道而是通过某些其它的途径,例如皮下、肌肉内、眼眶内、囊内、脊柱内、胸骨内或静脉内。
术语“活性化合物”是指本发明方法中使用的一种或多种sPLA2抑制剂。
术语“IBD治疗化合物”是指除1H-吲哚-3-乙醛酰胺sPLA2抑制剂之外的常用于治疗IBD的化合物,包括但不仅限于皮质类固醇、柳氮磺胺吡啶、5-氨基水杨酸(5-ASA)、6-巯基嘌呤(6-MP)、硫唑嘌呤。Ⅰ.可用于本发明方法的sPLA2抑制剂:
1H-吲哚-3-乙醛酰胺分泌磷脂酶A2(sPLA2)抑制剂可用于本发明方法的实践。1H-吲哚-3-乙醛酰胺sPLA2抑制剂及其制备方法记载于美国专利5,654,326,其公开的内容引入本文作为参考。这些1H-吲哚-3-乙醛酰胺化合物还记载于欧洲专利申请号95302166.4,公开号0675110(1995年10月4日公开)中。1H-吲哚-3-乙醛酰胺化合物的定义:
“酸接头长度”是指连接吲哚核的4或5位和酸性基团的连接基团-(La)-中最短的链中的原子数(不包括氢)。
两个X均是氧;
R2选自:卤素、环丙基、甲基、乙基和丙基;
R4和R5彼此独立地选自氢、无干扰的取代基或基团-(La)-(酸性基团);其中-(La)-是酸接头;条件是,R4的酸接头基团-(La)-选自:
条件是,R4和R5中至少有一个必需是基团-(La)-(酸性基团),其中,R4或R5的基团-(La)-(酸性基团)上的(酸性基团)选自-CO2H、-SO3H或-P(O)(OH)2;
R6和R7彼此独立地选自氢和无干扰的取代基,所述无干扰的取代基选自如下一组基团:C1-C6烷基、C2-C6链烯基、C2-C6链炔基、C7-C12芳烷基、C7-C12烷芳基、C3-C8环烷基、C3-C8环烯基、苯基、甲苯基、二甲苯基、苯甲基、C1-C6烷氧基、C2-C6链烯氧基、C2-C6链炔氧基、C2-C12烷氧基烷基、C2-C12烷氧基烷氧基、C2-C12烷基羰基、C2-C12烷基羰基氨基、C2-C12烷氧基氨基、C2-C12烷氧基氨基羰基、C2-C12烷基氨基、C1-C6烷硫基、C2-C12烷硫基羰基、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、C2-C6卤代烷氧基、C1-C6卤代烷基磺酰基、C2-C6卤代烷基、C1-C6羟基烷基、-C(O)O(C1-C6烷基)、-(CH2)n-O-(C1-C6烷基)、苄氧基、苯氧基、苯硫基、-(CONHSO2R)、-CHO、氨基、脒基、溴、氨基甲酰基、羧基、烷氧羰基、-(CH2)n-CO2H、氯、氰基、氰胍基、氟、胍基、酰肼、肼基、酰肼基(hydrazido)、羟基、羟基氨基、碘、硝基、膦酰基、-SO3H、硫缩醛、硫代羰基和C1-C6羰基;其中n是1-8。
特别优选的用于实践本发明方法的化合物是1H-吲哚-3-乙醛酰胺化合物及其所有的可药用盐、溶剂化物和前药衍生物,包括:(A)[[3-(2-氨基-1,2-二氧代乙基)-2-甲基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,(B)d1-2-[[3-(2-氨基-1,2-二氧代乙基)-2-甲基-1-(苯基甲基)-1H-吲哚-4-基]氧基]丙酸,(C)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-甲基-1H-吲哚-4-基]氧基]乙酸,(D)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-3-基甲基)-2-甲基-1H-吲哚-4-基]氧基]乙酸,(E)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-4-基甲基)-2-甲基-1H-吲哚-4-基]氧基]乙酸,(F)[[3-(2-氨基-1,2-二氧代乙基)-1-[(2,6-二氯苯基)甲基]-2-甲基-1H-吲哚-4-基]氧基]乙酸,(G)[[3-(2-氨基-1,2-二氧代乙基)-1-[4(-氟苯基)甲基]-2-甲基-1H-吲哚-4-基]氧基]乙酸,(H)[[3-(2-氨基-1,2-二氧代乙基)-2-甲基-1-[(1-萘基)甲基]-1H-吲哚-4-基]氧基]乙酸,(I)[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,(J)[[3-(2-氨基-1,2-二氧代乙基)-1-[(3-氯苯基)甲基]-2-乙基-1H-吲哚-4-基]氧基]乙酸,(K)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-乙基-1H-吲哚-4-基]氧基]乙酸,(L)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-丙基-1H-吲哚-4-基]氧基]乙酸,(M)[[3-(2-氨基-1,2-二氧代乙基)-2-环丙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,(N)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-环丙基-1H-吲哚-4-基]氧基]乙酸,(O)4-[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-5-基]氧基]丁酸,(P)(A)至(O)以任何组合方式形成的混合物。
一般来说,可以使用任何前药衍生物。但是,特别有用的式(Ⅰ)化合物以及命名为化合物(A)至(O)的前药是酯,特别是简单的芳香族和脂肪族酯,例如甲酯、乙酯、丙酯、异丙酯和吗啉代-N-乙基酯。
治疗炎症性肠疾病的方法中所用的1H-吲哚-3-乙醛酰胺化合物的合成可以按照欧洲专利申请号95302166.4,公开号0675110(1995年10月4日公开)的描述进行。所述合成方法还包括化学文献中记载的公知方法以及如下制备反应方案中所描述的方法:
为了得到在4-位被酸性功能基通过氧原子取代的乙醛酰胺,采用反应方案1中所列的反应(1至5的转化参见Robin D.Clark,Joseph M.Muchowski,Lawrence E.Fisher,Lee A.Flippin,David B.Repke,MichelSouchet,合成(Synthesis),1991,871-878,其公开的内容引入本文作为参考)。将邻硝基甲苯(1)用Pd/C作为催化剂还原成2-甲基苯胺(2)。还原反应可以在乙醇或四氢呋喃(THF)或二者的混合物中进行,采用低的氢气压力。将苯胺(2)与二碳酸二叔丁酯一起在THF中于回流的温度下加热时,以很好的收率转变成N-叔丁基羰基衍生物(3)。用仲丁基锂在-40℃至-20℃下产生(3)的双阴离子的二锂盐并与适宜取代的N-甲氧基-N-甲基烷酰胺反应。可将该产物(4)通过在己烷中结晶进行纯化,或者将其直接与三氟乙酸在二氯甲烷中反应得到1,3-未取代的吲哚(5)。将1,3-未取代的吲哚(5)与氢化钠在二甲基甲酰胺中室温(20-25℃)反应0.5-1.0小时。将得到的(5)的钠盐用1当量芳基甲基卤化物处理并将该混合物在0-100℃的温度范围内、通常在室温下搅拌4-36小时,得到1-芳基甲基吲哚(6)。将该吲哚(6)与三溴化硼一起在二氯甲烷中搅拌约5小时进行O-脱甲基化(参见Tsung-Ying Shem&Charles A Winter,药物研究进展(Adv.Drug Res.),1977,12,176,其公开的内容引入本文作为参考)。将4-羟基吲哚(7)用α-溴代链烷酸酯在二甲基甲酰胺(DMF)中、用氢化钠作为碱进行烷基化,其反应条件与将(5)转变成(6)的描述类似。将α-[(吲哚-4-基)氧基]链烷酸酯(8)与草酰氯在二氯甲烷中反应得到(9),所得到的(9)不经纯化直接与氨反应得到乙醛酰胺(10)。将该产物用1N氢氧化钠的甲醇溶液水解。最终的乙醛酰胺(11)以游离羧酸或其钠盐的形式或同时以两种形式分离得到。
用于实践本发明方法的首选化合物[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸(及其钠盐和甲酯)可以通过如下方法制备:
下式所示化合物[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸的制备:
步骤A.2-乙基-4-甲氧基-1H-吲哚的制备
将140mL(0.18mol)1.3M仲丁基锂的环己烷溶液缓慢加入到用干冰-乙醇浴将温度保持在-40℃以下的N-叔丁氧羰基-3-甲氧基-2-甲基苯胺(21.3g,0.09mol)的250mL THF溶液中。移走冷却浴使温度升至0℃,然后更换冷却浴。当温度降至-60℃后,滴加18.5g(0.18mol)N-甲氧基-N-甲基丙酰胺在等体积THF中的溶液。将反应混合物搅拌5分钟,移走冷却浴并继续搅拌18小时。然后将其倒入300mL乙醚和400mL 0.5N HCl的昆合物中。分出有机层,用水、盐水洗涤,用硫酸镁干燥然后减压浓缩得到25.5g 1-[2-(叔丁氧羰基氨基)-6-甲氧基苯基]-2-丁酮粗品。将该物质溶于250mL二氯甲烷和50mL三氟乙酸并搅拌共17小时。将混合物减压浓缩,向残余的油中加入乙酸乙酯和水。分出乙酸乙酯,用盐水洗涤,干燥(硫酸镁)然后浓缩。将残余物进行硅胶色谱3次,用20%乙酸乙酯/己烷洗脱得到13.9g 2-乙基-4-甲氧基-1H-吲哚。C11H13NO的元素分析
计算值: C,75.40; H,7.48; N,7.99
实测值: C,74.41; H,7.64; N,7.97
步骤B.2-乙基-4-甲氧基-1-(苯基甲基)-1H-吲哚的制备
将2-乙基-4-甲氧基-1H-吲哚(4.2g,24mmol)溶于30mL DMF并加入960mg(24mmol)60%NaH/矿物油。1.5小时后,加入2.9mL(24mmol)溴苄。4小时后,将混合物用水稀释并用乙酸乙酯萃取两次。将合并的乙酸乙酯用盐水洗涤,干燥(硫酸镁)然后减压浓缩。将残余物进行硅胶色谱,用20%乙酸乙酯/己烷洗脱,得到3.19g(49%产率)2-乙基-4-甲氧基-1-(苯基甲基)-1H-吲哚。
步骤C.2-乙基-4-羟基-1-(苯基甲基)-1H-吲哚的制备。
采用步骤B的方法,将3.1g(11.7mmol)2-乙基-4-甲氧基-1-(苯基甲基)-1H-吲哚用48.6mL 1M BBr3/CH2Cl2处理进行O-脱甲基化,将得到的物质进行硅胶色谱(用20%乙酸乙酯/己烷洗脱)得到1.58g(54%收率)2-乙基-4-羟基-1-(苯基甲基)-1H-吲哚,mp,86-90℃。C17H17NO的元素分析
计算值: C,81.24; H,6.82; N,5.57
实测值: C,81.08; H,6.92; N,5.41
步骤D.[[2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸甲酯的制备。
采用步骤C中描述的方法,将2-乙基-4-羟基-1-(苯基甲基)-1H-吲哚(1.56g,6.2mmol)用248mg(6.2mmol)60%NaH/矿物油处理,然后用0.6mL(6.2mmol)溴乙酸甲酯处理。将产物通过硅胶色谱纯化,用20%乙酸乙酯/己烷洗脱得到1.37g(69%收率)[[2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸甲酯,89-92℃。C20H21NO3的元素分析
计算值: C,74.28; H,6.55; N,4.33
实测值: C,74.03; H,6.49; N,4.60
步骤E.[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸甲酯的制备
采用步骤D的方法,将1.36g(4.2mmol)[[2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸甲酯首先与0.4mL(4.2mmol)草酰氯反应,然后再与过量的氨反应生成白色固体。将其与乙酸乙酯一起搅拌,分离出不溶物并干燥得到1.37g[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸甲酯和氯化铵的混合物。该混合物在172-187℃熔融。
步骤F.[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸的制备
将788mg(2mmol)[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸甲酯、10mL 1N NaOH和30mL甲醇的混合物加热回流0.5小时,室温搅拌0.5小时,和减压浓缩。将残余物加入乙酸乙酯和水中,分出水层并用1N HCl酸化至pH2-3。滤出沉淀并用乙酸乙酯洗涤得到559mg(74%收率)[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,mp.230-234℃。C21H20N2O5的元素分析:
计算值: C,65.96; H,5.80; N,7.33
实测值: C,66.95; H,5.55; N,6.99
步骤G.步骤F产物的钠盐可以通过与氢氧化钠(NaOH)反应然后通过常规的实验室方法分离产物制得,或者可以通过使用Na+阳离子交换树脂制得。
本发明的吗啉代-N-乙基酯前药化合物通过将原料的酸或盐的形式酯化制得。可以使用化学领域中常用的任何酯形成方法。其示范性的方法如下:((3-(2-氨基-1,2-二氧代乙基)-1-((1,1′-联苯基)-3-基甲基)-2-甲基-1H-吲哚-4-基)氧基)乙酸吗啉基乙酯的制备
在含有10mL二甲基甲酰胺的烧瓶中于搅拌下加入133mg 4-(2-氯乙基)吗啉盐酸盐(可从Aldrich Chemical Co.,Milwaukee,WisconsinUSA购买到,项目号C4,220-3)、231mg CsCO3和300mg((3-(2-氨基-1,2-二氧代乙基)-1-((1,1′-联苯基)-3-基甲基)-2-乙基-1H-吲哚-4-基)氧基)乙酸的钠盐。将浆液加热至60℃直至形成溶液。继续加热过夜直至反应结束。向烧瓶中加入20mL水并将有机溶解相用3×20mL乙酸乙酯萃取。将乙酸乙酯溶液用水洗涤然后用硫酸钠干燥。适用于本发明方法的制剂
本发明方法中所用的sPLA2抑制剂可以通过任何能够使活性物质与人体内的活性物质作用位点相接触的方法给药来治疗炎症性肠疾病。它们可以通过任何常用的给药方法进行给药,既可以作为单独的治疗剂给药,也可以与其它治疗剂联合给药。sPLA2抑制剂可以单独给药,但通常与药物载体一起给药,药物载体的选择取决于所选的给药途径和常规的药物实践。
适宜的制剂是那些含有治疗有效量的sPLA2抑制剂和可药用稀释剂或载体的制剂,组合物与所选择的具体给药途径相适应。“可药用”是指载体、稀释剂或赋形剂必需与制剂中的sPLA2抑制剂(“活性化合物”)相容并且对治疗对象无害。
对于药物制剂,可以使用本领域已知的任何适宜载体。在所述制剂中,载体可以是固体、液体或固体和液体的混合物。固体载体可以是一种或多种还起矫味剂、润滑剂、增溶剂、助悬剂、粘合剂、片剂崩解剂和包封材料作用的物质。
用于口服给药的片剂可以含有适宜的赋形剂如碳酸钙、碳酸钠、乳糖、磷酸钙以及崩解剂如玉米淀粉或藻酸和/或粘合剂如明胶或阿拉伯胶,润滑剂如硬脂酸镁、硬脂酸或滑石。在片剂中,将sPLA2抑制剂与具有所需粘合特性的载体以适宜的比例混合并压制成所需的形状和大小。散剂和片剂优选含有约1至约99%(重量)的sPLA2抑制剂。
无菌液体形式的制剂包括混悬液、乳液、糖浆和酏剂。可将活性化合物溶解或悬浮在可药用载体例如无菌水、盐水、葡萄糖溶液、无菌有机溶剂或二者的混合物中。
可将活性化合物以胶囊、片剂和散利等固体剂量形式给药,或以酏剂、糖浆和混悬液等液体剂量形式给药。还可以以无菌液体剂量形式胃肠外给药。还可以以鼻喷雾剂的形式吸入给药。还可以以软膏、霜剂、凝胶剂、糊剂、洗剂、溶液剂、喷雾剂、气雾剂、脂质体或贴剂的形式局部给药。用于给药活性化合物的剂量形式通常含有适宜的载体、稀释剂、防腐剂或其它赋形剂,参见本领域的标准参考书《Remington’s药物科学》,Mack Publishing Company。
明胶胶囊可以含有活性化合物和粉末状的载体,例如乳糖、蔗糖、甘露醇、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。类似的稀释剂还可用于制备压缩片和粉剂。片剂和胶囊均可制成缓释的产品以便在一段时间内连续地释放药物。可以对压缩片进行糖包衣或薄膜包衣以掩盖任何不适的味道并保护片剂防止空气的影响,或进行肠溶包衣以在胃肠道内选择性地崩解。
用于口服给药的液体剂量形式可以含有着色剂和矫味剂以使患者更容易接受。
对于胃肠外溶液,水、适宜的油、盐水、葡萄糖水溶液和有关的糖溶液以及二元醇如丙二醇或聚乙二醇是胃肠外溶液的适宜载体。用于胃肠外给药的溶液含有活性化合物、适宜的稳定剂,如需要,还可含有缓冲物质。适宜的稳定剂是抗氧剂如亚硫酸氢钠、亚硫酸钠或抗坏血酸,它们可单独使用,也可联合使用。还可以使用柠檬酸及其盐以及EDTA钠盐。此外,胃肠外溶液还可含有防腐剂如氯苄烷铵、对羟基苯甲酸甲酯或丙酯和氯丁醇。
局部用软膏、霜剂、凝胶剂和糊剂含有活性化合物和稀释剂,例如蜡、石蜡、淀粉、聚乙二醇、聚硅氧烷、膨润土、硅酸、动物和植物脂肪、滑石和氧化锌或它们混合物或其它稀释剂。
局部用溶液和乳液可以含有,例如,活性化合物、常用的稀释剂(不包括分子量低于200的溶剂,除非有表面活性剂存在),例如溶剂,溶解剂和乳化剂;具体的例子是水、乙醇、2-丙醇、碳酸乙酯、苄醇、丙二醇、油、甘油和山梨醇的脂肪酸酯或它们的混合物。局部给药的组合物还可以含有防腐剂或抗氧剂。
除活性化合物外,散剂和喷雾剂还可含有常用的稀释剂,例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。气溶胶喷雾剂可以含有常用的抛射剂。脂质体可以从能够形成脂质双层的动物或植物脂肪等原料制得,在所述脂质双层中可以掺入活性化合物。
含有本发明化合物的制剂可以通过经皮贴剂等装置通过皮肤给药。贴剂可以由聚丙烯酰胺等基质和由适宜的聚合物形成的用来控制材料向皮肤传递的速率的半透膜制成。其它适宜的经皮贴剂的配方和结构记载于美国专利5,296,222和5,271,940,其公开的内容引入本文作为参考。sPLA2抑制剂的亲脂性前药衍生物特别适用于经皮吸收给药和传递系统。
本发明范围内的制剂包括sPLA2抑制剂与治疗有效量的可有效治疗炎症性肠疾病的各种活性助剂的混合物,所述活性助剂包括但不仅限于皮质类固醇、柳氮磺胺吡啶、5-氨基水杨酸(5-ASA),据称它们可用于治疗、改善和/或预防肠道的炎症性肠疾病和/或相关的生理性病症,参见以下“活性助剂-联合治疗”部分中的描述。
对于上述所有制剂,优选的活性化合物是前述的1H-吲哚-3-乙醛酰胺化合物,其制备方法的描述参见美国专利5,654,326(其公开的内容引入本文作为参考)。1H-吲哚-3-乙醛酰胺化合物大类中的首选化合物是((3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基)氧基)乙酸、其钠盐及甲酯。用于本发明方法的活性化合物的比例和重量
1H-吲哚-3-乙醛酰胺化合物可以以制剂重量的0.1-99.9%的浓度使用。
药物制剂优选是单位剂量形式。单位剂量形式可以是胶囊或片剂本身,或者是适宜数量的胶囊或片剂。组合物的单位剂型中活性化合物的量可以在约0.1至约1000mg内改变,或者根据所涉及的具体治疗进行调节。
适于内部给药的组合物(剂量形式)每单位含有约1mg至约500mg活性化合物。在这些药物组合物中,活性化合物的含量通常为约0.5-95%(重量),以组合物的总重量计。
以下将描述适宜的药物组合物的例子及其各成分的比例:胶囊:胶囊可以通过用50mg粉末状的活性化合物、175mg乳糖、24mg滑石和6mg硬脂酸镁填充标准的两节的硬明胶胶囊制得。软明胶胶囊:制备活性化合物在大豆油中的混合物并用容积泵注射到明胶中形成含有50mg活性化合物的软明胶胶囊。将胶囊在石油醚中洗涤然后干燥。片剂:片剂可以通过常规的方法制得,从而使剂量单位含有50mg活性化合物、6mg硬脂酸镁、70mg微晶纤维素、11mg玉米淀粉和225mg乳糖。可以涂覆适宜的包衣以增加适口性或延缓吸收。混悬液:制备用于口服给药的含水混悬液,从而使每5mL含有25mg细分散的活性化合物、200mg羧甲基纤维素钠、5mg苯甲酸钠、1.0g山梨醇溶液(U.S.P.)和0.025mg香草醛。注射液:通过将1.5%(重量)的活性化合物在10%(体积)丙二醇和水中搅拌制得适于通过注射给药的胃肠外组合物。将溶液通过常用的技术灭菌。鼻喷雾剂:制备每1mL含有10mg活性化合物、1.8mg对羟基苯甲酸甲酯、0.2mg对羟基苯甲酸丙酯和10mg甲基纤维素的含水溶液。将溶液分装到1mL的小瓶中。活性化合物可以以制剂重量的0.1至99.9%的浓度使用。
气溶胶制剂可以分散成粒度为约0.5至约10微米并且含有足够量sPLA2抑制剂的颗粒,以在气管表面达到约10-10至10-2摩尔/升的抑制剂浓度。栓剂:可用于本发明实践的化合物还可以以用于直肠给药的栓剂形式给药。这些组合物可以通过,例如,将活性成分与载体、优选熔融的载体紧密混合制得。优选在掺入到熔融的载体中之前将活性成分研磨或过筛。然后可以将熔融的组合物倒入适宜的模具中。在包装之前,可以选择性地将栓剂用鲸蜡醇、聚乙二醇或聚乙烯醇和聚山梨酯包衣以延长崩解时间或进行润滑。本发明方法的实践
sPLA2抑制剂在本发明方法中的应用通过抑制或降低炎症程度而阻止了结肠和肠组织和功能的进行性恶化,而炎症可能是炎症性肠疾病的主要的病理学过程。本发明的方法优选在患有炎症性肠疾病的患者生命的早期使用。
本发明的方法可以用含有sPLA2抑制剂(优选在本说明书中所教导的优选的sPLA2抑制剂)的药物制剂或含有前一部分中所教导的sPLA2抑制剂的制剂来实现。
在某些情况下,本发明的方法可能无法阻止引起炎症性肠疾病的病因,但通过给药sPLA2抑制剂(及其制剂)将可以减轻症状的严重性或改善其程度。
当然,给药的剂量取决于已知的因素,例如具体试剂的药效学特点、其给药方式和途径;使用者的年龄、健康情况和体重;症状的性质和程度、并行治疗的种类、治疗的频率以及所希望的效果。通常,活性化合物的每日剂量可以从约0.1至200mg/kg体重。通常每天分成1-6次给药或以缓释的形式每天给药0.5-50、优选1-25mg/kg可以有效地获得所需的结果。
通常,可以将sPLA2抑制剂向患者给药以使其接受治疗有效量。对于具体的患者,治疗有效量可以通过以递增的剂量施用活性化合物并观察对患者的效果进行确定,例如炎症程度的减轻、出血减少、腹泻停止、肠梗阻的改善或与炎症性肠疾病有关的其它症状的减轻。
通常,必需将化合物以能够在患者中产生10-3000ng/mL、优选100-800ng/mL的sPLA2抑制剂血液浓度的方式和剂量给药。
炎症性肠疾病的治疗方案可以从数天到几个月或几年。优选口服给药,因为患者使用方便并且耐受性好。口服给药时,可以每天服用1-4次,每次约0.01-25mg/kg体重,优选的剂量为约0.1mg/kg至约2mg/kg。
在需要迅速缓解患者的痛苦时,通常优选胃肠外给药(特别是静脉内给药)。胃肠外给药的剂量为0.01-100mg/kg/天,可以连续给药或在一天内间歇给药。对于胃肠外给药,可将化合物在生理盐水载体(例如,0.9%生理盐水、0.45%生理盐水等)、葡萄糖载体(例如5%葡萄糖水溶液)或盐水和葡萄糖载体的组合(0.9%生理盐水的5%葡萄糖溶液)中给药。活性助剂-联合治疗
在本发明的方法中,还可将sPLA2抑制剂(即,本发明的活性化合物)与已知可用于缓解炎症性肠疾病症状的其它药理学活性物质联合给药。例如,可将本文所教导的sPLA2抑制剂与如下治疗剂联用:
1.抗炎剂,例如柳氮磺胺吡啶
2.控制肠道感染的药物
a.抗生素
(ⅰ)青霉素类,例如杆菌肽
(ⅱ)糖肽类,例如万古霉素
3.甾族化合物(糖皮质类固醇)
4.免疫抑制剂,例如硫唑嘌呤
5.控制腹泻的药物,例如消胆胺炎症性肠疾病的测试方法
炎症性肠疾病的诊断标准可以参见标准的医学参考书(例如《Harrison氏内科学原理》(Harrison’s Principles of Internal Medicine),第13版,1994,McGraw-Hill,Inc.,ISBN 0-07-032370-4,1194-1197页)。这些标准可用于确定什么时候开始使用本发明的方法、治疗的频率和程度,以及停止治疗的时间。
尽管以上通过具体的实施方案对本发明进行了说明,但这些实施方案并不限定所附权利要求所描述的本发明的范围。
Claims (18)
两个X均是氧;
R1选自:和其中R10是彼此独立地选自卤素、C1-C10烷基、C1-C10烷氧基、-S-(C1-C10烷基)和C1-C10卤代烷基的基团,并且t是0-5的数;
R2选自:卤素、环丙基、甲基、乙基和丙基;
条件是,R4和R5中至少有一个是基团-(La)-(酸性基团),其中,R4或R5的基团-(La)-(酸性基团)上的(酸性基团)选自-CO2H、-SO3H或-P(O)(OH)2;
R6和R7彼此独立地选自氢和无干扰的取代基,所述无干扰的取代基选自如下一组基团:C1-C6烷基、C2-C6链烯基、C2-C6链炔基、C7-C12芳烷基、C7-C12烷芳基、C3-C8环烷基、C3-C8环烯基、苯基、甲苯基、二甲苯基、苯甲基、C1-C6烷氧基、C2-C6链烯氧基、C2-C6链炔氧基、C2-C12烷氧基烷基、C2-C12烷氧基烷氧基、C2-C12烷基羰基、C2-C12烷基羰基氨基、C2-C12烷氧基氨基、C2-C12烷氧基氨基羰基、C2-C12烷基氨基、C1-C6烷硫基、C2-C12烷硫基羰基、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、C2-C6卤代烷氧基、C1-C6卤代烷基磺酰基、C2-C6卤代烷基、C1-C6羟基烷基、-C(O)O(C1-C6烷基)、-(CH2)n-O-(C1-C6烷基)、苄氧基、苯氧基、苯硫基、-(CONHSO2R)、-CHO、氨基、脒基、溴、氨基甲酰基、羧基、烷氧羰基、-(CH2)n-CO2H、氯、氰基、氰胍基、氟、胍基、酰肼、肼基、酰肼基、羟基、羟基氨基、碘、硝基、膦酰基、-SO3H、硫缩醛、硫代羰基和C1-C6羰基;其中n是1-8。
2.对患有炎症性肠疾病的人进行治疗的方法,所述方法包括,向需要治疗的所述的人施用治疗有效量的用于治疗IBD的1H-吲哚-3-乙醛酰胺化合物或其可药用盐、溶剂化物或前药衍生物,所述化合物选自化合物(A)至(P):(A)[[3-(2-氨基-1,2-二氧代乙基)-2-甲基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,(B)d1-2-[[3-(2-氨基-1,2-二氧代乙基)-2-甲基-1-(苯基甲基)-1H-吲哚-4-基]氧基]丙酸,(C)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-甲基-1H-吲哚-4-基]氧基]乙酸,(D)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-3-基甲基)-2-甲基-1H-吲哚-4-基]氧基]乙酸,(E)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-4-基甲基)-2-甲基-1H-吲哚-4-基]氧基]乙酸,(F)[[3-(2-氨基-1,2-二氧代乙基)-1-[(2,6-二氯苯基)甲基]-2-甲基-1H-吲哚-4-基]氧基]乙酸,(G)[[3-(2-氨基-1,2-二氧代乙基)-1-[(4-氟苯基)甲基]-2-甲基-1H-吲哚-4-基]氧基]乙酸,(H)[[3-(2-氨基-1,2-二氧代乙基)-2-甲基-1-[(1-萘基)甲基]-1H-吲哚-4-基]氧基]乙酸,(I)[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,(J)[[3-(2-氨基-1,2-二氧代乙基)-1-[(3-氯苯基)甲基]-2-乙基-1H-吲哚-4-基]氧基]乙酸,(K)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-乙基-1H-吲哚-4-基]氧基]乙酸,(L)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-丙基-1H-吲哚-4-基]氧基]乙酸,(M)[[3-(2-氨基-1,2-二氧代乙基)-2-环丙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,(N)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-环丙基-1H-吲哚-4-基]氧基]乙酸,(O)4-[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-5-基]氧基]丁酸,(P)(A)至(O)的混合物。
4.权利要求1或2或3中任意一项所述的方法,其中的给药是静脉内给药。
5.权利要求1或2或3或4中任意一项所述的方法,其中的给药是口服给药。
6.权利要求1或2或3或4中任意一项所述的方法,其中所治疗的是患有炎症性肠疾病的人,并且抑制剂以能够达到10至3000ng/mL人血液抑制剂浓度的治疗有效量给药。
7.权利要求1或2或3或4中任意一项所述的方法,其中的给药量为0.01mg/kg/天至100mg/kg/天。
8.权利要求1或2或3或4中任意一项所述的方法,其中的治疗有效量为含有化合物和适宜载体或赋形剂的药物制剂的形式。
9.选自1H-吲哚-3-乙醛酰胺的sPLA2抑制剂在生产用于治疗炎症性肠疾病的药物中的用途。
11.sPLA2抑制剂化合物在生产用于治疗炎症性肠疾病的药物中的用途,其中,所述化合物选自1H-吲哚-3-乙醛酰胺。
两个X均是氧;
R2选自:卤素、环丙基、甲基、乙基和丙基;
R4和R5彼此独立地选自氢、无干扰的取代基或基团-(La)-(酸性基团);其中-(La)-是酸接头;条件是,R4的酸接头基团-(La)-选自:条件是,R5的酸接头-(La)-选自: 其中R84和R85彼此独立地选自氢、C1-C10烷基、芳基、C1-C10烷芳基、C1-C10芳烷基、羧基、烷氧羰基和卤素;和
条件是,R4和R5中至少有一个是基团-(La)-(酸性基团),其中,R4或R5的基团-(La)-(酸性基团)上的(酸性基团)选自-CO2H、-SO3H或-P(O)(OH)2;
R6和R7彼此独立地选自氢和无干扰的取代基,所述无干扰的取代基选自如下一组基团:C1-C6烷基、C2-C6链烯基、C2-C6链炔基、C7-C12芳烷基、C7-C12烷芳基、C3-C8环烷基、C3-C8环烯基、苯基、甲苯基、二甲苯基、苯甲基、C1-C6烷氧基、C2-C6链烯氧基、C2-C6链炔氧基、C2-C12烷氧基烷基、C2-C12烷氧基烷氧基、C2-C12烷基羰基、C2-C12烷基羰基氨基、C2-C12烷氧基氨基、C2-C12烷氧基氨基羰基、C2-C12烷基氨基、C1-C6烷硫基、C2-C12烷硫基羰基、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、C2-C6卤代烷氧基、C1-C6卤代烷基磺酰基、C2-C6卤代烷基、C1-C6羟基烷基、-C(O)O(C1-C6烷基)、-(CH2)n-O-(C1-C6烷基)、苄氧基、苯氧基、苯硫基、-(CONHSO2R)、-CHO、氨基、脒基、溴、氨基甲酰基、羧基、烷氧羰基、-(CH2)n-CO2H、氯、氰基、氰胍基、氟、胍基、酰肼、肼基、酰肼基、羟基、羟基氨基、碘、硝基、膦酰基、-SO3H、硫缩醛、硫代羰基和C1-C6羰基;其中n是1-8。
13.1H-吲哚-3-乙醛酰胺化合物或其可药用盐、溶剂化物或前药衍生物在生产用于治疗炎症性肠疾病的药物中的用途,其中,所述化合物选自化合物(A)至(P):(A)[[3-(2-氨基-1,2-二氧代乙基)-2-甲基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,(B)d1-2-[[3-(2-氨基-1,2-二氧代乙基)-2-甲基-1-(苯基甲基)-1H-吲哚-4-基]氧基]丙酸,(C)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-甲基-1H-吲哚-4-基]氧基]乙酸,(D)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-3-基甲基)-2-甲基-1H-吲哚-4-基]氧基]乙酸,(E)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-4-基甲基)-2-甲基-1H-吲哚-4-基]氧基]乙酸,(F)[[3-(2-氨基-1,2-二氧代乙基)-1-[(2,6-二氯苯基)甲基]-2-甲基-1H-吲哚-4-基]氧基]乙酸,(G)[[3-(2-氨基-1,2-二氧代乙基)-1-[(4-氟苯基)甲基]-2-甲基-1H-吲哚-4-基]氧基]乙酸,(H)[[3-(2-氨基-1,2-二氧代乙基)-2-甲基-1-[(1-萘基)甲基]-1H-吲哚-4-基]氧基]乙酸,(I)[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,(J)[[3-(2-氨基-1,2-二氧代乙基)-1-[(3-氯苯基)甲基]-2-乙基-1H-吲哚-4-基]氧基]乙酸,(K)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-乙基-1H-吲哚-4-基]氧基]乙酸,(L)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-丙基-1H-吲哚-4-基]氧基]乙酸,(M)[[3-(2-氨基-1,2-二氧代乙基)-2-环丙基-1-(苯基甲基)-1H-吲哚-4-基]氧基]乙酸,(N)[[3-(2-氨基-1,2-二氧代乙基)-1-([1,1′-联苯基]-2-基甲基)-2-环丙基-1H-吲哚-4-基]氧基]乙酸,(O)4-[[3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-5-基]氧基]丁酸,(P)(A)至(O)的混合物。
15.用于治疗IBD的制剂,该制剂含有:
A).式(Ⅰ)所示的1H-吲哚-3-乙醛酰胺,或其可药用盐或酯前药衍生物;B).一种或多种除sPLA2抑制剂之外的其它活性助剂,其选自:a.抗炎剂,b.抗生素,c.甾族化合物,d.免疫抑制剂,和e.控制腹泻的药物;C).选择性的载体或稀释剂。
16.权利要求15的制剂,其中(A)和(B)的重量比为1∶100至100∶1。
17.权利要求15的制剂,其中(C)与(A)和(B)的总和的重量比为1∶50至50∶1。
18.治疗IBD的方法,该方法包括向需要治疗的哺乳动物、包括人施用治疗有效量的权利要求15的制剂。
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