CN1898197A - 新型化合物 - Google Patents
新型化合物 Download PDFInfo
- Publication number
- CN1898197A CN1898197A CNA2004800382388A CN200480038238A CN1898197A CN 1898197 A CN1898197 A CN 1898197A CN A2004800382388 A CNA2004800382388 A CN A2004800382388A CN 200480038238 A CN200480038238 A CN 200480038238A CN 1898197 A CN1898197 A CN 1898197A
- Authority
- CN
- China
- Prior art keywords
- compound
- dimethoxy
- biphenyl
- amino
- bromo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
本发明涉及新型苯基丙氨酸化合物、它们的制备方法、包含它们的组合物和它们在治疗或预防能通过细胞粘附抑制调节的疾病中的应用。
Description
技术领域
本发明涉及新型化合物、它们的制备方法、包含它们的组合物和它们在治疗或预防能通过抑制细胞粘附(cell adhesion)调节的疾病中的用途。更具体地,本发明涉及能抑制α4整联蛋白调节的细胞粘附并被认为用于治疗或预防炎症的新型苯基丙氨酸衍生物。
背景技术
白细胞和内皮细胞或细胞外基质蛋白之间的多重粘着相互作用是免疫和炎症调节中的关键因素。白细胞在炎症部位迁移出脉管系统时的最早事件包括白细胞滚动然后是整联蛋白亲合力的变化,这导致随后的牢固粘着(对于综述,参见Butcher,Cell 67:1033-1036(1991);Harlan,Blood 3:513-525(1985);Hemler;Annu.Rev.Immunol.8:365-400(1990);Osborn,Cell 62:3-6(1990);Shimizuet al.,Immunol.Rev.114:109-143(1990);Springer,Nature 346:425-434(1990)和Springer,Cell 76:301-314(1994))。响应趋化因子,白细胞通过两个邻近的内皮细胞迁移并进入部分由细胞外基质蛋白纤连蛋白(FN)(参见Wayner等人,J.Cell Biol 105:1873-1884(1987))和胶原(CN)(参见Bornstein等人,Ann.Rev.Biochem.49:957-1003(1980);和Miller,Chemistry of the collagens and their distribution,in“Extracellular Matrix Biochemistry”,K.A.Piez和A.H.Reddi,编者,Elsevier,Amsterdam,41-78(1983))组成的组织中。参与这些粘着反应的重要识别分子属于整联蛋白基因总科(对于综述,参见Hemler,Annu.Rev.Immunol.8:365-400(1990);Hynes,Cell 48:549-554(1987);Shimizu等人,Immunol.Rev.114:109-143(1990);和Springer,Nature 346:425-434(1990))。
整联蛋白为由称为α和β亚单元的非共价缔合亚单元组成的异二聚体。到目前为止,已确定可与16种不同α亚单元缔合形成至少23种不同整联蛋白的8种整联蛋白β亚单元。
α4β1整联蛋白,也称为VLA-4(最晚期抗原-4),构成上在白细胞包括淋巴细胞、单核细胞、嗜酸性粒细胞和嗜碱细胞的表面上被表达(参见Hemler等人,J.Bio.Chem.262:11478-11485(1987);和Bochner等人,J.Exp.Med.173:1553-1556(1991))。VLA-4被报道存在于败血症患者的嗜中性白细胞上(参见Ibbotson等人,NatureMed.7:465-470(2001))。VLA-4在活性内皮细胞上结合到血管细胞粘附分子-1(VCAM-1)上,造成白细胞的外渗(Elices等人,Cell 60:577-584(1990))。一旦细胞到达血管外空间,VLA-4就可结合到连接段1(CS-1)上,一个FN A链的可供选择叠接的区域(Wayne等人,J.Cell Biol.109:1321-1330(1989))。另外,已知VLA-4结合到骨桥蛋白(一种在动脉硬化斑中上调节的蛋白)上(参见Bayless等人,J.Cell Science 111:1165-1174(1998))。
α4β7整联蛋白,也称为LPAM-1(淋巴细胞-Peyer斑粘着分子-1),与三种已知的配体(VCAM-1、CS-1、MAdCAM-1)相互作用。对α4β7表现出独特特异性的一种配体是粘膜地址素细胞粘附分子-1(MAdCAM-1)(参见Andrew等人,J.Immunol.153:3847-3861(1994);Briskin等人,Nature 363:461-464(1993);和Shyjan等人,J.Immunol.156:2851-2857(1996))。MAdCAM-1在Peyer斑高内皮微静脉上、在肠系膜淋巴结中、和在肠鼓膜中层和乳腺微静脉中被高度表达(Berg等人,Immunol.Rev.105:5-18(1989))。整联蛋白α4β7和MAdCAM-1已被表明在调节淋巴细胞转运到正常肠中非常重要(Holzmann等人,Cell 56:37-46(1989))。
另外,描述了α4整联蛋白α4β1和α4β7的口服生物可用的非肽小分子拮抗剂可用于治疗或预防症状如哮喘、炎症肠疾病、类风湿性关节炎、多发性硬化和其它疾病(参见专利申请WO99/36393和WO02/18320,引入它们的内容作为参考)。
现在已经发现了落在专利申请WO99/36393一般范围内的新一类化合物,但其中没有具体公开。
发明内容
因此,本发明第一方面提供式(I)的化合物或它的可药用衍生物:
其中:
R1为溴;和
R2为卤素、C1-6烷基或C1-6烷氧基。
优选R2为卤素或C1-6烷氧基。
更优选R2为氟、甲氧基或乙氧基。
另一方面,本发明提供E1-E7(如下面所述)或它们的可药用衍生物,即:
(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基(methanoyl)]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸;
(S)-2-{[1-(2-溴-5-氟苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸;
(S)-2-{[1-(2-溴-5-甲氧基苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸;
(S)-2-{[1-(2-溴-5-甲基苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸);
(S)-2-{[(2-溴-5-氯苯基)甲酰氧基]氨基}-3-[4′-氰基-2′,6′-二甲氧基)联苯-4-基]丙酸;
(S)-2-{[(2,5-二溴苯基)甲酰氧基]氨基}-3-[4′-氰基-2′,6′-二甲氧基)联苯-4-基]丙酸;
(S)-2-{[(5-(异-丙氧基)-2-溴苯基)甲酰氧基]氨基}-3-[4′-氰基-2′,6′-二甲氧基)联苯-4-基]丙酸;
或它们的可药用衍生物。
在整个本说明书中,除非另外指明:
术语“卤素”用于描述选自氟、氯、溴或碘的组;
术语“C1-6烷基”用于描述包括含1-6个碳原子的直链或支链烷基的基团或基团部分;这类基团的例子包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基;
术语“C1-6烷氧基”用于描述其中氧原子键合到上述C1-6烷基的基团或基团部分;这类基团的例子包括甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基或己氧基。
本发明化合物的特征是在联苯核的4′-位引入氰基以及要求的2,5-二取代苯甲酰基。
式(I)的化合物或它的可药用衍生物对α4整联蛋白调节的细胞粘附具有有效的抑制活性。另外,发现某些实例在口服给药和/或全身给药后表现出优异的生物利用度。
E1、E2和E3(如下面所述)表现出上述特征的有利组合。
应认识到,式(I)的化合物或它的可药用衍生物可具有一个或一个以上的不对称碳原子,并因此可能作为非对映异构体出现。所有这种异构形式都包括在本发明内,包括它们的混合物。
可通过常规技术例如通过分级结晶、色谱法或HPLC实现非对映异构体的分离。化合物的单一立体异构形式还可由相应的光学纯中间体制备或通过使用合适的手性载体拆分相应的外消旋物如相应外消旋物的HPLC,或通过分级结晶由相应外消旋物与合适的旋光酸或碱适宜地反应形成的非对映异构盐。或者,可通过与合适手性化合物的化学反应形成新的共价键合的物种来分离对映异构体的混合物,例如外消旋羧酸与手性胺或醇偶合得到非对映异构的混合物(分别在酰胺或酯时),其可通过常规技术如柱色谱法、HPLC或分级结晶来分离。然后通过合适的化学如水解分裂新共价键将单一非对映异构体转化成所需化合物的单一对映异构体。
本文使用的术语“可药用衍生物”是指本发明化合物的任何可药用盐或前药如酯,当给药到接受者时,其能提供(直接或间接)本发明的化合物,或它的活性代谢产物或残余物。这类衍生物对本领域技术人员不用过多试验即可识别。尽管如此,还是参考Burger′sMedicinal Chemistry and Drug Discovery,5th Edition,Vol 1:Principles and Practice的教导,本文引入其作为参考至教导这类衍生物的程度。优选的可药用衍生物为盐和酯。
有机化学领域的那些技术人员能认识到许多有机化合物可与它们在其中反应或用于沉淀或结晶它们的溶剂形成络合物。这些络合物被称为“溶剂化物”。例如,与水的络合物称为“水合物”。本发明化合物的溶剂化物在本发明的范围内。
本文使用的术语“前药”是指在体内例如通过在血液中水解被转化成具有医学效果的活性形式的化合物。可药用前药描述在T.Higuchi和V.Stella,Prodrugs as Novel Delivery Systems,A.C.S.SymposiumSeries第14卷,Edward B.Roche,ed.,Bioreversible Carriers in DrugDesign,American Pharmaceutical Association and Pergamon Press,1987中,和在D.Fleisher,S.Ramon和H.Barbra “Improved oral drugdelivery:solubility limitations overcome by the use of prodrugs”,Advanced Drug Delivery Reviews(1996)19(2)115-130中,本文引入其中的每一个作为参考。
前药为当这类前药被给药到患者时能在体内释放式(I)的化合物或其可药用衍生物的任何共价键合载体。通常通过修饰官能团来制备前药,从而以这种方式利用常规处理或在体内来裂解修饰产生母体化合物。在为羧酸(-COOH)时,可使用酯,如甲酯、乙酯、双酯等。酯本身可为活性的和/或在人体中在体内条件下可水解。合适的可药用体内可水解酯基包括在人体内能容易地分解留下母体酸或其盐的那些。
本发明的化合物可为可药用盐的形式和/或可作为可药用盐给药。对于合适盐的综述,参见Berge等人,J.Pharm.Sci.,1977,66,1-19。
通常,通过使用合适的所需酸或碱可容易地制备可药用盐。盐可从溶液中沉淀并通过过滤收集,或可通过蒸发溶剂回收。
在为式(I)的化合物时,合适的可药用盐由可药用碱形成,包括铵盐、碱金属盐如钠盐和钾盐、碱土金属盐如钙盐和镁盐,和与有机碱的盐,包括伯胺、仲胺和叔胺的盐,如异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、N-甲基-D-葡糖胺和三(羟甲基)甲胺。
另一方面,本发明还提供制备式(I)的化合物的方法,其包括水解式(II)的羧酸酯衍生物:
其中R1和R2如式(I)中所定义,R为能形成羧酸酯的基团,和任选地然后形成它的可药用衍生物。
合适的R基团的例子为C1-6烷基如甲基或叔丁基,优选甲基。水解可通过酸性介质或碱性介质进行。在碱性介质中水解的例子是在合适的溶剂中用碱金属氢氧化物处理式(II)的化合物,例如在四氢呋喃水溶液中用氢氧化锂处理。在酸性介质中水解的例子是在合适的助溶剂中在高温下用无机酸处理式(II)的化合物,例如在60℃下在二烷中用5N盐酸处理过夜。本领域技术人员熟悉这类方法。
可通过使式(III)的化合物或它的酸加成盐与式(IV)的化合物反应来制备式(II)的化合物:
其中R如式(II)中所定义,
其中R1和R2如式(I)中所定义,X为羟基或离去基团。
式(III)化合物的酸加成盐的合适例子为盐酸盐。当X为离去基团时,离去基团X的合适例子为卤素,尤其是氯。式(III)和(IV)的化合物之间的反应一般在惰性有机溶剂如四氢呋喃或二氯甲烷或混合有机/水体系中在室温或高温下在合适的碱存在时进行,碱例如有机碱(如三乙胺)、碱金属碳酸盐(如碳酸钾)或碱金属碳酸氢盐(如碳酸氢钠)。当X为羟基时,使用标准偶合方法例如在干二甲基甲酰胺中在室温下搅拌O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲脲六氟磷酸盐、三乙胺过夜来进行式(III)和(IV)的化合物之间的反应。
具体实施方式
可通过使式(V)的化合物与式(VI)的化合物偶合然后除去保护基团Ra来制备式(III)的化合物:
其中Z为离去基团,Ra为保护基团,
离去基团Z的合适例子为卤素、链烷磺酰氧基(例如甲磺酰基)、卤代链烷磺酰氧基(例如三氟甲磺酰氧基)或芳基磺酰氧基(例如对甲苯磺酰氧基)。保护基团Ra的合适例子包括下面列出的那些,尤其是叔丁氧基羰基(Boc)。
还可通过使式(V)的化合物与式(VII)的化合物偶合然后除去保护基团Ra并将Rb转化成氰基来制备式(III)的化合物:
其中Rb为羟甲基。式(V)和式(VII)的化合物之间的反应可按照与式(V)和式(VI)的化合物之间的反应类似的方式进行。得到产物的保护基团可通过上述方法除去。使用本领域技术人员熟悉和本文描述的过程将基团Rb转化成氰基。
式(V)和式(VI)或式(VII)化合物之间的反应可在例如本领域技术人员熟悉的Suzuki偶合条件下进行。例如,可使用钯催化剂(例如四(三苯膦)钯(0))在合适的溶剂(例如1-甲基-2-吡咯烷酮)中在高温下在合适的碱(例如三乙胺)存在时进行反应。得到产物的保护基团可通过本领域技术人员熟悉的方法除去。当保护基团为叔丁氧基羰基时,可通过在适宜的溶剂(例如醇,如乙醇或异丙醇)中酸处理(例如用盐酸)来进行脱保护。
可使用本文描述的过程由市售4-溴-3,5-二甲氧基苯甲酸制备式(VI)的中间体化合物。式(II)、(III)和(IV)的中间体化合物被认为是新的,并构成本发明的又一方面。
本发明提供式(II)的化合物。本发明尤其提供其中R2为C1-6烷氧基或氟的式(II)的化合物。
本发明还提供式(III)的化合物或它的酸加成盐。
本发明还提供式(VI)的化合物。
中间体化合物(IV)和(V)为市售的,或可使用本文描述的方法、通过本领域技术人员已知的方法或类似于它们的方法来制备。
本领域技术人员能认识到,在制备式(I)的化合物或它的可药用衍生物时,必需和/或需要保护分子中的一个或多个敏感基团以防止不需要的副反应。按照本发明使用的合适保护基团对于本领域技术人员来说是熟知的,并可按常规方式使用。参见例如T.W.Greene和P.G.M.Wuts的“Protective groups in organic synthesis”(John Wiley&Sons 1991)或P.J.Kocienski的“Protective Groups”(Georg ThiemeVerlag 1994)。合适的氨基保护基团的例子包括酰基型保护基团(例如甲酰基、三氟乙酰基、乙酰基)、芳族尿烷型保护基团(例如苄氧基羰基(Cbz)和取代的Cbz)、脂肪族尿烷保护基团(例如9-芴基甲氧基羰基(Fmoc)、叔丁氧基羰基(Boc)、异丙氧基羰基、环己氧基羰基)和烷基型保护基团(例如苄基、三苯甲基、氯三苯甲基)。合适的氧保护基团的例子可包括例如烷基甲硅烷基,如三甲基甲硅烷基或叔丁基二甲基甲硅烷基;烷基醚如四氢吡喃基或叔丁基;或酯如乙酸酯。
可按照下面的分析测试本发明化合物的体外生物活性。
Jurkat J6闪烁近似分析(SPA)
使用Jurkat J6闪烁近似分析研究在Jurkat J6细胞膜上表达的VLA-4与试验化合物的相互作用。在包含50mM HEPES、100mM NaCl和1mM MnCl2的分析缓冲液(用4M NaOH调整pH到7.5)中,使J6细胞(1百万个细胞/孔)涂到麦芽凝集素涂敷的SPA珠(Amersham,1mg/孔)上。在合适的溶剂中溶解氚标记的3H标准化合物A(1-3nM最终分析浓度)和试验化合物,并在分析缓冲液中稀释(最高分析浓度为2.5μm;10点剂量响应曲线)。一式二份分析化合物,应用四参数曲线拟合。按照Cheng&Prusoff(Biochem Pharmacol.,22(23):3099-3108(1973))的方法计算每种化合物的平衡离解常数。数据表示为平均pKi。
标准化合物A为(2S)-3-[4-({[4-(氨基羰基)-1-哌啶基]羰基}氧)苯基]-2-[((2S)-4-甲基-2-{[2-(2-甲基苯氧基)乙酰基]氨基}戊酰基)氨基]丙酸钾盐,其描述在专利申请WO 00/37444(Glaxo Group Ltd.等)中。可使用常规方法制备氚标记的3H衍生物。
按照这种方法测试根据本发明制备的所有实施例样品,发现pKi≥8.6。
式(I)的化合物或它的可药用衍生物抑制α4整联蛋白调节的细胞粘附。认为α4整联蛋白调节的细胞粘附与一系列病症有关,如:类风湿性关节炎(RA);哮喘;过敏症状如鼻炎;成人呼吸窘迫综合症;AIDS-痴呆;Alzheimer病;心血管病;血栓形成或有害血小板凝集;血栓溶解后再阻塞;再灌注损伤;皮肤炎症疾病如牛皮癣、湿疹、接触性皮炎和特应性皮炎;糖尿病(例如胰岛素依赖性糖尿病、自身免疫性糖尿病);多发性硬化;全身性红斑狼疮(SLE);炎症性肠病如溃疡性结肠炎、Crohn病(局限性肠炎)和囊炎(pouchitis)(例如在直肠结肠切除术和回肠肛门吻合术(ileoanal anastomosis)后产生的);与白细胞浸润到胃肠道有关的疾病,如腹腔疾病、非热带口炎性腹泻、与血清反应阴性关节病有关的肠病、淋巴细胞或胶原性结肠炎和嗜酸性胃肠炎;与白细胞浸润到其它上皮衬里组织(epithelial lined tissue)如皮肤、尿道、呼吸气道和关节滑膜有关的疾病;胰腺炎;乳腺炎(乳腺);肝炎;胆囊炎;胆管炎或胆管周围炎(胆管和肝周围组织);支气管炎;鼻窦炎;导致间质性纤维化的肺炎症,如过敏性肺炎;胶原病(在SLE和RA中);肉样瘤病;骨质疏松;骨关节炎;动脉粥样硬化;肿瘤性疾病包括肿瘤或癌生长的转移;伤口(伤口愈合增强);一些眼疾病如视网膜脱离、变应性结膜炎和自身免疫性葡萄膜炎;Sjogren综合症;器官移植后的排斥(慢性和急性);寄主抗移植物或移植物抗寄主病;内膜增生;动脉硬化(包括移植后移植物动脉硬化);手术如经皮冠状动脉腔内成形术(PTCA)和经皮动脉腔内再通术后再梗塞或再狭窄;肾炎;肿瘤血管生成;恶性肿瘤;多发性骨髓瘤和骨髓瘤引起的骨再吸收;脓毒病;和中枢神经系统损伤,如卒中、外伤性脑损伤和脊髓损伤和Meniere疾病。
本发明的化合物可优选用于治疗或预防哮喘、过敏症状如鼻炎、炎症性肠病如溃疡性结肠炎和Crohn病、类风湿性关节炎、特应性皮炎、多发性硬化和器官移植后的排斥。本发明的化合物尤其可用于治疗或预防炎症性肠病或多发性硬化。
本发明还提供治疗或预防其中α4整联蛋白调节的细胞粘附的抑制剂有益的病症的方法,该方法包括为需要其的患者给药安全和有效量的式(I)的化合物或它的可药用衍生物。本发明尤其提供治疗或预防上述病症的方法。
本发明还提供式(I)的化合物或它的可药用衍生物在治疗中尤其是上述疾病治疗或预防中的应用。
另一方面,本发明提供式(I)的化合物或它的可药用衍生物在生产药物中的用途,该药物用于治疗或预防其中α4整联蛋白调节的细胞粘附的抑制剂有益的病症,尤其是上述疾病。
尽管可以单独给药本发明的化合物,但按照标准药物实践优选配制成药物组合物。因此,本发明还提供药物组合物,其包括治疗有效量的式(I)的化合物或它的可药用衍生物与可药用载体或稀释剂。
本发明还提供一种药物组合物,包括式(I)的化合物或它的可药用衍生物和另外的治疗活性药剂。
本发明还提供制备药物组合物的方法,该方法包括混合至少一种本发明的化合物或它的可药用衍生物和可药用载体或稀释剂。
药物组合物可以以人用药物或兽药的形式用于人或动物应用,一般包括可药用稀释剂、载体或赋形剂中的任意一种或多种。用于治疗应用的可接受载体或稀释剂在药物领域中是众所周知的,并描述在例如Remington′s Pharmaceutical Sciences,Mack Publishing Co.(A.R.Gennaro edit.1985)中。药物载体、赋形剂或稀释剂的选择可就预定的给药途径和标准药物实践来选择。载体或稀释剂在不会对其接受者有害的意义上必须是可接受的。可药用载体或稀释剂可为例如粘合剂(例如糖浆、阿拉伯树胶、明胶、山梨糖醇、黄蓍胶、聚乙烯吡咯烷酮)、赋形剂(例如乳糖、蔗糖、玉米淀粉、磷酸钾、山梨糖醇、甘氨酸)、润滑剂(例如硬脂酸镁、滑石、聚乙二醇、硅石)崩解剂(例如马铃薯淀粉)、润湿剂(例如十二烷基硫酸钠)等。
本发明组合物的给药(输送)途径包括但不限于以下一种或多种:口服(例如作为片剂、胶囊、或作为可吸收溶液)、局部、粘膜(例如作为鼻吸入用喷雾剂或气雾剂)、鼻、肠胃外(例如通过注射形式)、胃肠、脊柱内、腹膜内、肌内、静脉内、子宫内、眼内、皮内、头颅内、气管内、叶鞘内、脑室内(intracerebroventricular)、大脑内、皮下、眼(包括玻璃体腔内内或intracameral)、经皮、直肠、含服、硬膜上、舌下。
例如,可以以片剂、胶囊、胚珠(ovule)、酏剂、溶液或混悬液的形式口服给药化合物,它们可包含调味剂或着色剂,用于即释、延迟释放、改进释放、缓释、脉冲释放或控释应用。片剂可包含赋形剂如微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙和甘氨酸,崩解剂如淀粉(优选玉米、马铃薯或木薯淀粉)、乙醇酸淀粉钠、交联羧甲纤维素钠和某些复合硅酸盐,和造粒粘合剂如聚乙烯吡咯烷酮、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、蔗糖、明胶和阿拉伯树胶。另外,可包括润滑剂如硬脂酸镁、硬脂酸、山嵛酸甘油酯和滑石。还可使用类似类型的固体组合物作为明胶胶囊中的填充物。在这点上,优选的赋形剂包括乳糖、淀粉、纤维素、乳糖或高分子量聚乙二醇。对于含水混悬液和/或酏剂,药剂可联合有各种甜味剂或调味剂、着色剂或染料、乳化剂和/或悬浮剂,和稀释剂如水、乙醇、丙二醇和甘油,以及它们的组合。
可使用已知的研磨方法如湿磨来研磨本发明的化合物以得到适合于片剂形式和其它剂型的粒度。可通过本领域中已知的方法制备本发明化合物的细分散(纳米颗粒)制剂,例如参见国际专利申请WO02/00196(SmithKline Beecham)。
如果肠胃外给药本发明的化合物,则这种给药的例子包括以下中的一种或多种:静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、intrastemally、头颅内、肌内或皮下给药药剂;和/或通过使用输注技术。对于肠胃外给药,化合物最好以无菌水溶液的形式使用,该水溶液可包含其它物质如足够的盐或葡萄糖以使溶液与血液等渗。水溶液应适当地被缓冲(优选到3-9的pH),如果需要的话。利用本领域技术人员众所周知的标准药物技术可容易地实现无菌条件下合适肠胃外制剂的制备。
如所示,可鼻内或通过吸入给药本发明的化合物,并方便地以干粉末吸入器形式或利用合适的推进剂从加压容器、泵、喷雾器或nebuliser中提供气雾剂来输送本发明的化合物,推进剂的例子包括:二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氢氟链烷如1,1,1,2-四氟乙烷(HFA 134AT””)或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA)(例如来自Ineos Fluor)、二氧化碳或其它合适的气体。在为加压气雾剂时,通过提供输送计量数量的阀确定剂量单位。加压容器、泵、喷雾器或nebuliser可包含活性化合物的溶液或悬浮液,例如使用乙醇和推进剂的混合物作为溶剂,其还可包含润滑剂,如脱水山梨糖醇三油酸酯。用于吸入器或吹药器的胶囊和筒(由例如明胶制成)可被配制包含化合物和合适粉末基料如乳糖或淀粉的粉末混合物。
或者,可以以栓剂或阴道栓的形式给药本发明的化合物,或可以以凝胶、水凝胶、洗剂、溶液、乳膏、软膏剂或扑粉的形式局部施加本发明的化合物。还可在皮肤上或经皮给药本发明的化合物,例如,通过使用皮肤贴。还可通过肺部或直肠途径给药它们。还可通过眼睛途径给药它们。对于眼应用,化合物可被配制成在等渗、pH已调节的无菌盐水中的微粉化悬浮液,或优选地,为在等渗、pH已调节的无菌盐水中的溶液,任选地结合防腐剂如benzylalkonium氯。或者,可将它们配制成软膏剂如凡士林。
对于到皮肤的局部施加,本发明的药剂可被配制成包含悬浮或溶解在例如具有以下一种或多种的混合物中的活性化合物的合适软膏剂:矿物油、液体石蜡、白凡士林、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蜡和水。或者,它可被配制成合适的洗剂或乳膏,悬浮或溶解在例如具有以下一种或多种的混合物中:矿物油、脱水山梨糖醇单硬脂酸酯、聚乙二醇、液体石蜡、多乙氧基醚60、鲸蜡酯蜡、鲸腊醇、2-辛基十二烷醇、苄醇和水。
可通过直接注射给药本发明的组合物。
在优选的实施方案中,全身(如口服、含服、舌下)输送本发明的药剂,较优选口服。
因此,优选药剂为适合于口服输送的形式。
通常,医师将确定最适合于个体患者的实际剂量。对于任何特定个体的具体剂量水平和剂量频率是可变化的,并取决于各种因素,包括所用的具体化合物的活性、该化合物的新陈代谢稳定性和作用长度、年龄、体重、通常健康状况、性别、饮食、给药模式和时间、排泄速度、药物联合应用、特定病症的严重程度和进行治疗的个体。
对于口服和肠胃外给药到人,药剂的日剂量水平可为单次或分开的剂量。
对于为人(大约70kg体重)给药,根据本发明的化合物的建议剂量为0.1mg-2g、更一般为0.1mg-1g活性成分/单位剂量,以游离酸的重量表示。每天可给药例如1-4次单位剂量。剂量将取决于给药途径。应认识到,有必要根据患者的年龄和体重以及病症的严重程度对剂量作出常规变化。剂量还取决于给药途径。确切剂量和给药途径最终在于值班医师或兽医的判断。
本发明的化合物还可与其它治疗药剂联合使用。因此,再一方面,本发明提供包括本发明的化合物或其可药用衍生物和其它治疗药剂的联合。
当式(I)的化合物或它的可药用衍生物与对相同病症有活性的第二治疗药剂联合使用时,每种化合物的剂量可与其单独使用时的剂量不同。本领域技术人员能容易地认识到适宜的剂量。应认识到,用于治疗或预防所需要的本发明化合物的用量将随病症性质和患者的年龄和症状而变化,并最终在于值班医师或兽医的判断。可与式(I)的化合物或它的可药用衍生物联合的其它活性药剂的例子包括但不限于:(a)其它VLA-4拮抗剂;(b)H1组胺拮抗剂;(c)NSAID’s;(d)抗糖尿病药如格列酮(e)抗胆碱能药(f)COX-2抑制剂,如2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪(如专利申请WO99/12930中所公开);(g)PDE-IV抑制剂;(h)类固醇如皮质类甾醇;(i)β激动剂;(j)趋化因子受体例如CCR-2、CCR-3、CCR-5和CCR-8的拮抗剂;(k)合适的多发性硬化治疗药或预防药,如干扰素;(l)LFA-1拮抗剂;(m)TNF抑制剂;(n)柳氮磺胺呲啶(sulphasalazine)和5-氨基水杨酸盐和(o)免疫抑制剂。
上面提到的联合可方便地被提供用于药物制剂形式,因此包括如上所述的联合和可药用载体或赋形剂的药物制剂构成本发明的又一方面。可通过任何便利途径在分开或联合的药物制剂中依次或同时给药这种联合的各个成分。当给药为依次时,可首先给药本发明的化合物或第二种治疗药剂。当给药为同时时,可在相同或不同的药物组合物中给药该联合。
当在同一制剂中联合时,应认识到,两种化合物必须稳定并彼此以及和制剂的其它成分相容。当分开配制时,可在任何方便的制剂中提供它们,方便地以本领域中对于这种化合物来说是已知的方式。
本说明书中引用的全部出版物包括但不限于专利和专利申请在此引入作为参考,如同每个单独的出版物被专门和单独指明被引入本文作为参考,好象完全陈述一样。
下面的制备和实施例说明了本发明化合物的制备。
通用方法
在试验部分中这样指明,术语MDAP表示质量定向自动制备,一种通过制备HPLC纯化化合物、通过使用质谱仪联合制备HPLC系统检测和收集所需质量的自动系统。在下文中,使用Waters FractionLynx MDAP系统,该系统具有使用水/乙腈梯度的合适反相柱,其中两种溶剂都包含0.1%的甲酸。
制备1
(S)-2-叔丁氧基羰基氨基-3-(4-羟基苯基)丙酸甲酯(P1)
向盐酸L-酪氨酸甲酯(200g,0.86mol,Aldrich)和碳酸氢钠(100g,1.19mol)在二氯甲烷(1L)和水(1L)中的混合物中分批加入二叔丁基二碳酸酯(200g,0.92mol)。在室温下搅拌混合物2小时。分离有机层,用二氯甲烷(500mL)再萃取水相。用硫酸镁干燥合并的有机层,过滤并在减压下浓缩得到粗制标题化合物,为无色玻璃,其不经纯化而用于后续步骤;LC/MS(ES-ve):[M-H]-在m/z 294处(C15H21NO5要求[M-H]-在m/z 294处)。
制备2
(S)-2-叔丁氧基羰基氨基-3-(4-三氟甲磺酰氧苯基)丙酸甲酯(P2)
向粗制(S)-2-叔丁氧基羰基氨基-3-(4-羟基苯基)丙酸甲酯(P1,70.5g,0.24mol)在二氯甲烷(1L)中的溶液中在氩气下加入吡啶(58mL,0.72mol)。在冰中冷却溶液,然后在搅拌下滴加三氟甲烷磺酸酐(52mL,0.31mol)。加入完成后,在冰中搅拌混合物2小时,用2M盐酸(500mL)洗涤,用硫酸镁干燥,过滤并在减压下浓缩。通过用乙酸乙酯∶己烷(15∶85)洗脱的硅胶色谱法(Biotage 75L,800g二氧化硅)纯化粗产物得到标题化合物,为无色油,其缓慢凝固得到白色固体;LC/MS(ES+ve):[M-BOC+H]+在m/z328处,(C16H20NO7S要求[M+H]+在m/z 428处)。
制备3
4-羟甲基-2,6-二甲氧基苯基硼酸(P3)
在氩气下将(3,5-二甲氧基苯基)甲醇(53g,0.31mol,Aldrich)在干四氢呋喃(1L)中的溶液冷却至-50℃到-70℃,并在30分钟内用正丁锂(450mL,在己烷中1.6M,0.72mol)处理。加入后,使反应混合物在45分钟内升温至0℃,然后留下在室温中放置2小时。随后再冷却反应物到-60℃,并分批用硼酸三甲酯(135mL,1.15mol)处理。加入后,使混合物升温到室温并再搅拌18小时。通过分批加入柠檬酸的水溶液(75g柠檬酸在300mL水中)在0℃下冷却(quench)反应物。通过加入氯化钠使水层饱和,产物用乙酸乙酯(2×1L)萃取。用硫酸镁干燥合并的有机层,过滤并在减压下浓缩。向残余物中加入乙酸乙酯(100mL),通过过滤收集得到的无色沉淀并在40℃下在真空中干燥得到标题化合物,为无色固体,其用于下面的反应中而不用纯化。
制备4
(S)-2-叔丁氧基羰基氨基-3-(4’-羟甲基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(P4)
向(S)-2-叔丁氧基羰基氨基-3-(4-三氟甲磺酰氧苯基)丙酸甲酯(P2,42.73g,0.10mol)和4-羟甲基-2,6-二甲氧基苯基硼酸(P3,29.7g,0.14mol)的干二甲基甲酰胺(250mL)溶液中加入三乙胺(28mL,0.20mol)。在用氩气脱气后,加入四(三苯膦)钯(0)(5.8g,5mmol),在氩气和90℃下加热混合物1小时。[NB观察到轻微放热]。在使其冷却到室温后,用乙酸乙酯(1L)和水(700mL)稀释混合物,并分离。用水(2×300mL)洗涤有机层,用硫酸镁干燥,过滤并在减压下浓缩。通过用乙酸乙酯∶己烷(50∶50)洗脱的硅胶色谱法(Biotage75L,800g二氧化硅)纯化粗产物得到标题化合物,为无色固体;LC/MS(ES+ve):[M-BOC+H]+在m/z346处,(C24H31NO7要求[M+H]+在m/z446处)。
制备5
(S)-2-叔丁氧基羰基氨基-3-(4’-甲酰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(P5)
向(S)-2-叔丁氧基羰基氨基-3-(4’-羟甲基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(P4,28.98g,65.1mmol)在二氯甲烷(1L)中的溶液中分批加入二氧化锰(230g,2.64mol)。在室温下干燥得到的悬浮液1小时,然后通过硅藻土过滤,用另外的二氯甲烷(1L)洗涤硅藻土垫(pad)。在减压下浓缩滤液得到产物,为无色泡沫,其可不用进一步纯化就可使用;LC/MS(ES+ve):[M-BOC+H]+在m/z344处,(C24H29NO7要求[M+H]+在m/z 444处)。
制备6
(S)-2-叔丁氧基羰基氨基-3-[4’-(肟基甲基)-2’,6’-二甲氧基联苯-4-基]丙酸甲酯(P6)
向(S)-2-叔丁氧基羰基氨基-3-(4’-甲酰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(P5,23.6g,53mmol)在四氢呋喃(300mL)中的溶液中加入盐酸羟胺(7.4g,106mmol)和二异丙基乙胺(18mL,106mmol)。在回流下加热反应混合物2小时,然后使其冷却到室温。在减压下浓缩溶液,然后再溶解在乙酸乙酯(500mL)中,用10%柠檬酸水溶液、水和盐水(各500mL)洗涤,用硫酸镁干燥,过滤并在减压下浓缩得到无色泡沫,其可不经进一步纯化而用于后续步骤;LC/MS(ES+ve):[M-BOC+H]+在m/z 359处,(C24H30N2O7要求[M+H]+在m/z 459处)。
制备7
盐酸(S)-2-氨基-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(P7)
在0℃和氩气下向(S)-2-叔丁氧基羰基氨基-3-[4’-(肟基甲基)-2’,6’-二甲氧基联苯-4-基]丙酸甲酯(P6,46.5g,101mmol)在二氯甲烷(500mL)中的溶液中滴加亚硫酰氯(30mL,411mmol)。使反应物升温至室温并搅拌3天。通过过滤收集沉淀的固体,用二氯甲烷(200mL)洗涤,并在减压下在45℃下干燥。分离标题化合物,为白色固体;LC/MS(ES+ve):[M+H]+在m/z 341处,(C19H20N2O4要求[M+H]+在m/z 341处)。
制备8
2-溴-5-羟基苯甲酸甲酯(P8)
在氩气下在干二氯甲烷(600mL)中搅拌2-溴-5-甲氧基苯甲酸(30.0g,130mmol,Aldrich),在干冰/丙酮中冷却,在15分钟内加入三溴化硼(在二氯甲烷中1M,280mL,280mmol)。然后在环境温度下搅拌混合物2.5小时,产生沉淀物。然后在30分钟内谨慎滴加甲醇(300mL)(注意:开始强烈放热,并有沸腾),最后得到暗色均匀溶液,向其中加入浓硫酸(15mL)。在回流下搅拌溶液1小时,冷却,并在减压下浓缩。将残余物溶解在二氯甲烷(500mL)中,用盐水(500mL)洗涤,用硫酸镁干燥,过滤并在减压下浓缩得到标题化合物,为固体;LC/MS(ES+ve):[M+H]+在m/z 231,233处(C8H7BrO3要求[M+H]+在m/z 231,233处)。
制备9
2-溴-5-乙氧基苯甲酸甲酯(P9)
在氩气下在干二甲基甲酰胺(150mL)中搅拌氢化钠(在矿物油中60%,4.24g,106mmol),在冰中冷却,在15分钟内在干二甲基甲酰胺(150mL)中加入2-溴-5-羟基苯甲酸甲酯(P8,20.41g,88mmol)。在环境温度下搅拌混合物45分钟,在冰中再冷却,并用碘乙烷(8.5mL,106mmol)处理。在环境温度下搅拌该混合物3小时,在减压下浓缩,用乙酸乙酯(400mL)稀释,用水(3×400mL)和盐水(400mL)洗涤,用硫酸镁干燥,过滤和在减压下浓缩得到标题化合物,其被痕量相应的乙酯和残余的矿物油污染。这种材料可以不经进一步纯化而用于后续步骤中;LC/MS(ES+ve):[M+H]+在m/z259,261处,(C10H11BrO3要求[M+H]+在m/z 259,261处)。
制备10
2-溴-5-乙氧基苯甲酸(P10)
在四氢呋喃(600mL)中搅拌2-溴-5-乙氧基苯甲酸甲酯(P9,20.53g,79mmol),并用在水(200mL)中的氢氧化锂(18.2g,791mmol)处理。搅拌混合物4天,在减压下浓缩,用水(500mL)稀释,用5N盐酸酸化,并萃取到乙酸乙酯(2×300mL)中。用盐水(250mL)洗涤合并的萃取物,用硫酸镁干燥,过滤并在减压下浓缩得到浅白色固体。用己烷研磨,过滤和干燥得到标题化合物,为白色粉末;LC/MS(ES+ve):[M+H]+在m/z 245,247处,(C9H9BrO3要求[M+H]+在m/z245,247处)。
制备11
(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基]氨基}-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(P11)
在二氯甲烷(500mL)和水(400mL)中溶解盐酸(S)-2-氨基-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(P7,37.1g,98.5mmol),并在氩气下冷却到0℃。向反应混合物中加入碳酸氢钠(20.1g,239.3mmol),然后滴加2-溴-5-乙氧基苯甲酰氯(27.2g,103.7mmol){由2-溴-5-乙氧基苯甲酸(P10)通过标准过程使用草酰氯(4当量)在二氯甲烷和一滴二甲基甲酰胺中制备}。在0℃下搅拌反应物1小时,然后用碳酸氢钠饱和水溶液(200mL)稀释。在分离有机层后,用二氯甲烷(2×400mL)再萃取水层。在硫酸钠上干燥合并的有机层,过滤并在减压下浓缩。通过用乙酸乙酯∶二氯甲烷(3∶97)洗脱的硅胶色谱法(Biotage 75L,800g二氧化硅)纯化产物得到标题化合物,为无色固体;MS(ES+ve):[M+H]+在m/z 567,569处,(C28H27BrN2O6要求[M+H]+在m/z 567,569处)。
制备12
(S)-2-{[1-(2-溴-5-甲氧基苯基)甲酰氧基]氨基}-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸乙醋(P12)
在室温和氩气下向二甲基甲酰胺(25mL)中搅拌加入2-溴-5-甲氧基苯甲酸(0.355g,1.54mmol,Aldrich)、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(1.168g,2当量)和三乙胺(1.069mL,5当量)。0.5小时后,加入对应于P7(P13)的乙酯即盐酸(S)-2-氨基-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸乙酯(0.6g,1当量),并继续搅拌过夜。然后在减压下蒸发溶剂,并在乙酸乙酯和水之间分配残余物。在蒸干前,用水(×2)和碳酸氢钠饱和水溶液洗涤有机层。通过在二氧化硅上的柱色谱法利用二氯甲烷中0-10%甲醇的梯度纯化粗产物,随后通过制备HPLC得到标题化合物。
MS(AP+ve):[M+H]+在m/z 567,569处,(C28H27BrN2O6要求[M+H]+在m/z 567,569处)。
制备13
盐酸(S)-2-氨基-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸乙酯(P7-相应的乙酯)(P13)
在0℃和氩气下向(S)-2-叔丁氧基羰基氨基-3-[4’-(肟基甲基)-2’,6’-二甲氧基联苯-4-基]丙酸乙酯(12.5g,26.5mmol)[类似于顺序P1-P6制备,除了在制备1中用盐酸L-酪氨酸乙酯(来自Bachem)代替L-酪氨酸甲酯开始外]在二氯甲烷(250mL)中的溶液中在15分钟内滴加亚硫酰氯(7.71mL,105.7mmol)。在浴温(batch temperature)下再搅拌反应物15分钟,然后使其升温至室温并继续搅拌过夜。通过过滤收集沉淀的标题化合物,用二氯甲烷(2×15mL)洗涤,并在减压下干燥。LC/MS(ES+ve):[M+H]+在m/z 355处(C20H22N2O4要求[M+H]+在m/z 355处)。
实施例1
(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸(E1)
将(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基]氨基}-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(P11,51.5g,90.8mmol)在四氢呋喃(950mL)中的溶液冷却到0℃,并用0.5M氢氧化锂水溶液(700mL)处理。在0℃下搅拌反应混合物1小时,然后用5M盐酸酸化。在真空中蒸发四氢呋喃,并用乙酸乙酯稀释残余物。在分离有机层后,用乙酸乙酯再萃取水相。用水(×2)洗涤合并的有机层,然后用硫酸镁干燥,在真空中蒸发溶剂产生标题化合物,为无色固体;
1H NMRδ(DMSO-d6):1.29(3H,t,J 7.0Hz),2.96(1H,dd,J 13.9,10.9Hz),3.22(1H,dd,J 14.1,4.2Hz),3.71(6H,s),3.99(2H,q,J 7.0Hz),4.65(1H,ddd,J 10.9,8.4,4.3Hz),6.69(1H,d,J 3.0Hz),6.91(1H,dd,J 6.8,3.1Hz),7.14(2H,d,J 8.1Hz),7.24(2H,s),7.32(2H,d,J 8.1Hz,),7.47(1H,d,J 8.8Hz),8.77(1H,br.d,J 8.4Hz),12.83(1H,br.s);
MS(ES+ve)[M+H]+在m/z 553,555处,(C27H25BrN2O6要求[M+H]+在m/z 553,555处)。
实施例1-替代的合成方法
还使用下面的方法制备标题化合物。
4-溴-3,5-二甲氧基苯甲酰胺
向4-溴-3,5-二甲氧基苯甲酸(得自Jintan Baocheng,100g,0.38mol)在甲苯(700mL)和二甲基甲酰胺(1mL)中的搅拌悬浮液中加入亚硫酰氯(60mL,0.82mol)。在回流和氮气下搅拌反应物。2小时后HPLC表明酸完全消耗得到甲酯(来自酰基氯的甲醇淬灭)。通过蒸馏除去挥发物,得到的固体加入到0.88氨水(350mL)中。在环境温度下搅拌混合物45分钟。过滤产物,用水(2×200mL)洗涤,并在真空下干燥过夜得到标题化合物,为浅白色固体。
1H NMRδ(DMSO-d6):3.89(6H,s),7.23(2H,s),7.52(1H,s),8.2(1H,s)MS(ES+ve)[M+H]+在m/z 260,262处,(C9H10BrNO3要求[M+H]+在m/z 260,262处)。
4-溴-3,5-二甲氧基苄腈
向4-溴-3,5-二甲氧基苯甲酰胺(104g,0.38mol)在吡啶(127ml,1.57mol)和四氢呋喃(950mL)中的悬浮液中加入三氟乙酸酐(129mL,0.91mol)。用冰浴将温度保持在20-25℃。在20-25℃和氮气下搅拌橙色/棕色溶液1小时。HPLC表明4-溴-3,5-二甲氧基苯甲酰胺完全消耗得到产物。浓缩反应混合物至初始体积的大约50%。加入水(900mL),滤出产物,用水(2×250mL)洗涤,并在40℃下和真空中干燥得到标题化合物,为蓬松浅白色固体。
1H NMRδ(CDCl3):3.96(6H,s),6.8(2H,s)
4-氰基-2,6-二甲氧基苯基硼酸
在5-10℃下和氮气中向4-溴-3,5-二甲氧基苄腈(50g,0.207mol)在四氢呋喃(400mL)中的浆液中加入异丙基氯化镁(在四氢呋喃中的2M溶液,206mL,0.412mol)。使得到的溶液升温至环境温度。HPLC分析表明原料完全消耗。冷却反应混合物至5-10℃,并加入到硼酸三甲酯(103mL,0.92mol)在四氢呋喃(100mL)中的溶液中,在加入过程中保持温度低于10℃。使反应物升温至环境温度。HPLC表明完全反应至产物。冷却反应混合物至5-10℃,并加入1M盐酸(500mL),在加入过程中保持温度低于10℃。在环境温度下搅拌混合物30分钟,然后通过蒸馏除去挥发物。过滤产物,用水洗涤,并在40℃下和真空中干燥得到标题化合物,为浅白色固体。
1H NMRδ(DMSO-d6):3.78(6H,s),7.0(2H,s),9.25(2H,s)。
盐酸(S)-2-氨基-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯
在90℃下向(S)-甲基酪氨酸(来自Flamma,15.2g,77.9mmol)在甲苯(120mL)中的溶液中滴加二叔丁基二碳酸酯(17.9g,81.8mmol)在甲苯(60mL)中的溶液。在90℃下搅拌反应混合物至少30分钟。HPLC表明一旦完成,就冷却反应混合物到0℃,并保持温度在0℃情况下加入吡啶(19mL,0.23mol)。保持温度在0℃,滴加三氟甲磺酸酐(16.7mL)。在0℃下搅拌橙色浆液至少2小时。HPLC表明一旦完成,就保持温度在0℃加入2M盐酸(133mL)。分离层,用10%w/w碳酸钠水溶液(138mL)和36%w/w盐水(138mL)洗涤上部有机层。将有机层浓缩至大约60mL,加入固体氯化钠(30g),然后是正庚烷(300mL)。过滤混合物,滤液萃取到1甲基-2-吡咯烷酮(2×150mL)中。在真空中蒸馏残余的挥发性有机溶剂。加入4-氰基-2,6-二甲氧基苯基硼酸(17.5g,84.5mmol),并对溶液脱气。加入四(三苯膦)钯(0)(3g,2.7mmol)和三乙胺(19.8mL),加热反应混合物至70℃。在70℃下搅拌反应物至少2小时。HPLC表明一旦完成,就将反应混合物转移到另一容器中并用甲苯(300mL)稀释。加入2M盐酸(300mL)并过滤混合物。分离有机层并用水(300mL)洗涤。过滤有机层,并通过甲苯(90mL)洗涤。用Silicycle二氧化硅负载的N-官能化硫脲(11.7g)搅拌甲苯溶液至少15小时。过滤二氧化硅并用甲苯(30mL)洗涤。Azeotropically干燥溶液,然后在50℃下缓慢加入到氯化氢在异丙醇(155mL,5M浓度)的溶液中。在50℃下搅拌反应混合物30分钟直到HPLC表明完成。冷却混合物至20℃,并在真空中滤出产物,用甲苯(60mL)洗涤。在40℃下和真空中干燥固体得到标题化合物,为浅白色固体。
2-溴-5-羟基苯甲酸甲酯
在-15至-10℃下向2-溴-5-甲氧基苯甲酸(得自Wychem,20g,86.6mmol)在二氯甲烷(200mL)中的搅拌悬浮液中加入三溴化硼(18mL,190.5mmol)在二氯甲烷(18mL)中的溶液。使黄色悬浮液升温至0℃。HPLC分析表明酸完全消耗。通过加入甲醇(100mL)淬灭反应。在回流(大约45℃)下搅拌透明暗色溶液12小时,蒸发近干,在水(400mL)和乙酸乙酯(500mL)之间分配,并分离。用盐水(250mL)洗涤有机溶液,并蒸发产生标题化合物,为膏状固体。
2-溴-5-乙氧基苯甲酸甲酯
在70-75℃下和氮气中搅拌2-溴-5-羟基苯甲酸甲酯(18.9g,81.8mmol)、碳酸钾(34.4g,249.5mmol)和碘乙烷(13mL,163.7mmol)在甲基异丁基酮(190mL)中的混合物15小时。HPLC分析表明完全反应至产物。加入水(100mL)。除去水相,用盐水(100mL)洗涤甲基异丁基酮溶液,然后在真空中浓缩产生标题化合物,为橙色油。
2-溴-5-乙氧基苯甲酸
在环境温度下搅拌2-溴-5-乙氧基苯甲酸甲酯(20.7g,79.9mmol)和10M氢氧化钠(40mL,0.4mol)在四氢呋喃(100mL)中的混合物18小时。HPLC分析表明原料完全消耗。冷却反应物至0-5℃,并用5M盐酸酸化至pH1。除去有机相,用叔丁基甲醚(40mL)萃取水相。合并有机相,用盐水(50mL)洗涤,并在真空中浓缩产生标题化合物,为膏状固体。
(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基]氨基}-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯
向盐酸(S)-2-氨基-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(5g,13.3mmol)在四氢呋喃(100mL)中的悬浮液中加入三乙胺(5.5mL,39.8mmol)。在20℃下搅拌悬浮液60分钟。保持温度在0-5℃,在10分钟内滴加2-溴-5-乙氧基苯甲酰氯1(3.4g,13mmol)在甲苯(10mL)中的溶液。在0-5℃下搅拌混合物至少60分钟。HPLC表明一旦完成,就依次用2M盐酸(25mL)、10%w/w碳酸钠水溶液(25mL)和36%w/w盐水(25mL)洗涤反应混合物。通过蒸馏除去溶剂得到膏状固体。将其溶解在四氢呋喃(75mL)中并用Silicycle二氧化硅负载的N-官能化硫脲(Silicycle silica supported N-functionalised thiourea)(0.75g)搅拌过夜。过滤二氧化硅,四氢呋喃溶液浓缩至大约30mL。在45分钟内加入水(75mL)。在环境温度下搅拌浆液1小时。过滤产物,用水(30mL)洗涤并在40℃下和真空中干燥得到标题化合物,为浅白色固体。
1由2-溴-5-乙氧基苯甲酸(3.2g,13mmol)通过标准方法使用亚硫酰氯(3.3当量)在甲苯(16mL)中制备。
(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基]氨基}-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸四氢呋喃溶剂化物
将(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基]氨基}-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸甲酯(5g,8.8mmol)在四氢呋喃(25mL)中的溶液冷却到0-5℃。保持温度低于5℃,滴加2M氢氧化钠(4.5mL,9mmol)。在0-5℃下搅拌反应混合物至少18小时。HPLC表明一旦完成,就在用2M盐酸(大约10mL)调整到pH=1前用水(50mL)稀释混合物,在0-5℃下陈化(aged)得到的悬浮液至少30分钟。在真空中滤出固体并用水(20mL)洗涤,然后在40℃下和真空中干燥产物得到标题化合物,为浅白色固体。
(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸(E1)
将(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基]氨基}-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸四氢呋喃溶剂化物(5g)在甲醇(50mL)中的悬浮液加热至回流,并搅拌形成溶液。冷却溶液至60℃并过滤。然后在1.5小时内冷却溶液至0℃。在0℃下陈化得到的悬浮液2小时。在真空中滤出固体并用冷甲醇(5mL)洗涤。在40℃下和真空中干燥产物得到标题化合物,为白色结晶固体。
实施例2
(S)-2-{[1-(2-溴-5-氟苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸(E2)
使用P13和2-溴-5-氟苯甲酰氯(来自Apollo)按照类似于制备11和实施例1的方式制备标题化合物。[M+H]+在m/z527,529处。
实施例3
(S)-2-{[1-(2-溴-5-甲氧基苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸(E3)
实施例3a
可使用P7和2-溴-5-甲氧基苯甲酰氯(来自Avocado)按照类似于制备11和实施例1的方式制备标题化合物。
实施例3b
在室温下向(S)-2-{[1-(2-溴-5-甲氧基苯基)甲酰氧基]氨基}-3-(4’-氰基-2’,6’-二甲氧基联苯-4-基)丙酸乙酯(P12,0.539g,0.95mmol)在四氢呋喃(30mL)中的溶液中搅拌加入氢氧化锂水溶液(0.5M,25mL)。继续搅拌2小时,然后用过量的10%柠檬酸水溶液淬灭(quench)反应。然后用乙酸乙酯萃取混合物,用另外一部分柠檬酸然后用水(×2)洗涤有机层。蒸发有机层至干,通过MDAP纯化得到的粗产物得到标题化合物,为白色固体。[M+H]+在m/z539,541处。
实施例4
(S)-2-{[1-(2-溴-5-甲基苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸(E4)
使用P13和2-溴-5-甲基苯甲酸(来自Apin)按照类似于制备12的方式制备标题化合物,并通过实施例3b的方法水解得到的乙酯。[M+H]+在m/z523,525处。
实施例5
(S)-2-{[1-(2-溴-5-氯苯基)甲酰氧基]氨基}-3-[4′-氰基-2′,6′-二甲氧基联苯-4-基]丙酸(E5)
按照类似于实施例3b的方式由相应的乙酯制备标题化合物。使用制备12的方法由P13和2-溴-5-氯苯甲酸(来自Lancaster)制备乙酯。[M-H]-在m/z541,543,545处。
实施例6
(S)-2-{[1-(2,5-二溴苯基)甲酰氧基]氨基}-3-[4′-氰基-2′,6′-二甲氧基联苯-4-基]丙酸(E6)
按照类似于实施例3b的方式由相应的乙酯制备标题化合物。通过制备12的方法由P13和2,5-二溴-5-氯苯甲酸(来自Lancaster)制备乙酯。[M-H]-在m/z585,587,589处。
实施例7
(S)-2-{[1-(5-(异-丙氧基)-2-溴苯基)甲酰氧基]氨基}-3-[4′-氰基-2′,6′-二甲氧基联苯-4-基]丙酸(E7)
按照类似于实施例3b的方式由相应的乙酯制备标题化合物。通过制备12的方法由P13和5-异丙氧基-2-溴苯甲酸(类似于制备8-制备10来制备,除了在类似于制备9的烷基化步骤中使用异丙基溴外)制备乙酯。[M-H]-在m/z565,567处。
Claims (19)
1.式(I)的化合物或它的可药用衍生物:
其中:
R1为溴;和
R2为卤素、C1-6烷基或C1-6烷氧基。
2.根据权利要求1的化合物,其中R2为卤素或C1-6烷氧基。
3.根据权利要求2的化合物,其中R2为氟、甲氧基或乙氧基。
4.根据权利要求1的化合物,其选自:
(S)-2-{[1-(2-溴-5-甲基苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸);
(S)-2-{[(2-溴-5-氯苯基)甲酰氧基]氨基}-3-[4′-氰基-2′,6′-二甲氧基)联苯-4-基]丙酸;
(S)-2-{[(2,5-二溴苯基)甲酰氧基]氨基}-3-[4′-氰基-2′,6′-二甲氧基)联苯-4-基]丙酸;
(S)-2-{[(5-(异-丙氧基)-2-溴苯基)甲酰氧基]氨基}-3-[4′-氰基-2′,6′-二甲氧基)联苯-4-基]丙酸
或它们的可药用衍生物。
5.(S)-2-{[1-(2-溴-5-乙氧基苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸或它的可药用衍生物。
6.(S)-2-{[1-(2-溴-5-氟苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸或它的可药用衍生物。
7.(S)-2-{[1-(2-溴-5-甲氧基苯基)甲酰氧基]氨基}-3-(4′-氰基-2′,6′-二甲氧基联苯-4-基)丙酸或它的可药用衍生物。
或它的可药用衍生物。
8.制备式(I)的化合物的方法,其包括水解式(II)的羧酸酯衍生物:
其中R1和R2如式(I)中所定义,R为能形成羧酸酯的基团,和任选地然后形成它的可药用衍生物。
9.用于治疗的根据权利要求1至7中任意一项的化合物。
10.一种药物组合物,其包含与可药用载体或稀释剂混合的治疗有效量的根据权利要求1至7中任意一项的化合物。
11.一种药物组合物,其包含根据权利要求1至7中任意一项的化合物和另外的治疗活性药物。
12.根据权利要求1至7中任意一项的化合物的应用,用于生产治疗或预防其中α4整联蛋白调节的细胞粘附的抑制剂有益的病症的药物。
13.治疗或预防其中α4整联蛋白调节的细胞粘附的抑制剂有益的病症的方法,该方法包括为需要其的患者给药安全和有效量的根据权利要求1至7中任意一项的化合物。
14.根据权利要求13的方法,其中所述病症选自:类风湿性关节炎(RA);哮喘;过敏症状如鼻炎;成人呼吸窘迫综合症;AIDS-痴呆;Alzheimer病;心血管病;血栓形成或有害血小板凝集;血栓溶解后再阻塞;再灌注损伤;皮肤炎症疾病如牛皮癣、湿疹、接触性皮炎和特应性皮炎;糖尿病(例如胰岛素依赖性糖尿病、自身免疫性糖尿病);多发性硬化;全身性红斑狼疮(SLE);炎症性肠病如溃疡性结肠炎、Crohn病(局限性肠炎)和囊炎(例如在直肠结肠切除术和回肠肛门吻合术后产生的);与白细胞浸润到胃肠道有关的疾病,如腹腔疾病(Celiac disease)、非热带口炎性腹泻、与血清反应阴性关节病有关的肠病、淋巴细胞或胶原性结肠炎和嗜酸性胃肠炎;与白细胞浸润到其它上皮衬里组织如皮肤、尿道、呼吸气道和关节滑膜有关的疾病;胰腺炎;乳腺炎(乳腺);肝炎;胆囊炎;胆管炎或胆管周围炎(胆管和肝周围组织);支气管炎;鼻窦炎;导致间质性纤维化的肺炎症,如过敏性肺炎;胶原病(在SLE和RA中);肉样瘤病;骨质疏松;骨关节炎;动脉粥样硬化;肿瘤性疾病包括肿瘤或癌生长的转移;伤口(伤口愈合增强);一些眼疾病如视网膜脱离、变应性结膜炎和自身免疫性葡萄膜炎;Sjogren综合症;器官移植后的排斥(慢性和急性);寄主抗移植物或移植物抗寄主病;内膜增生;动脉硬化(包括移植后移植物动脉硬化);手术如经皮冠状动脉腔内成形术(PTCA)和经皮动脉腔内再通术后再梗塞或再狭窄;肾炎;肿瘤血管生成;恶性肿瘤;多发性骨髓瘤和骨髓瘤引起的骨再吸收;脓毒病;和中枢神经系统损伤,如卒中、外伤性脑损伤和脊髓损伤和Meniere疾病。
15.根据权利要求14的方法,其中所述病症为炎症性肠病或多发性硬化。
17.根据权利要求16的化合物,其中R2为C1-6烷氧基或氟。
18.式(III)的化合物或它的酸加成盐:
其中R为能形成羧酸酯的基团。
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