CN102007098A - 治疗性的取代的环戊烷 - Google Patents
治疗性的取代的环戊烷 Download PDFInfo
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- CN102007098A CN102007098A CN2009801135658A CN200980113565A CN102007098A CN 102007098 A CN102007098 A CN 102007098A CN 2009801135658 A CN2009801135658 A CN 2009801135658A CN 200980113565 A CN200980113565 A CN 200980113565A CN 102007098 A CN102007098 A CN 102007098A
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Abstract
本发明公开了治疗性化合物。还公开了相关的方法、组合物和药物。本发明公开的化合物用于治疗眼部病症、肠病和秃发。
Description
相关专利申请的交叉引用
本申请要求2008年3月18日提交的序列号为61/037,625的美国临时专利申请和2009年3月16日提交的序列号为12/404,753的美国非临时专利申请的优先权,所述申请均在此通过引用的方式全文纳入本文。
背景技术
降眼压剂可用于治疗多种不同的高眼压病症,如在术后和激光小梁切除术后的高眼压症状、青光眼;以及作为术前辅助。
青光眼是一种眼部疾病,其特征为眼内压增高。基于青光眼的病因学,已将其分为原发性或继发性。例如,成人的原发性青光眼(先天性青光眼)可以为开角型青光眼或者为急性或慢性闭角型青光眼。继发性青光眼由例如葡萄膜炎、眼内肿瘤或增大性白内障等预先存在的眼部疾病所引起。
原发性青光眼的基本病因还不清楚。增高的眼内张力是由于房水外流受阻而造成的。在慢性开角型青光眼中,前房及其解剖结构看起来均正常,但是房水的排出受到阻碍。在急性或慢性的闭角型青光眼中,前房变浅,虹膜角变窄,虹膜可在施累姆氏管(canal of Schlemm)的入口处堵塞小梁网。瞳孔的扩大将虹膜根部向前推向虹膜角,并可能造成瞳孔阻滞,由此促发急性发作。前房角狭窄的眼球容易造成不同严重程度的急性闭角型青光眼发作。
房水由后房流向前房并随后流入施累姆氏管的过程中受到的任何妨碍都会导致继发性青光眼。眼前段的炎性疾病可能通过导致虹膜膨起的完全虹膜后粘连,从而阻止液体的流出,并且可能使渗出物栓塞流出管道。其他常见原因有眼内肿瘤、增大性白内障、视网膜中央静脉阻塞、眼创伤、手术过程和眼内出血。
青光眼的所有类型加在一起,所有40岁以上人群中的患病率大约为2%,它可能在逐渐发展多年后才会造成视力的快速丧失。对于不建议手术的病例,局部用的β-肾上腺素受体拮抗剂通常是选择用于治疗青光眼的药物。
某些类花生酸类及其衍生物目前市售用于治疗青光眼。类花生酸类及其衍生物包括多种生物学上重要的化合物,例如前列腺素及其衍生物。前列腺素可描述为含有下列结构的前列腺烷酸衍生物。
根据前列腺烷酸骨架的结构和其脂肪环上所带的取代基,已知有多种类型的前列腺素。根据侧链上不饱和键的数目以及脂肪环上取代基的构型可以进行进一步的分类,前者可通过前列腺素属类后的数字下标表示[例如前列腺素E1(PGE1),前列腺素E2(PGE2)],后者可通过α或β表示[例如前列腺素F2α(PGF2β)]。
下面所示的前列腺素E类似物公开于以下文档中:美国专利5,462,968、美国专利5,698,598和美国专利第6,090,847,所述申请特此通过引用的方式纳入本文。
前列腺素EP2选择性激动剂可用于治疗青光眼,并被认为具有一些医药用途。例如,美国专利6,437,146指出前列腺素EP2选择性激动剂可用于“治疗或预防关节和肌肉的炎症和疼痛(如风湿性关节炎、风湿性脊椎炎、骨关节炎、痛风性关节炎、幼年型关节炎等),炎性皮肤病症(如晒伤、烧伤、湿疹、皮炎等),炎性眼部病症(如结膜炎等),有炎症问题的肺部病变(如哮喘、支气管炎、饲鸽者肺(pigeon fancier’s disease)、农民肺(farmer’s lung)等),与炎症有关的胃肠道病症(如口疮性溃疡、克罗恩氏病、萎缩性胃炎、痘疮样胃炎(gastritis varialoforme)、溃疡性结肠炎、乳糜泄(coeliac disease)、局限性肠炎(regional ileitis)、肠易激综合征等),龈炎,术后或创伤引起的炎症、疼痛和肿胀,与炎症有关的发热、疼痛和其他症状,变应性疾病,系统性红斑狼疮,硬皮病,多肌炎,腱炎,粘液囊炎,结节性动脉周炎,风湿热,舍格伦综合征,白塞氏病,甲状腺炎,I型糖尿病,糖尿病并发症(糖尿病微血管病、糖尿病视网膜病、糖尿病肾病(diabetic neohropathy)等),肾病综合症,再生障碍性贫血,重症肌无力,葡萄膜炎,接触性皮炎,牛皮藓,川崎氏病(Kawasaki disease),肉样瘤病(sarcoidosis),霍奇金氏病,阿尔茨海默病、肾功能紊乱(肾炎、肾炎综合征等),肝功能紊乱(肝炎、肝硬化等),胃肠功能紊乱(腹泻、炎性肠病等),休克,以异常骨代谢为特征的骨疾病如骨质疏松(尤其是绝经期后骨质疏松),高血钙症,甲状旁腺功能亢进,骨炎病(Paget’s bone disease),骨质溶解,有骨转移或无骨转移的恶性高血钙症,风湿性关节炎,牙周炎,骨关节炎,骨痛,骨膜炎,癌性恶病质,结石病(calculosis,lithiasis)(尤其是尿石症(urolithiasis)),实体癌,系膜增生性肾小球肾炎,水肿(如心源性水肿、脑水肿等),高血压如恶性高血压等,经前紧张症,尿结石(urinary calculus),少尿症如由急性或慢性衰竭引起的少尿症,高磷酸盐尿等。”
美国专利6,710,072指出EP2激动剂可用于治疗或预防“骨质疏松症、便秘、肾脏功能紊乱、性功能障碍、秃发、糖尿病、癌症和免疫调节障碍......各种病理生理疾病包括急性心肌梗死、血管血栓、高血压、肺动脉高压、缺血性心脏疾病、充血性心力衰竭和心绞痛。”
发明内容
本文公开的是可用于治疗青光眼、炎性肠病、刺激毛发生长和刺激毫毛转变为终毛的化合物。下面公开所述化合物。
具体实施方式
本文公开一种包括以下的化合物或其可药用盐或前药,
其中虚线表示存在或不存在的键。
由于虚线表示一个存在或不存在的键,因而可存在下面所示的化合物或者其可药用盐或前药。
具体地考虑到具有以下立体化学结构的化合物及其可药用盐和前药,但这不以任何方式限制本发明的范围。
本文公开的化合物可用于预防或治疗哺乳动物的青光眼或高眼压,或用于制造一种治疗青光眼或高眼压的药物。不仅如此,本文所述的化合物还可以用来治疗秃发。它们还可用于治疗本领域公开的那些前列腺素EP2激动剂能够治疗的疾病,如上文列举的那些。
“可药用盐”是保留母体化合物的活性,并且与母体化合物相比不会对被给药受试者和施用环境产生任何额外有害作用或不良作用的盐。可药用盐也指由于施用一种酸、另一种盐或一种能转化为酸或盐的前药而可在体内形成的任何盐。
具有酸性官能团的可药用盐可以从有机或无机碱衍生而来。所述盐可以包括单价或多价离子。特别关注的是无机离子锂、钠、钾、钙和镁。有机盐可使用胺制备,所述胺特别是铵盐如单烷基胺、二烷基胺和三烷基胺或乙醇胺。也可以用咖啡因、缓血酸胺和类似分子来形成盐。盐酸或一些其他可药用酸可与一种含有碱性基团(如氨基或哌啶环)的化合物形成盐。
“前药”是一种在给药后转化为治疗性地活性化合物的化合物,该术语在本文中应如本领域技术人员通常所理解的那样广义地解释。转化可通过酯基或其他一些生物学上不稳定基团的水解而进行,但这不以任何方式限制本发明的范围。通常,前药与其转化成的治疗性地活性化合物相比不具有活性或活性较低,但这不是必然的。尤其考虑的是本文所公开的化合物的酯类前药。酯可由C1羧酸(如天然前列腺素的末端羧酸)衍生而来,也可由分子的另一部分(如苯环)上的羧酸官能团衍生而来。酯可为烷基酯、芳基酯或杂芳基酯,但这不以任何方式限制本发明的范围。术语烷基具有本领域技术人员通常理解的含义,并且是指直链、支链或环状的烷基部分。C1-6烷基酯特别有用,其中所述酯的烷基部分具有1到6个碳原子,并包括但不局限于甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基异构体、己基异构体、环丙基、环丁基、环戊基、环己基及其具有1到6个碳原子的组合等。C1-6烷基酯具有一个与酯上的氧直接相连的具有1到6个碳原子的烷基部分。
还可考虑下列化合物,其任意可药用盐或任意前药也是本文尤其考虑的。除非指明,否则所有化合物均为非对映异构体的混合物:
一个实施方案为本文公开的任意化合物(包括上文公开的化合物)在制造用于治疗青光眼或高眼压的药物中的应用。
另一个实施方案为本文公开的任意化合物(包括上文公开的化合物)在制造用于治疗炎性肠病的药物中的应用。
另一个实施方案为一种方法,包括将本文公开的任意化合物(包括上文公开的化合物)局部施用于哺乳动物的眼部以治疗青光眼或眼高压。
另一个实施方案为本文公开的任意化合物(包括上文公开的化合物)在制造用于治疗秃发的药物中的应用。
本领域技术人员将易于理解,对于施用或制造药物而言,可将本文公开的化合物与本身为本领域中公知的可药用赋形剂混合。尤其是,对于全身性给药的药物而言,其可制成粉剂、丸剂、片剂等,或制成适于口服或肠胃外给药或吸入的溶液剂、乳剂、悬浮剂、气雾剂、糖浆或酏剂。
对于固体剂型或药物,无毒的固体载体包括,但不局限于:药用级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、聚亚烷基二醇、滑石、纤维素、葡萄糖、蔗糖和碳酸镁。固体剂型可以不包衣,也可以用已知方法包衣以延长在肠胃道中的崩解和吸收,从而在较长的时间段内持续作用。例如,可使用延时材料,如单硬脂酸甘油酯或者二硬脂酸甘油酯。它们也可通过美国专利4,256,108、4,166,452和4,265,874中所述的技术包衣以形成用于控制释放的渗透性治疗片剂。液体给药剂型可包括例如一种或多种本发明的有用化合物与可选的药用助剂在载体(如水、盐水、水性右旋糖、甘油、乙醇等)中的溶液或悬浮液,以形成溶液剂或悬浮剂。如果需要,待施用的药物组合物还可含有微量的无毒辅助性物质,如润湿剂或乳化剂、pH缓冲剂等。所述助剂的一般实例为乙酸钠、失水山梨醇单月桂酸酯、三乙醇胺、乙酸钠、三乙醇胺油酸酯等。制备此类剂型的实际方法对于本领域技术人员而言是已知的或显而易见的,例如参见Remington′s Pharmaceutical Science,Mack Publishing Company,Easton,Pa.,1980年第16版。总之,待施用的制剂组合物都包含一定量的一种或多种本发明的有用化合物,所述量可有效提供所需的治疗效果。
肠胃外给药的特征通常为注射,即皮下注射、肌肉注射或静脉内注射。注射剂可以以常规形式制备:可以是溶液剂或悬浮剂、适于注射前在液体中制成溶液或悬浮液的固体剂型,或乳剂。合适的赋形剂为例如水、盐水、右旋糖、甘油、乙醇等。此外,如果需要,待施用的注射型药物组合物也可以含有少量的无毒辅助性物质,如润湿剂或乳化剂、pH缓冲剂等。
本发明的一种或多种有用化合物的施用量取决于所需疗效、治疗的具体哺乳动物、哺乳动物病症的严重程度和性质、给药方式、使用的一种或多种特定化合物的药力和药效,以及开方医生的判断。本发明一种或多种有用化合物的有效治疗剂量可为约0.5或约1到约100mg/kg/天。
将可眼用液体配制以使其对眼部局部给药。应尽量使舒适度最大化,但有时除最佳舒适度外可能还必须考虑一些制剂注意事项(如药物稳定性)。在不能达到最理想舒适度的情况下,液体的配制也应达到在局部眼部施用时患者能够耐受的程度。此外,可眼用液体应当包装以单次使用,或含有一种防腐剂以在多次使用过程中避免污染。
对于眼部施用而言,溶液剂或药剂常常使用生理盐水作为主要赋形剂(vehicle)制备。眼用溶液剂应当优选使用合适的缓冲体系来维持令人舒适的pH值。所述制剂还可包含常规的可药用防腐剂、稳定剂和表面活性剂。
可用于本发明药用混合物的防腐剂包括但不局限于苯扎氯铵、氯丁醇、硫汞撒、醋酸苯汞和硝酸苯汞。可使用的表面活性剂为例如Tween 80。同样,本发明的眼用制剂中也可使用多种有用赋形剂。所述赋形剂包括但不局限于聚乙烯醇、聚烯吡酮(povidone)、羟丙基甲基纤维素、泊洛沙姆(poloxamer)、羧甲基纤维素、羟乙基纤维素和净化水。
为了需要或方便可加入渗透压调整剂(tonicity adjustor)。它们包括但不局限于盐(特别是氯化钠、氯化钾)、甘露醇和甘油,或者可眼用的其他任意合适的渗透压调整剂。
各种调节pH值的缓冲剂和方法均可使用,只要所得制剂可眼用即可。因此,缓冲剂包括醋酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂和硼酸盐缓冲剂。根据需要,可使用酸或碱来调节这些制剂的pH值。
同样地,用于本发明的可眼用抗氧化剂包括但不局限于偏亚硫酸氢钠、硫代硫酸钠、乙酰半胱氨酸、丁基化羟基苯甲醚和丁基化羟基甲苯。
眼用制剂中可包括的其他赋形剂组分为螯合剂。一种有用的螯合剂为乙二胺四乙酸二钠,但也可原位使用或与其一起使用其他螯合剂。
各成分通常以如下量使用:
成分 用量(%w/v)
活性成分 约0.001-5
防腐剂 0-0.10
赋形剂 0-40
渗透压调整剂 1-10
缓冲剂 0.01-10
pH调整剂 适量pH 4.5-7.5
抗氧化剂 随需而定
表面活性剂 随需而定
净化水 随需定容至100%
在局部使用的情况下,可使用含有本文的化合物的乳剂、软膏剂、凝胶剂、溶液剂或悬浮剂等。局部制剂通常可由药用载剂、助溶剂、乳化剂、渗透促进剂、防腐剂和软化剂组成。
本发明活性化合物的实际剂量取决于具体的化合物和待治疗的病症;本领域技术人员可在知识范围内选择合适的剂量。
本文公开的化合物也可与其他可用于治疗青光眼或其他病症的药物结合使用。
为治疗青光眼,可考虑与以下类别药物的组合治疗:
β-阻断剂(或β-肾上腺素能拮抗剂),包括喹酮心安(carteolol)、左布诺洛尔(levobunolol)、三甲醋心安(metiparanolol)、噻吗心安半水合物(timolol hemihydrate)、马来酸噻吗心安(timolol maleate),β1-选择性拮抗剂如倍他洛尔(betaxolol)等,或其可药用盐或前药。
肾上腺素能激动剂包括:
非选择性肾上腺素能激动剂如硼酸肾上腺素、盐酸肾上腺素、肾上腺素异戊酯(dipivefrin)等,或其可药用盐或前药;和
α2选择性肾上腺素能激动剂如阿可乐定(apraclonidine)、溴莫尼定(brimonidine)等,或其可药用盐或前药;
碳酸酐酶抑制剂如乙酰唑胺(acetazolamide)、二氯磺胺(dichlorphenamide)、甲醋唑胺(methazolamide)、布林唑胺(brinzolamide)、多佐胺(dorzolamide)等,或其可药用盐或前药;
胆碱能激动剂包括直接作用型胆碱能激动剂如碳酰胆碱(carbachol)、盐酸匹鲁卡品、硝酸匹鲁卡品,匹鲁卡品(pilocarpine)等,或其可药用盐或前药;
胆碱脂酶抑制剂如癸二胺苯酯(demecarium)、二乙氧磷酰硫胆碱(echothiophate)、毒扁豆碱(physostigmine)等,或其可药用盐或前药;
谷氨酸拮抗剂和其他神经保护剂如钙离子通道阻滞剂,如二甲金刚胺(memantine)、金刚烷胺(amantadine)、金刚烷乙胺(rimantadine)、硝化甘油、去甲右美沙芬(dextrophan)、右美沙芬(detromethorphan)、CGS-19755、二羟吡啶、戊脉安(verapamil)、依莫帕米(emopamil)、苯并噻氮卓(benzothiazepine)、苄普地尔(bepridil)、二苯基丁基哌啶、二苯基哌嗪、HOE166和相关药物、氟司必林(fluspirilene)、依利罗地(eliprodil)、艾芬地尔(ifenprodil)、CP-101,606、替巴洛新(tibalosine)、2309BT和840S、氟桂嗪(flunarizine)、尼卡地平(nicardipine)、硝苯地平(nifedimpine)、尼莫地平(nimodipine)、巴尼地平(barnidipine)、戊脉安、利多氟嗪(lidoflazine)、心可定(prenylamine lactate)、氨氯吡脒(amiloride)等,或其可药用盐或前药;
前列腺酰胺(prostamide)如比马前列素,或其可药用盐或前药;和前列腺素包括曲伏前列素(travoprost)、UFO-21、氯前列醇(chloprostenol)、氟前列醇(fluprostenol)、13,14-二羟-氯前列醇、异丙基乌诺前列酮(isopropyl unoprostone)、拉坦前列素(latanoprost)等。
大麻成分包括CB1激动剂如WIN-55212-2和CP-55940等,或其可药用盐或前药;
为治疗包括青光眼在内的影响眼部的疾病,这些化合物可以局部、眼周、眼内,或其它任何本领域已知有效的方式用药。
这些药物也可以用来治疗或预防影响眼后房的病症,包括黄斑病变/视网膜变性如非渗出型年龄相关的黄斑变性(ARMD),渗出型年龄相关的黄斑变性(ARMD),脉络膜新生血管化,糖尿病视网膜病变,急性黄斑视神经视网膜病变,中心浆液性脉络视网膜病变,囊样黄斑水肿和糖尿病黄斑水肿;葡萄膜炎/视网膜炎/脉络膜炎如急性多病灶鱼鳞板状色素上皮病,贝赫切特病(Behcet’s disease),鸟枪弹样脉络膜视网膜病变,传染病(梅毒、莱姆关节炎(lyme)、肺结核、弓形体病),中间葡萄膜炎(扁平部睫状体炎(pars planitis)),多病灶脉络膜炎,多发性一过性白点症(mewds),眼部结节病(ocular sarcoidosis),后巩膜炎,葡行性脉络膜炎,视网膜下纤维增生和葡萄膜炎综合征,伏格特-小柳综合征(Vogt-Koyanagi-and Harada syndrome);血管病/渗出性疾病如视网膜动脉闭塞病,视网膜中央静脉阻塞,弥散性血管内凝血,视网膜静脉分枝阻塞,高血压性眼底改变,眼部缺血性综合征,视网膜动脉微动脉瘤,视网膜毛细血管扩张病(Coat′s disease),旁中心凹毛细血管扩张,半侧视网膜静脉阻塞,乳头视网膜炎(papillophlebitis),视网膜中央动脉阻塞,视网膜分支动脉阻塞,颈动脉疾病(CAD),霜样树枝状视网膜血管炎,镰状红细胞性视网膜病变和其他血红蛋白病,血管样条纹症,家族性渗出性玻璃体视网膜病变,伊尔斯氏病(Eales disease);创伤性/手术性病症如交感性眼炎,葡萄膜视网膜病,视网膜脱落,外伤,激光引起的病症,光动力学疗法引起的病症,光凝固法引起的症状,手术过程中的灌注不足,辐射性视网膜病变,骨髓移植引起的视网膜病变,增生性病变如增生性玻璃体视网膜病变和增生性视网膜前膜,以及增生性糖尿病视网膜病变;感染病变如眼组织胞浆菌病、眼弓蛔虫病、眼假组织胞浆菌病综合征(POHS)、眼内炎、弓浆虫病,HIV感染相关的视网膜病变,HIV感染相关的脉络膜病变,HIV感染相关的葡萄膜炎,病毒性视网膜炎,急性视网膜坏死,进行性外层视网膜坏死,真菌性视网膜病,眼梅毒,眼结核,弥漫性单侧亚急性视神经视网膜炎和蝇蛆病;遗传性病变如视网膜色素变性,伴随视网膜营养不良的系统性疾病,先天性静止性夜盲症,视锥细胞营养不良,斯特格氏病(Stargardt’s disease),眼底黄色斑点症,贝斯特氏症(Best’s disease),视网膜色素上皮细胞的图形状营养不良(pattern dystrophy),X染色体连锁视网膜劈裂症,Sorsby眼底营养不良(Sorsby′s fundus dystrophy),良性同心性黄斑病变,Bietti结晶样视网膜营养障碍(Bietti′s crystalline dystrophy),弹性假黄色瘤,视网膜裂/孔如视网膜脱落、黄斑裂孔、巨大视网膜撕裂;肿瘤如与肿瘤相关的视网膜病、视网膜色素上皮细胞的先天性肥大、后部葡萄膜黑色素瘤(posterior uveal melanoma)、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移癌(choroidal metastasis)、视网膜和视网膜色素上皮细胞的联合错构瘤、视网膜母细胞瘤、眼底血管增生瘤、视网膜星细胞瘤和眼内淋巴瘤;还有各种其他影响眼后部的疾病如点状内层脉络膜病变、急性后部多灶性鳞状色素上皮病变、近视视网膜变性和急性视网膜色素上皮炎。优选地,所述疾病或病症是视网膜色素变性、增生性玻璃体视网膜病变(PVR)、年龄相关性黄斑病变(ARMD)、糖尿病视网膜病变、糖尿病黄斑水肿、视网膜脱落、视网膜裂孔、葡萄膜炎或巨细胞病毒视网膜炎。
刺激毛发生长的应用
在一个实施例中,本文公开的混合物可用于治疗秃发和/或脱发。秃头症(秃发)是指缺少正常毛发或异常毛发,主要是人类美容方面的问题。秃发是缺少终毛,终毛是易见的粗直径有色毛发。然而,称作秃发的人虽然明显缺少终毛,但是皮肤还有毫毛,毫毛为可能需要显微镜观察才能确定其存在的细的无色毛发。毫毛是终毛的前体。
本文所述的化合物可以用来刺激例如毫毛转变从而生长为终毛,也可以刺激终毛的生长速度。本文所述的化合物对刺激毛发生长的功效是如下发现的。
在治疗青光眼患者的过程中,治疗可能仅适于一只眼睛。在一项日常治疗中,发现一个经比马前列腺素——一种前列腺素类似物——治疗的患者的治疗眼睛比未经治疗的眼睛长出了更长、更浓密且更完全的睫毛。经检查,发现两眼睫毛的不同之处非常显著。治疗眼睛的睫毛更长并且具有更完全更浓密的外观。如果展示两侧睫毛的现象,治疗眼睛眼睑上的睫毛看起来会非常显眼。由于不对称性,从美容的角度看,一侧的长睫毛是令人烦恼的。对这种不对称现象进行了系统的检查。很快发现这种变化的外观不是一个个案。通过比较仅一只眼经比马前列腺素治疗的患者的眼睑,发现在一些病人中经比马前列腺素治疗的一侧的睫毛和邻近毛发有微小变化。所有经药物单侧治疗超过6个月的患者的睫毛和邻近毛发均可识别出不同程度的清晰差异。
一旦开始注意这个问题,肉眼检查就发现一些病人睫毛上的变化非常明显。那些有浅色毛发和睫毛的人,只有借助裂隙灯活组织显微镜的高放大倍数和照明能力才能容易地观察到改变之处。在青光眼随访检查过程中,注意力通常直接集中在眼部本身。由于所需放大倍数高,所以每次只能看到一只眼睛,而且眼部观察时的放大倍数高到不会对睫毛聚焦。在这种较高放大率下,很难发现两眼睫毛有任何的不对称,除非细致全面地比较两眼眼睑上的睫毛和邻近毛发。
观察到的参数给出这样的一个结论:在施用前列腺素类似物后,治疗区域的毛发生长更加浓密,而这些参数是多方面的。它们包括睫毛长度变长,沿正常睫毛线的睫毛数量增多,睫毛直径变粗且更有光泽,在邻近正常睫毛生长区域的过渡区域辅助性睫毛状终毛增多,在眼角区域中间和边缘辅助性睫毛状终毛增多,睫毛色素增多,邻近眼睑皮肤处的汗毛的数量、长度以及光泽度和厚度都有所增加,最后,睫毛和睫毛状终毛的垂直角度增大。因此,前列腺素类似物如比马前列腺素能够刺激毛发生长的结论并不是仅得到单一参数差异证据的支持,而是基于很多受试者的治疗区域与对照区域毛发外观的多种参数。
本文所述的化合物是前列腺素类似物,因此它们具有与比马前列腺素相似的活性,有结构相似性,所以预期它们能够刺激毛发的生长和毫毛向终毛的转变。在一个实施方案中,本文所述的化合物和它们的前药可用于刺激毛发生长。本文所说的毛发生长包括与头皮、眉、眼睑、胡须和动物皮肤其他区域有关的毛发。
在一个实施方案中,将化合物与一种皮肤相容性的赋形剂或载体混合。可用于制备本文所述组合物的赋形剂可包括,例如水性溶液如生理盐水、油性溶液或软膏剂。所述赋形剂还可含有皮肤相容性的防腐剂如苯扎氯铵,表面活性剂如聚山梨醇酯80,脂质体或聚合物如甲基纤维素、聚乙烯醇、聚乙烯吡咯烷酮和透明质酸;它们可用于增加粘性。此外,当施用药品时,还可施用可溶性或不溶性的药物导入剂。
在一个实施方案中,可配制用于刺激毛发生长的局部治疗用的皮肤病学组合物,其包括有效毛发生长刺激量的一种或多种上述定义的化合物和一种皮肤相容性载体。活性化合物的有效量可通过本领域的普通技术人员来确定,但是还根据所使用化合物、施用频率和所需效果而变化。所述化合物通常为皮肤病学组合物的约0.0000001到约50重量%。优选地,所述化合物为总皮肤病学组合物的约0.001到约50重量%,更优选地为所述组合物的约0.1到约30重量%。
在一个实施方案中,用于刺激毛发生长的本发明化合物可以用于哺乳动物物种,包括人和动物。对人来说,本文所述的化合物可施用于例如头皮、面部须、头部、阴部、上唇、眉和眼睑。对于为获取毛皮而饲养的动物(如貂),出于商业原因可将本文所述化合物施用于身体的整个表面上,以改善整个毛皮。所述方法也可出于美容原因而用于动物中,如施用于由于会导致一定程度脱发的兽疥癣或其他疾病而具有秃斑的狗和猫的皮肤。
可考虑的用于刺激毛发生长的药用组合物包括适合外用(topical)和局部(local)作用的药用组合物。本文所用术语“外用”是指掺入合适的药用载体中并施用于少发或秃发部位的本文所述化合物用于发挥局部作用的应用。因此,所述局部组合物包括那些其中化合物直接与待治疗的皮肤外部接触的药用剂型。此种用途的常规药用剂型包括软膏剂、搽剂、乳剂、洗发剂、洗剂、膏剂、凝胶剂、喷雾剂、气雾剂等,并且可根据待治疗的身体部位以贴片或浸渍敷料的形式使用。术语“软膏剂”包括具有油质的、水溶性的乳液型基体的制剂(包括乳剂),所述基体例如矿脂、羊毛脂、聚乙二醇,及其混合物。
通常,所述化合物可在一段持续的时间内反复地且外部施用于待治疗的身体部位,例如,眼睑、眉,皮肤或头皮。优选的给药方案通常包括在至少一个月、更优选至少三个月、最优选至少六个月的疗程内定期给药,如每天给药。
对于对眼睑和眉局部使用而言,活性化合物可通过添加可药用缓冲剂和盐而在具有生理可接受的渗透压浓度的水溶液剂、乳剂、软膏剂或油剂中进行配制。按照药剂师的要求,所述制剂可含有或不含防腐剂或抗氧化剂以及添加剂,所述防腐剂例如苯扎氯铵、洗必泰(chlorhexidine)、氯丁醇、对羟苯甲酸和苯汞盐如硝酸盐、氯化物、乙酸盐和硼酸盐,所述添加剂例如EDTA、山梨醇、硼酸等。此外,特别是水性溶剂可含有增粘剂,例如多糖如甲基纤维素,粘多糖如透明质酸和硫酸软骨素,或多聚醇如聚乙烯醇。还可使用各种缓释凝胶和基体以及可溶性或不溶性眼部导入剂,例如基于原位形成凝胶的物质。根据待使用的实际剂型和化合物,可使用各种量的药物和不同的给药方案。通常,用于治疗眼睑的化合物的日剂量为约0.1ng到约100mg/眼睑。
对于皮肤和头皮上的外部使用,化合物可有利地使用软膏剂、乳膏、搽剂或贴片作为活性成分的载体来进行配制。此外,根据药剂师和使用性能,所述制剂还可含有或不含防腐剂。所述防腐剂包括上述的防腐剂以及甲基对羟基苯甲酸、丙基对羟基苯甲酸或丁基对羟基苯甲酸、甜菜碱、洗必泰、苯扎氯铵等。也可使用用于缓释递送的各种基体。通常,根据化合物和制剂,待施用至头皮的剂量为约0.1ng到约100mg/天,更优选约1ng到约10mg/天,最优选约10ng到约1mg/天。为达到药物的日用量,根据制剂,所述具有或不具有抗氧化剂的化合物可每日给药一次或多次。
这些化合物还可用于治疗哮喘。
实施例
路线1
(a)I2,吡啶,CH2Cl2;(b)正戊基溴化镁(n-pentylMgBr);(c)TBSOTf,2,6-二甲基吡啶,CH2Cl2;(d)异丙基氯化镁(i-PrMgCl);催化剂CuCN,烯丙基溴;(e)9-BBN;(f)PdCl2(dppf),K3PO4,DMF;(g)t-BuLi;2-噻吩基氰铜酸锂(2-ThienylCuCNLi);(h)L-selectride;(i)MsCl,TEA;TBAC 40℃;(j)HF·哌啶0℃;(k)1M LiOH,THF;(l)1.ClCO2Et,Et3N,CH2Cl2,2.RCH2CH2OH。
(R)-4-(叔丁基-二甲基-硅烷氧基)-2-碘-环戊-2-烯酮(2)。按照与A.G.Myers和P.S.Dragovich J.Am.Chem.Soc.1993,115,7021中描述的相似的方法进行。将0℃的烯酮1(3.163g,14.9mmol,Evotec OAI,151Milton Park,Abington,Oxon,OX 144SD,UK)与吡啶(5mL)的二氯甲烷(5mL)溶液用I2(6.511g,25.7mmol)的吡啶(12mL)/二氯甲烷(12mL)溶液处理。将反应升温至室温,并在2小时后加入1M HCl(60mL)。将所得混合物倒入100mL的1M HCl中,然后用二氯甲烷(3×60mL)萃取。合并的二氯甲烷溶液用饱和NaHSO3溶液和盐水洗涤,然后干燥(Na2SO4)、过滤并蒸发。通过硅胶(5%乙酸乙酯/正己烷)快速色谱法进行纯化,得到化合物2(4.600g,91%)。
1-(4-溴-苯基)-己-1-醇(4)。将正戊基溴化镁(29mL,58mmol,2M/醚)加入0℃的4-溴苯甲醛(9.953g,54mmol)的THF(100mL)溶液中。1h后,加入200mL饱和氯化铵溶液淬灭反应。所得混合物用乙酸乙酯(3×100mL)萃取,并将合并的乙酸乙酯溶液干燥(Na2SO4)、过滤并蒸发。残留物通过硅胶快速色谱法进行纯化,得到化合物4(10.501g,76%)。
[1-(4-溴-苯基)-己氧基]-叔丁基-二甲基-硅烷(5)。将TBSOTf(2.9mL,12.6mmol)加入4(3.017g,11.7mmol)与2,6-二甲基吡啶(2,6-lutidine)(1.6mL,13.7mmol)的二氯甲烷(30mL)冰冷溶液中。反应在室温下搅拌2h,然后加入100mL饱和碳酸氢钠溶液。所得混合物用二氯甲烷(30mL)萃取,然后将二氯甲烷层用1M HCl(2×50mL)和盐水(50mL)洗涤。之后将二氯甲烷溶液干燥(MgSO4)、过滤并蒸发。残余物通过硅胶快速色谱法(己烷)进行纯化,得到化合物5(3.843g,88%)。
3-丙烯基-苯甲酸乙酯(7)。将3-碘苯甲酸乙酯(2.434g,8.8mmol)于40mL THF中的-45℃溶液用i-PrMgCl(4.8mL,9.6mmol,2M/醚)处理。1h后,加入烯丙基溴(1.6mL,18.9mmol),然后加入CuCN(79mg,0.88mmol)。反应搅拌1h,然后加入50mL饱和NH4Cl溶液淬灭。加入水(30mL),并将所得混合物用乙酸乙酯(3×50mL)萃取。将合并的乙酸乙酯溶液干燥(MgSO4)、过滤并蒸发。通过硅胶快速色谱法(5%乙酸乙酯/己烷→10%)进行纯化,得到化合物7(1.145g,68%)。
3-{3-[(R)-3-(叔丁基-二甲基-硅烷氧基)-5-氧代环戊-1-烯基]-丙基}-苯甲酸乙酯(8)。将7(303mg,1.6mmol)的THF(0.5mL)溶液加入9-BBN二聚体的THF(6mL)溶液中。4h后,加入0.1mL水。将溶液搅拌20min,然后用套管(cannula)转移至PdCl2(dppf)(78mg,0.11mmol)和2(387mg,2.0mmol)于DMF(3.2mL)的混合物中。加入K3PO4(0.7mL,2.1mmol,3M),并将该深色溶液搅拌1.25h。然后将溶液倒入50mL盐水中,并将所得混合物用乙酸乙酯(2×30mL)萃取。将合并的乙酸乙酯溶液干燥(MgSO4)、过滤并蒸发。通过硅胶快速色谱法进行纯化,得到292mg(46%)烯酮8。
1-8→→3-(3-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊烷}-丙基)-苯甲酸(13)。制取13的过程如路线1中所示及2004年12月10日提交的序列号为11/009,298的美国专利申请(目前为2006年8月15日公告的美国专利7,091,231)图5、6中所述完成,该申请特此通过引用的方式纳入本文。
化合物14a。室温下将三乙胺和氯甲酸乙酯依次加入化合物13的CH2Cl2溶液中。2.5h后,加入三乙胺和乙二醇。室温搅拌过夜后,使反应混合物在H2O和CH2Cl2之间分配。将各相分离,并将水相用CH2Cl2(2×)萃取。合并的有机相用1N HCl洗涤,然后干燥(MgSO4)、过滤并真空浓缩。残留物通过硅胶快速柱色谱法(10%CH3OH/CH2Cl2)进行纯化,得到化合物14a。
化合物14b。室温下将三乙胺和氯甲酸乙酯依次加入化合物13的CH2Cl2溶液中。2.5h后,加入三乙胺和4-(2-羟乙基)吗啡。室温搅拌过夜后,将反应混合物在H2O和CH2Cl2之间分配。将各相分离,并将水相用CH2Cl2(2×)萃取。合并的有机相用1N HCl洗涤,然后干燥(MgSO4)、过滤并真空浓缩。残留物通过硅胶快速柱色谱法(10%CH3OH/CH2Cl2)进行纯化,得到化合物14b。
5-(3-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-丙基)-噻吩-2-甲酸甲酯(5-(3-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-propyl)-thiophene-2-carboxylic acid methyl ester)。题述化合物使用与1-12中描述类似的方法由5-溴-噻吩-2-甲酸甲酯起始制备,5-溴-噻吩-2-甲酸甲酯由5-溴-噻吩-2-甲酸如下制备:将乙酰氯(6.87mL,96.6mmol)加入5-溴-噻吩-2-甲酸(4.0g,19.3mmol)的甲醇(30mL)溶液中。反应搅拌过夜,然后加热回流1.5h。将反应冷却至室温,然后蒸发。残留物用120mL饱和碳酸氢钠溶液处理,并将所得混合物用二氯甲烷(3×100mL)萃取。将合并的二氯甲烷溶液干燥(Na2SO4)、过滤并蒸发,得到3.57g(84%)的5-溴-噻吩-2-甲酸甲酯。
5-(3-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-丙基)-噻吩-2-甲酸。题述化合物使用2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)中描述的通过兔肝酯酶水解甲酯的方法制备。
5-(3-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-丙基)-噻吩-2-甲酸异丙酯。题述化合物使用2004年12月10日提交的流水号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)描述的常规方法由相应的酸制备。
路线2
(a)Pd(OAc)2,Et3N CH3CN 100℃;(b)H2,(Ph3P)3RhCl,EtOH;(c)Ph3P,I2,咪唑,ClCH2CH2Cl。
(E)-3-(3-羟甲基-苯基)-丙烯酸甲酯(17)。按照Reich,S.H.et.al.J.Med.Chem.2000,43,1670中描述的方法进行。将Pd(OAc)2(8.2mg,0.037mmol)和三乙胺(0.360ml,2.58mmol)加入3-碘苯甲醇15(0.27ml,2.13mmol)与丙烯酸甲酯16(0.220ml,2.44mmol)的CH3CN(4.5mL)溶液中。反应容器用聚四氟乙烯(Teflon)螺旋盖密封,在100℃下加热5h。此时将反应冷却到室温,并向管中再加入0.22mL丙烯酸甲酯、11.7mgPd(OAc)2和0.360mL三乙胺。将反应在100℃加热过夜,然后加入10mL饱和氯化铵溶液。所得混合物用二氯甲烷(3×40mL)萃取,并将合并的二氯甲烷干燥(Na2SO4)、过滤并蒸发。通过硅胶快速柱色谱法(30%乙酸乙酯/己烷)进行纯化,得到395mg(97%)化合物17。
3-(3-羟甲基-苯基)-丙酸甲酯(18)。将(Ph3P)3RhCl(11.5mg,0.012mmol)加入17(25mg,0.13mmol)的乙醇(0.400mL)溶液中。反应在1个大气压氢气球下搅拌20h,然后通过硅藻土过滤。蒸发干燥,并通过硅胶快速柱色谱法(30%乙酸乙酯/己烷)进行纯化,得到化合物18(21mg,82%)。
3-(3-碘甲基-苯基)-丙酸甲酯(19)。将Ph3P(36mg,0.14mmol)、I2(41mg,0.16mmol)和咪唑(10.5mg,0.15mmol)在1,2-二氯乙烷(0.40mL)中的混合物搅拌15min,然后通过套管加入18(20.5mg,0.11mmol)的1,2-二氯乙烷(0.1mL)溶液。将所得混合物搅拌1h,然后通过碱性氧化铝过滤,用乙酸乙酯洗涤。将滤液蒸发,并将残留物通过硅胶快速色谱法进行纯化,得到化合物19(26mg,81%)。
3-[3-((1R,2S,3R)-3-(叔丁基-二甲基-硅烷氧基)-2-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-5-氧代-环戊甲基)-苯基]-丙酸甲酯(20)。将芳基溴5(759mg,2.0mmol)的-78℃THF(3mL)溶液用叔丁基锂(2.6mL,4.4mmol,1.7M/戊烷)处理。30min后,加入Me2Zn(1.1mL,2.2mmol,2M/甲苯),并将所得溶液在0℃搅拌15min,然后再次冷却到-78℃。使用注射泵在1h内加入烯酮1(319mg,1.5mmol,Evotec OAI,151Milton Park,Abington,Oxon,OX 14 4SD,UK)的THF(1.7mL)溶液。将所得混合物在-78℃搅拌2h,然后依次加入HMPA(2.2mL,12.6mmol)和19(2.641g,8.7mmol)的THF(1.6mL)溶液。反应在-40℃下搅拌过夜,然后加入40mL饱和氯化铵溶液淬灭。加入少量水来溶解固体,并将所得混合物用乙酸乙酯(3×30mL)萃取。将合并的乙酸乙酯溶液干燥(MgSO4)、过滤并蒸发。通过硅胶快速色谱法(10%乙酸乙酯/己烷)进行纯化,得到掺有约35%苯甲基碘19的题述酮(438mg)。
路线3
(a)t-BuLi;Me2Zn;(b)L-selectride;(c)MsCl,TEA;TBAC 40℃;(d)HF·吡啶;LiOH溶液
3-[3-((1R,2S,3R,5S)-3-(叔丁基-二甲基-硅烷氧基)-2-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-5-羟基-环戊基甲基)-苯基]-丙酸甲酯(21)。使用2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)中描述的常规L-selectride法,得到224mg(22%来自烯酮1-1)纯化合物21。
3-2→→3-(3-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊甲基}-苯基)-丙酸(24)。所述过程如路线3所示使用2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)图6中所述的常规方法完成。
3-[3-((1R,2S,3R,5R)-5-氯-3-羟基-2-{3-[羟基-(1-丙基-环丁基)-甲基]-苯基}-环戊甲基)-苯基]-丙酸甲酯和3-[3-((1R,2S,3R,5R)-5-氯-3-羟基-2-{3-[羟基-(1-丙基-环丁基)-甲基]-苯基}-环戊甲基)-苯基]-丙酸。题述化合物由芳基溴3-6起始,与23/24类似地制备(如2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)的图1、4所述制备)。
路线4
(a)t-BuLi;Me2Zn;(b)烯丙基溴,HMPA;(c)L-selectride;(d)MsCl,TEA;TBAC 40℃;
(e)9-BBN;PdCl2(dppf),K3PO4,DMF 50℃;(f)HF·哌啶0℃;(g)LiOH溶液,THF。
(2R,3S,4R)-2-烯丙基-4-(叔丁基-二甲基-硅烷氧基)-3-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-环戊酮(27)。化合物27使用与20所述类似的方法制备。
27→(1S,2R,3S,4R)-2-烯丙基-4-(叔丁基-二甲基-硅烷氧基)-3-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-环戊醇(28)→1-[(1S,2R,3S,5R)-2-烯丙基-5-(叔丁基-二甲基-硅烷氧基)-3-氯-环戊基]-4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯(29)。此过程如2004年12月10日提交的序列号为11/009,298的美国专利申请(目前为2006年8月15日公告的美国专利7,091,231)中图6所述进行。
2-[3-((1R,2S,3R,5R)-3-(叔丁基-二甲基-硅烷氧基)-2-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-5-氯-环戊基)-丙基]-噻唑-5-甲酸乙酯(31)。将29(39mg,0.069mmol)的THF(0.2mL)溶液用套管转移至9-BBN二聚体(17mg,0.07mmol)于THF(0.2mL)的混合物中,并用0.2mL THF冲洗。将反应置于50℃油浴中2.5h,然后冷却至室温,并加入H2O(10μL)。30min后,将溶液用套管转移至2-溴噻唑-5-甲酸乙酯4-4(15mg,0.063mmol)与PdCl2(dppf)(5mg,0.007mmol)的DMF(0.2mL)溶液中。加入K3PO4(31μL,0.09mmol,3M),并将溶液置于50℃油浴中。将反应搅拌过夜,然后在15mL乙酸乙酯/15mL水(加入一些盐水)之间分配。水层进一步用15mL乙酸乙酯萃取,并将合并的乙酸乙酯溶液干燥(MgSO4)、过滤并蒸发。通过在硅胶上的制备型TLC(10%乙酸乙酯/己烷)进行纯化,得到化合物31(4mg,0.0057mmol,8%)。
31→2-(3-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-丙基)-噻唑-5-甲酸乙酯(32)→2-(3-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-丙基)-噻唑-5-甲酸(33)。此过程如2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)中图6所述进行。
33向34a和34b的转化。此过程如路线1的步骤l所述进行。
路线6
(a)MsCl,TEA;NaCN,DMSO 80℃;(b)HF·吡啶,0℃;(c)LiOH溶液,THF
(Z)-7-((1R,2S,3R,5R)-3-(叔丁基-二甲基-硅烷氧基)-2-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-5-氟-环戊烷)-庚-5-烯酸甲酯(36)。将35(109mg,0.17mmol)的二氯甲烷(0.5ml)溶液用套管转移至去氧氟[二(2-甲氧乙基)氨基三氟化硫(deoxofluor[bis(2-methoxyethyl)aminosulfur trifluoride,34μl,0.18mmol)的-78℃二氯甲烷(0.75mL)溶液中,用0.25mL二氯甲烷冲洗。将反应在-78℃搅拌2h,然后加入10mL饱和NaHCO3淬灭。将混合物用二氯甲烷(3×15mL)萃取,并将合并的二氯甲烷溶液干燥(MgSO4)、过滤并蒸发。通过硅胶快速色谱法(1%乙酸乙酯/己烷→2%)进行纯化,得到25mg(23%)的37和53mg杂质36。
(Z)-7-{(1R,2S,3R,5R)-5-氟-3-羟-2-[4-(1-羟-己基)-苯基]-环戊基}-庚-5-烯酸甲酯(38)。按照2004年12月10日提交的美国专利申请第11/009,298号(现在是2006年8月15日公布的美国专利第7,091,231号)中描述的HF·吡啶法(HF·pyridine procedure)进行,该方法在用硅胶(40%乙酸乙酯/己烷)快速色谱法后能够得到30mg不纯的37。用制备型TLC(35%乙酸乙酯/己烷)进一步纯化能得到7mg纯38。
(Z)-7-{(1R,2S,3R,5R)-5-氟-3-羟-2-[4-(1-羟-己基)-苯基]-环戊基}-庚-5-烯酸(39)。使用以前描述的LiOH法(LiOH procedure)(2004年12月10日提交的美国专利申请第11/009,298号,现在是2006年8月15日公布的美国专利第7,091,231号)。
39向40a和40b的转化。所述过程如路线1的步骤l所述进行。
路线7
(a)NaBH4;(b)MsCl,TEA;TBAC 80℃;(c)HF·吡啶,0℃;(d)兔肝酯酶
(Z)-7-((1R,2S,3R,5S)-3-(叔丁基-二甲基-硅烷氧基)-2-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-5-羟基-环戊基)-庚-5-烯酸甲酯(35)和(Z)-7-((1R,2S,3R,5R)-3-(叔丁基-二甲基-硅烷氧基)-2-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-5-羟基-环戊基)-庚-5-烯酸甲酯(42)。将NaBH4(9mg,0.24mmol)加入(Z)-7-{(1R,2S,3R)-3-(叔丁基-二甲基-硅烷氧基)-2-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-5-氧代-环戊基)-庚-5-烯酸甲酯(41)(55mg,0.087mmol,如2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231,图5)所述制备)的甲醇(0.5mL)溶液中。20min后,加入1MHCl(10mL),并将所得混合物用二氯甲烷(3×10mL)萃取。将合并的二氯甲烷溶液干燥(MgSO4)、过滤并蒸发。通过硅胶快速色谱法(10%乙酸乙酯/己烷→15%)进行纯化,得到27mg(49%)42和16mg(29%)35以及8mg混合级分。
(Z)-7-((1R,2S,3R,5S)-3-(叔丁基-二甲基-硅烷氧基)-2-{4-[1-(叔丁基-二甲基-硅烷氧基)-己基]-苯基}-5-氯-环戊基)-庚-5-烯酸甲酯(43)。将甲磺酰氯(15μL,0.19mmol)和三乙胺(30μL,0.21mmol)加入42(50mg,0.08mmol)的二氯甲烷(0.3mL)溶液中。1.5h后,加入饱和碳酸氢钠溶液(15ml),并将所得混合物用二氯甲烷(3×15mL)萃取。将合并的二氯甲烷溶液蒸发,得到粗的甲磺酸酯(mesylate)。
将粗的甲磺酸酯溶于0.7mL甲苯,加入(n-Bu)4NCI(246mg,0.90mmol)。将混合物在80℃搅拌1h,然后通过硅胶(20%乙酸乙酯/己烷)过滤,得到43(40mg,77%)。
43→(Z)-7-{(1R,2S,3R,5S)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-庚-5-烯酸甲酯(44)→(Z)-7-{(1R,2S,3R,5S)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-庚-5-烯酸(45)。此过程如路线7中所示按照2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)中所述方法完成。
45向46a和46b的转化。此过程如路线1的步骤l所述进行。
路线8
(a)正戊基溴化镁;(b)HF-吡啶0℃;(c)1M LiOH,THF;(d)2-碘丙烷,DBU,丙酮。
(Z)-7-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-庚-5-烯酸(50)。题述化合物如路线8所示,以与2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)图9中所述的方法类似的方法制备。
(Z)-7-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-庚-5-烯酸异丙酯(51)。此化合物使用2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)中所述的常规方法制备。
50的各个非对映异构体的制备。在48阶段时将各个非对映异构体用制备型HPLC分离:约5mg样品/次运行;Chiralcel OD semiprep column(1×25cm),流速为2.4mL/min,10%异丙醇/己烷;保留时间=17.6min和23.8min。然后将各个非对映异构体分别如路线8所示以及2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)中所述进行后续反应。50向51a和51b的转化。此过程如路线1的步骤l所述进行。
路线9
(a)4-甲氧基苄基氯,NaH;(b)DDQ;(c)TPAP,NMO;(d)RMgX;(e)HF-吡啶0℃;(f)1MLiOH,THF;(g)2-碘丙烷,DBU,丙酮。
(Z)-7-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(2-羟基-1,1-二甲基-庚基)-苯基]-环戊基}-庚-5-烯酸(第31项,表1)和(Z)-7-{(1R,2S,3R,5R)-5-氯-3-羟基-2-[4-(2-羟基-1,1-二甲基-己基)-苯基]-环戊基}-庚-5-烯酸。所述化合物如路线9中所示,以与2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)中图7-9所述的方法类似的方法制备。
路线10
(Z)-7-[(1R,2S,3R,5R)-5-氯-2-(4-己基-苯基)-3-羟基-环戊基]-庚-5-烯酸甲酯(61)。将Et3SiH(30μL,0.19mmol)和TFA(90μL,1.17mmol)依次加入49(23mg,0.046mmol)的二氯乙烷(0.10ml)溶液中。15min后,加入4ml饱和碳酸氢钠溶液淬灭反应。所得混合物用二氯甲烷(3×30mL)萃取,并将合并的二氯甲烷溶液干燥(Na2SO4)、过滤并蒸发。通过硅胶快速色谱法(10%乙酸乙酯/己烷→15%→20%)进行纯化,得到21mg 61(110%)。
(Z)-7-[(1R,2S,3R,5R)-5-氯-2-(4-己基-苯基)-3-羟基-环戊基]-庚-5-烯酸(62)。题述化合物使用2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)中所述的常规LiOH方法制备。
62向63a和63b的转化。所述过程如路线1步骤1中所述进行。
路线11
(a)正戊基溴化镁;EtOAc;(b)HF-吡啶0℃;(c)Ph3P,偶氮二甲酸二异丙酯,4-硝基苯甲酸,THF;(d)1M LiOH,THF。
(Z)-7-[(1R,2S,3R,5R)-2-[4-(1-乙酰氧基-己基)-苯基]-3-(叔丁基-二甲基-硅烷氧基)-5-氯-环戊基]-庚-5-烯酸甲酯(64)。将正戊基溴化镁(130μL,0.26mmol)加入47(114mg,0.24mmol)的0℃THF(0.9mL)溶液中。2.5h后,加入1mL乙酸乙酯,并将反应升温至室温。30min后,在室温下加入10mL饱和氯化铵溶液,并将所得混合物用乙酸乙酯(3×30mL)进行萃取。将合并的乙酸乙酯溶液干燥(Na2SO4)、过滤并蒸发。通过硅胶快速色谱法(10%乙酸乙酯/己烷)进行纯化,得到113mg的64(80%)。
(Z)-7-{(1R,2S,3R,5R)-2-[4-(1-乙酰氧基-己基)-苯基]-5-氯-3-羟基-环戊基}-庚-5-烯酸甲酯(65)。使用2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)所述的常规HF·嘧啶脱保护法。
4-硝基-苯甲酸(1S,2S,3R,4R)-2-[4-(1-乙酰氧基-己基)-苯基]-4-氯-3-((Z)-6-甲氧基羰基-己-2-烯基)-环戊酯(66)。将偶氮二甲酸二异丙酯(diisopropyl azodicarboxylate,11μL,0.057mmol)加入Ph3P(15.6mg,0.059mmol)、4-硝基苯甲酸(8.3mg,0.050mmol)和65(17mg,0.036mmol)于THF(0.600ml)中的混合物中。将反应搅拌过夜,然后真空蒸发挥发物。将残留物通过硅胶快速色谱法(30%乙酸乙酯/己烷)进行纯化,得到10mg(45%)的66。
(Z)-7-{(1R,2S,3S,5R)-5-氯-3-羟基-2-[4-(1-羟基-己基)-苯基]-环戊基}-庚-5-烯酸(67)。使用2004年12月10日提交的序列号为11/009,298的美国专利申请(目前是2006年8月15日公告的美国专利7,091,231)所述的常规LiOH水解法。
67向68a和68b的转化。此过程如方案1的步骤l所述进行。
体内实施例
对上述化合物进行体内测试以测定其降低眼内压的能力。用眼压正常(normotensive)的狗对化合物14a进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压(hypertensive)的猴子对化合物14a进行测试,IOP由基线降低。
用眼压正常的狗对化合物14b进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物14b进行测试,IOP由基线降低。
用眼压正常的狗对化合物25a进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物25a进行测试,IOP由基线降低。
用眼压正常的狗对化合物25b进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物25b进行测试,IOP由基线降低。
用眼压正常的狗对化合物34a进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物34a进行测试,IOP由基线降低。
用眼压正常的狗对化合物34b进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物34b进行测试,IOP由基线降低。
用眼压正常的狗对化合物40a进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物40a进行测试,IOP由基线降低。
用眼压正常的狗对化合物40b进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物40b进行测试,IOP由基线降低。
用眼压正常的狗对化合物46a进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物46a进行测试,IOP由基线降低。
用眼压正常的狗对化合物46b进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物46b进行测试,IOP由基线降低。
用眼压正常的狗对化合物51a进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物51a进行测试,IOP由基线降低。
用眼压正常的狗对化合物51b进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物51b进行测试,IOP由基线降低。
用眼压正常的狗对化合物60a进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物60a进行测试,IOP由基线降低。
用眼压正常的狗对化合物60b进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物60b进行测试,IOP由基线降低。
用眼压正常的狗对化合物63a进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物63a进行测试,IOP由基线降低。
用眼压正常的狗对化合物63b进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物63b进行测试,IOP由基线降低。
用眼压正常的狗对化合物68a进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物68a进行测试,IOP由基线降低。
用眼压正常的狗对化合物68b进行测试。眼内压(IOP)由基线降低。还用激光诱发高眼压的猴子对化合物68b进行测试,IOP由基线降低。
炎性肠病的治疗可通过将本文所述的化合物施用于患病的哺乳动物而实现。炎性肠病述及以肠部发炎为特征的多种疾病,包括但不限于溃疡性结肠炎和克罗恩氏病。治疗可通过口服、栓剂给药或肠胃外给药或一些其他适当方法进行。
可使用本领域已知的多种方法将本文公开的化合物经由口服剂型递送至结肠,而不以任何方式限制本发明的范围。例如,Chourasia和Jain在J Pharm Pharmaceut Sci 6(1):33-66,2003发表的综述以及Shareef等(AAPS PharmSci 2003;5(2)Article 17)描述了很多有用的方法。这些方法包括1)施用前药,包括基于偶氮或基于碳水化合物的前药;2)将药物用一种设计用于递送至结肠的聚合物包衣,或将该药物封装或注入所述聚合物中;3)缓释递送药物,4)使用一种生物粘附性体系等,但这不以任何方式限制本发明的范围。
不以任何方式囿于理论,认为肠道微生物丛能够将偶氮键还原性断裂,使两个氮原子成为胺官能团。在临床试验中,偶氮前药途径已用于将5-氨基水杨酸递送至人结肠以治疗炎性肠病,但这不以任何方式限制本发明的范围。还认为下胃肠道细菌也有可消化糖苷、葡糖苷酸(glucuronide)、环糊精、右旋糖苷和其他碳水化合物的酶,而由这些碳水化合物形成的酯类前药已被证明能将母体活性药物选择性地递送至结肠。例如,用地塞米松、泼尼松龙(prednisolone)、氢化可的松(hydrocortisone)和氟氢可的松(flufrocortisone)的前药对大鼠和豚鼠进行的体内和体外研究表明,糖苷缀合物可用于将类固醇递送至人结肠。其他体内研究也已表明,类固醇或非类固醇抗炎药物的葡糖苷酸、环糊精和右旋糖酐前药可用于将这些药物递送至下胃肠道。水杨酸和谷氨酸的氨化物已被证明可用于将水杨酸递送至兔和狗的结肠。
可使用碳水化合物聚合物例如淀粉酶、阿拉伯半乳聚糖、壳聚糖、硫酸软骨素、右旋糖苷、瓜尔胶、果胶、xylin等或含偶氮基的聚合物来对药物包衣,也可以将药物注入或封装进所述聚合物中。人们认为口服后,聚合物在上胃肠道中仍保持稳定,但可被下胃肠道中的微生物丛消化,从而将药物释放用于治疗。
由于结肠的pH比上胃肠道的pH高,所以也可使用对pH敏感的聚合物。这种聚合物是市售的。例如,Rohm Pharmaceuticals,Darmstadt,Germany提供pH依赖性的基于甲基丙烯酸酯的聚合物和共聚物,其根据聚合物中自由羧基的数目而在不同的pH范围内具有不同的溶解性,商标名为目前使用一些剂型来递送柳氮磺吡啶(salsalazine)以治疗溃疡性结肠炎和克罗恩氏病。还已经研究了缓释体系、生物粘附性体系和其他递送体系。
上述说明详细描述了可用于实现本发明的具体方法和组合物,并代表了可考虑的最佳方式。但是,对本领域的普通技术人员明显的是,可以以类似的方法制备具有所需药理特性的其他化合物,也可以通过不同的化学反应使用不同的起始化合物来制备所公开的化合物。类似地,还可制备和使用不同的药用组合物,并基本达到相同的效果。因此,无论前述文本内容看起来多么详尽,也不应该解释为限制本发明的总体范围,而应该仅由所附权利要求的法律结构来决定本发明的范围。
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EP (1) | EP2265576A1 (zh) |
JP (1) | JP2011515406A (zh) |
KR (1) | KR20100135264A (zh) |
CN (1) | CN102007098B (zh) |
AU (1) | AU2009225706B2 (zh) |
BR (1) | BRPI0910931A2 (zh) |
CA (1) | CA2718900A1 (zh) |
RU (1) | RU2501789C2 (zh) |
WO (1) | WO2009117388A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104684904A (zh) * | 2012-08-27 | 2015-06-03 | 阿勒根公司 | 通过使用β-氯环戊烷的亲水性酯前药减轻中央角膜增厚 |
CN106029643A (zh) * | 2014-02-20 | 2016-10-12 | 阿勒根公司 | 通过使用β-氯环戊烷的亲水性酯前药减少中心角膜增厚 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8569349B2 (en) * | 2008-05-09 | 2013-10-29 | Allergan, Inc. | Therapeutic compounds |
EP2303836A1 (en) * | 2008-05-09 | 2011-04-06 | Allergan, Inc. | Therapeutic cyclopentane derivatives |
US9090595B2 (en) | 2012-08-27 | 2015-07-28 | Allergan, Inc. | Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes |
US9340534B2 (en) * | 2014-07-25 | 2016-05-17 | Allergan, Inc. | Compounds and methods for treating ocular diseases |
CA2962766A1 (en) | 2014-10-02 | 2016-04-07 | Allergan, Inc. | Ester prodrugs of gamma-lactams and their use |
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WO2006063179A1 (en) * | 2004-12-10 | 2006-06-15 | Allergan, Inc. | 12-aryl prostaglandin analogs |
US20070129552A1 (en) * | 2005-12-06 | 2007-06-07 | Allergan, Inc. | Therapeutic Substituted Cyclopentanes |
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US4265874A (en) | 1980-04-25 | 1981-05-05 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
US4675182A (en) * | 1983-02-12 | 1987-06-23 | Bayer Aktiengesellschaft | Complexes of prostaglandins |
US5462968A (en) | 1994-01-19 | 1995-10-31 | Allergan, Inc. | EP2 -receptor agonists as agents for lowering intraocular pressure |
US5698598A (en) | 1995-08-04 | 1997-12-16 | Allergan | EP2 -receptor agonists as agents for lowering intraocular pressure |
US6090847A (en) | 1997-11-21 | 2000-07-18 | Allergan Sales, Inc. | EP2 -receptor agonists as neuroprotective agents for the eye |
US6437146B1 (en) | 1998-09-25 | 2002-08-20 | Fujisawa Pharmaceutical Co., Ltd. | Oxazole compounds as prostaglandin e2 agonists or antagonists |
US6410591B1 (en) * | 2001-05-08 | 2002-06-25 | Allergan Sales, Inc. | 3,7 or 3 and 7 thia or oxa prostanoic acid derivatives as agents for lowering intraocular pressure |
ATE305463T1 (de) * | 2001-11-05 | 2005-10-15 | Allergan Inc | Omega-zykloalkyl 17-heteroaryl prostaglandin-e2- analoga als ep2-rezeptoragonisten |
WO2004071428A2 (en) * | 2003-02-11 | 2004-08-26 | Allergan, Inc. | 10,10-dialkyl prostanoic acid derivatives as agents for lowering intraocular pressure |
TWI348386B (en) * | 2003-08-12 | 2011-09-11 | R Tech Ueno Ltd | Composition and method for promoting hair growth |
AU2009244541B2 (en) * | 2008-05-09 | 2014-01-09 | Allergan, Inc. | Therapeutic compounds |
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2009
- 2009-03-16 US US12/404,753 patent/US7732443B2/en not_active Expired - Fee Related
- 2009-03-17 JP JP2011500890A patent/JP2011515406A/ja active Pending
- 2009-03-17 AU AU2009225706A patent/AU2009225706B2/en not_active Expired - Fee Related
- 2009-03-17 WO PCT/US2009/037355 patent/WO2009117388A1/en active Application Filing
- 2009-03-17 CA CA2718900A patent/CA2718900A1/en not_active Abandoned
- 2009-03-17 BR BRPI0910931A patent/BRPI0910931A2/pt not_active IP Right Cessation
- 2009-03-17 CN CN200980113565.8A patent/CN102007098B/zh not_active Expired - Fee Related
- 2009-03-17 EP EP09723041A patent/EP2265576A1/en not_active Withdrawn
- 2009-03-17 KR KR1020107023241A patent/KR20100135264A/ko not_active Application Discontinuation
- 2009-03-17 RU RU2010141793/04A patent/RU2501789C2/ru not_active IP Right Cessation
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WO2006063179A1 (en) * | 2004-12-10 | 2006-06-15 | Allergan, Inc. | 12-aryl prostaglandin analogs |
US20070129552A1 (en) * | 2005-12-06 | 2007-06-07 | Allergan, Inc. | Therapeutic Substituted Cyclopentanes |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104684904A (zh) * | 2012-08-27 | 2015-06-03 | 阿勒根公司 | 通过使用β-氯环戊烷的亲水性酯前药减轻中央角膜增厚 |
CN104684904B (zh) * | 2012-08-27 | 2017-10-13 | 阿勒根公司 | 通过使用β‑氯环戊烷的亲水性酯前药减轻中央角膜增厚 |
CN106029643A (zh) * | 2014-02-20 | 2016-10-12 | 阿勒根公司 | 通过使用β-氯环戊烷的亲水性酯前药减少中心角膜增厚 |
Also Published As
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BRPI0910931A2 (pt) | 2019-09-24 |
AU2009225706A1 (en) | 2009-09-24 |
US20090239869A1 (en) | 2009-09-24 |
CA2718900A1 (en) | 2009-09-24 |
CN102007098B (zh) | 2014-05-07 |
RU2010141793A (ru) | 2012-04-27 |
KR20100135264A (ko) | 2010-12-24 |
RU2501789C2 (ru) | 2013-12-20 |
AU2009225706B2 (en) | 2014-07-31 |
JP2011515406A (ja) | 2011-05-19 |
US7732443B2 (en) | 2010-06-08 |
EP2265576A1 (en) | 2010-12-29 |
WO2009117388A1 (en) | 2009-09-24 |
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