CN102448965A - 前列腺素e受体拮抗剂 - Google Patents
前列腺素e受体拮抗剂 Download PDFInfo
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- CN102448965A CN102448965A CN201080024178XA CN201080024178A CN102448965A CN 102448965 A CN102448965 A CN 102448965A CN 201080024178X A CN201080024178X A CN 201080024178XA CN 201080024178 A CN201080024178 A CN 201080024178A CN 102448965 A CN102448965 A CN 102448965A
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Abstract
Description
相关申请
本申请要求2009年4月2日提交的序列号为61/166,107的美国临时专利申请的优先权,此申请的公开内容以引用的方式全部纳入本说明书。
技术领域
本发明提供了PGE受体拮抗剂,具体地,提供了PGE2-甘油酯受体的拮抗剂。
背景技术
需要获得前列腺素受体拮抗剂以协助从药理学上定义前列腺素受体,从而帮助确定对单独的前列腺素受体具有活性的化合物。
前列腺素F2α拮抗剂记载于美国专利4,632,928、5,747,660和5,955,575中。美国专利4,632,928的PGF2α拮抗剂是具有麦角灵(ergoline)骨架的吡唑衍生物。美国专利5,747,660的PGF2α拮抗剂是一种前列腺素F2α受体调节蛋白(FPRP),其能够抑制PGF2α结合到其受体上。
新的前列腺素F2α拮抗剂记载于美国专利6,369,089、6,407,250、6,509,364和6,511,999中。
具有EP4和D2活性的前列腺素受体拮抗剂分别公开于已公布的美国专利申请20050065200和20040162323中。
作为凝血噁烷(Thromboxane)A2受体拮抗剂使用的内亚苯基7-氧杂双环[2.2.1]庚烷噁唑类记载于美国专利5,100,889和5,153,327、欧洲专利申请0391652和J.Med.Chem.1993,36,1401-1417中。
凝血噁烷A2受体拮抗剂,例如7-氧杂二环庚基取代的杂环酰胺前列腺素类似物,无论单独使用或与抗炎剂一起使用,可以用于治疗溃疡性胃肠病症或痛经,如欧洲专利申请0448274和美国专利5,605,917中所公开的。
上述所有参考文件都通过引用的方式全文纳入本说明书。
发明内容
本发明涉及前列腺素受体拮抗剂(例如前列腺素E受体拮抗剂)以及它们用于确定对前列腺素E受体(包括其亚型)具有活性的化合物的用途,即前列腺素E4受体拮抗剂,以及它们用于治疗人类的多种疾病和病症(例如骨相关疾病)的用途。
可以用作本发明前列腺素E受体拮抗剂的化合物可用通式1表示。
其中R是C(O)R3-CH2-CH(OH)(CH2OH)或者C(O)R3-CH(CH2OH)2并且R3选自O、NR4、S或C(R5)2
其中R4代表选自H、烃基和杂原子取代的烃基基团的基团,其中所述杂原子选自卤素、O、S和N,即所包括的O、S和/或N可以为含O、S或N的基团形式,例如,R4是氢、烷基、烯基、炔基或芳基,或杂原子取代的烷基、烯基、炔基或芳基(杂芳基)基团;R5代表选自H、烃基和杂原于取代的烃基基团的基团,其中所述杂原子选自卤素、O、S和N,即所包括的O、S和/或N可以为含O、S或N的基团形式,例如H、烷基、烯基、炔基和芳基,或杂原子取代的烷基、烯基、炔基和芳基(杂芳基)基团;
m是1-3的整数,优选地为1或2;
n是0或1-4的整数,优选地为2-4;
A是具有6-14个碳原子的芳基或杂芳基,其中所述杂芳基可在杂芳环中被一个或多个氧、硫或氮所取代;以及其杂原子取代的衍生物;
R1和R2独立地选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C4-C12烷基环烷基、C6-C10芳基、C7-C12烷基芳基基团和它们的杂原于取代的衍生物,其中在所述基团中一个或多个氢或碳原子可被含有卤素、氧、氮或硫的基团所取代;以及其可药用盐。
用于R1和R2的优选取代基选自羟基、卤素(例如氟或氯)、COOR6、NO2、N(R6)2、SR6、次磺酰基(sulfoxy)、砜、CN和OR6,其中R6为H或C1-C6烷基。
这些化合物对于确定具有前列腺素E激动剂活性的化合物特别有用,也可以用于治疗很多疾病。已知PGE2为花生四烯酸酯级联(arachidonatecascade)的代谢物之一。也已知它具有多种活性,例如诱导疼痛的活性、炎症活性、子宫收缩活性、促进消化道蠕动的作用、唤醒活性、对胃酸分泌的抑制作用、降血压活性、血小板抑制活性、骨再吸收活性、血管生成活性等。
对前列腺素E敏感或对PGE2敏感的受体已被细分为四种亚型EP1、EP2、EP3和EP4,这些受体广泛分布于多种组织内。与EP1和EP3受体相关的作用可以被认为是刺激性的,并且被认为是通过刺激磷脂酰肌醇的周转(turnover)或抑制腺苷酸环化酶活性而来介导的,导致环状AMP的细胞内水平减少。相反,与EP2和EP4受体相关的作用可被认为是抑制性的,并且被认为与对腺苷环化酶的刺激相关,并增加细胞内环状AMP的水平。特别地,EP4受体可被认为与平滑肌舒张、消炎或促炎活性、淋巴细胞分化、抗过敏活性、系膜细胞舒张或增殖、胃或肠的粘液分泌等有关。
式(I)所表示的化合物或其盐对PGE2敏感的受体具有结合活性,因此它们具有PGE2拮抗或PGE2抑制活性。
因此,式(I)所表示的化合物或其盐可以用于预防或治疗PGE2介导的疾病,例如阻断PGE2-甘油酯的作用,例如人类或动物的炎症病症、多种疼痛等等。
更特别地,式(I)所表示的化合物及其盐类可以用于治疗或预防人类或动物中的关节和肌肉的炎症和疼痛(例如,类风湿性关节炎、类风湿性脊椎炎、骨性关节炎、痛风性关节炎、幼年型关节炎等)、炎性皮肤病症(例如,晒伤、烧伤、湿疹、皮炎等)、炎性眼病症(例如,结膜炎等)、涉及炎症的肺疾病(例如,哮喘、支气管炎、饲鸽者病(pigeon fancier’s disease)、农民肺等)、与炎症有关的胃肠道病症(例如,口疮性溃疡(aphthous ulcer)、克罗恩病(Chrohn′s disease)、萎缩性胃炎、痘疹状胃炎(gastritisvarialoforme)、溃疡性结肠炎、乳糜泻(coeliac disease)、局限性回肠炎、肠易激综合征等)、龈炎,手术或损伤后的炎症、疼痛和肿胀,与炎症有关的发热、疼痛和其他病症,变应性疾病、全身性红斑狼疮(systemiclupus crythematosus)、硬皮病、多肌炎、腱炎、滑囊炎、结节性动脉周围炎(periarteritis nodose)、风湿热、Sjogren氏综合征、眼-口-生殖器三联综合征(Behcet disease)、甲状腺炎、I类糖尿病、糖尿病并发症(糖尿病性微血管病、糖尿病性视网膜病变、糖尿病性肾病等)、肾病综合征、再生障碍性贫血、重症肌无力、葡萄膜炎、接触性皮炎、银屑病、川崎病、结节病、霍奇金病(Hodgkin′s disease)、阿尔茨海默病(Alzheimers disease)、肾功能障碍(肾炎、肾炎综合症等)、肝脏功能障碍(肝炎、肝硬化等)、胃肠道功能障碍(腹泻、炎性肠病等)、休克,以骨代谢异常为特征的骨病例如骨质疏松(特别是绝经后骨质疏松),高钙血症、甲状旁腺功能亢进、佩吉特骨病、骨溶解、具有或不具有骨转移的恶性高钙血症、类风湿性关节炎、牙周炎、骨性关节炎、骨痛、骨质减少、癌症恶病质、结石病(calculosis)、结石形成(lithiasis)(特别是尿石病)、实体瘤(solid caricinoma)等。例如,PGE2拮抗剂可用于治疗皮肤、毛发、内脏或其他被染色细胞的高色素性疾病。并且,前列腺素拮抗剂可用于抑制毛发生长,例如,用于多毛症或在需要减少或预防毛发生长的情况下。并且,前列腺素拮抗剂可用于治疗与疾病或手术有关的低眼压。最后,前列腺素拮抗剂可用于治疗炎症疾病和自身免疫性疾病,例如但不限于类风湿性关节炎、葡萄膜炎、结膜炎。
附图说明
图1显示了PG-2在人破骨细胞中不引起钙响应(Calcium Response);
图2显示了PG-2甘油酯在人破骨细胞中引起钙响应;
图3显示了由PGE2引发的钙响应被实施例1的化合物所阻断;
具体实施方式
在PGG2受体拮抗剂中,例如本发明的下述EP4或PGE2-甘油酯-特异性受体的拮抗剂,A可用以下通式表示
或
其中X选自H、R6、羟基、卤素(例如氟或氯)、COOR6、NO2、CF3、N(R6)2、CON(R6)2、SR6、次磺酰基、砜、CN和OR6,其中R6为H或C1-C6烷基;Y为O或S;Z为N或CH
优选地,所述前列腺素拮抗剂化合物可由通式II表示:
或由通式III表示
其中R的定义同上。
优选地,R1和R2选自H、C1-C6烷基、C3-C7环烷基和C4-C12烷基环烷基。
优选地,R4和R5选自H和C1-C6烷基。最优选地,R4和R5为H。
优选地,X选自氢或卤素例如氟。
优选地,R 为C(O)NH-CH2-CH(OH)(CH2OH)或C(O)NH-CH(CH2OH)2。
最优选的化合物可描述为3-(2-{(1R,2R,3S,4R)-3-[4-(4-环己基-丁基氨基甲酰)-噁唑-2-基]-7-氧杂-二环[2.2.1]庚-2-基甲基}-4-氟-苯基)丙酸的丝氨醇酰胺或二羟基丙酰胺衍生物,即其中1-OH分别被丝氨醇酰胺或二羟基丙酰胺取代。
在整个说明书中看使用下列定义。
“可药用盐”是指保持游离碱的生物有效性和特性的盐,这些盐是通过与无机酸反应而获得的,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。“可药用盐”也可指保持游离酸的生物有效性和特性的盐,这些盐是通过与无机碱或有机碱反应而获得的,所述无机碱例如氢氧化钠、氢氧化钾或氢氧化钙等,所述有机碱例如赖氨酸、精氨酸、乙醇胺等。
“烷基”是指直链的、支链的或环状的饱和脂肪烃。优选地,所述烷基基团具有1-12个碳。更优选地,它是具有1-6个碳的低级烷基,最优选具有1-4个碳。常用的烷基基团包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等。所述烷基基团可任选地被一个或多个选自以下的取代基所取代:羟基、氰基、烷氧基、=O、=S、NO2、卤素、二甲基氢基和SH。
“烯基”是指含有至少一个碳-碳双键的直链的、支链的或环状的不饱和烃基团。优选地,所述烯基基团具有1-12个碳。更优选地,它是具有1-7个碳的低级烯基,最优选具有1-4个碳。所述烯基基团可任选地被一个或多个选自以下的取代基所取代:羟基、氰基、烷氧基、=O、=S、NO2、卤素、二甲基氨基和SH。
“炔基”是指含有至少一个碳-碳三键的直链的、支链的或环状的不饱和烃。优选地,所述炔基基团具有1-12个碳。更优选地,它是具有1-7个碳的低级炔基,最优选具有1-4个碳。所述炔基基团可任选地被一个或多个选自以下的取代基所取代:羟基、氰基、烷氧基、=O、=S、NO2、卤素、二甲基氨基和SH。
“烷氧基”是指“O-烷基”基团。
“芳基”是指芳香族基团,其具有至少一个具有共轭pi电子体系的环,包括碳环芳基、杂环芳基和联芳基基团。所述芳基基团可任选地被一个或多个选自以下的取代基所取代:卤素、三卤代甲基、羟基、SH、OH、NO2、胺、硫醚、氰基、烷氧基、烷基和氨基。
“烷芳基”是指与芳基基团共价地结合的烷基。优选地,所述烷基为低级烷基。
“碳环芳基”是指其中环原子是碳的芳基基团。
“杂环芳基或杂芳基”是指具有1-3个杂原子作为环原子,其余的环原子为碳的芳基基团。
“杂原子”包括氧、硫和氮。因此,杂环芳基基团包括呋喃基、噻吩基、吡啶基、吡咯基、N-低级烷基吡咯并、嘧啶基、吡嗪基、咪唑基等。
“烃基”是指只具有碳原子和氢原子的烃基基团。优选地,所述烃基基团具有1-20个碳原子。更优选地具有1-12个碳原子,最优选地具有1-6个碳原子。
“杂原子取代的烃基”是指以下所述烃基基团,其中一个或多个但非全部的氢原子和/或碳原子被卤素、氮、氧或硫原子取代,或者被含有卤素、氮、氧或硫原子的基团所取代,例如,氟、氯、氰基、硝基、羟基、磷酸酯、巯基等。
“酰胺”是指-C(O)-NH-R′,其中R′是烷基、芳基、烷基芳基或氢。
“胺”是指-N(R″)R′″基团,其中R″和R′″独立地选自烷基、芳基和烷基芳基。
THF是指四氢呋喃。
DCM是指二氯甲烷。
DIBAL-H是指二异丁基氢化铝。
DMAP是指4-二甲基氨基吡啶。
以下的实施例描述了一种合成本发明的前列腺素拮抗剂化合物的方法,其中实施例的编号对应于美国专利7,217,725中所述反应路线中所示的不同中间体和最终产物的编号,此专利文件以引用的方式纳入本说明书。
实施例1
N-(1,3-二羟基丙-2-基)-3-(2-{(1R,2R,3S,4R)-3-[4-(4-环己基-丁基氨基甲酰基)-噁唑-2-基]-7-氧杂-二环[2.2.1]庚-2-基甲基}-4-氟-苯基)丙酰胺的合成。
内半缩醛中间体10的合成
(1)手性薄荷醇单酯
CO2R=L-薄荷醇酯
在0℃下,向L-薄荷醇(202g:1.3mole)的无水TMF(1L)的搅拌溶液中,加入正丁基锂(在己烷中为2.5M;510ml;1.28mole),保持温度在10℃以下。将所述反应冷却到-78℃,将间-7-氧杂二环[2.2.1]庚烷-2,3-二羧酸酐(177g;1.05mole)的无水THF(1.2L)溶液在大约20分钟内加入,保持温度低于-50℃。在加入之后,将所述反应置于-64℃持续另一小时,之后用稀盐酸(2M;800ml)在5分钟内将其淬灭,使得温度上升到大约-25℃。加入盐水(400ml),出现分层。用盐水(400ml)洗涤有机层。将合并的水层用DCM(1L)再萃取。合并的有机层用硫酸钠干燥然后真空蒸发。将剩余物溶解在DCM(700ml)和乙酸乙酯(2800ml)的沸腾混合物中。将所述溶液缓慢冷却到室温,于4℃下持续21小时,过滤,用乙酸乙酯(2x500ml)洗涤,然后真空干燥,得到所需的纯非对映异构体形式的薄荷醇单酯(手性纯度由NMR分析证实;111.5g;66%)。
(2)手性内酯
在薄荷醇单酯(65g;0.20mole)和三乙胺(用CaH2新蒸馏的;55ml)的0℃无水THF(650ml)溶液中加入氯甲酸乙酯(37ml;0.39mole),保持温度低于10℃。在加入后,将反应混合物于0℃放置1小时,之后加入醚(700ml;事前经分子筛干燥过)和石油醚(700ml)。将所述混合物用硫酸镁(200g)过滤然后用乙醚(2x400ml)洗涤。将滤液真空蒸干。将白色固体剩余物溶解到THF(550ml)中,冷却到5℃,加入无水乙醇(800ml),之后将硼氢化钠(15g;0.39mole)在2分钟内分批地加入。在15分钟后,加入稀盐酸(2M;600ml)和冰,用DCM(3x750ml)萃取此混合物。将合并的有机层用硫酸钠干燥,然后真空蒸发。将油状的残留物重新溶解于DCM(600ml)中,加入对甲苯磺酸一水合物(3.75g;0.02mole),将所述混合物搅拌25分钟。在用碳酸氢钠溶液(200ml)洗涤后,将有机层用硫酸钠干燥并真空蒸发。将残留物在石油醚(40-60℃;300ml)中煮沸,冷却到-20℃,过滤并用石油醚(3x50ml)洗涤,得到手性内酯(24.5g;79%)。
(3)手性内半缩醛中间体10
将DIBAL-H(25%的甲苯溶液;170ml)于-78℃下在40分钟内加入到内酯(25g;mole)的无水甲苯(400ml)溶液中。在加入过程中,将温度保持在-60℃以下。在30分钟后,将乙酸(50ml)小心地逐滴加入。将所述反应混合物升温至室温,之后加入稀盐酸(2M;250ml)。分离甲苯层,将水层用氯化钠饱和,然后用DCM(4x600ml)萃取。将合并的有机层用硫酸钠干燥,真空蒸干,与甲苯(2x300ml)共沸(azeotrope),得到中间体10(25g;99%)。
芳基溴化物中间体8的合成
(4)在30分钟内,向三苯基膦烯乙酸甲酯(methyl(triphenylphosphoranylidene)acetate)(233.3g;0.70mole)的无水THF(1.2L)悬液中逐滴加入2-溴-4-氟苯甲醛(中间体4;141.6g;0.70mole)的无水THF(150ml)溶液。将所述混合物搅拌过夜,然后将所述溶剂在真空下移除。将所得残留物在石油醚(b.p.40-60℃;1L)中研磨,然后通过二氧化硅(1Kg),用10%的溶于石油醚的乙酸乙酯洗脱,得到顺反异构体混合物形式的中间体5(176g;97%)。
(5)将中间体5(60g;0.23mole)和5%铑碳(10g)在THF(600ml)中的混合物在氢气中和室温下搅拌2天。将所述混合物通过硅藻土过滤,用THF(3x200ml)洗涤过滤板。将所得滤液真空蒸发,得到中间体6(60g;99%)。
(6)在20分钟内,向中间体6(26.1g;0.10mole)的-70℃无水甲苯(150ml)溶液中加入DIBAL-H(25%的甲苯溶液,140ml),保持温度低于-50℃。将所述混合物在-60℃下继续再搅拌30分钟,然后在0℃下再搅拌一小时。小心地加入盐酸(6M;150ml),保持温度低于40℃。分离所述有机层,用甲苯(2x50ml)萃取水层。将合并的有机萃取物用硫酸钠干燥,然后真空蒸发得到中间体7(23.3g;100%)。
(7)在20分钟内,向中间体7(81.5g;0.35mole)、三乙胺(56ml)和DMAP(1.75g;0.014mole)的无水DCM(700ml)溶液中逐滴加入二甲基叔己基氯化烷(dimethylthexylsilyl chloride)(70ml;0.355mole)。将所述混合物在室温放置过夜。加入水(200ml),出现分层。用二氯甲烷(2x100ml)萃取水层。将合并的有机层用硫酸钠干燥然后通过二氧化硅(500g),用DCM洗脱,得到中间体8(125g;95%)。
中间体8和10的格氏(GRIGNARD)偶联并细化为N-(1,3-二羟基丙-2-基)-3-(2-{(1R,2R,3S,4R)-3-[4-(4-环己基-丁基氨基甲酰基)-噁唑-2-基]-7-氧杂-二环[2.2.1]庚-2-基甲基}-4-氟苯基)丙酰胺
(8)将催化量的碘加入到镁屑(15g;0.62mole)和芳基溴化物中间体8(140g;0.37mole)在无水THF(500ml)中的混合物中。在初始反应平息后,将所述混合物加热至60℃,持续2小时,以完全地形成格氏化合物中间体9,之后将其冷却到室温。
在0-5℃下,将乙基溴化镁(1M的THF溶液;280ml;0.28mole)在15分钟内逐滴地加入至中间体10(45g;0.29mole)的无水THF(260ml)溶液中。将此溶液在0-5℃下再放置25分钟,之后在10分钟内用套管加入已制备的格氏溶液中间体9(如上文所述)。将所述反应混合物升温至室温,搅拌24小时,真空浓缩并在DCM(2L)和氯化铵溶液(1L)之间分配。在搅拌的所述混合物中加入稀盐酸(2M),从而将pH降低到8-9。分离有机层,用硫酸钠干燥并真空蒸发。将所得残留物用5-40%的溶于己烷中的乙酸乙酯进行层析,得到产物中间体11(111g;88%)。
(9)将格氏产物中间体11(111g;0.25mole)和乙酸酐(28ml;0.30mole)的无水吡啶(200ml)溶液在室温下搅拌过夜,然后真空蒸发。将所得残留物溶解在己烷(1.2L)中,用水(500ml)、稀盐酸(2x500ml)、水(500ml)、盐水(500ml)洗涤,用硫酸钠干燥,然后真空蒸发,得到产物中间体12(130g;存在极少量二乙酸酯/溶剂),其无需进一步纯化就可用于下一步。
(10)将粗制中间体12(38g)和10%钯碳(10g)在乙酸(200ml)中的混合物在氢气中和55℃下搅拌40小时。冷却后,加入乙酸乙酯(200ml),将所述混合物通过硅藻土过滤,用乙酸乙酯(3x200ml)洗涤过滤板。将所得滤液真空蒸发,并将所得残留物用10%的溶于己烷中的乙酸乙酯进行层析,首先洗脱脱羟基化的材料中间体12a(14.5g;0.030mole),之后用乙酸乙酯洗脱从而得到去甲硅烷基化且脱羟基化的材料中间体12b(6.5g;0.019mole)。自中间体11起经两个步骤的产率为68%。将这两个产物(如下所示)结合用于下一反应:
中间体12a:R=二甲基叔己基甲硅烷基
中间体12b:R=H
(11)将琼斯试剂(Jones′reagent)(35ml)加入到中间体12a和中间体12b(共21g;0.049mole)的上述混合物在丙酮(265ml)中的水冷却溶液中。30分钟后,加入2-丙醇(25ml),将所得的混合物搅拌15分钟,用硅藻土过滤并用丙酮洗涤。将所得滤液真空蒸发,溶解于DCM(500ml)中然后用水(200ml)洗涤。将有机层用硫酸钠干燥并真空蒸发。将所得残留物溶解在无水甲醇(100ml)中,在其中加入乙酰氯(2ml)并搅拌过夜。蒸发后,将所得残留物用60%的溶于己烷中的乙酸乙酯进行层析,得到产物中间体15(9.3g;59%)。
(12)将琼斯试剂(Jones′reagent)(24ml)加入到水冷却的中间体15(10.2g;0.032mole)的丙酮(260ml)溶液中。35分钟后,加入2-丙醇(16ml),将所得的混合物搅拌15分钟,用硅藻土过滤并用丙酮洗涤。将所得滤液真空蒸发,溶解于DCM(500ml)中并用水(200ml)洗涤。将所得有机层用硫酸钠干燥并真空蒸发,得到酸-酯产物中间体16(10.2g;95%),其无需进一步纯化就可用于下一步。
(13)向中间体16(10.7g;0.32mole)、L-丝氨酸苄酯氢氯化物(8.8g;0.038mole)和1-羟基苯并三唑(6.3g;0.046mole)在THF(150ml)中的0℃混合物中加入三乙胺(11.5ml)。5分钟后,加入二环己基碳二亚胺(1M在DCM中的溶液;45ml;0.045mole),然后将此反应混合物在室温下放置过夜。真空浓缩后,将所得残留物在乙酸乙酯(200ml)中浆化,然后过滤。将过滤垫用乙酸乙酯(3x50ml)洗涤,将所得滤液真空蒸发。将所得残留物用60-100%的溶于己烷中的乙酸乙酯进行层析,得到白色固体状的中间体17(13g;79%)。
(14)向中间体17(13g;0.025mole)、三苯基膦(19.5g;0.074mole)和二异丙基乙胺(12.9ml;用CaH2新鲜蒸馏的;0.074mole)在无水DCM(24ml)和无水乙腈(120ml)中的0℃溶液中加入四氯化碳(7.22ml;0.074mole)。将此混合物于室温下放置4小时,冷却到0℃,然后加入乙酸乙酯(300ml)和碳酸氢钠溶液(300ml)。剧烈搅拌5分钟后,将此混合物加入至乙酸乙酯(500ml)和盐水(400ml)中。分离出有机层,用硫酸钠干燥并真空蒸发。将所得残留物用60%的溶于己烷中的乙酸乙酯进行层析,得到灰白色乳状固体形式的中间体18(6.1g;49%)。
(15)向-10℃的中间体18(6.1g;0.012mole)的无水DCM(60ml)溶液中加入DBU(2ml),接着加入三氯溴甲烷(1.5ml)。将所述反应混合物塞住,在冰箱中放置过夜,然后用氯化铵溶液(150ml)洗涤。将水层分离出,并用DCM(100ml)进行反萃取。将合并的有机层用硫酸钠干燥并真空蒸发。将所得残留物用40%的溶于己烷中的乙酸乙酯进行层析,得到噁唑中间体19(4.7g;78%)。
(16)将中间体19(1.8g;3.65mmole)和氢氧化钯(20%;0.5g)在乙酸乙酯(35ml)中的混合物在氢气中搅拌2小时。冷却后,将所述混合物用硅藻土过滤,然后用乙酸乙酯(3x25ml)洗涤过滤垫。将所得滤液真空蒸发,得到白色固体状的产物中间体20(1.45g;99%)。
(17)将草酰氯(0.91g;0.61ml;7.15mmole)加入到中间体20(1.45g;3.60mmole)的无水DCM(15ml)溶液中。加入一滴N,N-二甲基甲酰胺催化所述反应。20分钟后,将所述混合物真空蒸发,并与无水甲苯(50ml)共沸,然后溶解于无水二氯甲烷(18ml)中,之后冷却到0℃。然后加入三乙胺(用CaH2新鲜蒸馏的;1.15ml)和4-环己基丁基氯化铵(1g;5.22mmole),之后将所述混合物升温至室温并持续1.5小时。将所述混合物加入稀盐酸(1M;50ml)中,然后用DCM(3x50ml)萃取。合并的有机层用硫酸钠干燥并真空蒸发。将所得残留物用50%的溶于己烷中的乙酸乙酯进行层析,得到中间体21(1.45g;75%)。
(18)向中间体21(8.8g;16.30mmole)在THF(50ml)和甲醇(230ml)中的溶液中加入氢氧化钠溶液(1M;90ml)。3小时后,加入乙酸(6.5ml),将所述溶液真空浓缩至大约100ml,溶解于乙酸乙酯(1L)中,用稀盐酸(2M;600ml)和盐水(300ml)洗涤,然后用硫酸钠干燥并真空蒸发。将所得残留物溶解在DCM(70ml)中,将石油醚(40-60℃;350ml)缓慢地加入升温的并且搅拌的所述溶液中。将结晶的混合物在20分钟内冷却至室温,过滤,用戊烷(2x50ml)洗涤,真空烘干,得到白色固体状的N-(1,3-二羟基丙-2-基)-3-(2-{(1R,2R,3S,4R)-3-[4-(4-环己基-丁基氨基甲酰基)-噁唑-2-基]-7-氧杂-二环[2.2.1]庚-2-基甲基}-4-氟-苯基)丙酰胺(7.60g;m.p.165-166℃;87%)。将母液真空蒸发,用5%的溶于二氯甲烷中的甲醇进行层析,然后用上述方法结晶,得到另一批N-(1,3-二羟基丙-2-基)-3-(2-{(1R,2R,3S,4R)-3-[4-(4-环己基-丁基氨基甲酰基)-噁唑-2-基]-7-氧杂-二环[2.2.1]庚-2-基甲基}-4-氟-苯基)丙酰胺(0.49g;m.p.165-166℃;5.7%)。
实施例2
通过替换合适的试剂或中间体,制得相应的丙酸或氧杂类似物。
实施例3
通过替换合适的试剂或中间体,制得相应的硫碳酸或硫化物类似物。
实施例4
通过替换合适的试剂或中间体,制得相应的亚甲基类似物。
实施例5-8
通过在实施例1-4的合成方法中替换合适的试剂或中间体,制得相应的二羟基丙基衍生物。
本发明的化合物特别适用于治疗哺乳动物(例如人类)的骨疾病和病症。
被称为成骨细胞和破骨细胞的两种主要细胞类型的活性之间错综复杂的平衡决定了一个人的总骨量。
骨重建从再吸收开始,这是破骨细胞的协调过程。破骨细胞通过溶解矿物并再吸收成骨细胞形成的基质从而分解骨。
成骨细胞形成胶原和羟基磷灰石。有一些成骨细胞被埋藏在它们的基质中,之后它们被称为骨细胞。剩余的成骨细胞覆盖新骨的表面。一批移入所述区域的成骨细胞形成新的骨层。
破骨细胞是更大的细胞,它们的功能是通过作用于矿物基质而溶解骨。它们生成酶,例如胶原酶(其分解胶原)。破骨细胞也分泌可溶解羟基磷灰石结构的多种酸。
存在控制成骨细胞和破骨细胞功能的多种信号。成骨细胞生成小的蛋白质,其中之一是OPG(骨保护素(osteoprotegrin))。OPG可以阻止破骨细胞活化。
成骨细胞改变其形状并且被埋藏在它们的基质中,只通过被称为小管(canaliculi)的稀疏突起而彼此连接。在成骨细胞被埋入骨中后,它们被称为骨细胞。骨细胞占骨骼中所有细胞的90%。
应理解,骨的建立和再吸收过程是非常重要的,因为这些过程中的异常会导致骨病。
特别地,过快的破骨细胞骨再吸收在骨质疏松和其他骨病的发病机理中起主要作用。对调节破骨细胞活性的分子路径的鉴别,为理解这些疾病的病因和开发新治疗方法提供了关键要素。已证明大麻素1型(CB1)受体失活的小鼠具有增加的骨量,并且被保护免遭卵巢切除术诱导的骨丢失。CB1和CB2受体的药理学拮抗剂预防体内的卵巢切除术诱导的骨丢失,并通过促进破骨细胞凋亡和抑制多种破骨细胞存活因子的产生而在体外引起对破骨细胞的抑制。因此,CB1受体在调节骨量和卵巢切除术诱导的骨丢失中起作用,并且CB1-和CB2-选择性大麻素受体拮抗剂是可用于治疗骨质疏松症和其他骨病的破骨细胞抑制剂。
本发明的前列腺素E2拮抗剂可用于测试具有前列腺素E2甘油基受体激动剂活性而对相应的前列腺素E2受体无活性的化合物,如下所述:
使对前列腺素E2-甘油酯和前列腺素E2响应的组织或细胞(例如猫虹膜括约肌组织XX)与多种浓度的所述前列腺素E-甘油酯接触,并以浓度依赖性方法测量第一个响应。(优选地,为用于以下测试的目的,可将所述猫虹膜括约肌组织切成四对试样)使所述组织或细胞与所述多种浓度的前列腺素E2-甘油酯在前列腺素拮抗剂存在的情况下接触,用浓度依赖性方法测量第二个响应。
使所述组织或细胞与多种浓度的化合物接触(评价所述化合物的前列腺素E2-甘油酯激动剂活性),用浓度依赖性方法测量第三个响应。使所述组织或细胞与多种浓度所述化合物(评价所述化合物的前列腺素E2-甘油酯激动剂活性)在所述前列腺素E2-甘油酯拮抗剂存在的情况下接触,用浓度依赖性方法测量第四个响应。
测定具有前列腺素E2-甘油酯激动剂活性的化合物作为以下所述的化合物,其中所述第三和第四响应之间的差异比所述第一和第二响应之间的差异更大。
优选地,所述第一和第二响应之间的差异为基本上可以忽略不计的,即前列腺素E2-甘油酯基本不具有前列腺素激动剂活性,因此前列腺素E2-甘油酯拮抗剂的存在不影响组织响应。因此,前列腺素E2-甘油酯激动剂是这样的化合物:即其中与前列腺素E2-甘油酯拮抗剂不存在时的响应相比,在前列腺素E2-甘油酯拮抗剂存在时的响应为可忽略不计的。
在本发明的另一个方面中,前列腺素E2-甘油酯激动剂的相对活性可通过以下方式测量:在存在特定浓度的本发明的前列腺素E2拮抗剂的情况下,将两种或多种前列腺素E2-甘油酯激动剂与对前列腺素E2-甘油酯激动剂有响应的组织或细胞相接触。通过比较所述组织或细胞的相对响应以测定各个所述的前列腺素E2-甘油酯激动剂的相对活性。
本领域技术人员容易理解,为了用于给药,可将本文中公开的化合物与本身在本领域中是熟知的可药用赋形剂混合。特别地,对于一种待全身给药的药物,它可被配制为粉剂、丸剂、片剂等,或配制为溶液、乳剂、悬浮剂、气雾剂、糖浆剂或酏剂(elixir),适合用于口服给药或肠胃外给药或吸入。
对于固体剂型,无毒的固体载体包括但不限于医药级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、聚亚烷基二醇(polyalkylene glycol)、滑石、纤维素、葡萄糖、蔗糖和碳酸镁。所述固体剂型可为不包衣的,或者它们可用已知技术包衣以延缓在胃肠道中的崩解和吸收,从而在较长时间内提供持续作用。例如,可以使用一种延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。所述固体剂型也可用美国专利4,256,108、4,166,452和4,265,874中所述的技术进行包衣,形成用于控制释放的渗透性治疗片剂。液体的可给药剂型可以,例如包括一种溶液或悬浮液,其中一种或多种目前可用的化合物和任选的药物助剂溶于载体(例如水、盐水、葡萄糖水溶液、甘油、乙醇等)中,从而形成溶液或悬浮液。如果需要,所述待给予的药物组合物还可包含极少量的无毒辅助物质,例如润湿剂或乳化剂、pH缓冲剂等。这种辅助剂的常用实例是乙酸钠、单月桂酸脱水山梨醇、三乙醇胺、乙酸钠、三乙醇胺油酸酯等。制备这些剂型的实用方法对本领域技术人员来说是已知的或显而易见的;例如,参见Remington′sPharmaceutical Sciences,Mack Publishing Company,Easton,Pa.,16thEdition,1980。无论如何,所述待给予的制剂的组成中含有一定量的一种或多种目前可用的化合物,其量可有效地提供所需的治疗效果。
肠胃外给药通常以注射为特征,可以为皮下注射、肌肉内注射或静脉内注射。注射剂可以制备为常规形式,液体溶液或悬浮液、适合用于在注射前溶于液体中形成溶液或悬浮液的固体形式、或者乳剂。合适的赋形剂为,例如水、盐水、葡萄糖、甘油、乙醇等。并且,如果需要,待给予的可注射药物组合物还可包含极少量的无毒辅助物质,例如润湿剂或乳化剂、pH缓冲剂等。所述化合物也可以与载体缀合以局部应用于骨,例如聚乙二醇化的基质或纤维蛋白凝血酶基质。
所给予的一种或多种目前可用的化合物的量,当然地,取决于所需的一种或多种治疗效果、所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、所使用的一种或多种特定化合物的效力和药效动力学、以及开处方医师的判断。目前可用的一种或多种化合物的治疗有效剂量优选为约0.5ng/kg/天或大约1ng/kg/天至约100mg/kg/天。
本发明的化合物可口服给药、肠胃外给药、或者局部给药于多种已知的哺乳动物种类,以便以有效量用于治疗皮肤、毛发、内脏或其他被染色细胞的高色素性疾病或者过度的毛发生长,例如可用于治疗人、猫、狗等,所述有效量的剂量范围为约0.1至约100mg/kg,优选为约0.2至约50mg/kg,更优选为约0.5至约25mg/kg(或约1至约2500mg,优选约5至约2000mg),每天给药一次或每天分2-4次给药。对于炎症疾病,本发明的化合物可局部给药、口服或局部注射,如上所述。
所述活性成分可以用于组合物(例如片剂、胶囊剂、溶液或悬浮剂)中,其中每单位剂量含有约5至约500mg的局部形式的式I、II或III的化合物或多种化合物的混合物,以用于减少色素沉着或毛发生长等(0.01-5重量%的式I化合物,每天1-5次)。可以用常规方法将它们与生理上可接受的载体(vehicle或carrier)、赋形剂、粘合剂、防腐剂、稳定剂、香味剂等复合,或者应公认药物实践的需要与局部载体(例如矿物油)复合。
前述说明详细地叙述了可以用于实施本发明的特定方法和组合物,并描述了预期的最佳方式。然而,对于本领域普通技术人员来说显而易见的是,可以用类似方法制备具有所需药理学性质的其他化合物,并且所公开的化合物也可以用不同的起始材料而获得。包括本发明的前列腺素拮抗剂的不同药物组合物可被制备并使用,并具有基本相同的结果。最后,尽管已参考式I的化合物对本发明进行了描述,这些化合物的明显变体也包括在本发明的范围内。
因此,不管上文中的描述有多么详细,这些描述都不能被认为是对本发明整体范围的限制;相反,本发明的范围仅由随附的权利要求的合法解释所决定。
Claims (17)
1.一种如通式1所示的具有前列腺素受体拮抗剂活性的化合物以及其可药用盐,
其中R是R3-C(O)CH2-CH(OH)(CH2OH)或者R3-C(O)CH(CH2OH)2并且R3选自O、NR4、S和C(R5)2
其中R4代表选自H、烃基和杂原子取代的烃基基团的基团,其中所述杂原子选自卤素、O、S和N,即所包括的O、S和/或N可以为含O、S或N的基团形式,R5代表选自H、烃基和杂原子取代的烃基基团的基团,其中所述杂原子选自卤素、O、S和N,即所包括的O、S和/或N可以为含O、S或N的基团形式;
m是1-3的整数;
n是0或1-4的整数;
A是具有6-14个碳原子的芳基或杂芳基,其中所述杂芳基可在杂芳环中被一个或多个氧、硫或氮所取代;以及其杂原子取代的衍生物;
R1和R2独立地选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C4-C12烷基环烷基、C6-C10芳基、C7-C12烷基芳基基团和它们的杂原子取代的衍生物,其中在所述基团中一个或多个氢或碳原子可被含卤素、氧、氮或硫的基团取代。
3.权利要求2的化合物,其中m是1或2。
4.权利要求2的化合物,其中n是2-4。
5.权利要求2的化合物,其中R1和R2选自H、C1-C6烷基、C3-C7环烷基和C4-C12烷基环烷基。
6.权利要求2的化合物,其中X是氢或卤素。
7.权利要求6的化合物,其中X是氟。
9.权利要求8的化合物,其中m为1或2。
10.权利要求8的化合物,其中n为2-4。
11.权利要求8的化合物,其中R1和R2选自H、C1-C6烷基、C3-C7环烷基和C4-C12烷基环烷基。
12.权利要求8的化合物,其中X为氢或卤素。
13.权利要求12的化合物,其中X是氟。
14.权利要求1的化合物,其中所述化合物为
3-(2-{(1R,2R,3S,4R)-3-[4-(4-环己基-丁基氨基甲酰基)-噁唑-2-基]-7-氧杂-二环[2.2.1]庚-2-基甲基}-4-氟苯基)丙酸,1,3-二羟基丙-2-基酯。
15.权利要求1的化合物,其中所述化合物为
3-(2-{(1R,2R,3S,4R)-3-[4-(4-环己基-丁基氨基甲酰基)-噁唑-2-基]-7-氧杂-二环[2.2.1]庚-2-基甲基}-4-氟苯基)-1,3-二羟基丙-2-基-丙酰胺。
16.权利要求1的化合物,其中所述化合物为
3-(2-{(1R,2R,3S,4R)-3-[4-(4-环己基-丁基氨基甲酰基)-噁唑-2-基]-7-氧杂-二环[2.2.1]庚-2-基甲基}-4-氟苯基)丙酸,1,2-二羟基丙-3-基酯。
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CN103965048B (zh) * | 2014-05-06 | 2016-02-17 | 西北农林科技大学 | 反式肉桂酸酯类化合物及其合成方法和应用 |
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