CN114644673B - 一种雌二醇衍生物、其制备方法及其在医药上的用途 - Google Patents
一种雌二醇衍生物、其制备方法及其在医药上的用途 Download PDFInfo
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Abstract
本发明涉及一种通式(I)所示化合物或其立体异构体、互变异构体或其药学上可接受的盐,以及医药中的应用,通式(I)化合物的结构如下所示,其基团定义与说明书定义一致。
Description
发明领域
本发明涉及一种雌二醇衍生物及其中间体和制备方法,以及在制备药物中的用途。
发明背景
雌二醇(estradiol),亦称“动情素”、“求偶素”。有α,β两种类型,雌激素的一种。含量最多,活性也最强。由卵巢内卵泡的颗粒细胞分泌。其代谢物是雌酮及雌三醇。含18个碳原子。可作为一种为经皮肤吸收的雌激素治疗剂。雌激素能促使细胞合成DNA、RNA和相应组织内各种不同的蛋白质。目前公开的专利和文献中,雌二醇采用注射给药,口服,贴片方式。
根据前药的原理,本发明将雌二醇的羟基进行前体改造,以期改善其溶解度、稳定性,以达到改善药物的理化性质、改善药物在体内的吸收、分布、代谢与排泄过程、提高口服生物利用度、提高药物对靶部位作用的选择性、降低药物的毒副作用、延长作用时间等的技术效果。这类药物进入体内后,可按照设计要求以一定的水解速度释放出雌二醇,从而补充雌激素不足,常用于治疗女性性腺功能不良、双侧卵巢切除术后、萎缩性阴道炎、外阴干燥、更年期综合征如潮热、出汗和精神、神经症状等;也可以采用雌激素治疗转移性乳腺癌,40%可以达到缓解;用以治疗晚期前列腺癌,症状明显改善,疼痛减轻,睾丸摘除后再加用雌激素治疗;防止骨质疏松,用于停经早期预防由于雌激素缺乏而引起的骨质快速丢失;白细胞减少症,用于恶性肿瘤经化疗或放疗引起的白细胞减少症,有明显升高白细胞的效果。
发明内容
本发明通过膦酰胺基团改变雌二醇的物理化学性质,如改变雌二醇原有的性状、稳定性、脂溶性等,进而改变体内跨膜吸收、分布及代谢行为。膦酰胺修饰的药物进入体内后,在体内水解酶作用下水解释放出雌二醇。通过控制膦酰胺药物水解速率可以延长药物在体内的存在时间,也可以通过水解酶的分布等特点达到提高药物对靶部位的特异性作用给药的目的。
本发明涉及一种通式(I)所示化合物、其立体异构体或其药学上可接受的盐,
其中:
R1选自C1-C6烷氧基或C3-C8环烷基氧基;
R2选自氢原子或C1-C6烷基;
R3和R4各自独立地选自氢原子或C1-C6烷基,其中所述的烷基任选进一步被一个或多个卤素所取代;
作为选择,R3和R4与其所连接的碳原子一起可以形成3至6元环,所述的环含有0至6个选自N、O或者S的杂原子,且所述环任选进一步被一个或多个选自羟基、卤素或氨基的取代基所取代;且
R5选自C1-C6烷基、C3-C8环烷基或苄基。
本发明的优选方案,一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其为一种通式(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐:
其中R1~R5的定义如通式(I)中所述。
本发明的优选方案,一种通式(I)或(II)所示化合物、其立体异构体或其药学上可接受的盐,其中R1选自甲氧基、乙氧基或异丙氧基。
本发明的优选方案,一种通式(I)或(II)所示化合物、其立体异构体或其药学上可接受的盐,其中R2选自氢原子、甲基或乙基。
本发明的优选方案,一种通式(I)或(II)所示化合物、其立体异构体或其药学上可接受的盐,其中R3选自氢原子;R4选自甲基。
本发明的优选方案,一种通式(I)或(II)所示化合物、其立体异构体或其药学上可接受的盐,其中R5选自乙基或异丙基。
本发明的典型化合物包括,但不限于:
或其立体异构体或其可药用的盐。
本发明涉及一种药物组合物,所述药物组合物含有治疗有效剂量的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐,以及药学上可接受的载体和赋形剂。
本发明涉及一种通式(I)所示的的化合物、其立体异构体或其药学上可接受的盐,或其组合物,在制备治疗和/或预防中枢神经系统相关的疾病中的用途,其中所述的中枢神经系统相关疾病选自震颤、抑郁症、失眠症、心境障碍、惊厥性障碍、记忆障碍、注意障碍、焦虑、双相型障碍、精神分裂、双相型障碍、情感分裂性精神障碍、心境障碍、焦虑障碍、人格障碍、精神病、强迫性障碍、创伤后应激障碍、自闭症谱系障碍、精神抑郁症、社交焦虑障碍、强迫症、疼痛、睡眠障碍、记忆障碍、痴呆、阿尔茨海默病、发作性疾病、创伤性脑损伤、中风、成瘾性障碍、自闭症、亨廷顿舞蹈症、帕金森病、Rett综合征、戒断综合征或耳鸣;其中优选为震颤或抑郁症;其中所述的抑郁症优选为产后抑郁症。
本发明涉及一种通式(I)所示的的化合物、其立体异构体或其药学上可接受的盐,或其药物组合物,在制备用于提高药物口服生物利用度、延长母体药物的药效学半衰期、降低给药剂量和频率或延长半衰期的药物中的用途。
发明的详细说明
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”当作一基团或一基团的一部分时是指包括1至20个碳原子的直链或者带有支链的脂肪烃基团。优选为1至10个烷基,更优选为1至6个烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的,当被取代时,取代基优选为一个或多个以下的基团:烷基、烷氧基、卤素、羟基、硝基、氰基、环烷基、环烷基氧基或氨基。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环,但没有一个环具有完全共轭的π电子的芳香环系统。优选为3至12元环烷基,更优选为3至8元环烷基,最优选为3至6元环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。
“稠环基”指5至18元,系统含有两个或两个以上环状结构彼此共用一对碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香环系统,优选为6至12元,更优选为7至10元。根据组成环的数目可以分双环、三环、吡啶酮或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于:
“桥环基”指5至18元,系统含有两个或两个以上环状结构,彼此共用两个不直接相连接碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香环系统,优选为6至12元,更优选为7至10元。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环桥环烷基,优选为双环、三环或吡啶酮,更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于:
“螺环烷基”指5至18元的单环之间公用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目,将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基。优选为单螺环烷基。螺环烷基的非限制性实施例包括但不限于:
环烷基可以是任选取代的或未取代的。当被取代时,取代基优选为一个或多个以下的基团:烷基、烷氧基、卤素、羟基、硝基、氰基、环烷基、环烷基氧基或氨基。
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“环烷基氧基”是指(环烷基-O-)的基团。其中,环烷基见本文有关定义。C3-C8的环烷氧基为优先选择。其实例包括,但不限于:环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。
“羟基”指-OH。
“氨基”指-NH2。
“卤素”是指氟、氯、溴和碘。
“DMSO”是指二甲基亚砜。
“Et”是指乙基。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的药物。本发明的前药通过修饰雌二醇中的功能基团来制备,该修饰可以通过常规的操作或者在体内被除去,而得到雌二醇。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“有效剂量”指引起组织、系统或受试者生理或医学反应的化合物的量,此量是所寻求的,包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。
1H NMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm),测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,q=四重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorba x SB-C18 100x 4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
在下列实施例中,除非另有指明,所有温度为摄氏温度。
除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于AldrichChemical Company,ABCR GmbH&Co.KG,Acros Organics,韶远化学科技(上海)有限公司,国药集团药业股份有限公司,百灵威科技有限公司等公司等处购买。
对化合物进行纯化,采用硅胶柱层析和薄层色谱法,其中洗脱剂体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:二氯甲烷:乙酸乙酯;D:石油醚:二氯甲烷体系;其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行调节,如醋酸或三乙胺等。
实施例1
(2S)-异丙基-2-((乙氧基羰基)(((8R,9S,13S,14S,17S)-3-羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊[a]菲-17-基)氧基)磷酰)氨基)丙酸酯
第一步
(双(三甲基硅烷基)氧基)甲酸乙酯
将甲磷酸三乙酯(100g,0.476mol)溶解于1L乙腈中,加入三甲基溴硅烷(220g,1.43mol),65℃搅拌反应3小时。降温至室温,旋干得到标题化合物1a(140g,黄色液体)直接用于下一步。
第二步
二氯磷酰甲酸乙酯
将1a(140g,0.47mol)溶解于1.5L二氯甲烷中,加入DMF(1ml),冰盐浴降温至0℃,滴加草酰氯(180g,1.41mol),后升温至室温反应过夜。旋干,油泵减压蒸馏得到标题产物1b(72g,淡黄色液体),产率:78.89%。
第三步
叔丁基((8R,9S,13S,14S,17S)-17-羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊[a]菲-3-基)碳酸酯
将β-雌二醇(15g,55.15mmol)溶解于150mL二氯甲烷中,加入DMAP(8.1g,66.2mmol),冰盐浴降温至0℃,滴加碳酸叔丁酯(13.22g,60.66mmol)的THF溶(50ml)。滴毕,升至室温反应过夜。反应液依次用1M盐酸,NaHCO3水溶液以及饱和盐水洗,有机相用无水硫酸钠干燥,过滤,旋干,得到标题化合物1c(20g,白色固体),直接用于下一步。
第四步
(2S)-异丙基-2-((((8R,9S,13S,14S,17S)-3-((叔丁氧羰基)氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊基[a]菲-17-基)氧基)(乙氧基羰基)磷酰基)氨基)丙酸酯
将二氯磷酰甲酸乙酯1b(14.67g,0.077mol)溶解于200mL二氯甲烷中,氩气保护下,降温至-60℃。加入三乙胺23.3g,0.23mol),加毕,滴加1c(20g,0.054mol)的二氯甲烷溶液(100ml)。滴毕,保温反应30min。再滴加L-丙氨酸异丙酯(13.2g,0.115mol)的二氯甲烷溶液(50ml),自然升温至室温反应3h。反应液依次用1M盐酸及饱和盐水洗,有机相用无水硫酸钠干燥,过滤,旋干。粗品用硅胶柱色谱法(乙酸乙酯/石油醚(V/V)=1:10-1:3)纯化,得到标题产物1d(20g无色油状物),产率:37.5%。
第五步
(2S)-异丙基-2-((乙氧基羰基)(((8R,9S,13S,14S,17S)-3-羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊[a]菲-17-基)氧基)磷酰)氨基)丙酸酯
将1d(20g,0.03mol)溶解于150mL二氯甲烷中,加入TFA(40mL),室温反应3h。反应液倒入500mL饱和碳酸钠水溶液中,搅拌10min,分液。水相用DCM萃取(200mL*2),合并有机相,用盐水洗,无水硫酸钠干燥,过滤,旋干。粗品用硅胶柱色谱法(乙酸乙酯/石油醚(V/V)=1:10-1:2)纯化,得到标题产物1(10g白色固体),产率:59.6%。
MS m/z(ESI):522.5[M+1]
1H NMR(400MHz,DMSO-d6):δ8.99(s,1H),7.04(d,1H),6.52(d,1H),6.45(s,1H),5.91-6.12(m,1H),4.81-4.91(m,1H),4.15-4.45(m,3H),3.73-3.85(m,1H),2.65-2.75(m,2H),1.55-2.35(m,7H),1.15-1.42(m,20H),0.76(d,3H)
生物学评价
测试例1、SD大鼠体内药动学研究
试验动物:健康成年SD大鼠9只,雄性,180-250g,购于成都达硕实验动物有限公司。
药物配制:精密称取一定量受试化合物,加入DMSO及Solutol HS-15使溶解,再加入生理盐水,旋涡混合均匀。最终给药溶剂配比为DMSO:Solutol HS-15:生理盐水(5:5:90,v/v/v),所有受试化合物均在临用前新鲜配制。
给药及检测:SD大鼠随机分成3组,每组3只;给药前禁食不少于8小时,自由饮水,给药后4小时方可进食。3组动物分别静脉注射(IV)给予雌二醇(IV,给药剂量为1mg/kg),灌胃(PO)给予雌二醇(PO,给药剂量为30mg/kg)和化合物1(PO,给药剂量为30mg/kg),于给药前及给药后不同时刻采集静脉血约0.1ml,肝素抗凝,离心分离出血浆,于-80℃保存。采用LC-MS/MS法分别测定血浆中的原形药物(前药)及水解代谢物(原药)浓度,计算主要药动学参数,结果如表1所示:
表1 SD大鼠药代动力学测试结果
备注:SD大鼠灌胃给予本发明化合物,各时刻血浆中均未检测到前药形式,仅检测雌二醇并计算药动学参数。
结论:化合物1大鼠灌胃给药后,吸收迅速,体内主要以雌二醇形式存在,根据雌二醇血浆中暴露水平计算口服绝对生物利用度分别为73.2%,表明具有良好的口服吸收特征。
Claims (10)
1.一种通式(I)所示的化合物或其可药用的盐:
其中:
R1选自甲氧基、乙氧基或异丙氧基;
R2选自氢原子;
R3选自氢原子;
R4选自甲基;
R5选自乙基或异丙基。
2.根据权利要求1所述的化合物或其可药用的盐,其为一种通式(II)所述的化合物或其可药用的盐:
其中:R1~R5的定义如权利要求1所述。
3.根据权利要求1~2任一项所述的化合物或其可药用的盐,其中所述的化合物选自:
。
4.一种药物组合物,所述的药物组合物含有有效剂量的根据权利要求1~3中任一项所述的化合物或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
5.根据权利要求1~3中任一项所述的化合物或其可药用的盐,或根据权利要求4所述的药物组合物在在制备治疗和/或预防中枢神经系统相关的疾病中的用途,其中所述的中枢神经系统相关疾病选自震颤、抑郁症、失眠症、惊厥性障碍、注意障碍、精神分裂、双相型障碍、心境障碍、焦虑障碍、人格障碍、强迫性障碍、创伤后应激障碍、自闭症谱系障碍、疼痛、记忆障碍、阿尔茨海默病、创伤性脑损伤、中风、成瘾性障碍、亨廷顿舞蹈症、Rett综合征、戒断综合征或耳鸣。
6.根据权利要求5所述的用途,其中所述的中枢神经系统相关疾病为震颤或抑郁症。
7.根据权利要求6所述的用途,其中所述的抑郁症为产后抑郁症。
8.根据权利要求6所述的用途,其中所述的抑郁症为精神抑郁症。
9.根据权利要求5所述的用途,其中所述的焦虑障碍为社交焦虑障碍。
10.根据权利要求5所述的用途,其中所述的精神分裂为情感分裂性精神障碍。
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CN105518015A (zh) * | 2013-06-25 | 2016-04-20 | 佛恩多制药有限公司 | 治疗活性的作为17β-羟基类固醇脱氢酶抑制剂的17-氮取代雌三烯噻唑衍生物 |
CN105518017A (zh) * | 2013-06-25 | 2016-04-20 | 佛恩多制药有限公司 | 治疗活性的作为1型17β-羟基类固醇脱氢酶抑制剂的雌三烯噻唑衍生物 |
CN110945007A (zh) * | 2017-06-08 | 2020-03-31 | 佛恩多制药有限公司 | 用于抑制17β-羟基类固醇脱氢酶的15β-[3-丙酰氨基]-取代的雌-1,3,5(10)-三烯-17-酮化合物及其17-肟 |
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CN105518015A (zh) * | 2013-06-25 | 2016-04-20 | 佛恩多制药有限公司 | 治疗活性的作为17β-羟基类固醇脱氢酶抑制剂的17-氮取代雌三烯噻唑衍生物 |
CN105518017A (zh) * | 2013-06-25 | 2016-04-20 | 佛恩多制药有限公司 | 治疗活性的作为1型17β-羟基类固醇脱氢酶抑制剂的雌三烯噻唑衍生物 |
CN110945007A (zh) * | 2017-06-08 | 2020-03-31 | 佛恩多制药有限公司 | 用于抑制17β-羟基类固醇脱氢酶的15β-[3-丙酰氨基]-取代的雌-1,3,5(10)-三烯-17-酮化合物及其17-肟 |
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