CN1177860C - 胆烯酸酰胺及其药物组合物 - Google Patents
胆烯酸酰胺及其药物组合物 Download PDFInfo
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- CN1177860C CN1177860C CNB998036935A CN99803693A CN1177860C CN 1177860 C CN1177860 C CN 1177860C CN B998036935 A CNB998036935 A CN B998036935A CN 99803693 A CN99803693 A CN 99803693A CN 1177860 C CN1177860 C CN 1177860C
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Abstract
式(I)的新型甾醇化合物,其中:R1表示羟基或保护的羟基,R2表示氢原子,并且在c处存在双键,或者R1和R2一起表示氧代,并且在b处存在双键或在a和b处都存在双键;R3表示具有α-或β-构型的甲基;R4和R5可以相同或不同,它们选自氢原子和脂族基、脂环族基、芳代脂族基和芳基,或者与它们所连的氮原子一起形成杂环基;以及X表示含2~5个碳原子的聚亚甲基,其含噁基的类似物,其中,除了连接到-CO.NR4R5部分的那个之外的一个亚甲基被氧原子替代,或是其含至多两个双键的不饱和类似物。本发明的活性化合物表现出对细胞生长和分化的调节的有效作用,并且由于其低钙血活性水平而具有有利的治疗比率。
Description
本发明涉及新型固醇衍生物,更具体地说,涉及这样的固醇衍生物:其中,17位侧链终止于酰氨基,而且,它们表现细胞调节活性。
人们熟知,9,10-闭联固醇(9,10-seco sterol)衍生物(例如维生素D3)通过促进钙和磷的肠吸收,保持适当的钙和磷的血清含量,以及在甲状旁腺激素的存在下刺激钙从骨液腔隙(bone fluid compart-ment)移动在钙代谢在方面起极其重要的作用。在发现了D维生素类在肝中(25位)和肾中(1α位)在体内被羟基化、并且生成的1α,25-二羟基代谢物是生物活性物质之后,人们对在例如1α位和24R或25位羟基化的维生素D类似物进行了大量研究。
另外还发现了天然代谢物1α,25-二羟基维生素D3影响细胞代谢,这些细胞调节作用包括:细胞成熟和分化的刺激、免疫抑制作用和免疫增强作用(例如通过刺激杀菌氧代谢物的生成和白细胞的趋化反应)。然而,例如1α,25-二羟基维生素D3这样的化合物对钙代谢的有效作用一般将阻止它们在该领域中的应用,因为足以诱发所需的细胞调节作用的剂量往往会导致不可接受的高钙血症。
这已导致了试图合成新的维生素D类似物,它们对钙代谢具有较小的作用,但它们仍表现所需的对细胞代谢的作用。这样的类似物的代表性实例以及早期解决该问题的尝试的总结都给出于WO-A-9309093、WO-A-9426707和WO-A-9525718中,将它们的内容并入本文作参考。
现在认为,这样的维生素D类似物通过涉及维生素D响应基因的调节的受体介导的(尤其是核受体介导的)过程起细胞生长和分化的一般调节剂作用(M.R.Waters,内分泌学综述(Endoc.Rev.)13,pp.719-764[1992])。迄今还认为,闭联类固醇5,7,10(19)-三烯体系或类似的19-去甲闭联类固醇5,7-二烯体系是任何形式的细胞调节活性的前提。所以,虽然研究维生素D类似物的工作者对A环和17位侧链作了改性,还在某些情况下对整个分子骨架作了更强烈的改性(例如C环和/或D环的改性或者甚至消除),但他们试图保留三烯或共轭二烯体系(Gui-DongZhu等,生物有机和医疗化学通讯(Bioorganic&Med.Chem.Lett.)6,pp.1703-1708[1996];K.Sabbe等,生物有机和医疗化学通讯6,pp.1697-1702[1996])。
研究者们最近报导了对维生素D类似物的非基因组迅速响应这一观察结果,他们认为这是由于与推定的细胞膜定位的维生素D受体的相互作用(A.W.Norman等,类固醇生物化学和分子生物学杂志(J.SteroidBiochem.and Mol.Biol.)56,pp.13-22[1996])。还报导了这种非基因组迅速作用可通过1α,3β,25-三羟基胆甾-5,7-二烯(即1α,25-二羟基维生素D3的前维生素形式,它不是闭联类固醇)诱导;这是由于所述前维生素模拟正常维生素D三烯的6,7-s-顺式构象的能力(Norman,见上面所引的文献)。但是,据报导,所述前维生素诱导基因组作用(被认为是细胞生长和分化的调节作用的基础)的能力很小(Norman,见上面所引的文献),还报导了所述前维生素不表现维生素D对皮肤的典型作用(R.Gniadecki等,英国皮肤病学杂志(British J.Dermatol.)132,pp.841-852[1995])。
本发明基于这一意外发现,即:一系列简单固醇衍生物(它们具有完整的四环核心,所以既没有维生素D类似物那样的闭联类固醇三烯体系,又没有模拟其共轭构象异构体的能力)表现出对细胞生长和分化的调节的有效作用,这是通过它们抑制各种癌细胞系的生长和促进其分化的能力估测的。所述化合物由于其低血钙活性水平而具有有利的治疗比率,例如由它们对大鼠血清钙和磷含量的作用确定的。
本发明的化合物包括具有一个5(6)位双键和酰胺封端的17位侧链的3β-固醇(极其O-保护的衍生物),以及相应的具有4-烯双键或1,4-二烯双键的17-取代的类固醇-3-酮。
因此,按本发明的一个实施方案,提供了式(I)的化合物
其中:
R1表示羟基或保护的羟基,R2表示氢原子,并且在c处存在双键,或者R1和R2一起表示氧代,并且在b处存在双键或在a和b处都存在双键;
R3表示具有α-或β-构型的甲基;
R4和R5可以相同或不同,它们选自氢原子和脂族基、脂环族基、芳代脂族基和芳基,或者与它们所连的氮原子一起形成杂环基;以及
X表示含2~5个碳原子的聚亚甲基,其含噁基的类似物,其中,除了连接到-CO.NR4R5部分的那个以外的一个亚甲基被氧原子替代,或是其含至多两个双键的不饱和类似物。
如果R1表示保护的羟基,这可能例如包括任何合适的可解离的O-保护基,例如本技术中通常已知的保护基。代表性的基包括:(i)醚化基,例如甲硅烷基(诸如三低级烷基甲硅烷基,例如三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基或叔丁基二甲基甲硅烷基;三芳基甲硅烷基,例如三苯基甲硅烷基;以及混合的烷基-芳基甲硅烷基),任选被一个氧原子间隔的低级(例如C1~6)烷基(例如甲基、甲氧基甲基或甲氧基乙氧基甲基)和环醚基(例如四氢吡喃基),以及(ii)酯化基,例如低级(例如C1~6)烷酰基(诸如乙酰、丙酰、异丁酰或新戊酰),芳酰基(例如含7-15个碳原子,诸如苯甲酰或4-苯基偶氮苯甲酰),低级(例如C1-6)烷磺酰(例如甲磺酰或卤代甲磺酰)以及芳基磺酰(例如对甲苯磺酰)。
式(I)的化合物的这种O-保护的衍生物可用于制备活性化合物(I)(其中,R1表示羟基),并且还可能(当该O-保护基在体内代谢上不稳定时)直接适用于治疗。
如果式(I)的中R3表示呈α构型的甲基,那么,所述化合物具有天然固醇(例如胆固醇)的20R构型特性;如果R3呈β构型,那么,所述化合物具有相应的表衍生物(epi-derivatives)的20S构型。应懂得,本发明还包括这两种异构体的混合物。
R4和R5表示的脂族基可例如包括低级(例如C1-6烷基,例如甲基、乙基、丙基和丁基。脂环族基可以例如包括低级(例如C3-8)环烷基,例如环丙基、环戊基和环己基。芳代脂族基可以例如包括C6-12芳基-C1~4烷基,例如苄基或苯乙基。芳基可以例如包括C6~12碳环芳基,例如苯基或萘基,任选带有一个或多个取代基,所述取代基例如选自下列基:卤基(例如氯或溴),低级(例如C1-4)烷基(例如甲基),低级(例如C1~4)烷氧基(例如甲氧基),低级(例如C2-4)烷酰基(例如乙酰),低级(例如C1~4)烷基氨基或二烷基氨基(例如甲氨基或二甲氨基),硝基,甲氨酰以及低级(例如C2-4)烷酰氨基(例如乙酰氨基)。
如果基R4R5N-表示杂环基,该基一般将含至少一个选自O、N和S的杂原子,并且可包括一个或多个环,例如每个环具有5或6个环原子。所以,代表性的杂环R4R5N-基包括N-连接的吡咯基、吡唑基、咪唑基、吲哚基、吲唑基、嘌呤基、吡咯烷基、咪唑烷基、吡唑烷基、哌啶基、吗啉代、噻唑烷基、噻吗啉代(thiamorpholino)。
基X例如可由式-CH2-(CH=CH)m-(CH2)n-表示,其中,m是0、1或2,并且n是0或整数,以致2m+n=1、2、3或4。X也可以是式-(CH2)p-O-(CH2)q的基,其中p是0、1、2或3,q是1、2、3或4,并且p+q不超过4。
本发明的化合物(包括O-保护的衍生物,其中,O-保护基是代谢上不稳定的)的细胞调节活性结合它们的基本缺乏钙血效果,使它们在肿瘤病,尤其髓细胞白血病以及脑、乳腺、胃、胃肠道、前列腺、胰腺、泌尿生殖道(雄性和雌性)的肿瘤病和肺瘤形成的治疗方面单独用或作为辅助剂都令人感兴趣。它们促进小鼠耳孔闭合的能力启示它们或者单独地、或者以辅助剂形式作为促进创伤愈合的作用剂的应用。它们还可能或者单独地、或者以辅助剂形式适用于感染的化疗和其它涉及单核吞噬细胞的治疗形式中,例如下列疾病的治疗:骨病(例如佝偻病或肾性骨营养不良中的骨质疏松症、骨质减少和骨营养不良),自身免疫病,宿主-移植物反应,移植物排斥反应、炎症(包括免疫炎性反应的调节),瘤形成和增生,肌病,肠病和脊椎炎性心脏病。它们还可能适用于甲状旁腺激素(例如血清钙体内稳态中)的抑制,如下疾病的治疗:皮肤病[例如包括痤疮、脱发、湿疹、瘙瘁、牛皮癣和皮肤老化(包括光致老化)],高血压,类风湿性关节炎,牛皮癣性关节炎,继发性甲状旁腺功能亢进,气喘,认知损伤和老年性痴呆(包括早老性痴呆);人和动物主体生育率的控制;以及涉及血液凝固的疾病(例如通过溶解现有的凝块和/或防止凝固)。本发明包括这些化合物在治疗或预防这样的病况中的应用和在制备用于这种治疗或预防的药剂中的应用。
本发明的活性化合物可被配制成供通过任何便利的途径施药,例如经口(包括舌下),胃肠外,经直肠或者通过吸入;这样配制的药物组合物包括本发明的特征。
如果需要的话,可经口施药的组合物可以包含一种或多种生理上相容的载体和/或赋形剂,并且可呈固态或液态。所述组合物可呈任何便利的形式,例如片剂、包衣片、胶囊、锭剂、水性或油性悬浮液、溶液、乳液、糖浆剂、酏剂和适合在应用前用水或另一种合适的液体载体复制的干制品。所述组合物可被有利地配成单元剂型。如果需要的话,本发明的片剂和胶囊可以包含常规组分,例如:粘合剂,诸如糖浆、阿卡胶、明胶、山梨糖醇、西黄蓍胶或聚乙烯吡咯烷酮;填充剂,例如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸;润滑剂,例如硬脂酸镁、滑石粉、聚乙二醇或二氧化硅;崩解剂,例如马铃薯淀粉;或者可接受的润湿剂,例如十二烷基硫酸钠。片剂可按本技术中熟知的方法包衣。
液体组合物可含常规添加剂,例如悬浮剂,诸如山梨糖醇糖浆、甲基纤维素、葡萄糖/蔗糖糖浆、明胶、羟甲基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂;乳化剂,例如卵磷脂、失水山梨糖醇单油酸酯或阿卡胶;非水载体,它们可以包括:食用油,例如植物油,诸如花生油、杏仁油、分馏椰子油、鱼肝油,油性酯(例如聚山梨酯80),丙二醇或乙醇;以及防腐剂,例如对羟基苯甲酸甲酯或丙酯或者山梨酸。液态组合物可就便被包胶于例如明胶中而给出呈单元剂型的制品。
供胃肠外施药的组合物可应用可注射的液态载体(例如灭菌无热原水、灭菌无过氧化物的油酸乙酯、无水酒精或丙二醇或者无水酒精/丙二醇混合物)配制,而且可通过静脉内、腹膜内或肌内注射。
供直肠施药的组合物可应用常规栓剂基质(例如可可脂或另一种甘油酯)配制。
通过吸入施药的组合物就便被配制成自身喷射送递的剂型(例如呈计量的剂型),例如作为喷射剂(诸如卤代烃)中的悬浮液(被注入装有计量分配阀的气溶胶容器)。
可能有利的是,在本发明的组合物中掺入抗氧化剂(例如抗坏血酸、丁基化羟基苯甲醚或氢醌)而提高它们的储存期限。
如果任何上述组合物被制备成单元剂型,这些组合物例如可以包含每单元剂型为0.2~2500μg(例如0.4~500μg)本发明的活性化合物。如果需要的话,所述组合物可掺和一种或多种其它的活性组分。
本发明的活性化合物合适的日剂量例如可在每天为0.4~5000μg(例如0.8~1000μg)的范围内,这取决于这样的因素:例如,受治疗病况的严重性以及患者的年龄、体重和病况。
本发明的化合物可通过任何常规方法制备,例如,将含所需侧链的母体的化合物分一步或多步与一种或多种起形成所需的17位侧链的作用的反应物反应,接着,如果必要的话和/或如果需要的话除去任何O-保护基,将3β-醇氧化成3-酮,然后将5(6)烯异构化成4-烯,再氧化而形成1,4-二烯。
形成所需侧链的合适的技术包括前述WO-A-9309093和WO-A-9426707中描述的那些。
例如,式(I)的化合物[其中,X是上文定义的基-CH2-(CH=CH)m-(CH2)n-]可通过式(II)化合物的适当反应制备
其中:
R1a表示保护的羟基,
R3如上文定义,以及
Y表示氧代或亚膦基(phosphoranylidene group);金属化硅烷或砜基;基-(CH2)xL,其中,x是0、1或2,L表示离去基(例如:磺酸酯基,诸如低级烷基磺酰氧基、低级氟烷基磺酰氧基或芳基磺酰氧基,或者卤原子,例如氯、溴或碘);或者基-(CH2)yR6,其中y是0、1、2或3,R6表示氰基或者酯化羧基或硫代羧基(例如烷氧羰基、芳代烷氧羰基、芳氧羰基、烷基硫代羰基、芳烷基硫代羰基或芳基硫代羰基)。
可用于制备式(I)化合物[其中,X表示聚亚甲基(即,m=0时)]的反应包括:
(1)将式(II)的化合物[其中,Y表示上文定义的基-(CH2)xL]与式(III)酰胺的金属化盐或二金属化盐反应
CH3.CO.NR4R5 (III)
(其中,R4和R5如前文定义)。
代表性的盐包括碱金属盐(例如锂盐),可通过与碱(例如二异丙基氨化锂)反应制备。
(2)式(III)化合物[其中,Y表示上文定义的基-(CH2)yR6]的反应,将酯基、硫代酯基或氰基R6转化成所需的酰胺基(例如直接通过酯或硫代酯的氨解或者间接通过相应的游离酸,该游离酸是通过酯、硫代酯或腈的水解获得的,或者间接通过从其中获得的酰基卤)。应懂得,式(II)的腈可被部分地水解以便直接生成化合物(I)(其中,R4和R5都是氢原子)。
(3)将式(II)的化合物[其中,Y表示上文定义的基-(CH2)xL]与试剂(例如能引入一个碳片段的金属氰化物或金属化三噻烷(trithiane))反应,再将这样引入的基转化成所需的-CO.NR4R5基(例如按方法(2)描述的那样)。
可被用于制备式(I)化合物[其中,X是不饱和的(即,m=1或2时)]的反应包括:
(4)按维悌希(Wittig)型反应将式(II)的化合物(其中,Y表示氧代)例如与式(IV)的正膦反应
(Rh)3P=CH-(X1)z-Rc (IV)
其中,X1是含至多2个碳原子的亚烷基或亚链烯基;z是0或1;Rh是烃基[例如烷基或芳烷基或芳基(诸如苯基)];Rc是如上文定义的甲氨酰基-CO.NR4R5或可转化成该基的母体基(例如酯基、硫代酯基或氰基)。如果Rc表示一个母体基,该反应之后接着进行转化而生成基-CO.NR4R5(例如按方法(2)描述的那样)。正膦(IV)也可被金属化硅烷(V)
(Rh)3Si-CHM-(X1)z-Rc (V)替代,或者被金属化砜(VI)替代
RhSO2-CHM-(X1)z-Rc (VI)
其中,X1、z、Rh和Rc都如上文定义,M表示金属原子(例如碱金属,诸如锂或钠)。在最后这种情况下,反应后紧接着将中间体羟基砜还原而形成所需的双键(例如应用钠汞齐)。应懂得,这类反应还可应用式(II)化合物(其中,Y是亚膦基=P(Rh)3)或化合物(II)的金属化衍生物(其中,Y是-Si(Rh)3或-SO2Rh)与式(VII)的醛而进行
OHC-(X1)z-Rc (VII)(Rh、X1、z和Rc具有上述意义)。
式(I)化合物(其中,X是上文定义的基-(CH2)p-O-(CH2)q)例如可这样制备:
(5)将式(VIII)的化合物
(其中,R1a、R3和p都如上文定义)与式(IX)的化合物反应
L.(CH2)q.Rc (IX)
(其中,Rc、L和q都如上文定义,L优选是卤原子),如果必要的话,接着转化母体基Rc而产生所需的基-CO.NR4R5(例如按上述方法(2)描述的那样)。
(6)将式(X)的化合物
(其中,R1q、R3、L和p都如上文定义,L优选是高反应性的离去基,例如三氟乙酸基、甲苯磺酸基或三氟甲磺酸基)与式(XI)的化合物反应
HO.(CH2)q.Rc (XI)
(其中,Rc和q都如上文定义),如果必要的话,接着转化母体基Rc而产生所需的基-CO.NR4R5(例如按前述那样)。
(7)如果q是2,通过碱催化的、前述定义的式(VIII)化合物与丙烯酸酯(例如式(XII)的丙烯酸酯)的迈克尔加成
CH2=CH.CO.ORe (XII)
(其中,Re是酯化基,例如烃基,诸如低级烷基或芳基),接着,将酯基转化成所需的基-CO.NR4R5(例如按前述那样)。
诸如式(IX)化合物(其中,Rc是甲氨酰基-CO.NR4R5)这样的试剂例如可通过合适的ω-卤代烷酰氨(例如4-溴丁酰氯,此处需要合成其中q是3的本发明化合物)与胺R4R5NH(其中R4和R5都如上文定义)的反应制备。就便现场(即随后不用纯化)制备这样的试剂,优选应用摩尔过量的胺,以便余下足够过量的碱与在接着进行的与式(VIII)化合物的偶联反应中释放的酸反应。
产物中保护的羟基R1a向羟基R1的转化例如可通过常规去保护法(例如许多文献中描述的方法)实现。例如,酯化保护基可通过碱解(例如应用碱金属醇盐在烷醇中)除去。醚化保护基(例如甲硅烷基)可通过酸解或通过用氟化物盐(例如四烷基氟化铵,诸如四丁基氟化铵)处理而除去。应懂得,鉴于这类反应中通常应用的强碱性条件,在形成所需的17位侧链的认可步骤中应用酸不稳定但碱稳定的甲硅烷基保护基可能是特别有利的。
式(I)的3β-醇向相应的3-酮的转化可应用任何合适的氧化剂(例如Swern氧化)进行;该氧化通常伴随着自发向4-烯-3-酮的异构化。如果需要1,4-二烯-3-酮,另外的那个双键例如可通过与二氧化硒在叔丁醇中反应生成,或者通过应用2,3-二氯-5,6-二氰基-1,4-苯醌脱氢而生成。
式(II)(其中,Y表示氧代)的原料可从已知的孕甾烯醇酮(XIII)
(其中,R1a如前述定义)通过与烷氧基亚甲基正膦或其它一碳原子烷氧基内鎓盐的维悌希反应而制备。
或者,可将已知的类固醇-5(6)-烯-17-酮进行维悌希反应而生成式(XIV)的化合物
(其中,R1a和R3都如前述定义),然后可将它与亲双烯体(例如甲醛或其官能等价物,或者炔丙基酯)反应而生成式(XV)的化合物
(其中,R1a和R3都如前述定义,并且Z或是-CH2OH或是-CH=CH.CO.ORh,其中,Rh如上文定义)。如果Z是-CH2OH,可将该基转化成-CH2Y基,例如,通过氧化而形成一种化合物(其中,Y是氧代),或者通过磺酸酯的形成(例如甲苯磺酰化),优选还用卤化物离子亲核置换,生成一种其中Y是-(CH2)xL(其中,x是0)的化合物。该16,17-双键容易被还原并且可通过在反应程序的任何合适步骤氢化而除去。
上述原料和适用于制备本发明化合物的其它中间体的制备被描述于如下文献中:Batcho等,瑞士化学学报(Helv.Chim.Acta.)64,pp.1682-1687[1981],Midland等,四面体通讯(Tetrahedron Lett.)23(20),pp.2077-2080[1982],Krubiner等,有机化学杂志(J.Org.Chem.)31,pp.24-26[1965]以及Dauben等,美国化学学会会志(J.Am.Chem.Soc.)103,pp.237-238[1980]。
如下非限制性的实施例起阐释本发明的作用。
制备1
3β-三异丙基甲硅氧基孕甾-5(6)-烯-20-甲醛[式(II)-R 1a=(i-Pr)3SiO,R3 =CH3,Y=O]
在0℃下,用二异丙基氨化锂(14.46ml的1.5M四氢呋喃溶液)处理甲氧甲基三苯基氯化鏻(9.87g)于四氢呋喃(50ml)和甲苯(50ml)的混合物中的溶液。30分钟后,滴加3β-三异丙基甲硅氧基孕甾-5(6)-烯-20-酮(6.3g)的甲苯(4ml)溶液,接着滴加甲苯洗液(2ml),在0℃下将形成的混合物搅拌1小时,让它暖至室温,在搅拌下贮存一夜。然后,用氯化铵处理该混合物,用乙酸乙酯萃取而给出中间体20-甲氧基亚甲基化合物,将它通过色谱法纯化:NMR(CDCl3)δ0.63(18-H′s),3.33(OCH3),5.6(6-H)。
将上述中间体(全部)用乙酸(54ml)、水(2.4ml)和四氢呋喃(27ml)的混合物吸收,用对甲苯磺酸(240mg)处理,在搅拌下贮存一夜。用乙酸乙酯萃取该产物,用碳酸氢钠水溶液洗涤,除去溶剂后给出标题化合物的3-脱甲硅基化类似物(4.23g):NMR(CDCl3)δ0.63,0.72(两个信号,18-H′s),1.0(19,20-H′s),5.23(6-H),10.7(HC=O);IR(CDCl3)νmax1770cm-1。
用三异丙基甲硅烷基氯(1.86ml)处理所述脱甲硅基化中间体(全部)于含咪唑(2.415g)的二氯甲烷(8.5ml)中的溶液,在室温和搅拌下将形成的混合物贮存一夜。用乙酸乙酯萃取该产物,用水洗涤,通过柱色谱法分离而给出
标题化合物。
制备2
20α-和20β-羟甲基-3β-三异丙基甲硅氧基孕甾-5(6)-烯[式(II)-R 1a =(i-Pr)3SiO,R3=CH3,Y=OH]
用硼氢化钠(800mg)处理制备1的20-甲醛(1.2g)于甲醇(12ml)和苯(1.2ml)混合物中的溶液,在室温下搅拌1小时,冷却,用氯化铵处理,再用乙酸乙酯萃取。除去萃取液中的溶剂后给出
标题化合物,通过色谱法将它解析成较小极性和较大极性的异构体,暂时分别指定为20α-和20β-构型。
制备3
20α-甲苯磺酰氧基甲基-3β-三异丙基甲硅氧基孕甾-5(6)-烯[式(II)-R 1a =(i-Pr)3SiO,R3=β-CH3,Y=OTs]
用甲苯磺酰氯(243mg)处理制备2的较大极性的醇(310mg)于含吡啶(0.355ml)的二氯甲烷中的溶液,在室温下搅拌3小时,用碳酸氢钠水溶液和二氯甲烷处理,搅拌一夜,用1,8-双二甲氨基萘(25mg)处理。用二氯甲烷萃取该产物,依次用2%盐酸、碳酸氢钠和水洗涤萃取液,真空干燥并浓缩。色谱处理而给出
标题化合物(380mg)。
制备4
20β-溴甲基-3β-三异丙基甲硅氧基孕甾-5(6)-烯[式(II)-R 1a=(i-Pr)3SiO,R 3=β-CH3,Y=Br]
将制备3的甲苯磺酸酯(380mg)溶于含1,8-双二甲氨基萘(33mg)的乙腈(12ml)和1,2-二氯乙烷(12ml)的混合物,用溴化锂(621mg)处理,在搅拌和回流下加热3小时。用二氯甲烷萃取该产物,洗涤,通过色谱法纯化而给出
标题化合物:NMR(CDCl3)δ0.66(18-H′s),5.06(6-H)。
实施例1
a)3β-三异丙基甲硅氧基-20-表-胆-5(6)-烯酸,哌啶酰胺[式(I)-R 1 =(i-Pr)3SiO,R2 =H,R 3=β-CH3,R4 +R 5=(CH2)5,X=(CH2)2,c处有双键]
将二异丙基氨化锂(3ml的2M四氢呋喃溶液)于四氢呋喃(10ml)中的溶液冷却到-78℃。添加N-乙酰哌啶(914mg)的四氢呋喃(1ml和1ml洗液)溶液,将该混合物暖到室温达1小时,再冷却到-78℃。倒出三分之二的混合物,往残余物中添加制备4的溴化物(107mg)的四氢呋喃(1ml和1ml洗液)溶液。然后,添加六甲基磷酰胺,在-78℃下将形成的混合物搅拌1小时,再在室温下搅拌一夜。用氯化铵处理后,用乙酸乙酯萃取产物,洗涤,干燥,通过色谱法纯化而给出
标题化合物(120mg):NMR(CDCl3)δ0.63(18-H′s),3.30-3.2(m,N-CH2′s),5.03(6-H);IR(CDCl3)νmax1620,1440cm-1。
b)3β-羟基-20-表-胆-5(6)-烯酸,哌啶酰胺[式(I)-R 1=OH,R2=H,R3 =β-CH3,R4 +R 5=(CH2)5,X=(CH2)2,c处有双键]
用四丁基氟化铵(1ml的1M四氢呋喃溶液)处理溶于四氢呋喃(1ml)的上述(a)的产物(120mg),在室温和搅拌下放置一夜。用二氯甲烷萃取该产物,用水洗涤,通过色谱法纯化而给出
标题化合物(88mg):NMR(CDCl3)δ0.66(18-H′s),0.93(19,21-H′s),1.53(哌啶环的3-5H′s),3.26-3.2(m,N-CH2′s),5.06(6-H);IR(CDCl3)νmax3400,1620,1440cm-1。
实施例2
3-氧代-20-表-胆-4-烯酸,哌啶酰胺[式(I)-R 1 + R 2 = O, R 3 =β-CH3,
R 4 + R 5 =(CH2)5,
X =(CH2)2,
b处有双键]
将异丙醇铝(96mg)的甲苯(2.5ml)溶液滴加到回流下的实施例1(b)(80mg)于含环己酮(0.5ml)的甲苯(4.8ml)中的溶液中。继续加热2小时,然后将该混合物冷却,用乙酸乙酯萃取产物,通过色谱法纯化而给出
标题化合 物(46mg):NMR(CDCl3)δ0.66(18-H′s),0.93(21-H′s),1.1(19-H′s),3.63(m,N-CH2′s),5.46(4-H);IR(CDCl3)νmax1660,1620,1440cm-1。
实施例3
a) 3β-三异丙基甲硅氧基胆-5(6)-烯酸,哌啶酰胺[式(I)-R 1 =(i-Pr)3SiO,
R 2 = H, R 3 =α-CH3,
R 4 + R 5 =(CH2)5,
X =(CH2)2,
c处有双键]
按制备3和4和实施例1(a)的操作方法处理得自制备2的极性较小的醇而提供
标题化合物:NMR(CDCl3)δ0.66(18-H′s),3.56(m,N-CH2′s),5.03(6-H);IR(CDCl3)νmax1620,1440cm-1。
b) 3β-羟基胆-5(6)-烯酸,哌啶酰胺 [式(I)-R 1 =OH,
R 2 =H,
R 3 =α-CH3,R 4 + R 5 =(CH2)5,
X =
(CH2)2,
c处有双键]
按实施例1(b)的操作方法处理得自上述(a)的产物而给出
标题化合物:NMR(CDCl3)δ0.66(18-H′s),0.96(19,21-H′s),1.6(哌啶环的3-5H′s),3.3(m,N-CH2′s),5.1(6-H);IR(CDCl3)νmax3600,1620,1440cm-1。
实施例4
3-氧代胆-4-烯酸,哌啶酰胺[式(I)-R 1 +R 2 =O,R 3=α-CH3,R4 +R 5 =(CH2)5,X=(CH2)2,b处有双键]
按实施例2的操作方法处理得自实施例3(b)的产物而给出
标题化合物:NMR(CDCl3)δ0.7(18-H′s),1.1,1.21(19,21-H′s),3.26(m,N-CH2′s),5.33(4-H);IR(CDCl3)νmax1660,1620cm-1。
实施例5
3β-羟基胆-5(6)-烯酸,吗啉酰胺[式(I)-R 1=OH,R2=H,R3=α-CH3,R4 +R 5=(CH2)2O(CH2)2,X=(CH2)2,c处有双键]
重复实施例3的操作方法,用N-乙酰吗啉代替(a)中的N-乙酰哌啶而给出标题化合物:NMR(CDCl3)δ0.63(18-H′s),0.96(19-H′s),3.2-3.7(m,吗啉-CH2′s),5.1(6-H);IR(CDCl3)νmax3640-3200,1620,1430cm-1。
实施例6
3-氧代胆-4-烯酸,吗啉酰胺[式(I)-R 1 +R 2=O,R3=α-CH3,R4
+R5=(CH2)2O(CH2)2,X=(CH2)2,b处有双键]
按实施例2的操作步骤处理实施例5的产物而给出
标题化合物:
NMR(CDCl3)δ0.66(18-H′s),3.1-3.7(m,吗啉-CH2′s),5.5(4-H)。
实施例7
3β-羟基胆-5(6)-烯酸,噻吗啉酰胺(thiamorpholine amide) [式(I)-R 1 =OH,R2=H,R3=α-CH3,R4 +R 5=(CH2)2S(CH2)2,X=(CH2)2,c处有双键]
重复实施例3的操作方法,用N-乙酰噻吗啡代替(a)中的N-乙酰哌啶而给出
标题化合物:NMR(CDCl3)δ0.63(18-H′s),0.93(19-H′s),2.3-2.7(m,噻吗啉-CH2′s),3.1-3.8(m,N-CH2′s),5.0-5.3(b,6-H);IR(CDCl3)νmax3640-3100,1620,1430cm-1。
实施例8
3-氧代胆-4-烯酸,噻吗啉酰胺[式(I)-R 1 +R 2=O,R3=α-CH3,R4 +R 5 =(CH2)2S(CH2)2,X=(CH2)2,b处有双键]
按实施例2的操作步骤处理实施例7的产物而给出
标题化合物:
NMR(CDCl3)δ0.66(18-H′s),1.13(19-H′s),2.3-2.7(m,噻吗啉-CH2′s),3.4-3.9(m,N-CH2′s),5.5(4-H)。
实施例9
3β-羟基胆-5(6)-烯酸,二异丙基酰胺[式(I)-R 1=OH,R2=H,R3α-CH3,R 4 +R 5=CH(CH3)2,X=(CH2)2,c处有双键]
重复实施例3的操作方法,用N-乙酰二异丙胺代替(a)中的N-乙酰哌啶而给出
标题化合物:NMR(CDCl3)δ0.63(18-H′s),0.96(19-H′s),3.0-3.8(m,3-H,N-CH′s),5.0-5.3(b,6-H);IR(CDCl3)νmax3640-3100,1610,1440cm-1。
实施例10
3-氧代胆-4-烯酸,二异丙基酰胺[式(I)-R 1 +R 2 =O,R 3=α-CH3,R4 +R 5 =CH(CH3)2,X=(CH2)2,b处有双键]
按实施例2的操作步骤处理实施例9的产物而给出
标题化合物:
NMR(CDCl3)δ0.7(18-H′s),1.17(19-H′s),3.0-4.0(m,N-CH′s),5.57(s,4-H)。
实施例11
3β-羟基-24,24a-双高-胆-5(6)-烯酸,哌啶酰胺[式(I)-R 1=OH,R2=H,R3=α-CH3,R4 +R 5=(CH2)5,X=(CH2)4,c处有双键]
标题化合物是这样从3β-三异丙基甲硅氧基胆-5(6)-烯酸制备的:用氢化铝锂还原,接着进行实施例3的操作步骤。
实施例12
3-氧代-24,24a-双高-胆-4-烯酸,哌啶酰胺[式(I)-R 1 +R 2 =O,R 3=α-CH3,R 4 +R 5=(CH2)5,X=(CH2)4,c处有双键]
按实施例2的操作步骤处理实施例11的产物而给出
标题化合物。
实施例13
3β-羟基-20-表-24-高-22-氧杂胆-5(6)-烯酸,哌啶酰胺[式(I)-R 1=OH,R2 =H,R3=β-CH3,R4 +R 5=(CH2)5,X=O(CH2)2,c处有双键]
在室温下,将3β-三异丙基甲硅氧基孕甾-5(6)-烯-20β-醇(390mg)、丙烯酸乙酯(2.3ml)、氢氧化钠(9.2ml,50%水溶液)、四丁基氢氧化铵(.038ml,40%水溶液)和甲苯(23ml)的混合物搅拌一夜,然后,用乙醚稀释,先后用水和盐水洗涤。真空浓缩有机部分,通过色谱法分离产物(3β-三异丙基甲硅氧基-20-表-24-高-22-氧杂胆-5(6)-烯酸,乙酯)。
用哌啶基N,N-双(三甲基甲硅烷基)氨化锡[通过双(N,N-双(三甲基甲硅烷基氨化)锡(264mg)在己烷(6ml)中与哌啶(51mg)反应而制备的)的溶液(滴加)处理-78℃下该酯(60mg)的己烷(6ml)溶液。将反应混合物暖至室温,用乙酸乙酯稀释,然后,依次用5M氟化钾和盐水洗涤,真空干燥并浓缩。通过色谱法分离标题产物的3-三异丙基甲硅烷基醚(20mg):NMR(CDCl3)δ0.63(18-H′s),3.0-3.9(m,3-H,20-H,-O-CH′s,N-CH′s),4.9-5.2(b,6-H);IR(CDCl3)νmax1640,1470cm-1。按实施例1(b)那样脱甲硅基而提供
标题化合物:NMR(CDCl3)δ0.66(18-H′s),1.0(19-H′s),3.1-4.0(m,3-H,20-H,-O-CH′s,N-CH′s),5.2-5.5(b,6-H);IR(CDCl3)νmax3640-3300,1620,1445cm-1。
实施例14
3β-羟基-20-表-22-氧杂胆-5(6)-烯酸,哌啶酰胺[式(I)-R 1=OH,R2=H,R3=β-CH3,R4 +R 5=(CH2)5,X=O(CH2),c处有双键]
将18-冠-6(264mg)的四氢呋喃溶液滴加到3β-三异丙基甲硅氧基孕甾-5(6)-烯-20β-醇(474mg)和氢化钾(0.3ml的在矿物油中的35wt.%分散液)于四氢呋喃(1ml)中的混合物中。在室温下将形成的混合物搅拌30分钟,冷却到-10℃,然后,用N-α-溴乙酰哌啶(0.5ml)的四氢呋喃(1ml)溶液(滴加)处理。30分钟后将反应混合物暖至室温,放置一夜。再通过添加饱和氯化铵水溶液猝灭反应混合物,用乙醚萃取产物,再用水和盐水洗涤,真空除去溶剂。通过色谱法分离标题产物的3-三异丙基甲硅烷基醚(360mg):NMR(CDCl3)δ0.7(18-H′s),3.1-3.6(m,3-H,20-H,N-CH′s),3.83(s,-O-CH2-C=O),4.9-5.3(b,6-H);IR(CDCl3)νmax1640,1450cm-1。
按实施例1(b)的操作步骤脱甲硅基而提供
标题化合物:NMR(CDCl3)δ0.7(18-H′s),1.0(19-H′s),3.2-3.7(m,3-H,20-H,N-CH′s),3.9-4.1(d,-O-CH2-C=O),5.1-5.4(b,6-H);IR(CDCl3)νmax3640-3300,1640,1450cm-1。
实施例15
3-氧代-20-表-22-氧杂胆-4-烯酸,哌啶酰胺[式(I)-R 1 +R 2=O,R3=β-CH3,R 4 +R 5=(CH2)5,X=O(CH2),b处有双键]
按实施例2的操作步骤氧化实施例14的产物而给出
标题化合物:NMR(CDCl3)δ0.7(18-H′s),1.1(19-H′s),3.0-3.5(m,3-H,20-H,N-CH′s),3.7-4.0(d,-O-CH2-C=O),5.43(b,6-H);IR(CDCl3)νmax1640,1450cm-1。
实施例16
3β-羟基胆-5(6),22-二烯酸,哌啶酰胺[式(I)-R 1=OH,R2=H,R3=α-CH3,R 4 +R 5=(CH2)5,X=CH=CH,c处有双键]
通过与乙酸乙酯的三苯基亚膦衍生物[式(IV)-Rc=CO.OC2H5,Rh=C6H5,z=0]反应而将制备1的醛转化为相应的5(6),22-不饱和胆烯酸乙酯,再通过与实施例13的锡试剂反应,接着按实施例1(b)的操作步骤脱甲硅基而将后者转化为标题化合物。
实施例17
3-氧代-20-表-胆-1,4-二烯酸,哌啶酰胺[式(I)-R 1 +R 2 =O,R 3=β-CH3,R4 +R 5=(CH2)5,X=(CH2)2,a和b处都有双键]标题化合物是通过用2,3-二氯-5,6-二氰基-1,4-苯醌使实施例2的产物脱氢而制备的。
实施例18
3-氧代胆-1,4-二烯酸,哌啶酰胺[式(I)-R 1 +R 2 =O,R 3=α-CH3,R4 +R 5 =(CH2)5,X=(CH2)2,a和b处都有双键]
标题化合物是通过用2,3-二氯-5,6-二氰基-1,4-苯醌使实施例4的产物脱氢而制备的。
实施例19
3β-羟基-20-表-24-高-23-氧杂胆-5(6)-烯酸,哌啶酰胺[式(I)-R 1OH,R2 =H,R3=β-CH3,R4 +R 5=(CH2)5,X=(CH2)O(CH2),c处有双键]
标题化合物是按实施例14的操作步骤从制备2的较大极性产物制备的。
实施例20
3-氧代-20-表-24-高-23-氧杂胆-4-烯酸,哌啶酰胺[式(I)-R1 +R 2 =O,R 3=β-CH3,R4 +R 5=(CH2)5,X=(CH2)O(CH2),b处有双键]
标题化合物是通过按实施例2的操作步骤氧化实施例19的产物制备的。
Claims (9)
1.式(I)的化合物
其中:
R1表示羟基或保护的羟基,R2表示氢原子,并且在c处存在双键,或者R1和R2一起表示氧代,并且在b处存在双键或在a和b处都存在双键;
R3表示具有α-或β-构型的甲基;
R4和R5可以相同或不同,它们选自氢原子和脂族基、脂环族基、芳代脂族基和芳基,或者与它们所连的氮原子一起形成杂环基;以及
X表示基团-CH2-(CH=CH)m-(CH2)n-,其中m是0、1或2,并且n是0或者是使得2m+n=1、2、3或4的整数,或者X表示基团-(CH2)p-O-(CH2)q-,其中p是0、1、2或3,q是1、2、3或4,并且p+q不超过4,条件是:
i)当R3是α-CH3并且X是(CH2)2时,那么R4R5N-不表示氨基、二甲氨基、二乙氨基、咪唑基或三唑基;
ii)当R3是α-CH3并且X是(CH2)3时,那么R4R5N-不是吗啉代;以及
iii)当R3是α-CH3并且X是O(CH2)2时,那么R4R5N不是二甲氨基。
2.权利要求1的式(I)化合物,其中,R1表示羟基或被代谢上不稳定的O-保护基取代的羟基。
3.权利要求1或权利要求2的式(I)化合物,其中,R4和R5选自氢原子、C1-6烷基、C3-8环烷基、C6-12芳基-C1-4烷基、C6-12碳环芳基以及带有选自卤素、C1-4烷基、C1-4烷氧基、C2-4烷酰基、C1-4烷氨基、二(C1-4烷基)氨基、硝基、氨基甲酰基和C2-4烷酰基氨基的取代基的C6-12碳环芳基。
4.权利要求1或权利要求2的式(I)化合物,其中,R4R5N-表示杂环基,它包括一个或多个5员和/或6员环,并且含至少一个选自O、N和S的杂原子。
5.权利要求4的式(I)化合物,其中,R4R5N-表示哌啶子基、吗啉代或噻吗啉代。
6.权利要求1的化合物,其是:
3β-羟基-20-表-胆-5(6)-烯酸,哌啶酰胺;
3-氧代-20-表-胆-4-烯酸,哌啶酰胺;
3β-羟基胆-5(6)-烯酸,哌啶酰胺;或
3-氧代胆-4-烯酸,哌啶酰胺。
7.权利要求1的化合物,其是:
3β-羟基胆-5(6)-烯酸,吗啉酰胺;
3-氧代胆-4-烯酸,吗啉酰胺;
3β-羟基胆-5(6)-烯酸,噻吗啉酰胺;
3-氧代胆-4-烯酸,噻吗啉酰胺;
3β-羟基胆-5(6)-烯酸,二异丙基酰胺;
3-氧代胆-4-烯酸,二异丙基酰胺;
3β-羟基-24,24a-双高-胆-5(6)-烯酸,哌啶酰胺;
3-氧代-24,24a-双高-胆-4-烯酸,哌啶酰胺;
3β-羟基-20-表-24-高-22-氧杂胆-5(6)-烯酸,哌啶酰胺;
3β-羟基-20-表-22-氧杂胆-5(6)-烯酸,哌啶酰胺;
3-氧代-20-表-22-氧杂胆-4-烯酸,哌啶酰胺;
3β-羟基胆-5(6),22-二烯酸,哌啶酰胺;
3-氧代-20-表-胆-1,4-二烯酸,哌啶酰胺;
3-氧代胆-1,4-二烯酸,哌啶酰胺;
3β-羟基-20-表-24-高-23-氧杂胆-5(6)-烯酸,哌啶酰胺;或
3-氧代-20-表-24-高-23-氧杂胆-4-烯酸,哌啶酰胺。
8.权利要求1-7中任一项的但不受权利要求1的条件限制的式(I)活性化合物在制备药物中的用途,所述药物用于人或动物体中的创伤愈合、甲状旁腺激素的抑制、生育率的控制或者下列疾病的治疗或预防:肿瘤病、感染、骨病、自身免疫病、宿主-移植物反应、移植物排异反应、炎症、瘤形成、增生、肌病、肠病、脊椎炎性心脏病、皮肤病、高血压、类风湿性关节炎、牛皮癣性关节炎、继发性甲状旁腺功能亢进、气喘、认知损伤或老年性痴呆。
9.药物组合物,它包含与一种或多种生理上可接受的载体或赋形剂掺和的权利要求1~7任一项的但不受权利要求1的条件限制的式(I)活性化合物。
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US11524015B2 (en) | 2013-03-15 | 2022-12-13 | Brigham Young University | Methods for treating inflammation, autoimmune disorders and pain |
US11690855B2 (en) | 2013-10-17 | 2023-07-04 | Brigham Young University | Methods for treating lung infections and inflammation |
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