CN114106077B - 阿比特龙衍生物及其制备与应用 - Google Patents
阿比特龙衍生物及其制备与应用 Download PDFInfo
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- CN114106077B CN114106077B CN202110948115.3A CN202110948115A CN114106077B CN 114106077 B CN114106077 B CN 114106077B CN 202110948115 A CN202110948115 A CN 202110948115A CN 114106077 B CN114106077 B CN 114106077B
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- abiraterone
- decahydro
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- phenanthryl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
本发明公开一种阿比特龙衍生物及其制备方法,本发明所提供的阿比特龙衍生物相对于阿比特龙表现相对较少的腹胀现象,具有更好药效和耐受性,药代动力学实验表明,等摩尔剂量灌胃给药后M1的血药浓度显著高于阿比特龙醋酸酯。具有显著优于阿比特龙的抑制前列腺癌的作用,并且胃肠道副作用较阿比特龙小。本发明所提供的化合物同时具有治疗痤疮的作用。
Description
技术领域
本发明属于医药领域,具体涉及阿比特龙衍生物及其制备与应用。
背景技术
阿比特龙(Abiraterone),其结构式为:
化学名称17-(3-吡啶基)雄甾-5,16-二烯-3β-醇,为CYP17抑制剂,临床上主要适用于与泼尼松联用为治疗既往接受含多烯紫杉醇化疗转移去势难治性前列腺癌患者,醋酸阿比特龙(ZYTIGA)在体内被转化为阿比特龙,一种雄激素生物合成抑制剂,抑制17α-羟化酶/C17,20-裂解酶(CYP17)。在睾丸,肾上腺,和前列腺肿瘤组织中表达此酶,为雄激素生物合成所需。阿比特龙在临床上是以阿比特龙醋酸酯的形式使用,阿比特龙醋酸酯需要在空腹时服用,这是由于食物对于醋酸阿比特龙酯的吸收影响较大,个体之间的差异也比较大。阿比特龙醋酸酯的代谢物之一,简称M1,化学名为:
17-(3-吡啶)-4,(16-二烯雄-3-酮,英文名为: 17-(3-pyridine)-4,16-dieneandrost-3-one),为醋酸阿比特龙的代谢物之一。
在我们的前期研究中发现,腹腔注射醋酸阿比特龙的Vcap(人前列腺癌细胞)接种的肿瘤模型小鼠在接受腹腔注射药物后部分出现腹胀,并出现死亡现象,解剖后发现部分药物未吸收。
发明内容
本发明提供一种阿比特龙衍生物及其制备方法,本发明所提供的阿比特龙衍生物相对于阿比特龙表现相对较少的腹胀现象,具有更好药效和耐受性,药代动力学实验表明,等摩尔剂量灌胃给药后M1的血药浓度显著高于阿比特龙醋酸酯,代谢物中检测到有M2,而醋酸阿比特龙的代谢物中则没有M2。具有显著优于阿比特龙的抑制前列腺癌的作用,并且胃肠道副作用较阿比特龙小。本发明所提供的化合物同时具有治疗痤疮的作用。
本发明所提供的阿比特龙衍生物,其结构式如式I所示:
其中,R1、R2独立地选自下述基团中的任意一种:H、(C3-C8)碳环烷基、取代或未取代的(C1-C18)(具体可为C2-C6)烷烃(其中,取代基可为氨基(氨基在末端时不含活泼氢)、羧基(羧基在末端时不含活泼氢)、卤素、(C3-C8) 杂环烷基)、(C2-C8)烯基或含有取代基的(C2-C8)烯基、(C2-C8)炔基或含有取代基的(C2-C8)炔基、(C6-C20)芳基或含有取代基的(C6-C20)芳基、 (C2-C20)杂环基或含有取代基的(C2-C20)杂环基;
或R1、R2相互成环为(C3-C8)杂环烷基或取代(C3-C8)杂环烷基、(C6-C20) 杂芳基或取代(C6-C20)杂芳基;
所述化合物的取代基不包括末端取代基为羟基、氨基、羧基、磷酰基、磺酰基,但包括羟基、氨基、羧基、磷酰基,磺酰基活泼氢被取代的化合物。通过实验证明,末端带活泼氢基团的化合物均不稳定,在实验中发现,R1、R2为未取代的氨基或R1、R2的末端为未取代的氨基时,不能够得到稳定的化合物样品,R1和R2的末端为羧基时同样不能得到稳定的化合物样品。
末端氨基被取代或成酰胺键时,如下所示化合物则可以得到,并具有本发明所述特征。末端为羧基时,也由于稳定性原因不能得到化合物样品,但当羧基与醇或取代的醇成酯、与胺或取代的胺成酰胺,末端不为氨基、羧基的取代,能够得到稳定的样品,并具有发明所述特征。
具体地,上述式I所示阿比特龙衍生物具有代表意义的形式如下:
上述式I所示阿比特龙衍生物根据反应流程图,通过包括如下步骤的方法制备得到:
1)以阿比特龙为原料,在异丙醇铝和环己酮存在下,氧化反应得到化合物 a;
2)在碱性条件下,使化合物a与盐酸羟胺发生缩合反应,得到化合物b;
3)化合物b与片段R的羰基化合物直接酯化反应,得到I所示阿比特龙衍生物;或者化合物b与羰基二咪唑形成活化物,然后与片段R相应的醇、氨缩合,得到I所示阿比特龙衍生物。
上述式I所示阿比特龙衍生物在如下方面的应用也属于本发明的保护范围:
1)在制备真核生物肿瘤细胞增殖抑制剂中的应用;
2)在制备预防和/或治疗肿瘤药物中的应用。
所述真核生物为哺乳动物;
所述肿瘤细胞为癌细胞;
所述癌细胞为前列腺癌细胞;
所述肿瘤为癌;所述癌为前列腺癌。
所述前列腺癌为既往接受含多烯紫杉醇化疗转移去势难治性前列腺癌。
本发明还提供一种真核生物肿瘤细胞增殖抑制剂,其包含式I所示阿比特龙衍生物。
式I所示化合物在制备治疗痤疮药物中的应用也属于本发明的保护范围。
本发明还提供一种治疗痤疮的药物,其包含式I所示阿比特龙衍生物。
本发明所提供的阿比特龙衍生物相对于阿比特龙表现相对较少的腹胀现象,具有更好药效和耐受性,药代动力学实验表明,等摩尔剂量灌胃给药后M1 的血药浓度显著高于阿比特龙醋酸酯,代谢物中检测到有M2,而醋酸阿比特龙的代谢物中则没有M2。具有显著优于阿比特龙的抑制前列腺癌的作用,并且胃肠道副作用较阿比特龙小。本发明所提供的化合物同时具有治疗痤疮的作用。
具体实施方式
下面通过具体实施例对本发明进行说明,但本发明并不局限于此。
下述实施例中所使用的实验方法如无特殊说明,均为常规方法;下述实施例中所用的试剂、材料等,如无特殊说明,均可从商业途径得到。
实施例1
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-((2-(二甲氨基)乙基)氨基甲酰基)肟的合成
1)(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮
分别称量阿比特龙(35.0g,100mmol,1.0eq.)、异丙醇铝(20.5g,100 mmol,1.0eq.),环己酮(29.5g,300mmol,3.0eq.)于圆底反应瓶中,加入甲苯(210mL),氮气保护,100℃加热反应16h。冷却反应液,加入食盐水,硅藻土过滤不溶物,分离有机层,柱层析纯化得到白色固体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮(30.2 g,87.0%)。1H NMR(DMSO-d6400MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29 (m,2H),5.96(m,1H),5.85(s,1H),2.99(m,2H),2.37-1.27(m,21H).ESI-MS m/z:348.1[M+H]+.
2)(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟
称量(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮(30.0 g,86.5mmol,1.0eq.)溶解于无水乙醇(250mL)中,然后加入盐酸羟胺(12.0 g,173mmol,2.0eq.)、乙酸钠(21.3g,260mmol,3.0eq.),室温反应3h。向反应液中加入过量水,析出白色固体。过滤粗品,乙醇重结晶得到(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟 (25.0g,80.0%)。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H), 7.77-7.29(m,2H),5.96(m,1H),5.85(s,1H),4.62(s,1H),2.99(m,2H),2.37-1.27(m,21H).ESI-MS m/z:363.1[M+H]+.
3)(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-(1H- 咪唑-1-羰基)肟
将(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟(2.0 g,5.52mmol,1.0eq.)溶解于二氯甲烷(20mL)中,分别加入三乙胺(1.11 g,11.0mmol。2.0eq.)、羰基二咪唑(1.78g,11.0mmol。2.0eq.),室温搅拌8h。反应液加水萃取,浓缩有机相,柱层析得到 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-(1H- 咪唑-1-羰基)肟(2.0g,79.5%)。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H), 8.33(d,1H),8.14(s,1H),7.77-7.14(m,4H),5.96(m,1H),5.85(s,1 H),2.99(m,2H),2.37-1.27(m,21H).ESI-MS m/z:457.1[M+H]+.
4)(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮 O-((2-(二甲氨基)乙基)氨基甲酰基)肟
将(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-(1H- 咪唑-1-羰基)肟(2.0g,4.39mmol,1.0eq.)溶解于二氯甲烷(10mL)中,滴加N,N-二甲基乙二胺(0.58g,6.58mmol,1.5eq.),室温搅拌5h。反应液浓缩,柱层析纯化得到固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶 -3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮 O-((2-(二甲氨基)乙基)氨基甲酰基)肟(1.5g,7.8%)。1H NMR(DMSO-d6 400 MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.85 (s,1H),3.28-3.26(d,4H),2.36(s,6H),2.37-1.27(m,23H).ESI-MS m/z:477.1[M+H]+.
实施例2
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-二甲氨基甲酰基肟的合成
将(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟(2.0 g,5.52mmol,1.0eq.)、三乙胺(1.11g,11.0mmol。2.0eq.)分别溶解于二氯甲烷(20mL)中,滴加入二甲氨基甲酰氯(1.19g,11.0mmol,2.0eq.),室温反应5h。反应液浓缩,柱层析得到白色固体(8S,9S,10R,13S,14S)-10,13- 二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-二甲氨基甲酰基肟(2.0g,83.7%)。1H NMR(DMSO-d6 400 MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.85 (s,1H),3.47(s,6H),2.37-1.27(m,23H).ESI-MS m/z:434.1[M+H]+.
实施例3
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(双 (2-氯乙基)氨基甲酰基)肟的合成
综合实施例1-2的合成方法,双(2-氯乙基)氨基甲酰氯与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(双(2-氯乙基)氨基甲酰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1 H),7.77-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.64(m,4H),3.24(m,4 H),2.37-1.27(m,23H).ESI-MS m/z:532.1[M+H]+.
实施例4
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯[a]菲基-3(2H)-酮 O-([1,4'-联哌啶]-1'-羰基)肟的合成
综合实施例1-2的合成方法,[1,4'-联哌啶]-1'-碳酰氯与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯[a]菲基-3(2H)-酮 O-([1,4'-联哌啶]-1'-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33 (d,1H),7.77-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.39(m,4H),2. 62-2.42(m,5H),2.37-1.27(m,33H).ESI-MS m/z:557.1[M+H]+.
实施例5
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(2- 甲基苯甲酰基)肟的合成
综合实施例1-2的合成方法,邻甲基苯甲酰氯与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(2- 甲基苯甲酰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H), 7.88-7.29(m,6H),5.96(m,1H),5.62(s,1H),2.37-1.27(m,26H).ESI-MS m/z:481.1[M+H]+.
实施例6
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-(3-(甲氨基)丙酰基)肟的合成
综合实施例1-2的合成方法,3-甲氨基丙酸与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后脱保护得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-(3-(甲氨基)丙酰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1 H),7.77-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.62(s,3H), 2.83-2.63(m,4H),2.37-1.27(m,23H).ESI-MS m/z:448.1[M+H]+.
实施例7
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-乙酰肟的合成
综合实施例1-2的合成方法,乙酸酐与中间体(8S,9S,10R,13S,14S)-10,13- 二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a] 菲基-3(2H)-酮肟酯化后脱保护得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-乙酰肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1 H),7.77-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.37-1.27(m,26 H).ESI-MS m/z:405.1[M+H]+.
实施例8
((((((8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-7,8,9,11,12,13,14,15-八氢-1H-环戊烯并[a]菲基-3(2H,6H,10H)-亚基) 氨基)氧)羰基)氧)甲基异丁酸酯的合成
综合实施例1-2的合成方法,氯甲酸氯甲酯与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化,然后与异丁酸成酯得到白色固体((((((8S,9S,10R,13S,14S)-10,13-二甲基 -17-(吡啶-3-基)-7,8,9,11,12,13,14,15-八氢-1H-环戊烯并[a]菲基 -3(2H,6H,10H)-亚基)氨基)氧)羰基)氧)甲基异丁酸酯。1H NMR(DMSO-d6 400 MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),6.95(s,1H),5.96 (m,1H),5.62(s,1H),2.67-1.14(m,30H).ESI-MS m/z:507.1[M+H]+.
实施例9
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-((2-吗啉乙氧基羰基)肟的合成
综合实施例1-2的合成方法,2-吗啉乙醇与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟在三光气环境下形成碳酸酯(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-((2-吗啉乙氧基羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33 (d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),4.43(m,2H),3.65 (m,4H),2.97(m,2H),2.36(m,4H),2.12-1.12(m,23H).ESI-MS m/z:520.1[M+H]+.
实施例10
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-哌啶-4-羰基肟的合成
综合实施例1-2的合成方法,4-哌啶甲酸与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-哌啶-4-羰基肟。1HNMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H), 7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.79(m,4H),2.33-1.27(m,28 H).ESI-MS m/z:474.1[M+H]+.
实施例11
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1- 甲基哌啶-4-羰基)肟的合成
综合实施例1-2的合成方法,1-甲基哌啶-4-甲酸与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1- 甲基哌啶-4-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H), 7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.79(m,4H),2.33-1.27(m,31 H).ESI-MS m/z:488.1[M+H]+.
实施例12
1-(4-(((((8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-7,8,9,11,12,13,14,15-八氢-1H-环戊烯并[a]菲基-3(2H,6H,10H)-亚基) 氨基)氧)羰基)哌啶-1-基)乙酮的合成
综合实施例1-2的合成方法,1-乙酰基哌啶-4-甲酸与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体1-(4-(((((8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-7,8,9,11,12,13,14,15-八氢-1H-环戊烯并[a]菲基-3(2H,6H,10H)-亚基) 氨基)氧)羰基)哌啶-1-基)乙酮。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33 (d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.39(m,4 H),2.33-1.27(m,31H).ESI-MSm/z:516.1[M+H]+.
实施例13
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-(1-(2-(二甲氨基)乙基)哌啶-4-羰基)肟的合成
综合实施例1-2的合成方法,1-(2-(二甲氨基)乙基)哌啶-4-甲酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1-(2-(二甲氨基)乙基)哌啶-4-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47 (s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1 H),2.66(m,6H),2.41-2.37(m,8H),2.36-1.27(m,28H).ESI-MS m/z:545.1[M+H]+.
实施例14
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-(1-(环丙烷硫酰基)哌啶-4-羰基)肟的合成
综合实施例1-2的合成方法,1-(环丙烷硫酰基)哌啶-4-甲酸与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-(1-(环丙烷硫酰基)哌啶-4-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1 H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.91(m,4 H),2.36-1.27(m,33H).ESI-MSm/z:578.1[M+H]+.
实施例15
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-(1-(环丙烷甲基)哌啶-4-羰基)肟的合成
综合实施例1-2的合成方法,1-(环丙烷甲基)哌啶-4-甲酸与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-(1-(环丙烷甲基)哌啶-4-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H), 8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.41(m,4 H),2.36-1.27(m,35H).ESI-MS m/z:528.1[M+H]+.
实施例16
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-((S)-1-甲基吡咯烷-2-羰基)肟的合成
综合实施例1-2的合成方法,(S)-1-甲基吡咯烷-2-甲酸与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮 O-((S)-1-甲基吡咯烷-2-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H), 8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.08(m,1 H),2.36-1.27(m,32H).ESI-MS m/z:474.1[M+H]+.
实施例17
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-四氢-2H-吡喃-4-羰基肟的合成
综合实施例1-2的合成方法,四氢吡喃-4-甲酸与中间体 (8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-四氢-2H-吡喃-4-羰基肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H), 7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.55(m,4H),2.36-1.27(m,28 H).ESI-MS m/z:475.1[M+H]+.
实施例18
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-烟酰肟的合成
综合实施例1-2的合成方法,烟酸与中间体(8S,9S,10R,13S,14S)-10,13- 二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a] 菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基 -17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基 -3(2H)-酮O-烟酰肟。1H NMR(DMSO-d6400MHz)δ8.88(s,1H),8.65(d,1 H),8.47(s,1H),8.33(d,1H),7.70-7.29(m,4H),5.96(m,1H),5.62(s,1 H),2.36-1.27(m,23H).ESI-MS m/z:468.1[M+H]+.
实施例19:前列腺肿瘤药效学实验
测试化合物ZONK1901系列化合物(发明化合物)和ZONK1901-10(阿比特龙醋酸酯)对人前列腺癌细胞VCaP裸鼠移植瘤模型肿瘤体内生长的抑制作用。
受试样品:实施例1化合物(B)、实施例2化合物(C)、实施例3化合物 (D)、实施例4(E)、实施例5(F)、实施例6(G)、实施例7(H)及ZONK1901-19、 ZONK1901-10(I)(醋酸阿比特龙)
ZONK1901-19(J组)
试剂
DMEM培养液;胎牛血清;胰蛋白酶;青-链双抗;二甲基亚砜(DMSO); TPGS;Matrigel;PBS(pH7.4,0.01M)
雄性BALB/c裸小鼠(只数:90只;周龄:6-7周)从北京维通利华实验动物技术有限公司购买,饲养于苏州圣苏新药开发有限公司SPF动物房,温度20~25℃,相对湿度40%~70%,明暗照明各12小时;动物自由饮水及采食。正常喂养约6天后,经兽医检验,体征状况良好的小鼠可入选本实验。分组前使用记号笔于动物尾根部进行标识,分组后每只动物均用耳部剪缺方式标识。
人前列腺癌细胞VCaP,来源于中科院上海细胞库(CAS,本实验室液氮冻存)
在5%CO2、37℃培养条件下,VCaP细胞在含10%胎牛血清的DMEM 培养基中进行常规细胞培养。以0.25%胰酶消化传代,根据细胞生长情况,每周传代2-3次,传代比例为1:3至1:5。
收取对数生长期VCaP细胞,细胞计数后重悬于含50%的DMEM基础培养基和50%的Matrigel Matrix中,调整细胞浓度至5×107细胞/mL;将细胞置于冰盒中,用1mL注射器吸取细胞悬液,注射到裸鼠前右侧腋窝皮下,每只动物接种200μL(1×107细胞/只),建立VCaP移植瘤模型。定期观察动物状态,使用电子游标卡尺测量瘤径,数据输入Excel电子表格,计算肿瘤体积,监测肿瘤生长情况。待肿瘤体积达到100~300mm3,挑选健康状况良好、肿瘤体积相近的动物60只,根据肿瘤体积采用随机区组法分为 10组(n=6),同时尽量保证每组平均体重保持一致。以分组当天为实验第一天(D1),实验开始后每周测量2次瘤径,计算肿瘤体积,同时称量动物体重并记录。
肿瘤体积(TV)计算公式如下:
TV(mm3)=l×w2/2
其中,l表示肿瘤长径(mm);w表示肿瘤短径(mm)。
DMSO&PEG400&PG(v:v:v,10:60:30)配制:分别吸取适量体积 DMSO、PEG400和PG,混合均匀。混合液中DMSO PEG400和PG的比例为10:60:30(v:v:v),作为空白溶媒,室温保存。
给药制剂配制
称取适量的受试化合物至玻璃瓶中,加入适量体积溶媒DMSO,涡旋超声,然后依次加入适量体积的PEG400和PG,涡旋混匀,得终浓度为0.05M的给药制剂。分装后保存于2-8℃冰箱,每次给药前涡旋振荡搅拌均匀。每7天配制一次,分装保存于4度冰箱。
ZONK1901-10给药制剂配制。
称取适量的ZONK1901-10至玻璃瓶中,加入适量体积的玉米油,涡旋振荡搅拌均匀,得终浓度为19.58mg·mL-1(0.05M)的给药制剂。分装后保存于2-8℃冰箱,每次给药前涡旋振荡搅拌均匀。每7天配制一次,分装保存于4度冰箱。
动物分组及给药方案见表1。于分组当天开始给予受试样品,28天后或溶剂对照组肿瘤体积达到2000mm3结束实验(以先达到指标为准),给药体积均为10mL·kg-1。A组为空白溶剂组,灌胃给予空白溶媒 (DMSO&PEG400&PG(v:v:v,10:60:30)),每天1次(QD)。其他组均灌胃给予受试化合物,每天1次(QD)。I组灌胃给予ZONK1901-10,给药剂量为195.8mg·kg-1(0.5mmol·kg-1),每天1次(QD)。
表1.裸鼠移植瘤模型药效实验给药方案
实验最后一天,称量体重、测量瘤径后动物安乐死(CO2)。剥取肿瘤组织、称重并拍照,计算瘤重抑瘤率。对动物进行大体解剖,肉眼观察内脏器官有无异常。动物尸体及瘤组织放入尸体存放冰箱统一处理。
数据记录、计算公式
相对肿瘤体积(RTV)的计算公式为:
RTV=TVt/TVinitial
其中,TVinitial为分组给药时测量到的肿瘤体积;TVt为给药期间每一次测量时的肿瘤体积。
相对肿瘤增殖率(%T/C)的计算公式为:
%T/C=100%×(RTVT/RTVC)
其中,RTVT表示治疗组RTV;RTVC表示溶剂对照组RTV。
肿瘤生长抑制率TGI(%)的计算公式为:
TGI=100%×[1-(TVt(T)-TVinitial(T))/(TVt(C)-TVinitial(C))]
其中,TVt(T)表示治疗组每次测量的肿瘤体积;TVinitial(T)表示分组给药时治疗组的肿瘤体积;TVt(C)表示溶剂对照组每次测量的肿瘤体积;TVinitial(C)表示分组给药时溶剂对照组的肿瘤体积。
动物体重下降率的计算公式为:
动物体重下降率=100%×(BWinitial-BWt)/BWinitial
其中,BWt表示给药期间每次测量的动物体重;BWinitial表示分组给药时的动物体重。
瘤重抑瘤率IR(%)的计算公式为:
IR=100%×(WC-WT)/WC
其中,WC表示对照组瘤重;WT表示治疗组瘤重。
给药期间各组动物肿瘤体积及肿瘤生长抑制率
给药期间各组动物肿瘤体积及肿瘤生长抑制率
组别 | A(溶剂) | B | C | D | E | F | G | H | I | J |
第1天 | 226±12 | 228±14 | 230±12 | 225±7 | 238±16 | 280±15 | 227±21 | 228±14 | 274±18 | 252±21 |
第25天 | 1103±66 | 384±32<sup>**</sup> | 393±25<sup>**</sup> | 478±64<sup>**</sup> | 377±37<sup>**</sup> | 410±44<sup>**</sup> | 405±15<sup>*</sup> | 492±30<sup>**</sup> | 765±46<sup>*</sup> | 790±49<sup>*</sup> |
抑瘤率(GI) | 82.2%<sup>**</sup> | 81.4%<sup>**</sup> | 71.2%<sup>**</sup> | 84.2%<sup>**</sup> | 85.2%<sup>**</sup> | 80.7%<sup>**</sup> | 69.3<sup>**</sup> | 44.1%<sup>*</sup> | 38.7%<sup>*</sup> |
注:“*”表示肿瘤体积与溶剂对照组比较,存在显著性差异(P<0.05);“**”表示肿瘤体积与溶剂对照组比较,存在极显著性差异(P<0.01)
实施例20:药代动力学实验
研究在小鼠体内灌胃给药后的药代动力学性质。
45只雄性小鼠随机分为9组(每组含5只),实施例1化合物(B)、实施例2化合物(C)、实施例3化合物(D)、实施例4(E)、实施例5(F)、实施例6(G)、及ZONK1901-19(H)、ZONK1901-10(I)(醋酸阿比特龙)。
每只小鼠采集2-3个不连续的时间点。
建立测定小鼠全血中ZONK1901-1、ZONK1901-2浓度的LC-MS/MS分析方法。所得血药浓度数据同时采用药动学处理软件Pharsight Phoenix WinNonlin8.0 非房室模型计算相关药代动力学参数。
各组灌胃给药后代谢物ZONK1901-1和ZONK1901-2的主要药代动力学参数如下表:
实施例21:痤疮药效学试验
健康日本大耳白兔140只,体重2.0~2.5kg,全雄。动物适应性饲养1周后按体重随机选取10只作为正常对照组,剩余130家兔于耳道口外2cm处2×2cm2 范围,每日涂煤焦油一次,厚度约为0.5mm。(涂前先将煤焦油水浴加热融化,每次涂煤焦油前先将上次涂的煤焦油焦壳取下;正常对照组涂橄榄油,方法同前。)造模3周后,130只家兔按皮损程度轻重随机分为13组,分别为模型对照组、实施例1化合物(1组)、实施例2化合物(2组)、实施例3化合物(3组)、实施例4(4组)、实施例5(5组)、实施例6(6组)、实施例7(7组)、实施例8(8组)、实施例9(9组)、实施例10(10组)、实施例11(11组)、实施例12(12组)、实施例13(13组),每组10只。分组后,各剂量组每日上午继续涂煤焦油,下午去除煤焦油后在病损局部涂抹受试药物或对照药物(均为 0.01%/10g膏,按1g膏/只涂抹),1次/日,连续2周(模型对照组和正常对照组涂等量基质)。末次给药后24小时,空气栓塞处死动物,取耳部给药处皮肤(全层),4%多聚甲醛溶液固定,HE染色,进行常规病理观察。
1、实验结果
对实验性兔耳痤疮模型毛囊内角化物的影响
*表示与模型对照组相比,P<0.05;**表示与模型对照组相比,P<0.01;
由上表可知,与模型对照组相比,各组兔耳毛囊内角化物均有改善。
3. 2对实验性兔耳痤疮模型炎细胞浸润程度的影响
**表示与模型对照组相比,P<0.01;*表示与模型对照组相比,P<0.05
由上表可知,与模型对照组相比,各组兔耳炎细胞浸润程度有所改善。
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