CN106061990B - 一种阿比特龙衍生物及其制备方法和医药用途 - Google Patents
一种阿比特龙衍生物及其制备方法和医药用途 Download PDFInfo
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- CN106061990B CN106061990B CN201580002033.2A CN201580002033A CN106061990B CN 106061990 B CN106061990 B CN 106061990B CN 201580002033 A CN201580002033 A CN 201580002033A CN 106061990 B CN106061990 B CN 106061990B
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- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- -1 methoxyl group Chemical group 0.000 claims description 87
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
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- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 4
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000005864 Sulphur Substances 0.000 description 6
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Abstract
本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,以及在制备用于预防和治疗癌症药物中的用途,通式(I)化合物的结构如下所示,A的定义与说明书定义一致;
Description
技术领域
本发明涉及一种阿比特龙衍生物及其立体异构体或药学上可接受的盐,以及在制备用于预防和治疗癌症相关药物中的用途。
背景技术
前列腺癌是常见的恶性致死性癌症,近年我国的该病的发病率呈上升趋势,其市场需求将持续快速增长。
雄激素是前列腺癌发生的关键因素。雄激素生物合成首先通过17α-羟化酶活化将孕烯醇酮和孕酮转化为17α-羟基衍生物,再通过C17,20-裂解酶活形成脱氢表雄酮和雄烯二酮,两者均为睾酮的前体。在这个过程中,细胞色素P450是物合成途径中的关键酶。CYP17是一种细胞色素P450酶,它能催化两种独立调节类固醇17α-羟化酶和C17,20-裂解酶的酶活性,从而调节睾丸和身体其他部位的性类固醇前体的体内合成。
醋酸阿比特龙为阿比特龙前体药物,是一种CYP17酶抑制剂,于2011年在美国批准上市,适用于前列腺癌(CRPC)患者的治疗,推荐剂量为口服给予1000mg每天1次与泼尼松5mg口服给药每天2次联用。
目前有文献报道了阿比特龙的前体药物。
CN102477061公开了吡啶雄甾衍生物及其在制备预防和/或治疗前列腺癌药物中的用途,其中Rx选自多种酯类、碳酸酯类或胺类等前体药物基团,该文献涉及的通式结构如下:
CN102686600公开了甾体CYP17抑制剂/抗雄激素物质的新型药物前体,其中Y选自Z-L-C(=O)O-,Z是在正常生理条件下带有电荷的带电基团,其中带电基团是具有化学式(R3N+)-的季铵基团,该文献涉及的通式结构如下:
CN104017045公开了甾体CYP17抑制剂的新型药物前体,所述的前体药物可用于治疗泌尿生殖系统、雄激素相关的癌症,该文献涉及的结构如下:
WO2014111815公开了阿比特龙类似物及其在预防和/或治疗前列腺癌药物中的用途,其中R选自低链烷基、环烷基、胺基等,该文献涉及的结构如下:
本发明的目的在于提供一种新颖的具有高稳定性、良好溶解度、高生物利用度、低剂量、低毒副作用或具备长效潜力的阿比特龙前体药物,为癌症患者提供新的选择,所述癌症可选自泌尿生殖系统、雄激素相关的疾病,如前列腺癌。
发明内容
本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,
其中:A选自-RA-R1;RA为C(=O);
R1选自3元杂环、4元杂环、5元杂环、6元杂环、7元杂环、8元杂环、9元杂环或10元杂环,优选5元杂环、6元杂环、7元杂环或8元杂环,进一步优选5元杂环或6元杂环,更优选且当杂环为饱和环时,与RA相连接的原子为杂环上的碳原子;所述的杂环、任选进一步被0至4个选自F、Cl、Br、I、OH、NH2、-NHC(=O)C1-4烷氧基、C(=O)C1-4烷氧基、C(=O)R1h、S(=O)2R1h、R1h或4至6元杂环的取代基所取代,优选杂环任选进一步被0至4个选自H、NH2、-(CH2)2N(C1-4烷基)2、-NHC(=O)OC(CH3)3、-C(=O)OC(CH3)3、C(=O)R1h、S(=O)2R1h、R1h、吡啶或氮杂五元环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R1h各自独立的选自C1-4烷基、C1-4烷基-NH2、C1-4烷氧基或C3-6碳环,所述的NH2、烷基、烷氧基和碳环任选进一步被0至4个选自F、Cl、Br、I、OH、C1-4烷基、C1-4烷氧基或C3-6碳环的取代基所取代,优选进一步被0至4个选自F、Cl、Br、OH、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、环丙基、环丁基或环戊基的取代基所取代;
R1h各自独立的优选取代或未取代的甲基、乙基、2-氨基乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基,当被取代时,任选进一步被1至4个选自F、Cl、Br、OH、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基的取代基所取代。
本发明优选方案,一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,
A选自C(=O)R1;
R1选自取代或为取代的如下结构之一:
当被取代时,任选进一步被1至4个选自NH2、-(CH2)2N(CH3)2、-NHC(=O)OC(CH3)3、-C(=O)OC(CH3)3、C(=O)R1h、S(=O)2R1h、R1h或吡啶的取代基所取代;
R1h各自独立的选自取代或未取代的甲基、乙基、2-氨基乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基,当被取代时,任选进一步被1至4个选自F、Cl、Br、OH、甲基、乙基或环丙基的取代基所取代。
本发明优选方案,一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,其中该化合物选自如下结构之一:
本发明还提供一种药物组合物,所述药物组合物含有治疗有效剂量的本发明化合物及其立体异构体或药学上可接受的盐,以及药学上可接受的载体和赋形剂。
进一步,本发明还提供本发明所述的化合物及其立体异构体或药学上可接受的盐,以及本发明化合物的组合物在制备治疗与癌症相关疾病药物中的用途。
本发明优选方案,其中所述的癌症为前列腺癌。
本发明还提供一种治疗与癌症相关疾病的方法,所述方法包括给药本发明所述的化合物或其立体异构体或药学上可接受的盐,或本发明所述的组合物。
根据本发明所述的方法,其中所述的癌症为前列腺癌。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”是指直链和支链的饱和脂肪族烃基团,主链包括1至20个碳原子,优选为1至12个碳原子,进一步优选为1至8个碳原子,更优选为1至6个碳原子,再进一步优选1至4个碳原子的直链与支链基团,最优选1至2个碳原子;烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基;烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“烷氧基”是指-O-烷基,其中烷基如本文上述定义。烷氧基可以是取代的或未取代的,烷氧基实施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、仲丁氧基、正戊氧基和正己氧基;当被取代时,取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“氨基”是指-NH2,可以是取代的或未取代的,当被取代时,取代基优选为1至3个以下基团,独立地选自烷基、环烷基、卤代烷基、硫醇、羟基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“杂环”或“杂环基”是指取代的或未取代的饱和或不饱和的至少含有1至5个选自N、O、S、S(=O)或S(=O)2原子或基团的非芳香环系统,所述的非芳香环系统包含3至20个环原子,优选3至10个环原子,更优选3至8个环原子;杂环基环中选择性取代的N、S可被氧化成各种氧化态;非限制性实施例包括氧杂环丙烷基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环己基、氧杂环辛基、氮杂环丙烷基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环丙烯基、1,3二氧环戊基、1,4-二氧环戊基、1,3-二氧环戊基、1,3-二氧环己基、1,3-二硫环己基、氮杂环庚烯基、吗啉基、哌嗪基、吡啶基、呋喃基、噻吩基、吡咯基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、硫代吗啉基、二氢吡喃、噻二唑基、噁唑基、噁二唑基、吡唑基、1,4-二氧杂环己二烯基、2H-1,2-噁嗪基或2,5-二氢噻吩基等;当被取代时,取代基为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“碳环”是指饱和或者不饱和的芳香环或者非芳香环,芳香环或者非芳香可以是3至8元的单环,4至12元双环或者10至15元三环系统,碳环可以连接有桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环戊烯、环己二烯、环庚三烯、苯基、萘基、苯并环戊基、二环[3.2.1]辛烷基、二环[5.2.0]壬烷基、三环[5.3.1.1]十二烷基、金刚烷基或螺[3.3]庚烷基等。碳环可以被取代,当被取代时,取代基优选为1至5个,独立地选自F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、烷巯基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧酸、羧酸酯或杂环烷基巯基。
“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。
“取代”是指基团中一个或多个氢原子被其它基团取代的情形,如果所述的基团被氢原子取代,形成的基团与被氢原子取代的基团相同。基团被取代的情形,例如氨基、C1-4烷基、C1-4烷氧基、C3-6碳环、3至6元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、氰基、氨基、C1-4烷基或C1-4烷氧基的取代基所取代,形成的基团包括但不限于甲基、氯甲基、三氯甲基、羟基甲基、-CH2OCH3、-CH2SH、-CH2CH2CN、-CH2NH2、-NHOH、-NHCH3、-OCH2Cl、-OCH2OCH2CH3、-OCH2CH2NH2、-OCH2CH2SH、-OCH2CH2OH、1-羟基环丙基、2-羟基环丙基、2-氨基环丙基、4-甲基呋喃基、2-羟基苯基、4-氨基苯基、苯基。
“取代或未取代的”是指基团可以被取代或不被取代的情形,若在本发明中没有指出基团可以被取代,则表示该基团为未取代的情形。
“作为选择”是指“作为选择”之后的方案与“作为选择”之前的方案为并列关系,而不是在前方案中的进一步选择情形。
“药学上可接受的盐”或“其药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或有机碱,或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),氘代乙腈(CD3CN),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
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。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
BOC:叔丁氧基羰基;
DMAP:4-二甲氨基吡啶;
DCC:二环己基碳二亚胺;
EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
实施例1
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]imidazole-1-carboxylate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(20.0g,57.2mmol)溶于二氯甲烷(200mL)中,加入N'N-羰基二咪唑(18.5g,114.4mmol),50℃下反应2小时。向上述反应液中加入水(200mL×3)洗涤,无水硫酸钠干燥,减压浓缩得到白色固体状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(22.4g,产率88%)。
MS m/z(ESI):444.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.63(d,1H),8.47(dd,1H),8.14(s,1H),7.65(d,1H),7.42(s,1H),7.23(dd,1H),7.07(s,1H),6.08–5.94(m,1H),5.49(d,1H),4.96–4.77(m,1H),2.53(m,2H),2.28(m,1H),2.08(m,4H),1.97(m,1H),1.83–1.49(m,7H),1.24(m,2H),1.13(s,3H),1.06(s,3H)。
实施例2
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-2-甲酸酯(化合物2)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2-carboxylate
第一步:(2S)-1-叔丁氧基羰基吡咯烷-2-羧酸(2b)
(2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid
将二碳酸二叔丁酯(30.8mL,144mmol)溶于四氢呋喃(150mL)中,冰浴下缓慢滴加至的L-脯氨酸(2a)(15.07g,131mmol)和饱和碳酸氢钠(200mL)体系中,室温搅拌16小时,用2N的盐酸调节pH<3,用乙酸乙酯(150mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩,得到白色固状的(2S)-1-叔丁氧基羰基吡咯烷-2-羧酸(2b)(25.18g,产率89%)。
1H NMR(400MHz,CDCl3)δ4.30(d,1H),3.45(t,2H),2.32(d,1H),2.15–1.74(m,3H),1.46(d,9H)。
第二步:O1-叔丁基O2-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-1,2-二羧酸酯(2c)
O1-tert-butylO2-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrro-lidine-1,2-dicarboxylate
向反应瓶中依次加入(2S)-1-叔丁氧基羰基吡咯烷-2-羧酸(2b)(2.59g,12mmol)、阿比特龙(1.68g,4.81mmol)、4-二甲氨基吡啶(DMAP)(0.18g,1.44mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(2.3g,12mmol)和二氯甲烷(120mL),室温反应24小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到得到白色固状的O1-叔丁基O2-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-1,2-二羧酸酯(2c)(1.6g,产率61%)。
MS m/z(ESI):547.3[M+1]。
1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.47(d,1H),7.69(d,1H),7.29–7.23(m,1H),6.02(s,1H),5.42(s,1H),4.65(d,1H),4.33–4.16(m,1H),3.47(m,2H),2.42–2.12(m,4H),2.07(m,3H),2.00–1.80(m,5H),1.80–1.55(m,6H),1.49(m,1H),1.45(d,9H),1.24(d,2H),1.08(d,3H),1.05(s,3H)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]-(2S)-吡咯烷-2-甲酸酯(化合物2)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2-carboxylate
将O1-叔丁基O2-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]-(2S)-吡咯烷-1,2-二羧酸酯(2c)(1.1g,2.0mmol)溶于二氯甲烷(20mL),冰浴,缓慢滴加三氟乙酸(4mL),加完恢复室温反应2小时。冰浴下,体系加入氨水调节pH>7,用二氯甲烷(100mL×2)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-2-甲酸酯(化合物2)(0.86g,产率88%)。
MS m/z(ESI):447.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(m,1H),7.21(m,1H),5.99(m,1H),5.42(d,1H),4.77–4.57(m,1H),3.80(m 1H),3.13(m,1H),2.97(m,1H),2.36(d,2H),2.27(m,1H),2.23–2.12(m,1H),2.11–2.00(m,3H),1.93–1.54(m,11H),1.51(m,1H),1.18(m 2H),1.08(s,3H),1.05(s,3H)。
实施例3
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-3-甲酸酯(化合物3)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-3-carboxylate
第一步:O1-叔丁基O3-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-1,3-二甲酸酯(3b)
O1-tert-butyl O3-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-1,3-dicarbox ylate
向反应瓶中依次加入(3S)-1-叔丁氧基羰基吡咯烷-3-羧酸(3a)(1.06g,3.57mmol)、(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(1.68g,4.81mmol)、4-二甲氨基吡啶(DMAP)(0.18g,1.44mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(2.3g,12mmol)和二氯甲烷(120mL),室温反应8小时,体系加入水(100mL),用二氯甲烷(100mL×3)萃取,合并有机相,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到得到白色固状的O1-叔丁基O3-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-1,3-二甲酸酯(3b)(1.49g,产率78%)。
MS m/z(ESI):547.4[M+1]。
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.47(d,1H),7.69(dd,1H),7.25(m,1H),6.02(d,1H),5.42(d,1H),4.64(m,1H),3.50(m,4H),3.00(d,1H),2.34(m,2H),2.28(m,1H),2.07(m,5H),1.87(m,2H),1.67(m,6H),1.15(m,1H),1.47(d,9H),1.19(m,2H),1.09(s,3H),1.05(d,3H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-3-甲酸酯(化合物3)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-3-carboxylate
将O1-叔丁基O3-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-1,3-二甲酸酯(3b)(1.28g,2.34mmol)溶于二氯甲烷(40mL),冰浴,缓慢滴加三氟乙酸(4mL),加完恢复室温反应2小时。冰浴下,体系加入氨水调节pH>7,用二氯甲烷(100mL×2)萃取,合并有机相,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-3-甲酸酯(化合物3)(0.91g,产率87%)。
MS m/z(ESI):447.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(m,1H),7.21(m,1H),5.99(m,1H),5.42(d,1H),4.63(m,1H),3.13(m,3H),2.91(m,2H),2.43(m,1H),2.34(d,2H),2.27(m 1H),2.04(m,5H),1.88(m,2H),1.63(m,7H),1.17(m,2H),1.09(s,3H),1.05(s,3H)。
实施例4
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯(化合物4)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylpiperidine-4-carboxylate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(10.49g,30mmol)、1-甲基哌啶-4-甲酸(8.6g,60mmol)、4-二甲氨基吡啶(1.1g,9.0mmol)和二氯甲烷(300mL)加入反应瓶中,搅拌下分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(17.26g,90mmol),室温搅拌反应10小时。向反应液中加入水(300mL),搅拌5分钟,静置分层,有机层用无水硫酸钠干燥,过滤,减压浓缩干,残留物用硅胶柱层析分离(二氯甲烷:甲醇(v/v)=50:1)得白色固体状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯(化合物4),(7.8g,产率:55%)。
MS m/z(ESI):475.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.66(dt,1H),7.24(dd,1H),6.00(dd,1H),5.43(d,1H),4.66-4.59(m,1H),2.84-2.81(m,2H),2.34-2.22(m,7H),2.10-2.02(m,5H),1.93-1.45(m,13H),1.20-1.05(m,8H)。
实施例5
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-4-carboxylate
第一步:O1-叔丁基O4-[(3S8R,9S,10R,13,14S)-10,1 3-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基哌啶-1,4-二羧酸酯(5b)
O1-tert-butyl O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-1,4-dicarboxylate
向反应瓶中依次加入1-叔丁氧基羰基哌啶-4-羧酸(5a)(1.87g,8.2mmol)、阿比特龙(2.8g,8.0mmol)、4-二甲氨基吡啶(DMAP)(0.29g,2.4mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(3.83g,20mmol)和二氯甲烷(150mL),室温反应7小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到白色固状的O1-叔丁基O4-[(3S 8R,9S,10R,13,14S)-10,1 3-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基哌啶-1,4-二羧酸酯(5b)(3.13g,产率70%)。
MS m/z(ESI):561.4[M+1]。
1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.46(d,1H),7.66(d,1H),7.23(dd,1H),6.00(dd,1H),5.42(d,1H),4.63(m,1H),3.99(m,2H),2.85(t,2H),2.34(m,4H),2.07(m,3H),1.87(m,4H),1.62(m,9H),1.46(s,9H),1.17(m,2H),1.08(s,3H),1.05(s,3H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-4-carboxylate
冰浴,反应瓶中依次加入O1-叔丁基O4-[(3S 8R,9S,10R,13,14S)-10,1 3-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基哌啶-1,4-二羧酸酯(5b)(2.0g,3.57mmol),缓慢滴加3N浓度的盐酸乙酸乙酯溶液(15mL,45mmol),加完恢复室温反应1.5小时。体系抽滤,得到的白色盐酸盐用乙酸乙酯(10mL×2)洗,得到的白色固体用水溶解,体系加入氨水调节pH>7,用二氯甲烷(100mL×2)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.45g,产率88%)。
MS m/z(ESI):461.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(d,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.62(m,1H),3.11(d,2H),2.67(t,2H),2.34(m,5H),2.06(m,3H),1.87(m,4H),1.61(m,9H),1.15(m,2H),1.08(s,3H),1.05(s,3H)。
实施例6
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-甲基吡咯烷-3-羧酸酯(化合物6)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylpyrrolidine-3-carboxylate
向反应瓶中依次加入1-甲基吡咯烷-3-甲酸盐酸盐(42a,2.25g,13.5mmol)、阿比特龙(3.15g,9mmol)、DMAP(0.6g,4.9mmol)、DCC(7.5g,36mmol)和二氯甲烷(300mL),室温反应8小时。向反应液中加入二氯甲烷(200mL),用水(100mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱色谱分离(二氯甲烷/甲醇(v/v)=50:1)得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-甲基吡咯烷-3-羧酸酯(化合物6)(3.02g,产率76%)。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.63(m,1H),7.21(m,1H),5.99(dd,1H),5.41(d,1H),4.63(m,1H),,3.10–2.97(m,1H),2.90(m,1H),2.72–2.61(m,2H),2.59–2.47(m,1H),2.39(s,3H),2.34(m,2H),2.27(m,1H),2.15–1.99(m,3H),1.98–1.83(m,3H),1.82–1.44(m,7H),1.42–1.28(m,1H),1.16(m,2H),1.09(s,3H),1.05(s,3H)。
MS m/z(ESI):461.2[M+H]。
实施例7
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]四氢吡喃-4-羧酸酯(化合物7)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]tetrahydropyran-4-carboxylate
向反应瓶中依次加入四氢吡喃-4-甲酸(7a)(0.78g,6.0mmol)、阿比特龙(1.4g,4.0mmol)、4-二甲氨基吡啶(DMAP)(0.25g,2.0mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(3.07g,16mmol)和二氯甲烷(100mL),室温反应6小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]四氢吡喃-4-羧酸酯(化合物7)(0.89g,产率60%)。
1H NMR(400MHz,CDCl3)δ8.63(d,1H),8.53–8.40(m,1H),7.69(m,1H),7.26(m,1H),6.02(dd,1H),5.42(d,1H),4.73–4.54(m,1H),3.96(dt,2H),3.43(td,2H),2.56–2.44(m,1H),2.39–2.21(m,3H),2.13–2.00(m,3H),1.92–1.40(m,13H),1.20–1.10(m,2H),1.08(m,3H),1.05(s,3H)。
MS m/z(ESI):462.1[M+H]。
实施例8
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基](2S)-1-甲基吡咯烷-2-羧酸酯(化合物8)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-1-methylpyrrolidine-2-carboxylate
第一步:N-甲基-L-脯氨酸(8b)
N-Methyl-l-Proline
向反应瓶中依次加入L-脯氨酸(8a)(2.0g,17.4mmol)、甲醛(1.4mL,19.1mmol)、钯碳(0.5g)和甲醇(20mL),氢气氛下室温反应20小时,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=1:1)得到得到白色固状的N-甲基-L-脯氨酸(8b)(0.8g,产率36%)。
1H NMR(400MHz,MeOD)δ3.81(dd,1H),3.73(ddd,1H),3.22–3.06(m,1H),2.94(s,3H),2.61–2.40(m,1H),2.22–2.07(m,2H),2.02–1.90(m,1H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基](2S)-1-甲基吡咯烷-2-羧酸酯(化合物8)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-1-methylpyrrolidine-2-carboxylate
向反应瓶中依次加入N-甲基-L-脯氨酸(8b)(0.68g,5.26mmol)、阿比特龙(1.22g,3.51mmol)、4-二甲氨基吡啶(DMAP)(0.13g,1.05mmol)、DCC(1.81g,8.78mmol)和二氯甲烷(100mL),室温反应72小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基](2S)-1-甲基吡咯烷-2-羧酸酯(化合物8)(0.54g,产率34%)。
1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.56(d,1H),7.95(d,1H),7.49(m,1H),6.15(dd,1H),5.44(d,1H),4.73(m,1H),2.95(s,3H),2.58–2.00(m,11H),1.91-1.40(m,,10H),1.26–1.12(m,2H),1.09(s,3H),1.07(s,3H),0.92-0.88(m,1H)。
MS m/z(ESI):461.2[M+H]。
实施例9
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2,2,2-三氟乙酰基)哌啶-4-羧酸酯(化合物9)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2,2,2-trifluoroacetyl)piperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.61g,3.5mmol)、三氟乙酸酐(2.2g,10.5mmol)和二氯甲烷(30mL),40℃反应5小时,减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=100:1)得到得到无色油状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2,2,2-三氟乙酰基)哌啶-4-羧酸酯(化合物9)(1.6g,产率82%)。
1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.76(d,1H),8.37(d,1H),7.85(dd,1H),6.50–6.30(m,1H),5.43(d,1H),4.79–4.50(m,1H),4.39–4.16(m,1H),3.94(d,1H),3.39–3.24(m,1H),3.10(dd,1H),2.61(m,1H),2.44–2.27(m,3H),2.23–1.96(m,5H),1.94–1.43(m,11H),1.29-1.33(m,2H),1.11(d,3H),1.10(s,3H)。
MS m/z(ESI):557.2[M+H]。
实施例10
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-乙酰哌啶-4-羧酸酯(化合物10)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-acetylpiperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.38g,3mmol)、吡啶(1.42g,18mmol)和二氯甲烷(50mL),室温下滴加乙酰氯(0.94g,12mmol),室温反应0.5小时,体系加入水(100mL),用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-乙酰哌啶-4-羧酸酯(化合物10)(1.2g,产率80%)。
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.66(d,1H),7.32–7.10(m,1H),6.00(dd,1H),5.42(d,1H),4.64(m,1H),4.39(d,1H),3.85–3.68(m,1H),3.14(m,1H),2.90–2.72(m,1H),2.51(m,1H),2.39–2.22(m,3H),2.13–2.08(m,4H),2.08-1.99(m,2H),1.97–1.81(m,4H),1.81–1.44(m,9H),1.29-1.33(m,2H),1.09(s,3H),1.05(s,3H)。
MS m/z(ESI):503.4[M+H]。
实施例11
O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1异丙哌啶-1,4-二羧酸酯(化合物11)
O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-isopropylpiperidine-1,4-dicarboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(0.45g,0.98mmol)、吡啶(0.233g,2.94mmol)和二氯甲烷(30mL),室温下滴加氯甲酸异丙酯(0.24g,1.95mmol),室温反应0.5小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到白色固状O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1异丙哌啶-1,4-二羧酸酯(化合物11)(0.45g,产率88%)。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.51–8.42(m,1H),7.68–7.58(m,1H),7.22(dd,1H),5.99(dd,1H),5.42(d,1H),4.91(m,1H),4.71–4.54(m,1H),4.04(d,2H),2.95–2.80(m,2H),2.43(m,1H),2.38–2.16(m,3H),2.14–1.99(m,3H),1.86(m,4H),1.81–1.42(m,10H),1.25(m,7H),1.08(s,3H),1.05(s,3H)。
实施例12
O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1乙基哌啶-1,4-二羧酸酯(化合物12)
O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-ethyl piperidine-1,4-dicarboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(2.21g,4.8mmol)、吡啶(1.4g,14.4mmol)和二氯甲烷(50mL),室温下滴加氯甲酸乙酯(1.04g,9.6mmol),室温反应5小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到白色固状O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1乙基哌啶-1,4-二羧酸酯(化合物12)(2.1g,产率82%)。
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.65(d,1H),7.22(dd,1H),6.00(dd,1H),5.42(d,1H),4.63(m,1H),4.16-4.10(m,2H),4.07–3.96(m,2H),2.91(t,2H),2.43(m,1H),2.37–2.22(m,3H),2.12–2.00(m,3H),1.93–1.81(m,4H),1.80–1.38(m,9H),1.26(t,3H),1.22-1.10(m,2H),1.08(s,3H),1.05(s,3H)。
MS m/z(ESI):533.3[M+H]。
实施例13
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-羟丙基)哌啶-4-羧酸酯(化合物13)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-hydroxypropyl)piperidine-4-carboxylate
向密封瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(0.16g,0.35mmol)、环氧丙烷(0.02g,0.35mmol)和乙醇(4mL),90℃反应5小时,减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/二氯甲烷/甲醇(v/v/v)=20:20:1)得到黄色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-羟丙基)哌啶-4-羧酸酯(化合物13)(0.11g,产率60%)。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(m,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.72–4.56(m,1H),3.82(dd,1H),2.99(d,1H),2.77(d,1H),2.41–2.16(m,7H),2.13–1.96(m,4H),1.69(m,14H),1.23–1.15(m,1H),1.16–1.01(m,10H)。
MS m/z(ESI):260.1[M+2H/2]。
实施例14
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-乙基哌啶-4-羧酸酯(化合物14)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-ethylpiperidine-4-carboxylate
第一步:N-乙基-4-哌啶甲酸乙酯(14b)
1-ethyl-piperidine-4-carboxylic acid ethyl ester
向反应瓶中依次加入4-哌啶甲酸乙酯(14a)(4.72g,30mmol)、碘乙烷(5.15g,33mmol)和乙醇(100mL),80℃反应16小时,过滤,将滤液减压浓缩,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯/甲醇(v/v/v)=5:5:1)得到黄色油状N-乙基-4-哌啶甲酸乙酯(14b)(3.8g,产率68%)。
第二步:N-乙基-4-哌啶甲酸(14c)
1-ethyl-piperidine-4-carboxylic acid
向反应瓶中依次加入N-乙基-4-哌啶甲酸乙酯(14b)(3.8g,20mmol)、浓盐酸(39mL,468mmol)和水(20mL),100℃反应8小时,减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/甲醇(v/v)=5:1)得到黄色固体N-乙基-4-哌啶甲酸(14c)(2.5g,产率70%)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-乙基哌啶-4-羧酸酯(化合物14)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-ethylpiperidine-4-carboxylate
向反应瓶中依次加入N-乙基-4-哌啶甲酸(14c)(0.71g,4.5mmol)、阿比特龙(1.05g,3mmol)、4-二甲氨基吡啶(DMAP)(0.11g,0.9mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(1.73g,9.0mmol)和二氯甲烷(60mL),室温反应5小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-乙基哌啶-4-羧酸酯(化合物14)(0.9g,产率61%)。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.70–7.58(m,1H),7.21(ddd,1H),5.99(dd,1H),5.42(d,1H),4.76–4.50(m,1H),2.91(d,2H),2.50–2.37(m,2H),2.37–2.20(m,4H),2.17 1.43(m,18H),1.33-1.06(m,11H)。
MS m/z(ESI):489.3[M+1]。
实施例15
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-(3-吡啶基)哌啶-4-羧酸酯(化合物15)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(3-pyridyl)piperidine-4-carboxylate
第一步:1-吡啶基-3-哌啶-4-甲酸乙酯(15b)
1-pyridin-3-ylpiperidine-4-carboxylic acid ethyl ester
向反应瓶中依次加入4-哌啶甲酸乙酯(15a)(20g,127mmol)、3-溴吡啶(21.1g,133.5mmol)、叔丁醇钠(18.4g,191mmol)、1,1'-联萘-2,2'-双二苯膦(BINAP)(0.83g,13.3mmol)、三(二亚苄基茚丙酮)二钯(0.62g,0.68mmol)和二氧六环(300mL),86℃反应6小时,减压浓缩,体系加入800mL二氯甲烷,饱和食盐水(600mL×1)洗涤,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到得到黄色油状的1-吡啶基-3-哌啶-4-甲酸乙酯(15b)(8.0g,产率26%)。
1H NMR(400MHz,CDCl3)δ8.31(d,1H),8.08(dd,1H),7.23–7.10(m,2H),4.16(q,2H),3.65(dt,2H),2.85(td,2H),2.46(ddd,1H),2.11–1.96(m,2H),1.94–1.78(m,2H),1.27(t,3H)。
第二步:1-吡啶基-3-哌啶-4-甲酸(15c)
1-pyridin-3-ylpiperidine-4-carboxylic acid
向反应瓶中依次加入1-吡啶基-3-哌啶-4-甲酸乙酯(15b)(4.36g,18.6mmol)、八水氢氧化钡(10.57g,33.5mmol)、乙醇(50ml)和水(40mL),60℃反应2.5小时,减压浓缩,加水30mL,分批加入碳酸铵(7.3g,74.4mmol),室温反应2小时。抽滤,将滤液减压浓缩得到黄色固体1-吡啶基-3-哌啶-4-甲酸(15c)(2.5g,产率66%)。
1H NMR(400MHz,DMSO)δ8.29(d,1H),7.96(dd,1H),7.31(ddd,1H),7.19(dd,1H),3.67(dt,2H),2.80(td,2H),2.37(tt,1H),2.03–1.80(m,2H),1.71–1.55(m,2H)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-(3-吡啶基)哌啶-4-羧酸酯(化合物15)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(3-pyridyl)piperidine-4-carboxylate
向反应瓶中依次加入1-吡啶基-3-哌啶-4-甲酸(15c)(2.06g,10mmol)、阿比特龙(3.5g,10mmol)、4-二甲氨基吡啶(DMAP)(0.37g,3.0mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(5.75g,30mmol)和二氯甲烷(100mL),室温反应8小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/二氯甲烷/甲醇(v/v/v)=30:30:1)得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-(3-吡啶基)哌啶-4-羧酸酯(化合物15)(3.7g,产率69%)。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),8.31(d,1H),8.08(dd,1H),7.64(dt,1H),7.24–7.07(m,3H),5.99(dd,1H),5.43(d,1H),4.66(tdd,1H),3.65(dt,2H),2.87(td,2H),2.45(ddd,1H),2.40–2.32(m,2H),2.27(ddd,1H),2.06(ddd,5H),1.94–1.81(m,4H),1.81–1.39(m,7H),1.22-1.10(m,2H),1.09(s,3H),1.05(s,3H)。
MS m/z(ESI):538.3[M+H]+。
实施例16
[(3S,8R,9S,10R,13S,14S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(2-二甲氨基乙基)哌啶-4-羧酸酯(化合物16)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-dimethylaminoethyl)piperidine-4-carboxylate
第一步:1-(2-二甲基氨基-乙基)-哌啶-4-羧酸乙酯(16b)
1-(2-dimethylamino-ethyl)-piperidine-4-carboxylic acid ethyl ester
向反应瓶中依次加入二甲氨基氯乙烷盐酸(14a)(2.88g,20mmol)、4-哌啶甲酸乙酯(1.57g,10mmol)、碳酸钠(2.12g,20mmol)和甲苯(30mL),120℃反应16小时,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=25:1)得到黄色油状的1-(2-二甲基氨基-乙基)-哌啶-4-羧酸乙酯(16b)(0.83g,产率36%)。
1H NMR(400MHz,CDCl3)δ4.13(q,2H),2.89(dt,2H),2.51–2.36(m,4H),2.33–2.18(m,7H),2.04(td,2H),1.94–1.83(m,2H),1.83–1.70(m,2H),1.24(t,3H)。
第二步:1-(2-二甲基氨基-乙基)-哌啶-4-羧酸(16c)
1-(2-dimethylamino-ethyl)-piperidine-4-carboxylicacid
向反应瓶中依次加入1-(2-二甲基氨基-乙基)-哌啶-4-羧酸乙酯(16b)(3.3g,14.4mmol)、八水氢氧化钡(8.19g,26mmol)、乙醇(50ml)和水(40mL),60℃反应2.5小时,减压浓缩,加水30mL,分批加入碳酸铵(7.3g,74.4mmol),室温反应2小时。抽滤,将滤液减压浓缩得到黄色固体1-(2-二甲基氨基-乙基)-哌啶-4-羧酸(16c)(2.5g,产率87%)。
第三步:[(3S,10R,13S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(2-二甲氨基乙基)哌啶-4-羧酸酯(化合物16)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-dimethylaminoethyl)piperidine-4-carboxylate
向反应瓶中依次加入1-(2-二甲基氨基-乙基)-哌啶-4-羧酸(16c)(2.0g,10mmol)、阿比特龙(3.5g,10mmol)、4-二甲氨基吡啶(DMAP)(0.37g,3.0mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(5.75g,30mmol)和二氯甲烷(100mL),室温反应8小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/二氯甲烷/甲醇(v/v/v)=30:30:1)得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(2-二甲氨基乙基)哌啶-4-羧酸酯(化合物16)(2.2g,产率41%)。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.45(dd,1H),7.64(dt,1H),7.21(dd,1H),6.04–5.94(m,1H),5.41(d,1H),4.73–4.51(m,1H),2.55–2.40(m,4H),2.35–2.19(m,10H),2.11–1.99(m,7H),1.94–1.54(m,13H),1.28–1.09(m,2H),1.08(s,3H),1.04(s,3H)。
MS m/z(ESI):532.5[M+1]。
实施例17
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯2盐酸盐(化合物17)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylate dihydrochloride
第一步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯(化合物17b)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.61g,3.5mmol)、1-溴-2-氟乙烷(2.22g,17.5mmol)碳酸钾(2.9g,21mmol)和丙酮(30mL),回流反应6小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到褐色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯(化合物17b)(0.38g,产率20%)。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.68–7.58(m,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.64(s,2H),4.53(s,1H),2.93(s,2H),2.72(d,2H),2.39–2.24(m,4H),2.12–2.01(m,3H),1.95–1.79(m,6H),1.74–1.40(m,9H),1.14(ddd,2H),1.08(s,3H),1.05(s,3H)。
MS m/z(ESI):507.2[M+H]。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯2盐酸盐(化合物17)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylate dihydrochloride
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯(17b)(0.38g,0.75mmol)盐酸乙酸乙酯溶液(4N,10mL,40mmol),室温反应1小时,过滤,滤饼用乙酸乙酯(5mL×2)洗,得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯2盐酸盐(化合物17)(0.35g,产率86%)。
1H NMR(400MHz,MeOD)δ8.87(s,1H),8.72(d,1H),8.65(d,1H),8.05(dd,1H),6.50(dd,1H),5.48(d,1H),4.94(d,1H),4.62(d,1H),3.72(d,2H),3.63–3.47(m,2H),3.16(t,2H),2.70(s,1H),2.42(ddd,3H),2.34–2.20(m,3H),2.20–2.06(m,3H),2.03–1.82(m,5H),1.82–1.51(m,6H),1.23(dt,2H),1.17(s,3H),1.16(s,3H)。
MS m/z(ESI):507.2[M+H]。
实施例18
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-甲基磺酰哌啶-4-羧酸酯(化合物18)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylsulfonylpiperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.38g,3mmol)、甲基磺酰氯(0.29g,3.6mmol)、吡啶(0.36g,4.5mmol)和二氯甲烷(50mL),室温反应6小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-甲基磺酰哌啶-4-羧酸酯(化合物18)(1.4g,产率87%)。
1H NMR(400MHz,DMSO)δ8.63(d,1H),8.48(d,1H),7.85(d,1H),7.41(dd,1H),6.17(s,1H),5.41(d,1H),4.52(dd,1H),3.48(dd,3H),3.43–3.10(m,3H),2.86(s,2H),2.84–2.76(m,2H),2.49–2.42(m,1H),2.36–2.18(m,3H),2.14–1.98(m,3H),1.98–1.35(m,12H),1.06(s,3H),1.04(s,3H)。
MS m/z(ESI):539.2[M+H]。
实施例19
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-环丙基磺酰基哌啶-4-羧酸酯(化合物19)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-cyclopropylsulfonylpiperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(2.21g,4.8mmol)、环丙基磺酰氯(2.7g,19.2mmol)、吡啶(2.28g,28.8mmol)和二氯甲烷(60mL),室温反应10小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-环丙基磺酰基哌啶-4-羧酸酯(化合物19)(1.2g,产率44%)。
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.47(d,1H),7.68(d,1H),7.26–7.22(m,1H),6.01(dd,1H),5.43(d,1H),4.64(ddd,1H),3.71(dt,2H),3.05–2.90(m,2H),2.48–2.38(m,1H),2.38–2.20(m,4H),2.15–1.93(m,6H),1.93–1.41(m,12H),1.17(dd,2H),1.09(s,3H),1.05(s,3H),1.01–0.93(m,2H)。
MS m/z(ESI):565.3[M+H]。
实施例20
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯(化合物20)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylate
第一步:1-(环丙基甲基)哌啶-4-羧酸(20b)
1-(cyclopropylmethyl)piperidine-4-carboxylate
向反应瓶中依次加入4-哌啶甲酸(20a)(1.29g,10mmol)、环丙甲醛(4.2g,60mmol)、Pd/C(0.26g)和甲醇(30mL),氢气氛下室温反应42小时,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=1:1)得到得到淡黄色油状1-(环丙基甲基)哌啶-4-羧酸(20b)(1.6g,产率87%)。
1H NMR(400MHz,MeOD)δ3.37–3.20(m,2H),2.90–2.78(m,2H),2.76(d,2H),2.20(dd,1H),1.90(dd,2H),1.75(d,2H),0.97–0.82(m,1H),0.61–0.47(m,2H),0.24–0.15(m,2H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯(化合物20)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylate
向反应瓶中依次加入1-(环丙基甲基)哌啶-4-羧酸(20b)(1.47g,8mmol)、阿比特龙(1.4g,4mmol)、4-二甲氨基吡啶(DMAP)(0.25g,2.0mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(3.3g,16mmol)和二氯甲烷(100mL),室温反应5小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯/甲醇(v/v/v)=50:50:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯(化合物20)(0.56g,产率28%)。
1H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.69–7.58(m,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.70–4.56(m,1H),3.02(d,2H),2.43–2.17(m,6H),2.10-2.03(m,5H),1.99–1.42(m,13H),1.23–1.10(m,2H),1.08(s,3H),1.05(s,3H),0.92-0.86(m,1H),0.53-0.51(m,2H),0.11-0.10(m,2H)。
MS m/z(ESI):515.3[M+1]。
生物测试例
1、大鼠药代动力学实验
雄性SD大鼠(购自北京维通利华实验动物中心,动物生产许可证号SCXK(京)2012-0001)180-220g,禁食给水过夜,3只大鼠口服灌胃100mg/kg(以阿比特龙原形药物计)。于给药前及给药后30分钟,1.0,2.0,4.0,6.0,8.0,12.0,24.0h由眼眶采血0.1ml,肝素抗凝,4℃3000rpm离心10分钟后分离血浆,于-80℃保存。取各时间点大鼠血浆30μL,加入内标含维拉帕米7.5ng/的乙腈溶液800μL混合后,涡旋混合1.5分钟,13000转/分钟离心10分钟,取上清液10μL进行LC-MS/MS(AB SCIEX公司,API4000+)分析。主要药代动力学参数用WinNonlin6.3软件非房室模型分析。测试结果见表1。
表1大鼠药代动力学实验结果
结论:本发明化合物具有良好的药代动力学特征。
2、猴药代动力学实验
健康雄性恒河猴,3~5kg,适应观察5天后禁食给水过夜,胶囊口服给药醋酸阿比特龙50mg/kg或实施例化合物50mg/kg、20mg/kg、10mg/kg(以阿比特龙原形药物计),给药后5小时给食。于给药前及给药后15分钟,30分钟,1.0,2.0,4.0,6.0,8.0,12.0,24.0小时以肝素抗凝真空采血管静脉采血0.5ml,4℃3000rpm离心10分钟后分离血浆,于-80℃保存。各时刻血浆样品经乙腈沉淀蛋白处理后,进行LC-MS/MS(AB SCIEX公司,API4000+)分析,WinNonlin 6.3(Pharsight公司)软件非房室模型计算主要药动学参数。测试结果见表2。
表2猴药代动力学实验结果
结论:在50mg/kg的剂量下,化合物4和化合物20的暴露量大约分别是醋酸阿比特龙的9倍和4倍,特别是化合物4,在给药剂量仅为醋酸阿比特龙的1/5、2/5的剂量下,暴露量仍高于醋酸阿比特龙,约分别为醋酸阿比特龙的1.6倍和3倍,表明本发明化合物与醋酸阿比特龙相比具有更好的生物利用度。
Claims (8)
1.一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,
其中:A选自-RA-R1;RA为C(=O);
R1选自取代或未 取代的如下结构之一:
当被取代时,任选进一步被0至4个选自F、Cl、Br、I、OH、NH2、-(CH2)2N(C1-4烷基)2、-NHC(=O)C1-4烷氧基、C(=O)C1-4烷氧基、C(=O)R1h、S(=O)2R1h、R1h、吡啶或氮杂五元环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R1h各自独立的选自C1-4烷基、C1-4烷基-NH2、C1-4烷氧基或C3-6碳环,所述的NH2、烷基、烷氧基和碳环任选进一步被0至4个选自F、Cl、Br、I、OH、C1-4烷基、C1-4烷氧基或C3-6碳环的取代基所取代。
2.根据权利要求1所述的化合物及其立体异构体或药学上可接受的盐,
R1选自取代或未取代的如下结构之一:
当被取代时,任选进一步被0至4个选自F、Cl、Br、I、OH、NH2、-(CH2)2N(C1-4烷基)2、NHC(=O)C1-4烷氧基、C(=O)C1-4烷氧基、C(=O)R1h、S(=O)2R1h、R1h、吡啶或氮杂五元环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R1h各自独立的选自C1-4烷基、C1-4烷氧基、C1-4烷基-NH2或C3-6碳环,所述的烷基、NH2、烷氧基和碳环任选进一步被0至4个选自F、Cl、Br、OH、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、环丙基、环丁基或环戊基的取代基所取代。
3.根据权利要求2所述的化合物及其立体异构体或药学上可接受的盐,其中:
R1选自取代或未取代的如下结构之一:
当被取代时,任选进一步被0至4个选自NH2、-(CH2)2N(CH3)2、-NHC(=O)OC(CH3)3、-C(=O)OC(CH3)3、C(=O)R1h、S(=O)2R1h、R1h、吡啶或氮杂五元环的取代基所取代;
R1h各自独立的选自取代或未取代的甲基、乙基、2-氨基乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基,当被取代时,任选进一步被1至4个选自F、Cl、Br、OH、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基的取代基所取代。
4.根据权利要求3所述的化合物及其立体异构体或药学上可接受的盐,其中:
A选自C(=O)R1;
R1选自取代或未取代的如下结构之一:
当被取代时,任选进一步被1至4个选自NH2、-(CH2)2N(CH3)2、-NHC(=O)OC(CH3)3、-C(=O)OC(CH3)3、C(=O)R1h、S(=O)2R1h、R1h或吡啶的取代基所取代;
R1h各自独立的选自取代或未取代的甲基、乙基、2-氨基乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基,当被取代时,任选进一步被1至4个选自F、Cl、Br、OH、甲基、乙基或环丙基的取代基所取代。
5.根据权利要求1所示的化合物及其立体异构体或药学上可接受的盐,其中该化合物选自如下结构之一:
6.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1~5中任意一项所述的化合物或其立体异构体或药学上可接受的盐,以及药学上可接受的载体和赋形剂。
7.权利要求1~5中任意一项所述的化合物或其立体异构体或药学上可接受的盐、以及权利要求6所述的组合物在制备治疗与癌症相关疾病药物中的用途。
8.根据权利要求7所述的用途,其中所述的癌症为前列腺癌。
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CN102686600A (zh) * | 2009-02-05 | 2012-09-19 | 托凯药业股份有限公司 | 甾体cyp17抑制剂/抗雄激素物质的新型药物前体 |
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US20150337003A1 (en) * | 2013-01-18 | 2015-11-26 | Cortendo Ab (Publ) | Abiraterone and analogs thereof for the treatment of diseases associated with cortisol overproduction |
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CN102477061A (zh) * | 2010-11-23 | 2012-05-30 | 苏州波锐生物医药科技有限公司 | 吡啶雄甾衍生物及其在制备预防和/或治疗前列腺癌药物中的用途 |
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