CN111533712A - 一种阿法骨化醇杂环衍生物及其制备方法和用途 - Google Patents
一种阿法骨化醇杂环衍生物及其制备方法和用途 Download PDFInfo
- Publication number
- CN111533712A CN111533712A CN202010348856.3A CN202010348856A CN111533712A CN 111533712 A CN111533712 A CN 111533712A CN 202010348856 A CN202010348856 A CN 202010348856A CN 111533712 A CN111533712 A CN 111533712A
- Authority
- CN
- China
- Prior art keywords
- alfacalcidol
- compound
- heterocyclic derivative
- group
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学和药理学技术领域,具体涉及一种阿法骨化醇杂环衍生物,本发明还涉及阿法骨化醇杂环衍生物的制备方法,由阿法骨化醇与与氢氧化钠、相应的二溴烷烃在二甲亚砜中反应得到3‑O‑溴烷基阿法骨化醇,然后再与无水碳酸钾、相应的杂环在N,N’‑二甲基甲酰胺中反应而制得。本发明中提供的阿法骨化醇杂环衍生物,此类化合物结构中引入了杂环侧链结构,并且通过体外肿瘤细胞增殖抑制实验发现此类化合物具有较强的肿瘤细胞增殖抑制活性,与阳性对照药骨化三醇相当或优于骨化三醇,可应用于防治乳腺癌、结肠癌、肺癌、肝癌的药物的制备。
Description
技术领域
本发明属于药物化学和药理学技术领域,具体涉及一种阿法骨化醇杂环衍生物及其制备方法和应用。
背景技术
阿法骨化醇(alfacalcidol)是维生素D类化合物中的脂溶性甾醇,是一类参与钙、磷的内环境稳定和骨的矿化过程的物质。阿法骨化醇最早由美国骨保健国际公司(BoneCare International)研制,并先后在以色列、德国、日本、意大利获得批准上市。用于治疗因维生素D代谢障碍而引起的钙代谢紊乱,临床用于骨质疏松症、慢性肾功能不全、甲状旁腺功能减退症、抗维生素D佝偻症、骨软化症等。近些年来,阿法骨化醇的类似物骨化三醇和度骨化醇被发现具有抗肿瘤活性,抗肿瘤作用机制与抑制Hh信号通路有关,其中骨化三醇正在临床研究中。阿法骨化醇衍生物的抗肿瘤活性报道较少,因此通过结构修饰来发现新的阿法骨化醇衍生物来开发新型抗肿瘤药物具有较高的研究价值。
发明内容
发明目的:有鉴于此,本发明的目的在于提供一种阿法骨化醇杂环衍生物,这些衍生物具有与骨化三醇相当或更优的抑制肿瘤细胞增殖活性,可用于制备抗肿瘤药物。
技术方案:本发明提供了一种阿法骨化醇杂环衍生物,该阿法骨化醇杂环衍生物具有式(I)所示结构:
其中,n表示直链亚烷基的碳原子数,n=2-5,R表示吗啉基、N-氨基吗啉基、羟乙基哌嗪基、N-甲基哌嗪基、哌啶基、4-羟基哌啶基、3-羟基哌啶基、4-哌啶基哌啶基、四氢吡咯基或咪唑基。
进一步的,所述阿法骨化醇杂环衍生物具有如式2a~f中任意一项所示的结构:
其中,n为2,R为N-甲基哌嗪基时,该阿法骨化醇杂环衍生物为式2a所示结构的化合物;化合物2a:3-O-[2’-(N-甲基哌嗪基)-乙基]-阿法骨化醇;
n为2,R为4-羟基哌啶基时,该阿法骨化醇杂环衍生物为式2b所示结构的化合物;化合物2b:3-O-[2’-(4”-羟基哌啶基)-乙基]-阿法骨化醇;
n为2,R为吗啉基时,该阿法骨化醇杂环衍生物为式2c所示结构的化合物;化合物2c:3-O-[2’-(吗啉基)-乙基]-阿法骨化醇;
n为4,R为N-甲基哌嗪基时,该阿法骨化醇杂环衍生物为式2d所示结构的化合物;化合物2d:3-O-[4’-(N-甲基哌嗪基)-正丁基]-阿法骨化醇;
n为4,R为4-羟基哌啶基时,该阿法骨化醇杂环衍生物为式2e所示结构的化合物;化合物2e:3-O-[4’-(4”-羟基哌啶基)-正丁基]-阿法骨化醇;
n为4,R为吗啉基时,该阿法骨化醇杂环衍生物为式2f所示结构的化合物;化合物2f:3-O-[4’-(吗啉基)-正丁基]-阿法骨化醇。
本发明还提供了一种阿法骨化醇杂环衍生物的制备方法,包括以下步骤:
由阿法骨化醇与氢氧化钠、相应的二溴烷烃在二甲亚砜中反应得到3-O-溴烷基阿法骨化醇,然后再与无水碳酸钾、相应的杂环在N,N’-二甲基甲酰胺中反应而制得。
其中,所述反应的反应式为:
本发明还提供了一种上述的阿法骨化醇杂环衍生物在制备防治乳腺癌、结肠癌、肺癌、肝癌的药物中的应用。
有益效果:与现有技术相比,本发明中提供的阿法骨化醇杂环衍生物,此类化合物结构中引入了杂环侧链结构,并且通过体外肿瘤细胞增殖抑制实验发现此类化合物具有较强的肿瘤细胞增殖抑制活性,与阳性对照药骨化三醇相当或优于骨化三醇,可应用于防治乳腺癌、结肠癌、肺癌、肝癌的药物的制备。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,以使本领域的技术人员能够更好的理解本发明的优点和特征,从而对本发明的保护范围做出更为清楚的界定。本发明所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例,基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
将阿法骨化醇(200mg,0.5mmol)溶于DMSO(10mL)中,室温下搅拌5min后加入NaOH(160mg,4mmol)和1,2-二溴乙烷(130mg,0.7mmol)进行室温反应。TCL检测反应结束后加用乙酸乙酯稀释,水洗3次,饱和NaHCO3洗,无水Na2SO4干燥,加压浓缩,柱层析得白色固体270mg。将该白色固体溶于DMF(10mL)中,室温下搅拌5min后加入K2CO3(690mg,4mmol)和N-甲基哌嗪(100mg,1mmol),室温反应,TCL检测反应结束后加用乙酸乙酯稀释,水洗3次,饱和NaHCO3洗,无水Na2SO4干燥,加压浓缩,柱层析(prtroleum ether:EtOAc=2:1,Rf=0.3)得到白色固体2a(188mg,两步产率71%)。
对3-O-[2’-(N-甲基哌嗪基)-乙基]-阿法骨化醇(2a)进行核磁共振检测,结果为:1HNMR(400MHz,CDCl3)δ:6.37(1H,d,J=11.3Hz,H-6),6.01(1H,d,J=11.3Hz,H-7),5.32(1H,t,J=1.5Hz,H-19Z),5.00(1H,s,H-19E),4.43(1H,dd,J=7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),3.53-3.51(m,2H,OCH2),2.91(t,J=5.6Hz,2H,NCH2),2.83(1H,dd,J=11.8,3.8Hz,H-14),2.67(s,4H,NCH2),2.60(1H,dd,J=13.4,3.3Hz,H-4a),2.50(s,4H,NCH2),2.32-2.31(m,4H,NCH3,H-4b),0.92(3H,d,J=6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3);HRMS(ESI):m/z calcd for C34H59N2O2:527.4571;found:527.4576[M+H]+.
实施例2-6
根据以上实施例1的方法制备以下实施例化合物。
下面列出是2b-2f各化合物的理化数据:
2b:1H NMR(400MHz,CDCl3)δ:6.37(1H,d,J=11.3Hz,H-6),6.01(1H,d,J=11.3Hz,H-7),5.32(1H,t,J=1.5Hz,H-19Z),5.00(1H,s,H-19E),4.43(1H,dd,J=7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),3.76(m,1H,CH),3.53-3.51(m,2H,OCH2),2.91(t,J=5.6Hz,2H,NCH2),2.90(t,J=5.7Hz,2H,NCH2),2.83(1H,dd,J=11.8,3.8Hz,H-14),2.60(1H,dd,J=13.4,3.3Hz,H-4a),2.36(m,2H,NCH2),2.32-2.31(m,1H,H-4b),1.95(m,2H,CH2),1.64(m,2H,CH2),0.92(3H,d,J=6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3);HRMS(ESI):m/z calcd for C34H58NO3:528.4411;found:528.4408[M+H]+.
2c:1H NMR(400MHz,CDCl3)δ:6.37(1H,d,J=11.3Hz,H-6),6.01(1H,d,J=11.3Hz,H-7),5.32(1H,t,J=1.5Hz,H-19Z),5.00(1H,s,H-19E),4.43(1H,dd,J=7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),4.24(t,J=6.4Hz,2H,OCH2),3.73-3.71(m,4H,OCH2×2),2.83(1H,dd,J=11.8,3.8Hz,H-14),2.60(1H,dd,J=13.4,3.3Hz,H-4a),2.46(t,J=7.3Hz,6H,NCH2),2.32-2.31(m,1H,H-4b),0.92(3H,d,J=6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3);HRMS(ESI):m/z calcd for C33H56NO3:514.4255;found:514.4257[M+H]+.
2d:1H NMR(400 MHz,CDCl3)δ:6.37(1 H,d,J=11.3Hz,H-6),6.01(1 H,d,J=11.3Hz,H-7),5.32(1H,t,J=1.5Hz,H-19Z),5.00(1 H,s,H-19E),4.43(1H,dd,J=7.8,4.3Hz,H-1b),4.26-4.24(1H,m,H-3a),3.53-3.51(m,2H,OCH2),2.92(t,J=5.6 Hz,2H,NCH2),2.82(1H,dd,J=11.8,3.8Hz,H-14),2.66(s,4H,NCH2),2.60(1H,dd,J=13.4,3.3 Hz,H-4a),2.50(s,4H,NCH2),2.32-2.31(m,4H,NCH3,H-4b),1.96(m,2H,CH2),1.80(m,2H,CH2),0.92(3H,d,J=6.5 Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3);HRMS(ESI):m/zcalcd for C36H63N2O2:555.4884;found:555.4889[M+H]+.
2e:1H NMR(400 MHz,CDCl3)δ:6.37(1 H,d,J=11.3Hz,H-6),6.00(1 H,d,J=11.3Hz,H-7),5.31(1H,t,J=1.5Hz,H-19Z),5.00(1 H,s,H-19E),4.42(1H,dd,J=7.8,4.3Hz,H-1b),4.26-4.24(1H,m,H-3a),3.75(m,1H,CH),3.53-3.51(m,2H,OCH2),2.91(t,J=5.6 Hz,2H,NCH2),2.90(t,J=5.7 Hz,2H,NCH2),2.83(1H,dd,J=11.8,3.8 Hz,H-14),2.60(1H,dd,J=13.4,3.3 Hz,H-4a),2.36(m,2H,NCH2),2.32-2.31(m,1H,H-4b),1.96(m,4H,CH2),1.80(m,2H,CH2),1.63(m,2H,CH2),0.91(3H,d,J=6.5Hz,CH3),0.88-0.86(6H,m,CH3×2),0.54(3H,s,CH3);HRMS(ESI):m/zcalcd for C36H62NO2:540.4775;found:540.4782[M+H]+.
2f:1H NMR(400 MHz,CDCl3)δ:6.37(1 H,d,J=11.3Hz,H-6),6.01(1 H,d,J=11.3Hz,H-7),5.32(1H,t,J=1.5Hz,H-19Z),5.00(1 H,s,H-19E),4.43(1H,dd,J=7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),4.24(t,J=6.4Hz,2H,OCH2),3.73-3.71(m,4H,OCH2×2),2.83(1H,dd,J=11.8,3.8Hz,H-14),2.60(1H,dd,J=13.4,3.3Hz,H-4a),2.46(t,J=7.3Hz,6H,NCH2),2.32-2.31(m,1H,H-4b),1.95(m,2H,CH2),1.80(m,2H,CH2),0.92(3H,d,J=6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3);HRMS(ESI):m/z calcd forC35H60NO3:542.4568;found:542.4561[M+H]+.
为了更好地理解本发明的实质,下面分别用本发明提供的阿法骨化醇杂环衍生物对四种肿瘤细胞株的生长的抑制作用的药理实验结果,说明其在抗肿瘤药物研究领域中的新用途。药理实施例给出了代表性化合物的部分活性数据。必须说明,本发明的药理实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
药物实验例1:化合物2a~2f和骨化三醇对乳腺癌细胞(MCF-7)细胞毒活性测试
人乳腺癌细胞MCF-7用RPMI1640培养基培养,培养基中含有10%的胎牛血清,100U/mL青霉素和100U/mL的链霉素。细胞以每孔5×103的浓度加入到96孔板中,在37℃含有5%CO2的潮湿空气的培养箱中培养24小时。
将化合物2a~2f溶于DMSO中,配制1×10-2mol/L的母液,用完全培养基将母液稀释到相应浓度取对数生长期细胞接种于96孔板,24h贴壁后加入不同浓度的化合物溶液,每个浓度设4个平行孔,培养68h后加入四甲基偶氮唑盐(MTT)溶液,继续培养4h,弃去培养液,加入二甲亚砜150μL,振荡10min,用酶标仪测定570nm吸收度(A)值,计算半数抑制浓度(IC50),具体如表1所示。根据表1可知,化合物2a的IC50为27×10-9M,而阳性对照骨化三醇对MCF-7细胞的IC50为16×10-9M。
药物实验例2-4:化合物2a~2f和骨化三醇对人结肠癌细胞(HCT-116),人肺腺癌细胞(A549),人肝癌细胞(HepG2)细胞毒活性测试。
采用药物实验例1所示方法,对人结肠癌细胞(HCT-116),人肺腺癌细胞(A549),人肝癌细胞(HepG2)的生长抑制作用进行药理实验,计算半数抑制浓度(IC50),具体如表1所示。
表1化合物2a~2f和紫杉醇的细胞毒活性测试结果
根据表1可知,本发明提供的阿法骨化醇杂环衍生物具有重要的生物活性,体外对人乳腺癌细胞(MCF-7),人结肠癌细胞(HCT-116),人肺腺癌细胞(A549),人肝癌细胞(HepG2)共四种肿瘤细胞的细胞毒活性试验表明:此类式(1)所示结构的阿法骨化醇杂环衍生物对肿瘤细胞生长具有抑制作用,有可能发展成为新的防治肿瘤药物。从以上药理实施例中我们可以看出这些化合物对这四种肿瘤细胞都显示了较强的细胞毒活性,细胞毒活性超过或与阳性对照骨化三醇相当,具有开发成抗肿瘤药物的潜力。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (4)
2.根据权利要求1所述的阿法骨化醇杂环衍生物,其特征在于,所述阿法骨化醇杂环衍生物具有如式2a~f中任意一项所示的结构:
其中,n为2,R为N-甲基哌嗪基时,该阿法骨化醇杂环衍生物为式2a所示结构的化合物;化合物2a:3-O-[2’-(N-甲基哌嗪基)-乙基]-阿法骨化醇;
n为2,R为4-羟基哌啶基时,该阿法骨化醇杂环衍生物为式2b所示结构的化合物;化合物2b:3-O-[2’-(4”-羟基哌啶基)-乙基]-阿法骨化醇;
n为2,R为吗啉基时,该阿法骨化醇杂环衍生物为式2c所示结构的化合物;化合物2c:3-O-[2’-(吗啉基)-乙基]-阿法骨化醇;
n为4,R为N-甲基哌嗪基时,该阿法骨化醇杂环衍生物为式2d所示结构的化合物;化合物2d:3-O-[4’-(N-甲基哌嗪基)-正丁基]-阿法骨化醇;
n为4,R为4-羟基哌啶基时,该阿法骨化醇杂环衍生物为式2e所示结构的化合物;化合物2e:3-O-[4’-(4”-羟基哌啶基)-正丁基]-阿法骨化醇;
n为4,R为吗啉基时,该阿法骨化醇杂环衍生物为式2f所示结构的化合物;化合物2f:3-O-[4’-(吗啉基)-正丁基]-阿法骨化醇。
4.一种根据权利要求1所述的阿法骨化醇杂环衍生物在制备防治乳腺癌、结肠癌、肺癌及肝癌的药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010348856.3A CN111533712B (zh) | 2020-04-28 | 2020-04-28 | 一种阿法骨化醇杂环衍生物及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010348856.3A CN111533712B (zh) | 2020-04-28 | 2020-04-28 | 一种阿法骨化醇杂环衍生物及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111533712A true CN111533712A (zh) | 2020-08-14 |
CN111533712B CN111533712B (zh) | 2023-06-09 |
Family
ID=71971366
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010348856.3A Active CN111533712B (zh) | 2020-04-28 | 2020-04-28 | 一种阿法骨化醇杂环衍生物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111533712B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114656413A (zh) * | 2022-03-30 | 2022-06-24 | 南通华山药业有限公司 | 一种阿法骨化醇杂环酯类衍生物及其制备方法 |
CN114681467A (zh) * | 2022-03-30 | 2022-07-01 | 南通华山药业有限公司 | 一种阿法骨化醇杂环酯类衍生物在制备抗肿瘤药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1055924A (zh) * | 1990-04-06 | 1991-11-06 | 舍林股份公司 | 维生素d类中的24-氧杂-衍生物 |
WO2003000634A1 (en) * | 2001-06-20 | 2003-01-03 | The Government Of The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services | Vitamin d receptor antagonists and related compositions and methods of use |
CN109516938A (zh) * | 2018-12-21 | 2019-03-26 | 江苏卓和药业有限公司 | 一类阿法骨化醇衍生物及其制备方法 |
-
2020
- 2020-04-28 CN CN202010348856.3A patent/CN111533712B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1055924A (zh) * | 1990-04-06 | 1991-11-06 | 舍林股份公司 | 维生素d类中的24-氧杂-衍生物 |
WO2003000634A1 (en) * | 2001-06-20 | 2003-01-03 | The Government Of The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services | Vitamin d receptor antagonists and related compositions and methods of use |
US20040152668A1 (en) * | 2001-06-20 | 2004-08-05 | Julianna Barsony | Vitamin d receptor antagonists and related compositions and methods of use |
CN109516938A (zh) * | 2018-12-21 | 2019-03-26 | 江苏卓和药业有限公司 | 一类阿法骨化醇衍生物及其制备方法 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114656413A (zh) * | 2022-03-30 | 2022-06-24 | 南通华山药业有限公司 | 一种阿法骨化醇杂环酯类衍生物及其制备方法 |
CN114681467A (zh) * | 2022-03-30 | 2022-07-01 | 南通华山药业有限公司 | 一种阿法骨化醇杂环酯类衍生物在制备抗肿瘤药物中的应用 |
CN114681467B (zh) * | 2022-03-30 | 2024-03-12 | 南通华山药业有限公司 | 一种阿法骨化醇杂环酯类衍生物在制备抗肿瘤药物中的应用 |
CN114656413B (zh) * | 2022-03-30 | 2024-04-09 | 南通华山药业有限公司 | 一种阿法骨化醇杂环酯类衍生物及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN111533712B (zh) | 2023-06-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
BR112013013127B1 (pt) | Processo para a preparação de derivados de morfolinil antraciclina, compostos derivados de morfolinil antraciclina e composição farmacêutica compreendendo estes compostos | |
CN111533712A (zh) | 一种阿法骨化醇杂环衍生物及其制备方法和用途 | |
CN111171011A (zh) | 一种山荷叶素杂环衍生物及其制备方法和应用 | |
Sanchez-Fernandez et al. | Synthesis of polyfluoroalkyl sp2-iminosugar glycolipids and evaluation of their immunomodulatory properties towards anti-tumor, anti-leishmanial and anti-inflammatory therapies | |
CN110229168A (zh) | 11,20-二羰基济源冬凌草甲素及其l-氨基酸-14-酯三氟乙酸盐 | |
CN111440105B (zh) | 阿法骨化醇氨基甲酸酯衍生物及其制备方法和用途 | |
CN110862422B (zh) | β-半乳烯糖氮苷的合成方法及其在制药中的应用 | |
CN103739616A (zh) | 含噻唑基雷帕霉素类衍生物及其应用 | |
CN111808117B (zh) | 青蒿素-苯胺基喹唑啉类d类衍生物及其药物组合物和应用 | |
EP3434685B1 (en) | Uridine phosphoramide prodrug, preparation method therefor, and medicinal uses thereof | |
CN107629098A (zh) | 齐墩果酸型皂苷类化合物及其组合物 | |
CN110028482B (zh) | 布雷菲德菌素a的4-位拼合美法仑类氮芥衍生物及其制备方法和用途 | |
US9828406B2 (en) | Antitumor agent | |
KR20200118118A (ko) | 시클로부탄 디카르복실산 백금 착체, 그의 중간체, 그의 제조방법, 의약 조성물 및 사용 | |
CN110857295A (zh) | 具有选择性抗肝癌作用的黄酮-川芎嗪类化合物ch-x及其制备方法和应用 | |
CN104829619A (zh) | 一种取代芳基苦参碱类化合物及其制备方法与应用 | |
CN101691384A (zh) | 含磷的二苯乙烯类化合物及其制备方法和用途 | |
CN114681467B (zh) | 一种阿法骨化醇杂环酯类衍生物在制备抗肿瘤药物中的应用 | |
CN114656413B (zh) | 一种阿法骨化醇杂环酯类衍生物及其制备方法 | |
CN104672191B (zh) | 胡枝子酚e1类化合物及制备方法和应用 | |
CN112812145B (zh) | 一种苯并咪唑衍生物bi293及其制备方法和应用 | |
CN111303095B (zh) | 一种基于α-亚甲基-γ-内酯环结构的硫化氢供体及其制备方法和应用 | |
CN112920241B (zh) | 一种苯并咪唑衍生物bi308及其制备方法和应用 | |
CN107903247B (zh) | 含有羟基哌啶结构的作为sglt-2抑制剂的化合物 | |
CN103232394B (zh) | 含吡唑类化合物、其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |