CN1226253A - 甾体二膦酸酯 - Google Patents
甾体二膦酸酯 Download PDFInfo
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Abstract
羟基甾体二膦酸酯衍生物,该类衍生物是骨吸收抑制剂或骨形成刺激剂,在衍生物的甾体分子中,至少有一个羟基被基团A取代,基团A如下式(A),其中,X是:(i)St-O-CO-,其中St是除去一个羟基后的羟基甾体残基;(ii)R1-O-CO,R1为烷基、链烯基、环烷基、芳烷基或芳基,其中任一个基团都可以任选地被取代;或者(iii)一个氢原子,以及这些化合物的盐与溶剂化物。该甾体典型地是17β-雌二醇、雌甾酮、睾酮、炔诺酮、雄甾酮、诺生卓隆与诺龙。该类衍生物可以用于治疗骨骼疾病,如骨质疏松症。
Description
本发明涉及甾体衍生物,特别是羟基甾体的二膦酸酯衍生物,其可以用于防治骨质疏松症及有关的骨骼疾病。
羟基甾体(hydroxy steroids),例如雌二醇和睾酮,已被用于治疗骨质疏松症,其或者通过抑制骨吸收,或者通过促进骨的形成而起作用。而且二膦酸盐,如:羟乙二膦酸二钠和氯甲双磷酸盐都是已知的骨吸收抑制剂。近来,在欧洲专利EP-A-0496520和EP-A-0548884中,也提出了甾体的某些二膦酸酯衍生物的这种作用。在欧洲专利EP-A-0496520中,化合物的甾体基团通过氨基甲酸酯(carbamate)或碳酸酯(carbonate)基团与二膦酸酯基团相连接。在欧洲专利EP-A-0548884中,记载了甾体二磷酸(酯)醚。
现在,我们发现了这类甾体中的一组新的二膦酸酯衍生物,这些衍生物通过羧基基团连接,由于二膦酸酯基团对骨具有亲和性,因此该甾体的二膦酸酯衍生物具有将活性甾体选择性的作用于骨上,并通过水解作用在作用位点释放活性物质的潜在可能性。因此,本发明化合物可用于防治骨质疏松症及其它骨骼病,如Paget氏病,骨转移与恶性高钙血症。
其中,X是:
(ⅰ)St-O-CO-,其中St是除去一个羟基后的羟基甾体残基,
(ⅱ)R1-O-CO,其中R1为烷基、链烯基、环烷基、芳烷基或芳基,其中任一个基团都可以任选地被取代,
(ⅲ)一个氢原子。本发明还包括这些化合物的盐与溶剂化物。
本发明化合物的分子式为St-A,其中St与A如上所述,尤其是具有下式的化合物:
(St-O-CO)2CHCH2CH(PO(OH)2)2 (1)
(St-O-CO)(R1-O-CO)CHCH2CH(PO(OH)2)2 (2)
(St-O-CO)CH2CH2CH(PO(OH)2)2 (3)
其中,该甾体中含有一个以上的羟基,通常只有一个羟基被基团A取代,但本发明也包括二个或更多个羟基被A取代的上述化合物的衍生物。
本发明化合物结构的多样性,使得可根据需要调整其水解特性。例如,大多数已知甾体-二膦酸酯缀合物(conjuate),特别是雌二醇-二膦酸酯,水解速度较快,但往往需要的是缓慢水解,这样可以使甾体释放速度减慢。上述式(1)化合物,如下面的含有两个甾体单元的化合物(4)能够抑制水解,因此当需要甾体缓慢释放时,这种抑制作用是有益的。另一方面,仅含有一个甾体单元的化合物抑制水解作用弱,因此当需要甾体迅速释放时,这种弱抑制水解作用将是有益的。式(1)化合物也可以在同一分子内含有两个不同的甾体单元,其可以在同一时间释放不同活性的甾体。
母体羟基甾体可以为雌激素、雄激素、组成代谢甾体(anabolic steroid)、糖皮质激素或孕激素,这些物质能抑制骨的吸收或刺激骨的生成,如17β-雌二醇、雌甾酮、睾酮、炔诺酮、雄甾酮、诺生卓隆与诺龙。这些化合物通常在3位或17位或这两处具有羟基,可利用的羟基甾体的其它实例可见欧洲专利EP-A0496520。
在基团X中,R1可以是C1-6烷基(如甲基、乙基、异丙基或叔丁基),C2-6链烯基(如烯丙基),C3-8环烷基(如环戊烷或环已烷)、苯基C1-6烷基或单环或双环的芳基(如苯基、萘基)。该烷基和链烯基,例如,可以被一个或多个卤原子(如氯)取代,并且环烷基可被一个或多个C1-4烷基或卤原子(如氯)取代。芳基可被一个或多个羟基取代,如萘酚分子中的羟基。
本发明化合物能够与碱形成盐,如碱金属盐(钠盐),碱土金属盐(钙盐)。本发明的化合物中的一些以对映异构体形式存在,这些异构体也包括在本发明中。
下式化合物尤其重要:
本发明化合物可用于防治骨质疏松症及前述其它人类和动物的某些骨骼疾病。为此目的,可将这些化合物与一种或多种药用载体、赋形剂或稀释剂制成药物组合物。这些药物中的活性组分例如可为上式(4)、(5)、(6)所示的化合物。
本发明药物组合物可以口服剂、口腔含片(buccal)、胃肠外或局部用药的形式给药。
对于口服给药形式,可将组合物制成片剂、锭剂或胶囊等,并且在这些剂型中含有药用赋形剂,如粘合剂、填充剂、润滑剂、崩解剂或润湿剂。可用已知方法对片剂进行包衣。口服液体制剂可为溶液、糖浆或混悬液,其中可以含有药用添加剂如混悬剂、乳化剂、非水性赋形剂及防腐剂。
也可将组合物制成注射剂,其可以单位剂量形式存在,如安瓿。注射用组合物可为混悬剂、溶液或乳剂,以油或水为赋形剂,并且可以含有成形剂,如混悬剂、稳定剂、增溶剂和/或分散剂。
该组合物也可制成局部使用药物,如透皮贴片、软膏、霜剂及洗剂。
本发明化合物也可以与其它药物活性成分联合使用。
本发明化合物在药物中的日总剂量范围为0.001-10.0毫克/千克体重,可以分次给药,如每日1-4次。
(此处,R2和R3是C1-6烷基,如乙基,并且R2和R3可以相同或不同),生成膦酸酯(8),其式为(St-O-CO)2CHCH2CH(PO(OR3)2)2,膦酸酯基水解后,可制得所需的二膦酸。
碱性催化剂,如DMAP(二甲氨吡啶)的存在,会影响式(7)的酯基转移作用,例如在烃溶剂中,在任意适当温度至回流温度下进行反应时。
若母体羟基甾体中还含有羟基,并且在终产物中仍需要保留该羟基时,则在酯基转移反应中应对该羟基进行保护(例如制成苄基醚),然后再除去保护基。
可使用三(C1-6烷基)甲硅烷基卤化物(三甲基甲硅烷基溴)例如在卤化烃溶剂中将酯(8)进行水解。
与仲甲醛(paraformaldehyde)(例如在碱性催化剂如二乙胺的存在下)反应,然后再除去甲醇,得到亚甲基化合物(methylidene compound)10,
再在碱性催化剂(如乙醇钠)存在下,让化合物(10)与二烷基丙二酸酯反应(其中,烷基是上述定义的R2)。当化合物中的X是基团(ⅲ)时,如为上述式(3)化合物时,可用酸(11)与羟基甾体(StOH)发生酯化反应而制备。该反应可以在一种碱和一种活化剂如EDCI(N-(3-乙基二甲基氨丙基)-N’-乙基碳化二亚胺盐酸)的存在下进行。然后可以用上述方法水解除去膦酸酯基,得到所需的二膦酸。
同样,若羟基甾体中还含有要保留的羟基时,则在反应过程中要保护该羟基,而后除去保护基。
酸(11)的制备可在非亲核性碱性催化剂存在下,用上述甲烯化合物(10)加入丙二酸二苄基酯得到酯(12),然后氢解(如用钯炭),再脱羧(如加热)。
当化合物中的X是基团(ⅱ)时,如制备上述式(2)化合物时,可用羟基甾体的丙二酸酯(13)
下面的实施例用于说明本发明。
实施例1
将亚甲基二膦酸四乙酯(47.4克,0.165摩尔,1.0当量),仲甲醛(24.75克,0.825摩尔,5.0当量)和二乙胺(17.1毫升,12.1克,0.165摩尔,1.0当量)加入甲醇(470毫升)中。反应混合物在60℃加热,直到混合物成为无色溶液(30分钟),再在室温下继续搅拌15小时。减压浓缩该混合物,然后加入150毫升甲苯。减压除去溶剂。加入甲苯后再次浓缩有助于从中间产物15的粘性粗品中除去甲醇。 δH(CDCl3)1.29
(12H,t,J=8,P-OCH2CH3),2.67(1H,tt,JH-P=24,JH-H=
5,P2CHCH2OCH3),3.32(3H,s,-OCH3),3.86(2H,td,JH-P=
将对甲苯磺酸(0.15克,催化量)加入到粗品二甲氧基亚乙基二膦酸四乙酯(15)的250毫升甲苯溶液中。然后将该反应混合物加热回流过夜,经过这段时间后,消去反应进行完全。用水(3×100毫升)洗反应混合物,减压除去溶剂,得到油状物16(43.16克,两步产率88%);
νmax3020,2960,1485,1452,1402,1270(b),以及
1050(b);δH(CDCl3)1.30(12H,t,J=8.0,P-OCH2CH3),4.0-4.2(8H,m,P-OCH2CH3),和6.94(2H,dd,反式JP-H=40.0,顺式JP-H=36.4,P2C=CH2);δC(CDCl3)16.15(4C,t,J=3.4,P-OCH2CH3),63.08(4C,d,J=3.4,P-OCH2CH3),132.58(1C,t,J=127,P-C-P)和149.11(1C,s,-P2C=CH2);质谱(CI)m/z 301(M++H).实施例23,3-二(氧羰基)亚丙基二膦酸六乙基酯(17)的合成
将金属钠(0.23克,10毫摩尔,0.1当量)溶于乙醇(100毫升)中,在0℃、氮气中搅拌。使该混合物升至室温直到所有钠溶解。将该新制备的乙醇钠溶液经由一个套管加入到化合物16(30.0克,100毫摩尔,1.0当量)和丙酸二乙酯((15.20毫升,16.02克,100毫摩尔,1.0当量)的50毫升乙醇溶液中。反应混合物在氮气中室温搅拌30分钟。用1M盐酸(3×100毫升)洗反应混合物,用200毫升二氯甲烷提取。收集有机层,用无水硫酸镁干燥。减压除去溶剂,剩余的微量溶剂用高真空蒸馏除去。分离出所需的产物17,为一油状物,产率很高(43.8克/95.1%)。
(实测值:C43.97 H7.55,C17H34O10P2理论值:C44.35 H7.44)νmax
3010,1749,1732,1270(b),和1045(b)cm-1;δH(CDCl3)
1.28(6H,t,J=7.10,CO2CH2CH3),1.35(12H,t,J=
7.12,PO2CH2CH3),2.33-2.75(3H,m),3.97(1H,t,J=
7.68,-CH(CO2Et)2),和4.12-4.27(12H,m);δC(CDCl3)
14.48(2C,s,-CO2CH2CH3),16.71(4C,d,JCP=PO2CH2CH3),
25.29(1C,t,JCP=5,-CHCH2CH-),34.71(1C,t,JCP=
132,P-C-P),50.51(1C,t,JCP=8,-CH2CH(CO2Et)2,61.97
(2C,s,-CO2CH2CH3),63.22(4C,t,JCP=,PO2CH2CH3),和
169.31(2C,s,-CO2Et);δPCDCl3)22.33;m/z(CI)461
(M++H).
实施例3
4-(N,N-二甲氨基)吡啶(0.013克,0.11毫摩尔,0.1当量)和3-苄基-17β-雌二醇(0.861克,2.39毫摩尔,2.2当量)加入到17(0.50克,1.09毫摩尔,1.0当量)的10毫升甲苯溶液中,在氮气中将反应混合物加热回流11天。减压除去溶剂,将粗产物吸附于硅胶上,用硅胶闪蒸塔色谱法(flash columnchromatography)纯化,其中用含1-3%甲醇的二氯甲烷作为洗脱剂洗脱,得到所需产物,为一油状粘液(0.80克,收率67%)。
νmax3017,2936,1724,1605,1498,
1203(b),和929;δH(CDCl3)0.84(3H,s,18′-CH3),0.88
(3H,s,18′-CH3),1.23-1.97(21H,m),1.35(12H,t,J=
7),2.15-2.36(13H,m),4.72-4.81(2H,m,17′H),
5.05(4H,s,-OCH2Ph),6.74(2H,s,4′H),6.80(d,2H,J
=9,2′H),7.23(d,2H,J=9,1′H),和7.30-7.47(m,
10H);δC(CDCl3)13.09,13.20,17.43,17.51,24.35,
26.19,27.24,28.29,28.53,30.82,35.51(t,JCP=132,
PCP),37.95,44.15,44.31,44.84,50.80,51.38(t,JCP=
7.3,-CHCH2CH(CO2R)2),63.83(t,JCP=6.9,-CH2CH(CO2R)2),
71.00,85.02(d,JCP=10.4,PO2CH2CH3),113.39,115.92,
127.42,128.49,128.89,129.59,133.73,138.39,138.95,
157.84,和169.96(d,JCP=3.5,-CH(CO2R)2);δP(CDCl3)
20.4;m/z(+ve ion FAB)1094(M++H,100).
实施例4
{3,3-二-[雌-l,3,5-三烯-3-羟基-17β-基氧羰基]亚丙基}二膦酸四乙基酯(19)的合成
在含有18(692毫克,0.633毫摩尔,1当量)的四氢呋喃/甲醇(1∶1,10毫升)溶液中加入10%钯炭140毫克。将该反应混合物在1巴的氢气下振荡6小时。过滤反应混合物,倒入二氯甲烷中,用盐水洗。收集有机层,用无水硫酸镁干燥。减压除去溶剂。产品用硅胶闪蒸塔色谱法再次纯化,其中用含3-5%甲醇的二氯甲烷作为洗脱剂洗脱。用高真空蒸馏再次除去溶剂,得到一泡沫状产物。(557毫克,收率96.4%)。
(实测值:C,64.68;H,7.76.
C49H70O12P2理论值:C,64.46;H,7.73);δH(CDCl3)0.775
(3H,s,18′-CH3),0.781(3H,s,18′-CH3),1.15-1.87
(21H,m),1.34(12H,t,J=6.8,P-OCH2CH3),2.09-2.33
(6H,m),2.49(2H.七重峰,J=7.6,P2CHCH2CH(CO2R)2),2.66
(1H,tt,JP-H=24,JH-H=7.2 P2CHCH2CH(CO2R)2),2.81(4H,
m),4.05(1H,t,J=7.6,P2CHCH2CH(CO2R)2),4.16-4.24
(8H,m,P-OCH2CH3)4.71(2H,q,9.2,17′H),6.58(2H,s,
4′H),6.66(2H,d,J=8,2′H),和7.08(2H,d,J=
8.8,1′H);δC(CDCl3)11.93(1C,18′C),12.03(1C,18′C),
16.29(4C,d,J=5,P-OCH2CH3),23.22(2C),24.95(1C,b
-P2CHCH2CH-),26.16(2C),27.18(1C),27.37(1C),29.53
(2C),34.17(1C,t,J=134,P-C-P),36.81(2C),38.56
(2C),42.98(2C),43.17(1C),43.68(1C),49.64(2C),
50.23(1C,t,J=9,P2CHCH2CH(CO2R)2)63.06(4C,t,J=
7,P-OCH2CH3),83.95(1C,17′C),84.09(1C,17′C),112.77
(2C),115.31(2C),126.22(2C),131.48(2C),131.53
(2C),137.79(2C),154.23(2C),和168.84(2C,-CO2R);
δP(CDCl3)20.7(s);m/z(+ve ion FAB)913(M++H,76),159
(100).
实施例5
3,3-二-(雌-1,3,5-三烯-3-羟基-17β-基氧羰基)亚丙基二膦酸(20)的合成
在含有19(250毫克,0.275毫摩尔,1.0当量)的四氯化碳/三氯甲烷(1∶1,3毫升)溶液中加入三甲基甲硅烷基溴(1.24毫升,1.47克,9.62毫摩尔,35当量),将该反应混合物在氮气下搅拌24小时。加入5毫升水,形成一近白色的固体。过滤出沉淀物,用冷水和二氯甲烷洗。产物在高真空下干燥,得到近白色粉末(206毫克,94%),该粉末在180℃分解。
δH(CD3OD)0.85(3H,s,18′-CH3),
0.86(3H,s.18′-CH3),1.20-2.05(21H,m),2.10-2.30
(5H,m),2.38-2.50(3H,m),2.70-2.81(4H,m),4.08
(1H,t,J=7,-CH2CH(CO2H)2),4.72(2H,t,J=8,
17′H),6.47(2H,d,J=2,4′H),6.53(2H,dd,J=9,J
=2,2′H),和7.05(2H,d,J=9,1′H);δC(CD3OD)12.64
(1C,18′C),12.71(1C,18′C),24.22(2C),26.37(1C,b,
-P2CHCH2CH-),27.44(2C),28.45(2C),28.52(2C),30.63
(2C),36.79(1C,t,J=127,P-C-P),38.16(2C,b),40.18
(2C),44.28(1C,13′C),44.40(1C,13′C),45.10(2C),
50.94(2C),52.04(1C,b,-CH(CO2R)2),85.26(1C,17′C),
85.34(1C,17′C),113.79(2C),116.08(2C),127.21(2C),
132.36(2C),138.73(2C),155.94(2C,3′C),和170.49
(2C,-CO2R);δP(CD3OD)22.6;m/z(-ve ion FAB)799(M--H,
100).
实施例6
将亚乙基二膦酸四乙基酯16(1.00克,3.33毫摩尔,1.0当量)和丙二酸二苄酯(0.83毫升,0.946克,3.33毫摩尔,1.0当量)溶于四氢呋喃(15毫升)中。向该反应混合物中加入二(三甲基甲硅烷基)氨化锂的四氢呋喃(1M)溶液(0.33毫升,0.33毫摩尔,0.1当量),室温下搅拌1小时。向反应混合物中加入50毫升饱合氯化铵水溶液,用100毫升萃取产物。收集有机层,用无水硫酸镁干燥,减压除去溶剂。粗产物吸附于硅胶上,用硅胶闪蒸塔色谱法纯化,其中用含2-3%甲醇的二氯甲烷作为洗脱剂洗脱,分离出的产物为一无色油状物(1.12克,收率58%)。
δH(CDCl3)1.30(6H,t,J=7.1,-OCH2CH3),1.31(6H,t,J
=7.1,-OCH2CH3),2.37-2.74(3H,m),4.07-4.24(9H,
m),5.14(4H,s,-OCH2Ph),和7.24-7.35(10H,m);
δC(CDCl3)16.10(2C,-OCH2CH3),16.24(2C,-OH2CH3),24.81
(1C,m,-CH2CHP2)34.11(1C,t,JC-P=132.1,P-C-P),
49.93(1C,t,JC-P=7.8,-C(O)CHRC(O)),62.66(4C,m,
-OCH2CH3),67.11(2C,-OCH2Ph),128.03(4C,邻位C),
128.22(2C,对位C),128.40(4C,间位C),135.12(2C,1′
在苯环上)和168.41(2C,-OC(O)CH);δP(CDCl3)32.19;m/z
(+ve ion FAB)(M++H)585(36),369(7),和91(100);
HRMS(M++H)(实测值:585.20184 C27H39P2O10理论值:
585.20185).HRMS:高分辨率质谱仪
实施例7
3,3-二(膦酸基)四乙基酯-亚丙基二羧酸(22)的合成
将化合物21(0.698克,1.19毫摩尔)溶于10毫升四氢呋喃中并加入钯炭(0.10克,催化量的)。反应混合物于室温在氢气下搅拌过夜。过滤反应混合物,用50毫升饱合氯化铵水溶液洗,产物用二氯甲烷提取,用无水硫酸镁干燥,减压除去溶剂。产物在高真空下干燥,为一白色固体。(0.42克,收率88%)。 δH(MeOD)1.35(12H,t,J=
6.6,-P-O-CH2CH3),1.74(2H,七重峰,J=7.7,P2CHCH2CH-),
2.08(1H,tt,JP-H=23.1,J=6.6,P-CHRP),3.18(1H,t,
J=6.6,-CH2CH(CO2H)2),3.48-3.63(8H,m,P-O-CH2CH3);
δC(MeOD)16.55(2C,P-O-CH2CH3),16.68(2C,P-O-CH2CH3),
25.95(1C,t,JP-C=4.0,P2CHCH2CH-),35.01(1C,t,JP-C=
133.4,P-CHRP),51.10(1C,m,-CH(CO2H)2),64.45(4C,dd,
J=9.4,6.7,P-O-CH2CH3),171.84(2C,-CO2H);δP(MeOD)
22.8;m/z(+ve ion FAB)(M++D)406(100),以及(M++H)405
(90)
实施例8
将化合物22(0.200克,0.495毫摩尔)在恒稳的氮气流中于130℃下加热3小时。所得产物为一无色油状物。(0.174克,收率99%);δH(MeOD)
1.35(12H,t,J=7.7,-OCH2CH3),2.06-2.25(2H,m,
P2CHCH2CH2-),2.63-2.69(1H,m,-CDHCO2H),2.81(1H,tt,
JP-H=24.2,J=6.6,-PCHP-),4.11-4.25(8H,m,
P-O-CH2CH3);δC(MeOD)16.57(2C,P-O-CH2CH3),16.71(2C,
P-O-CH2CH3),21.82-22.10(1C,m,P2CHCH2CH2-),32.53-33.07
(1C,m P2CHCH2CH2CO2H),35.87(1C,t,J=133.4,P-CHR-P),
64.07-64.36(4C,m,P-O-CH2CH3),以及175.85(1C,
-CO2H);δP(MeOD)24.95;m/z(-ve ion FAB)361(100)(M--
H,氘化产品);HRMS(+ve ion FAB)
(实测值:363.12997 C12H25D2O8P2理论值:363.13067).
HRMS:高分辨率质谱仪
实施例9
将化合物23(0.071克,0.20毫摩尔,1.0当量)、3-氧-苯甲酰基-17β-雌二醇(0.089克,0.24毫摩尔,1.2当量)和4-(N,N-二甲氨基)吡啶(0.005克,0.04毫摩尔,0.2当量)溶于5毫升二氯甲烷中,在氮气下于0℃搅拌。向反应混合物中加入EDCI(0.0455克,0.24毫摩尔,1.2当量),缓慢升至室温,同时搅拌过夜。用30毫升水洗反应混合物,用二氯甲烷萃取产物。收集有机层,用无水硫酸镁干燥,减压除去溶剂。粗产物吸附于硅胶上,用硅胶闪蒸塔色谱法纯化,其中用含1-3%甲醇的二氯甲烷作为洗脱剂洗脱,产物在高真空下干燥,分离出无色油状物(0.048克,收率33%)。
νmax3053,2983,1729,1601,1243,和1025;
δH(CDCl3)0.84(3H,s,18′-CH3),1.25-1.93(11H,m),
1.35(12H,t,J=7.2,P-OCH2CH3),1.12-2.74(7H,m),
2.87-2.92(2H,m),4.12-4.28(8H,m,P-OCH2CH3),4.70
(1H,dd,J=8.8,7.1,17′H),6.92-7.00(2H,m),7.33
(1H,d,J=8.2,1′H),7.46-7.67(3H,m),和8.20
(2H,dt,J=8.3,1.6,邻位H′S在苯环上);δC(CDCl3)12.06
(1C,18′-CH3),16.32(2C,P-OCH2CH3),16.43(2C,
P-OCH2CH3),21.04(1C,m,P2CHCH2CH2-),23.25(1C),26.03
(1C),27.00(1C),27.59(1C),29.50(1C),35.68(1C,t,
J=132.1,P2-CHR),36.86(1C),38.18(1C),38.35(1C),
42.87(1C),43.9B(1C),49.80(1C),62.61(4C,t,J=
6.7,P-OCH2CH3),82.74(1C,17′C),118.67(1C),121.58
(1C),126.43(1C),128.49(2C),129.70(1C),130.10
(2C),133.45(1C),137.84(1C),138.19(1C),148.68
(1C),和172.72(2C);δP(CDCl3)23.2;m/z(+ve ion FAB)721(M++H,用于含有2D的产品),720(M++H,用于含有1D的产品),和719(M++H).可用实施例4和5的方法除去苄基和乙基。实施例1017-氧雌-1,3,5-三烯-3-氧丙二酸乙酯(25)的合成
将雌甾酮(0.54克,2.0毫摩尔,1.0当量)和三乙胺(0.56毫升0.405克,4.0毫摩尔,2.0当量)溶于15毫升四氢呋喃中,在氮气下于0℃搅拌。向反应混合物中缓慢加入乙基丙二酰基氯(0.76毫升,0.903克,6.0毫摩尔,3.0当量),缓慢升至室温,同时搅拌过夜。用50毫升水洗反应混合物二次,用二氯甲烷萃取产物并用无水硫酸镁干燥。减压除去溶剂。粗产物吸附于硅胶上,用硅胶闪蒸塔色谱法纯化,其中用含0.5%甲醇的二氯甲烷作为洗脱剂洗脱,分离出的产物为一无色油状物(0.144克,收率19%)。
δH(CDCl3)0.90(3H,s,18′-CH3),
1.32(3H,t,J=7.1,-OCH2CH3),1.36-1.75(6H,m),
1.88-2.59(7H,m),2.91(2H,dd,J=8.3,3.8),3.59
(2H,s,丙二酸酯H),4.26(2H,q,7.1,-OCH2CH3),6.86-
6.91(2H,m),和7.29(1H,d,J=8.2,1′H);δC(CDCl3)
13.65,13.95,21.41,25.60,26.13,29.21,31.39,35.68,
37.83,41.47,43.98,47.75,50.26,61.58,118.35,
121.18,126.30,137.65,138.00,148.22(3′C),165.25(
-CO2Et),166.09(-CO2Ph),和214.04(17′C);m/z(+ve ion
FAB)385(38)(M++H),115(100).
实施例11
将化合物25(0.112克,0.291毫摩尔,1.0当量)和化合物16(0.087克,0.291毫摩尔,1.0当量)溶于四氢呋喃中,在氮气中于室温下搅拌。向反应混合物中加入二(三甲基甲硅烷基)氨化锂的四氢呋喃(1M)溶液(0.03毫升,0.03毫摩尔,0.1当量),搅拌3小时。向反应混合物中加入饱合氯化铵水溶液,使其骤然冷却。用二氯甲烷萃取产物。收集有机层,用无水硫酸镁干燥。减压除去溶剂,粗产物吸附于硅胶上,用硅胶闪蒸塔色谱法纯化,其中用含0.5-3%甲醇的二氯甲烷作为洗脱剂洗脱,分离产物,在高真空下干燥,得到一无色油状物(0.060克,收率30%)。
δH(CDCl3)0.91(3H,s,18′-CH3),1.27-1.72
(8H,m),1.37(12H,t,J=7.2,P-O-CH2CH3),1.90-2.95
(13H,m),4.13-4.33(11H,m),6.82-6.90(2H,m),和
7.30(1H,d,J=8.8,1′H);δC(CDCl3)13.76(1C,18′C),
14.06(1C,-CO2CH2CH3),16.24(2C,-PO2CH2CH3),16.35(2C,
-PO2CH2CH3),21.53(1C,P2CHCH2CH-),24.96(1C,m),25.70
(1C),26.24(1C),29.32(1C),31.50(1C),34.28(1C,t,
J=132.1,P-C-P),35.76(1C),37.97(1C),44.11(1C),
17.86(1C),49.93-50.23(1C,m,-C(O)CHRC(O)-),50.42
(1C),61.77(1C,-CO2CH2CH3),62.66-62.98(4C,m,
P-O-CH2CH3),118.35(1C),121.18(1C),126.36(1C),137.70
(1C),138.08(1C),14 8.38(1C),167.73(1C),168.54(1C),
and 214.15;δP(CDCl3)22.34,和22.44;m/z(+ve ion FAB)
685(57)(M++H),239(100);HRMS(实测值:685.29124
C33H50O11P2理论值:685.29066).HRMS:高分辨率质谱仪
用实施例5的方法可将(26)转化为相应的二膦酸。
实施例12
{3,3-二[雄甾-4-烯-3-酮-17β-基氧羰基]亚丙基}二膦酸四乙基酯(27)的合成
睾酮(0.500克,1.73毫摩尔,2.2当量)、化合物17(0.363克,0.788毫摩尔,1.0当量)和4-(N,N-二甲氨基)吡啶溶于7毫升甲苯中,在氮气下加热回流。回流10天后,向反应混合物中再次加入睾酮(0.250克,0.86毫摩尔,1.1当量),再加热回流6天。停止反应,用饱和氯化铵水溶液洗反应混合物,用二氯甲烷萃取产物,用无水硫酸镁干燥。减压除去溶剂,粗产物吸附于硅胶上,用硅胶闪蒸塔色谱法纯化,其中用含3%甲醇的二氯甲烷作为洗脱剂洗脱,在高真空下分离出的产物为一泡沫状物(0.61克,收率82%,3次)。
δH(CDCl3),0.76(3H,s,18′-CH3),0.78(3H,
s,18′-CH3),0.80-1.80(20H,m),1.12(6H,s,19′-CH3),
1.28(12H,t,J=7.2),1.94-1.98(2H,m),2.05-2.57
(13H,m),3.94(1H,t,J=7.6,丙二酸酯H),4.58(2H,
q,J=8,17′H),和5.66(2H,s,4′H);δC(CDCl3),11.91
(1C),12.02(1C),16.31(2C),16.42(2C),17.39(2C),
20.49(2C),23.45(2C),24.82-25.02(1C,m),27.31
(2C),31.43(2C),32.67(2C),33.88(2C),34.34(1C,t,
J=133.4),35.34(2C),35.69(2C),36.53(2C),38.57
(2C),42.56-42.72(2C,m),50.17(2C),53.61(2C),
61.51(1C),62.61-62.92(4C,m),83.50(1C),83.64
(1C),123.97(2C),168.80(1C),168.88(1C),170.77
(2C),和199.37(2C);δP(CDCl3),22.98;m/z(+ve ion
FAB)(M++H)946(14),703(87),和461(100).
用实施例5的方法可将(27)转化为相应的二膦酸。
Claims (7)
2、根据权利要求1所述的式(1)化合物。
(St-O-CO)2CHCH2CH(PO(OH)2)2 (1)
3、根据权利要求1或2所述的化合物,其中甾体是雌激素、雄激素、组成代谢甾体、糖皮质激素或孕激素。
4、根据权利要求1或2所述的化合物,其中甾体是17β-雌二醇、雌甾酮、睾酮、炔诺酮、雄甾酮、诺生卓隆或诺龙。
6、一种药物组合物,其含有一种或多种上述任意一项权利要求中所述的化合物及一种或多种药用载体、赋形剂或稀释剂。
7、权利要求1所述的化合物的制备方法,包括
其中,R2和R3是C1-6烷基,并且R2和R3可以相同或不同,生成式(St-O-CO)2CHCH2CH(PO(OR3)2)2的膦酸酯(8),然后水解除去膦酸酯基;
(C)当制备X是基团(ⅱ)的化合物时,用羟基甾体的丙二酸酯(13)
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EP2214716B1 (en) | 2007-10-23 | 2021-11-17 | Nektar Therapeutics | Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom |
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DE4029499A1 (de) * | 1990-09-18 | 1992-03-19 | Boehringer Mannheim Gmbh | Neue 17-(beta)-oestradiolderivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
EP0496520A1 (en) * | 1991-01-22 | 1992-07-29 | Merck & Co. Inc. | Novel bone acting agents |
FR2683527A1 (fr) * | 1991-11-12 | 1993-05-14 | Bretagne Occidentale Universit | Prodrogues gem-bisphosphonates de sterouides derives de la cortisone. |
JP3141053B2 (ja) * | 1991-12-26 | 2001-03-05 | アベンティス ファーマ株式会社 | ビスホスホン酸誘導体 |
JP2746041B2 (ja) * | 1992-02-14 | 1998-04-28 | 三菱化学株式会社 | 新規なステロイド誘導体 |
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Cited By (1)
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CN100345548C (zh) * | 1999-08-19 | 2007-10-31 | 罗亚尔·亚历山德拉儿童医院 | 用于治疗骨折的药物 |
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BG103123A (en) | 1999-10-29 |
IL127781A0 (en) | 1999-10-28 |
EP0912598A1 (en) | 1999-05-06 |
US6140518A (en) | 2000-10-31 |
WO1998000438A1 (en) | 1998-01-08 |
ZA975749B (en) | 1998-07-27 |
AU3350697A (en) | 1998-01-21 |
NO986112D0 (no) | 1998-12-23 |
NO986112L (no) | 1999-02-23 |
PL330781A1 (en) | 1999-06-07 |
HUP9902880A3 (en) | 2001-09-28 |
TR199900490T2 (xx) | 1999-05-21 |
SK175198A3 (en) | 1999-06-11 |
CA2259309A1 (en) | 1998-01-08 |
BR9710074A (pt) | 2000-01-18 |
CZ432398A3 (cs) | 1999-05-12 |
HUP9902880A2 (hu) | 2000-03-28 |
GB9613722D0 (en) | 1996-08-28 |
JP2000513372A (ja) | 2000-10-10 |
YU59898A (en) | 1999-11-22 |
EE9800454A (et) | 1999-06-15 |
KR20000022262A (ko) | 2000-04-25 |
IS4931A (is) | 1998-12-22 |
AP9801431A0 (en) | 1998-12-31 |
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