CN1073677A - 20-甲基取代维生素d衍生物 - Google Patents
20-甲基取代维生素d衍生物 Download PDFInfo
- Publication number
- CN1073677A CN1073677A CN92114249A CN92114249A CN1073677A CN 1073677 A CN1073677 A CN 1073677A CN 92114249 A CN92114249 A CN 92114249A CN 92114249 A CN92114249 A CN 92114249A CN 1073677 A CN1073677 A CN 1073677A
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- CN
- China
- Prior art keywords
- methyl
- dihydroxyl
- vitamins
- necessity
- hydroxyl
- 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
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- 238000000034 method Methods 0.000 claims abstract description 11
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- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 2
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- 210000004185 liver Anatomy 0.000 description 1
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- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- A—HUMAN NECESSITIES
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Abstract
式I新20-甲基取代维生素D衍生物及其制造
方法,其中R1为氢,羟基或1—12碳烷酰氧基如苯
甲酰氧基,R2为氢,1—12碳烷酰基如苯甲酰基和R3
为饱和或不饱和直链或支链最多18碳烃基,必要时
含环结构,必要时可由一或多个羟基,氧,氨基和/或
一或多个卤原子取代且必要时可含一或多个氧,硫和
/或氮原子作为烃基中的连接链节。这些新化合物
与钙三醇相比具有更强的细胞分化(HL-60)诱导作
用并适用于药剂制造。
Description
本发明涉及式Ⅰ20-甲基取代维生素D衍生物,其制造方法,含该化合物的药剂及其在药剂制造过程中的应用
其中
R1为氢,羟基或1-12碳烷酰氧基和苯甲酰氧基,
R2为氢,1-12碳烷酰基和苯甲酰基和
R3为饱和或不饱和直链或支链最多18碳烃基,必要时含环结构,必要时可由一或多个羟基,氧,氨基和/或一或多个卤原子取代且必要时可含一或多个氧。硫和/或氮原子作为烃基中的连接链节。
R1和R2中的1-12碳烷酰氧基和烷酰基特别源自饱和羧酸,可为环状,无环,脂环或杂环,必要时也可不饱和,优选源自C1-C9,特别是C2-C5烷酸如乙酰(氧)基,丙酰(氧)基,丁酰(氧)基。
R3为可使维生素D有效的所有侧链如见于以下专利申请:
US-Patent 4 927 815(22.5.1990,De Luca et al.)EP-A-0 421 561(Kirsch et al.)
US-Patent 4 906 785(6.3.1990,Baggiolini et al.)EP-A-0 441 467(Neef et al.)
US-Patent 4 897 387(30.1.1990,Ikekawa et al)EP-A-0 450 743(Neef et al.)
US-Patent 4 866 048(12.9.1989,Calverley et al.)
US-Patent 4 857 518(15.8.1989,De Luca et al.)
US-Patent 4 851 401(25.7.1989,De Luca et al.)
优选R3为下列式侧链:
R=C1-C4-烷基,-羟烷基,-O-烷基。
可特别举出以下本发明化合物:
1α,25-二羟基-20,26,27-三甲基-23-氧维生素D3,
1(S),3(R)-二羟基-20-(5-羟基-5-甲基己-1E,3E-二烯-1-基)-20-甲基-9,10-断孕-5Z,7E,10(19)-三烯,
1α-25-二羟基-20-甲基维生素D3,
1α,25-二羟基-20-甲基-24-高维生素D3,
1α,24(S)-二羟基-20-甲基维生素D3,
1α,25-二羟基-20-甲基-23-氧维生素D3,
1α,24(R),25-三羟基-20-甲基维生素D3,
1α,24(S),25-三羟基-20-甲基维生素D3,
1α,25-二羟基-20-甲基-24-氧维生素D3,
(5Z,7E)-(1S,3R)-20-甲基-20-乙烯基-9,10-断孕-5,7,10(19)-三烯-1,3-二醇,
(5Z,7E)-(1S,3R)-20-乙基-20-甲基-9,10-断孕-5,7,10(19)-三烯-1,3-二醇,
(5Z,7E)-(1S,3R)-20-羟甲基-20-甲基-9,10-断孕-5,7-10(19)-三烯-1,3-二醇,
1α,25-二羟基-20-甲基-23-脱氢维生素D3和
1α,25-二羟基-20,26,27-三甲基-23-脱氢维生素D3。
天然维生素D2和D3(见式Ⅵ)生物上无活性,先于肝中在25位及肾中在1位羟基化后可转化成其生物活性代谢物。维生素D2和D3的作用在于使血浆中Ca++和磷酸盐含有量稳定,这些物质可阻止血浆中Ca++含有量下降。
及角骨化醇:Ra=Rb=H,Rc=CH3,维生素D2
胆钙化醇:Ra=Rb=Rc=H, 维生素D3
25-羟基胆钙化醇:Ra=Rc=H,Rb=OH,
1α-羟基胆钙化醇:Ra=OH,Rb=Rc=H,
1α,25-二羟基胆钙化醇:Ra=Rb=OH,Rc=H,钙三醇。
由于其具有对钙和磷酸盐物质代谢的突出作用,所以维生素D2和D3及其合成衍生物也具有阻止增生和细胞分化作用(见H.F.De Luca,“The Metabolism and Function of Vitamin D”,Biochemistry of Steroid Hormones,Hrsg.H.L.J.Makin,2nd Edition,BlackwellScientific Publications 1984.S.71-116)。
但在维生素D应用过程中易出现过量现象(钙质过多)。
在24位羟基化的1α-胆钙化醇已见于DE-AS-25 26 981,比相应的未羟基化1α-胆钙化醇毒性低。羟基化化合物可选择性活性经肠钙吸收并且骨吸收作用要比1α-胆钙化醇弱。
PCT申请WO 87/00834所述24-羟基维生素D类似物可用于治疗人体中不正常细胞增生和/或细胞分化引起的紊乱。
对于不同的1,25-二羟基高维生素D衍生物,有关骨吸收作用和HL-60细胞分化性的分离是刚从De Luca得知的。体外骨吸收性因此是体内钙活动的直接尺度。
式Ⅰ新维生素D衍生物通过碳原子20上的附加甲基可使已知侧链改性化合物具有维生素D活性。这样位置C-20就失去了非对称中心性。
除了因此使中间产物和最终产物合成和提纯过程得以简化而外,还可制成具有惊人的高生物活性的新化合物。严格以钙三醇(1α-25-二羟基维生素D3)标准而言,本发明物质在可比较的对钙三醇受体的亲和性方面显示出的细胞分化(HL-60)诱导性要好几十次方并且因此而特别适宜于治疗以过量增生和紊乱性细胞分化为特征的病症如皮肤过量增生性病(牛皮癣)和恶性肿瘤(白血病,结肠癌,乳腺癌)。
本发明特别优选方式中可在治疗前证明目的器官中的钙三醇受体。
此外这些化合物还可以类似于已知维生素D衍生物的方式用于治疗钙代谢紊乱,免疫抑制和减缓皮肤老化。
本发明化合物的维生素D活性可由钙三醇受体试验确定,可用取自小猪肠的特异性受体蛋白进行,其中含受体结合蛋白与3H-钙三醇(5×10-10mol/l)以0.270ml的反应体积在不存在或存在试验检测物质情况下于试管中4℃培养2小时。为分离游离和受体结合钙三醇可进行木炭-糊精吸收,向每试管加入250μl木炭-糊精悬浮体并4℃培养20分钟,然后4℃10000xg下将试料离心分离5分钟,倒出上层清液,平衡1小时后在β-计数器中用Picofluor 15TM测定。
用不同浓度的试验物质以及对照物质(未标示钙三醇)在恒定浓度参考物质(3H-钙三醇)得到的对比(Kompetition)曲线相互关联起来得到对比因子(KF)。
该因子定义为各试验物质和对照物质达到50%对比所需浓度之商:
KF= (50%对比的试验物质浓度)/(50%对比的参照物质浓度)
1(S),(3R)-二羟基-20-(5-羟基-5-甲基-己-1E,3E-二烯-1-基)-20-甲基-9,10-断孕-5Z,7E,10(19)-三烯和1α,25-二羟基-20,26,27-三甲基-23-氧维生素D3的KF值为3,4和1.6。
新化合物更好地诱导细胞分化可从下述试验得知。
由文献(Mangelsdorf,D.J.et al,J。Cell.Biol.98:391-398(1984))已知,用钙三醇体外治疗人体白血病细胞(早幼粒细胞谱系HL60)会诱发细胞分化成为巨噬细胞。
HL60细胞在组织培养基(RPMI-10%胎牛血清)37℃在空气中5%CO2的气氛中培养。
为进行物质试验可离心分出细胞并以2.8×105细胞/ml加入无酚红组织培养基中。试验物质溶于乙醇并用无酚红组织培养基稀释成要求浓度。稀释液和细胞悬浮体以1∶10的比例混合并将各加有100μl加物质悬浮体滴入96Loch-Platte的洞中。作为对比,悬浮体中类似加入溶剂。
37℃空气中5%CO2培养96小时后在96Loch-Platte的每一洞中向细胞悬浮体中滴加入100μlNBT-TPA-溶液(硝基blautetrazolium(NBT),加料中终浓度1mg/ml,十四烷酰佛波醇肉豆蔻酸酯-13-乙酸酯(TPA),加料中终浓度2×10-7mol/l。
37℃空气5%CO2中培养2小时,由于细胞内氧自由基释放出来,可经TPA刺激,其中分化成巨噬细胞的细胞NBT还原成不溶性甲。
反应结束后,从96-Loch-Platte洞中取出悬浮体并且加甲醇而固定粘附细胞后干燥。
作为分化诱导HL60-细胞成为巨噬细胞的尺度,可采用甲浓度。试验物质相对效果定为ED50试验物质/ED50钙三醇之商。
因此本发明还涉及药物制剂,其中含有至少一种式Ⅰ化合物和药用载体。这些化合物可配制成药用溶剂或载体中的溶液或乳液,悬浮液或分散液或用固体载体按已知方式制成丸,片或胶囊。局部应用时可将化合物配制成乳液或软膏或类似的宜于局部应用的形式。这些配方中均可含有其它药用非毒性助剂如稳定剂,抗氧化剂,粘合剂,着色剂,乳化剂或调味剂。这些化合物服用方式还可为注射或静脉内注射合适的无菌溶液或经食道口服或以乳剂,软膏,洗剂或适宜的皮肤用膏剂局部涂用,正如EP-A-0387077所述。
日服用量为
0.1-1000μg/人/天,
优选
1.0-500μg/人/天。
此外,本发明还涉及式Ⅰ化合物在药剂制造过程中的应用。
本发明式Ⅰ化合物制造方法是式Ⅱ化合物
其中
R1′为氢或被保护羟基和
R2′为碱性稳定的羟基保护基以及
R3′意义同于最终要求式Ⅰ化合物中的R3,其中必要时存在的羟基被保护。
经脱羟基保护基并必要时部分或完全酯化羟基而转化成式Ⅰ化合物。
碱性稳定的羟基保护基优选为叔丁基二甲基甲硅烷基,叔丁基二苯基甲硅烷基或其它叔甲硅烷基。脱叔甲硅烷基可用四正丁基铵氟化物进行。
脱保护基后的游离羟基必要时成酯。各个游离的羟基可用相应酰卤(卤化物=氯化物,溴化物)或酸酐部分或完全成酯。
本发明式Ⅱ初始化合物可用式Ⅲ已知醛进行制备
其中R1′和R2′同上式Ⅱ(M.J.Calverley,Tetrahedron 43,4609,1987;G.Neef et al.Tetrahedron Lett.1991,5073)。
该化合物按常法α-烷基化可得式Ⅳ二甲基化醛,然后同样按已知方法通过三重态敏化的旋光异构化而转化成式Ⅴ中心中间化合物。
进行甲基化可用碘甲烷或二甲基硫酸酯,其中存在碱(如碱金属氢氧化物,氢化物,酰胺),用非质子溶剂如四氢呋喃,乙醚,己烷,乙二醇二甲醚或甲苯,必要时加四烷铵盐作为相转化催化剂。
在所谓的“三重态敏感剂”(本发明中可用蒽)存在下经紫外线照射可将式Ⅳ化合物转化成式Ⅴ化合物。通过5,6-双键的Pi键分开,A-环绕5,6-单键转动180°并重新确立5,6-双键就可使该立体异构体回转成5,6-双键。
然后必须经式Ⅴ醛与适宜于偶合的R3′,这可类似于已知方法进行,该法的试验过程如见于M.J.Calverley,Tetrahedren 43,4609,1987;G.Neef和A.Steinmeyer,Tetrahedron Lett.1991,5073;国际专利WO91/00855,DE-A-39 33 034和DE-A-40 11 682,作为例子可举出:式Ⅴ醛与Wittig试剂反应或醛还原成醇后通过与相应ω-卤代化合物反应而使其链增长。
下述实施例详述本发明。
实施例1
1α,25-二单元基-20,26,27-三甲基-23-氧维生素D3
a.冰冷条件下向213mg氢化钠(80%于油中)的42ml无水THF悬浮体中滴加4.5g1(S)-(叔丁基二甲基甲硅烷氧基)-3-(R)-(叔丁基二苯基甲硅烷氧基)-20(S)-甲酰基-9,10-断孕-5E,7E,10(19)-三烯的40ml无水THF溶液。加1.18ml碘甲烷后室温搅拌2小时,倒入水中用乙酸乙酯萃取。
浓缩所得粗产物放入400ml甲苯中,加432mg蒽和0.2ml三乙胺后室温下在烟幕装置(Pyrex-Glas)中用水银高压灯(Philips HPK 125)照射20分钟。反应液浓缩后剩余物用硅胶(己烷/乙酸乙酯)色谱提纯而得2.38gl(S)-(叔丁基二甲基甲硅烷氧基)-3(R)-(叔丁基二苯基甲硅烷氧基)-20-甲酰基-20-甲基-9,10-断孕-5Z,7E,10(19)-三烯,为无色油状。1H-NMR(COCl3,300MHz):δ=0.52ppm(S,3H,H-18);4.23(m,1H,H-3);4.46(m,1H,H-1);4.85和5.21(m,je 1H,H-19);6.04和6.11(d,J=11Hz,je 1H,H-6和H-7);7.66(s,1H,CH3)。
b.向2.35g步骤a所得醛的25mlTHF和25ml甲醇溶液中滴加1.41gCeCl3(水合物)的25ml甲醇液。加91mg硼氢化钠后25℃搅拌90分钟,然后倒入水中并用乙酸乙酯萃取。再用硅胶(己烷/乙酸乙酯)色谱提纯而得1.86g1(S)-(叔丁基二甲基甲硅烷氧基)-20-羟甲基-20-甲基-9,10-断孕-5Z,7E,10(19)-三烯,为无色油状。
c.由10.1ml的25%NaOH,2.74ml溴乙酸叔丁酯,1.6g步骤所得醇在25ml甲苯和48mg四丁铵硫酸氢盐组成的中间相体系50-60℃搅拌6小时。冷却后用甲苯稀释,分出甲苯后用水洗涤,Na2SO4干燥后浓缩。硅胶(己烷/乙酸乙酯)色谱提纯而得830mg1(S)-(叔丁基二甲基甲硅烷氧基)-3(R)-(叔丁基二苯基甲硅烷氧基)-20-(叔丁氧羰基甲氧甲基)-20-甲基-9,10-断孕-5Z,7E,10(19)-三烷,为黄色油状。
d.用490mg镁(屑)和1.5ml溴甲烷在13ml无水THF中以常规方法制成镁有机化合物。滴加810mg步骤c中得到的叔丁酯后室温搅拌3小时。反应液倒入NH4Cl溶液中处理后用乙酸乙酯萃取。
e.浓缩所得油状粗产物溶于15mlTHF中,加1.3g四丁铵氟化物后50℃搅拌2小时。常规方法处理后用中性氧化铝(己烷/乙酸乙酯)色谱提纯并且主要成分经异丙醚/乙酸乙酯结晶而得145mg标题化合物,熔点:146-148℃。
1H-NMR(CDCl3,300MHz):δ=0.63ppm(s,3H);0.92(s,3H);1.00(s,3H);3,16(s,2H);3,23(AB-q,J=9μ.7Hz,2H);4.23(m,1H);4.43(m,1H);4.98(m,1H);5.32(m,1H);5.90(d,J=11Hz,1H);6.38(d,J=11Hz,1H).
实施例2
1(S),3(R)-二羟基-20-(5-羟基-5-甲基-己-1E,3E-二烯-1-基)-20-甲基-9,10-断孕-5Z,7E,10(19)-三烯
PCT申请WO 91/00855所述反应顺序用2.12g例1a中所得醛进行,其中用甲氧羰基三苯基正磷进行Wittig反应,用二异丙基铝氢化物还原,用吡啶鎓二铬酸盐氧化,再用甲氧羰基三苯基磷进行Wittig烯化,将所得酯与甲基锂反应并用四丁铵氟化物脱保护基而得600mg题示化合物,为无色油状。
[α]D-65,5°(CDCl3,C=0.525).
1H-NMR(CDCl3,300MHz):δ=0.57ppm(s,3H);1.04(s,3H);1.09(s,3H);1,34(s,6H);4,23(m,1H);4.43(m,1H);4.98(m,1H);5.32(m,1H);5.72(d,J=15Hz,1H);5,87(d,J=10Hz,1H);5.88(dd,J=15u,10Hz,1H);6.00(d,J=11Hz,1H);6.19(dd,J=15u,10Hz,1H);6.37(d,J=11Hz,1H).
实施例3
(5Z,7E)-(1S,3R)-20-羟甲基-20-甲基-9,10-断孕-5,7,10(19)-三烯-1,3-二醇
在实施例1e条件下将实施例1b所得醇脱甲硅烷基醚可得题示化合物,熔点183-185℃。
1H-NMR(CDCl3+DMSO-d6,300MHz):δ=0.22,0.46 und 0.58ppm(3 xs,je 3H,H-18u.20-methyl);3.73(m,1H,H-3);3.95(m,1H,H-1);4.49 und 4.90(2 xs,je 1H,H-19);5.62 und 5.87(2 xd,J=11Hz,je 1H,H-6 und H-7).
实施例4
(5Z,7E)-(1S,3R)-20-甲基-20-乙烯基-9,10-断孕-5,7,10(19)-三烯-1,3-二醇
将实施例1a所述醛与亚甲三苯基正磷反应后按实施例1e脱甲硅烷基醚而得题示化合物,熔点139-142℃〔α〕D-23.9°(CHCl3,C=0.255)。
1H-NMR(CDCl3,300MHz):δ=0.57ppm(s,3H,H-18);1.03u.1.08(2xs,je 3H,20-methyl);4.22(m,1H,H-3);4.43(m,1H,H-1);4.82-4.93(m,2H,vinyl-CH2);4.99 u.5.32(2xs,Je 1H,H-19);5.93-6.05(m,2H,H-6 und vinyl-CH);6.37(d,J=11Hz,1H,H-7).
实施例5
(5Z,7E)-(1S,3R)-20-乙基-20-甲基-9,10-断孕-5,7,10(19)-三烯-二醇
将例1a所得醛同系化(如按M.J.Calverley Synlett1990,155进行)后按例1b还原,将这样得到的醇转化成相应碘化物(如按G.L.Lange和C.Gottardo,Synth,Commun,1990,20,1473),在THF中用LiAlH4还原碘化物后脱甲硅烷基醚而得题示化合物。1H-NMR(CDCl3,300MHz):δ=0.64ppm(s,3H,H-18);0.87 u.0.93(2xs,je 3H,20-methyl);4.23(m,1H,H-3);4.42(m,1H,H-1);5.01 u.5.34(2xs,je 1H,H-19);6.01 u.6.39(2xd,J=11Hz,je 1H,H-6 u.H-7).
实施例6
1α,25-二羟基-20-甲基-23-脱氢维生素D3
将例1a所述醛同系化(如按Synlett 1990,155进行),用二甲基膦乙酸甲酯将所得同系醛Wittig-Horner烯化(NaH,THF),在THF中将甲基镁溴化物与所得不饱和酯反应并脱甲硅烷基醚而得无色油状题示化合物。
1H-NMR(CDCl3,300MHz):δ=0.64ppm(s,3H,H-18);0.89 u.0.95(2xs je 3H,20-methyl);1.33(s,6H,25-methyl);4.23(m,1H,H-3);4.43(m,1H,H-1);5.00 u,5.33(2xs,je 1H,H-19);5.55-5.72(m,2H,H-23 u.H-24);6.00 u.6.38(2 xd,J=11Hz,je,1H,H-6 u.H-7).
实施例7
1α,25-二羟基-20-甲基-24-氧维生素D3
将例1a所述醛同系化(如按Synlett 1990,155进行),用二乙基膦乙氧乙酸乙酯进行Wittig-Horner烯化(按W.Grell和H.Machleiteidt,Liebigs Ann Chem.699,53,1966),加甲基镁溴化物,脱烯醇醚(70%)乙酸)并脱甲硅烷基醚保护基而得题示化合物,熔点141-144℃。〔α〕D
+14.7°(CHCl3,c=0.505).1H-NMR(CDCl3,300MHz):δ=0.65ppm(s,3H,H-18);0.90 u.0.98(2xs,je 3H,20-methyl);1.40(s,6H,25-methyl);4.23(m,1H,H-3);4.44(m,1H,H-1);5.00 u.5.33(2xbreites s,je 1H,H-19);6.01 u.6.38(2xd,J=11Hz,je 1H,H-6 u.H-7).
Claims (7)
3、1α,25-二羟基-20,26,27-三甲基-23-氧维生素D3,1(S),3(R)-二羟基-20-(5-羟基-5-甲基己-1E,3E-二烯-1-基)-20-甲基-9,10-断孕-5Z,7E,10(19)-三烯,
1α,-25-二羟基-20-甲基维生素D3,
1α,25-二羟基-20-甲基-24-高维生素D3,
1α,24-(S)-二羟基-20-甲基维生素D3,
1α,25-二羟基-20-甲基-23-氧维生素D3,
1α,24(R),25-二羟基-20-甲基维生素D3,
1α,24(S),25-三羟基-20-甲基维生素D3,
1α,25-二羟基-20-甲基-24-氧维生素D3,
(5Z,7E)-(1S,3R)-20-甲基-20-乙烯基-9,10-断孕-5,7,10(19)-三烯-1,3-二醇,
(5Z,7E)-(1S,3R)-20-乙基-20-甲基-9,10-断孕-5,7,10(19)-三烯-1,3-二醇,
(5Z,7E)-(1S,3R)-20-羟甲基-20-甲基-9,10-断孕-5,7-10(19)-三烯-1,3-二醇,
1α,25-二羟基-20-甲基-23-脱氧维生素D3和
1α,25-二羟基-20,26,27-三甲基-23-脱氢维生素D3。
6、药剂,其特征是其中含至少一种权利要求1-3的化合物和药用载体。
7、权利要求1-3的化合物在药剂制造过程中的应用。
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DE4141746A DE4141746A1 (de) | 1991-12-13 | 1991-12-13 | 20-methyl-substituierte vitamin d-derivate |
DEP4141746.1 | 1991-12-13 |
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CN1073677A true CN1073677A (zh) | 1993-06-30 |
CN1035177C CN1035177C (zh) | 1997-06-18 |
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US (1) | US5446035A (zh) |
EP (1) | EP0637299B1 (zh) |
JP (1) | JP3280975B2 (zh) |
KR (1) | KR100271462B1 (zh) |
CN (1) | CN1035177C (zh) |
AT (1) | ATE138366T1 (zh) |
AU (1) | AU670585B2 (zh) |
CA (1) | CA2125476C (zh) |
CZ (1) | CZ286579B6 (zh) |
DE (2) | DE4141746A1 (zh) |
DK (1) | DK0637299T3 (zh) |
ES (1) | ES2089585T3 (zh) |
FI (1) | FI108226B (zh) |
GR (1) | GR3020097T3 (zh) |
HU (1) | HUT68263A (zh) |
IL (1) | IL104074A (zh) |
MX (1) | MX9207101A (zh) |
NO (1) | NO305949B1 (zh) |
NZ (1) | NZ246052A (zh) |
PL (1) | PL171403B1 (zh) |
SK (1) | SK280450B6 (zh) |
TW (1) | TW275060B (zh) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1049653C (zh) * | 1993-11-24 | 2000-02-23 | 弗·哈夫曼-拉罗切有限公司 | 维生素d3类似物及含它的药物组合物 |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4220757A1 (de) * | 1992-06-24 | 1994-01-05 | Schering Ag | Derivate in der Vitamin D-Reihe mit Modifikationen in der 20-Position, Verfahren zu ihrer Herstellung, Zwischenprodukte für dieses Verfahren, diese Derivate enthaltende pharmazeutische Präparate sowie deren Verwendung zur Herstellung von Arzneimitteln |
GB9220272D0 (en) * | 1992-09-25 | 1992-11-11 | Leo Pharm Prod Ltd | Chemical compounds |
IL107185A (en) * | 1992-10-06 | 1998-02-22 | Schering Ag | History of 52-carboxylic acid, processes for their preparation and pharmaceutical preparations containing them |
US6407082B1 (en) * | 1996-09-13 | 2002-06-18 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of a vitamin D compound |
US20040167106A1 (en) * | 1993-06-04 | 2004-08-26 | Rodriguez Gustavo C. | Prevention of ovarian cancer by administration of a Vitamin D compound |
GB9315253D0 (en) * | 1993-07-23 | 1993-09-08 | Res Inst Medicine Chem | Chemical compounds |
US5981597A (en) * | 1995-02-13 | 1999-11-09 | Trustees Of The University Of Pennsylvania | Differentiating agents for the treatment of inflammatory intestinal diseases |
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DE19619036A1 (de) | 1996-04-30 | 1997-11-13 | Schering Ag | Neue Vitamin D-Derivate mit carbo- oder heterocyclischen Substituenten an C-25, Verfahren zu ihrer Herstellung und die Verwendung zur Herstellung von Arzneimitteln |
SG70010A1 (en) * | 1996-05-23 | 2000-01-25 | Hoffmann La Roche | Fluorinated vitamin d3 analogs |
US6511970B1 (en) | 1996-09-13 | 2003-01-28 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of products that induce transforming growth factor-beta and/or apoptosis in the ovarian epithelium |
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US6034074A (en) | 1996-09-13 | 2000-03-07 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of a Vitamin D compound |
DE69814109T2 (de) * | 1997-09-08 | 2004-02-26 | F. Hoffmann-La Roche Ag | 1,3-dihydroxy-20,20-dialkyl-vitamin d3 analoga |
ES2368824T3 (es) | 1998-03-27 | 2011-11-22 | Oregon Health & Science University | Vitamina d y sus análogos en el tratamiento de tumores y otros desórdenes hiperproliferativos. |
US20030188756A1 (en) * | 2002-08-19 | 2003-10-09 | Cantorna Margherita T | Treatment of inflammatory bowel disease with vitamin d compounds |
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US6358939B1 (en) | 1999-12-21 | 2002-03-19 | Northern Lights Pharmaceuticals, Llc | Use of biologically active vitamin D compounds for the prevention and treatment of inflammatory bowel disease |
US20010044431A1 (en) * | 2000-03-21 | 2001-11-22 | Rodriguez Gustavo C. | Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium |
WO2002013832A1 (fr) * | 2000-08-17 | 2002-02-21 | Chugai Seiyaku Kabushiki Kaisha | Agent therapeutique destine au traitement de l'osteoporose |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1049653C (zh) * | 1993-11-24 | 2000-02-23 | 弗·哈夫曼-拉罗切有限公司 | 维生素d3类似物及含它的药物组合物 |
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