CN1090573A - 维生素d3同型物 - Google Patents
维生素d3同型物 Download PDFInfo
- Publication number
- CN1090573A CN1090573A CN93114532A CN93114532A CN1090573A CN 1090573 A CN1090573 A CN 1090573A CN 93114532 A CN93114532 A CN 93114532A CN 93114532 A CN93114532 A CN 93114532A CN 1090573 A CN1090573 A CN 1090573A
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- CN
- China
- Prior art keywords
- compound
- formula
- phenyl
- independently
- alkyl
- 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
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- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 206010020718 hyperplasia Diseases 0.000 claims abstract description 11
- 208000015390 Sebaceous gland disease Diseases 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 29
- -1 butyl dimethylsilyl Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000005466 alkylenyl group Chemical group 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 9
- 206010000496 acne Diseases 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
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- 206010039793 Seborrhoeic dermatitis Diseases 0.000 claims description 7
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 7
- 208000008742 seborrheic dermatitis Diseases 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000006303 photolysis reaction Methods 0.000 claims description 6
- 230000003595 spectral effect Effects 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 3
- 238000003672 processing method Methods 0.000 claims 3
- FCKFHVFZPCZMDQ-UHFFFAOYSA-N hexyl(dimethyl)silane Chemical compound CCCCCC[SiH](C)C FCKFHVFZPCZMDQ-UHFFFAOYSA-N 0.000 claims 1
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- 150000002431 hydrogen Chemical class 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
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- 238000003756 stirring Methods 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
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- 239000001301 oxygen Substances 0.000 description 13
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- 239000000047 product Substances 0.000 description 11
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 230000000699 topical effect Effects 0.000 description 6
- 241000699800 Cricetinae Species 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
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- 235000019359 magnesium stearate Nutrition 0.000 description 5
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- 125000003118 aryl group Chemical group 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical class CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000004278 EU approved seasoning Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 description 3
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- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- JPVUWCPKMYXOKW-UHFFFAOYSA-N 4-phenylbenzoyl chloride Chemical compound C1=CC(C(=O)Cl)=CC=C1C1=CC=CC=C1 JPVUWCPKMYXOKW-UHFFFAOYSA-N 0.000 description 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
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Abstract
式I化合物,其R1和R2是氢或酰基,条件是R1
和R2中只有一个是氢,可以用于治疗过度增生性皮
肤病和皮脂腺疾病。
Description
本发明涉及式Ⅰ化合物:
式中,R1和R2是氢或酰基,条件是R1和R2中只有一个是氢。
本发明进一步涉及使用上述化合物作为治疗活性剂和使用所说的化合物制造治疗过度增生性皮肤病(如牛皮癣)和皮脂腺疾病(如痤疮和皮脂溢性皮炎)的医药。本发明还涉及一种含有效量式Ⅰ化合物的组合物以及制备式Ⅰ化合物的方法,还涉及制备如下定义的式Ⅳ、Ⅵ、Ⅶ、Ⅷ和Ⅸ的中间体的方法。
本文使用的术语“酰基”,指式R3CO-基团,其中R3是低级烷基或芳基(可以被选自低级烷基、芳基、烷氧基和酰氧基中的一个或多个基团所取代或未取代)。术语“低级烷基”,指含1-4个碳原子的直链或支链烷基,如甲基、乙基、丙基、异丙基和丁基。术语“芳基”指由芳烃衍生的基团。上述化合物能促使人体角质细胞的分化并减少其增殖,因此可以用作治疗过度增生性皮肤病(如牛皮癣、基底细胞癌)、角质化疾病和角化病的药物,它们也可以用作治疗皮脂腺疾病(如痤疮或皮脂溢性皮炎)的药物。
式Ⅰ化合物中,R1优选酰基,最好是R3CO,其中R3是低级烷基或芳基,而且R2是氢或乙酰基。本发明的优选式Ⅰ化合物包括(3β,5Z,FE)-9,10-断胆甾-5,7,10(19),16-四烯-23-炔-3,25-二醇二乙酸酯和(3β,5Z,7E)-9,10-断胆甾-5,7,10(19),16-四烯-23-炔-3,25-二醇3-(4-苯基)苯甲酸酯。
式Ⅰ化合物可以按下面在反应路线Ⅰ-Ⅳ中所述方式制备:
路线Ⅰ
式中R4、R5和R6各自独立地是C1-C6烷基或苯基。
在路线Ⅰ中,式Ⅱ化合物(已知化合物)通过与例如三烷基氯代硅烷(如一氯二甲基己基硅烷)在非质子有机溶剂中,(如二氯甲烷)在碱(如咪唑)存在下反应,被转化为式Ⅲ化合物。式Ⅲ化合物与亚乙基三苯膦在非质子有机溶剂(如甲苯)中反应生成相应的式Ⅳ化合物。
式中,R7、R8和R9各自独立地是C1-C6烷基或苯基。
在路线Ⅱ中,3-羟基-3-甲基丁炔(已知化合物)通过与例如叔丁基二甲基氯代硅烷在N,N-二甲基甲酰胺和咪唑的混合物中反应转化为式Ⅴ化合物。该化合物Ⅴ通过与正丁基锂和N,N-二甲基甲酰胺在无水THF中反应转化为相应的化合物Ⅵ。
其中,R4、R5、R6、R7、R8和R9各自独立地是C1-C6烷基或苯基;X是C(S)R10,而R10是咪唑-1-基、-NHph,-oph、-N(CH3)2或-SCH3。
在路线Ⅲ中,化合物Ⅳ通过在路易斯酸(二甲基铝氯化物)存在下于非质子有机溶剂(如己烷)中与化合物Ⅵ反应转化为相应的化合物Ⅶ;化合物Ⅶ通过与例如1,1′-硫代羰基二咪唑、氯代碳羰甲酸苯酯、二甲基硫代氨甲酰氯、二硫化碳或(最好)异硫代氰酸苯酯在非质子溶剂(如THF)中和碱(如氢化钠)存在下反应,被转化成化合物Ⅷ。化合物Ⅷ通过与例如氢化三丁基锡在非质子有机溶剂(如己烷)中在游离基引发剂[如2,2′-偶氮双(2-甲基丙腈)]存在下反应,被转化成相应的化合物Ⅸ。该化合物Ⅸ在THF中与氟化物盐(如四丁基氟化铵)反应生成化合物Ⅹ。
其中R1和R2各自独立地是氢或酰基。
式Ⅰ化合物可以制取如下:使化合物Ⅹ酰化生成式Ⅺ化合物,然后使之光解和热异物化。所说的光解过程优选使用中压汞灯进行,为了阻挡大约290-320nm的光,此过程中应存在有4-烷基氨基苯甲酸酯(如4-二甲氨基苯甲酸乙酯)作为滤光器。另外,此式Ⅰ化合物也可以制取如下:使化合物Ⅹ经历上述的光解和热异物化生成化合物Ⅶ,然后用例如4-苯基苯甲酰氯或乙酐在非质子传递溶剂(如二氯甲烷)中于碱(如三乙胺)存在下酰化。
式Ⅰ化合物可以给需要这种治疗的温血动物口服给药,以治疗过度增生性皮肤病(如牛皮癣、基底细胞癌、角质化疾病和角化病)。更具体讲,可以给成年人口服给药大约0.1-1000μg/天(优选约7-70μg/天)剂量的式Ⅰ化合物作此治疗。治疗人体痤疮时,可以口服给药大约0.7-700μg/天(优选7-70μg/天)剂量的式Ⅰ化合物。
式Ⅰ化合物可以给需要这种治疗的温血动物局部给药,以便治疗过度增生性皮肤病(如牛皮癣、基底细胞癌、角质化疾病和角化病)或治疗皮脂腺疾病(如痤疮或皮脂溢性皮炎)。更具体讲,可以局部给药的剂量大约为1-1000μg式Ⅰ化合物/克局部制剂/天作这种治疗用。
式Ⅰ化合物作为治疗过度增生性皮肤病治疗剂的有用活性,可以用下面的人体角质细胞抗增生试验加以证明:用标准操作方法从新生的包皮上皮的角质细胞获得细胞培养物;将此细胞置于6排孔多孔板的孔中,每孔置25,000个细胞;24小时之后,给细胞供给角质细胞生长介质(补充到1.5mm CaCl2,并含试验化合物或赋形剂)。制备了试验化合物的乙醇溶液,试验了四种浓度下的试验化合物,每种浓度在三个孔中平行三份。对照孔中只补充最高浓度(如0.1%乙醇溶液)的赋形剂。试验终止时,用电子细胞计数器数细胞数目,此计数器定期校准角质细胞的尺寸。按所使用的稀释因数计算细胞数目,结果用与对照培养液中得到的细胞数相比的抑制百分数表示。对于(3β,5Z,7E)-9,10-断胆甾-5,F,10(19),16-四烯-23-炔-3,25-二醇二乙酸酯而言,ED50(抑制该细胞的50%增生所需的有效剂量)为0.3μM。
在<皮肤病学研究杂志>(Journal of Investigative Dermatology)92,(1989)475上披露了使用1α,25-二羟基胆钙化甾醇作为降低雄性锡兰仓鼠耳中皮脂腺尺寸的药剂。式Ⅰ化合物作为治疗痤疮或皮脂溢性皮炎等皮脂腺疾病药剂的有用活性,可以通过评价其口服给药该化合物后对该仓鼠耳皮脂腺的影响加以证明。将200μl本发明化合物溶解在丙二醇中作为日剂量,给雄性锡兰仓鼠给药(每周五天)。四周后将试验动物杀死,处置仓鼠耳作组织学评定。用图像分析法对组织学上制备的耳横断面测量皮脂腺的面积。由此试验获得的数据汇于下表中:
化合物 剂量 仓鼠耳皮脂腺断面
μM/Kg/天 尺寸分析时的变化(%)
(3β,5Z,7E)-9,10-断 0.105 -20
胆甾-5,7,10(19),16 1.05 -27
-四烯-23-炔-3,25- 10.5 -31
二醇3-(4-苯基)苯甲酸脂 105 -40
(3β,5Z,7E)-9,10-断 0.150 -18
胆甾-5,7,10(19),16 1.5 -28
-四烯-23-炔-3,25- 15.0 -37
二醇二乙酸脂 150 -42
上面的数据证明:本发明化合物可以用作治疗痤疮或皮脂溢性皮炎等皮脂腺疾病的药剂。
包含式Ⅰ化合物的口服剂形,可以与药学上可接受的载体物质共同掺入胶囊或片剂等之中。这种载体物质的代表性实例,是粘合剂(如黄蓍树胶、阿拉伯胶、玉米淀粉或明胶)、赋形剂(如磷酸氢二钙、崩解剂(如玉米淀粉、土豆淀粉和藻酸)、润滑剂(如硬脂酸镁)、增甜剂(如蔗糖、乳糖或糖精)、调味剂(如薄荷、青油或樱桃油)。各种其它物质也可以作为包衣使用或者用于改变该剂量单位的外形。例如,片剂可以用虫胶和/或糖包衣。糖浆剂或酏剂可以含所说的活性化合物、蔗糖(作增甜剂)、对羟基苯甲酸甲酯和丙酯(作为防腐剂)、染料和调味剂(如樱桃或橙调味剂)。
含式Ⅰ化合物的局部剂形,包括:软膏和霜剂,其中包括石油、含水羊毛脂和聚乙酯等含油的吸附性、水溶性和乳液形基质。洗剂是一些液体制剂,其中包括从简单溶液至含有充分分散物质的水剂或水醇制剂。洗剂可以含有悬浮剂或分散剂。例如乙基纤维素甲基纤维素之类的纤维素衍生物,明胶或树胶(它们使活性成分结合到由水、醇或甘油组成的赋形剂之中)。凝胶是利用在载体赋形剂中使活性成分溶液或悬浮液胶凝的方法制备的半固体制剂。使用羧基聚乙烯(Carboxy polymethylene)等使所说的赋形剂(水质或非水质的)胶凝后,用氢氧化钠和胺(如聚乙烯可可胺)之类碱中和到适当的凝胶稠度。本文所用的术语“局部的”指在发炎处施用被渗入适当药物载体中的活性成分,对局部产生作用。因此,局部组合物包括那些利用与皮肤直接接触在外部施用所说化合物的药物制剂。这种局部剂形包括凝胶、霜剂、洗剂、软膏、粉剂、气雾剂和其它施药于皮肤上的传统剂形,这些制剂是利用将式Ⅰ化合物与已知的药物局部用载体物质混合而制的。除了施药于皮肤上之外,本发明的局部组合物还可以用于治疗粘膜的炎症,但是被处置的粘膜应当是能局部施药的。例如,此局部组合物可以施于口或下部结肠的粘膜外层之上。
实施例1
将149.9克(3β)-3-羟基雄甾-5,7-二烯17-酮和56.9克咪唑在500ml二氯甲烷中形成的混合物冷却到3℃后,滴加144ml二甲基己基氯代硅烷并保持温度低于6℃。室温下搅拌过夜后,水洗该混合物,水层用二氯甲烷萃取。有机层用饱和的NaHCO3水液洗涤后,干燥和浓缩之。将得到的固体悬浮在700ml其中含14ml三乙胺的甲醇中,回流20分钟。冷却后,过滤沉淀,经甲醇-水(9∶1)洗涤,干燥得出185.1克(3β)-3-[[(1,1,2-三甲基丙基)二甲基硅烷基]氧]雄甾-5,7-二烯-17-酮。mp119-125℃。
实施例2
240.2克(乙基)三苯磷溴化物、72.5克叔丁醇钾和1升甲苯的混合物搅拌1小时后,加入185克实施例1的产品和50ml甲苯,保持温度低于25℃。搅拌过夜后,用24.5ml乙酸熄灭反应。搅拌后,过滤除去固体,用甲苯洗涤。浓缩滤液和洗液,加入200ml甲醇,再次浓缩混合物。将残余物溶解在由650ml甲醇、65ml水和650ml己烷组成的混合物中,用325ml己烷萃取此甲醇一水层。浓缩合并的己烷层。然后,加入200ml甲醇,再次浓缩此混合物。将得到的固体悬浮在含8ml三乙胺的800ml甲醇中,回流此悬浮液。冷却过夜后,过滤沉淀,用甲醇洗涤,干燥后得出178.1克(3β,17Z)-(1,1,2-三甲基丙基)(孕甾-5,7,17(20)-三烯-3-基-氧)二甲基硅烷,mp94-97℃,[α]D-62.8°(浓度:0.94,乙醇)。
实施例3
a)在-70℃,向50.0克(1,1-二甲基乙基[(1,1-二甲基-2-丙炔基)氧]二甲基硅烷在200ml THF中的溶液内,滴加112ml 2.5M丁基锂己烷溶液,并保持温度低于-55℃。搅拌此混合物后滴加50mlDMF。然后加入32ml乙酸熄灭反应。混合物温热至-20℃后,加入200ml己烷和200ml水。水层用己烷萃取。合并的有机层先后用饱和NH4Cl水液和盐水洗涤。干燥后,将溶液蒸干。从残余物中蒸馏得出48.8克4-[[(1,1-二甲基乙基)-二甲基硅烷基]氧]-4-甲基-2-戊炔/醛,b.p.50℃(0.5mm Hg)。
b)将由57.65克((3β,17Z)-(1,1,2-三甲丙基)(孕甾-5,7,17(20)-三烯3-3基氧)二甲基硅烷、34.11克实施例3a)的产物和800ml己烷形成的混合物冷却到大约-40℃。然后滴加185ml1M二甲基氯化铝的己烷液。-40℃下搅拌后,滴加400ml 5%(W/V)磷酸氢二钠水液,将混合物温热至5℃。然后在0-5℃下滴加300ml3NHCl,接着加入40克硅藻土。过滤固体,用己烷洗涤。水层用己烷萃取。合并己烷液,依次用水、10%NaHCO3水液和盐水洗涤。己烷层干燥后浓缩得出90克粗品(3β)-25-[[(1,1-二甲基乙基)二甲基硅烷基]氧]-3-[[二甲基(1,1,2-三甲基丙基)硅烷基]氧]胆甾5-7,16-三烯-23-炔-22-醇(5∶1的C22位差向异物体混合物),此物质用于下一步骤之中。
实施例4
将氢化钠(60%分散液,6.55克)悬浮在200ml THF中后,5℃下加入446mg咪唑。在8-10℃下向此悬浮液中滴加93克(3β)-25-[[(1,1-二甲基乙基)二甲基硅烷基]氧]-3-[[二甲基(1,1,2-三甲基丙基)硅烷基]氧]胆甾-5,7,16-三烯-23-炔-22-醇在700ml THF中的溶液。形成的悬浮液搅拌后,加入17.3ml异硫代氰酸苯酯的THF溶液,并在10℃下搅拌此混合物。滴加500ml 10%NaHCO3水液熄灭此反应后,加入70克硅藻土。搅拌后,滤出固体用乙酸乙酯洗涤。水层用乙酸乙酯萃取。合并有机层,依次用10%NaHCO3水液和盐水洗涤,干燥后浓缩至干。将132克此残余物溶解在3%乙酸乙酯的己烷溶液中,用硅胶过滤,以除去一些杂质。硅胶用3%乙酸乙酯的己烷溶液洗涤。收集流出液后浓缩压干,得出粗品苯基氨基硫代甲酸的邻-[(3β)-25-[[(1,1-二甲基乙基)二甲基硅烷基]氧]-3[[二甲基(1,1,2-三甲基丙基)硅烷基]氧]胆甾-5,7,16-三烯-23-炔-22-基]酯,此物质用于下步操作。
实施例5
在80℃,向由70.5ml三丁基锡氢化物和1.08克2,2′-偶氮双(2-甲基丙腈)(AIBN)在50ml己烷中组成的混合物内,加入117克实施例4中产物于1.5升己烷中的溶液。回流之后,加入35ml氢化三丁基锡和1.07克AIBN。回流之后,将混合物冷却至室温并搅抖之。过滤沉淀,浓缩滤液。残余物溶解在己烷中后经硅胶过滤。硅胶柱用己烷淋洗后,用20%甲苯的己烷液淋洗。合并含产物的馏分,经浓缩得出114克粗品[[(3β)-25-[[(1,1-二甲基乙基)二甲基硅烷基]氧]胆甾-5,7,16-三烯-23-炔-3-基]氧]二甲基(1,1,2-三甲基丙基)硅烷,此物质用于下一步操作。分析样品是经色谱提纯后用乙酸乙酯-甲醇(1∶1)结晶得到的,mp62-66℃。
实施例6
向114克实施例5的产品在500ml THF中的溶液内加入200克氟化四丁铵水合物和500ml THF。搅拌后,混合物用500ml乙酸乙酯和500ml 10%氯化铵水液稀释;水层用乙酸乙酯萃取。有机层依次用10%氯化铵水液、水和盐水洗涤,再加以干燥和浓缩。形成的悬浮液搅拌后,贮存在冰箱中过夜。滤出固体,用乙酸乙酯洗涤后干燥之。将产物悬浮于甲醇中,回流此混合物。然后滴加水。悬浮液在60℃下搅拌后贮存在冰箱中过夜。滤出沉淀,用50%甲醇水液洗涤,45℃干燥,得出25.4克(3β)-胆甾-5,7,16-三烯-23-炔-3,25-二醇,mp185-192℃。
实施例7
向75.3克(3β)-胆甾-5,7,16-三烯-23-炔-3,25-二醇在450ml二氯甲烷中的冷悬浮液内,加入107ml乙酐和160ml三乙胺。悬浮液冷却到2℃后,加入4.6克4-二甲基氨基吡啶。移走冷浴,混合物室温下搅抖过夜。再用冰-水浴冷却后,加入30.7ml甲醇。混合物在室温下搅拌,水洗,水层用二氯甲烷萃取。合并的有机层用1NHCl洗涤,水层用二氯甲烷萃取。合并有机层,用饱和NaHCO3水液洗涤,干燥,浓缩至干。残余物溶解在95%甲醇中。加入种晶后,将悬浮液贮存在冰箱中。滤出沉淀,用90%甲醇洗涤。干燥后得到了82.5克(3β)-胆甾-5,7,16-三烯-23-炔-3,25-二醇二乙酸酯,mp98-101℃。
实施例8
用一只450瓦的中压灯透过石英浸没管辐照处于-20℃下的由16.4克(3β)-胆甾-5,7,16-三烯-23-炔-3,25-二醇二乙酸酯和1.64克4-二甲氨基苯甲酸乙酯于1.7升甲基叔丁基醚中形成的溶液。光解期间,电弧室持续用缓慢的氮气流冲扫。于0~-20℃下辐照8小时后,将铀滤光片插入该电弧室中后,向溶液中加入66mg9-乙酰基蒽。在0~-20℃下透过此滤光片辐照1小时45分钟后,将溶液温热至室温过夜,之后用3N HCl洗涤。有机层用饱和NaHCO3水液洗涤后干燥之。浓缩此溶液至干,残余油状物用硅胶柱色谱提纯,3升7%的乙酸乙酯之己烷液洗脱。合并所需的馏分,浓缩后得出13克清沏油状物。五次这样的试验由84克(3β)-胆甾-5,7,16-三烯-23-炔-3,25-二醇二乙酸酯共产出65克粗光解产物。该粗品光解产物的乙酸乙酯液回流四小时后,冷却至室温,浓缩之;将残面的半固体状物溶于甲醇中;溶液冷却到室温后贮存于冰箱中过夜。过滤晶状物质,用95%甲醇洗涤。该晶状物干燥后得出33.0克(3β,5Z,7E)-9,10-断胆甾-5,7,10(19),16-四烯-23-炔-3,25-二醇二乙酸酯,mp94-95℃。
实施例9
用450瓦中压灯透过石英浸管辐照处-20℃下的由18.0克(3β)-胆甾-5,7,16-三烯-23-炔-3,25-二醇、3.6克二甲氨基苯甲酸乙酯和1.7升乙醇组成的溶液7小时。在电弧室中插入铀滤光片后,向溶液中加入180mg 9-乙酰基蒽。透过该滤光片在0~-20℃下辐照2小时后,将溶液温热至室温过夜。减压除去溶剂,用甲苯共蒸发除去残余的乙醇。然后,将残余物悬浮在甲苯中。用己烷稀释后,将悬浮液贮存在冰箱之中。滤出沉淀,用甲苯-乙烷(1∶1)洗涤后再用甲苯洗涤。浓缩合并的滤液和洗液,在90~100℃下搅拌得到的溶液,然后冷却至室温。浓缩该溶液至干后,用硅胶柱色谱纯化,经5-10%CH3CN的CH2Cl2液洗脱,得到8.35克(3β,5Z,7E)-9,10-断胆甾-5,7,10(19),16-四烯-23-炔-3,25-二醇,该物质不经提纯直接用于下一步操作之中。
实施例10
向冰冷的、由8.35克(3β,5Z,7E)-9,10-断胆甾-5,7,10(19),16-四烯-23-炔-3,25-二醇、513mg 4-二甲氨基吡啶和5.3ml三乙胺在二氯甲烷中组成的溶液内,加入5.99克(4-苯基)苯甲酰氯。室温下搅拌后,该混合物用二氯甲烷稀释,水洗。水层用二氯甲烷萃取,合并的二氯甲烷层用饱和NaHCO3水液洗涤。每个水层均用二氯甲烷萃取。干燥和浓缩合并的有机层。残余物用硅胶色谱纯化。产物溶于甲醇中,溶液在搅拌下冷却到室温。接着将悬浮液保存在冰箱中。滤出沉淀,用95%甲醇洗涤。固体经干燥得出5.73克(3β,5Z,7E)-9,10-断胆甾-5,7,10(19),16-四烯-23-炔-3,25-二醇3-(4-苯基)苯甲酸酯,mp105-110℃。
实施例11
向处于搅抖下的和冰浴冷却的、25克3-羟基-3-甲基丁炔、50ml无水DMF和44.5克咪唑的混合物中,加入50克叔丁基二甲基氯代硅烷。在冰浴上继续搅拌后,于室温下搅拌过液。加入250mg二甲氨基吡啶后,在70℃下加热反应混合物,然后倒入冷水中,用乙醚萃取。有机萃取液经盐水洗涤后,干燥并蒸发至干。蒸馏提纯此产物,产出3-(叔丁基二甲基硅烷基)氧-3-甲基丁炔。向处于氢气氛中冷却到-78℃的10克3-(叔丁基二甲基硅烷基)氧-3-甲基丁炔在25mlTHF中的溶液内,滴加40ml1.6M N-丁基锂己烷溶液,然后加入31mlDMF。在-78℃下搅拌反应混合物,然后加入冰和倒入盐水中熄灭反应。用戊烷萃取,戊烷萃取液用饱和氯化铵溶液、水和盐水洗涤,干燥并蒸发至干。蒸馏提纯此产物得出8.88克4-(叔丁基二甲基硅烷基)氧-4-甲基戊炔醛。
按照本身已知的方式制备了下列盖仑氏制剂。
实施例A
湿粒剂
成分 mg/片
(3β,5Z,7E)-9,10-断胆甾-
5,7,10(19),16-四烯-23-
炔-3,25-二醇[二乙酸酯或
3-(4-苯基)苯甲酸酯] 0.1 0.5 5.0 5.0
无水乳糖 106.9 106.5 102.0 118.0
微晶纤维素 15.0 15.0 15.0 25.0
改性淀粉 7.0 7.0 7.0 10.0
硬脂酸镁 1.0 1.0 1.0 2.0
130.0 130.0 130.0 160.0
实施例B
胶囊剂
成分 mg/胶囊
(3β,5Z,7E)-9,10-断胆甾
-5,7,10(19),16-四烯-23
-炔-3,25-二醇[二乙酸酯或
3-(4-苯基)苯甲酸酯] 0.1 0.5 5.0 25.0
含水乳糖 168.9 168.5 159.0 123.0
玉米淀粉 20.0 20.0 25.0 35.0
滑石粉 10.0 10.0 10.0 15.0
硬脂酸镁 1.0 1.0 1.0 2.0
200.0 200.0 200.0 200.0
实施例C
片剂(湿粒剂)
成分 mg/片
(3β,5Z,7E)-9,10-断胆甾
-5,7,10(19),16-四烯-23
-炔-3,25-二醇[二乙酸酯或
3-(4-苯基)苯甲酸酯] 25 100 500
无水乳糖 105 30 150
预糊化的淀粉 6 6 30
微晶纤维素 30 30 150
硬脂酸镁 1 1 5
167 167 835
实施例D
胶囊剂
成分 mg/胶囊
(3β,5Z,7E)-9,10-断胆甾
-5,7,10(19),16-四烯-23
-炔-3,25-二醇[二乙酸酯或
3-(4-苯基)苯甲酸酯] 25 100 500
预糊化的玉米淀粉 83 8 40
改性淀粉 4 4 20
滑石粉 4 4 20
硬脂酸镁 1 1 5
117 117 585
Claims (10)
2、根据权利要求1的化合物,其中R1是R3CO,R3是低级烷基或酰基,而且R2是氢或乙酰基。
3、根据权利要求1的化合物,选自(3β,5Z,7E)-9,10-断胆甾-5,7,10(19),16四烯-23-炔-3,25-二醇二乙醇酯和(3β,5Z,7E)-9,10-断胆甾-5,7,10(19),16四烯-23-炔-3,25-二醇3-4(-苯基)苯甲酸酯。
4、一种化合物,其结构由式(Ⅳ)、(Ⅶ)、(Ⅷ)、(ⅩⅢ)或式(Ⅵ)表示:
其中R4、R5和R6各自独立地是C1-C6烷基或苯基,尤其其中R4和R5是甲基而且R6是己基;
其中R4-R9各自独立地是C1-C6烷基或苯基;尤其是其中R4、R5、R7和R8是甲基,R6是己基,R9是叔丁基;
其中R4-R9各自独立地是C1-C6烷基或苯基,而且X是-C(S)R10,其中R10是咪唑-1-基、-NHph、-Oph,-N(CH3)2或-SCH3;尤其是其中R4、R5、R7和R8为甲基,R6是己基,R9为叔丁基且R10是-NHph,并且ph是苯基,
其中R11和R12各自独立地是-Si(R4,R5R6)、氢或酰基,而R4、R5和R6各自独立地是C1-C6烷基或苯基;尤其是其中R11是二甲基己基硅烷基而且R12是叔丁基二甲基硅烷基;或者其中R11和R12是氢;或者其中R11和R12是乙酰基;
其中R7、R8和R9各自独立地是C1-C6烷基或苯基。
5、根据权利要求1、2或3的化合物,用作治疗活性剂,尤其是用于治疗皮肤过度增生性疾病,例如牛皮癣,和用于治疗皮脂腺疾病,例如痤疮和皮脂溢性皮炎。
9、一种药物组合物,尤其是治疗牛皮癣之类皮肤过度增生性疾病和治疗痤疮和皮脂溢性皮炎之类皮脂腺疾病用组合物,它包含有效量的权利要求1之式Ⅰ化合物和药物可按受的载体。
10、使用权利要求1、2或3中的化合物制造用于治疗牛皮癣等皮肤过度增生性疾病和痤疮和皮脂溢性皮类等皮脂腺疾病的药物。
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JPH10316652A (ja) * | 1997-05-02 | 1998-12-02 | Duphar Internatl Res Bv | 16−デヒドロビタミンd化合物の製造方法 |
US8404667B2 (en) * | 2006-12-29 | 2013-03-26 | Wisconsin Alumni Research Foundation | Compounds, compositions, kits and methods of use to orally and topically treat acne and other skin conditions by 19-Nor vitamin D analog |
AU2005303773A1 (en) | 2004-11-12 | 2006-05-18 | Bioxell Spa | Combined use of vitamin D derivatives and anti-proliferative agents for treating bladder cancer |
WO2015115796A1 (ko) | 2014-01-29 | 2015-08-06 | 주식회사 휴메딕스 | 페길레이션된 7-디하이드로콜레스테롤 유도체 |
KR101702076B1 (ko) | 2015-02-25 | 2017-02-02 | 주식회사 휴메딕스 | 지방산 컨쥬게이션된 7-데하이드로콜레스테롤 유도체 |
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US3970676A (en) * | 1974-10-29 | 1976-07-20 | The Upjohn Company | Novel process and intermediate compounds used is preparation of -Δ5,7- steroid dienes |
US4116985A (en) * | 1976-07-26 | 1978-09-26 | The Upjohn Company | Novel method for preparing cholesta-5,7-diene 3β,25-diol and derivatives thereof |
US4360471A (en) * | 1981-12-11 | 1982-11-23 | Wisconsin Alumni Research Foundation | 23-Dehydro-25-hydroxyvitamin D3 |
US4456553A (en) * | 1982-05-07 | 1984-06-26 | Teijin Limited | Vitamin D3 derivatives, process for preparation thereof, and antigens comprising said derivatives to be used for preparation of antibodies for immunochemical assay and antibodies prepared therefrom |
US4448721A (en) * | 1982-09-20 | 1984-05-15 | Wisconsin Alumni Research Foundation | Hydroxyvitamin D2 compounds and process for preparing same |
JPS63264452A (ja) * | 1986-10-20 | 1988-11-01 | Sumitomo Pharmaceut Co Ltd | フッ素化ビタミンd↓3誘導体 |
WO1988007545A1 (en) * | 1987-03-30 | 1988-10-06 | Kuraray Co., Ltd. | Pregnane derivatives and process for their preparation |
US5087619A (en) * | 1988-01-20 | 1992-02-11 | Hoffman-La Roche Inc. | Vitamin D3 analogs |
ZA8923B (en) * | 1988-01-20 | 1989-09-27 | Hoffmann La Roche | 16-dehydro-vitamin d3-derivatives |
US5145846A (en) * | 1988-01-20 | 1992-09-08 | Hoffmann-La Roche Inc. | Vitamin D3 analogs |
US4804502A (en) * | 1988-01-20 | 1989-02-14 | Hoffmann-La Roche Inc. | Vitamin D compounds |
WO1990000560A1 (fr) * | 1988-07-05 | 1990-01-25 | Kuraray Co., Ltd. | Composes steroidiques |
US4973584A (en) * | 1989-03-09 | 1990-11-27 | Deluca Hector F | Novel 1α-hydroxyvitamin D2 epimer and derivatives |
NZ232734A (en) * | 1989-03-09 | 1991-11-26 | Wisconsin Alumni Res Found | 19-nor vitamin d derivatives and pharmaceutical compositions |
CA1333616C (en) * | 1989-03-09 | 1994-12-20 | Hector F. Deluca | 19-nor-vitamin d compounds |
ATE99942T1 (de) * | 1989-05-18 | 1994-01-15 | Hoffmann La Roche | Dehydrocholecalciferolderivate. |
JPH04505332A (ja) * | 1989-09-11 | 1992-09-17 | ウイスコンシン アラムナイ リサーチ フオンデーシヨン | エイズウイルスの複製を抑制するビタミンd化合物の新規な用途 |
CZ280203B6 (cs) * | 1990-02-06 | 1995-11-15 | Schering Aktiengesellschaft | Deriváty vitaminu D s homology bočního řetězce a způsob jejich výroby |
DE4101953A1 (de) * | 1991-01-19 | 1992-07-23 | Schering Ag | 23-oxa-derivate in der vitamin-d-reihe, verfahren zu ihrer herstellung diese derivate enthaltende pharmazeutische praeparate sowie deren verwendung als arzneimittel |
DE4105503A1 (de) * | 1991-02-19 | 1992-08-20 | Jenapharm Gmbh | Ausgangsverbindungen zur herstellung von calcitriol sowie dessen abkoemmlingen, verfahren zur herstellung dieser ausgangsverbindungen sowie zwischenprodukte fuer dieses verfahren |
US5206230A (en) * | 1991-06-05 | 1993-04-27 | Daikin Industries, Ltd. | Fluorine-containing vitamin D3 analogues and pharmaceutical composition containing the same |
DE69213844T2 (de) * | 1991-07-05 | 1997-04-10 | Duphar Int Res | Vitamin-D Derivat, Verfahren zu dessen Herstellung sowie Zwischenprodukte dafür |
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1993
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- 1993-10-20 CA CA002108848A patent/CA2108848A1/en not_active Abandoned
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- 1993-11-05 DE DE69307478T patent/DE69307478T2/de not_active Expired - Fee Related
- 1993-11-05 ES ES93117951T patent/ES2097423T3/es not_active Expired - Lifetime
- 1993-11-05 AT AT93117951T patent/ATE147728T1/de not_active IP Right Cessation
- 1993-11-12 ZA ZA938478A patent/ZA938478B/xx unknown
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- 1993-11-15 IL IL10761493A patent/IL107614A/en not_active IP Right Cessation
- 1993-11-15 HU HU9303227A patent/HU213609B/hu not_active IP Right Cessation
- 1993-11-15 AU AU50697/93A patent/AU669222B2/en not_active Ceased
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- 1993-11-17 JP JP5311371A patent/JP2502931B2/ja not_active Expired - Lifetime
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- 1993-11-18 KR KR1019930024594A patent/KR940011443A/ko not_active Application Discontinuation
- 1993-11-19 CZ CZ932489A patent/CZ284415B6/cs not_active IP Right Cessation
- 1993-11-19 CN CN93114532A patent/CN1051762C/zh not_active Expired - Fee Related
- 1993-11-19 UY UY23678A patent/UY23678A1/es not_active IP Right Cessation
- 1993-11-19 NO NO934197A patent/NO304022B1/no not_active IP Right Cessation
- 1993-11-19 PL PL93301103A patent/PL176017B1/pl unknown
- 1993-11-19 BR BR9304780A patent/BR9304780A/pt not_active Application Discontinuation
- 1993-11-22 US US08/155,663 patent/US5342833A/en not_active Expired - Lifetime
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1994
- 1994-06-07 US US08/255,012 patent/US5393900A/en not_active Expired - Lifetime
- 1994-11-23 US US08/344,421 patent/US5747478A/en not_active Expired - Lifetime
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1995
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1997
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