CN1045396A - 新的甾二醇,含它们的药物组合物和制备它们的方法 - Google Patents
新的甾二醇,含它们的药物组合物和制备它们的方法 Download PDFInfo
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- CN1045396A CN1045396A CN90101248A CN90101248A CN1045396A CN 1045396 A CN1045396 A CN 1045396A CN 90101248 A CN90101248 A CN 90101248A CN 90101248 A CN90101248 A CN 90101248A CN 1045396 A CN1045396 A CN 1045396A
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- hydrogen
- diketone
- hydroxyls
- pregnane
- pregnant steroid
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- 150000003431 steroids Chemical class 0.000 title claims description 7
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- 238000002360 preparation method Methods 0.000 claims abstract description 15
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- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 150000003128 pregnanes Chemical class 0.000 claims description 16
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 13
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- 238000006243 chemical reaction Methods 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 230000003647 oxidation Effects 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
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- 150000001342 alkaline earth metals Chemical class 0.000 claims description 5
- 229910052728 basic metal Inorganic materials 0.000 claims description 5
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- 239000003814 drug Substances 0.000 claims description 5
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- 229910052736 halogen Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- SNOFKGQEUYMNCE-UHFFFAOYSA-N 2,2,2-trifluoro-1-$l^{1}-oxidanylethanone Chemical compound [O]C(=O)C(F)(F)F SNOFKGQEUYMNCE-UHFFFAOYSA-N 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
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- 239000012043 crude product Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
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- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000002992 thymic effect Effects 0.000 description 2
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- 240000006409 Acacia auriculiformis Species 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
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- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
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- 238000011161 development Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
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- 229960000785 fluocinonide Drugs 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229960002800 prednisolone acetate Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0092—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by an OH group free esterified or etherified
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及新的通式(I)△14-16α,17-羟孕甾烷衍生物,含它们的药物组合物及制备它们的方法。通式(I)结构式中各符号定义及它们的药物组合物和制备它们的方法详见说明书。
Description
本发明涉及通式(Ⅰ)的新△14-16α,17-二羟基孕甾烷衍生物,含生理有效剂量的这些化合物的药用组合物和制备这些化合物及其组合物的方法,
其中:
A代表氢,羟基或三氟乙酰氧基;
X代表氢或卤素,条件是如A为氢,则X也为氢;
R代表氢,苯甲酰基或C1-8烷酰基;和
另外,本发明还涉及使用这些化合物或组合物的治疗方法。
本发明的通式Ⅰ新的△14-16α,17-二羟孕甾烷衍生物具有价值的抗炎作用,
因此它们可用作药物组合物中的活性成份,另一方面,它们也可用于制备其它具有治疗作用的相似甾类衍生物。
本说明书中,卤素是指氟,氯,溴和碘,优选氟或氯;C1-8烷酰基是指甲酰基,乙酰基,丙酰基或任何一种丁酰基,戊酰基,己酰基,庚酰基或辛酰基;除上述基团之外,酰基还包括苯甲酰基。C2-4链烷酸包括乙酸,丙酸,正和异丁酸。
在本发明说明书和权利要求书中,碱金属指锂,钠和钾或它们的阳离子及具有相似功能的铵离子。优选的碱金属是钠和钾。碱土金属为镁,钙,锶和钡。
早于1949年就已知可用可的松成功地治疗类风湿性关节炎患者(L.Fieser和M.Fieser:Steroids,Reinhold Pobl.Co.,poge 650,1967)。但用可的松或氢化可的松进行广泛治疗不久后发现,天然皮质甾类化合物除了具有抗炎作用外,还产生了许多不希望的付作用(这些有害付作用包括盐和水失调疾病,水潴留,骨质疏松,治愈的胃溃疡的复发等)。
通过对可的松和氢化可的松的结构进行多种修饰消除了这些付作用并增强了所需要的抗炎作用。
这些研究工作导致发现了强的松龙、氟烃氢化泼尼松,地塞米松,肤轻松及3-氯孕甾烷衍生物(见匈牙利专利说明书No.182,775)。这些药物的在现代医学中作用直到现在也没有减小。
在我们工作中所合成的衍生物与那些已知化合物相比,具有更优良的效果,现已发现通式(Ⅰ)新的△14-16α,17-二羟孕甾烷衍生物显示出优良
的抗炎作用,而且它们可用做制备其它具有高效抗炎作用类皮质激素的起始物。
本发明另一方面是提供了制备通式(Ⅰ)新化合物的方法,该方法特征在于:在水和选择性丙酮存在下,在C2-4链烷酸介质中,将通式(Ⅱ)的孕甾烷衍生物用碱金属或碱土金属的高锰酸盐
R为氢)。
在本发明的方法中,将羟基引入到16α-和17-位及形成△14双键是在含△16双键的通式(Ⅱ)化合物所进行的一步反应中完成的。由于用高锰酸盐氧化不饱和键的这种转化在文献中从没有谈到过,因此,本发明的这种转化是出人意料的。相似的转化仅在文献(J.Chem.Soc.1955,4383)中报道过,它谈的是氧化3β-乙酰氧孕甾-5,16-二烯-20-酮;在氧化中,除生成3β-乙酰氧-16α,17α-二羟孕甾-5-烯-20-酮外,由于付反应,还生成了14,15-脱氢衍生物。付产物产率是低的并且在上文中没有进行详细讨论。
根据本发明方法的优选实施例,将用作起始物的通式(Ⅱ)孕甾烷衍生物溶于乙酸和丙酮的混合物或冰乙酸中;在使用乙酸和丙酮混合物的条件下,于0℃以下(宜在-20℃~25℃下)或在使用冰乙酸条件下,于约10℃,将高锰酸钾水溶液分批加到上面的溶液中。高锰酸钾水溶液对甾族化合物的用量应超过计算的0.8至1.0摩尔。根据所使用的起始物,该反应进行5至30分钟。在这期间,混合物的温度保持恒定。反应终止后,将该混合物倒入水中,从而沉淀出R为C1-8烷酰基或苯甲酰基的通式(Ⅰ)△14-16α,17-二羟孕甾烷衍生物。
由此得到的R为C1-8烷酰基或苯甲酰基的通式(Ⅰ)化合物可通过先将其溶于保护性溶剂如
甲醇,然后用碱金属碳酸盐水溶液或最好用高氯酸水溶液处理来水解。
本发明式(Ⅰ)△14-16α,17-二羟孕甾烷衍生物具有有价值的糖皮质激素作用。
对局部使用的甾类抗炎药物有两个基本要求:a)它们应在用于研究抗炎作用的各种动物实验中尽可能地有活性;b)它们应具有最低的有害全身性付作用。后者的作用是以胸腺重量降低作用(退化)为特征的。
用于研究本发明化合物抗炎作用的实验在后面叙述。在这些实验中的对照药物是强的松龙(11β,17α,21-三羟孕甾1,4-二烯-3,20-二酮)。
1)噁唑酮诱发的接触性皮炎模型
(Br.J.pharmae.43.403(1971)
本实验使用的是体重20-24g的雄性CFLP小鼠。将鼠腹部皮肤毛刮净,然后往其上涂0.1ml2%唑酮的橄榄油溶液。处理七天后,通过将10μl2%噁唑酮的丙酮溶液加到鼠的左耳中引发炎症反应,鼠的右耳用作对照。24小时后,割下鼠的耳朵并称重。将试验化合物以各种浓度加到含噁唑酮的丙酮溶液中。为了评价效果,与不用活性剂处理的对照组相比较,耳朵增重的减小用“抑制百分比”表示。每组用10只鼠。
2)局部肉芽囊肿模型
〔Recent progr.Hormone Res.8,117(1953);Arzneim.-Forsch.27,11(1977)〕
该方法是用来研究局部用糖皮质激素的抗渗出作用。在同样的实验动物上可观察到全身性付作用(胸腺退化)。
每组含10只雌性RG Hann Wister大鼠(每只重130至150g)。剃去背上的毛后,把25ml空气注射到背部皮下,将诱发炎症的1ml2%已至油注入空气囊。5天后吸出囊中内溶物,受试的糖皮质激素或强的松龙分别悬浮在0.5ml吐温80中,它们通过注射给药一次给药量为3剂量。在实验开始后第10天,处死动物,测定囊渗出液体积(以ml表示)。根据与对照相比,通过渗出物体积的减少来计算抗炎作用的百分比。
然后,切下动物的胸腺,通过将试验化合物处理过的动物胸腺重量与未处理的对照组动物胸腺重量之比,以百分率计算受试化合物的有害全身作用。
上面的研究得出下面的结果。
对噁唑酮诱发的接触性皮炎模型的抗炎作用化合物 剂量 耳增重 抑制
(μg/耳) (%) (%)
对照 0 108.8 6
强的松龙 0.3 86.1 20.8
强的松龙 1.0 76.9 29.3
强的松龙 3.0 68.6 36.9
实施例3 0.3 86.2 20.8
实施例3 1.0 75.5 30.6
实施例3 3.0 58.1 46.6
实施例4 0.3 77.2 29.1
实施例4 1.0 68.8 36.8
实施例4 3.0 60.4 44.5
2)对局部肉芽囊肿模型的抗炎作用
化合物 剂量 渗出液 抑制 胸腺退化
(mg/囊) (ml) (%) (%)
对照 0 15.3 0 0
强的松龙 1 11.7 23.6 27.2
强的松龙 3 9.2 39.9 44.1
强的松龙 9 5.8 62.2 55.5
实施例3 1 10.3 32.7 28.7
实施例3 3 9.2 39.9 33.1
实施例3 9 3.8 74.9 37.7
实施例4 1 10.4 32.1 21.1
实施例4 3 7.5 50.8 23.8
实施例4 9 5.8 62.3 33.9
从上面研究结果可明显看出:与对照物相比,本发明新的通式(Ⅰ)△14-16α,17-二羟孕甾烷衍生物对两种炎症模型都具有明显高的局部抗炎活性,并且它们的有害全身性付作用(胸腺退化)低于强的松龙。
本发明通过下面的实施例进行详细描述,但本发明并不限于这些实施例。
实施例1
11β,16α,17,21-四羟孕甾-4,14-二烯-3,20-二酮-21-乙酸酯的制备
将含1g(2.588mmol)11β,21-二羟孕甾-4,16-二烯-3,20-二酮-21-乙酸酯的40ml冰乙酸溶液冷却到13至15℃,然后在同一温度下将溶于40ml水的0.45g(2.847mmol)的高锰酸钾分批加到上面溶液中,用时5-10分钟。加毕后,通过加0.6g焦亚硫酸钠的4.0ml水溶液到反应混合物中来分解过量的氧化剂。搅拌15分钟后,将该反应混合物倒入500ml去离子水中,再搅拌1小时,然后过滤,用水洗涤沉淀直到中性。干燥该产物后,用乙酸乙酯重结晶该产物,得0.48g(44.3%)标题化合物,熔点:220-225℃。
实施例2
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-乙酸酯的制备
于15℃将10g(26.0mmol)11β,21-二羟孕甾-1,4,16-三烯-3,20-二酮-21-乙酸酯溶于400ml冰乙酸中,然后于同一温度下,将溶于400ml水的4.52g(28.6mmol)高锰酸钾分批加入,费时5-10分钟。然后通过加入5.94g焦亚硫酸钠的40ml水溶液分解过量的高锰酸盐。搅拌20分钟后,将该反应混合物倒入10升水中。再搅拌1小时后,过滤该悬浮液,并洗至中性,然后干燥。用乙酸乙酯重结晶所得到的粗产物,得到5.11g(47.2%)标题化合物,熔点:238-243℃。
实施例3
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-乙酸酯的制备
将55g(143.1mmol)11β,21-二羟孕甾-1,4,16-三烯-3,20-二酮-21-乙酸酯溶于1100ml冰乙酸后,加入1650ml丙酮,然后将该溶液冷却到-20℃至-25℃。
将20.35g(128.8mmol)高锰酸钾溶于440ml水并冷却到0℃,然后于-25℃将高锰酸钾溶液分批加到甾类溶液中,用时10-15分钟。5分钟后,用薄层层析(DC Alufol-ien Kieselgel 60 F254(Merck),用含氯仿/乙醚/甲醇(70∶30∶2,V/V)的展开系统,用磷酸检测)来检测该反应混合物。约15分钟后,在反应混合物中未检测到起始物。于搅拌下,将该混合物倒入含27g焦亚硫酸钠的27.5升冰水中。于0℃搅拌所得到的悬浮液1小时,然后过滤。洗涤沉淀至中性,然后干燥,用乙酸乙酯重结晶得36.14g(60.7%)标题化合物,熔点:240-243℃。
实施例4
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮的制备
于氮气氛下,将0.40g(2.87mmol)碳酸钾的6ml水溶液加到2g(4.78mmol)11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-乙酸盐的400ml甲醇溶液中。15分钟后,通过加入乙酸将该溶液的pH调至6.5,然后减压蒸发该混合物到15至20ml体积,将残余物倒入500ml冰-水中。搅拌30分钟后,过滤该悬浮液,干燥沉淀。用1∶3(体积比)氯仿/甲醇混合物重结晶所得粗产物,得到1.2g(66.7%)标题化合物。熔点:240-242℃。
实施例5
16α,17,21-三羟孕甾-4,14-二烯-3,20-二酮-21-乙酸酯的制备
将于20℃溶于5ml水的0.5g(3.373mmol)高锰酸钾分批加到于室温溶于10ml冰乙酸的1g(2.699mmol)21-羟孕甾-4,16-二烯-3,20-二酮-21-乙酸酯的溶液中,用时5分钟。加毕后,通过加6.72g焦亚硫酸钠5ml水溶液到反应混合物中来分解过量的高锰酸盐,然后将该混合物倒入含16.7g碳酸氢钾的500ml水中。搅拌1小时后,过滤悬浮液,用水洗涤沉淀,然后干燥,得到0.50g (46.0%)标题化合物,熔点:215-220℃。
实施例6
16α,17,21-三羟孕甾-1,4,14-三烯-3,20-二酮-21-乙酸酯的制备
将11ml丙酮加到含0.35g(0.95mmol)21-羟孕甾-1,4,16-三烯-3,20-三酮-21-乙酸酯的7ml冰乙酸溶液中并将该溶液冷却到-20℃至-25℃。然后在同一温度下,将溶于2ml水的0.23g(1.45mmol)高锰酸钾分批加入。15分钟后,将该反应混合物倒入含0.3g焦亚硫酸钠的200ml冰水中。搅拌45分钟后,过滤该悬浮液,洗涤沉淀并干燥,得到0.20g(52.6%)标题化合物,熔点:220-223℃。
实施例7
9α-氟-11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-乙酸酯的制备
将1.0g(2.48mmol)9α-氟-11β,21-二羟孕甾-1,4,16-三烯-3,20-二醇-21-乙酸酯溶于20ml冰乙酸中,往其中加入30ml丙酮,然后将该溶液冷却到-20℃至-25℃。在同一温度下,往其中分批加入含0.36g(2.28mmol)高锰酸钾的10ml水溶液。20分钟后,将该反应混合物倒入含0.5g焦亚硫酸钠的500ml冰水中。搅拌1小时后,过滤该悬浮液,用冷水洗涤该沉淀,然后干燥,得到0.79g(73.2%)标题化合物,熔点:242-247℃。
实施例8
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-11-三氟乙酸酯-21-乙酸酯的制备
将5g(10.41mmol)11β-三氟乙酰氧-21-乙酰氧孕甾-1,4,16-三烯-3,20-二酮溶于100ml冰乙酸和150ml丙酮的混合物后,将该溶液冷却到-20℃至-25℃,然后在同一温度下,往其中加入1.48g(9.37mmol)高锰酸钾的25ml水溶液。通过加入2.0g亚硫酸氢钠的10ml水溶液来分解过量的氧化剂,然后将该混合物倒入2500ml冰水中。搅拌1小时后,过滤悬浮液,用少量冷水洗涤该沉淀,然后干燥,得到3.20g(60.0%)标题化合物,熔点:119-124℃。
实施例9
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-苯甲酸酯的制备
将150ml丙酮加到5g 11β,21-二羟孕甾-1,4,16-三烯-3,20-二酮-21-苯甲酸酯的100ml冰乙酸溶液中,然后将所得溶液冷却到-20℃至-25℃,于同一温度下,往其中加入1.59g高锰酸钾的25ml水溶液。通过加入溶于10ml水的2.5g亚硫酸氢钠来分解过量的氧化剂,然后将该混合物倒入2500ml冰水中。搅拌1小时后,过滤悬浮液,用少量冷的丙酮-水混合物洗涤该沉淀,然后干燥,得到3.83g (71.5%)标题化合物,熔点:155-158℃。
下面的通式(Ⅰ)△14-16α,17-二羟孕甾烷衍生物也按实施例1至9所述制备:
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-丁酸酯;和
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-己酸酯。
Claims (11)
1、新的通式(Ⅰ)△14-16α,17-二羟孕甾烷衍生物
其中:
A为氢,羟基或三氟乙酰氧基;
X为氢或卤素,其条件是A为氢,X也为氢;
R为氢,苯甲酰基或C1-8烷酰基;
代表两个相邻碳原子间的单或双键。
2、选自下列化合物的一化合物:
11β,16α,17,21-四羟孕甾4,14-二烯-3,20-二酮-21-乙酸酯,
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-乙酸酯,
16α,17,21-三羟孕甾-4,14-二烯-3,20-二酮-21-乙酸酯,
16α,17,21-三羟孕甾-4,14-二烯-3,20-二酮,
16α,17,21-三羟孕甾-1,4,14-三烯-3,20-二酮-21-乙酸酯,
9α,-氟-11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-乙酸酯,
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-11-三氟乙酸酯-21-乙酸酯,和
11β,16α,17,21-四羟孕甾-1,4,14-三烯-3,20-二酮-21-苯甲酸酯。
5、权利要求4所要求的方法,其包括在冰乙酸介质中,用碱或碱土金属高锰酸盐水溶液进行氧化。
6、权利要求4所要求的方法,其包括:在丙酮存在下,于冰乙酸介质中,用碱金属或碱土金属高锰酸盐进行氧化。
7、权利要求4-6任一权利要求所要求的方法,其包括用高锰酸钾作碱金属高锰酸盐。
8、权利要求5要求的方法,其包括在温度为0℃至20℃进行氧化反应。
9、权利要求6所要求的方法,其包括于-10℃至-30℃进行氧化反应。
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CN1058724C (zh) * | 1991-02-04 | 2000-11-22 | 阿斯特拉公司 | 新的甾族化合物在制药中的应用 |
CN110078785A (zh) * | 2019-06-04 | 2019-08-02 | 博诺康源(北京)药业科技有限公司 | 一种布地奈德杂质ep-ze的合成方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2675146A1 (fr) * | 1991-04-10 | 1992-10-16 | Roussel Uclaf | Nouveaux derives sterouides de la pregna-1,4-diene-3,20-dione, leur preparation, leur application a la preparation de derives 16,17-methylene dioxy substitues et nouveaux intermediaires. |
DE69942578D1 (de) | 1998-05-22 | 2010-08-26 | Univ R | Bifunktionelle moleküle sowie darauf basierende therapien. |
EP3827747A1 (en) | 2005-04-28 | 2021-06-02 | Otsuka Pharmaceutical Co., Ltd. | Pharma-informatics system |
US9062126B2 (en) | 2005-09-16 | 2015-06-23 | Raptor Pharmaceuticals Inc. | Compositions comprising receptor-associated protein (RAP) variants specific for CR-containing proteins and uses thereof |
NZ616673A (en) | 2009-02-20 | 2014-08-29 | To Bbb Holding B V | Glutathione-based drug delivery system |
ES2942923T3 (es) | 2009-05-06 | 2023-06-07 | Laboratory Skin Care Inc | Composiciones de administración dérmica que comprenden complejos de agente activo-partículas de fosfato de calcio y métodos de uso de las mismas |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3167545A (en) * | 1959-02-07 | 1965-01-26 | Syntex Corp | 16beta-methyl-16alpha, 17 alpha-dihydroxy pregnenes and the 16alpha, 17alpha-cyclic ketals and acetals thereof |
US3345362A (en) * | 1961-07-27 | 1967-10-03 | Lilly Co Eli | Novel pregnenolone acetonides |
US4036831A (en) * | 1975-10-28 | 1977-07-19 | Steroid Development Company Establishment | Trimethyl siloxane steroid intermediates |
WO1989001482A1 (en) * | 1987-08-14 | 1989-02-23 | The Upjohn Company | IMPROVED 9alpha-DEHALOGENATION PROCESS |
-
1989
- 1989-03-09 HU HU891156A patent/HU203562B/hu not_active IP Right Cessation
-
1990
- 1990-02-21 IL IL9347890A patent/IL93478A/en not_active IP Right Cessation
- 1990-02-28 IN IN185/CAL/90A patent/IN170846B/en unknown
- 1990-03-01 CA CA002011282A patent/CA2011282A1/en not_active Abandoned
- 1990-03-05 PH PH40143A patent/PH26676A/en unknown
- 1990-03-07 ZA ZA901752A patent/ZA901752B/xx unknown
- 1990-03-08 KR KR1019900003056A patent/KR930009445B1/ko not_active IP Right Cessation
- 1990-03-08 AU AU51102/90A patent/AU623503B2/en not_active Ceased
- 1990-03-08 NO NO901103A patent/NO177147C/no unknown
- 1990-03-08 PT PT93375A patent/PT93375A/pt not_active Application Discontinuation
- 1990-03-08 JP JP2055162A patent/JPH06104679B2/ja not_active Expired - Lifetime
- 1990-03-09 US US07/491,683 patent/US5082835A/en not_active Expired - Fee Related
- 1990-03-09 FI FI901199A patent/FI901199A0/fi not_active IP Right Cessation
- 1990-03-09 AR AR90316352A patent/AR244700A1/es active
- 1990-03-09 EP EP19900302544 patent/EP0387091A3/en not_active Ceased
- 1990-03-09 CN CN90101248A patent/CN1045396A/zh active Pending
- 1990-03-11 EG EG16090A patent/EG19411A/xx active
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1058724C (zh) * | 1991-02-04 | 2000-11-22 | 阿斯特拉公司 | 新的甾族化合物在制药中的应用 |
CN110078785A (zh) * | 2019-06-04 | 2019-08-02 | 博诺康源(北京)药业科技有限公司 | 一种布地奈德杂质ep-ze的合成方法 |
Also Published As
Publication number | Publication date |
---|---|
JPH06104679B2 (ja) | 1994-12-21 |
ZA901752B (en) | 1991-05-29 |
EG19411A (en) | 1995-01-31 |
AU5110290A (en) | 1990-09-13 |
AR244700A1 (es) | 1993-11-30 |
NO901103D0 (no) | 1990-03-08 |
EP0387091A2 (en) | 1990-09-12 |
IN170846B (zh) | 1992-05-30 |
IL93478A0 (en) | 1990-11-29 |
NO177147C (no) | 1995-07-26 |
US5082835A (en) | 1992-01-21 |
JPH02279695A (ja) | 1990-11-15 |
PH26676A (en) | 1992-09-15 |
KR930009445B1 (ko) | 1993-10-04 |
HU203562B (en) | 1991-08-28 |
PT93375A (pt) | 1990-11-07 |
FI901199A0 (fi) | 1990-03-09 |
NO901103L (no) | 1990-09-10 |
AU623503B2 (en) | 1992-05-14 |
IL93478A (en) | 1994-11-11 |
NO177147B (no) | 1995-04-18 |
EP0387091A3 (en) | 1992-05-06 |
KR900014422A (ko) | 1990-10-23 |
CA2011282A1 (en) | 1990-09-09 |
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