CN1086218A - 抗炎剂膦酰基乙酸酯和酸 - Google Patents
抗炎剂膦酰基乙酸酯和酸 Download PDFInfo
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- CN1086218A CN1086218A CN93116258A CN93116258A CN1086218A CN 1086218 A CN1086218 A CN 1086218A CN 93116258 A CN93116258 A CN 93116258A CN 93116258 A CN93116258 A CN 93116258A CN 1086218 A CN1086218 A CN 1086218A
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- Prior art keywords
- methyl
- phenyl
- oxo
- phosphinyl
- dihydro
- Prior art date
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- -1 phosphine acyl acetic acid ester Chemical class 0.000 title claims description 28
- 229940121363 anti-inflammatory agent Drugs 0.000 title abstract description 7
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- 229910000073 phosphorus hydride Inorganic materials 0.000 title description 10
- 239000002253 acid Substances 0.000 title description 7
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
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- 125000002252 acyl group Chemical group 0.000 description 4
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- 150000004663 bisphosphonates Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
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- 230000004060 metabolic process Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical group CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Abstract
可用于治疗炎症、结构如式I所示的化合物,这
些化合物可用作抗炎剂和抗关节炎剂。所述式I化
合物的结构如上,式中符号的定义见说明书。
Description
本发明涉及可用作抗炎剂和抗关节炎剂的式Ⅰ膦酰基乙酸酯、酸及其药学上可接受的盐。
本发明化合物可用于人和低等动物以安全和有效地治疗以不正常的磷酸盐和钙代谢为特征的疾病和治疗炎症。这些疾病包括骨质疏松症、佩吉特氏病、牙周疾病、类风湿性关节炎、骨关节炎、神经炎、粘液囊炎、软组织矿物质紊乱(soft tissue mineral disorders)、关节强硬性脊椎炎、动脉粥样硬化、骨的多发性骨髓瘤、转移性骨疾病(metastatic bone disease)和二尖瓣瓣膜钙化(mitral valve calcification)。它们代表治疗炎症的新方法。
就目前的技术发展水平而言,美国专利4746654公开了可用作抗炎剂的二膦酸酯;澳大利亚专利A-51534/85公开了可用于治疗不正常的钙和亚磷代谢以及可用于治疗关节炎的二膦酸酯;以及美国专利3683080公开了可用于抑制动物组织中的磷酸钙的异常沉积和移动的多膦酸酯,具体来讲是二膦酸酯。
一方面,本发明是结构由下式Ⅰ表示的膦酰基乙酸酯、酸以及它们的药学上可接受的盐:
式中:R1是H,C1-C6烷基,苄基,苯基,被1-5个F、Cl、Br、I、NO2、OCH3或C1-C4烷基取代的苯基;R2是H,C1-C6烷基,苄基,苯基,被1-5个F、Cl、Br、I、NO2、OCH3或C1-C4烷基所取代的苯基,或者两个R2一起形成CH2-CH2,CH2-CH2-CH2或CH2-C(CH3)2-CH2以生成含键合P原子和两个0原子的杂环;X或Y中,一个是H,另一个选自以下基团:
或者X和Y一起形成选自下列环的一个环:
另一方面,本发明包括这些化合物在人和低等动物中作为安全和有效地治疗慢性炎性疾病的手段的应用。这些疾病包括牙周疾病、类风湿性关节炎、骨关节炎、肺尘埃沉着病、克罗恩氏病、慢性肠炎(chronic inflammatory bowel disease)、慢性气喘、动脉粥样硬化、多发性硬化和肉样瘤病。
还有另一个方面,本发明是通过给需要这样的治疗的动物服用抗炎有效量的式Ⅰ化合物来治疗炎症的方法。给药途径包括口服、肌内、静脉内、经皮肤、关节内、皮下或腹膜内。有效量是能减轻炎症或关节炎的症状如疼痛和不适或能增强受损部位的可动性的用药量。通过用具体的给药,用途及给药频率的模型测定剂量,得出典型的剂量范围在约0.001mg至1.0g内。
本发明包括由上式Ⅰ表示并可用作抗炎剂和抗关节炎剂的膦酰基乙酸酯、酸以及它们的药学上可接受的盐。这些化合物尤其可用于治疗关节炎及其相关症状如炎症和过度的骨生长或重塑(remodelling)。在式Ⅰ中,变量的意义被进一步定义如下。
各烃组成部分的碳含量用指定该部分中的碳原子的最大数和最小数的词头来表示,即词头Ci-Cj表示存在的碳原子数自整数“i”到整数“j”。因此,C1-C3烷基表示自1个碳原子到3个碳原子的烷基,即甲基、乙基、丙基和异丙基。
根据上述,C1-C6烷基是甲基、乙基、丙基、丁基、戊基、己基及其异构形式。缩写“ph”用于结构和式中来表示苯基。
“卤”(“halo”)一词包括氟、氯、溴和碘。
药学上可接受的盐表示有助于服用本发明化合物或该化合物在体外或体内可以采取的可用的形式的盐,它包括钾盐、钠盐、盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、乙酸盐、丙酸盐、乳酸盐、甲磺酸盐(mesylate)、马来酸盐、丙二酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐等。这些盐可以是水合的形式。
可用作抗炎剂和抗关节炎剂的膦酰基乙酸酯、酸及衍生物(式Ⅰ)按实施例1-16中所示来制备。在化学文献中有许多膦酰基乙酸酯的资料,它们可作为Horner-Wadsworth-Emmons反应(Wittig反应的改良法)的原料用于合成链烯烃,参见A.W.Johnson,“Ylid Chemistry”,Academic Press,第205-212页(1966);以及B.M.Trost(编辑),“Comprehensive Organic Synthesis”,Pergammon Press,第1卷,761-71页(1991)。
简言之,直链化合物通过活性亚甲基化合物与膦酰基丙烯酸酯于-78℃的Michael型加成反应来制备。吡唑啉通过适当的重氮基衍生物与膦酰基丙烯酸酯的偶极环加成来制备,在该反应中生成环丙烷副产物。
氮丙啶由氮宾与膦酰基丙烯酸酯加成产生。
相应的膦酸可以通过用三甲基甲硅烷基溴处理该酯,然后用水处理来制备。
本发明式Ⅰ化合物已在用于炎症的延迟型过敏性肉芽肿测定(DTH GRA)模型上进行了实验。该测定由Dunn,C.J等人在“研究慢性免疫引起的炎性疾病的小鼠延迟型过敏性肉芽肿模型的发展”一文(Agents and Actions,27,3/4(1989)和“鼠的延迟型过敏性肉芽肿(Int.J.Immunopharmc.,(12卷,第8期,899-904页(1990))一文中作了描述。
简言之,mBSA致敏的小鼠具DTH肉芽肿(DTH GRA)损害,该损害由经皮下植入mBSA浸泡的滤纸所致,该滤纸在9天后切除。给该鼠服用本发明化合物以测定它们对该损害的作用。结果用抑制百分数表示。抑制百分数越高,化合物越有效。10-20%的抑制被认为显示出抗肉芽肿活性。抑制高于30%是较好的活性。
由式Ⅰ化合物得到的DTH GRA数据列在表2中。这些化合物按下述标准评价:抑制在10-20%,为有抗炎活性;抑制高于30%,为较好的活性。
“化合物的命名”与实施例的命名一致。指定的具体化合物如下
实施例1
α-(二乙氧基氧膦基)-δ-氧代苯戊酸乙酯
将溶于THF(15ml)的乙酰苯(0.51ml,4.4mmol)冷却至-78℃并用Li HMDS(4.8ml,4.8mmol)处理。搅拌30分钟后,加入2-膦酰基丙烯酸,三乙酯(0.94g,4.0mmol)的THF(5ml)溶液。将混合物于-78℃搅拌30分钟,然后温至0℃15分钟,用饱和氯化铵溶液终止反应,真空除去溶剂,将残留物溶于乙酸乙酯并用2×1N HCl、水、3×饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,然后用硫酸镁干燥。过滤,真空除去溶剂,并将油状粗品在SiO2(50g)上进行层析,以1∶1乙酸乙酯/己烷为洗脱剂。得0.85g(2.4mmol,60%)α-(二乙氧基氧膦基)-δ-氧代苯戊酸乙酯,为浅色油状物。
质谱:m/e 356(M+),328,311,237,224,105,77
红外:vmax(cm-1)1733,1685,1598,1581,1449,1391,1368,1252
NMR:δ(CDCl3)7.94(d,2H),7.57(m,1H),7.46(t,2H),4.26-4.13(m,8H),3.21-3.00(m,3H).
非对映的:(2.42-2.31(dt,2H),1.37-1.26(m,12H)。
实施例2
α-(二甲氧基氧膦基)-3-氟-δ-氧代苯戊酸甲酯
膦酰基丙烯酸,三甲酯与3-氟乙酰苯的反应按下述进行。将3-氟乙酰苯(0.75g,5.43mmol)溶于四氢呋喃(10ml)中,置氮气条件下并冷却至-78℃。在10-15秒钟的时间里用注射器和隔片加入1M六甲基二硅叠氮化锂的THF溶液(5.70ml,5.70mmol)。搅拌45分钟后,用30秒的时间加入膦酰基丙烯酸,三甲酯(1.0g,5.15mmol)。将反应温度升至室温并搅拌过夜。加入饱和氯化铵溶液(10ml)并将大部分THF用旋转蒸发器蒸除。将残留物在二氯甲烷(100ml)和1N HCl(20ml)中进行分配。有机层用水(20ml)、5%碳酸氢钠溶液(20ml)和盐水(50ml)洗涤。用硫酸镁干燥该黄色溶液,过滤并蒸发,得琥珀色胶状物(1.4g)。将其在硅胶(150g,40-60μm)上进行层析,用75%乙酸乙酯-己烷洗脱除去未反应的3-氟乙酰苯,用100%乙酸乙酯梯度洗脱,然后用1%甲醇-乙酸乙酯洗脱,得洗脱液约700ml。蒸发后,得膦酰基乙酸酯-α-(二甲氧基氧膦基)-3-氟-δ-氧代苯戊酸甲酯,为淡黄色粘性油(730mg,43%)。
质谱:m/e332(2),304(9),301(12),195(23),182(66),163(12),151(15),124(18),123(100),109(11),95(25)
红外:vmax 2957,1737,1690,1589,1445,1255,1152,1054,1032,830,783cm-1
NMR:δ(CDCl3);2.29-2.45(m,2H,CH2);2.97-3.30(m,3H,CH plus CH2CO);3.72-3.90(m,9H,3xCH3O);7.27(m,1H,芳 H5);7.45(m,1H,芳 H4);7.63(m,1H,芳,H6);7.74(m,1H,芳 H2)。
实施例3
α-(二乙氧基氧膦基)-δ-氧代-γ-苯基苯戊酸乙酯
将溶于THF(15ml)并冷却至-78℃的脱氧苯偶姻(0.86g,4.4mmol)用Li HMDS(4.8ml,4.9mmol)处理,然后搅拌30分钟,加入2-膦酰基丙烯酸,三乙酯(0.94g,4.0mmol)的THF(5ml)溶液。搅拌30分钟后,将反应混合物温至0℃30分钟。用饱和氯化铵溶液终止反应并真空除去溶剂。将残留物溶于乙酸乙酯并用2×HCl、水、3×饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,然后用硫酸镁干燥。过滤,真空除去溶剂并在SiO2(50g)上用2∶3乙酸乙酯/己烷进行层析,得1.24g(2.8mmol,72%)α-(二乙氧基氧膦基)-δ-氧代-γ-苯基苯戊酸乙酯,为浅色油状物。
质谱:m/e 432(M+),387,328,327,224,105,77
红外:vmax(cm-1)1732,1681,1598,1580,1492,1447,1391,1368,1254,1153 NMR:δ(CDCl3)7.93(t,J=7.2,2H),7.49-7.45(m,1H),7.40-7.20(m,7H),非对映的(4.74(t,J=9.1),4.72(t,J=9.1),1H),4.29-3.97(m,6H),非对映的(3.09(ddd,Jd1=4.7,Jd2=10.2,Jd3=23),2.86(ddd,Jd1=4.8,Jd2=10,Jd3=23),1H),2.79-2.60(m,1H),2.53-2.35(m,1H),1.37-1.12(m,9H)。
实施例4
α-(二甲氧基氧膦基)-δ-氧代3-吡啶戊酸甲酯
膦酰基丙烯酸,三甲酯和3-乙酰基吡啶的反应按下述进行。将3-乙酰基吡啶(0.63g,5.21mmol)溶于THF(10ml)中,置氮气条件下并冷却至-78℃。用注射器和隔片加入1M六甲基二硅叠氮化锂的THF溶液(5.50ml,5.50mmol)并将该冷却的混合物搅拌35分钟。用1分钟的时间加入膦酰基丙烯酸,三甲酯(1.0g,5.15mmol)的THF(3ml)溶液,用3小时的时间将混合物升至室温,这时加入饱和氯化铵溶液(10ml)。用旋转蒸发器蒸除大部分THF,残留物用乙酸乙酯(100ml)和水(20ml)处理,有机层用盐水(30ml)洗涤并干燥(硫酸钠)。过滤并蒸发,得琥珀色油(1.2g),将该油用硅胶(150g,40-60μm)层析,用100%乙酸乙酯至4%甲醇-乙酸乙酯梯度洗脱,在较后的流份中得产物α-(二甲氧基氧膦基)-δ-氧代3-吡啶戊酸甲酯,为淡黄色油(670mg,41%)。
实施例5
(4-(二甲氧基氧膦基)-5-甲氧基-1,5-二氧代戊基)二茂铁
膦酰基丙烯酸,三甲酯和乙酰基二茂铁的反应按下述进行。在氮气条件下将乙酰基二茂铁(1.17g,5.13mmol)在THF(10ml)中搅拌并冷却至-78℃。用1分钟的时间加入1M六甲基二硅叠氮化锂的THF溶液(5.15ml,5.15mmol)并搅拌30分钟。加入膦酰基丙烯酸,三甲酯(1.0g,5.15mmol)的THF(3ml)溶液,并使反应温度与室温平衡过夜。加入饱和氯化铵溶液(10ml),用旋转蒸发器蒸除THF。加入乙酸乙酯(100ml)并用水(50ml)和盐水(50ml)洗涤,干燥(硫酸钠)后过滤并蒸发,得血红色油(1.9g)。硅胶(1.50g,40-60μm)层析,用1%甲醇-氯仿洗脱,得二茂铁基膦酰基乙酸酯-(4-(二甲氧基氧膦基)-5-甲氧基-1,5-二氧代戊基)二茂铁,为深红色粘性油(900mg,42%)。
质谱:m/e423(12),422(51),358(17),357(100),267(15),237(17),219(6),207(10),189(7),121(12).
红外:vmax2955,1736,1666,1455,1257,1053,1029,827cm-1.
NMR:δ(CDCl3):2.24-2.40(m,2H,CH2);2.72-2.98(m,2H,CH2CO);3.17-3.34(m,1H,CH);3.80(s,3H,CO2CH3);3.84(d,J=11.0Hz,6H,2xCH3OP);4.20(s,5H,C5H5);4.45-4.54(m,2H,环戊二烯基);4.73-4.82(m,2H,环戊二烯基)。
实施例6(A部分)
α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸甲酯
膦酰基丙烯酸,三甲酯和2,3-二甲基-6-苯基嘧啶酮的反应按下述进行。在氮气条件下,将2,3-二甲基-6-苯基嘧啶酮(1.03g,5.15mmol)在THF(10ml)中搅拌然后冷却至-78℃。用注射器和隔片加入1M六甲基二硅叠氮化锂的THF溶液(5.50ml,5.50mmol)。于-78℃搅拌40分钟后,将膦酰基丙烯酸,三甲酯(1.0g,5.15mmol)的THF(3ml)溶液加至该橙色溶液中。使反应温度升至室温搅拌过夜。加入饱和氯化铵溶液(10ml)并用旋转蒸发器蒸除大部分THF。将乙酸乙酯(100ml)和水(20ml)加到该残留物中。有机层用1N HCl(25ml)、盐水(25ml)洗涤,干燥(硫酸钠),过滤并蒸发,得粘结固体(1.74g)。用少量甲基叔丁基醚将该固体从烧瓶中洗下来,得奶油色固体(1.33g,65%)。用丙酮-己烷重结晶,得膦酰基乙酸酯-α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸甲酯(1.05g),为半透明的淡黄色结晶,mp114-115℃。
实施例6(B部分)
α-(二甲氧基膦酸)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸甲酯
将α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸甲酯水解,得其酸衍生物。将膦酰基乙酸酯(300mg,0.76mmol)在氯仿(15ml)中搅拌并加入三甲基甲硅烷基溴(1.0ml,1.16g,7.58mmol)。将混合物加热回流18小时,冷却并除去溶剂,得透明胶状物。加入乙酸乙酯(25ml)和水(10ml),得不透明的混合物。将混合物过滤,得胶质固体,将其用水(10ml)洗涤,真空干燥过夜,得白色硬固体,为膦酸(260mg,93%),mp225-227℃。
实施例7
3-氰基-α-(二甲氧基氧膦基)-2,5-二甲基吡唑并(1,5-a)嘧啶-7-丁酸甲酯
膦酰基丙烯酸,三甲酯和吡唑并嘧啶的反应按下述进行,在氮气及冰-乙醇浴冷却条件下将2,5,7-三甲基吡唑并(1,5-a)嘧啶-3-碳腈(carbononitrile)(0.96g,5.15mmol)在吡啶(10ml)中搅拌。加入1M六甲基二硅叠氮化锂的THF溶液(5.50ml,5.50mmol),得深红色溶液。搅拌20分钟后,加入膦酰基丙烯酸,三甲酯(1.0g,5.15mmol)的THF(3ml)溶液。用2小时将混合物温至室温。加入饱和氯化铵溶液(10ml)并用旋转蒸发器蒸除大部分溶剂。将残留物与甲苯(100ml)共沸并用乙酸乙酯(100ml)和水(50ml)处理。有机层用盐水(30ml)洗涤,干燥(硫酸钠),过滤并蒸发,得胶状物(1.57g),当加入甲基叔丁基醚时析出结晶,用丙酮-己烷重结晶,得3-氰基-α-(二甲氧基氧膦基)-2,5-二甲基吡唑并(1,5-a)嘧啶-7-丁酸甲酯(1.21g,62%),为奶油色晶体,mp164-165℃。
实施例8
3-乙氧甲酰基-5-(二甲氧基氧膦基)-4,5-二氢1H-吡唑-5-羧酸甲酯
膦酰基丙烯酸,三甲酯和重氮基乙酸乙酯的反应如下进行。将膦酰基丙烯酸,三甲酯(1.0g,5.15mmol)溶于甲基叔丁基醚中,随后加入重氮基乙酸乙酯(0.60g,5.26mmol)。搅拌过夜后过滤,将生成的固体(880mg,55%)用丙酮-己烷重结晶,得吡唑啉-3-乙氧甲酰基-5-(二甲氧基氧膦基)-4,5-二氢1H-吡唑-5-羧酸甲酯(699mg),为灰白色颗粒,mp100-102℃。
实施例9
3-苯甲酰基-5-(二甲氧基氧膦基)-4,5-二氢1H-吡唑-5-羧酸甲酯
膦酰基丙烯酸,三甲酯和重氮基乙酰苯的反应按下述进行。将重氮基乙酰苯(0.75g,5.14mmol)溶于甲基叔丁基醚(20ml)中,随后加入膦酰基丙烯酸,三甲酯(1.0g,5.15mmol)。于室温搅拌5小时后,滤出生成的沉淀(180mg)并鉴定为吡唑啉。将滤液蒸发,得黄色粘性油。将其置冰箱中放置一周。尽量将该油溶于少量50%己烷-乙醚中,得较多固体(230mg),将其过滤并与第一次得到的沉淀合并(合并后为410mg,23%)。用丙酮-己烷重结晶,得吡唑啉-3-苯甲酰基-5-(二甲氧基氧膦基)-4,5-二氢1H-吡唑-5-羧酸甲酯(338mg),为白色结晶,mp,152℃。
实施例10
2-苯甲酰基-1-(二甲氧基氧膦基)环丙烷羧酸甲酯
将从实施例9得到的反应混合物滤液进行层析(SiO2,40-60μm,150g)用梯度25-50%丙酮-己烷洗脱。环丙烷(60mg,4%)-2-苯甲酰基-1-(二甲氧基氧膦基)环丙烷羧酸甲酯被洗脱至较后的流份中,为无色胶状物,缓慢结晶析出白色固体,mp62-64℃。
实施例11
1-(1,3-二氢-1,3-二氧代-2H-异氮杂茚-2-基)-2-(二甲氧基氧膦基)2-氮丙啶羧酸甲酯
在膦酰基丙烯酸,三甲酯存在下N-氨基苯邻二甲酰亚胺的氧化按下述进行。将N-氨基苯邻二甲酰亚胺(1.0g,6.17mmol)和膦酰基丙烯酸,三甲酯(2.5g,12.9mmol)在二氯甲烷(25ml)中搅拌并用3分钟的时间加入四乙酸铅(95%)(2.75g,5.89mmol)。搅拌1小时后,过滤并蒸发。将得到的胶状物进行层析(SiO2,500g,40-60μm),用1-4%甲醇-氯仿梯度洗脱,在较后的流份中洗脱出氮丙啶,为黄色胶状物(2.84g)。加入少量的己烷并将该胶状物置冰箱中放置2天。从冰箱中取出后晶体开始形成,滤出粘结的固体,用丙酮-己烷重结晶,得氮丙啶(780mg,36%)。经第二次重结晶,得白色晶体:1-(1,3-二氢-1,3-二氧代-2H-异氮杂茚-2-基)-2-(二甲氧基氧膦基)2-氮丙啶羧酸甲酯(680mg,31%),mp123-124℃。
实施例12
α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸
将α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸甲酯(0.969g,2.46mmol)在2N KOH(5ml)中加热回流20小时。冷却后,用水稀释以溶解固体,然后用水洗脱使其通过Bio-Rad AG 50W-X4树脂床(H+型,10cm×2.5cm2柱,200-400筛目),将样品真空浓缩,得0.84g(2.3mmol,93%)。
NMR:δ(CD3OD)8.08(m,2H),7.47(m,3H),6.83(s,1H),3.77(d,J=11.3H),3.57(s,3H),3.33(m,1H),3.04(m,2H),2.51(m,2H)。
实施例13
α-膦酰基-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸
将α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸(0.403g,1.1mmol)(得自上面的实施例12)混悬于溴代三甲基甲硅烷(4ml,30mmol)中加热回流16小时。除去溶剂,将样品溶于水中。搅拌1小时后,将其分配于乙酸乙酯和水中,收集水层并冻干,将粗产物再溶于水中并收集得到的固体:150mg(0.4mmol,39%),mp185-187℃。
实施例14
α-(二甲氧基氧膦基)-δ-氧代苯戊酸,二甲基乙基酯
将二甲氧基膦酰基乙酸叔丁酯(25.74g,0.115mol)溶于甲醇(380ml)中。然后用多聚甲醛(20.0g,0.670mol)和二乙胺(14.0ml,0.134mol)处理。将反应混合物于22℃搅拌60小时,然后真空浓缩。加入乙酸乙酯并用3×1NHCl、水、3×饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,用硫酸镁干燥。将该甲酯粗品真空浓缩,得41.6g无色油。加入磷酸(85%,1.1ml)并将该产物蒸馏,得2-(二甲氧基氧膦基)丙烯酸叔丁酯:17.7g(75mmol,65%),bp0.2110-115℃。
将溶于THF(25ml)并冷却至-78℃的3-氟乙酰苯(1.85ml,15.1mmol)用LiHMDS(15.4ml,15.4mmol)处理并搅拌30分钟。加入2-(二甲氧基氧膦基)丙烯酸叔丁酯(3.56g,15.1mmol)的THF(5ml)溶液,搅拌10分钟,然后温至0℃2小时。用饱和氯化铵溶液终止反应。溶于乙酸乙酯中,用3×1N HCl、水、3×饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,用硫酸镁干燥,然后除去溶剂。样品用去层析法(SiO2,己烷/乙酸乙酯)纯化,得635mg(1.7mmol,63%)。
NMR:δ(CDCl3)7.74(d,J=7.7,1H),7.63(m,1H),7.45(m,1H),7.27(m,1H),3.82(d,J=11.3H),3.81(d,J=11.3H),3.20-3.00(m,3H),2.32(m,2H),1.48(s,9H)
实施例15
α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸,二甲基乙基酯
将溶于无水THF(10ml)且冷却至-78℃的2,3-二甲基-6-苯基-嘧啶-4(3H)-酮(1.017g,5.08mmol)用LiHMDS(5.3ml,5.3mmol)处理并搅拌30分钟。加入2-(二甲氧基氧膦基)丙烯酸叔丁酯(1.14g,4.82mmol)的THF(5ml)溶液,搅拌10分钟,然后温至0℃30分钟。用饱和氯化铵溶液终止反应,溶于乙酸乙酯,用3×1N HCl、水、3×饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,用硫酸镁干燥,然后除去溶剂。样品用层析法(SiO2,10%MeOH/乙酸乙酯)纯化,得1.31g。样品在静置时固化,用甲基叔丁基醚重结晶,得0.90g(2.0mmol,43%),mp94.5-96℃。
实施例16
α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸
将α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸,二甲基乙基酯(3.007g,6.89mmol)(得自上面的实施例16)在甲酸(55ml)中加热回流2小时,然后冷却并除去过量的溶剂。固体用水处理,搅拌1小时,然后滤出沉淀物,真空干燥,得2.4g(6.3mmol,91%),mp150℃。
Claims (4)
2、权利要求1的化合物,它们是:
a.α-(二乙氧基氧膦基)-δ-氧代苯戊酸乙酯
b.α-(二甲氧基氧膦基)-3-氟-δ-氧代苯戊酸甲酯
c.α-(二乙氧基氧膦基)-δ-氧代-γ-苯基苯戊酸乙酯
d.α-(二甲氧基氧膦基)-δ-氧代3-吡啶戊酸甲酯
e.(4-(二甲氧基氧膦基)-5-甲氧基-1,5-二氧代戊基)二茂铁
f.α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸甲酯
g.α-(二甲氧基膦酸)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸甲酯
h.3-氰基-α-(二甲氧基氧膦基)-2,5-二甲基吡唑并(1,5-a)嘧啶-7-丁酸甲酯
i.3-乙氧甲酰基-5-(二甲氧基氧膦基)-4,5-二氢1H-吡唑-5-羧酸甲酯
j.3-苯甲酰基-5-(二甲氧基氧膦基)-4,5-二氢1H-吡唑-5-羧酸甲酯
k.2-苯甲酰基-1-(二甲氧基氧膦基)环丙烷羧酸甲酯
l.1-(1,3-二氢-1,3-二氧代-2H-异氮杂茚-2-基)-2-(二甲氧基氧膦基)2-氮丙啶羧酸甲酯
m.α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸
n.1,6-二氢-1-甲基-6-氧代-4-苯基α-膦酰基2-嘧啶丁酸
o.α-(二甲氧基氧膦基)-δ-氧代苯戊酸乙酯
p.α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸,二甲基乙基酯
q.α-(二甲氧基氧膦基)-1,6-二氢-1-甲基-6-氧代-4-苯基2-嘧啶丁酸
3、式Ⅰ化合物制备可用于治疗炎症的药物的应用,它包括:给需要治疗的动物包括人服用有效量的式Ⅰ化合物。
4、权利要求3的应用,其中所述的式Ⅰ化合物按抗炎有效量0.001mg-1.0g给予需要它的病人,给药途径为口服、肌内、静脉内、经皮肤、关节内、皮下或腹膜内。
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US92687992A | 1992-08-07 | 1992-08-07 | |
US926,879 | 1992-08-07 |
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CN1086218A true CN1086218A (zh) | 1994-05-04 |
Family
ID=25453835
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN93116258A Pending CN1086218A (zh) | 1992-08-07 | 1993-08-07 | 抗炎剂膦酰基乙酸酯和酸 |
Country Status (13)
Country | Link |
---|---|
US (2) | US5565441A (zh) |
EP (1) | EP0654035B1 (zh) |
JP (1) | JPH07509712A (zh) |
CN (1) | CN1086218A (zh) |
AT (1) | ATE157097T1 (zh) |
AU (1) | AU4407493A (zh) |
DE (1) | DE69313291D1 (zh) |
IL (1) | IL106435A0 (zh) |
MX (1) | MX9304780A (zh) |
PH (1) | PH30956A (zh) |
TW (1) | TW226021B (zh) |
WO (1) | WO1994003463A1 (zh) |
ZA (1) | ZA935380B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100372162C (zh) * | 2003-01-22 | 2008-02-27 | 威伦斯技术公司 | 锂电池组 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3683080A (en) * | 1970-08-28 | 1972-08-08 | Procter & Gamble | Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue |
DE2310450A1 (de) * | 1973-03-02 | 1974-09-05 | Henkel & Cie Gmbh | Komplexbildner fuer mehrwertige metallionen |
DE2360797C2 (de) * | 1973-12-06 | 1985-05-23 | Henkel KGaA, 4000 Düsseldorf | Pharmazeutische Präparate |
FR2531088B1 (fr) * | 1982-07-29 | 1987-08-28 | Sanofi Sa | Produits anti-inflammatoires derives de l'acide methylenediphosphonique et leur procede de preparation |
PH27078A (en) * | 1984-12-21 | 1993-02-01 | Procter & Gamble | Pharmaceutical compositions containing geminal diphosphonates |
IL84731A0 (en) * | 1986-12-19 | 1988-05-31 | Norwich Eaton Pharma | Heterocycle-substituted diphosphonic acids and salts and esters and pharmaceutical compositions containing them |
US5071840A (en) * | 1986-12-19 | 1991-12-10 | Norwich Eaton Pharmaceuticals, Inc. | Certain heterocyclic substituted diphosphonate compounds pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism |
IT1242565B (it) * | 1990-09-14 | 1994-05-16 | Marposs Spa | Apparecchiatura per il controllo di una pluralita' di pezzi meccanici e relativo metodo di controllo. |
EP0521622B1 (en) * | 1991-07-03 | 1997-08-13 | PHARMACIA & UPJOHN COMPANY | Pyrazolopyrimidine and pyrimidinyl bisphosphonic esters as anti-inflammatories |
US5312814A (en) * | 1992-12-09 | 1994-05-17 | Bristol-Myers Squibb Co. | α-phosphonocarboxylate squalene synthetase inhibitors |
-
1993
- 1993-06-09 EP EP93914399A patent/EP0654035B1/en not_active Expired - Lifetime
- 1993-06-09 DE DE69313291T patent/DE69313291D1/de not_active Expired - Lifetime
- 1993-06-09 AU AU44074/93A patent/AU4407493A/en not_active Abandoned
- 1993-06-09 AT AT93914399T patent/ATE157097T1/de active
- 1993-06-09 JP JP6505275A patent/JPH07509712A/ja active Pending
- 1993-06-09 WO PCT/US1993/005365 patent/WO1994003463A1/en active IP Right Grant
- 1993-07-16 TW TW082105671A patent/TW226021B/zh active
- 1993-07-21 IL IL106435A patent/IL106435A0/xx unknown
- 1993-07-26 ZA ZA935380A patent/ZA935380B/xx unknown
- 1993-08-06 PH PH46642A patent/PH30956A/en unknown
- 1993-08-06 MX MX9304780A patent/MX9304780A/es unknown
- 1993-08-07 CN CN93116258A patent/CN1086218A/zh active Pending
-
1995
- 1995-02-01 US US08/382,240 patent/US5565441A/en not_active Expired - Fee Related
-
1996
- 1996-05-29 US US08/654,801 patent/US5643895A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JPH07509712A (ja) | 1995-10-26 |
TW226021B (zh) | 1994-07-01 |
EP0654035A1 (en) | 1995-05-24 |
WO1994003463A1 (en) | 1994-02-17 |
AU4407493A (en) | 1994-03-03 |
EP0654035B1 (en) | 1997-08-20 |
DE69313291D1 (de) | 1997-09-25 |
US5643895A (en) | 1997-07-01 |
IL106435A0 (en) | 1993-11-15 |
ZA935380B (en) | 1995-01-26 |
ATE157097T1 (de) | 1997-09-15 |
MX9304780A (es) | 1994-02-28 |
PH30956A (en) | 1997-12-23 |
US5565441A (en) | 1996-10-15 |
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C01 | Deemed withdrawal of patent application (patent law 1993) | ||
WD01 | Invention patent application deemed withdrawn after publication |