CN1036772A - 酚取代的偕二膦酸酯衍生物，它们的制备方法和含有它们的药用组合物 - Google Patents
酚取代的偕二膦酸酯衍生物，它们的制备方法和含有它们的药用组合物 Download PDFInfo
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- CN1036772A CN1036772A CN89101830A CN89101830A CN1036772A CN 1036772 A CN1036772 A CN 1036772A CN 89101830 A CN89101830 A CN 89101830A CN 89101830 A CN89101830 A CN 89101830A CN 1036772 A CN1036772 A CN 1036772A
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- compound
- bisphosphonates
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- butyl
- oet
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- 239000000203 mixture Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 82
- 229940122361 Bisphosphonate Drugs 0.000 claims description 81
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 60
- -1 alkylidene dioxygen Chemical compound 0.000 claims description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 150000004663 bisphosphonates Chemical class 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 150000001721 carbon Chemical group 0.000 claims description 19
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
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- JJJOZVFVARQUJV-UHFFFAOYSA-N 2-ethylhexylphosphonic acid Chemical compound CCCCC(CC)CP(O)(O)=O JJJOZVFVARQUJV-UHFFFAOYSA-N 0.000 claims description 11
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- 239000003795 chemical substances by application Substances 0.000 claims description 8
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- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 3
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- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
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- 229910001420 alkaline earth metal ion Inorganic materials 0.000 claims description 2
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- 150000003818 basic metals Chemical group 0.000 claims description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003999 initiator Substances 0.000 claims description 2
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- 125000001424 substituent group Chemical group 0.000 claims description 2
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims 6
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- LUHPUPVJIVTJOE-UHFFFAOYSA-N 1-phosphonoethenylphosphonic acid Chemical class OP(O)(=O)C(=C)P(O)(O)=O LUHPUPVJIVTJOE-UHFFFAOYSA-N 0.000 claims 1
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- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
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- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims 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
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- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- CHHHXKFHOYLYRE-STWYSWDKSA-M potassium sorbate Chemical class [K+].C\C=C\C=C\C([O-])=O CHHHXKFHOYLYRE-STWYSWDKSA-M 0.000 description 1
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- 238000001556 precipitation Methods 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
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- 150000003254 radicals Chemical class 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
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- 238000004611 spectroscopical analysis Methods 0.000 description 1
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- NCPXQVVMIXIKTN-UHFFFAOYSA-N trisodium;phosphite Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])[O-] NCPXQVVMIXIKTN-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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Classifications
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- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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Abstract
本发明是关于由酚取代的新的偕二膦酸酯类衍
生物(式I)，以及它们的制备方法和含有它们的药用
组合物。
Description
本发明是关于一类新的化合物——酚取代的偕二膦酸酯衍生物及制备该类化合物的方法。本发明还涉及含有上述化合物的药用组合物，尤其是治疗高血脂的药用组合物。
广泛的流行病学研究表明，血清中胆固醇高的人非常容易患冠状动脉疾病。脂研究——临床预肪冠状动脉疾病的初步试验报告(脂研究——临床预防冠状动脉疾病的初步试验结果：I.心脏冠状动脉疾病发生率的下降，Journal of the American Medical Association 251，p.351-364，1984；脂研究——临床预防冠状动脉疾病的初步试验结果，II.心脏冠状动脉疾病发生率的下降与胆固醇降低的关系，Jourral of the American Medical Assso-ciation 251，P，365-374，1984)提供的有力和明确的证据表明，用降低胆固醇药物可以降低心脏冠状动脉疾病的发生率。
此外，赫尔辛基(Helsinki)最近的研究报告指出，用二甲苯氧庚酸进行治疗可使血清中脂蛋白和血浆中三酸甘油酯含量减少，从而可以降低由于脂血症所引起人体心脏冠状动脉疾病的发生率(The New England Journal of Medicine 317(20)，P.1237-1245，1987)。
用本发明的酚取代的偕二膦酸酯进行试验，发现它们是有效的降低血脂剂和脂变换剂，此外还发现其中有些具有降低血压的作用。因此上述偕二膦酸酯可以用作血脂症和有关心血管疾病的有效治疗剂。
H.Gross及其合作者叙述了(3，5-二叔丁基-4-羟苯基)亚甲基二膦酸及其甲酯、乙酯和丙酯的合成[Journal f.Prakt.Chemie 317(6)，P，890-896(1975)；同上，318(3)，P.403-408(1976)和同上，320(2)，P.344-350(1978)]。但是未曾叙述上述化合物的有效作用。
W.Lehnert曾报道了简单的苯基亚乙基-二膦酸酯及其羧基膦酸酯的制备方法[Tetrahedron 30，P.301-305(1974)]，但是未曾报道它们有效的作用。
Symphar S.A.在美国专利4,696,920(1987年)中曾报道了四乙基和四丁基2-(3，5-二叔丁基-4-羟基)苄基-1，3-亚丙基二膦酸酯的制备方法，并报道它们可用于治疗钙通道功能障碍所引起或与钙通道障碍有关的心血管疾病。
Symphar S.A.在英国专利2,043,072(1979年)中报道了未取代的苯基-和苯氧基-亚烷基-1，1-二膦酸及其甲酯和乙酯的合成，并报道了它们作为抗动脉粥样硬化剂的应用。
本发明涉及式I化合物，其中Z1、Z2、Z3和Z4可以相同或不同，它们可以是-OR，其中R为氢、有1-8个碳原子的直链或带支链的或环状的烷基，
-OM，其中M为碱金属或碱土金属离子，或为铵基NR4，其中R的定义同上，
-NR2，其中R的定义同上，
-Z1与Z2、Z3与Z4可以形成有2-8个碳原子的亚烷基二氧环。
X1、X2可以相同或不同，它们可以是氢、卤原子、有1-8个碳原子的直链、带支链的或环状的烷基或烷氧基，
X3为氢、有1-4个碳原子的烷基R1、酰基C(O)R1、氨基甲酰基C(O)NHR1，其中R1的定义同上；X3O与两个另外的取代基X1和X2中之一可以形成有1-4个碳原子的亚烷基二氧环，
A为-CH＝CH-CH2-、-(CH2)n-、-O(CH2)n-、-S-、SO2、-S(CH2)n-、SO2(CH2)n-，其中n为整数1-7，-(CH＝CH)k-(CH2)d-CH＝，其中k为零或1，d为整数零-4，
B为氢、有1-4碳原子的烷基，
t为零或1，条件是只有当A为(CH＝CH)k-(CH2)d-CH＝(其中k和d的定义同上)时，t为零。
式I化合物包括酚取代的亚烷基二膦酸酯(Ia)和酚取代的亚链烯基二膦酸酯(Ib)
其中X1、X2、X3、A、B、k、d、Z1、Z2、Z3、Z4的定义同上。
结构式(Ia)化合物中，例如
X1、X2可以相同或不同，它们可以是有1-8个碳原子的烷基，
X3为氢，
A为CH＝CH＝CH2(CH2)n、S、SO2、S-(CH2)n、SO2-(CH2)n，其中n为1-7，
B为氢或C1-C4烷基，
Z1、Z2、Z3、Z4可以相同或不同，它们可以是羟基，有1-8个碳原子的烷氧基，或者Z1与Z2及Z3与Z4中一对或两对为有2-8个碳原子的亚烷基二氧基。
结构式(Ib)化合物中，例如
X1、X2可以相同或不同，它们可以是有1-8个碳原子的烷基，
X3为氢，
k为零或1，d为零-4，
Z1、Z2、Z3、Z4可以相同或不同，它们可以是羟基，有1-8个碳原子的烷氧基，或者Z1与Z2及Z3与Z4中一对或两对为有2-8个碳原子的亚烷基二氧基。
制备式(I)化合物的方法
本发明还涉及制备偕二膦酸酯(Ia)和(Ib)的方法。
制备(Ia)的实验方法包括使化合物二膦酸酯(III)与碱(例如氢化钠、金属钠、烃氧基钠、正丁基锂 或二异丙基氨基锂)反应。然后起始化合物II与生成的化合物III的阴离子在原处反应，得到取代的二膦酸酯(Ia)。反应在溶剂，例如己烷、庚烷、苯、甲苯、四氢呋喃、二噁烷、二甲氧基乙烷、甲基叔丁基醚或N，N-二甲基甲酰胺中进行。可以应用单一的溶剂，或者应用混合溶溶剂，这主要根据所要求的溶剂极性而定。反应的温度范围为-78℃～溶剂或混合溶剂的沸点之间。反应时间可为数小时～数天。在其中A为硫原子的情况下，合适的起始化合物II为双(取代的苯酚)二硫化物，并且优先选用的碱为正丁基锂。
制备(Ib)的方法包括应用四氯化钛和叔胺(例如甲基吗啉或吡啶)作为催化剂，使合适的醛IV与化合物二膦酸酯V反应，反应在醚类溶剂，例如四氢呋喃、二噁烷或二甲氧基乙烷中进行。通过加入非极性溶剂，例如四氯甲烷，可以容易地改变反应介质的极性。反应温度可为-15℃～40℃，最好为0℃～30℃。
可以将所得到的亚链烯基-二膦酸酯氢化，得到相应的亚烷基-二膦酸酯(Ia)(其中B＝H)。在结构式(Ib)中含有两个双键的特定情况下，即当k＝1时，还原条件可以生成下述两个(Ia)化合物：部分饱和的化合物，其中A＝(CH＝CH)k-(CH2)d-CH，B＝H；或者为完全饱和的化合物，其中A＝(CH-CH)k-(CH2)d-CH2，B＝H。
在极性溶剂(例如甲醇、乙醇)中，将其中k＝1的(Ib)于温度-15°～室温下，用复氢化合物试剂(例如硼氢化钠或硼氢化锂)进行还原时，主要得到其中A＝(CH＝CH)k-(CH2)d-CH2，B＝H的部分饱和化合物(Ia)。
从其中k＝1的(Ib)，以甲醇或乙醇作为溶剂，于室温～回流温度下，用过量的复氢化合物试剂(例如硼氢化钠或硼氢化锂)进行还原，可以得到其中A＝(CH2-CH2)k-(CH2)d-CH2，B＝H的完全饱和化合物(Ia)。另一方便的还原方法是用吸附在活性碳上的钯或铂作为催化剂进行催化氢化。合适的溶剂有甲醇、乙醇、二甲氧基乙烷、二噁烷、四氢呋喃和乙酸。还原反应在室温下，于1-4大气压下进行。
通过第7页所述方法之一得到的化合物(I)可以派生出带有各种酯基团的其它产物。其中的方法之一包括用盐酸或溴代三甲基硅烷/水使化合物四乙基酯(I)(Z1～Z4＝OEt)水解，得到相应的二膦酸(I)(Z1～Z4＝OH)。用三烷基原甲酸酯使二膦酸(I)进行烷基化，得到相应的四烷基酯。另一方法是使四乙基酯衍生物与溴代三甲基硅烷/五氯化磷反应，生成二膦酰基四氯化物。该中间体用各种醇或二醇进行酯化，得到新的衍生物(I)，其中两对取代基Z1与Z2以及Z3与Z4可以为独立的烷氧基，或者形成亚烷基二氧基环。
第7和第8页列出了上面所述的合成方法。合成方法制备(Ia)II III (Ia)Y＝Cl，Br or 
只有当A为S时制备(Ib)和(Ia)，其中B＝H，A＝(CH＝CH)k-(CH2)a-CH2和(CH2CH)k-(CH2)d-CH2，其中k为零或1，d为零至4
合成方法(续) 
Z1与Z2以及Z8与Z4每对形成亚烷基二氧基
当A为S-(CH2)n或O-(CH2)n时，(Ia)还可以在碱存在下，由溴代亚烷基二膦酸酯(VIII)分别与硫代氢醌衍生物(VI)或氢醌衍生物(VII)反应制得。
当A为S-(CH2)n(其中n≥3)时，另一个制备(Ia)的方法是在基团引发剂，例如过氧化苯甲酰或过氧化氢存在下，使VI与亚链烯基二膦酸酯(IX)反应。
应用过酸(例如间氯过苯甲酸)或过氧化物盐(例如高锰酸钾或过硫酸氢钾)作为氧化剂，可以将硫醚基转变成高氧化态的砜基。
其中X3不是氢的式(I)化合物可以应用其中X3≠H的相应起始化合物(II)制备。另一方法是用一般的合成方法使化合物(I)中的酚羟基派生：用烷基化剂(如烷基卤或二烷基硫酸酯)使酚盐阴离子进行烷基化；用酰化剂(如酸酐或酰卤)进行酯化，生成相应的酯，或者与异氰酸酯反应，生成相应的氨基甲酸酯。
市场上买不到的起始化合物V可由下述两个方法之一制备。
烷基亚磷酸酯与卤代甲基膦酸酯之间进行的Arbuzov反应，
亚甲基二膦酸乙基酯的酯基转移，
上述两个方法提供了新的起始化合物V，其中取代基Z1、Z2、Z3、Z4可以是独立的烷氧基，或者其中取代基对Z1与Z2和/或Z3与Z4形成亚烷基二氧基环。
式(I)化合物的结构可以通过元素分析、红外光谱(IR)、质谱(MS)和核磁共振谱(NMR)确定。化合物的纯度可通过薄层层析(硅胶，以CH2Cl2/MeoH和CHCl3/MeoH为洗脱剂)、气液色谱(聚甲基硅氧烷柱)或高压液相色谱(十八烷基硅烷反相柱)检验。
本专利申请中所应用的缩写注释如下：
在表1和表2中，n表示正，i表示异，See表示仲，t表示叔。在NMR谱中，S表示单峰，d表示双峰，t表示三重峰，m表示多重峰。温度为摄氏，熔点未经校正。沸点是指在球管型蒸馏装置(Kugelrohr)中，用短路蒸馏得到的数值。
用实例1-23典型的合成方法进一步详细叙述本发明。
实例1(化合物7)
四丁基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯
将3，5-二叔丁基-4-羟苄基溴(2.48g，8.3mmol)在30ml二恶烷中的溶液加到12.5mmol四丁基亚甲基二膦酸酯钠(由等摩尔量的NaH和四丁基亚甲基二膦酸酯反应制得)的30ml四氢呋喃溶液中。反应混合物回流16小时，然后在H2O和CHCl3间进行分配。用MgSO4干燥有机相，蒸发，残余物经柱层析(SiO2，依次用CHCl3和95/5 CHCl3/MeoH洗脱)纯化，得2.9g(4.6mmol，56％)四丁基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯。
IR(薄膜法)：2980cm-1：脂肪族C-H
1440：t-C4H9
1240：P＝O
1020-970：P-O-C
NMR(CDCl3)：
δ＝7.05(s，2H)：芳族H
5.08(s，1H)OH
4.1-3，95(m，8H)：P-O-CH2-C3H7
3.18(txd，J＝7和16Hz，2H)：Ph-CH2-
2.66(txt，J＝7和24Hz，1H)：Ph-CH2-CH
1.60(六重峰J＝7 Hz，8H)：P-O-CH2CH2-C2H5
1.44(s，18H)：t-C4H9
1.38(多重峰，J＝7Hz，8H)：P-O-C2H4-CH2-CH3
0.90(2xt，J＝7Hz，12H)：P-O-C3H6-CH3
实例2(化合物5)
四乙基3，5-二叔丁基-4-羟基苯硫基-亚甲基二膦酸酯
于-78℃在氮气流下，向四乙基亚甲基二膦酸酯(2.43g，8.43mmol)的15ml无水四氢呋喃溶液中加入5.3ml(8.43mmol)1.6M正丁基锂己烷溶液，然后向上述溶液中加入4.0g(8.43mmol)双(3，5-二叔丁基-4-羟苯基)二硫化物(按T.Fujisawa等，Synthesis 1972，P.624-625制备)的15ml四氢呋喃溶液。混合物在-78℃保持1小时，再于25℃搅拌3天，用20ml饱和NH4Cl溶液进行水解，混合物用乙醚萃取3次，每次40ml。有机相用MgSO4干燥，蒸发，残余物经柱层析(SiO2，用95/5 CH2Cl2/MeoH洗脱)纯化，得到2.2g(4.2mmol)黄色油状物，该油状物结晶缓慢，产率为49％。
mp＝78～80℃
mp＝78-80℃
元素分析，C23H42O7P2S
计算值(％)C52.66 H8.07 P11.88 S6.11
实测值(％)C52.13 H7.77 P11.65 S6.62
IR(薄膜法)：3600+3450cm-1：OH
1430：t-C4H9
1250：P＝O
1040：P-O-C
NMR(CDCl3)：
δ＝7.5(s，2H)：芳族H
5.4(s，1H)：OH
4.35-4.2(m，8H)：P-O-CH2CH3
3.55(t，J＝21Hz，1H)：-C H-PO3Et2
1.45(s，18H)：t-C4H9
1.35(t，J-7Hz，12H)：P-O-CH2-CH3
MS：524(M+)
实例3(化合物4)
四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯
将分散在矿物油中的80％氢化钠(2.2g，73.5mmol)悬浮于70m1无水苯中，于室温下向其中加入四乙基亚甲基二膦酸酯(21.2g，73.5mmol)。向该四乙基亚甲基二膦酸酯钠溶液中加入20g(66.8mmol)3，5二叔丁基-4-羟苄基溴(按H.Gross.H.Seibt和I.Keitel，Journal fur prakt.chemie 317(6)，p.890-896(1975)制备)的30ml甲苯溶液。所得的混合物回流16小时。已冷却的甲苯相用H2O萃取，用MgSO4干燥并蒸发至干。残余物经柱层析(Si2O，依次用CHCl3和95/5 CHCl3/MeoH溶液洗脱)纯化，得到21.3g(产率为63％)四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯。
mp＝62-63℃
元素分析，C24H44O7P2
计算值(％)C56.90 H8.76 P12.23
实测值(％)C56.76 H8.53 P12.15
IR(KBr)：3400cm-1：O-H
2850：脂肪族C-H
1440：叔丁基
1240：P＝O
1040：P-O-C
NMR(CDCl3)：
δ＝7.1(s，2H)：芳族H
5.1(s，1H)：OH
4.15-4.05(m，8H)：P-O-CH2CH3
3.18(txd，J＝6和17Hz，2H)：Ph-CH2
2.65(txt，J＝6和24Hz，1H)：Ph-CH2-CH
1.45(s，18H)：tC4H9
1.26(两个重叠的三重峰，J＝7Hz，12H)：P-O-CH2-CH3
实例4(化合物13)
四乙基2-(3，4-亚甲基二氧-6-氯苯基)-亚乙基-1，1-二膦酸酯
向四乙基亚甲基二膦酸酯钠(22mmol)在15ml无水二甲氧基乙烷的溶液中加入4.1g(20mmol)6-氯代胡椒基氯。回流16小时后，反旌衔镌贓t2O(3×20ml)和H2O(20ml)间进行分配，有机相用MgSO4干燥，经短路蒸馏(Kugelrohr)得到3.1g(8.5mmol，43％)标题化合物。
bp＝200℃/0.05mmHg
IR(薄膜法)：2950cm-1：脂肪族C-H
1240：P＝O
1030：P-O-C+OCH2O
元素分析，C17H27ClO8P2
计算值(％)C44.70 H5.96 P13.56 Cl7.56
实测值(％)C44.51 H6.21 P13.41 Cl7.65
NMR(CDCl3)：
δ＝6.76(s，1H)：芳族H
6.70(s，1H)：芳族H
5.84(s，2H)：O-CH2-O
4.10-3.96(m，8H)：P-O-CH2CH3
3.10-3.20(m，2H)：Ph-CH2
2.80(txt，J＝7和24Hz，1H)：Ph-CH2CH
1.12(两个重叠的三重峰，J＝7Hz，12H)：P-O-CH2CH3
实例5(化合物30)
四乙基2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙基-1，1-二膦酸酯
在氮气流下将300ml无水四氢呋喃置于500ml反应器内，并冷却至0℃。向其中滴加四氯化钛(27.5g，145mmol)，随后再加10g(52mmol)3-叔丁基-4-羟基-5-甲基苯甲醛(按G.A.Nikiforov等，I zv.A kad.Nauk SSSR，Otd.Khim.Nauk 1962，P.1836-8；Chem.Abst.58，7856f(1963)方法合成)，再依次加入四乙基亚甲基二膦酸酯(21g，72mmol)和吡啶(22.9g，290mmol)。混合物在室温下搅拌3小时并真空浓缩。将残余物在Et2O和H2O之间进行分配，乙醚相用NaHCO3溶液洗涤至PH为7，干燥并蒸发至干。得到18.5g(40mmol，产率77％)标题化合物，经气液色谱检验，为纯品。
IR(薄膜法)：3400cm-1：OH
2950：脂肪族C-H
1240：P＝O
1060：P-O-C
NMR(CDCl3)：
δ＝8.2(dxd，J＝30和50Hz，1H)：Ph-CH＝CP2
7.7-7.6(m，2H)：芳族 H
4.25-4.05(m，8H)：P-O-CH2CH3
2.25(s，3H)篊H3
1.4(s，9H)：t-C4H9
1.35和1.2(2xt，12H)：P-O-CH2-CH3
实例6(化合物33)
四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯
在氮气流下700ml无水四氢呋喃置于1升反应器内。向冷却至0℃的THF溶液中加入四氯化钛(96.5g，0.51mol)，随后加入40.0g(0.17mol)3，5-二叔丁基-4-羟基苯甲醛，再滴加四乙基亚甲基二膦酸酯(69.1g，0.24mol)，接着加入甲基吗啉(97.6g，0.97mol)，所得的混合物于室温下搅拌4小时。反应混合物于H2O和乙醚之间进行分配，洗涤乙醚相直至PH为中性，干燥并蒸发。残余物用丙酮重结晶，母液经柱层析(SiO2，依次用CHCl3和95/5C HCl3/MeoH洗脱)纯化，合并各部分，得53g(0.11mol，产率62％)四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙烯将-1，1-二膦酸酯。
mp＝120～121℃
元素分析，C24H42O7P2
计算值(％)C57.14 H8.39 P12.28
实测值(％)C56.89 H8.23 P12.05
IR(KBr)：3200cm-1：OH
2850：脂肪族 C-H
1570：C＝C
1440：叔丁基
1240：P＝O
1060：P-O-C
NMR(CDCl3)：
δ＝8.25(dxd，J＝30和48Hz，1H)：Ph-CH＝C-P2
7.7(m，2H)：芳族H
5.65(s，1H)：OH
4.2-4.0(2xm，8H)：P-O-CH2-CH3
1.5和1.45(2xs，18H)：t-C4H9
1.4和1.2(2xt，12H)：P-O-CH2CH3
实例7(化合物38)
四乙基2-(3，4-亚甲基二氧苯基)-亚乙烯基-1，1-二膦酸酯
在氮气流下，向200ml冷却至0℃的无水THF中滴加TiCl4(11ml，100mmol)，随后依次加入胡椒醛(7.5g，50mmol)溶于30ml THF的溶液、四乙基亚甲基二膦酸酯(14.4g，50mmol)和N-甲基吗啉(20.2g，200mmol)。混合物于室温下搅拌90分钟，向其中加入HO(50ml)，所得混合物用Et2O萃取3次，每次100ml。有机相的残余物经柱层析(SiO2，用95/5 CHCl3/MeoH洗脱)纯化，得到13.7g(32.6mmol，产率为66％)标题化合物。
IR(薄膜法)：2980，1560(C＝C)，1250(P＝O)，1030(P-O-C)
元素分析，C17H26O8P2
计算值(％)C48.58 H6.24 P14.74
实测值(％)C48.20 H6.01 P14.21
NMR(CDCl3)：
δ＝8.26-8.04(dxd，J＝48和30 Hz，1H)：Ph-CH＝C
7.52(S，1H)：芳族H
7.28(d，1H)：芳族H
6.80(d，1H)：芳族H
5.98(S，2H)：O-CH2-O
4.15和4.05(两个多重峰，8H)：P-O-CH2-CH3
1.30和1.16(两个三重峰，12H)：P-O-CH2-CH3
实例8(化合物1)
四乙基2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙基-1，1-二膦酸酯
向4.65g(123mmol)NaBH4的EtOH溶液中加入11.4g(24.6mmol)四乙基2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙烯基-1，1-二膦酸酯，将混合物回流90分钟。蒸发乙醇溶液，残余物在2.5N HCl和Et2O之间进行分配，有机相干燥并蒸发，得到油状物，该油状物经短路蒸馏纯化，得9.9g(产率为87％)四乙基2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙基-1，1-二膦酸酯
bp＝190℃(0.05mmHg)
元素分析，C21H38O7P2
计算值(％)C54.30 H8.25 P13.34
实测值(％)C54.04 H8.15 P12.94
IR(薄膜法)：3400cm-1：OH
2850：脂肪族C-H
1240：P＝O
1060：P-O-C
NMR(CDCl3)：
δ＝7.0-6.9(m，2H)：芳族H
4.2-4.05(m，8H)：P-O-CH2-CH3
3.14(dxt，J＝6和18Hz，2H)：Ph-CH2
2.6(txt，J＝6和24Hz，1H)：Ph-CH2-CH
2.2(s，3H)：CH3
1.4(s，9H)：t-C4H9
1.25(2xt，12H)：P-O-CH2-CH3
实例9(化合物4)
四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯
在氮气流下向硼氢化锂(3.3g，15mmol)在250ml乙醇的悬浮液中加入四乙基2-(3，5-二叔丁基4-羟苯基)-亚乙烯基-1，1-二膦酸酯(25.3g，50mmol)(化合物33)的80ml乙醇溶液，混合物回流1小时。蒸除溶剂，残余物溶于乙醚中。乙醚相用10％ HCl溶液、水洗涤直至PH为6，然后用MgSO4干燥。蒸发乙醚溶液，得24g(47mmol，产率为95％)四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯。
化合物33的还原也可以通过催化氢化进行。
将化合物33(1g，2mmol)和20mg 10％钯/活性碳(10％Pd//C)在50ml乙酸中的混合物于室温和1.5大气压下氢化16小时。滤去催化剂并蒸发溶剂，得1.0g(2mmol，100％)标题化合物。
应用铂/活性碳(10％ Pt/C)也能得到同样好的结果。化合物33(1g，2mmol)和20mg 10％ Pt/C在50ml乙酸中的混合物于室温和1.2大气压下氢化16小时，处理后得到1g化合物4(2mmol，100％)。
由上述还原方法制得的化合物其物理和光谱涉及与实例3所述方法制得的化合物一致。
实例10(化合物8)
2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸
在无水条件下，向四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯(1.95g，3.86mmol)的10ml四氯化碳溶液中滴加三甲基溴代硅烷(5ml，38.6mmol)。混合物于室温下搅拌30小时，蒸除过量的BrSiMe3，残余物加20ml H2O处理2小时，蒸发水溶液，得1.43g(3.6mol，94％)二膦酸。
mp＝177-178℃
IR(KBr)：3600cm-1：OH
3000-2500：P-O-H
1430：t-C4H9
1200：P＝O化合物8也可以用盐酸水解制得。将化合物4(2.5g，50mmol)在10ml 37％HCl中的混合物加热至115℃，保持16小时。蒸发至干，得1.9g(4.8mmol，96％)2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸。
实例11(化合物10)
四甲基2-(3，5-二叔丁基-4-羟苯基)-亚乙基1，1-二膦酸酯
将3.5g(8.9mmol)2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸和10g(94mmol)三甲基原甲酸酯的混合物回流1小时。蒸馏除去生成的甲酸甲酯和甲醇。另外再加入新鲜的三甲基原甲酸酯(10g，94mmol)，混合物回流1小时。除去过量的试剂并经短路蒸馏(200℃，0.05mmHg)，得2.5g(65％)四甲基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯。
mp＝77-78℃
IR(KBr)：3400cm-1：O-H
2850：脂肪族 C-H
1430：叔丁基
1245：P＝O
1185：P-O-Me
1030：P-O-C。
NMR(CDCl3)：
δ＝7.25和7.05(m，2H)：芳族H
5.0(s，1H)：OH
3.7-3.65(两个二重峰，J＝11Hz，12H)：P-O-CH3
3.1(txd，J＝6和17Hz，2H)：Ph-CH2
2.6(txt，J＝6和24Hz，1H)：Ph-CH2-CH
1.35(s，18H)： t-C4H9实例12(化合物15)四乙基1-(3，5-二叔丁基-4-甲氧基苯基)亚丙基2，2-二膦酸酯
向80％NaH(40mg，1.3mmol)在20ml无水THF的悬浮液中加入四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯(500mg，1mmol)。再加入甲基碘(1.3ml，6mmol)，将反应混合物回流16小时。用Et2O萃取后，有机相经干燥和蒸发。通过柱层析(SiO2，用95/5 CHCl3/MeoH洗脱)后得到440mg(0.84mmol，84％)标题化合物。
IR：2980cm-1：脂肪族C-H
1240：P＝O
1030：P-O-C
MS：534(M+)，397(100％，M-PO3Et2)+，233
实例13(化合物41)
四乙基2-(3，5-二叔丁基-4-乙酸基苯基)-亚乙烯基-1，1-二膦酸酯
将四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙烯基-1，1-二膦酸酯(3g，6mmol)和催化量(50mg)的H2SO4在3g乙酐中的混合物加热至80℃，保持3小时。反应混合物倾入冰中并萃取到Et2O中。有机相用H2O洗涤，用MgSO4干燥并蒸发至干。残余物经柱层析(SiO2，用95/5 CHCl3/MeoH洗脱)纯化，得2.32g(4.2mmol，产率为71％)标题化合物。
IR：2840cm1：脂肪族C-H
1760：C＝O
1560：C＝C
1240：P＝O
1030：P-O-C
实例14(化合物17)
四乙基4-(3，5-二叔丁基-4-羟苯硫基)-亚丁基-1，1-二膦酸酯
将1.0g(3.04mmol)四乙基3-亚丁烯基-1，1-二膦酸酯(由四乙基亚甲基二膦酸酯和烯丙基溴反应制得、0.8g(3.36mmol)3，5-二叔丁基-4-羟基苯硫酚和0.022g(0.09mmol)过氧化二苯甲酰置于苯中回流过夜。蒸发溶剂后粗产品经柱层析分离，得到0.44g(产率为25％)四乙基4-(3，5-二叔丁基-4-羟基苯硫基)-亚丁基-1，1-二膦酸酯。
IR(薄膜法)：3400cm-1：O-H
2850：脂肪族C-H
1430：叔丁基
1240：P＝O
1020：P-O-C
MS：566(M+)，429(M-PO3Et2)+
实例15(化合物19)
二乙基1-双(二甲氨基)氧膦基-2-(3，5-二叔丁基-4-羟苯基)乙基膦酸酯
按P.Savignac等[Tetrahedron letters 26(37)，P.4435～4438(1985)]的方法，用二异丙基氨基锂的THF溶液使二乙基甲基膦酸酯和双(二甲氨基)磷酰氯反应制备二乙基双(二甲氨基)氧膦基甲基膦酸酯。
在室温下向80％NaH(0.15g，5mmol)在20ml无水四氢呋喃的悬浮液中加入二乙基双(二甲氨基)氧膦基甲基膦酸酯(1.4g，5mmol)。再加入3，5-二叔丁基-4-羟苄基溴(1.5g，5mmol)在20ml二噁烷中的溶液，将混合物回流过夜。蒸发溶剂后，残余物在H2O和CHCl3之间进行分配。有机相蒸发，残余物经柱层析(SiO2，用95/5 CHCl3/MeoH洗脱)纯化，得到490mg(产率为20％)标题化合物。
IR(薄膜法)：3400cm-1：OH
2860：脂肪族C-H
1440：t-C4H9
1240+1220：P＝O
1030：P-O-C
MS：(m/e)+：504(M+)；369(100％，M+-PO(NMe2)2)；135(PO(NMe2)2)+
NMR(CDCl3)
δ＝7.08(s，2H)：芳族H
5.08(s，1H)：OH
4.1-3.9(m，4H)：P-O-CH2CH3
3.25-3.1(大m，2H)：Ph-CH2-CH
2.9-2.7(大m，1H)：Ph-CH2-CH
2.5 and 2.55(两个d，J＝9Hz，12H)：N-CH3
1.38(s，18H)：t-C4H9
1.15(两鰐，J＝7Hz，6H)：P-O-CH2CH3
实例16(化合物16)
四乙基3，5-二叔丁基-4-羟基苯磺酰基亚甲基二膦酸酯
在搅拌和冰浴下，向400mg四乙基3，5-二叔丁基-4-羟基苯硫基-亚甲基二膦酸酯(化合物5)(0.84mmol)在5ml CH2OH的溶液中加入800mg(1.26mmol)49.5％KHSO5(过硫酸氢钾，“OXohe”)在0.8ml H2O中的溶液。所得泥浆状物搅拌过夜，浓缩混合物以除去MeoH。残余物在H2O和CH2Cl2之间进行分配。有机相用H2O洗涤直至PH为中性，浓缩，残余物经柱层析(CHCl3/MeoH)纯化，得到200mg(0.36mmol，29％)四乙基3，5-二叔丁基-4-羟基苯磺酰基亚甲基二膦酸酯。
mp＝118-120℃
MS：(m/e)：556(M+)，492((M-SO2)+，100％)，355(M-PO3Et2)+
将化合物5(400mg，0.76mmol)和85％间氯过苯甲酸(0.5g，2.5mmol)在5ml CH2Cl2中的混合物于室温下搅拌16小时。有机溶液用饱和NaHSO3、饱和NaHCO3萃取，用MgSO4干燥。经柱层析(CHCl3/MeoH)纯化，得到160mg化合物16(0.28mmol，38％)。
实例17(化合物42)
二丁基二乙基2-(3，5-二叔丁基-4-羟苯基)-亚-乙烯基-1，1-二膦酸酯
由二丁基亚磷酸钠和二乙基氯代甲基膦酸酯反应制得二丁基二乙基亚甲基二膦酸酯，产率为43％，bp＝140℃(0.05mmHg)(Kuggelrohr)。
将TiCl4(4.94g，26mmol)、3，5-二叔丁基-4-羟基苯甲醛(3g，13mmol)、二丁基二乙基亚甲基二膦酸酯(4.4g，13mmol)和N-甲基吗啉(5.25g，52mmol)置于20ml THF中于室温下进行反应，制得二丁基二乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙烯基-1，1-二膦酸酯。经柱层析(95/5 CHCl3/MeoH)得到2.6g(4.6mmol，36％)标题化合物。
IR(薄膜法)：2980cm-1：脂肪族C-H
1560：C＝C
1430：t-C4H9
1240：P＝O
1020-970：P-O-C
MS：(m/e)：560(M+)，423(M-PO3Et2)+，367(M-PO3Bu2)+，311
实例18(化合物21)
四乙基1-(3，5-二叔丁基-4-羟苯基)-亚丁基-2，2-二膦酸酯
在NaH的四氢呋喃溶液存在下，由四乙基亚甲基二膦酸酯和乙基碘反应，制得四乙基亚丙基-1，1-二膦酸酯，产率为65％。
向80％NaH(0.143g?.75mmol)在无水THF(10ml)的悬浮液中加入四乙基亚丙基-1，1-二膦酸酯(1.5g，4.75mmol)，将混合物搅拌直至NaH消失。向其中加入3，5-二叔丁基-4-羟基苄基溴(1.42g，4.75mmol)的5ml THF溶液，混合物回流4小时。处理后经柱层析(SiO2，用95/5 CHCl3/MeoH洗脱)纯化，得到0.9g(1.7mmol，36％)标题化合物，mp＝107～110℃。
IR(薄膜法)：3400cm-1：OH
2850：脂肪族C-H
1440：叔丁基
1240：P＝O
1040：P-O-C
NMR(CDCl3)
δ＝7.15(m，2H)：芳族H H
5.1(s，1H)：OH
4.2-4.04(m，8H)：O-CH2-CH3
3.2(两个d，J＝12和16Hz，2H)：Ph-CH2-CP2
2.1-1.9(m，2H)：-C(P2)-CH2-CH3
1.45(s，18H)：tC4H9
1.3-1.15(数个t，J＝7Hz，15H)：-C(P2)-CH2-CH3+O-CH2CH3
实例19(化合物20)
四乙基7-(3，5-二叔丁基-4-羟基苯硫基)-亚庚基-1，1-二膦酸酯
由四乙基亚甲基二膦酸酯钠与1，6-二溴己烷反应制备四乙基7-溴亚庚基-1，1-二膦酸酯。
将含有4.2mmol 3，5-二叔丁基-4-羟基苯硫基的20ml四氢呋喃溶液加到含有1.89g(4.2mmol)四乙基7-溴亚庚基-1，1-二膦酸酯的20ml四氢呋喃溶液中。反应混合物于室温下搅拌过夜。水解并用Et2O萃取后，粗产品用柱层析(SiO2，95/5CHCl3/MeooH)纯化，得到1.6g(2.63mmol，62％)标题化合物。
IR(薄膜法)：3400cm-1：OH
2940：脂肪族C-H
1430：t-C4H9
1250：P＝O
1030+980：P-O-C
MS：(m/e)：608(M+)，371，288(100％)，152
实例20(化合物24)
2-(3，5-二叔丁基-4-羟苯基)亚乙基-1，1-双(2-氧代-1，3，2-二氧杂磷杂环己烷)
将四乙基2-(3，5-二叔丁基-4-羟苯基)-亚乙基-1，1-二膦酸酯与BrSiMe3反应，得到相应的四(三甲基甲硅烷基)二膦酸酯。按照T.Morita等所述反应条件(Chemistry LeettersP.435-438(1980))，使四(三甲基甲硅烷基)二膦酸酯在四氯化碳中与五氯化磷反应，得到2-(3，5-二叔丁基-4-羟苯基)亚乙基-1，1-二膦酰四氯化物。
于55℃，向7.86g(78mmol)三乙胺在80ml二噁烷的溶液中同时加入上述二膦酰基四氯化物(9.0g，19mmol)的40ml二噁烷溶液和1，3-丙二醇(2.9g，38mmol)的40ml二噁烷溶液。加入结束后，反应混合物回流3小时。过滤除去三乙胺盐酸盐沉淀，滤液经柱层析(SiO2，用CHCl3/MeoH 95/5洗脱)纯化，得到标题化合物1.35g(2.9mmol，产率15％)。mp＝175-176℃
IR(KBr)＝3400，1430，1260(P＝O)，1040(P-O-C)
MS(m/e)+＝474(M+)，353(100％，M-PO3(C3H6)2)+
NMR(CDCl3)
δ＝7.25和7.1(m，2H)：芳族H
5.1(s，1H)：OH
4.45，4.3和4.1(3m，8H)：P-O-(CH2)-
3.26(dxt，J＝6和17Hz，2H)：Ph-CH2-
2.80(txt，J＝7和23Hz，1H)：Ph-CH2-CH
2.1和1.9(2m，4H)：P-O-CH2-CH2-CH2
1.4(s，18H)：t-C4H9
实例21(化合物43)
四乙基4-(3，5-二叔丁基-4-羟苯基)-1，3-丁间二烯亚基-1，1-二膦酸酯
于氮气流下，将四氯化钛(3.14g，0.017mol)滴加到冰浴中冷却的40ml无水THF中。依次加入2.15g(0.008mol)3，5-二叔丁基-4-羟基-肉桂醛、2.39g(0.008mol)四乙基亚甲基二膦酸酯和3.25g(0.033mol)甲基吗啉。生成的混合物再保持在冰浴中1小时，然后使其升温至室温过夜。加入50ml水，生成的混合物用乙醚萃取3次，每次50ml。合并的有机相用盐水洗涤3次，每次50ml，经硫酸镁干燥并蒸发。残余物经柱层析(SiO2，95/5 CHCl3/MeoH)纯化，得到3.6g(0.0068mol，产率82％粗的标题化合物。用丙酮重结晶，得到2.1g(0.0040mol，产率48％)纯的产物。熔点为141-143℃，熔融时为深红色溶液。
IR(KBr)：3360cm-1：OH
1600，1550和1530：C＝C
1420和1430：tC4H9
1200：P＝O
1020：P-O-C
MS：m/e：530(M+)，515(M-Me)，393(M-PO3Et2)
NMR(CDCl3)
δ＝8.05-7.7(数个m，2H)：C＝CH-CH＝C
7.4(s，2H)：芳族H
7.04(d，J＝15Hz，1H)：Ph-CH＝C
5.6(s，1H)：OH
4.2(m，8H)：P-O-CH2CH3
1.45(s，18H)：t-C4H9
1.35(t，J＝7Hz，12H)：P-O-CH2CH3
实例22(化合物45)
二乙基2-(3，5-二叔丁基-4-羟苯基)-1-(2-氧代-1，3，2-二氧杂磷杂环己-2-基)乙烯基-1-膦酸酯
使三乙基亚磷酸酯与2-氯甲基-2-氧代-1，3，2-二氧杂磷杂环己烷进行A rbuzov反应，制得二乙基(2-氧代-1，3，2-二氧杂磷杂环己-2-基)甲基膦酸酯(IR：1260和1030)。
应用二乙基(2-氧代-1，3，2-二氧杂磷杂环己-2-基)甲基膦酸酯作为膦酸酯试剂，按实例6所述一般反应条件进行。处理后，经柱层析纯化，得到标题化合物，为油状物，产率63％。
IR(薄膜法)：3450cm-1，1570(C＝C)，1420，1260，1030(P-O-C)
MS：488(M+)，367(M-PO3Et2)+，351(M-PO3(CH2)3)+，57(t-Bu)
NMR(CDCl3)
＝8.2(dxd，J＝30和48Hz，1H)：Ph-CH＝CP2
7.75(m，2H)：芳族H
5.65(m，1H)：OH
4.3-4.0(数个m，8H)：P-O-CH2-CH3 and P-O-CH2-(CH2)2
2.1-1.6(数个m，2H)：P-O-CH2-CH2-CH2
1.4(s，18H)：t-C4H9
1.4(t，J＝7Hz)：P-O-CH2-CH3
实例23(化合物28)
四乙基4-(3，5-二叔丁基-4-羟苯基)-亚丁基-1，1-二膦酸酯
将0.5g(0.94mmol)四乙基4-(3，5-二叔丁基-4-羟苯基)-1，3-丁间二烯亚基-1，1-二叔酸酯(化合物43)、0.23g 10％钯-碳的25ml冰醋酸溶液置于帕尔(Parr)氢化装置中，加3个大气压的氢气进行催化氢化，直至不再吸收氢为止。滤出催化剂。滤液用等体积的水稀释，并用氯仿萃取。氯仿相依次用10％氢氧化钠、水洗涤，经MgSO4干燥。蒸去溶剂得0.4g标题化合物(经气相色谱检验，纯度为98％)。
IR(薄膜法)：3400cm-1：O-H
2940：脂肪族C-H
1440：叔丁基
1250：P＝O
1020：P-O-C
NMR(CDCl3)：
δ＝6.96(s，2H)：芳族H
5.03(s，1H)：OH
4.24-4.10(m，8H)：P-O-CH2-CH3
2.52(t，J＝7 Hz，2H)：Ph-CH2-
2.28(txt，J＝6和24Hz，1H)：Ph-CH2-CH2-CH2-CHP2
2.04-1.78(2xm，4H)：Ph-CH2-CH2-CH2-CHP2
1.40(s，18H)：tC4H9
1.28(两个重叠的t，J＝7Hz，12H)：P-O-CH2-CH3
MS：534(M+)
经色谱和光谱分析，该化合物与由3-(3，5-二叔丁基-4-羟苯基)-丙基溴(mp为52～54℃)和四乙基亚甲基二膦酸酯的钠盐在苯中反应所分离的物质是相同的。
表1：酚取代的偕二膦酸酯(Ia)
| 化合物 X1 X2 X3 A B Z1 Z2 Z3 Z4 | mp or bp(mm Hg)，℃ | 分子式a |
| 1 3-Me 5-t-Bu 4-H CH2 H OEt OEt OEt OEt2 3-i-Pr 5-i-Pr 4-H CH2 H OEt OEt OEt OEt3 3-sec-Bu 5-sec-Bu 4-H CH2 H OEt OEt OEt OEt4 3-t-Bu 5-t-Bu 4-H CH2 H OEt OEt OEt OEt5 3-t-Bu 5-t-Bu 4-H S H OEt OEt OEt OEt6 3-t-Bu 5-t-Bu 4-H CH2 H Oi-Pr Oi-Pr Oi-Pr Oi-Pr7 3-t-Bu 5-t-Bu 4-H CH2 H On-Bu On-Bu On-Bu On-Bu8 3-t-Bu 5-t-Bu 4-H CH2 H OH OH OH OH9 3-t-Bu 5-t-Bu 4-H S H OH OH OH OH10 3-t-Bu 5-t-Bu 4-H CH2 H OMe OMe OMe OMe11 3-OMe 5-OMe 4-H CH2 H OEt OEt OEt OEt12 3-OMe 5-OMe 4-Me CH2 H OEt OEt OEt OEt13 6-Cl 3，4-OCH2- CH2 H OEt OEt OEt OEt14 3-t-Bu 5-t-Bu H (CH2)2 H OEt OEt OEt OEt15 3-t-Bu 5-t-Bu Me CH2 Me OEt OEt OEt OEt16 3-t-Bu 5-t-Bu 4-H SO2 H OEt OEt OEt OEt | 190(0.05)195(0.05)200(0.05)62-6378-80104-105b177-178183-18577-78b205(0.05)200(0.05)bb118-120 | C21H38O7P2C22H40O7P2C24H44O7P2C24H44O7P2C23H42O7P2SC28H52O7P2C32H60O7P2ccC20H36O7P2dC19H34O9P2C17H27ClO8P2C25H46O7P2C26H48O7P2C23H42O9P2S |
表1(续)
| 化合物 X1 X2 X3 A B Z1 Z2 Z3 Z4 | mp or bp(mm Hg)，℃ | 分子式a |
| 17 3-t-Bu 5-t-Bu 4-H S(CH2)3 H OEt OEt OEt OEt18 3-t-Bu 5-t-Bu 4-H CH2 H OEt OEt On-Bu On-Bu19 3-t-Bu 5-t-Bu 4-H CH2 H OEt OEt NMe2 NMe220 3-t-Bu 5-t-Bu 4-H S(CH2)6 H OEt OEt OEt OEt21 3-t-Bu 5-t-Bu 4-H CH2 Et OEt OEt OEt OEt22 3-t-Bu 5-t-Bu 4-H S H Oi-Pr Oi-Pr Oi-Pr Oi-Pr23 3-t-Bu 5-t-Bu 4-H CH2 H On-Pr On-Pr On-Pr On-Pr24 3-t-Bu 5-t-Bu 4-H CH2 H O-(CH2)3-O O-(CH2)3O25 3-t-Bu 5-t-Bu 4-H CH2 H OEt OEt Oi-Pr Oi-Pr26 3-sec-Bu 5-sec-Bu 4-H CH2 H Oi-Pr Oi-Pr Oi-Pr Oi-Pr27 3-t-Bu 5-t-Bu 4-H CH2 H OCH2-CMe2-CH2O OCH2-CMe2-CH2O28 3-t-Bu 5-t-Bu 4-H (CH2)3 H OEt OEt OEt OEt29 3-t-Bu 5-t-Bu 4-H CH＝CH-CH2 H OEt OEt OEt OEt | bbbb107-110106-10873-74173-17459-60b66-67bb | dC28H52O7P2C24H46N2O5P2C29H54O7P2SC26H48O7P2C17H50O7P2SC28H52O7P2C22H36O7P2C26H48O7P2C28H52O7P2C26H44O7P2dd |
a＝C，H，P分析，结果在理论值0.4％以内
b＝径柱层析纯化
c＝用NaOH滴定鉴定
d＝用红外和质谱鉴定
表2：酚取代的偕二膦酸酯(Ib)
| 化合物 X1 X2 X3 k d Z1 Z2 Z3 Z4 | mp or bp(mm Hg)，C | 分子式a |
| 30 3-Me 5-t-Bu 4-H 0 0 OEt OEt OEt OEt31 3-i-Pr 5-i-Pr 4-H 0 0 OEt OEt OEt OEt32 3-sec-Bu 5-sec-Bu 4-H 0 0 OEt OEt OEt OEt33 3-t-Bu 5-t-Bu 4-H 0 0 OEt OEt OEt OEt34 3-t-Bu 5-t-Bu 4-H 0 0 Oi-Pr Oi-Pr Oi-Pr Oi-Pr35 3-t-Bu 5-t-Bu 4-H 0 0 On-Bu On-Bu On-Bu On-Bu36 3-t-Bu 5-t-Bu 4-H 0 0 OH OH OH OH37 3-OMe 5-OMe 4-H 0 0 OEt OEt OEt OEt38 H 3，4-OCH2- 0 0 OEt OEt OEt OEt39 H 3，4-O(CH2)2- 0 0 OEt OEt OEt OEt40 3-t-Bu 5-t-Bu 4-Me 0 0 OEt OEt OEt OEt41 3-t-Bu 5-t-Bu 4-MeCO 0 0 OEt OEt OEt OEt42 3-t-Bu 5-t-Bu 4-H 0 0 OEt OEt OBu OBu43 3-t-Bu 5-t-Bu 4-H 1 0 OEt OEt OEt OEt44 3-t-Bu 5-t-Bu 4-H 0 2 OEt OEt OEt OEt45 3-t-Bu 5-t-Bu 4-H 0 0 O(CH2)3O OEt OEt | b97-100102-105120-121131-13259-61135-13753-55bbbbb141-143bb | C21H36O7P2C22H38O7P2C24H42O7P2C24H42O7P2C28H50O7P2C32H58O7P2cC18H30O9P2C17H26O8P2C18H28O8P2C24H44O7P2C26H44O8P2C28H50O7P2C26H44O7P2dC23H48O7P2 |
表2(续)
| 化合物 X1 X2 X3 k d Z1 Z2 Z3 Z4 | mp or bp(mm Hg)，℃ | 分子式a |
| 46 3-t-Bu 5-t-Bu 2-H 0 0 OEt OEt OEt OEt47 3-t-Bu 5-t-Bu 4-H 0 0 OMe OMe OMe OMe48 3-t-Bu 5-t-Bu 4-H 0 0 On-Pr On-Pr On-Pr On-Pr49 3-t-Bu 5-t-Bu 4-H 0 0 OEt OEt Oi-Pr Oi-Pr50 3-sec-Bu 5-sec-Bu 4-H 0 0 Oi-Pr Oi-Pr Oi-Pr Oi-Pr51 3-t-Bu 5-t-Bu 4-H 0 0 O(CH2)3O O(CH2)3O | 143-14595-9685-87106-107b207-213 | C24H42O7P2C20H34O7P2C28H50O7P2C26H46O7P2C28H50O7P2C22H34O7P2 |
a＝C，H，P分析，结果在理论值0.4％以内
b＝径柱层析纯化
c＝用NaOH滴定鉴定
d＝甲红外和质谱鉴定
偕二膦酸酯(式I)的药理活性
在常规筛选中，发现了偕二膦酸酯衍生物的药理活性谱。最明显的作用降血脂(降低血胆固醇和或甘油三酯)。有些二膦酸衍生物具有抗炎作用，有些二膦酸酯可降血压。还发现具有利尿和增强收缩力作用。
另外，在偕二膦酸酯的结构上含有二烷基羟苯基部分时，还可能具有抗氧化剂和自由基消除作用。已经知道，自由基清除剂可防止由氧化作用而引起的若干疾病的病理变化。因此，偕二膦酸酯对于下列疾病可能是有用的：
组织缺血，例如心脏和脑缺血
肌肉营养不良
慢性阻塞性肺脏疾病
病毒感染
老年性角化病(Senile Caractogehesis)
维生素E缺乏症
A.降血脂作用
为寻找新的降血脂的药物，将本专利申请所论述的新的二膦酸酯用口服途径给予小白鼠， 
齿类动物血脂含量比较接近人(一般高于150mg/dl)。例如喂以通常饲料的小白鼠，血中胆固醇和甘油三酯的浓度在100mg/dl范围内，大白鼠接近50mg/dl。有些科学家最近将巳知能降低人高血脂的药物同新的试药进行了比较研究，发现这种动物可用作筛选降血脂药物动物模型(非诺贝特、二甲苯氧庚酸和烟酸对正常鼠和高血脂鼠中血脂蛋白水平的影响，筛选药物推荐的模型，olivier，P.等A therosclerosis 70：P.107-114，1988)。
1)方法：
每次过筛试验用30只OF1品系的小白鼠，体重25-35克，分成五组，每组6只，其中四组给以受试化合物或者对照药物。第五组用作对照。化合物溶解于乙醚中，将此溶液加入食丸中，醚可自然挥发。
所有被试化合物在动物饲料中的最终浓度均为0.1％，动物每天吃入的药量大约相当于180mg/kg。连续给药10天，然后断食一夜，动物用乙醚麻醉，断头处死，采血，装入含EDTA的试管内。
用酶法(Ames Kit №6376和№6630)测定血浆胆固醇和甘油三酯。接受试药或对照药的每组动物，其平均胆固醇和甘油三酯的含量，用对照组动物平均值的百分率表示。
2)结果
表3表明，若干二膦酸酯衍生物(化合物3，4，5，6，7，18，21，22，23，24，33，34，37，47和48)具有明显的降低胆固醇作用，其中，化合物33和34的作用最强(-40％和-41％)。临床上用于治疗高血脂病的氯贝丁酯、二甲苯氧庚酸和非诺贝特，降低胆固醇的作用低于许多试验的二膦酸酯类化合物。非诺贝特是试验对照药中作用最强的，其效果也仅为-15％。上述文献(olivier，P.等)中还报道给小白鼠服用上述的对照药，观察类似的降胆固醇活性。
化合物3，5，6，7，21，22，23，24，30，31，33，37，47和48，具有明显的降低甘油三酯作用。应该特别指出的是，化合物3，19，24，30，37和47，降低血浆甘油三酯的作用高于44％，所用的对照药均未显出这样的作用。二甲苯氧庚酸是降低甘油三酯作用最强的对照物，其作用为-35％，与文献报道的作用强度一致。
这些二膦酸酯降低血脂的确切机制尚不清楚，但用体外标本的研究表明，这些化合物可抑制和干扰某些重要的涉及到胆固醇合成和代谢的酶，如酰基辅酶A：胆固醇酰基转移酶(ACAT)、脂酶等，从而提示了其可能的作用位置。
B.抗炎活性
1)方法：用大鼠脚爪肿胀模型，研究了四个经选择的二膦酸酯对角叉菜胶所致炎症反应的作用。每组有8只动物。将角叉菜胶溶液溶于0.9％的氯化钠溶液中，其浓度为1％(w/v)，取0.1ml注入每只动物右后肢的蹠部腱膜内，制成肿胀模型。角叉菜胶注射前1小时，用胃管给予受试化合物(100mg/kg)和对照药(吲哚美辛，30mg/kg)。
注射角叉菜胶后0，1，2.5和4小时，测定每只动物右脚爪的溶积(本文中仅列出4小时的结果)。
2)结果
正如所料，吲哚美辛完全防止了脚爪肿胀的增加，化合物8和36显示明显的抑制作用，而它们中相应的乙酯却仅有很小的活性。
这些结果表明，在上述动物模型上，二膦酸类(如化合物8)具有抗炎作用。
C.高血压动物的口服降压作用
自发性高血压大鼠(SHR)是一种良好的人体动脉高血压的动物模型。将偕二膦酸酯(式I)给予大鼠(SHR)时，可产生明显的降压作用。
在过筛试验中，将各种偕二膦酸酯溶于吐温-80，并给予大鼠(SHR)。用尾套法测量血压，每小时一次，给药后两小时测得的降压作用列于表5。
化合物4，6，7和18可使血压降低30～50％，其降压作用与所用的对照药相似。这些对照药是用于治疗心绞痛和高血压的药物。
偕二膦酸酯(式I)可松弛平滑肌，在治疗心血管疾病方面可能是很有用的。这些化合物的主要适应症将是治疗心绞痛，充血性心力衰竭和高血压。
表3
二膦酸酯(式I)和对照药的降血脂活性
| 化合物(I) | 胆固醇(对照的％) | 甘油三酯(对照的％) |
| 124678101935333031353638 | -2+6-12-37-23-2-5-6-19-22-40+2+40-9-5 | -28-17-1-34-15+19-19-44-46-24-21-45-11+7-5-6 |
表3(续)
| 化合物(I) | 胆固醇(对照的％) | 甘油三酯(对照的％) |
| 1318202122232432343739414243464748对照药氯贝丁酯二甲苯氧庚酸非诺贝特 | -5-31+5-16-21-15-20+8-41-16+4-3+12-5+1-31-21+4-7-15 | +38+60+13-28-37-33-71+9+11-70+17+6+1-14-12-45-36-5-35-2 |
表4
二膦酸酯(式I)和吲哚美辛的抗炎活性
对大鼠右后脚瓜容积增加的抑制作用
(引起肿胀后4小时的结果)
| 化合物(I) | 对照的％ |
| 化合物4″8″33″36对照药吲哚美辛 | +1.5-54.2-5.8-25.0-92.3 |
表5
偕二膦酸酯(式I)对高血压大鼠血压的影响
(给药后2小时)
| 化合物(I) | 血压降低的％ |
| 467183对照药地尔硫硝苯啶 | -34-64-30-41-20-38-47 |
给药方式
因此，式(I)偕二膦酸酯可以用于治疗高血脂症和/或高血压，并且最好以胶囊剂、片剂和颗粒剂形式服用。为此，有效的组成部分应该与药用载体充分混匀。
此外所用的术语“药用载体”是指固体或液体填充剂、稀释剂或胶囊材料。用作为药用载体的实例有糖、淀粉、纤维素及其衍生物、粉末状黄蓍胶、麦芽、明胶、滑石、硬脂酸、硬脂酸镁、硫酸钙、植物油、多元醇、聚乙二醇、琼脂、藻酸、无热原水、等渗盐水和磷酸盐缓冲溶液以及用于药物制剂中其它无毒的可配位的物质。还可以应用湿润剂、润滑剂，例如硫酸月桂酯钠)，也可以应用着色剂，调味剂和防腐剂。
药用载体与本发明的膦酸酯一起应用，组合物的浓度足以提供有效的剂量。药用载体最好约占整个组合物重量的0.1％～99％。按通常的方法，应用下述实例所述的液体或结晶形式的偕二膦酸酯制备胶囊剂和片剂：胶囊剂的实例成分 mg/胶囊化合物7 300明胶 100聚乙二醇1000 600山梨酸钾 0.5片剂的实例成分 mg/片化合物33 500羟丙基甲基纤维素 500硬脂酸镁 3
为了治疗具体的疾病，服用含有药学上适用的偕二膦酸酯的组合物可以按溶液剂、混悬剂、乳剂的形式给药，或者经真皮内注射、肌内注射、静脉注射或腹膜内注射给药。将有效成分加到普通的透明冻胶基质中制备栓剂，偕二膦酸酯可以径直肠给药。
Claims (16)
1.制备酚取代的偕二膦酸酯类衍生物(式I)的方法，
其中
Z1、Z2、Z3和Z4可以相同或不同，它们可以是
OR，其中R为氢、有1-8个碳原子的直链、带支链或环状的烷基，
OM，其中后为碱金属或碱土金属离子，或者为铵基NR4，其中R的定义同上，
NR2，其中R的定义同上，
Z1与Z2及Z3与Z4可以形成有2-8个碳原子的亚烷基二氧基环，
X1、X2可以相同或不同，它们可以是氢、卤原子、有1-8个碳原子的直链、带支链或环状烷基或烷氧基，
X3为氢、有1-4个碳原子的烷基R1、酰基C(O)R1、氨基甲酰基C(O)NHR1，其中R1的定义同上；X3O与其它两个取代基X1或X2中之一可以形成有1-4个碳原子的亚烷基二氧环，
A为-CH＝CH-CH2-、-(CH2)n-、-O(CH2)n-、-S-、-SO2-、-S(CH2)n-、-SO2(CH2)n-、其中n为整数1-7，-(CH＝CH)k-(CH)d-CH＝，其中k为零或1，并且d为整数零～4，
B为氢、有1-4个碳原子的烷基，
t为零或1，条件是只有当A为(CH＝CH)k-(CH2)d-CH＝(其中k和d的定义同上)时，t为零，该方法包括在四氢化钛和叔胺存在下，于对质子有惰性的溶剂中，在0℃～30℃，使醛(式IV)与二膦酸酯(式V)反应，
得到酚取代的亚链烯基二膦酸酯(式Ib)然后，使化合物(Ib)与还原剂反应，得到酚取代的亚烷基二膦酸酯(Ia)
其中A＝(CH＝CH)k-(CH2)d-CH2或(CH2-CH2)k-(CH2)d-CH2。
2.按照权利要求1所述制备(Ib)的方法，其中催化剂为四氯化钛，叔胺为吡啶或甲基吗啉，对质子呈惰性的溶剂为四氢呋喃、二噁烷、二甲氧基乙烷、四氯化碳，或者是上述溶剂的混合物。
3.按照权利要求1所述制备式中A＝(CH＝CH)k-(CH2)d-CH2的化合物(Ia)的方法，其中化合物(Ib)中亚乙烯基-二膦酸酯的双键用复氢化合物，例如硼氢化钠或硼氢化锂在乙醇或甲醇中，于温度-15℃-25℃进行有选择地还原。
4.按照权利要求1所述制备式中A＝(CH2-CH2)k-(CH2)d-CH2的化合物(Ia)的方法，其中化合物(Ib)的双键用过量的复氢化物，例如硼氢化钠或硼氢化锂在乙醇或甲醇中，于温度30℃～80℃进行完全的还原。
5.按照权利要求1所述制备式中A＝(CH2-CH2)k-(CH2)d-CH2的化合物(Ia)的方法，其中化合物(Ib)的双键用吸附在活性碳上的钯或铂作为催化剂，以氢气作为试剂，在极性溶剂，例如甲醇、乙醇、二甲氧基乙烷、二噁烷、四氢呋喃或乙酸中，于室温下，在1-4个大气压下，通过催化氢化进行完全的还原。
6.制备其中X1、X2、X3、A、B、Z1、Z2、Z3、Z4如权利要求1所述的式(Ia)化合物的方法，
7.按照权利要求6所述的方法，该方法在于，使由III与碱(如氢化钠)反应生成的化合物二膦酸酯(III)的阴离子与式II的卤化物(II，Y＝Cl或Br)在对质子呈惰性的溶剂中，于温度65℃～110℃进行反应，对质子呈惰性的溶剂有烃(如甲苯、苯)或醚(如四氢呋喃、二噁烷、二甲氧基乙烷)或上述两种溶剂的混合物。
8.按照权利要求6制备式中A＝S的化合物(Ia)的方法，该方法在于，使由III与碱(如正丁基锂)反应生成的化合物二膦酸酯(III)的阴离子与二硫化物(式II)在溶剂(如四氢呋喃或苯)中，于温度-78℃～40℃进行反应。
9.制备权利要求1所定义的化合物二膦酸(I，其中Z1＝Z2＝Z3＝Z4＝OH)的方法，该方法在于，在回流温度下用浓盐酸使二膦酸酯(式I，其中Z1＝Z2＝Z3＝Z4＝OEt)进行水解，或者先用溴代三甲基硅烷，然后用水进行处理。
10.制备权利要求1所定义的化合物四甲基二膦酸酯(I，其中Z1＝Z2＝Z3＝Z4＝OMe)的方法，该方法在于，在回流温度下，使权利要求9所述的二膦酸与三甲基原甲酸酯进行反应。
11.制备权利要求1所定义的环状二膦酸酯(I，其中两对取代基Z1与Z2以及Z3与Z4各自形成有2-8个碳原子的亚烷基二氧环)的方法，该方法是在极性醚溶剂(如二噁烷)中，于叔胺存在下，在温度20℃～100℃，使二膦酰四氯化物与二醇反应，二膦酰四氯化物是由四乙基二膦酸酯(I，其中Z1＝Z2＝Z3＝Z4＝OEt)先与三甲基溴代硅烷，然后与五氯化磷反应制得的。
12.制备权利要求1所定义的其中A＝-S-(CH2)n-或-O-(CH2)n-的化合物(I)的方法，该方法是在碱存在下，使苯硫酚(式VI)或氢醌(式VII)分别与溴代亚烷基二膦酸酯(式VIII)反应。
13.制备权利要求1所定义的其中A＝-S(CH2)n-，n≥3的化合物(I)的方法，该方法包括在基本的引发剂(如过氧化二苯甲酰)存在下，使苯硫酚(式VI)与亚链烯基二膦酸酯(式IX)反应。
14.制备权利要求1所定义的其中A为-SO2(CH2)n-的化合物(I)的方法，该方法是用间-氯过苯甲酸或过硫酸氢钾使其中A＝-S-(CH2)n-的化合物(I)氧化。
15.按照权利要求1所述方法制备选自以下一组式(I)化合物中之一的方法：
四乙基2-(3，5-二叔丁基-4-羟苯基)亚乙烯基-1，1-二膦酸酯，
四乙基2-(3-叔丁基-4-羟基-5-甲基苯基)亚乙烯基-1，1-二膦酸酯，
四异丙基2-(3，5-二叔丁基-4-羟苯基)亚乙烯基-1，1-二膦酸酯，
四甲基2-(3，5-二叔丁基-4-羟苯基)亚乙烯基-1，1-二膦酸酯，
2-(3，5-二叔丁基-4-羟苯基)亚乙烯基-1，1-二膦酸，
四乙基2-(3，5-二仲丁基-4-羟苯基)亚乙烯基-1，1-二膦酸酯，
四异丙基2-(3，5-二叔丁基-4-羟苯基)亚乙烯基-1，1-二膦酸酯，
四丁基2-(3，5-二叔丁基-4-羟苯基)亚乙烯基-1，1-二膦酸酯，
四乙基2-(3，5-二叔丁基-4-羟苯基)亚乙烯基-1，1-二膦酸酯，
四乙基2-(3，5-二叔丁基-4-羟基苯硫基)亚甲基二膦酸酯，
2-(3，5-二叔丁基-4-羟苯基)亚乙基-1，1-双(2-氧代-1，3，2-二氧杂磷杂环己烷)，以及
2-(3，5-二叔丁基-4-羟苯基)亚乙基-1，1-二膦酸。
16.制备药用组合物的方法，该药用组合物包括至少一个权利要求1所述治疗上有效量的化合物二膦酸酯(式I)以及药学上适用的载体。
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| Application Number | Priority Date | Filing Date | Title |
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| CH1239/88A CH675422A5 (zh) | 1988-03-31 | 1988-03-31 | |
| CH01239/88-2 | 1988-03-31 |
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| CN93116289A Division CN1086820A (zh) | 1988-03-31 | 1989-03-30 | 酚取代的偕二膦酸酯衍生物的制备方法 |
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| Publication Number | Publication Date |
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| CN1036772A true CN1036772A (zh) | 1989-11-01 |
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| CN89101830A Expired - Fee Related CN1024555C (zh) | 1988-03-31 | 1989-03-30 | 酚取代的偕二膦酸酯衍生物的制备方法 |
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| EP (1) | EP0339237B1 (zh) |
| JP (1) | JPH0822865B2 (zh) |
| KR (1) | KR0147830B1 (zh) |
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| WO1993005052A1 (fr) * | 1991-09-05 | 1993-03-18 | Toray Industries, Inc. | Derive d'acide methanediphosphonique, sa production et son utilisation comme remede |
| JPH06172372A (ja) * | 1991-11-06 | 1994-06-21 | Takeda Chem Ind Ltd | スクアレン合成酵素阻害剤およびその用途 |
| EP0541037A3 (en) * | 1991-11-06 | 1997-02-26 | Takeda Chemical Industries Ltd | Squalene synthetase inhibitory composition and use thereof |
| FR2683529B1 (fr) * | 1991-11-12 | 1994-02-04 | Bretagne Occidentale Universite | Composes pharmaceutiques gem-diphosphonates analogues du cis-platine. |
| CH683996A5 (fr) * | 1992-03-05 | 1994-06-30 | Symphar Sa | Dérivés aminophosphonates substitués, leur procédé de préparation et compositions pharmaceutiques les contenant. |
| KR100272907B1 (ko) * | 1992-07-10 | 2001-03-02 | 히라이 가쯔히꼬 | 메탄디포스폰산 유도체, 이의 제조방법 및 이의 의약 용도 |
| US5332728A (en) * | 1992-11-23 | 1994-07-26 | Bristol-Myers Squibb Company | Method for treating a fungal infection |
| US5434288A (en) * | 1992-12-01 | 1995-07-18 | Monsanto Company | PLA2 inhibitors |
| ZA941088B (en) * | 1993-02-19 | 1995-09-27 | Symphar Sa | Substituted ketophosphonates the processes for their preparation and pharmaceutical compositions containing them |
| WO1994019359A1 (en) * | 1993-02-25 | 1994-09-01 | Toray Industries, Inc. | Process for producing methanediphosphonate compound |
| US5419845A (en) * | 1994-03-15 | 1995-05-30 | Basf Corporation | Perfluorinated gemdiphosphonates as corrosion inhibitors for antifreeze coolants and other functional fluids |
| EP0725070B1 (en) * | 1994-08-24 | 2003-03-26 | Toray Industries, Inc. | Process for producing methanediphosphonic acid compound |
| CH690163A5 (fr) * | 1995-07-28 | 2000-05-31 | Symphar Sa | Dérivés gem-diphosphonates substitués utiles en tant qu'agents anti-cancers. |
| GB9603637D0 (en) * | 1996-02-21 | 1996-04-17 | Smithkline Beecham Plc | Process |
| EP0952834A2 (en) * | 1996-05-15 | 1999-11-03 | The University of Sheffield | Isopentenyl pyrophosphate isomerase (ipi) and/or prenyl transferase inhibitors |
| AU750041B2 (en) | 1997-05-14 | 2002-07-11 | Atherogenics, Inc. | Compounds and methods for the inhibition of the expression of VCAM-1 |
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| IL125336A0 (en) * | 1998-07-14 | 1999-03-12 | Yissum Res Dev Co | Compositions for inhibition and treatment of restinosis |
| AUPQ872800A0 (en) * | 2000-07-12 | 2000-08-03 | Heart Research Institute, The | Compositions and methods for treating cardiovascular disorders |
| GB0019272D0 (en) * | 2000-08-04 | 2000-09-27 | Symphar Sa | Pharmaceutical compounds |
| AU2002320025A1 (en) * | 2001-04-11 | 2002-11-11 | Atherogenics, Inc. | Probucol monoesters and their use to increase plasma hdl cholesterol levels and improve hdl functionality |
| EP1435970A4 (en) * | 2001-10-18 | 2005-05-04 | Ilex Products Inc | METHOD OF TREATING SKIN WITH DIPHOSPHONATE DERIVATIVES |
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| EP2001486A4 (en) * | 2006-03-17 | 2010-12-29 | Univ Illinois | BIPHOSPHONATE COMPOUNDS AND CORRESPONDING METHODS |
| WO2008118948A1 (en) * | 2007-03-26 | 2008-10-02 | Atherogenics, Inc. | Methods and compositions of derivatives of probucol for the treatment of diabetes |
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1988
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