CN1057842A - 用作抗动脉粥样硬化剂的新的双[4-(2,6-二-烷基)酚]硅烷衍生物 - Google Patents
用作抗动脉粥样硬化剂的新的双[4-(2,6-二-烷基)酚]硅烷衍生物 Download PDFInfo
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- CN1057842A CN1057842A CN91104474A CN91104474A CN1057842A CN 1057842 A CN1057842 A CN 1057842A CN 91104474 A CN91104474 A CN 91104474A CN 91104474 A CN91104474 A CN 91104474A CN 1057842 A CN1057842 A CN 1057842A
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- methylene
- silylene
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- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- OWSBHFWSKFIEGF-UHFFFAOYSA-M sodium;methyl carbonate Chemical compound [Na+].COC([O-])=O OWSBHFWSKFIEGF-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 210000003684 theca cell Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
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Abstract
本发明是关于用作为LDL脂类过氧化作用抑
制剂和抗动脉粥样硬化剂的某些双[4-(2,6-二-烷
基)苯酚]硅烷衍生物。
Description
这是申请系列号07/548,051(申请日期1990年7月5日)的部分继续申请。
与其主要的临床并发症局部缺血心脏病所显示的结果一样,动脉粥样硬化在工业化国家里仍然是引起死亡的一个主要原因。现在有理由确认,动脉粥样硬化可以由动脉内皮局部损伤开始,然后从中层到内膜层的动脉平滑肌细胞增生,同时在损伤处脂类沉积和泡沫细胞累积。由于动脉粥样硬化斑块的发展,它逐渐阻塞越来越多受损伤的血管,并且最终能够导致局部缺血或梗死。因此,最理想的是对需治疗的患者提供抑制动脉粥样硬化发展的方法。
现在有大量的证据表明,血胆甾醇过多是与心脏病有关的重要的危险因素。例如,1984年12月,National
Institut of Heonsensus DevelopmentConference Panel指出,确切地降低升高的血胆甾醇含量(特别是低密度脂蛋白胆甾醇的血液含量)可以减少由于冠状心脏病所引起的心脏病发作的危险。
通常,胆甾醇以某种脂类蛋白质复合物的形式〔如乳糜微粒、极低密度脂蛋白(VLDL)、低密度脂蛋白(LDL)和高密度脂蛋白(HDL)〕输入温血动物的血液中。现已广泛地确认,LDL作用的方式是直接导致LDL胆甾醇沉积在血管壁上;HDL作用的方式直接导致LDL胆甾醇沉积在血管壁上;HDL作用的方式是导致HDL从血管壁得到胆甾醇,将它输送到肝脏,并且在肝脏进行代谢〔Brown和Goldstein,Ann.Rev.Biochem.52,223(1983);Miller,Ann.Rev.Med.31,97(1980)〕。例如,在各种流行病学研究中发现,LDL胆甾醇含量与冠状心脏病的危险具有密切的关系,而HDL胆甾醇含量与冠状心脏病的危险具有相反的关系〔Patton等,Clin.Chem.29,1890(1983)〕.熟悉本技术领域的专业人员通常认为,降低异常高的LDL胆甾醇含量不仅在治疗血胆甾醇过多中,而且在治疗动脉粥样硬化中均是有效的治疗方法。
此外,根据动物试验和实验室研究有证据证明,LDL脂类(如LDL胆甾醇酯和磷脂的不饱和脂肪酸部分)的过氧化促进了胆甾醇在最终转变成泡沫细胞的单核细胞/巨细胞里的累积,并且在血管壁的内皮下间隙沉淀。泡沫细胞在血管壁的累积被认为是形成动脉粥样硬化斑块的前兆。因此,可以认为LDL脂类的过氧化作用是促使胆甾醇在血管壁沉积和以后形成动脉粥样硬化斑块的重要前提。例如现已表明,单核细胞/巨噬细胞溶解和以较低的速度降解原来的LDL,结果没有明显的胆甾醇累积。相反,氧化了的LDL由上术单核细胞/巨噬细胞以较高的速度吸收,结果有明显的胆甾醇累积〔Parthasarathy等,J.Clin.Invest.77,641(1986)〕。因此最好是对需治疗的患者提供抑制LDL脂类过氧化作用的方法。
本发明是关于可以用作为LDL脂类过氧化作用抑制剂和作为抗动脉粥样硬化剂的某些双〔4-(2,6-二-烷基)酚〕硅烷衍生物。
本发明提供了具有式(1)的新化合物,
其中R1、R2、R3和R4各自独立地为C1-C6烷基;
Z为硫、氧或亚甲基;
A为C1-C4亚烷基。
本发明还提供了抑制需治疗的患者动脉粥样硬化发展的方法,该方法包括给所述患者服用抗动脉粥样硬化有效剂量的式(1)化合物。
此外,本发明也提供了抑制需治疗的患者LDL脂类过氧化作用的方法,该方法包括给所述患者服用抗氧化有效剂量的式(1)化合物。
这里所用的述语“C1-C6烷基”是指由1-6个碳原子组成的直链、支链或环状结构的饱和烃基。在该述语的范围内它包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基、环己基等。
同样,术语“C1-C4亚烷基”是指由1-4个碳原子组成的直链或支链结构的饱和烃二基。在该术语的范围内它包括亚甲基、1,2-亚乙基、1,1-亚乙基、1,3亚丙基、1,2-亚丙基、1,3-亚丁基、1,4-亚丁基等。
式(1)化合物可以由熟悉本技术领域一般技术的专业人员用已知的方法和技术进行制备。制备其中Z为硫或氧的式(1)化合物的一般合成方法见合成路线A,除非另有说明,否则其中所有取代基的定义同前。
合成路线A
Z′=硫或氧
X=氯或溴
一般来说,式1a双酚可以于合适的非质子传递溶剂如二甲基甲酰胺或二甲基乙酰胺中,使合适的2,6-二烷基-4-巯基酚或2,6-二烷基氢醌(式2)(或合适受保护的衍生物)与非亲核的碱(如氢化钠或碳酸钾)和0.5个当量合适的双-卤代亚烷基硅烷(式3)反应制得。
熟悉本技术领域的一般专业人员可以容易地得到用于合成路线A所示一般合成方法的起始原料。例如,其中Z为硫的各种式(1)化合物的某些酚起始原料(例如,2,6-二叔丁基-4-巯基酚)在美国专利3,576,883、3,952,064、3,479,407和日本专利申请73-28425中已有叙述。各种式(1)化合物的甲硅烷基起始原料容易买到,并且可以按照本技术领域已知的一般技术和方法进行制备。
在上述例子中,如果在反应条件下式三化合物的1-酚官能团可以与式3化合物反应,那么式2化合物的1-酚官能团可以用本技术领域熟悉的一般酚保护基进行保护。熟悉本技术领域的专业人员对具体保护基选择和应用是非常了解的。一般来说,应该选择在下面合成步骤中能够适当地保护该酚,并且在不会引起所需产物发生降解的条件下容易脱去的保护基。
合适的酚保护基的实例有醚类,如甲氧基甲基、2-甲氧基乙氧基甲基、四氢吡喃基、叔丁基和苄基;甲硅烷基醚类,如三甲基甲硅烷基和叔丁基二甲基甲硅烷基;酯类,如乙酸酯和苯甲酸酯;碳酸酯类,如甲基碳酸酯和苄基碳酸酯;以及磺酸酯类,如甲磺酸酯和甲苯磺酸酯。
在上述例子中,如果R1和R2各自为叔丁基,那么通常不用保护1-酚官能团就可以进行反应路线A的反应。
下面的实例叙述了合成路线A所示具有代表性的合成方法,应当明白,下面实例仅是为了详细介绍本发明,无论如何不应看作是限制本发明的范围。下面所用的术语所指的意思是:“g”指克,“mmol”指毫摩尔;“ml”指毫升;“bp”指沸点;“℃”指摄氏度;“mmHg”指毫米汞柱;“mp”指熔点;“mg”指毫克;“uM”指微摩尔;“ug”指微克。
实例1
4,4′-〔(二甲基亚甲硅基)双(亚甲硫基)〕-双〔2,6-二-叔丁基〕苯酚
将2,6-二-叔丁基-4-巯基酚(2.4g,10mmol)、碳酸钾(1.4g,10mmol)、双(氯甲基)二甲基硅烷(0.8g,5mmol)和二甲基甲酰胺(50ml)混合,并在氩气流下于室温搅拌过夜。用乙醚稀释,倒入冰水中并分层。依次用水和盐水洗涤醚层经fluorosil-Na2SO4过滤,并蒸发至呈黄色油状物(2.8g)。首先经蒸馏(180-220℃,0.15mmHg)纯化,然后经硅胶层析纯化(Cl4),得到标题化合物,为白色固体(2.9g),mp.116-118℃(己烷)。
元素分析,C32H52O2S2Si
计算值:C,68.51;H,9.34;S,11.43
实测值:C,68.55;H,9.36;S,11.08
实例2/;4,4′-〔(二甲基亚甲硅基)双(亚甲氧基)〕-双-〔2,6-二甲基〕苯酚
将2,6-二甲基氢醌(2.8g,20mmol)、碳酸钾(2.8g,20mmol)、双(氯甲基)二甲基硅烷(1.6g,10mmol)和二甲基甲酰胺(100ml)混合。在惰性气流下于室温搅拌,直至反应完成。用乙醚稀释,倒入冰水中并分层。依次用水和盐水洗涤醚层,经fluorosil-Na2SO4过滤,并蒸发,得到标题化合物。经硅胶层析纯化。
按上述实例1和2所述类似的方法制备下列化合物:
4,4′-〔(二甲基亚甲硅基)双(亚甲硫基)〕双〔2,6-二甲基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲硫基)〕双〔2,6-二甲基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲硫基)〕双〔2,6-二甲基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲硫基)〕双〔2,6-二乙基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲硫基)〕双〔2,6-二乙基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲硫基)〕双〔2,6-二乙基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲硫基)〕双〔2,6-二丙基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲硫基)〕双〔2,6-二丙基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲硫基)〕双2,6-二丙基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲硫基)〕双2,6-二异丙基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲硫基)〕双2,6-二异丙基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲硫基)〕双2,6-二异丙基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲硫基)〕双2,6-二丁基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲硫基)〕双2,6-二丁基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲硫基)〕双2,6-二丁基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲硫基)〕双2,6-二异丁基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲硫基)〕双2,6-二异丁基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲硫基)〕双2,6-二异丁基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲硫基)〕双2,6-二-叔丁基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲硫基)〕双2,6-二-叔丁基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲硫基)〕双2,6-二-叔丁基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲氧基)〕双2,6-二甲基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲氧基)〕双2,6-二甲基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲氧基)〕双2,6-二甲基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲氧基)〕双2,6-二乙基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲氧基)〕双2,6-二乙基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲氧基)〕双2,6-二乙基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲氧基)〕双2,6-二丙基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲氧基)〕双2,6-二丙基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲氧基)〕双2,6-二丙基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲氧基)〕双2,6-二异丙基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲氧基)〕双2,6-二异丙基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲氧基)〕双2,6-二异丙基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲氧基)〕双2,6-二丁基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲氧基)〕双2,6-二丁基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲氧基)〕双2,6-二丁基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲氧基)〕双2,6-二异丁基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲氧基)〕双2,6-二异丁基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲氧基)〕双2,6-二异丁基〕苯酚
4,4′-〔(二甲基亚甲硅基)双(亚甲氧基)〕双2,6-二-叔丁基〕苯酚
4,4′-〔(二乙基亚甲硅基)双(亚甲氧基)〕双2,6-二-叔丁基〕苯酚
4,4′-〔(二丁基亚甲硅基)双(亚甲氧基)〕双2,6-二-叔丁基〕苯酚
制备其中Z为亚甲基的式1化合物的一般合成方法以下面合成路线B表示,除非另有说明,否则其中所有取代基的定义同前。
合成路线B
通常,式1b双-酚可按合成路线B的二步法制备。在步骤a中,将合适的双-卤代亚烷基硅烷(式3)与金属镁在合适的非质子传递溶剂(例如乙醚)中进行反应,得到双(卤化镁)盐。然后将双(卤化镁)盐(格利雅试剂)与2个当量合适的3,5-二烷基-4-羟基-苯甲醛(式4)(或合适受保护的衍生物)进行反应,得到式5二醇。在步骤b中,用本技术领域已知的各种还原技术和方法将式5二醇还原成所需的双酚(式1b)。例如可以按Birch反应使式5二醇与钠在液氨中反应,从而使其还原。
用于合成路线B所示一般合成方法中的起始原料是容易买到的,并且按一般的技术和方法可以容易地制得。如果需要防止不需要的副反应,那么可以在进行格利雅反应以前如前面合成路线A所述,用一般的酚保护基将反应路线B中3,5-二烷基-4-羟基-苯甲醛(式4)的1-酚官能团进行保护。
以下实例叙述了合成路线B所示具有代表性的合成方法。应该理解,该实例仅是为了详细叙述本发明,无论如何不是限制本发明的范围。
实例3
4,4′-〔(二甲基亚甲硅基)二-2,1-亚乙基〕双〔2,6-二甲基〕苯酚
步骤a:
在惰性气流下将镁屑(480mg,20mmol)和无水乙醚混合。加入双(氯甲基)-二甲基硅烷(1.9g,10mmol)在无水乙醚中的溶液。搅拌,直至金属镁溶解。加入3,5-二甲基-4-羟基-苯甲醛(3.0g,20mmol)在无水乙醚中的溶液。搅拌,直至反应完成。将反应混合物冷却至0℃,并加入饱和氯化铵溶液。分离醚层,用水洗涤并干燥(MgSO4)。蒸发,并经硅胶层析纯化,得到α,α′-〔(二甲基亚甲硅烷)双(亚甲基)〕-双〔4-羟基-3,5-二甲基〕苯甲醇。
步骤b:
将金属钠(1.4g,61mmol)和液态氨(26ml)混合。向该反应混合物中滴加α,α′-〔(二甲基亚甲硅基)双(亚甲基)〕双〔4-羟基-3,5-二甲基〕苯甲醇(3.6g,10mmol)在乙醇(0.5g)和乙醚(5ml)中的溶液。兰色消失后小心地加入水,用乙醚萃取,干燥(MgSO4),并蒸发,得到标题化合物。经硅胶层析纯化。
另外,其中Z为亚甲基的式(1)可按下面合成路线C所示的方法制备,除非另有说明,否则其中所有取代基的定义同前。
合成路线C
通常,式1b双酚可以按下法制备:首先将合适的双-卤代亚烷基硅烷(式3)与2个相当量的金属镁在合适的非质子传递溶剂(例如乙醚)中进行反应,生成相应的双(卤化镁)盐。然后将双(卤化镁盐)盐(格利雅试剂)与2个相当量合适的3,5-二烷基-4-羟基-苄基卤(式6)(或合适受保护的衍生物)进行反应,得到所需的式1b双-酚。
用于路线C所示一般合成方法中的起始原料是容易买到的,并且按一般技术和方法可容易地制得。例如,制备3,5-二甲基-4-乙酰氧基-苄基溴在Tetrahedron33,3097-103(1977)中有叙述。按照一般的水解方法,可以将3,5-二甲基-4-乙酰氧基-苄基溴转变成相应酚的起始原料。
如果需要防止不希望的副反应,那么可以在进行格利雅反应以前如上面合成路线A所述,用一般的酚保护基将合成路线C中3,5-5二烷基-4-羟基-苄基卤(式6)的1-酚官能团进行保护。
以下实例提供了合成路线C所示具有代表性的合成方法。应该理解,该实例仅是为了详细叙述本发明,无论如何不是限制本发明的范围。
实例4
4,4′〔(二甲基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二乙基〕苯酚
在惰性气流下将镁屑(480mg,20mmol)和无水乙醚混合。加入双(氯甲基)-二甲基硅烷(1.9g,10mmol)在无水乙醚中的溶液。搅拌,直至金属镁溶解。加入4-溴甲基-2,6-二乙基苯酚(4.86g,20mmol)在无水乙醚中的溶液,使混合物回流直至反应完成。倒入冰/盐酸的混合物中,并分层。用水洗涤醚层,干燥(MgSO4)并蒸发,得到标题化合物,经硅胶层析纯化。
按上述实例3和4所述类似的方法制备下列化合物:
4,4′-〔(二甲基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二丙基〕苯酚
4,4′-〔(二乙基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二丙基〕苯酚
4,4′-〔(二丁基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二丙基〕苯酚
4,4′-〔(二甲基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二丁基〕苯酚
4,4′-〔(二乙基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二丁基〕苯酚
4,4′-〔(二丁基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二丁基〕苯酚
4,4′-〔(二-叔丁基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二丁基〕苯酚
4,4′-〔(二甲基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二异丙基〕苯酚
4,4′-〔(二-乙基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二异丙基〕苯酚
4,4′-〔(二丁基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二异丙基〕苯酚
4,4′-〔(二甲基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二异丁基〕苯酚
4,4′-〔(二乙基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二异丁基〕苯酚
4,4′-〔(二丁基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二异丁基〕苯酚
4,4′-〔(二甲基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二-叔丁基〕苯酚
4,4′-〔(二乙基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二-叔丁基〕苯酚
4,4′-〔(二丁基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二-叔丁基〕苯酚
4,4′-〔(二甲基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二甲基〕苯酚
4,4′-〔(二乙基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二甲基〕苯酚
4,4′-〔(二丁基亚甲硅基)二-2,1-亚乙基〕-双〔2,6-二甲基〕苯酚
本发明还涉及应用式(1)化合物抑制LDL脂类的过氧化作用和抑制需治疗患者动脉粥样硬化的发展。
这里所用的术语“患者”是指温血动物或哺乳动物,包括啮齿类动物和患有动脉粥样硬化的需治疗的人体。
动脉粥样硬化是一种疾病,其特征在于动脉粥样硬化损伤或斑块。需治疗的动脉粥样硬化患者的鉴别诊断是熟悉本技术领域的专业人员凭其能力和知识很容易达到的。例如,临床上明显的动脉粥样硬化式处于演变成临床上明显的动脉粥样硬化危险的患者是需要治疗的病人。通过应用临床试验、物理检查和医疗史/家族史,熟悉本技术领域的临床医师可以容易的确定是否是需治疗的动脉粥样硬化患者。
式(1)化合物抗动脉粥样硬化的有效剂量是抑制需治疗患者的动脉粥样硬化发展或加重的剂量。因此,成功地治疗患者的动脉粥弱硬化应理解为包括有效地慢慢中断、抑制或停止动脉粥样硬化损伤或斑块的发展或加重,而不一定需要动脉粥样硬化全部消失。此外熟悉本技术领域的专业人员还应理解和懂得,成功地治疗动脉粥样硬化还应包括预防动脉粥样硬化损伤或形成斑块。
LDL脂类的过氧化作用,如LDL胆甾醇酯和磷脂的未饱和脂肪酸部分的过氧化,已知可以促进胆甾醇沉积于巨噬细胞,然后在血管中沉淀,并转化成泡沫细胞。需要抑制LDL脂类过氧化作用的鉴别诊断是熟悉本技术领域的专业人员凭其能力和知识能够做到的。例如,以上所述需要治疗的动脉粥样硬化的病人也是需要抑制LDL脂类过氧化的患者。式(1)化合物有效的抗氧化的剂量是抑制患者血液中LDL脂类过氧化的有效剂量。
应用一般的技术和通过在类似情况下所得到的观察结果,可以容易地确定抗动脉粥样硬化或抗氧化的有效剂量。在确定有效剂量中,要考虑许多因素,这些因素包括(但不限于):患者的种属性别、体重、年令及一般的健康状况;所患的具体疾病;所患疾病的程度或涉及的情况或严重性;各个患者的敏感性;可服用的具体化合物;服用的方式;所服用制剂的生物利用度;所选用的剂量服法;所应用的并用药物。
式(1)化合物抗动脉粥样硬化和抗氧化的有效剂量通常由1毫克/公斤体重/天(mg/kg/dag)-5克/公斤体重/天(mg/kg/dag)变化。每天的剂量为1mg/kg-500mg/kg较好。
在患者进行治疗中,可以按任一形式或方式服用式(1)化合物,该形式或方式是在有效剂量下使所用化合物在生物上有效,其中包括口服和非经胃肠道给药。例如,化合物可以口服、皮下给药、肌肉给药、静脉给药、经皮肤给药、鼻内给药、直肠给药等。通常口服给药是较好的。根据需治疗的疾病状况、疾病的程度以及其他有关的情况,熟悉制剂配方技术领域的专业人员可以容易地选择合适的服用形式和方法。
式(1)化合物可以以药用组合物或药剂的形式服用,药用组合物或药剂是通过式(1)化合物与药用载体或赋形剂混合制得,选用的药用载体或赋形剂的比例及性质可以根据选用的给药途径和一般的药剂学经验确定。
药用组合物或药剂可以按照制剂技术已知的方法进行制备。载体或赋形剂可以是固体、半固体或液体物质,它们可以用作为有效成分的媒介物或介质。合适的载体或赋形剂是本技术领域熟知的。药用组合物可以适用于口服或非经胃肠道给药,并且可以以片剂、胶囊剂、栓剂、溶液剂、混悬剂等形式给患者服用。
药用组合物可以口服,例如有效成分与惰性稀释剂或可食载体组成的药用组合物。可以将药用组合物封装在明胶胶囊内或压制成片剂。为了口服进行治疗,可以将式(1)化合物与赋形剂一起混合,并且以片剂、锭剂、胶囊剂、驰剂、混悬剂、糖浆剂、糯米纸囊剂、口香糖等形式应用。上述制剂应含有至少4%式(1)化合物(有效成分),但是可以根据具体的剂型进行变化,并且通常可以占单位重量的4%-70%。在组合物中有效成分的剂量应该适合于服用的单位剂量形式。
片剂、小丸剂、胶囊剂、锭剂等还可以含有一种或多种以下的辅助剂:粘合剂,如微晶纤维素、西黄蓍胶或明胶;赋形剂,如淀粉或乳糖;崩解剂,如藻酸、淀粉羧甲基醚钠盐、玉米淀粉等;润滑剂,如硬脂酸镁或硬脂酸类润滑粘结剂;助流剂,如胶体二氧化硅;甜味剂,如可以加入蔗糖或糖精;矫味剂,如薄荷、水杨酸甲酯或柑桔类香精。如果剂量单位形式为胶囊剂,那么除了以上类型的物质外还可以含有液体载体,如聚乙二醇或脂肪油。别的剂量单位形式可以含有能够改变剂量单位物理形式的其他不同的物质,例如作为包衣材料的物质。因此,片剂或小丸剂可以用糖、虫胶或其他肠包衣剂进行包衣。糖浆剂除含有效成分外还可以含有蔗糖(作为甜味剂)和某些防腐剂、染料、着色剂和芳香剂。用于制备上述各种组合物的物质应该是药用纯的,并且在应用剂量下是无毒的。
对于非经胃肠道给药,可以将式(1)化合物配制成溶液或混悬液。这类制剂应该含有至少0.1%本发明化合物,但可以在0.1-50%重量之间进行变化。在该类组合物中有效成分的量应能提供得到合适的剂量。
溶液剂或混悬剂还可以有一种或多种下述辅助剂:无菌稀释剂,如注射用水、生理盐水溶液、固定油、聚乙二醇、甘油、丙二醇或其他合成的溶剂;抗菌剂,如苄醇或羟苯甲酸甲酯;抗氧化剂,如抗坏血酸或亚硫酸氢钠;螯合剂,如二乙胺四乙酸;缓冲剂,如乙酸盐、柠檬酸盐或磷酸盐,以及调节毒性的试剂,如氯化钠或葡萄糖。非经胃肠道制剂可以封装在由玻璃或塑料制成的安瓿、一次性注射管或多倍剂量药瓶内。
下面的实例详细叙述了本发明式(1)化合物的应用。下述实例仅为了详细叙述本发明,无论如何不是限制本发明的范围。
实例5
抑制LDL脂类过氧化作用
用Yagi等的方法〔Vitamins39,105(1968)〕测定抑制LDL脂类过氧化作用的程度。
将0.5ml含有250ug人LDL的溶液与试验化合物(其量为0-30ug变化)一起于42℃保温30分钟。向上述混合物中加入1ml硫酸铜溶液(最终浓度为2.5um),并将该混合物于37℃保温2.5小时。用硫代巴比土酸试验测定LDL脂类过氧化作用的量。测定抑制50%LDL脂类过氧化作用所需试验化合物的浓度(ID50)。
表1
试验化合物抑制LDL过氧化作用的效果
试验化合物aID50
A 9.5uM
a化合物A=4,4′-〔(二甲基亚甲硅基)双(亚甲硫基)〕-双〔2,6-二-叔丁基〕苯酚
正如结构上有关的具有特定的类属效用的任何一组化合物的情况一样,式(1)化合物的某些基团和构型在它们的目的应用中是较好的。就取代基R1和R2而论,其中R1和R2为叔丁基的式(1)化合物通常是较好的。就R3R4而论,其中R3和R4为甲基或乙基的式(1)化合物通常是较好的,而甲基尤其地好。关于基团Z,其中Z为硫的式(1)化合物是较好的。关于基团A,其中A为亚甲基的式(1)化合物是较好的。
此外,式(1)化合物可以用于通常遭受氧化变质的有机物质(如橡胶、塑料、脂肪、石油产品等)中作为化学抗氧化添加剂。通常将其浓度是以抑制需保护物质氧化变质的预防量的式(1)化合物与遭受氧化作用的物质混合。所用预防变质的式(1)化合物的量一般在0.01%-1.0%(按重量计)变化。
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FR2707989B1 (fr) * | 1993-07-22 | 1995-10-13 | Pf Medicament | Nouveaux dérivés de benzylamines silylées, leurs sels, leurs procédés de fabrication et les compositions pharmaceutiques les renfermant. |
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US5449679A (en) * | 1994-07-29 | 1995-09-12 | Leonard; Robert J. | Process and products for reducing biological fluid levels of a lipid soluble waste |
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US6121463A (en) * | 1997-06-24 | 2000-09-19 | Hoechst Marion Roussel, Inc. | Alkyl-4-silylheterocyclic phenols and thiophenols useful as antioxidant agents |
US6133467A (en) * | 1997-06-25 | 2000-10-17 | Hoechst Marion Roussel, Inc. | 2,6-di-t-butyl-4-[(dimethyl-4-methoxyphenylsilyl)-methyl-oxy]phenol and 2,6-di-t-butyl-4-[(dimethyl-2-methoxy-phenylsilyl)methyloxy]phenol |
AUPO787897A0 (en) * | 1997-07-14 | 1997-08-07 | Cardiac Crc Nominees Pty Limited | Silicon-containing chain extenders |
KR102067384B1 (ko) * | 2011-12-30 | 2020-01-17 | 다우 실리콘즈 코포레이션 | 고체 조명 장치 및 형성 방법 |
KR20220145860A (ko) * | 2020-02-24 | 2022-10-31 | 다우 글로벌 테크놀로지스 엘엘씨 | 금속-리간드 착물 촉매의 헤테로원자-가교 전구체의 비-극저온 합성 |
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US3506674A (en) * | 1967-07-03 | 1970-04-14 | Gen Electric | Certain pyridyl thio ether silanes |
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- 1991-07-01 NZ NZ238807A patent/NZ238807A/en unknown
- 1991-07-02 CA CA002046050A patent/CA2046050C/en not_active Expired - Lifetime
- 1991-07-02 IL IL9871191A patent/IL98711A/en not_active IP Right Cessation
- 1991-07-02 TW TW080105145A patent/TW213919B/zh active
- 1991-07-03 AU AU80114/91A patent/AU639807B2/en not_active Ceased
- 1991-07-03 KR KR1019910011223A patent/KR0186006B1/ko not_active IP Right Cessation
- 1991-07-04 DE DE69115771T patent/DE69115771T2/de not_active Expired - Lifetime
- 1991-07-04 HU HU912271A patent/HU210695B/hu not_active IP Right Cessation
- 1991-07-04 NO NO912629A patent/NO179914C/no unknown
- 1991-07-04 CN CN91104474A patent/CN1029614C/zh not_active Expired - Fee Related
- 1991-07-04 IE IE234191A patent/IE72155B1/en not_active IP Right Cessation
- 1991-07-04 PT PT98219A patent/PT98219B/pt not_active IP Right Cessation
- 1991-07-04 JP JP3189499A patent/JP2963557B2/ja not_active Expired - Lifetime
- 1991-07-04 FI FI913253A patent/FI101704B1/fi active
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- 1991-07-05 DK DK91111220.9T patent/DK0464844T3/da active
- 1991-07-05 EP EP91111220A patent/EP0464844B1/en not_active Expired - Lifetime
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1992
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1996
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1092517C (zh) * | 1993-12-10 | 2002-10-16 | 默里尔药物公司 | 利用2,6-二烷基-4-甲硅烷基-苯酚降低血清胆固醇水平的方法 |
CN104817581A (zh) * | 2015-05-07 | 2015-08-05 | 衢州学院 | 一种含硅二元酚及其制备方法 |
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