CN1191070C - 成骨细胞特异性促细胞分裂剂和含有这种化合物的药物 - Google Patents
成骨细胞特异性促细胞分裂剂和含有这种化合物的药物 Download PDFInfo
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- CN1191070C CN1191070C CNB988094193A CN98809419A CN1191070C CN 1191070 C CN1191070 C CN 1191070C CN B988094193 A CNB988094193 A CN B988094193A CN 98809419 A CN98809419 A CN 98809419A CN 1191070 C CN1191070 C CN 1191070C
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Abstract
本发明涉及式(I)化合物,其中R1=具有6-24个碳原子的烷基,烯基或炔基;N=0-12;X=氧或NH;和生理安全的盐,酯,光学活性体,外消旋体,和可以在体内代谢产生通式(I)化合物的它们的衍生物,它们的制备方法,和用于治疗骨代谢紊乱的含有所述化合物的药品。
Description
技术领域
本发明涉及成骨细胞特异性促有丝分裂的式(I)化合物,其制备方法和含有该化合物的药物。
背景技术
健康个体骨的形成和降解实际上处于平衡状态,即成骨细胞和破骨细胞的活性是平衡的。然而,如果有利于破骨细胞而不利于成骨细胞破坏平衡,就会造成骨质减少和骨结构和功能负变化的结果。
迄今为止,骨再吸收抑制剂如雌激素、降血钙素和二磷酸盐主要用于骨代谢紊乱的治疗。但是这些物质应用受到限制,并且不能在所有条件下都能得到满意结果。因此对骨形成具有刺激作用和促进已经减少骨质增生的化合物对治疗骨代谢紊乱特别重要。欧洲专利申请EP-A-625,522和EP-A-524,023描述了对骨质疏松症具有骨形成代谢作用物质。
已知溶血磷脂酸(LPA)在大量的组织和细胞中起到细胞内脂类信使的作用(生物化学杂志,270(22),12949-52,1995;当今细胞生物学观点,7(2),203-10,1995)。
令人奇怪地,现在发现本发明的溶血磷脂酸衍生物对骨形成具刺激作用,因此适于骨代谢紊乱的一般治疗。特别地,它们可以很好地用于骨形成紊乱的治疗,例如它们特别适用于骨骼系统骨质减少的治疗,如骨质疏松症(例如成骨不全,以及骨再生和骨诱导的局部促进),如整形外科和正牙,骨折治疗,骨结合术,假关节和骨移植物结合在一起。
而且,由于对骨代谢的影响,因此含有本发明的溶血磷脂酸衍生物作为活性物质的药物,对于风湿性关节炎,骨关节炎和变质性关节炎的局部和系统治疗打下了基础。
发明内容
本发明涉及通式(I)新的溶血磷脂酸衍生物
其中
R1=具有6-24个碳原子的烷基,烯基或炔基;
N=0-12;
X=氧或NH;
其先决条件是,当X代表氧时,在-(CH2)n-CH3基团中n不代表数字7,9,11,13或15,和生理上可耐受的盐,酯,光学活性体,外消旋体,和可以在体内代谢产生通式(I)化合物的它们的衍生物,并且不包括化合物(全-顺-5,8,11,14)-二十碳四烯酸2-羟基-3-膦酰氧基丙酯,顺-9,顺-12-十八碳二烯酸2-羟基-3-膦酰氧基丙酯,(全-顺-9,12,15)-十八碳三烯酸2-羟基-3-膦酰氧基丙酯,或顺-9-十八碳烯酸2-羟基-3-膦酰氧基丙酯,和所述的化合物在生产药物中的应用。
合成上面化合物的方法,其中X=氧,-(CH2)n-CH3中n=13,是公知的(例如,Chem.Ber.71,1075(1938),Hoppe-Seyler’s Z.,生理化学(Physiol.Chem.)347,94-101(1966))。合成所述化合物的方法,其中X=氧,-(CH2)n-CH3中n=15,是公知的(例如,Chem.Phys.Lipids 1,317(1966/67))。合成所述化合物的方法,其中X=氧,-(CH2)n-CH3中n=7,是公知的(例如,Chem.Phys.Lipids 18,316(1977))。
化合物(全-顺-5,8,11,14)-二十碳四烯酸2-羟基-3-膦酰氧基丙酯,顺-9,顺-12-十八碳二烯酸2-羟基-3-膦酰氧基丙酯,(全-顺-9,12,15)-十八碳三烯酸2-羟基-3-膦酰氧基丙酯被描述具有收缩小鼠结肠的作用(药物药理学杂志(J.Pharm.Pharmacol.)43,774-78(1991))。化合物其中X=氧,-(CH2)n-CH3中n=9,11,13,15,以及顺-9-十八碳烯酸2-羟基-3-膦酰氧基丙酯,顺-9,顺-12-十八碳二烯酸2-羟基-3-膦酰氧基丙酯,(全-顺-9,12,15)-十八碳三烯酸2-羟基-3-膦酰氧基丙酯,被描述对血压有影响(Arzneim.Forsch.35,587-92(1985))。
可以理解每个烷基代表C6-C18直链或支链烷基,如己基,异己基,2,2-二甲基己基,5-甲基己基,庚基,异庚基,6-甲基庚基,辛基,异辛基,壬基,异壬基,癸基,异癸基,十一烷基,异十一烷基,十二烷基,异十二烷基,十三烷基,异十三烷基,十四烷基,异十四烷基,十五烷基,异十五烷基,十六烷基,十七烷基,异十七烷基,或十八烷基,特别是庚基,癸基,十二烷基。
每个烯基代表含有6-20个碳原子和一个或更多不饱和键的基团,如△1-己烯基,△1-辛烯基,△9-壬烯基,△1-癸烯基,△10-癸烯基,△1,4-癸二烯基,△1,4,7-癸三烯基,△1,4,7,10-十六碳四烯基,△1-十二碳烯基,△5-十二碳烯基,△1,4-十一碳二烯基,△1,4-十四碳二烯基,特别是△1-癸烯基,△1,4-癸二烯基,△1,4,7癸三烯基,其中双键可以为顺式或反式,和具有多个未饱和基团化合物所有可能的结合。
每个炔基代表含有6-20个碳原子和一个或更多不饱和键的基团,△1-己炔基,△1-壬炔基,△1,3-十四碳二炔基,△1,3-十六碳二炔基,△1,3-十八碳二炔基,特别是△1-己炔基。
特别优选其中X代表NH的化合物。
式(I)化合物生理可使用的盐的实例为和生理可耐受的矿物酸如盐酸,硫酸,亚硫酸,磷酸,有机酸如甲磺酸,对-甲苯亚磺酸,醋酸,三氟乙酸,柠檬酸,富马酸,马来酸,酒石酸,琥珀酸,或水杨酸,所成的盐。式(I)化合物具有的游离羧基也可以和生理可耐受的碱成盐。这些盐的实例包括碱金属,碱土金属,铵,和烷基铵盐,如钠,钾,钙,或四甲基铵盐。
通式(I)化合物含有至少一个不对称的碳原子,因此本申请还涉及通式(I)的光学活性化合物。
X为氧的通式(I)化合物纯的对映异构体,可以使用光学活性醇得到,该醇可以购买或按照公知的方法制备,例如通过使用光学活性酸经形成盐进行常规外消旋物的拆分。
X为NH的通式(I)化合物纯的对映异构体,可以使用光学活性氨基醇得到,该醇可以购买或按照公知的方法制备,例如通过使用光学活性酸经形成盐进行常规外消旋物的拆分,或通过光学活性氨基酸还原。
X为氧的通式(I)化合物,按照实质上已知的方法除去R2保护基团,从通式(II)化合物制备。
其中R2代表羟基通常使用的保护基团。
通式(II)化合物,按照本身已知的方法,优选通式(III)的醇
其中R3和R4代表羟基通常使用的保护基团,优选1,2-二醇的保护基团,如环状缩醛和酮缩醇,和通式(IV)的羧酸衍生物,
其中R1和n具有上面提到的含义,Y可以为羟基或活性基团,如果Y代表羟基,可以按照二亚胺碳法进行羧基的活化,如果Y代表活性基团,末端可能是混合酐,特别是和碳酸低级烷基酯,如乙基或异丁基酯,或活化酯,特别是对-硝基苯,2,4,5-三氯苯,N-羟基琥珀酰亚胺,或1-羟基苯并三唑酯反应,
得到通式(V)化合物。
通式(III)化合物,按照实质上已知的方法制备,优选在丙三醇加上保护基团,或可以购买。
通式(IV)化合物,按照公知的方法,从通式(VI)化合物制备。
R1-(CH2)n-1-COOH (VI)
其中R1和n具有上面规定的含义。
通式(VI)化合物,按照链延伸或羧酸合成的公知方法制备,或可以购买。
通过除去R3和R4的保护基团,通式(V)化合物转化为通式(VII)化合物。
在通式(VII)化合物中,两个羟基通过引入常用的羟基保护基团R2和R6正交型保护,优选在伯羟基引入三苯甲游基(R6),在仲羟基引入安息香酸盐或甲硅烷基保护基团如四-丁基二苯甲硅烷(R2),得到通式(VIII)化合物。
开始通式(VIII)化合物按照实质上已知的方法选择性去保护,然后和磷酰氯反应转化为通式(II)化合物。
通式(I)化合物(其中X=NH),按照实质上已知的方法,从通式(IX)化合物,通过除去R2保护基团制备。
其中R2代表羟基通常使用的保护基团。
通式(IX)化合物,按照实质上已知的方法,优选和通式(X)的胺反应制备。
其中R7和R8单独为氢或羟基通常使用的保护基团,优选为1,2-二醇的保护基团,如环状缩醛和酮缩醇,
和通式(IV)的羧酸衍生物
其中R1和Y具有上面提到的含义,
生成通式(XI)化合物
当R7和R8代表氢时,通式(XI)化合物采用类似于上面描述的X为氧的方法,和通式(XII)化合物进一步反应得到。
当R7和R8不是正交保护基团时,开始按照常规的方法除去保护基,其它步骤与R7和R8是氢的情况相同。
如果R7和R8为正交保护基团,首先选择性去保护伯醇,然后和磷酰氯反应生成通式(IX)化合物,其中R2=R7。
在制备通式(I)化合物中,代替使用磷酰氯,可以将适当保护的通式(XII)化合物的氯磷酸盐
其中R9和R10常用的保护基团,特别是甲基,乙基或芳基,与通式(XIII)化合物反应。
其中R2代表羟基保护基团,优选安息香酸盐或甲硅烷基保护基团。通式(XII)化合物可以商业得到或按照文献公知的方法制备(Houben-Weyl)。
通式(I)化合物可以按照公知的方法,通过除去R9和R10的保护基团制得。
R2,R3,R4,R5,R6,R7,R8,R9和R10作为保护基团,原则上可能是所有适于羟基的公知保护基团,如Th.Greene,P.在“有机合成保护基团”第二版,1991,J.Wiley & Sons所描述的一样。按照其中描述的常用方法进行引入和除去。
通式(I)化合物可以以液体或固体或气溶胶,和所有常用非毒性、药学上可接受载体,辅料和添加剂,经口,肠道,非肠道,局部,鼻腔,肺部或直肠给药。通式(I)化合物还可以局部给药于骨表面/内部(外科手术可选择)。“非肠道”包括皮下,静脉内和肌肉内给药或灌注。口服给药剂型可以为,例如片剂,胶囊,包衣片,糖浆剂,溶液,混悬剂,乳剂,酏剂等,其可以含有一种或更多的下组的添加剂,例如,风味物质,甜味剂,着色剂,防腐剂。口服剂型含有活性成分和无毒性、药学上可接受的适于用作片剂,胶囊,包衣片等制剂的载体,如碳酸钙,碳酸钠,乳糖,磷酸钙或磷酸钠;淀粉,甘露醇,甲基纤维素,滑石粉,高分散硅酸,高分子量脂肪酸(如硬脂酸),花生油,橄榄油,石蜡,miglyol,凝胶,琼脂,硬脂酸镁,蜂蜡,鲸蜡醇,卵磷脂,甘油,动物和植物油脂,固体高分子量聚合物(如聚乙二醇)。片剂,胶囊,包衣片等可以采用适当的包衣剂如单硬脂酸甘油酯或双硬脂酸甘油酯进行包衣,以防止胃中不理想的副作用,或因延缓胃肠道吸收而达到缓释效果。无菌注射水溶液或油溶液或混悬剂优选使用注射介质,其中可以含有常用的添加剂如稳定剂和助溶剂。这些添加剂可以为,例如水,等渗压盐溶液,丁二醇,脂肪酸(如油酸)单和双甘油酯,或miglyol。对于直肠给药,可以使用在常温下为固体、在直肠温度下为液体的非刺激性的所有适合的添加剂,如可可豆脂和聚乙二醇。对于气溶胶给药,可以使用药学上常用的载体介质。对于外用给药,乳剂,酊剂,凝胶,溶液或混悬液等,可以使用药学上常用的载体介质。
剂量可以依赖许多因素,如给药方式,种族,年龄和/或个体条件。每日给药剂量大约1-1000mg/人,优选在大约10-250mg/人,每日给药间隔可以一次服用或分几次给药。
式(I)化合物还可以局部给药于骨表面/内部(外科手术可选择)。直接给药于骨表面/内部(外科手术可选择)可以以溶液或混悬液方便地灌注或注射,或与载体结合局部应用。例如式(I)化合物与载体结合,可以以凝胶,软膏固体或以包衣灌输给药。
载体使用生物相容性和生物降解性好的材料。优选本身还可以使伤口愈合或骨形成的材料。
对于局部给药,优选将式(I)化合物包埋在聚合凝胶或薄膜中,以使其固定不动,在治疗中将该制剂直接应用于骨部位。基本聚合凝胶或薄膜包括,例如甘油,甲基纤维素,透明质酸,聚乙烯氧化物和/或polyoxamers。例如在WO 93/00050和WO 93/20859中描述了胶原蛋白,凝胶和海藻酸盐也是适合应用的。其它聚合物可以为聚乳酸(PLA)和乳酸共聚物和羟基乙酸(PLPG)(Hollinger等,J.Biomed.Mater.Res.17,71-82(1983)),和“脱矿物质骨基质”(DBM)骨衍生物(Guterman等,kollagen Rel.Res.8,419-4319(1988))。例如EP-A 0,616,814和EP-A0,567,391中描述的用于TGFβ吸收的聚合物,以及按照WO 91/18558的合成骨基质,也是适合应用的。
植入时使用的骨替代品或其它治疗活性物质也适合作为式(I)化合物的载体。这些化合物也依赖于,例如硫酸钙,磷酸三钙,羟磷灰石和它们的生物可降解产物,和聚酐。除了这些生物可降解载体,那些不能生物降解,但生物相容的载体也是适合的。例如这些载体可以为烧结羟磷灰石,生物玻璃,铝酸盐或其它陶瓷物质(例如磷酸铝酸钙)。这些物质优选和所述的生物可降解物质共同使用,特别是如聚乳酸,羟磷灰石,胶原蛋白或磷酸三钙。例如美国专利4,164,560描述的其它非降解聚合物。
特别优选使用在作用部位可以持续释放式(I)化合物的载体。尤其适合这个目的的是,例如美国创新研究所Teledo,Ohio的“缓释小球”。特别优选使用释放式(I)化合物超过几天,优选直到100天,每天剂量为1-10mg/kg每天的小球。
剂量可以依赖许多因素,如给药方式,种族,年龄和/或个体条件。每日活性物质给药剂量大约为0.01mg-100mg/公斤体重,优选在大约0.1-10mg/公斤体重,可以一次服用或分几次给药。
除了实施例中提到的化合物,和来源于结合权利要求中提到的所有取代基的化合物,下列溶血磷脂酸衍生物,以及它们的钠盐和钾盐为本发明优选的化合物。
优选化合物(PC):
(1)辛酸2-羟基-3-膦酰氧基丙酯
(2)7-甲基辛酸2-羟基-3-膦酰氧基丙酯
(3)7,7-二甲基辛酸2-羟基-3-膦酰氧基丙酯
(4)壬酸2-羟基-3-膦酰氧基丙酯
(5)4-甲基壬酸2-羟基-3-膦酰氧基丙酯
(6)8-甲基壬酸2-羟基-3-膦酰氧基丙酯
(7)十一烷酸2-羟基-3-膦酰氧基丙酯
(8)10-甲基十一烷酸2-羟基-3-膦酰氧基丙酯
(9)11-甲基十二烷酸2-羟基-3-膦酰氧基丙酯
(10)十三烷酸2-羟基-3-膦酰氧基丙酯
(11)12-甲基十三烷酸2-羟基-3-膦酰氧基丙酯
(12)13-甲基十四烷酸2-羟基-3-膦酰氧基丙酯
(13)十五烷酸2-羟基-3-膦酰氧基丙酯
(14)14-甲基十五烷酸2-羟基-3-膦酰氧基丙酯
(15)15-甲基十六烷酸2-羟基-3-膦酰氧基丙酯
(16)十七烷酸2-羟基-3-膦酰氧基丙酯
(17)16-甲基十七烷酸2-羟基-3-膦酰氧基丙酯
(18)17-甲基十八烷酸2-羟基-3-膦酰氧基丙酯
(19)十九烷酸2-羟基-3-膦酰氧基丙酯
(20)18-甲基十九烷酸2-羟基-3-膦酰氧基丙酯
(21)二十烷酸2-羟基-3-膦酰氧基丙酯
(22)19-甲基二十烷酸2-羟基-3-膦酰氧基丙酯
(23)19-甲基二十烷酸2-羟基-3-膦酰氧基-丙酯
(24)二十一烷酸2-羟基-3-膦酰氧基丙酯
(25)二十二烷酸2-羟基-3-膦酰氧基丙酯
(26)二十三烷酸2-羟基-3-膦酰氧基丙酯
(27)二十四烷酸2-羟基-3-膦酰氧基丙酯
(28)二十七烷酸2-羟基-3-膦酰氧基丙酯
(29)二十八烷酸2-羟基-3-膦酰氧基丙酯
(30)三十烷酸2-羟基-3-膦酰氧基丙酯
(31)6-庚烯酸2-羟基-3-膦酰氧基丙酯
(32)反-9-十六烷酸2-羟基-3-膦酰氧基丙酯
(33)(全-顺-11,14,17)-二十碳三烯酸2-羟基-3-膦酰氧基丙酯
(34)顺-10-十七碳烯酸2-羟基-3-膦酰氧基丙酯
(35)顺-10-十九碳烯酸2-羟基-3-膦酰氧基丙酯
(36)顺-3,顺-6-壬二烯酸2-羟基-3-膦酰氧基丙酯
(37)顺-10-十五碳烯酸2-羟基-3-膦酰氧基丙酯
(38)顺-12-十八碳烯酸2-羟基-3-膦酰氧基丙酯
(39)顺-13-十八碳烯酸2-羟基-3-膦酰氧基丙酯
(40)顺-7-十八碳烯酸2-羟基-3-膦酰氧基丙酯
(41)顺-8-二十烷酸2-羟基-3-膦酰氧基丙酯
(42)反-9-十四碳烯酸2-羟基-3-膦酰氧基丙酯
(43)反-9-十八碳烯酸2-羟基-3-膦酰氧基丙酯
(44)(全-反-9,11,13,15)-十八碳四烯酸2-羟基-3-膦酰氧基丙酯
(45)(全-顺-9,11,13,15)-十八碳四烯酸2-羟基-3-膦酰氧基丙酯
(46)顺-11-十八碳烯酸2-羟基-3-膦酰氧基丙酯
(47)(全-顺-13,16,19)-二十二碳三烯酸2-羟基-3-膦酰氧基丙酯
(48)(全-顺-13,16,19)-二十二碳三烯酸2-羟基-3-膦酰氧基丙酯
(49)(全-顺-8,11,14)-二十碳三烯酸2-羟基-3-膦酰氧基丙酯
(50)反-11-十八碳烯酸2-羟基-3-膦酰氧基丙酯
(51)反-13-二十二碳烯酸2-羟基-3-膦酰氧基丙酯
(52)反-9,反-12-十八碳二烯酸2-羟基-3-膦酰氧基丙酯
(53)顺-9-十四碳烯酸2-羟基-3-膦酰氧基丙酯
(54)顺-9-十六碳烯酸2-羟基-3-膦酰氧基丙酯
(55)10-十一碳烯酸2-羟基-3-膦酰氧基丙酯
(56)顺11-,顺14-二十碳二烯酸2-羟基-3-膦酰氧基丙酯
(57)顺11-二十碳烯酸2-羟基-3-膦酰氧基丙酯
(58)顺-15-二十四碳烯酸2-羟基-3-膦酰氧基丙酯
(59)11-十二碳烯酸2-羟基-3-膦酰氧基丙酯
(60)9-癸烯酸2-羟基-3-膦酰氧基丙酯
(61)16-十七碳烯酸2-羟基-3-膦酰氧基丙酯
(62)(全-顺-11,14,17)-二十碳三烯酸2-羟基-3-膦酰氧基丙酯
(63)顺-13-二十碳烯酸2-羟基-3-膦酰氧基丙酯
(64)(全-顺-7,10,13,16)-二十二碳四烯酸2-羟基-3-膦酰氧基丙酯
(65)22-二十三碳烯酸2-羟基-3-膦酰氧基丙酯
(66)9-十四碳炔酸2-羟基-3-膦酰氧基丙酯
(67)13-二十碳炔酸2-羟基-3-膦酰氧基丙酯
(68)10,12-二十九碳二炔酸2-羟基-3-膦酰氧基丙酯
(69)10,12-十八碳二炔酸2-羟基-3-膦酰氧基丙酯
(70)9-十八碳炔酸2-羟基-3-膦酰氧基丙酯
(71)10-十一碳炔酸2-羟基-3-膦酰氧基丙酯
(72)10,12-二十三碳二炔酸2-羟基-3-膦酰氧基丙酯
(73)10,12-二十五碳二炔酸2-羟基-3-膦酰氧基丙酯
(74)10,12-二十七碳二炔酸2-羟基-3-膦酰氧基丙酯
(75)辛酸2-羟基-3-膦酰氧基丙酰胺
(76)7-甲基辛酸2-羟基-3-膦酰氧基丙酰胺
(77)7,7-二甲基辛酸2-羟基-3-膦酰氧基丙酰胺
(78)壬酸2-羟基-3-膦酰氧基丙酰胺
(79)4-甲基壬酸2-羟基-3-膦酰氧基丙酰胺
(80)8-甲基壬酸2-羟基-3-膦酰氧基丙酰胺
(81)癸酸2-羟基-3-膦酰氧基丙酰胺
(82)十一烷酸2-羟基-3-膦酰氧基丙酰胺
(83)10-甲基十一烷酸2-羟基-3-膦酰氧基丙酰胺
(84)十二烷酸2-羟基-3-膦酰氧基丙酰胺
(85)11-甲基十二烷酸2-羟基-3-膦酰氧基丙酰胺
(86)十三烷酸2-羟基-3-膦酰氧基丙酰胺
(87)12-甲基十三烷酸2-羟基-3-膦酰氧基丙酰胺
(88)十四烷酸2-羟基-3-膦酰氧基丙酰胺
(89)13-甲基十四烷酸2-羟基-3-膦酰氧基丙酰胺
(90)十五烷酸2-羟基-3-膦酰氧基丙酰胺
(91)14-甲基十五烷酸2-羟基-3-膦酰氧基丙酰胺
(92)十六烷酸2-羟基-3-膦酰氧基丙酰胺
(93)15-甲基十六烷酸2-羟基-3-膦酰氧基丙酰胺
(94)十七烷酸2-羟基-3-膦酰氧基丙酰胺
(95)16-甲基十七烷酸2-羟基-3-膦酰氧基丙酰胺
(96)十八烷酸2-羟基-3-膦酰氧基丙酰胺
(97)17-甲基十八烷酸2-羟基-3-膦酰氧基丙酰胺
(98)十九烷酸2-羟基-3-膦酰氧基丙酰胺
(99)18-甲基十九烷酸2-羟基-3-膦酰氧基丙酰胺
(100)二十烷酸2-羟基-3-膦酰氧基丙酰胺
(101)19-甲基二十烷酸2-羟基-3-膦酰氧基丙酰胺
(102)19-甲基二十烷酸2-羟基-3-膦酰氧基-丙酰胺
(103)二十一烷酸2-羟基-3-膦酰氧基丙酰胺
(104)二十二烷酸2-羟基-3-膦酰氧基丙酰胺
(105)二十三烷酸2-羟基-3-膦酰氧基丙酰胺
(106)二十四烷酸2-羟基-3-膦酰氧基丙酰胺
(107)二十七烷酸2-羟基-3-膦酰氧基丙酰胺
(108)二十八烷酸2-羟基-3-膦酰氧基丙酰胺
(109)三十烷酸2-羟基-3-膦酰氧基丙酰胺
(110)6-庚烯酸2-羟基-3-膦酰氧基丙酰胺
(111)反-9-十六烷酸2-羟基-3-膦酰氧基丙酰胺
(112)(全-顺-11,14,17)-二十碳三烯酸2-羟基-3-膦酰氧基丙酰胺
(113)(全-顺-5,8,11,14)-二十碳三烯酸2-羟基-3-膦酰氧基丙酰胺
(114)顺-10-十七碳烯酸2-羟基-3-膦酰氧基丙酰胺
(115)顺-10-十九碳烯酸2-羟基-3-膦酰氧基丙酰胺
(116)顺-3,顺-6-壬二烯酸2-羟基-3-膦酰氧基丙酰胺
(117)顺-10-十五碳烯酸2-羟基-3-膦酰氧基丙酰胺
(118)顺-12-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺
(119)顺-13-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺
(120)顺-7-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺
(121)顺-8-二十烷酸2-羟基-3-膦酰氧基丙酰胺
(122)反-9-十四碳烯酸2-羟基-3-膦酰氧基丙酰胺
(123)顺-9,顺-12-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺
(124)反-9-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺
(125)顺-9-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺
(126)(全-反-9,11,13,15)-十八碳四烯酸2-羟基-3-膦酰氧基丙酰胺
(127)(全-顺-9,11,13,15)-十八碳四烯酸2-羟基-3-膦酰氧基丙酰胺
(128)顺-11-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺
(129)(全-顺-13,16,19)-二十二碳三烯酸2-羟基-3-膦酰氧基丙酰胺
(130)(全-顺-13,16,19)-二十二碳三烯酸2-羟基-3-膦酰氧基丙酰胺
(131)(全-顺-9,12,15)-十八碳三烯酸2-羟基-3-膦酰氧基丙酰胺
(132)(全-顺-8,11,14)-二十碳三烯酸2-羟基-3-膦酰氧基丙酰胺
(133)反-11-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺
(134)反-13-二十二碳烯酸2-羟基-3-膦酰氧基丙酰胺
(135)反-9,反-12-十八碳二烯酸2-羟基-3-膦酰氧基丙酰胺
(136)顺-9-十四碳烯酸2-羟基-3-膦酰氧基丙酰胺
(137)顺-9-十六碳烯酸2-羟基-3-膦酰氧基丙酰胺
(138)10-十一碳烯酸2-羟基-3-膦酰氧基丙酰胺
(139)顺11-,顺14-二十碳二烯酸2-羟基-3-膦酰氧基丙酰胺
(140)顺11-二十碳烯酸2-羟基-3-膦酰氧基丙酰胺
(141)顺-15-二十四碳烯酸2-羟基-3-膦酰氧基丙酰胺
(142)11-十二碳烯酸2-羟基-3-膦酰氧基丙酰胺
(143)9-癸烯酸2-羟基-3-膦酰氧基丙酰胺
(144)16-十七碳烯酸2-羟基-3-膦酰氧基丙酰胺
(145)(全-顺-11,14,17)-二十碳三烯酸2-羟基-3-膦酰氧基丙酰胺
(146)顺-13-二十碳烯酸2-羟基-3-膦酰氧基丙酰胺
(147)顺-13,顺-13-二十二碳二烯酸2-羟基-3-膦酰氧基丙酰胺
(148)(全-顺-7,10,13,16)-二十二碳四烯酸2-羟基-3-膦酰氧基丙酰胺
(149)22-二十三碳烯酸2-羟基-3-膦酰氧基丙酰胺
(150)9-十四碳炔酸2-羟基-3-膦酰氧基丙酰胺
(151)13-二十碳炔酸2-羟基-3-膦酰氧基丙酰胺
(152)10,12-二十九碳二炔酸2-羟基-3-膦酰氧基丙酰胺
(153)10,12-十八碳二炔酸2-羟基-3-膦酰氧基丙酰胺
(154)9-十八碳炔酸2-羟基-3-膦酰氧基丙酰胺
(155)10-十一碳炔酸2-羟基-3-膦酰氧基丙酰胺
(156)10,12-二十三碳二炔酸2-羟基-3-膦酰氧基丙酰胺
(157)10,12-二十五碳二炔酸2-羟基-3-膦酰氧基丙酰胺
(158)10,12-二十七碳二炔酸2-羟基-3-膦酰氧基丙酰胺
一些可以用于合成本发明化合物的不同方法,将在下面的实施例中给出,但是它不能被认为是限定本发明的主题。化合物的结构采用1H,31P和任选13C核磁共振光谱确定。化合物的纯化采用C,H,N,P分析和薄层色谱测定。
实施例1
顺-9-十八碳烯酸2-羟基-3-膦酰氧基丙酯
顺-9-十八碳烯酸2,3-O-异丙基亚丙酯(1)
在室温下向15.3g(116mmol)的2,2-二甲基-4-羟甲基二氧戊烷的100ml吡啶溶液中,逐滴加入41.2g(116mmol)的85%油酸氯化物。12小时后在室温下除去吡啶,残渣加入2×50ml甲苯中挥发浓缩。残渣溶解于200ml乙醚,用50ml的1N HCl和50ml饱和NaCl溶液提取两次。乙醚相用MgSO4干燥,过滤浓缩。残渣用庚烷/乙酸乙酯(9∶1)硅胶发光柱纯化。产量:26.3g(61%)。
顺-9-十八碳烯酸2,3-二羟丙酯(2)
23g(60.5mmol)的
1溶解于THF/水(6∶1)的混合溶液中,冷却至0℃。然后逐滴加入三氟乙酸(24ml),混合物在0℃下再搅拌3小时后,升温至室温。12小时后冷却至0℃,用浓氨水进行中和。蒸干THF,残渣用乙醚提取。将有机相用MgSO4干燥,过滤浓缩。残渣用庚烷/乙酸乙酯(1∶1)硅胶柱纯化。产量:68%的无色油状物。
顺-9-十八碳烯酸2-羟基3-三苯甲氧基丙酯(3)
在室温搅拌下、48小时中,将
2(21mmol)的80ml的二氯甲烷/吡啶(1∶1)溶液逐滴加入到三苯甲基氯化物(27mmol)中。除去溶剂,将残渣两次溶解于50ml甲苯中,浓缩。残渣用100ml水稀释,用50ml的二氯甲烷提取3次。有机相用50ml冷5%HCl和50ml饱和NaCl溶液洗涤,MgSO4干燥,过滤浓缩。残渣用庚烷/乙酸乙酯(5∶1)硅胶色谱纯化。产量:88%的无色油状物。
顺-9-十八碳烯酸2-叔-丁基二苯硅氧基-3-三苯甲氧基丙酯(4)
在0℃下,向
3(5mmol)的30ml DMF溶液中加入咪唑(20mmol)。然后将叔-丁基二苯硅氯化物逐滴加入到混合物中。混合物缓慢升温至室温。6小时后,在室温下将其倒入冰水中,用乙酸乙酯提取。有机相用饱和NaCl溶液洗涤,MgSO4干燥,过滤浓缩。残渣用异己烷/乙酸乙酯(9∶1)硅胶色谱纯化。产量:95%的无色油状物。
顺-9-十八碳烯酸2-叔-丁基二苯硅氧基-3-三羟基丙酯(5)
在室温下,4ml的三氟乙酸逐滴缓慢加入到
4(4.65mmol)的50ml二氯甲烷溶液中。3小时后,用水和饱和碳酸氢钠溶液洗涤。有机相用MgSO4干燥,过滤浓缩。残渣用异己烷/乙酸乙酯(7∶1)硅胶发光色谱纯化。产量:54%的无色油状物。
顺-9-十八碳烯酸2-叔-丁基二苯硅氧基-3-膦酰氧基丙酯(6)
磷酰氯(3mmol)的5ml四氢呋喃溶液在通氮条件下冷却至0℃,将5(2.75mmol)和吡啶(9.3mmol)的15ml四氢呋喃溶液逐滴加入到其中。混合物在0℃下搅拌30分钟。然后加入3ml水,在室温下搅拌20小时。随后逐滴加入1N HCl酸化,分别用25ml乙酸乙酯提取3次。有机相用MgSO4干燥,过滤浓缩。残渣用开始用乙酸乙酯、然后用甲醇硅胶色谱纯化。产量:71%的无色油状物。
顺-9-十八碳烯酸2-羟基-3-膦酰氧基丙酯
6(1mmol)溶解于10ml二氯甲烷溶液中,加入25ml 1%的NaOH甲醇溶液。20小时后在室温下浓缩,残渣用1N HCl酸化,混合物用乙酸乙酯提取。有机相用20ml水洗涤,MgSO4干燥,过滤浓缩。残渣用甲醇处理。产量:78%的无色结晶。
实施例2
顺-9-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺
顺-9-十八碳烯酸丁二酰亚胺(8)
二环己基碳二亚胺(24.1g,117mmol)溶解于THF中,在0℃下加入到油酸(30g,106.2mmol)的150ml THF溶液中。20分钟后,将N-羟基丁二酰亚胺(13.5g,117mmol)加入到混合物中。混合物缓慢升温至室温。18小时后,从室温冷却至0℃,析出沉淀。滤液浓缩,用乙酸乙酯/庚烷(1∶3)的硅胶柱纯化。产量:83%的无色蜡状物。
顺-9-十八碳烯酸2,3-二羟基丙酰胺(9)
向顺-9-十八碳烯酸丁二酰亚胺(18.3g,48.2mmol)的50ml乙腈溶液中,加入1-氨基2,3-二丙醇(4.4g,48.2mmol)的50ml水溶液中。室温下搅拌12小时后,蒸干乙腈,残渣用乙酸乙酯提取。有机相用饱和NaCl溶液提取。有机相用MgSO4干燥,过滤浓缩。残渣在异己烷中结晶。产量:87%的无色粉末。
顺-9-十八碳烯酸2-羟基-3-三苯甲氧基丙酰胺(10)
在室温搅拌下、48小时中,将
9(28mmol)的80ml的二氯甲烷/吡啶(1∶1)溶液逐滴加入到三苯甲基氯化物(36mmol)中。除去溶剂,将残渣两次溶解于50ml甲苯中,浓缩。残渣用100ml水稀释,用50ml的二氯甲烷提取3次。有机相用50ml冷5%HCl和50ml饱和NaCl溶液洗涤,MgSO4干燥,过滤浓缩。残渣用庚烷/乙酸乙酯(5∶1)硅胶色谱纯化。产量:81%的无色油状物。
顺-9-十八碳烯酸2-苯酰氧基-3-三苯甲氧基丙酰胺(11)
在0℃下,将苯甲酰氯(30mmol)逐滴加入到
10(27.3mmol)的80ml二氯甲烷/吡啶(1∶1)的溶液中。缓慢升温至室温,在室温下再连续搅拌4小时。然后将混合物两次溶解于50ml甲苯中,浓缩。残渣加入100ml水,用100ml的二氯甲烷提取3次。有机相用50ml冷5%HCl和50ml饱和NaCl溶液洗涤,MgSO4干燥,过滤浓缩。残渣用庚烷/乙酸乙酯(3∶1)硅胶色谱纯化。产量:81%的无色油状物。
顺-9-十八碳烯酸2-苯酰氧基-3-膦酰氧基丙酰胺(12)
磷酰氯(7.1mmol)的10ml(22mmol)THF溶液在通氮条件下,逐滴加入至
11的30ml四氢呋喃溶液中。混合物在0℃下搅拌30分钟。然后加入5ml水,在室温下搅拌20小时。随后逐滴加入1N HCl酸化,用50ml乙酸乙酯提取3次。有机相用MgSO4干燥,过滤浓缩。残渣用开始用乙酸乙酯、然后用甲醇硅胶色谱纯化。产量:54%的无色油状物。
顺-9-十八碳烯酸2-羟基-3-膦酰氧基丙酰胺(13)
12(1.76mmol)溶解于20ml二氯甲烷溶液中,加入50ml 1%的NaOH甲醇溶液。20小时后在室温下浓缩,残渣用1N HCl酸化,混合物用乙酸乙酯提取。有机相用50ml水洗涤,MgSO4干燥,过滤浓缩。残渣用甲醇处理。产量:82%的无色结晶。
实施例3
应用DNA合成分析,在胎鼠头骨成骨细胞的原始培养物中,检测式(I)的化合物。实验按照Pfeilschifter等,内分泌学(endocrinology)126,703(1990)的方法进行。
实验详述:BrdU方法
作为增殖代用参数的DNA合成能力采用增殖细胞ELISA,BrdU(比色分析)(Boehringer Mannheim,Mannheim,Germany)测定。
用胶原酶从胎鼠头骨中连续消化提取原始成骨细胞,由此得到5组细胞。混合第3-5组细胞离体培养。细胞在相对湿度95%、CO2含量5%、温度37℃的培养箱中培养。检测第一、二、或第三代培养物中的实验物质。
为了检测,在应用实验物质之前至少96小时,将细胞以每孔7×103个细胞(在100μl培养基中)的细胞数接种到平底微孔平板(MWP)中。在该阶段的末期,用加有5%胎牛血清(FCS)和盘尼西林(100U/ml)/链霉素(0.1mg/ml)的MEM Dulbecco(加有4.5g/l葡萄糖,3.7g/lNaHCO3,不含谷氨酰胺)作为培养基。
就在将实验物质加入细胞培养物之前,培养基替换为用1mg/ml牛血清白蛋白(BSA)代替FCS的100μl培养基。将实验物质以所需浓度加入含BSA的培养基。浓度为0.1-0.2ng/ml的TGFβ1(转化生长因子β1)作为阳性对照。每组(阳性)对照和各浓度的实验物质分别测量三次。
将含实验物质的细胞培养物培养24小时以上,在最后3小时中另加入BrdU探针(加有10μl 100μM的5-溴-2′-脱氧尿苷溶液)。
培养周期结束时,在室温下用200μl的FixDenatTM溶液固定细胞群落30分钟,同时使DNA变性。随后用100μl的抗-BrdU-POD溶液覆盖固定的细胞群落,室温下保温90分钟。用200μl的PBS溶液冲洗三次后,将100μl的底物溶液(TMB=N四甲联苯胺)加入MWP孔,然后在室温下保温5分钟。
用SLT公司的ATTC 340MTP读数仪测定光密度,其中测定光波的波长为370nm,参照光波的波长为492nm。用SLT公司的“easy WINbasic″软件记录和处理源数据。
评价中,用单独应用含BSA培养基的细胞培养物作为对照(100%)。表I:L-α-顺-9-十八碳烯酸2-羟基-3-膦酰氧基丙酯对胎鼠头骨成骨细胞DNA合成速率的影响
浓度(μg/ml) | 0.3 | 1.0 | 3.0 | 10.0 |
相对于对照的影响率%(对照=100%) | 161±13 | 185±12 | 253±30 | 284±22 |
平均值±标准差,n=8
还在体内实验模型中用Balb/c鼠检测了式(I)化合物的骨形成刺激作用。按照Mackie和Trechsel(转化生长因子-β的体内骨形成刺激作用:编织骨的重塑和消炎痛抑制作用的消失,骨(Bone)11,295-300,1990)的描述进行实验。
Table II:对照组和随后L-α-顺-9-十八碳烯酸-2-羟基-3-
磷酰氧丙酯对小鼠头盖骨局部给药骨质的比较
平均值±标准差,n=6
表III:相对于对照组,随后L-α-顺-9-十八碳烯酸
2-羟基-3-膦酰氧基丙酯对小鼠头盖骨局部给药骨质增加%
质量 | X-线密度 | |
0.6mg/动物/天 | +37% | +58% |
1.6mg/动物/天 | +23% | +30% |
平均值,n=6
Claims (4)
2.式(I)化合物
其中
R1=具有6-24个碳原子的烯基或炔基;
n=0-12;
X=氧;
或生理上可耐受的盐,酯,光学活性体,或外消旋体,不包括化合物(全-顺-5,8,11,14)-二十碳四烯酸2-羟基-3-膦酰氧基丙酯,顺-9,顺-12-十八碳二烯酸2-羟基-3-膦酰氧基丙酯,(全-顺-9,12,15)-十八碳三烯酸2-羟基-3-膦酰氧基丙酯,顺-9-十八碳烯酸2-羟基-3-膦酰氧基丙酯,和芥酸2-羟基-3-膦酰氧基丙酯。
3.一种含有至少一种按照权利要求2的式(I)化合物和常规的载体和佐剂的药物。
4.按照权利要求2的式(I)化合物在制备用于治疗骨代谢疾病的药物中的应用。
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