CN1326841C - 具有内皮素拮抗剂活性的芳烷烃-磺胺类化合物 - Google Patents
具有内皮素拮抗剂活性的芳烷烃-磺胺类化合物 Download PDFInfo
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- CN1326841C CN1326841C CNB01815896XA CN01815896A CN1326841C CN 1326841 C CN1326841 C CN 1326841C CN B01815896X A CNB01815896X A CN B01815896XA CN 01815896 A CN01815896 A CN 01815896A CN 1326841 C CN1326841 C CN 1326841C
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- phenyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
本发明涉及新型芳烷烃-磺胺类化合物及其作为活性组分在制备药物组合物中的应用。本发明还涉及相关的方面包括:上述化合物的制备步骤,含有一种或多种上述化合物的药物组合物,尤其是这些药物组合物作为内皮素受体拮抗体的应用。
Description
本发明涉及通用分子式I的新型芳烷烃-磺胺类化合物及其作为活性组分在制备药物组合物中的应用。本发明还涉及相关的方面包括:这些新型芳烷烃-磺胺类化合物的制备工艺,含有一种或多种通用分子式I化合物的药物组合物,尤其是这些药物组合物作为内皮素受体拮抗体的应用。
内皮素(ET-1,ET-2和ET-3)是一类21-氨基酸多肽类化合物,产生并活跃于几乎所有的组织中(Yanagi sawa M et al.;Nat ure(1988)332:411)。内皮素类化合物是心脏功能、肾功能、内分泌功能和免疫功能的有效血管收缩药和重要介质(McMillen MA et al.;J Am Coll Surg(1995)180:621)。它们参与支气管收缩,调节神经传递素的释放、炎性细胞的活化、纤维变性、细胞增殖、细胞分化等生理过程(Rubanyi GM et al.;Pharmacol Rev(1994)46:328)。
已经克隆了两种内皮素受体并在哺乳动物上实验(RTA,ETB)(Arai Het al.;Nature(1990)348:730;Sakurai T et al.;Nature(1990)348:372)。ETA受体的特征在于对ET-1和ET-2比对ET-3有更高的亲和力。它在血管平滑肌和介质的血管收缩和增殖反应中起主导作用(Ohlstein EHet al.;Drug Dev Res(1993)29:108)。相反地,ETB受体对3种内皮素异多肽类化合物有相同的亲和力,并且可以结合内皮素,4-丙氨酸内皮素和撒腊菌素S6C(Ogawa Y et al.;BBRC(1991)178:248)。这种受体存在于血管内皮和平滑肌中,还特别大量存在于肺和脑中。存在于内皮细胞的血管扩张剂中的ETB受体通过释放一氧化氮和/或环前列腺素来对ET-1和ET-3起反应,而存在于平滑肌细胞的ETB受体是通过血管收缩来产生作用的(Sumner MJ et al.;Brit J Pharmacol(1992)107:858)。ETA和ETB受体在结构上极为相似,都属于G-蛋白质偶合受体的总科。
在多种疾病如高血压、败血症、粥样动脉硬化症、急性心肌梗塞、充血性心力衰竭、肾衰竭、偏头痛和哮喘等观察过程中,通过血浆和组织中ET-1的含量的增加来进行病理和生理过程鉴定,内皮素受体拮抗剂在作为治疗学上有效的药剂被广泛地研究。内皮素受体拮抗剂在治疗各种疾病如脑动脉痉挛伴随蛛网膜下出血、心力衰竭、肺动脉及系统性高血压、神经性炎症、肾衰竭和心肌梗塞等方面已经显示出临床上的和/非临床上的功效。
现在,内皮素受体拮抗剂还没有投放市场,一些在作临床试验。然而,这些化合物分子有许多弱点,如合成过程复杂、溶解性低、分子量高、药物代谢性差和存在安全方面问题(例如肝脏中酶的增加)等。
通用分子式I的化合物对内皮素受体的抑制活性可通过下述测试步骤显现出来。
为了评价通用分子式I化合物的能力和功效,使用了下列测试:
1)对内皮素结合CHO细胞膜运输人类ET受体的抑制的测试方法:
为了调查结合能力,使用了表示人体内ETA或ETB受体的CHO细胞的细胞膜进行研究,制备了重组CHO细胞的微粒体细胞膜,并且用先前描述的方法进行了结合能力的测定(Breu V.,et al,FEBS Lett 1993;334:210)。
化验在聚丙烯微量滴定盘中进行,内含有200微升50毫摩尔/升的三羟甲基氨基甲烷/盐酸缓冲液,pH值等于7.4,并含有25毫摩尔/升的二氯化锰、1毫摩尔/升的乙二胺四乙酸和0.5%(质量/体积比)BSA(无蛋白酶牛血清白蛋白)。将含有0.5微克蛋白质的细胞膜和8pM[125I]的E T-1(4000cpm)的溶液在20℃孵化2小时,并且增加未标定的抗体的浓度。在不含和含有100纳摩尔/升的ET-1的情况下,分别测定最大和最小的结合力。2小时后,细胞膜用含有GF/C过滤器的滤盘过滤(所使用的唯一的过滤盘购于Canberra Packard S.A.苏黎士,瑞士)。并加入50微升的闪烁鸡尾酒溶液(MicroScint 20,Canberra PackardS.A.苏黎士,瑞士),滤盘用一个微盘计数器(TopCount,CanberraPackard S.A.苏黎士,瑞士)计数。
所有被测试的化合物加入二甲亚砜溶解并稀释,化验在含有2.5%的二甲亚砜的条件下进行,已经鉴定二甲亚砜对结合力的测量没有明显的干扰作用。IC50被用作为具有50%抑制ET-1结合作用的浓度。对于参照物,用以下的方法测量
IC50值:ETA细胞:对于ET-1,其浓度为0.075纳摩尔/升(n=8),对于ET-3,其浓度为118纳摩尔/升(n=8);ETB细胞:对于ET-1,其浓度为0.067纳摩尔/升(n=8),对于ET-3,其浓度为0.092纳摩尔/升(n=3)。
所得到的分子式I所示的化合物的IC50的值见表1。
表1:
化合物例 | IC50ETA[nM] | IC50ETB[nM] |
例1例2例5例7例10例13例14例19例29例39例46例47例49例52例61例71例81 | 2720349463103724451011524 | 66508993233310241036802230193046026123602720249017701140>10000824 |
2)对分离出的老鼠主动脉环(ETA受体)和老鼠气管环(ETB受体)中的内皮素诱导的收缩作用的抑制作用的测试方法:
内皮素抗体的功能化抑制效力,是通过它们对于由老鼠主动脉环(ETA受体)中的ET-1诱导的收缩作用的抑制能力,和对于由老鼠气管环(ETB受体)中的撒腊菌素S6c诱导的收缩作用的抑制能力进行测试而评价的。成年大白鼠被麻醉后放血,胸部的大动脉或气管被切除、分割开形成3-5毫米的环。通过轻轻地摩擦内膜表面来除去内皮细胞/上皮细胞。每个脉管环悬泡在10毫升装有Krebs-Henseleit溶液(单位:毫摩尔/升;氯化钠:115,氯化钾:4.7,硫酸镁:1.2,磷酸二氢钾:1.5,碳酸氢钠:25,氯化钙:2.5,葡萄糖:10)的隔离池中,保持37℃并充入95%的氧气和5%的二氧化碳气体。脉管环连接到一个力传感器上并记录恒长度拉伸力(EMKA Technologies SA,巴黎,法国)。测量脉管环拉伸到静止的3克(对于动脉管)或2克(对于气管)的拉伸力。在与待测化合物以及它们的载体一起孵化10分钟后,加入渐增剂量的ET-1(对于动脉管)或撒腊菌素S6c(对于气管),通过计算浓度比值,也即是通过计量不同浓度的待测化合物诱导EC50向右侧的漂移,来评价待测化合物的功能化抑制效力。EC50是达到收缩的半峰值所需的内皮素的浓度,pA2是诱导EC50值二次折叠移动的抗体浓度的负对数值。
所得到的分子式I所示的化合物的pA2值见表2。
表2:
化合物例 | pA2(主动脉回路) | pA2(气管) |
例5例7例8例34例61例75 | 8.388.837.437.677.837.76 | 7.027.07--7.07- |
由于它们具有抑制内皮素结合的能力,所述的化合物可以用来治疗由内皮素增加引起的与血管收缩、细胞增殖、炎症相关的疾病。关于这类疾病的例子有高血压、冠心病、心力衰竭、肾和心肌萎缩、肾衰竭、脑缺血、痴呆、偏头痛、蛛网膜下腔出血、雷纳氏症候群、门静脉高压症、肺动脉高血压等等。它们也可以用于治疗动脉硬化症,气球或扩张血管成形术后再狭窄的预防、胃和十二指肠溃疡、癌症、前列腺增生、勃起功能障碍、听力丧失、失明、慢性支气管炎、哮喘、革兰氏染色阴性败血病、休克、镰刀形红细胞贫血症、血管球性肾炎、肾绞痛、青光眼、糖尿病并发症的治疗和预防、脉管或心脏手术或器官移植后的并发症、环孢霉素治疗后的并发症、目前已知的与内皮素相关的痛苦和疾病。
化合物可以口服、直肠给药、注射给药等等方式,例如制备成静脉注射、肌肉注射、皮下注射、胸内或皮肤给药、舌下给药、眼药制备或气雾剂形式的药物。具体应用方式的例子是制成胶囊、药片、口服悬浮液或溶液、栓剂、注射剂、滴眼药、药膏或气雾剂/喷雾器。
优选的应用方式是静脉注射、肌肉注射、口服药或滴眼药。药物的用量取决于特殊活性成份的类型、也取决于病人的年龄以及需求和使用的方式。通常用量的考虑范围是每公斤人体体重每天使用0.1-50毫克。含有分子式I的化合物的药物的制备中通常加入惰性剂或也加入具有药效活性的赋形剂。制备成的药片或颗粒中通常可以含有一定数量的粘合物、充填赋形剂、载体物质或稀释剂。
本发明涉及通用分子式I的芳烷烃-磺胺类化合物,其中
R1和R2代表芳基;杂芳基;
R3代表苯基;一、二或三取代苯基,取代基选自低级烷基、低级烯基、低级炔基、苯基、低级烷氧基、氨基、低级烷基氨基、氨基-低级烷基、三氟甲基、三氟甲氧基、卤素、低级烷基硫代、羟基、羟基-低级烷基、氰基、羧基、低级烷酰基、甲酰基;苯并呋喃基;芳基;杂芳基;
R4代表氢;卤素;三氟甲基;低级烷基;低级烷基-氨基;低级烷氧基;低级烷基-亚磺基;低级烷基-亚硫酰基;低级烷基硫代;低级烷基硫代低级烷基;羟基-低级烷基;低级烷基-氧代-低级烷基;羟基-低级烷基-氧代-低级烷基;羟基-低级烷基-氨基;低级烷基-氨基-低级烷基;氨基;二-低级烷基-氨基;[N-(羟基-低级烷基)-N-低级烷基]-氨基;芳基;芳基-氨基;芳基-低级烷基-氨基;芳基硫代;芳基-低级烷基-硫代;芳氧基;芳基-低级烷氧基;芳基-低级烷基;芳基-亚硫酰基;杂芳基;杂芳氧基;杂芳基-低级烷氧基;杂芳基-氨基;杂芳基-低级烷基-氨基;杂芳基-硫代;杂芳基-低级烷基-硫代;杂芳基-低级烷基;杂芳基-亚硫酰基;杂环基;杂环基-低级烷氧基;杂环基-氧代;杂环基-氨基;杂环基-低级烷基-氨基;杂环基-硫代;杂环基-低级烷基-硫代;杂环基-低级烷基;杂环基-亚硫酰基;环烷基;环烷基-氧代;环烷基-低级烷基-氧代;环烷基-氨基;环烷基-低级烷基-氨基;环烷基-硫代;环烷基-低级烷基-硫代;环烷基-低级烷基;环烷基-亚硫酰基;
X代表氧;硫;NH;CH2或者键;
Y代表氧;硫或者-NH-;
Z代表氧;硫,-NH-或者键;
Q代表-(CH2)k-;-(CH2)m-C≡C-(CH2)p-,当p是0时,Z代表键;-CH2-环丙基-CH2-;
k代表数字2,3;4,5,或者6;
m代表数字1,2,或者3;
p代表数字0,1,2或者3;
n代表数字1,2,或者3;
或其纯的非对映异构体,非对映异构体的混合物,非对映异构体的外消旋物,非对映异构体外消旋物和内消旋物的混合物或其药用许可的盐类。
在通用分子式I的定义中,除非另有说明,所说的低级烷基或低级烷氧基是指含有1到7个碳原子的直链和支链基团,优选是含有1到4个碳原子。低级烷基和低级烷氧基基团的例子是甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,戊基,己基,庚基,甲氧基,乙氧基,丙氧基,正丁氧基,异丁氧基,仲丁氧基和叔丁氧基。低级亚烷二氧基基团优选亚甲二氧基,亚乙二氧基,亚丙二氧基和亚丁二氧基基团。低级烷酰基基团的例子是乙酰基,丙酰基和丁酰基。低级亚烯基是指例如1,2-亚乙烯基、1,2-亚丙烯基和1,2-亚丁烯基。低级烯基和低级炔基是指例如1,2-亚乙基、1,2-亚丙基、1,2-亚丁基、2-甲基丙烯基,和亚乙炔基、亚丙炔基、亚丁炔基、亚戊炔基、2-甲基亚戊炔基等的基团。低级烯氧基是指烯丙氧基、乙烯氧基、丙烯氧基及同类基团。所说的环烷基是指含有3到7个碳原子的饱和环烃,如环丙基、环丁基、环戊基、环己基、环庚基;并可被低级烷基、羟基-低级烷基、氨基-低级烷基、低级烷氧基-低级烷基和低级亚烯基所取代。所说的杂环基是指含有一到二个相同的或不同的氮、氧或硫原子的饱和的或部分不饱和的四、五、六或七元环,并且该四、五、六或七元环可适当的被低级烷基、氨基、硝基、羟基、低级烷氧所取代,以及带有上述取代基的四、五、六或七元环的取代衍生物,其中的取代基例如是哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡喃基、二氢吡喃基、1,4-二噁烷基、吡咯烷基、四氢呋喃基、二氢吡咯基、二氢咪唑基、二氢吡唑基、吡唑烷基、5-氧-1,2,4-噁二唑基、5-氧-1,2,4-噻二唑基、5-硫-1,2,4-噁二唑基、2-氧-1,2,3,5-噁噻二唑基等(例[7])。所说的杂芳基是指含有一到四个氮原子的六元芳环,含有一到三个氮原子的苯并六元芳环,含有一个氧原子或一个氮原子或一个硫原子的五元芳环,含有一个氧原子或一个氮原子或一个硫原子的苯并五元芳环,含有一个氧原子和一个氮原子五元芳环及其苯并衍生物,含有一个硫原子和一个氮原子的五元芳环及其苯并衍生物,含有两个氮原子的五元芳环及其苯并衍生物,含有三个氮原子的五元芳环及其苯并衍生物,或四唑基环;例如呋喃基、噻吩基、吡咯基、吡啶基、嘧啶基、吲哚基、喹啉基、异喹啉基、咪唑基、三嗪基、噻嗪基、噻唑基、异噻唑基、哒嗪基、噁唑基、异噁唑基等;上述环可带有取代基低级烷基、低级烯基、氨基、氨基-低级烷基、卤素、羟基、低级烷氧基、三氟甲氧基、三氟甲基、羧基、酰胺基、硫代酰胺基、脒基、氰基、羟基-低级烷基、低级烷氧基-低级烷基或另一个杂芳环(优选四唑基)或杂环(优选5-氧-1,2,4-噁二唑基、5-氧-1,2,4-三唑基、5-氧-1,2,4-噻二唑基、5-硫-1,2,4-噁二唑基、2-氧-1,2,3,5-噁噻二唑基等(例[7]))。所说的芳基是指没有取代基团的以及一、二或三取代的6到10个碳原子的芳环,如苯环或萘环,并可被芳基、卤素、羟基、低级烷基、低级烯基、低级炔基、低级烷氧基、低级烯氧基、低级炔基-低级烷氧基、低级亚烯基、低级亚烷氧基、低级亚烷氧基或低级亚烷二氧基与苯环形成一个五或六元环、羟基-低级烷基、羟基-低级烯基、羟基-低级烷基-低级炔基、低级烷氧基-低级烷基、低级烷氧基-低级烷氧基、三氟甲基、三氟甲氧基、环烷基、羟基-环烷基、杂环基、杂芳基所取代。
可以理解,为了清楚起见,关于环烷基、杂环基、杂芳基和芳基所指代的取代基团在权利要求1到11的通式I到V中省略了,但通式I到V和权利要求1到11中的定义应按其中包括了这些指代的取代基团去理解。
特别优选的化合物是通式I的化合物,其中R3代表苯基或者单取代苯基,其取代基是低级烷氧基,较好的是甲氧基,X代表氧。
第二组特别优选的通式I的化合物是,其中R3代表苯基或者单取代苯基,其取代基是低级烷氧基,特别是甲氧基,其中X、Y和Z代表氧。
第三组特别优选的通式I的化合物是,其中R3代表苯基或者单取代苯基,其取代基是低级烷氧基,特别是甲氧基,其中X、Y和Z代表氧,Q代表-(CH2)k-,且k=2或3。
第四组特别优选的通式I的化合物是,其中R2代表杂芳基,R3代表苯基或者单取代苯基,其取代基是低级烷氧基,特别是甲氧基,X、Y和Z代表氧,Q代表-(CH2)k-,且k=2或3。
第五组特别优选的通式I的化合物是,其中R2代表杂芳基,R3代表苯基或者单取代苯基,其取代基是卤素、低级烷基、低级烯基、甲氧基、氨基、低级烷基-氨基、低级烷基-硫代、羟基、羟甲基和低级烷酰基,X、Y和Z代表氧,Q代表-(CH2)2-。
另一组优选的化合物是分子式II的化合物,其中R1、R2、R3、R4、Y、Q、Z和n的定义同上述通式I,或分子式II化合物的药用许可的盐类。
还有优选的分子式III的化合物,其中R1、R2、R4、Y、Q、Z和n的定义同上述通式I,或分子式III化合物的药用许可的盐类。
分子式III
还有优选的分子式IV的化合物,其中R1、R2、R4、Q和n的定义同上述通式I,或分子式IV化合物的药用许可的盐类。
分子式IV
另一组特别优选的化合物是分子式V的化合物或其药用许可的盐类,其中R1、R2的定义同上述通式I。
分子式V
在分子V的一组化合物中特别优选的化合物是,其中R2代表杂芳基。
所说的药用许可的盐类包括与无机酸或有机酸形成的盐类,这些无机酸或有机酸有氢卤酸,例如氢氯酸或氢溴酸,硫酸、磷酸、硝酸、柠檬酸、甲酸、乙酸、马来酸、酒石酸、甲磺酸、对甲苯磺酸及类似的酸;或者如果通式I的化合物本身是酸性的,与无机碱形成的盐类,这些无机碱有碱金属碱或稀土碱金属碱,例如氢氧化钠、氢氧化钾、氢氧化钙等。
通用分子式I的化合物可能含有一个或多个非对称的碳原子,并可制成光学纯的对映异构体或非对映异构体,几种对映异构体或非对映异构体的混合物,非对映异构体的外消旋物,非对映异构体外消旋物的混合物,及相应的内消旋物的形式。本发明包括所有上述形态。混合物可通过现有已知的方法,如柱色谱法、薄层色谱法、HPLC、结晶法等分离。
通用分子式I所描述的化合物及其药用许可的盐类由于能抑制内皮素的结合,所以可用于治疗由内皮素引起的血管收缩、增生、炎症加剧的相关疾病。这样疾病的例子有高血压、冠心病、心机能不全、肾和心肌缺血、肾衰竭、脑缺血、痴呆、偏头痛、蛛网膜下出血、雷诺氏综合征、门静脉高血压和肺动脉高血压。它们也可用于动脉粥样硬化、气囊或扩张方法血管重建术后的再狭窄、炎症、胃和十二指肠溃疡、癌症、前列腺肥大、勃起功能障碍、听力丧失、黑内障、慢性支气管炎、哮喘、格兰氏阴性败血症、休克、镰状细胞性贫血、肾小球性肾炎、肾绞痛、青光眼、糖尿病并发症的预防与治疗、血管或心脏手术或器官移植后的并发症、环孢子菌素治疗的并发症、疼痛及其它已知的与内皮素有关的疾病。
这些组合物可以下述形式作为药物使用:肠内或口服形式,例如片剂、糖锭剂、胶囊、乳剂、溶液或悬浊液;鼻内形式,如喷雾剂;直肠用药的形式如栓剂。这些化合物也可以肌肉内、肠道外、静脉内的形式如注射方式使用。
这些药用组合物可能即含有通式I的化合物,又含有其药用许可的盐类,还协同使用了制药工业中常用到的无机和/或有机赋形剂如乳糖、玉米及其衍生物、滑石粉、硬脂酸(stearinic acid)及其盐类。
在胶囊中,可使用植物油、植物蜡、植物油脂、液态或半液态多元醇等。在制备药水和糖浆中,使用如水、多元醇、蔗糖、葡萄糖等。注射剂制备中使用如水、多元醇、醇类、甘油、植物油、卵磷脂、脂质体等。栓剂制备中使用天然或氢化的油、蜡、脂肪酸(油脂),液态或半液态多元醇等。
这些组合物可能还含有防腐剂、稳定剂、增粘剂或粘度调节剂、增溶剂、甜味剂、染料、调味剂、改变渗透压的盐类、缓冲剂、抗氧化剂等。
通式I的化合物也可以与一个或多个其它有治疗功效的物质协同使用,例如:α-和β-受体阻滞剂如芬妥胺、苯氧苄胺、氨酰心安、心得安、噻吗心安、甲氧乙心安、卡替洛尔等;血管舒张药如肼苯哒嗪、米诺地尔、二氮嗪、福洛奎南(flosequinan)等;钙拮抗药如地尔硫卓、尼卡地平、尼莫地平、维拉帕米、硝苯地平等;ACE-抑制剂如硅氨(cilazapril)、卡托普利、依那普利(enalapril)、赖洛普利(lsinopril)等;钾活化剂如吡那地尔(pinacidil)等;血管紧缩素II拮抗药;利尿药如双氢氯噻嗪、氯噻嗪、艾斯托拉明(acetolamide)、布美他尼、速尿灵、美托拉宗、氯噻酮等;交感神经阻滞药如甲基多巴、可乐定、胍那苄、利血平等;以及用来治疗高血压或心律不齐的其它治疗药。
剂量可在宽范围内变动,但应适应具体的情况。通常每日口服剂量应界于约3mg至约3g,较好的界于约10mg至约1g,最好界于5mg至300mg,以体重约70kg的成人为基准。该剂量最好按每日1至3次等量分服。照例,儿童应按其体重和年龄减量服用。
本发明通用分子式I的化合物可按照下述通常的反应顺序制备。为了简洁清楚起见,有时仅描述部分生成通式I化合物的合成可能。括号[]中的参考文献列在本节末。
可能性A:
所需要的通用分子式I的化合物可由分子式1的化合物,与分子式2的化合物或其盐反应制得:
分子式1
其中G1是反应基,优选氯原子,其它符号的定义同前面的通式I;
分子式2
其中符号的定义同前面的通式I。
可能性B:
通用分子式I化合物也可由分子式3的化合物或其盐,与分子式4的化合物反应制得:
其中符号的定义同前面的通式I;
其中G2是反应基,例如卤素原子,R2的定义同前面的通式I。
可能性C:
通用分子式I化合物也可由分子式5的化合物或其盐,与分子式6的化合物或其盐反应制得:
分子式5
其中G3是低级烷基磺酰基或苯磺酰基或卤素原子,其它符号的定义同前面的通式I;
H-R4
分子式6
其中R4的定义同前面的通式I。
可能性A到C参见[5]。
方案1:母体1和3的制备,其中X、Y和Z代表氧:
a)NaOMe,MeOH,然后NH4Cl或LiN(Si(CH3)3)2,然后HC]/i-PrOH;
b)K2CO3,丙酮;c)NaOMe,MeOH;d)POCl3;e)NH3/THF,然后KOtBu,MeOH;f)DMSO;g)NaH,THF,DMF;
脒8的合成是按标准方法[1],将适合的腈7与甲醇钠在甲醇中反应后加入氯化铵,或者将适合的腈7与六甲基二硅氧烷锂反应后加入溶于异丙醇的氢氯酸。2-取代的丙二酸酯10的制备是按己公开的步骤[2],将氯代内二酸二甲酯9与适合的醇11在丙酮和碳酸钾的基质中反应。化合物10溶解在甲醇中,加入甲醇钠,持续搅拌大约30min,随后加入一种脒衍生物8。室温下再继续搅拌8h。在逐渐达到酸性顶点后,4,6-二羟基嘧啶类1 2可分离出来,产率70-90%[2]。化合物12或其异构体在升温(60-120℃)N,N-二甲基苯胺存在下,与三氯氧磷反应转变为二氯衍生物13,产率40-75%[3]。有时通过加入PCl5或苄基三乙基氯化铵可获得更高的产率。二氯衍生物13与过量的适合的磺胺钾盐15(由磺酰氯14(14的制备参见例[9],[10])按标准方法制得)在室温下DMSO中反应,再经过从EA/二乙醚的重结晶或用EA/庚烷通过硅胶的色谱法,得到产率70-90%的嘧啶16。嘧啶衍生物16是转变为所要的通式I的最终产物的重要中间体,可通过可能性A所述的步骤,或者通过先将嘧啶衍生物16与一种二羟基化合物17在一种碱如氢化钠存在下、一种溶剂如THF中、室温到90℃范围内反应转变为衍生物18,再通过上述可能性B所述的步骤转变为通式I的最终产物。
进一步的实验说明参见[1],[2],[3],[6]。
X,Y或Z不是氧而是其它基团的化合物的合成,可通过相似的方法实现。
方案2:母体5的制备,其中X、Y和Z代表氧:
a)i)硫脲,NaOMe,MeOH,室温;ii)CH3I,DMSO,室温;iii)POCl3,二甲基苯胺安,100-120℃;b)R1-(CH2)n-SO2-NHK,DMSO,室温;c)R2-O-Q-OH、NaH、THF/DMF、室温或60-80℃,或者HO-Q-OH、NaH、THF/DMF、室温或60-80℃之后G2-R2、NaH、THF、60-80℃;d)MCPBA,DCM,室温;
进一步的实验说明参见[1],[2],[3],[5],[6]。磺酰基取代物尤其参见[5]。X,Y或Z不是氧而是其它基团的化合物的合成,可通过相似的方法实现。
方案3:X代表一个键的通式I化合物的产物母体的制备[5]:
方案1到3中符号的指代同上述通式I的定义。
[1]W.Gohring,J.Schildknecht,M.Federspiel;Chimia,50(1996),538-543.
[2]W.Neidhart,V.Breu,D.Bur,K.Burri,M.Clozel,G.Hirth,M.Muller,H.P.Wessel,H.Ramuz;Chimia,50(1996),519-524及其引用的参考文献.
[3]W.Neidhart,V.Breu,K.Burri,M.Clozel,G.Hirth,U.Klinkhammer,T.Giller,H.Ramuz;Bioorg.Med.Chem.Lett.,7(1997),2223-2228.R.A.Nugent,S.T.Schlachter,M.J.Murphy,G.J.Cleek,T.J.Poel,D.G.Whishka,D.R.Graber,Y.Yagi,B.J.Keiser,R.A.Olmsted,L.A.Kopta,S.M.Swaney,S.M.Poppe,J.Morris,W.G.Tarpley,R.C.Thomas;J.Med.Chem.41(1998),3793-3803.
[4]J.March;Advanced Organic Chemistry,th Ed.,1994,499页及其引用的参考文献
[5]EP 0 743 307 A1;EP 0 658 548 B1;EP 0 959 072 A1(Tanabe Seiyaku)
[6]EP 0 633 259 B1;EP 0 526 708 A1;WO 96/19459(F.Hoffmann-LaRoche)
[7]for the Synthesis of 5-membered heterocycles see:Y.Kohara等;J.Med.Chem.,39(1996),5228-5235及其引用的参考文献
[8]EP 0 882 719 A1(Yamanouchi Pharmaceutical Co.,Ltd.)
[9]Z.Zhong,J.A.Bibbs,W.Yuan,C.H.Wong,J.Am.Chem.Soc.113,(1991),2259-2263.
[10]D.J.Kempf,L.Codavoci,X.C.Wang,W.E.Kohlbrenner,N.E.Wideburg,A.Saldivar,S.Vasavanonda,K.C.Marsh,P.Bryant,H.L.Sham,B.E.Green,D.A.Betebenner,J.Erikson,D.W.Norbeck,J.Med.Chem.36(1993),320-330.
参考实施例(母体的合成):
缩略语表:
CyHex 环己烷
DCM 二氯甲烷
DME 1,2-二甲氧基乙烷
DMF 二甲基甲酰胺
DMSO 二甲亚砜
EA 乙酸乙酯
Hex 己烷
HV 高真空条件
MCPBA 间氯过苯甲酸
min 分钟
rt 室温
THF 四氢呋喃
sat. 饱和的
tR 保留时间
下述参考实施例说明本发明,但不由此限制本发明的范围。
下述化合物是按照以上所描述的和方案1到3所显示的步骤制备的。所有的化合物用以下的仪器进行鉴定:1H核磁共振谱(300兆赫)并且有时13C核磁共振谱(75兆赫)(Varian牛津,300兆赫;相对使用的溶剂所给出的化学位移以ppm(百万分之一)为单位;多重峰的定义:s=单峰,d=双峰,t=三重峰,m=多重峰,偶合常数J单位是Hz)、液相色谱-质谱(Waters Micromass;带有电喷雾(ESI)探针和Alliance 2790HT的ZMD平台;柱子:2×30毫米,Gromsil ODS4,3微米,120 A;梯度:水相中0-100%乙腈,6分钟,含有0.05%甲酸,流动:0.45毫升/分钟;tR的单位是分钟)、薄层色谱(薄层色谱板:Merck,硅胶60F254)和偶尔用熔点鉴定。所有的温度单位是℃。
参考实施例1
a)甲醇钠(17g)于0℃溶解在甲醇(600ml)中。在30min内加入溶解在150ml甲醇中的2-对甲苯基丙二酸二乙酯(24.5ml,Aldrich商品)。持续搅拌1小时,并缓慢将混合物升到室温。加入盐酸甲脒(9.9g,Fluka商品)并持续搅拌16小时。蒸发溶剂,向残余物中加入2M盐酸(200ml),之后缓慢加入10M氢氧化钠调节PH值到5。沉淀产物经过滤,再依次用水和二乙醚冲洗,干燥后得到5-对甲苯基嘧啶-4,6-二二醇(17.7g)。1H-NMR(300MHz,d6-DMSO):8.0(s,1H);7.4(d,2H);7.1(d,2H);2.25(s,3H)。
b)5-对甲苯基嘧啶-4,6-二醇(17.2g)溶解在三氯氧磷(250ml)中,并加入N,N-二甲基苯胺(25ml)。混合物在70℃搅拌16小时后真空浓缩。残余物倒入冰水中,并用二乙醚萃取(3x)。结合的有机萃取物依次用1N盐酸溶液和饱和氯化钠溶液冲洗,经硫酸镁干燥,过滤,蒸发滤液。棕色的粗产品用异丙醇重结晶,得到4,6-二氯-5-对甲苯基嘧啶(13.5g)。1H-NMR(CDCl3):8.78(s,1H);7.35(d,2H);7.20(d,2H);2.41(s,3H)。
c)2-苯基乙磺酰氯的制备是按照[9]中的步骤用N-氯丁二酰亚胺氧化苯基乙硫醇。
d)2-苯基乙磺酰氯(40.94g)的THF(250ml)溶液冷却到-20℃后,用饱和氨水(50ml)处理。棕色的悬浊液在室温下搅拌16小时。混合物用盐酸溶液调成中性,并蒸发有机溶剂。剩余的悬浊液用水稀释,用EA萃取四次。有机层结合并蒸发,得到2-苯基乙磺酸酰胺(33.06g)的橙色固体。1H-NMR(300MHz,CDCl3):3.15-3.21(m,2H),33.38-3.45(m,2H),4.59(s br,2H),7.21-7.37(m,5H)。
e)向2-苯基乙磺酸酰胺(33.06g)的甲醇(300ml)溶液中加入叔丁醇钾(22.03g)。所得溶液搅拌15min后蒸发。残余物用二乙醚(400ml)冲洗,高真空干燥,得到2-苯基乙磺酸酰胺钾盐(37.93g)的橙色粉末。
f)2-苯基乙磺酸酰胺钾盐(3.0g)、4,6-二氯-5-对甲苯基嘧啶(2.15g)和Hunig’s碱(1.57ml)溶解在DMSO(50ml)中,在室温下搅拌20小时后,加水(500ml)稀释,再用二乙醚(250ml)萃取两次。水相用乙酸酸化。所得悬浊液冷却到5℃过滤。固体物质用水和二乙醚冲洗,40℃高真空干燥后,得到2-苯基乙磺酸(6-氯-5-对甲苯基嘧啶-4-基)-酰胺(2.08g)的灰色粉末。LC-MS:tR=5.23min,[M+1]+=388.18,[M-1]-=386.14。g)2-苯基乙磺酸(6-氯-5-对甲苯基嘧啶-4-基)-酰胺(850mg)加入叔丁醇钾(1.1g)的乙二醇(15ml)溶液中。混合物在120℃搅拌27小时后,用水(100ml)稀释,用10%柠檬酸水溶液(13ml)酸化。所得沉淀物收集起来,用水和二乙醚冲洗,干燥后得到2-苯基乙磺酸[6-(2-羟基乙氧基)-5-对甲苯基嘧啶-4-基]-酰胺(716mg)的淡棕色粉末。LC-MS:tR=4.44min,[M+1]+=414.18,[M-1]-=412.13。
参考实施例2
a)室温向钠(0.23g)的甲醇(40ml)溶液中加入4-氰基吡啶(10.62g)。持续搅拌6小时后,加入氯化铵(5.9g)并再持续搅拌10小时。然后加入二乙醚(120ml),30分钟后滤出沉淀物并用二乙醚(20ml)冲洗一次。产物经高真空干燥,得到4-脒基吡啶盐酸盐(14.95g)的白色粉末。
b)甲醇钠(6.8g)的甲醇(200ml)溶液冷却到0℃。缓慢加入2-对甲苯基-丙二酸二乙酯(10.3g)的甲醇(50ml)溶液。添加溶液完成后,允许恢复到室温并加入4-脒基吡啶盐酸盐(7.57g)。混合物在室温搅拌16小时。最后,减压去除溶剂,剩余的残余物溶解在2M盐酸中。溶液用二乙醚萃取,然后加入10M氢氧化钠溶液调整PH到5。产生沉淀物。将沉淀物收集,用冷水冲洗,60℃高真空干燥。得到4,6-二羟基-2-(4-吡啶基)-5-对甲苯基嘧啶(8.77g)(或异构体)的橙色晶体。
c)5-对甲苯基4,6-二羟基嘧啶(8.0g)和POCl3(100ml)组成的混合物在室温加入二乙胺(25ml)。混合物在60℃搅拌16小时。过量的POCl3减压蒸馏出。剩余的油状物溶解在DCM(300ml)中,并用水(300ml)处理。分离出的水相用DCM萃取三次。结合的有机相用水和盐水冲洗,经MgSO4干燥,蒸发干燥。所得残余物悬浮在异丙醇中。将固体物质收集,用异丙醇冲洗,再用二乙醚冲洗,干燥后得到4,6-二氯一2-(4-吡啶基)-5-对甲苯基嘧啶(7.2g)的白色晶体粉末。LC-MS:tR=5.49min,[M+1]+=315.89。
d)4,6-二氯-2-(4-吡啶基)-5-对甲苯基嘧啶(1.5g)、2-苯基乙磺酸酰胺钾盐(1.44g,实施例1e)和Hunig’s碱(1ml)溶解在DMSO(20ml)中,在室温搅拌24小时后,用水(150ml)稀释,用二乙醚萃取两次。水相用乙酸酸化。将沉淀物收集,用硅胶上己烷∶EA 1∶1洗提的柱色谱法进一步提纯,得到2-苯基乙磺酸(6-氯-2-吡啶-4-基-5-对甲苯基-嘧啶-4-基)酰胺(480 mg)的泡沫。LC-MS:tR=5.08min,[M+1]+465.13,[M-1]-=462.96。
e)2-苯基乙磺酸(6-氯-2-吡啶-4-基-5-对甲苯基-嘧啶-4-基)酰胺(480mg)加入叔丁醇钾(580mg)的乙二醇(5ml)溶液中。混合物在110℃搅拌72小时后,加水(100ml)稀释,加入10%柠檬酸水溶液(13ml)酸化。将所得的沉淀物收集,用水和二乙醚冲洗,干燥后得到淡2-苯基乙磺酸[6-(2-羟基-乙氧基)-2-吡啶-4-基-5-对甲苯基-嘧啶-4-基]酰胺的棕色粉末。LC-MS:tR=4.17min,[M+1]+=491.24,[M-1]-=489.08。
参考实施例3
2-苯基乙磺酸[6-(2-羟基-乙氧基)-5-对甲苯基-[2,2’]双嘧啶基-4-基]-酰胺是由2-脒基嘧啶盐酸盐(参见EP 0 526 708 A1)按照实施例2公开的步骤制备的。LC-MS:tR=4.42min,[M+1]+=492.30,[M-1]-=490.27。
参考实施例4
2-苯基乙磺酸[5-(4-溴苯基)-6-(2-羟基-乙氧基)-嘧啶-4-基]-酰胺的制备是按与实施例15类似的步骤,在a)步用4-溴苯基乙酸甲酯代替4-氯苯基乙酸甲酯,在d)步用2-苯基乙磺酸酰胺钾盐代替2-噻吩-2-基-乙磺酸酰胺钾盐。LC-MS:tR=4.60min,[M+1]+=480.07,[M-1]-=475.76。
参考实施例5
a)(与J.Am.Chem.Soc.122(2000),1360-1370公开的步骤类似)向Pd(OAc)2(455mg)、2-(二叔丁基膦基)联苯(1.21g)和K3PO4(39.6g)组成的THF(200ml)悬浊液中,氩气保护下加入丙二酸二甲酯(12.85g)和1-溴-3,4-二甲基苯(15.0g)。混合物经回流16小时后,冷却到室温,用EA(300ml)稀释,过滤。滤液蒸发,得到的褐色油状物经硅胶上己烷∶EA 4∶1到1∶1的洗提提纯,得到2-(3,4-二甲基苯基)丙二酸二甲酯(16.2g)的无色油状物并慢慢结晶。1H-NMR(300MHz,CDCl3):2.25(s,3H),2.26(s,3H),3.75(s,6H),4.59(s,1H),7.10-7.20(m,3H)。
b)2-苯基乙磺酸[5-(3,4-二甲基苯基)-6-(2-羟基-乙氧基)嘧啶-4-基]-酰胺是用上述2-(3,4-二甲基苯基)-丙二酸二甲酯按与实施例1类似的步骤制备的。LC-MS:tR=4.61min,[M+1]+=428.19,[M-1]-=426.07。
参考实施例6
a)(与J.Am.Chem.Soc.122(2000),1360-1370公开的步骤类似)向Pd(OAc)2(758mg)、2-(二叔丁基膦基)联苯(2.02g)和K3PO1(65.95g)组成的THF(350ml)悬浊液中,氩气保护下加入丙二酸二甲酯(21.42g)和1-溴-2,4-二甲基苯(25g)。混合物经回流96小时后,冷却到室温,加EA(300ml)稀释,过滤。滤液蒸发,得到的褐色油状物经硅胶上己烷∶EA 4∶1到1∶1洗提和随后蒸馏(沸点95-100℃,压力0.064mbar)的提纯后,得到2-(2,4-二甲基苯基)丙二酸二甲酯(5.66g)的无色油状物。1H-NMR(300MHz,CDCl3):2.30(s,6H),3.75(s,6H),4.87(s,1H),6.98-7.05(m,2H),7.25-7.28(m,1H)。
b)2-苯基乙磺酸[5-(2,4-二甲基苯基)-6-(2-羟基-乙氧基)嘧啶-4-基]-酰胺是用上述2-(2,4-二甲基苯基)-丙二酸二甲酯按与实施例1类似的步骤制备的。LC-MS:tR=4.54min,[M+1]+=428.23,[M-1]-=426.07。
参考实施例7
a)向碳酸钾(70.8g)、丙酮(48ml)搅拌的悬浊液中,缓慢加入2-甲氧基苯酚(愈创木酚)(48ml)后,升温至45℃。然后20min内加入氯代丙二酸二甲酯(63.2ml)的丙酮(50ml)溶液。反应混合物加热回流16小时。溶剂减压蒸发,残余物放入水中,用DCM萃取。结合的有机相经硫酸钠干燥,蒸发干燥。油状产物从甲基叔丁基醚中结晶,得到(2-甲氧基苯氧基)丙二酸二甲酯(86g)。
b)向甲醇钠(9.7g)、甲醇(100ml)的搅拌溶液中,15分钟内加入(2-甲氧基苯氧基)丙二酸二甲酯(21.7g)的甲醇(50ml)溶液,继续搅拌30分钟后,加入4-脒基吡啶盐酸盐(15g,实施例2),继续在室温搅拌20小时。反应混合物经真空浓缩。固体残余物和二乙醚一起搅拌。所得粉末滤出,溶解于水(300ml)中。加入乙酸,使PH=4。沉淀产物滤出,用水冲洗,50℃真空干燥。得到5-邻甲氧基苯氧基-4,6-二羟基-2-(4-吡啶基)-嘧啶(20.1g,可能还存在其异构体5-(2-甲氧基苯氧基)-2-(4-吡啶基)-四氢嘧啶-4,6-二酮)的白色粉末。
c)5-(2-甲氧基苯氧基)-4,6-二羟基-2-(4-吡啶基)-嘧啶(10g)、N-乙基二异丙胺(11.2g)、四乙基氯化铵(11g)和五氯化磷(13.8g)溶解在氧氯化磷(25ml)中,加热回流3小时。混合物经真空蒸发干燥,加入甲苯,混合物再经蒸发干燥。残余物放入DCM中,倒入冰水混合物。两相分开,有机相用水冲洗,经硫酸钠干燥,蒸发干燥。经丙酮中重结晶后,得到纯的4,6-二氯-5-(2-甲氧基苯氧基)-2-(4-吡啶基)-嘧啶(6.52g)。
d)4,6-二氯-5-(2-甲氧基苯氧基)-2-(4-吡啶基)-嘧啶(2g)和2-苯基乙磺酸酰胺钾盐(2.82g,实施例1e)溶解在DMF(50ml)中,室温下搅拌16小时。大量的溶剂蒸发后,加二乙醚(50ml)稀释。混合物加10%柠檬酸水溶液酸化。将形成的沉淀物收集,用二乙醚(100ml)冲洗,干燥后得到2-苯基乙磺酸[6-氯-5-(2-甲氧基苯氧基)-2-吡啶-4-基-嘧啶-4-基]-酰胺(2.23g)的淡棕色粉末。LC-MS:tR=4.93min,[M+1]+=497.22,[M-1]-=494.96。
e)向NaH(644mg,60%矿物油分散液)、DME(15ml)的悬浊液中加入乙二醇(15ml)。在气体放出停止后,加入2-苯基乙磺酸[6-氯-5-(2-甲氧基苯氧基)-2-吡啶-4-基-嘧啶-4-基]-酰胺(800mg),所得溶液在90℃搅拌16小时。加入另一部分NaH(322mg),在90℃继续搅拌4d。混合物用EA(200ml)稀释,用10%柠檬酸水溶液冲冼一次,用水冲洗三次。有机相蒸发干燥,残余物悬浮在二乙醚中。将固体物质收集,用二乙醚冲洗,干燥后得到2-苯基乙磺酸[6-(2-羟基-乙氧基)-5-(2-甲氧基苯氧基)-2-吡啶-4-基-嘧啶-4-基]-酰胺(513mg)的淡棕色固体。LC-MS:tR=4.05min,[M+1]+=528.10,[M-1]-=521.24。
参考实施例8
a)2-苯基乙磺酸[6-氯-5-(2-甲氧基苯氧基)-2-(2-嘧啶基)-4-嘧啶基]-酰胺是按与实施例7类似的步骤,由4,6-二氯-5-(2-甲氧基苯氧基)-2-(2-嘧啶基)-嘧啶(制备参见[6])和2-苯基乙磺酰胺钾盐(实施例1)制得的。LC-MS:tR=4.85min,[M+1]+=498.38,[M-1]-=496.19。
b)向NaH(803mg,60%矿物油分散液)、DMF(15ml)的悬浊液中小心加入乙二醇(15ml)。在H2气体放出停止后,加入2-苯基乙磺酸[6-氯-5-(2-甲氧基苯氧基)-2-(2-嘧啶基)-4-嘧啶基]-酰胺(1g)。所得溶液加热到90℃并搅拌16小时。然后将淡黄色溶液冷却到室温,用10%柠檬酸水溶液(100ml)稀释,用EA(50ml)萃取三次。结合的有机相再次用10%柠檬酸水溶液(50ml)和盐水(50ml)冲洗,蒸发干燥。剩余的残余物悬浮在水(15ml)中。固体物质经过滤,甲醇(50ml)冲洗,二乙醚(50ml)冲洗,干燥。得到2-苯基乙磺酸[6-(2-羟基-乙氧基)-5-(2-甲氧基苯氧基)-2-(2-嘧啶基)-4-嘧啶基]-酰胺(766mg)的白色固体。LC-MS:tR=4.32min,[M+1]+=524.47,[M-1]-=522.29。
参考实施例9
2-苯基乙磺酸[6-(2-羟基-乙氧基)-5-(2-甲氧基苯氧基)-2-吡嗪-2-基-嘧啶-4-基]-酰胺是按实施例7公开的步骤,由2-脒基吡嗪盐酸盐制备的。LC-MS:tR=4.37min,[M+1]+=524.18,[M-1]-=522.44。
参考实施例10
2-苯基乙磺酸[6-(2-羟基-乙氧基)-5-(2-甲氧基苯氧基)-2-吗啉-4-基-嘧啶-4-基]-酰胺是按实施例7公开的步骤,由吗啉-4-羰基脒氢溴酸盐制备的。LC-MS:tR=4.75min,[M+1]+=531.25,[M-1]-=529.50。
参考实施例11
2-苯基乙磺酸[6-(2-羟基-乙氧基)-5-(2-甲氧基苯氧基)-嘧啶-4-基]-酰胺是按实施例7公开的步骤,由甲脒盐酸盐制备的。LC-MS:tR=4.35min,[M+1]+=446.15,[M-1]-=444.11。
参考实施例12
a)向3-甲氧基苯酚(115g)的丙酮(1000ml)溶液中,加入K2CO3(115g)。悬浊液在40℃搅拌15分钟。在45分钟内加入氯代丙二酸二甲酯(133ml)的丙酮溶液。所得的棕色悬浊液在70℃搅拌一整夜。最后,减压去除溶剂,残余物取出放入水(1000ml)中并用DCM(500ml)萃取两次。结合的有机相用水(500ml)冲洗,经Na2SO4干燥,蒸发干燥后得到橙色油状的(3-甲氧基苯氧基)丙二酸二甲酯(230g)粗品。产物未进一步提纯。
b)向(3-甲氧基苯氧基)丙二酸二甲酯(11.19g)的甲醇(100ml)溶液中,加入甲醇钠(6.48g)。黄色溶液在室温搅拌6小时。然后,加入吗啉-4-羰基脒氢溴酸盐(8.40g),混合物在室温搅拌16小时。真空去除溶剂,残余物溶解在水(150ml)中并用二乙醚(150ml)中萃取两次。水相用10%柠檬酸水溶液酸化。将分离的固体收集,用水冲洗,从EA蒸发干燥两次,高真空干燥后得到5-(3-甲氧基苯氧基)-2-吗啉-4-基-嘧啶-4,6-二醇(9.66g)的淡棕色粉末。LC一MS:tR=2.88min,[M+1]+=320.19,[M-1]-=318.02。
c)5-(3-甲氧基苯氧基)-2-吗啉-4-基-嘧啶-4,6-二醇(9.66g)分批加入POCl3(100ml)和Hunig’s碱(50ml)的混合物中。黑色悬浊液加热到110℃并搅拌16小时。冷却混合物,加入N,N-二甲基苯胺后再持续加热24小时。蒸发出大量的溶剂,剩余的油状物倒入水中。深色的溶液经木炭处理后,用EA(300ml)萃取两次。有机相经盐水和水冲洗,MgSO4干燥,蒸发干燥。剩余的油状物经硅胶上己烷∶EA洗提的色谱法分离。产物从2-丙醇中重结晶,淡黄色晶体经二乙醚冲洗,得到4[4,6-二氯-5-(3-甲氧基苯氧基)-嘧啶-2-基]-吗啉(7.48g)。LC-MS:tR=5.56min,[M+1]+=355.99。
d)4[4,6-二氯-5-(3-甲氧基苯氧基)-嘧啶-2-基]-吗啉(1.0g)、2-苯基乙磺酸酰胺钾盐(1.57g,实施例1e)和DMSO(15ml)组成的溶液在60℃搅拌24小时。溶液加水(75ml)稀释,用二乙醚(75ml)萃取两次后,加入10%柠檬酸水溶液酸化。混合物用EA(150ml)萃取两次。有机相用水(50ml)冲洗。蒸发溶剂析出产物。将固体收集,用二乙醚冲洗,干燥后得到2-苯基乙磺酸[6-氯-5-(3-甲氧基苯氧基)-2-吗啉-4-基-嘧啶-4-基]-酰胺(1.28g)的米白色粉末。LC-MS:tR=5.34min,[M+1]+=505.12,[M-1]-=502.97。
e)2-苯基乙磺酸[6-氯-5-(3-甲氧基苯氧基)-2-吗啉-4-基-嘧啶-4-基]-酰胺(1.27g)的乙二醇(12ml)悬浊液用叔丁醇钾(2.82g)处理。所得的溶液在100℃搅拌12d。溶液冷却到室温,加10%柠檬酸水溶液(150ml)稀释,用EA(150ml)萃取两次。有机相用水(50ml)冲洗,蒸发干燥。粗产物经硅胶上己烷∶EA 1∶1到1∶2洗提的色谱法提纯,得到2-苯基乙磺酸[6-(2-羟基乙氧基)-5-(3-甲氧基苯氧基)-2-吗啉-4-基-嘧啶-4-基]-酰胺(1.1g)的白色固体。LC-MS:tR=4.66min,[M+1]+=531.20,[M-1]-=529.14。
参考实施例13
2-苯基乙磺酸[6-(2-羟基乙氧基)-5-(3-甲氧基苯氧基)-嘧啶-4-基]-酰胺是按实施例12公开的步骤,由甲脒盐酸盐制备的。1H-NMR(300MHz,CDCl3):3.14-3.21(m,2H),3.70-3.74(m,2H),3.79(s,3H),3.94-4.01(m,2H),4.40-4.46(m,2H),6.41(dd,J=2.4,8.4,1H),6.47(t,J=2.4,1H),6.66(dd,J=1.8,8.4,1H),7.1 6-7.32(m,6H),8.37(s,1H);LC-MS:tR=4.33min,[M+1]+=446.27,[M-1]-=444.05。
参考实施例14
a)2-噻吩-2-基-乙磺酰氯是由商品2-(2-溴乙基)-噻吩按照文献(J.Am.Chem.Soc.103,(1981),1525-1533)公开的步骤制备的。
b)2-噻吩-2-基-乙磺酰氯(25g)粗品的THF(400ml)溶液,在0℃用饱和氨水(60ml)处理。混合物在室温搅拌16小时后,用25%HCl水溶液(60ml)调成中性。蒸发出大量的THF。水溶液用EA萃取两次。有机相用水冲洗,蒸发干燥。剩余的油状物通过硅胶上己烷∶EA 1∶1洗提的色谱法提纯。产物进一步通过从二乙醚/戊烷重结晶的方法提纯,得到2-噻吩-2-基-乙磺酸酰胺(8.46g)的米白色晶体。1H-NMR(300MHz,CDCl3):3.36-3.50(m,4H),4.54(s,br,2H),6.89-6.92(m,1H),6.95(dd,J=3.5,5.1,1H),7.20(dd,J=1.1,5.0,1H)。
c)2-噻吩-2-基-乙磺酸酰胺(3.77g)的甲醇(200ml)溶液用叔丁醇钾(2.21g)处理,在室温搅拌15分钟,高真空蒸发干燥后,得到2-噻吩-2-基-乙磺酸酰胺钾盐(4.5g)的淡棕色粉末。
d)2-噻吩-2-基-乙磺酸[6-(2-羟基乙氧基)-5-对甲苯基嘧啶-4-基]-酰胺是用上述2-噻吩-2-基-乙磺酸酰胺钾盐按照实施例1公开的步骤制备的。1H-NMR(300MHz,CDCl3):2.42(s,3H),3.33-3.41(m,2H),3.81-3.86(m,2H),3.99-4.07(m,2H),4.46-4.51(m,2H),6.82-6.86(m,1H),6.92(dd,J=3.5,5.1,1H),7.13-7.18(m,3H),7.28-7.32(m,2H),8.51(s,1H);LC-MS:tR=4.18min,[M+1]+=420.24,[M-1]-=418.20。
参考实施例15
a)4-氯苯基乙酸甲酯(52g)的THF(170ml)溶液在35℃、70min内小心的加入NaH(15.6g)的无水THF(550ml)悬浊液中。不加热持续搅拌40分钟,温度降至29℃。气体释放停止后,逐滴加入碳酸二甲酯(94.8ml)并保持混合物的温度在25-28℃。气体释放终止后,混合物用THF(200ml)稀释并在室温持续搅拌72小时。混合物小心加入HCl水溶液酸化后,真空去除大量的THF。残余物溶解在二乙醚(1200ml)中,经1N HCl水溶液冲洗三次,盐水冲洗一次,MgSO4干燥,蒸发干燥。将形成的残余物收集,用二乙醚冲洗,干燥后得到2-(4-氯苯基)-丙二酸二甲酯(42g)的白色晶体。
b)2-(4-氯苯基)-丙二酸二甲酯(18.90g)的甲醇(200ml)溶液在0℃逐滴加入甲醇钠(14.60g)的甲醇(150ml)溶液中。混合物在0℃搅拌1h后,加入甲脒盐酸盐(7.66g)。悬浊液在室温搅拌20h。溶剂去除,残余物悬浮在2N HCl水溶液(200ml)中。加入10 M NaOH(20ml)仔细调节悬浊液的PH值到4-5,并继续搅拌30min。将白色沉淀物收集,用水和二乙醚冲洗,干燥后得到5-(4-氯苯基)-嘧啶-4,6-二醇(16.44g)的白色粉末。LC-MS:tR=2.75min,[M+H]+=222.96,[M-H]-=220.92。
c)向5-(4-氯苯基)-嘧啶-4,6-二醇(16.44g)的POCl3(165ml)悬浊液中,小心加入N,N二甲基苯胺(16.5ml)。混合物回流1.5小时。深绿色溶液蒸发干燥,残余物倒入冰/水混合物中。悬浊液用2N HCl(200ml)和水(800ml)稀释,在2℃搅拌1小时。将沉淀物收集,用水冲洗,干燥后得到4,6-二氯-5-(4-氯苯基)-嘧啶(18.66g)的微绿色粉末。
d)4,6-二氯-5-(4-氯苯基)-嘧啶(848mg)、2-噻吩-2-基-乙磺酸酰胺钾盐(1.5g,实施例14)和Hunig’s碱(1ml)溶解在DMSO(20ml)中,在室温搅拌24小时后,用水(200ml)稀释,用二乙醚萃取两次。水相加乙酸酸化。将沉淀物收集,用水和二乙醚冲洗,干燥后得到2-噻吩-2-基-乙磺酸[6-氯-5-(4-氯苯基)-嘧啶-4-基]-酰胺(930mg)的淡棕色粉末。LC-MS:tR=5.01min,[M+1]+=413.49,[M-1]-=411.93。
e)2-噻吩-2-基-乙磺酸[6-氯-5-(4-氯苯基)-嘧啶-4-基]-酰胺(930mg)加入叔丁醇钾(1.16g)的乙二醇(10ml)溶液中。混合物在110℃搅拌12小时后,加水(150ml)稀释,用10%柠檬酸水溶液(13ml)酸化。将所得的沉淀物收集,用水和二乙醚冲洗,干燥后得到2-噻吩-2-基-乙磺酸[5-(4-氯苯基)-6-(2-羟基乙氧基)-嘧啶-4-基]-酰胺(820mg)的淡棕色粉末。LC-MS:tR=4.43min,[M+1]+=440.01,[M-1]-=437.99。
参考实施例16
2-噻吩-2-基-乙磺酸[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)2-吡啶-4-基-嘧啶-4-基]-酰胺是按照实施例7公开的步骤,用2-噻吩-2-基-乙磺酸酰胺钾盐(实施例14)制备的。LC-MS:tR=4.00min,[M+1]+=529.29,[M-1]-=526.97。
参考实施例17
2-噻吩-2-基-乙磺酸[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)2-吗啉-4-基-嘧啶-4-基]-酰胺是按照实施例10公开的步骤,用2-噻吩-2-基-乙磺酸酰胺钾盐(实施例14)制备的。LC-MS:tR=4.62min,[M+1]+=537.21,[M-1]-=534.96。
参考实施例18
a)2-吡啶-2-基-乙磺酰氯盐酸盐是由商品2-吡啶2-乙磺酸,按照J.Med.Chem.36(1993),320-330公开的步骤制备的。
b)2-吡啶-2-基-乙磺酸酰胺钾盐是用上述2-吡啶-2-基-乙磺酰氯盐酸盐,按照实施例14b和14c公开的步骤制备的。
c)4,6-二氯-5-(2-甲氧基苯氧基)-2-(4-吡啶基)-嘧啶(1.75g,实施例7)和2-吡啶-2-基-乙磺酸酰胺钾盐(1.13g)与DMSO(30ml)组成的溶液在室温搅拌24小时。加入三乙胺(657mg)并继续搅拌96小时后,混合物加乙酸乙酯(150ml)稀释,用4%柠檬酸水溶液和水冲洗。水相用EA萃取至少三次。有机相经MgSO4干燥,蒸发干燥。粗产物通过硅胶上含有0-10%甲醇的EA洗提的柱色谱法提纯,得到2-吡啶-2-基-乙磺酸[6-氯-5-(2-甲氧基苯氧基)-2-吡啶-4-基-嘧啶-4-基]-酰胺(950mg)的棕色粉末。LC-MS:tR=3.63min,[M+1]+=498.31,[M-1]-=496.10。
d)向NaH(701mg,60%矿物油分散液)的DMF(15ml)悬浊液中,加入乙二醇(15ml)。气体释放停止后,加入2-吡啶-2-基-乙磺酸[6-氯-5-(2-甲氧基苯氧基)-2-吡啶-4-基-嘧啶-4-基]-酰胺(800mg),所得溶液在90℃搅拌40小时。溶液用2 N HCl水溶液(7ml)调成中性后,蒸发干燥。棕色的残余物的提纯是通过准备的tlc-盘上EA∶甲醇∶饱和氨水10∶2∶1洗提的色谱法。产物通过从甲醇∶二乙醚∶戊烷的重结晶进一步提纯,得到2-吡啶-2-基-乙磺酸[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-吡啶-4-基-嘧啶-4-基]-酰胺(280mg)的淡棕色晶体。1H-NMR(300MHz,CDC3):3.36-3.43(m,2H),3.86-3.90(m,2H),3.94(s,3H),4.23-4.30(m,2H),4.56-4.62(m,2H),6.91(dt,Jd=1.5,Jt=7.7,1H),7.00(dd,J=1.7,8.2,1H),7.08-7.20(m,4H),7.57(dt,Jd=1.8,Jt=7.9,1H),8.15(dd,J=1.7,4.6,2H),8.43(d,J=4.4,1H),8.72(dd,J=1.7,4.6,2H);LC-MS:tR=3.23min,[M+1]+=524.48,[M-1]-=522.25。
参考实施例19
a)苯基-甲磺酰胺钾盐是用商品苯基-甲磺酰氯,按与实施例1d和1e公开的相类似的步骤制备的。1H-NMR(300MHz,DSMO):3.73(s,2H),7.13-7.30(m,5H)。
b)N-[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-吡啶-4-基-嘧啶-4-基]-C-苯基-甲磺酰胺是用上述苯基-甲磺酰胺钾盐,按与实施例7类似的步骤制备的。LC-MS:tR=3.99min,[M+1]+=509.32,[M-1]-=507.31。
参考实施例20
N-[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-[2,2’]双嘧啶基-4-基]-C-苯基-甲磺酰胺是用苯基-甲磺酰胺钾盐(实施例19),按与实施例8类似的步骤制备的。LC-MS:tR=4.15min,[M+1]+=510.34,[M-1]-=508.54。
参考实施例21
N-[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)--2-吗啉-4-基-嘧啶-4-基]-C-苯基-甲磺酰胺是用苯基-甲磺酰胺钾盐(实施例19),按与实施例10类似的步骤制备的。LC-MS:tR=4.54min,[M+1]+=517.32,[M-1]-=515.07。
参考实施例22
a)对甲苯基-甲磺酰氯是按与[9]公开的相类似的步骤,用N-氯丁二酰亚胺氧化商品对甲苯基-甲硫醇制备的。
b)对甲苯基-甲磺酰胺钾盐是按与实施例1d和1e公开的相类似的步骤制备的。1H-NMR(300MHz,CDCl3)(磺酰胺):2.36(s,3H),4.27(s,2H),4.63(s,br,2H),7.20(d,J=7.9,2H),7.30(d,J=8.1,2H)。
c)N-[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-吡啶-4-基-嘧啶-4-基]-C-对甲苯基-甲磺酰胺是用上述对甲苯基-甲磺酰胺钾盐,按与实施例7公开的相类似的步骤制备的。LC-MS:tR=4.18min,[M+1]+=523.22,[M-1]-=521.19。
参考实施例23
N-[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-吡嗪-2-基-嘧啶-4-基]-C-对甲苯基-甲磺酰胺是用上述对甲苯基-甲磺酰胺钾盐,按与实施例9公开的相类似的步骤制备的。LC-MS:tR=4.46min,[M+1]+=524.20,[M-1]-=521.93。
参考实施例24
a)3-苯基丙烷-1-磺酰氯是按与[9]公开的相类似的步骤,用N-氯丁二酰亚胺氧化商品与3-苯基丙烷-1-硫醇制备的。
b)3-苯基丙烷-1-磺酸酰胺钾盐是按与实施例1d和1e公开的相类似的步骤制备的。1H-NMR(300MHz,CDCl3)(磺酰胺):2.11-2.23(m,2H),2.76(d,J=7.5,2H),3.05-3.13(m,2H),4.85(s,br,2H),7.14-7.40(m,5H)。
c)3-苯基丙烷-1-磺酸[6-(2-羟基乙氧基)-5-对甲苯基-嘧啶-4-基]-酰胺是用上述对3-苯基丙烷-1-磺酸酰胺钾盐,按与实施例1公开的相类似的步骤制备的。LC-MS:tR=4.66min,[M+1]+=428.24,[M-1]-=426.21。
参考实施例25
3-苯基丙烷-1-磺酸[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-吡啶-4-基-嘧啶-4-基]-酰胺是用3-苯基丙烷-1-磺酸酰胺钾盐(实施例24),按与实施例7公开的相类似的步骤制备的。LC-MS:tR=4.14min,[M+1]+=537.45,[M-1]-=535.41。
参考实施例26
3-苯基丙烷-1-磺酸[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-[2,2’]双嘧啶基-4-基]-酰胺是用3-苯基丙烷-1-磺酸酰胺钾盐(实施例24),按与实施例8公开的相类似的步骤制备的。LC-MS:tR=4.37min,[M+1]+=538.38,[M-1]-=536.27。
参考实施例27
3-苯基丙烷-1-磺酸[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-吗啉-4-基-嘧啶-4-基]-酰胺是用3-苯基丙烷-1-磺酸酰胺钾盐(实施例24),按与实施例10公开的相类似的步骤制备的。LC-MS:tR=4.80min,[M+1]+=545.40,[M-1]-=543.52。
参考实施例28
N-[6-(3-羟基丙氧基)-5-(2-甲氧基苯氧基)-[2,2’]双嘧啶基-4-基]-C-苯基-甲磺酰胺是用丙烷-1,3-二醇代替乙二醇,按与实施例20公开的相类似的步骤制备的。LC-MS:tR=4.13min,[M+1]+=524.34,[M-1]-=522.19。
参考实施例29
3-苯基丙烷-1-磺酸[6-(3-羟基丙氧基)-5-对甲苯基-嘧啶-4-基]-酰胺是用丙烷-1,3-二醇代替乙二醇,按与实施例24公开的相类似的步骤制备的。LC-MS:tR=4.72 min,[M+1]+=442.28,[M-1]-=440.22。
例
下述例子用于说明本发明,但不由此限制本发明的范围。
为了制备列出的例子,根据或类似于文献中的步骤合成了下述试剂:5-溴-2-氯嘧啶(Aust.J.Chem.17(1964),794-802;J.Org.Chem.25(1960),1916-1919);2,5-二氯嘧啶(类似于5-溴-2-氯嘧啶,用氯代替溴);2-氯-5甲基嘧啶(J.Med.Chem.6(1963),697-701;Aust.J.Chem.30(1977),2515-2525);2-甲磺酰基-5-甲氧基嘧啶(J.Chem.Soc.PerkinTrans.1,1999,3265-3268;J.Org.Chem.27(1962),3614-3617);2-氯-5-甲磺酰基嘧啶(II Farmaco 43(1988),277-292;French Patent1 549 494(1968));2-甲磺酰基-5-三氟甲基嘧啶(Tetrahedron Lett.37(1996),1829-1832);2-甲磺酰基-4,6-二甲氧基嘧啶是由4,6-二氯-2-甲磺酰基嘧啶按标准方法制备的。
其它的试剂都是商品。
例1
向氢化钠(50mg,60%矿物油分散液)中,依次加入THF(25ml),2-苯基乙磺酸[6-(2-羟基乙氧基)-5-对甲苯基-嘧啶-4-基]-酰胺(150mg,实施例1)。混合物在室温搅拌1小时后,加入2-氯嘧啶(86mg)。在80℃继续搅拌17小时。蒸发掉溶剂,向残余物中加入二乙醚(20ml)。滤出沉淀物,用二乙醚冲洗,溶解在水(20ml)中,用柠檬酸酸化,用EA(50ml)萃取两次。有机相用水冲洗,经Na2SO4干燥,蒸发干燥。残余物悬浮在2-丙醇(15ml)中,70℃搅拌10min,冷却到0℃后,将固体物质收集,用2-丙醇(2ml)冲洗,高真空干燥后得到2-苯基乙磺酸{6-[2-(嘧啶-2-基氧)-乙氧基]-5-对甲苯基-嘧啶-4-基}-酰胺(133mg)的白色粉末。LC-MS:tR=4.97min,[M+1]+=492.34,[M-1]-=490.28。
例2
向氢化钠(27mg,60%矿物油)中,依次加入THF(15ml),2-苯基乙磺酸[6-(2-羟基乙氧基)-5-对甲苯基-嘧啶-4-基]-酰胺(80mg,实施例1)。混合物在室温搅拌1小时后,加入2-氯-5-三氟甲基吡啶(86mg)。在80℃继续搅拌17小时。蒸发掉溶剂,残余物溶解在水(20ml)中,用柠檬酸酸化。悬浊液用己烷(15ml)处理。将固体物质收集,用己烷∶EA 1∶1(20ml)冲洗,干燥后得到2-苯基乙磺酸{5-对甲苯基-6-[2-(5-三氟甲基吡啶-2-基氧)-乙氧基]-嘧啶-4-基}-酰胺(96mg)的淡棕色粉末。LC-MS:tR=5.86min,[M+1]+=559.20,[M-1]-=557.37。
例3
向NaH(17mg,60%矿物油分散液)的DME(5ml)悬浊液中,加入2-(4-溴苯氧基)-乙醇(111mg)。混合物在50℃搅拌1小时后,加入2-苯基乙磺酸[6-氯-5-对甲苯基嘧啶-4-基]-酰胺(100mg,实施例1f)和叔丁醇钾(25mg)混合物在70℃搅拌16小时。加入另一部分叔丁醇钾(50mg),继续在70℃搅拌12小时,在室温再搅拌72小时。蒸发掉溶剂。残余物用水(40ml)处理,用10%柠檬酸水溶液酸化,用EA(50ml)萃取两次。有机相用水冲洗,蒸发干燥。粗产物通过从2-丙醇中结晶,得到2-苯基乙磺酸{6-[2-(4-溴苯氧基)-乙氧基]-5-对甲苯基-嘧啶-4-基}-酰胺(127mg)的淡棕色粉末。LC-MS:tR=6.14min,[M+1]+=568.38,[M-1]-=570.15。
例4
向NaH(29mg,60%矿物油分散液)与DMF和THF混合溶剂(各2.5ml)组成的悬浊液中,加入2-苯基乙磺酸[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-(2-嘧啶基)-4-嘧啶基]-酰胺(150mg)。气体释放停止后,加入2-氯嘧啶(82mg)。所得的淡黄色悬浊液在70℃搅拌4小时。冷却到室温,用EA(75ml)稀释,依次用10%柠檬酸水溶液(50ml)和水(50ml)冲洗。有机相蒸发干燥,剩余的残余物通过在准备好的tlc盘(硅胶,0.5mm层厚)上用EA∶甲醇∶饱和氨水8∶2∶1洗提的方法提纯。得到2-苯基乙磺酸{5-(2-甲氧基苯氧基)-6-[2-(嘧啶-2-基氧)-乙氧基]-2-(2-嘧啶基)-4-嘧啶基}-酰胺的淡黄色粉末。LC-MS:tR=4.60min,[M+1]+=602.69,[M-1]-=600.43。
例5
向NaH(29mg,60%矿物油分散液)与DMF和THF混合溶剂(各2.5ml)组成的悬浊液中,加入2-苯基乙磺酸[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-(2-嘧啶基)-4-嘧啶基]-酰胺(150mg)。气体释放停止后,加入2-氯-5-溴嘧啶(138mg)。所得的橙色悬浊液在70℃搅拌4小时。再依次加入另一份NaH(29mg,60%矿物油分散液)和2-氯-5-溴嘧啶(138mg)。加热持续搅拌25小时。最后,反应混合物冷却到室温,用EA(75ml)稀释,依次用10%柠檬酸水溶液(50ml)和水(50ml)冲洗。有机相蒸发干燥,剩余的残余物通过在准备好的tlc盘(硅胶,0.5mm层厚)上用EA∶甲醇∶饱和氨水8∶2∶1洗提的方法提纯。得到2-苯基乙磺酸{5-(2-甲氧基苯氧基)-6-[2-(5-溴嘧啶-2-基氧)-乙氧基]-2-(2-嘧啶基)-4-嘧啶基}-酰胺的淡黄色粉末。LC-MS:tR=5.11min,[M+1]+=680.23,[M-1]-=678.36。
例6
向NaH(29mg,60%矿物油分散液)与DMF和THF混合溶剂(各2.5ml)组成的悬浊液中,加入2-苯基乙磺酸[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-(2-嘧啶基)-4-嘧啶基]-酰胺(150mg)。气体释放停止后,加入4,6-二甲氧基-2-甲基磺酰嘧啶(156mg)。所得的黄色悬浊液在70℃搅拌4h。最后,反应混合物冷却到室温,用EA(75ml)稀释,依次用10%柠檬酸水溶液(50ml)和水(50ml)冲洗。有机相蒸发干燥,剩余的残余物通过在准备好的tlc盘(硅胶,0.5mm层厚)上用EA∶甲醇∶饱和氨水8∶2∶1洗提的方法提纯。得到2-苯基乙磺酸{5-(2-甲氧基苯氧基)-6-[2-(4,6-二甲氧基-嘧啶-2-基氧)-乙氧基]-2-(2-嘧啶基)-4-嘧啶基}-酰胺的淡黄色粉末。LC-MS:tR=5.21min,[M+1]+=662.69,[M-1]-=660.23。
例7-86
表1到表8列举的例子是用使用实施例1至实施例29作为原始材料,按与例1到例6类似的方法制备的。
表1
表1续
表1续
表1续
表2
表3
表4
表5
表6
表7
Claims (22)
1.通用分子式I的化合物,
通用分子式I
其中
R1和R2代表芳基;或杂芳基;
R3代表苯基;一、或二取代苯基,取代基选自烷基、烷氧基、或卤素;
R4代表氢;芳基;杂芳基;或吗啉基;
X代表氧;或者键;
Y代表氧;
Z代表氧;
Q代表-(CH2)k-;
k代表数字2,3;4,5,或者6;
n代表数字1,2,或者3;
烷基是指含有1到7个碳原子的直链和支链基团;
烷氧基是指含有1到7个碳原子的直链和支链基团;
芳基是指苯环,并可带有取代基团卤素、烷基、烷氧基、或三氟甲基、或三氟甲氧基;
杂芳基是指由噻吩基、吡啶基和嘧啶基组成的成员环,上述环可带有取代基烷基、卤素、烷氧基、三氟甲氧基、三氟甲基、或氰基;
或其药用许可的盐类。
2.根据权利要求1的通用分子式I的化合物,其中R1、R2、R4、Y、Q、Z和n的定义同权利要求1通式I,X代表氧,R3代表苯基或者单取代苯基,其取代基是卤素、烷基、或烷氧基
或其药用许可的盐类。
3.根据权利要求1的通用分子式I的化合物,其中R1、R2、R4和Y、Z和n的定义同权利要求1中通用分子式I,X代表氧,和Q代表-(CH2)k-且k=2或3,R3代表苯基或者单取代苯基,其取代基是卤素、烷基、或烷氧基;
或其药用许可的盐类。
4.根据权利要求1的通用分子式I的化合物,其中R1、R4和Y、Z、n的定义同权利要求1中通用分子式I,X代表氧,Q代表-(CH2)k-且k=2或3,和R2代表杂芳基,R3代表苯基或者单取代苯基,其取代基是卤素、烷基、或烷氧基、
或其药用许可的盐类。
5.根据权利要求1的通用分子式I的化合物,其中R1、R4和Y、Z、n的定义同权利要求1通式I,X代表氧,Q代表-(CH2)2-,R2代表杂芳基,R3代表苯基或者单取代苯基,其取代基是卤素、烷基或甲氧基;
或其药用许可的盐类。
6.根据权利要求1的化合物,为分子式II的化合物,其中R1、R2、R3、R4、Y、Q、Z和n的定义同上述权利要求1通用分子式I;
或分子式II的化合物的药用许可的盐类
分子式II
9.根据权利要求8的分子式V的化合物,其中分子式V的R2代表杂芳基;或其药用许可的盐类。
10.根据权利要求1的化合物,选自下述化合物:
2-苯基乙磺酸[6-[2-[5-溴嘧啶-2-基-氧]-乙氧基]-5-对甲苯基-嘧啶-4-基]-酰胺、
2-苯基乙磺酸[6-[2-[5-溴嘧啶-2-基-氧]-乙氧基]-5-对甲苯基-[2,2’]双嘧啶基-4-基]-酰胺、
2-苯基乙磺酸[5-[2-甲氧基-苯氧基]-6-[2-[嘧啶-2-基-氧]-乙氧基]-[2,2’]双嘧啶基-4-基]-酰胺、
2-苯基乙磺酸[5-[2-甲氧基-苯氧基]-6-[2-[5-甲氧基嘧啶-2-基-氧]-乙氧基]-[2,2’]双嘧啶基-4-基]-酰胺、
2-噻吩-2-基乙磺酸[6-[2-[5-溴嘧啶-2-基-氧]-乙氧基]-5-[4-氯苯基]-嘧啶-4-基]-酰胺、
2-噻吩-2-基乙磺酸[5-[4-氯苯基]-6-[2-[5-甲氧基嘧啶-2-基-氧]-乙氧基]-嘧啶-4-基]-酰胺、或
2-吡啶-2-基乙磺酸[6-[2-[5-溴嘧啶-2-基-氧]-乙氧基]-5-[2-甲氧基-苯氧基]-2-吡啶-4-基-嘧啶-4-基]-酰胺,
或其药用许可的盐类。
11.用于治疗与内皮素作用有关的紊乱病症的药物组合物,所述紊乱病症选自血循环紊乱和增生病症,所述药物组合物含有权利要求1到10的任一化合物,以及常用的载体和佐药。
12.根据权利要求11的药物组合物,其中,所述紊乱病症选自高血压、局部缺血、血管痉挛、心绞痛和癌症。
13.用于治疗与内皮素作用有关的紊乱病症的药物组合物,所述紊乱病症选自偏头痛、哮喘和炎症,所述药物组合物含有权利要求1到10的任一化合物,以及常用的载体和佐药。
14.权利要求1到10中任一项的化合物在制备作为治疗与内皮素作用有关的紊乱病症的药物中的应用,所述紊乱病症选自血循环紊乱、增生病症、偏头痛和炎症。
15.根据权利要求14的应用,其中,紊乱病症选自高血压、局部缺血、血管痉挛、心绞痛,癌症和偏头痛。
16.权利要求1到10中任一项的化合物在制备作为治疗与内皮素作用有关的紊乱病症,并且需要混合ETA和ETB封闭治疗的药物中的应用。
17.权利要求1到10中任一项的化合物在制备作为治疗与内皮素作用有关的紊乱病症,并且需要选择性的ETA封闭治疗的药物中的应用。
18.权利要求1到10中任一项的化合物在制备作为治疗与内皮素作用有关的紊乱病症,并且需要选择性的ETB封闭治疗的药物中的应用。
19.权利要求1到10中任一项的一个或多个化合物作为活性组分用于制备治疗与内皮素作用有关的紊乱病症的药物组合物,所述紊乱病症选自血循环紊乱和增生病症。
20.权利要求1到10中任一项的一个或多个化合物作为活性组分用于制备治疗与内皮素作用有关的紊乱病症的药物组合物,所述紊乱病症选自高血压、局部缺血、血管痉挛、心绞痛和癌症。
21.权利要求1到10中任一项的一个或多个化合物作为活性组分用于制备治疗与内皮素活动有关的紊乱病症的药物组合物,所述紊乱病症选自偏头痛、哮喘和炎症。
22.用于治疗与内皮素作用有关的紊乱病症,且含有权利要求1到10中任一项的一个或多个化合物作为活性组分的药物组合物的制备步骤包括:按原有已知方式将一一个或多个活性组分与药用许可的赋形剂混合。
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- 2001-08-28 CN CNB01815896XA patent/CN1326841C/zh not_active Expired - Fee Related
- 2001-08-28 AU AU1217102A patent/AU1217102A/xx active Pending
- 2001-08-28 WO PCT/EP2001/009894 patent/WO2002024665A1/en active IP Right Grant
- 2001-08-28 US US10/381,568 patent/US7091201B2/en not_active Expired - Fee Related
- 2001-08-28 CA CA2423351A patent/CA2423351C/en not_active Expired - Fee Related
- 2001-08-28 KR KR1020037003599A patent/KR100835770B1/ko not_active Expired - Fee Related
- 2001-08-28 BR BR0114082-5A patent/BR0114082A/pt not_active Application Discontinuation
- 2001-08-28 JP JP2002529075A patent/JP2004509874A/ja not_active Ceased
- 2001-08-28 IL IL15436401A patent/IL154364A0/xx unknown
- 2001-08-28 AT AT01980288T patent/ATE446289T1/de active
- 2001-08-28 DE DE60140263T patent/DE60140263D1/de not_active Expired - Lifetime
- 2001-08-28 NZ NZ524172A patent/NZ524172A/en unknown
- 2001-08-28 AU AU2002212171A patent/AU2002212171B2/en not_active Ceased
- 2001-09-24 AR ARP010104490A patent/AR032896A1/es not_active Application Discontinuation
-
2003
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- 2003-03-24 NO NO20031332A patent/NO20031332D0/no not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1146990A (zh) * | 1995-05-16 | 1997-04-09 | 田边制药株式会社 | 氨磺酰衍生物和它的制备方法 |
EP0882719A1 (en) * | 1995-12-20 | 1998-12-09 | Yamanouchi Pharmaceutical Co. Ltd. | Arylethenesulfonamide derivatives and drug composition containing the same |
WO1998057938A1 (fr) * | 1997-06-19 | 1998-12-23 | Yamanouchi Pharmaceutical Co., Ltd. | Derives d'alcanesulfonamide inferieur substitue et composition pharmaceutique les contenant |
Also Published As
Publication number | Publication date |
---|---|
ATE446289T1 (de) | 2009-11-15 |
NO20031332L (no) | 2003-03-24 |
CA2423351C (en) | 2010-12-21 |
NZ524172A (en) | 2004-09-24 |
HUP0303364A3 (en) | 2004-04-28 |
WO2002024665A8 (en) | 2002-06-06 |
BR0114082A (pt) | 2003-07-22 |
ZA200302292B (en) | 2004-06-30 |
ES2333409T3 (es) | 2010-02-22 |
US20040102464A1 (en) | 2004-05-27 |
IL154364A0 (en) | 2003-09-17 |
AU2002212171B2 (en) | 2006-12-14 |
CA2423351A1 (en) | 2002-03-28 |
WO2002024665A1 (en) | 2002-03-28 |
NO20031332D0 (no) | 2003-03-24 |
DE60140263D1 (de) | 2009-12-03 |
KR100835770B1 (ko) | 2008-06-09 |
JP2004509874A (ja) | 2004-04-02 |
KR20030029979A (ko) | 2003-04-16 |
CN1633418A (zh) | 2005-06-29 |
HUP0303364A2 (hu) | 2004-03-01 |
AR032896A1 (es) | 2003-12-03 |
US7091201B2 (en) | 2006-08-15 |
AU1217102A (en) | 2002-04-02 |
MXPA03001991A (es) | 2003-06-24 |
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