CN1028758C - 吡唑并嘧啶酮类抗心绞痛剂的制备方法 - Google Patents
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Abstract
具有下式的化合物及其可药用盐,是CGMPPDE的选择性抑制剂,可用于治疗心血管疾病,如心绞痛、高血压、心力衰竭和动脉粥样硬化。式中R1、R2、R3、R4、R5的含义如说明书所述。本发明还提供了所述化合物的制备方法。
Description
本发明涉及一系列吡唑并〔4,3-d〕嘧啶-7-酮类化合物,它们是环鸟苷3′,5′-单磷酸磷酸二酯酶(cGMP PDE)的强效选择性抑制剂,可应用于许多治疗领域,包括治疗各种心血管疾病,例如心绞痛、高血压、心力衰竭和动脉粥样硬化。
本发明的化合物能选择性地抑制cGMP PDE而不抑制环腺苷3′,5′-单磷酸磷酸二酯酶(cAMP PDE),这些选择性抑制PDE的结果使cGMP水平升高,而这又能产生有利的血小板抗凝集活性、抗血管痉挛活性和血管扩张活性,以及得自内皮的松弛因子(EDRF)和硝化血管扩张剂的增效作用。因此,这些化合物可应用于治疗多种疾病,包括稳定的、不稳定的和变异(Prinzmetal)心绞痛、高血压、充血性心力衰竭、动脉粥样硬化、血管开放功能减弱症状(例如经皮透照冠状血管成形术后血管开放功能减弱症状)、外周血管疾病、中风、支气管炎、慢性哮喘、过敏性哮喘、过敏性鼻炎、青光眼、以及以肠道运动紊乱为特征的疾病(例如应激性肠道综合症(IBS))。
欧洲专利申请EP-A-0201188公开了某些吡唑并〔4,3-d〕嘧啶-7-酮类化合物是腺苷受体拮抗剂和PDE抑制剂,可用于治疗某些心血管疾病如心力衰竭或心机能不全。但这些化合物既不是特别高效的PDE抑制剂,也未被指明是cGMP PDE的选择性抑制剂。
本发明的化合物为式(Ⅰ)化合物及其可药用盐:
其中R1为H、C1-C3烷基、C3-C5环烷基或C1-C3全氟烷基;
R2为H、可被OH、C1-C3烷氧基或C3-C6环烷基取代的C1-C6烷基、或C1-C3全氟烷基;
R3为C1-C6烷基、C3-C6链烯基、C3-C6炔基、C3-C7环烷基、C1-C6全氟烷基或(C3-C6环烷基)C1-C6烷基;
R4与它所连的氮原子一起构成吡咯烷基、哌啶子基、吗啉代、或4-N-(R6)-哌嗪基;
R5为H、C1-C4烷基、C1-C3烷氧基、NR7R8或CONR7R8;
R6为H、C1-C6烷基、(C1-C3烷氧基)C2-C6烷基、羟基C2-C6烷基、(R7R8N)C2-C6烷基、(R7R8NCO)C1-C6烷基、CONR7R8、CSNR7R8或C(NH)NR7R8;
R7和R8彼此独立地各为H、C1-C4烷基、(C1-C3烷氧基)C2-C4烷基或羟基C2-C4烷基。
在上述定义中,除非另外指出,含有三个或更多个碳原子的烷基或全氟烷基可以是直链或支链。此外,含有4个或更多个碳原子的链烯基或炔基,或含有3个碳原子的烷氧基,可以是直链或支链。
式(Ⅰ)化合物可以含有一个或更多个不对称中心,因此可以以对映体或非对映异构体存在。本发明既包括它们的混合物也包括独立的单个异构体。
式(Ⅰ)化合物还可以以互变异构形式存在,本发明既包括它们的混合物也包括独立的单个互变异构体。
本发明还包括式(Ⅰ)化合物的放射标记衍生物,这些衍生物适于进行生物学研究。
含有碱性中心的式(Ⅰ)化合物的可药用盐,为与可药用酸形成的酸成盐。其实例包括盐酸盐、氢溴酸盐、硫酸盐或硫酸氢盐、磷酸盐或磷酸氢盐、乙酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、乳酸盐、马来酸盐、琥珀酸盐和酒石酸盐。式(Ⅰ)化合物还可以与碱形成可药用的金属盐,特别是碱金属盐。其实例包括钠盐和钾盐。
一组优选的式(Ⅰ)化合物为这样一些式(Ⅰ)化合物:其中R1为H、甲基或乙基;R2为可被OH或甲氧基取代的C1-C3烷基;R3为C2-C3烷基或烯丙基;R4与其所连的氮原子一起构成哌啶子基或4-N-(R6)-哌嗪基;R5为H、NR7R8或CONR7R8;R6为H、C1-C3烷基、羟基C2-C3烷基、CONR7R8、CSNR7R8或C(NH)NR7R8;R7和R8彼此独立
地各为H或甲基。
一组特别优选的式(Ⅰ)化合物为这样一些式(Ⅰ)化合物:其中R1为甲基;R2为正丙基;R3为乙基、正丙基或烯丙基;R4与它所连的氮原子一起构成4-N-(R6)哌嗪基;R5为H;R6为H、C1-C3烷基或2-羟基乙基。
本发明极为优选的单个化合物包括:
5-〔2-烯丙氧基-5-(4-甲基哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-〔2-乙氧基-5-(哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-〔2-乙氧基-5-(4-甲基哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-{2-乙氧基-5-〔4-(2-丙基)哌嗪基磺酰基〕苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-{2-乙氧基-5-〔4-(2-羟基乙基)哌嗪基磺酰基〕苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
1-甲基-5-〔5-(哌嗪基磺酰基)-2-正丙氧基苯基〕-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-{5-〔4-(2-羟基乙基)哌嗪基磺酰基〕-2-正丙氧基苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮。
通式(Ⅰ)的化合物可以通过通式(Ⅱ)化合物与通式(Ⅲ)化合物的反应来制备:
其中R1、R2和R3如前面所限定,Y代表卤原子,优选氯原子。
其中R4和R5如前面所限定。
该反应一般在室温下进行,优选在一种溶剂如含1-3个碳原子的链烷醇存在下进行,并采用过量的(Ⅲ)以清除酸副产物(HY)。
通式(Ⅱ)的化合物可以应用将SO2Y基团(其中Y如前面所限定)引入芳香环的已知方法,由通式(Ⅳ)的化合物来制备,例如,当Y代表氯原子时,在0℃或接近0℃下借助氯磺酸的作用进行制备。
其中R1、R2和R3如前面所限定。
如果R3是易于在氯磺酰化反应条件下脱除的基团,如烯丙基,则该基团可在该合成的最后步骤引入。例如,可以如实施例25所述,由通式(Ⅳ)化合物的O-烯丙基类似物经Pd催化的脱保护反应得到R3为H的通式(Ⅳ)的酚(其中R1和R2如前面所限定),使该酚经氯磺酰化得到通式(Ⅱ)化合物,其中Y为Cl,R3为H,R1和R2如前面所限定。然后使后一化合物与适当的胺(Ⅲ)反应,得到通式(Ⅰ)的化合物,其中R3为H,R1、R2、R4和R5如前面所限定,最后将其O-烷基化得到通式(Ⅰ)的化合物,其中R1、R2、R3、R4和R5如对式(Ⅰ)所限定。该烷基化反应可在标准条件下进行,即,使用适当的卤代烷如烯丙基溴,在碱如碳酸钾存在下,于合适的溶剂如2-丁酮中,在反应混合物的回流温度下进行反应。此外,该烷基化反应也可以在常规的Mitsunobu反应条件下进行。
在不宜采用氯磺酰化反应条件的另一些式(Ⅳ)化合物的场合,例如R2为羟基C1-C6烷基的化合物,可以用酰基如乙酰基或苯甲酰基来保护羟基。随后在该合成的最后步骤,在标准的碱水解条件
下脱除所述保护基,得到通式(Ⅰ)的化合物,其中R2为羟基C1-C6烷基,R1、R3、R4和R5如对式(Ⅰ)所限定。后一些化合物也可以作为相应烷氧基类似物的氯磺酰化反应的副产物而附带地得到,即,使R2为(C1-C3烷氧基)C1-C6烷基的通式(Ⅳ)化合物氯磺酰化,接着使粗产物与所需的胺(Ⅲ)反应,如实施例48所述。
通式(Ⅳ)的化合物可以应用形成嘧啶酮环的已知环化方法,由通式(Ⅴ)的化合物来制备:
其中R1、R2和R3如前面所限定。例如,环化反应可在如下条件下进行:在有或没有过氧化氢存在时,在乙醇-水介质中,于回流温度下用碱如氢氧化钠或碳酸钾处理(Ⅴ)2-40小时。在这些条件下,也可以采用通式(Ⅵ)的相应腈(其中R1、R2和R3如前面所限定)作(Ⅳ)的前体。
也可以用另一种环化方法得到通式(Ⅳ)的化合物,即用多磷酸在140℃或接近140℃下处理(Ⅴ)6-18小时。
通式(Ⅴ)和(Ⅵ)的化合物可以分别由通式(Ⅶ)和(Ⅷ)的
化合物与通式(Ⅸ)的化合物反应来制备:
其中R1和R2如前面所限定。
其中R3和Y如前面所限定。
该反应一般采用过量的(Ⅸ),在惰性溶剂如二氯甲烷中于0℃-25℃下进行2-6小时,反应中有过量的脂肪族叔胺如三乙胺存在以起到清除酸副产物(HY)的作用,反应中也可有催化剂如4-二甲氨基吡啶存在。
式(Ⅲ)的胺类、式(Ⅶ)和(Ⅷ)的氨基吡唑类、以及式(Ⅸ)的酰卤,如果在市场上买不到,可以根据文献的先例按常规合成法由易得的原料来制取,并使用标准试剂和反应条件。
某些通式(Ⅰ)化合物,即其中的R4与它所连的氮原子一起构成4-N-(R6)-哌嗪基,R6如前面所限定但不为氢,可以由4-N位未取代的相应哌嗪类似物用适当的标准合成法直接制备,该
类似物即为R6为氢的通式(Ⅰ)化合物。
所有上述反应都完全是常规反应,只要参考普通教科书和后面给出的实施例,便可以很容易地确定进行这些反应的适当试剂和条件。各种方案和变动对本领域技术人员来说也是显而易见的,从而能够制备出式(Ⅰ)所限定的所有化合物。
本发明化合物的生物活性用下列测试方法测定。
磷酸二酯酶活性
化合物对cGMP PDE和cAMP PDE的亲和性,通过测定其IC50值(抑制50%的酶活性所需的抑制剂浓度)来进行评定。基本上按照W.J.Thompson等的方法(Biochem.,10:311,1971),从家兔血小板和大鼠肾中分离PDE酶。由家兔血小板制取依赖钙/钙调蛋白(Ca/CAM)的cGMP PDE酶和受cGMP抑制的cAMP PDE酶,同时在大鼠肾的四种主要的PDE酶中分离依赖Ca/CAM的cGMP PDE(部分Ⅰ)。用经过修改的W.J.Thompson和M.M.Appleman的“分批”法进行测定(Biochem.,18:5228,1979)。这些测试的结果表明,本发明化合物对两种cGMP PDE都是强效选择性抑制剂。
血小板抗凝集活性
评价此活性的方法是,测定某一化合物抑制由血小板激活因子(PAF)诱导的体外血小板凝集作用的能力,以及增强鸟苷酸环化酶激活剂(如硝普盐和EDRF)的体外血小板抗凝集作用的能力。基本按J.F.Mustard等人的方法(Methods in Enzymol.,169:3,1989)制备洗涤过的血小板,利用如G.V.R.Born所述的标准比浊技术(J.Physiol.(Lond),162:67P,1962)
测定凝集作用。
抗高血压活性
此活性的评定在将某一化合物静脉或口服给予自发高血压大鼠后进行。通过埋植在清醒或麻醉态大鼠颈动脉内的插管记录血压。
为治疗或预防心绞痛、高血压或充血性心力衰竭而对人给药时,化合物的口服剂量对成年患者(平均体重70千克)来说一般是每日4-800毫克的范围。例如,对典型的成年患者来说,各个片剂或胶囊剂含有配在合适药用载体中的2-400毫克活性化合物,以单剂量或多剂量给药,每日一次或若干次。静脉给药、向颊给药或舌下给药的剂量,根据需要一般在每个单次剂量1-400毫克的范围内。实际上,医生会确定最适合于个别患者的具体给药方案,这种方案将随特定患者的年龄、体重和反应而变。上述剂量只举了一般情况的例子,但可能会有需要更高或更低剂量范围的个别情况,这些情况在本发明的范围之内。
用于人体时,式(Ⅰ)化合物可以单独给药,但一般是与药用载体混合给药,该载体根据预期的给药途径和标准药学实践进行选择。例如,这些化合物可以口服、向颊给药或舌下给药,其形式可以是含有赋形剂(如淀粉或乳糖)的片剂、或者是单独的或与赋形剂混合的胶囊剂或阴道栓剂、或者是含有调味剂或着色剂的酏剂或悬浮剂。这些化合物也可以肠胃外注射,例如静脉注射、肌内注射、皮下注射或心内注射。肠胃外给药时,最好以无菌水溶液的形式使用,水溶液中可以含有其它物质,例如足够的盐或葡萄糖,以使溶液与血液等渗。
因此,本发明的另一方面提供一种药物组合物,该组合物包含一种式(Ⅰ)化合物或其可药用盐,该组合物用于医药,特别是用于治
人类的心绞痛、高血压或充血性心力衰竭。
本发明还包括式(Ⅰ)化合物或其可药用盐在药物制备中的应用,这种药物用于治疗稳定性、不稳定性和变异性(Prinzmetal)心绞痛、高血压、充血性心力衰竭、动脉粥样硬化、中风、外周血管疾病、血管开放功能减弱症状(例如经皮透照冠状血管成形术后血管开放功能减弱症状、慢性哮喘、支气管炎、过敏性哮喘、过敏性鼻炎、青光眼、以及以肠道运动紊乱为特征的疾病(例如应激性肠道综合症)。
下面将参照实验实施例更为具体地说明本发明化合物的制备方法。用Merck Kieselgel 60 F254层析板进行薄层层析(TLC),对化合物的纯度进行常规检测。用Nicolet QE-300分光计记录1H-核磁共振光谱,这些光谱在所有情况下都与假设的结构一致。
实施例1
1-甲基-3-正丙基吡唑-5-甲酸乙酯
将3-正丙基吡唑-5-甲酸乙酯(24.1g,0.132mol)(按Chem.Pharm.Bull.,32:1568,1984的方法制得)和硫酸二甲酯(16.8g,0.133mol)的混合物于90℃下加热2.5小时。将该混合物溶于二氯甲烷中,并用碳酸钠溶液洗涤该溶液。分出有机相,干燥(MgSO4),减压蒸发得到固体物。在硅胶(300g)上进行层析,用二氯甲烷洗脱,得到无色油状产物(20.4g,79%)。Rf0.8(硅胶;二氯甲烷/甲醇/乙酸80∶20∶1)。
实施例2
1-甲基-3-正丙基吡唑-5-甲酸
将1-甲基-3-正丙基吡唑-5-甲酸乙酯(20.2g,0.10
mol)悬浮于6N氢氧化钠水溶液(50ml,0.30mol)中。将该混合物于80℃下加热2小时,然后用水(50ml)稀释,用浓盐酸(25ml)酸化。过滤后得到浅棕色羧酸晶体(12.3g,71%),m.p.150-154℃。实验值:C,56.99,H,7.25;N,16.90。C8H12N2O2理论值为C,57.13;H,7.19;N,16.66%。
实施例3
1-甲基-4-硝基-3-正丙基吡唑-5-甲酸
将1-甲基-3-正丙基吡唑-5-甲酸(12.1g,0.072mol)分批加到发烟硫酸(13ml)和发烟硝酸(11ml)的混合物中,同时保持温度低于60℃。加完后,于60℃将混合物加热过夜,再冷至室温,然后倒在冰上。滤出沉淀物得到白色固体状的硝基吡唑(11.5g,75%),m.p.124-127℃。实验值:C,45.43;H,5.22;N,19.42。C8H11N3O4理论值:C,45.57;H,5.20;N,19.71%。
实施例4
1-甲基-4-硝基-3-正丙基吡唑-5-甲酰胺
将1-甲基-4-硝基-3-正丙基吡唑-5-甲酸(11.3g,0.053mol)加到硫酰氯(50ml)中,所得混合物加热回流3小时。然后将反应混合物冷却,减压蒸除过量硫酰氯。将油状残余物溶于丙酮(50ml)中,并将该溶液小心地加到冰(50g)和浓氢氧化铵水溶液(50ml)的混合物中。滤集沉淀物,得到浅黄色固体状的吡唑甲酰胺(8.77g,78%),m.p.141-143℃。实验值:C,45.22;H,5.71;N,26.12。C8H12N4O3
理论值:C,45.28;H,5.70;N,26.40%。
实施例5
4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺
将1-甲基-4-硝基-3-正丙基吡唑-5-甲酰胺(3.45g,16.2mmol)和氯化锡二水合物(18.4g,81mmol)悬浮于乙醇中,将该混合物加热回流2小时。将所得溶液冷却至室温,加入2N氢氧化钠水溶液碱化至pH9,并用二氯甲烷萃取(3×150ml)。合并有机萃取液,干燥(MgSO4),减压蒸发。残余物加乙醚研磨,得到灰白色固体状的氨基吡唑(2.77g,94%),m.p.98-101℃。实验值:C,52.84;H,7.81;N,30.38。C8H14N4O理论值:C,52.73;H,7.74;N,30.75%。
实施例6
4-(2-乙氧基苯甲酰氨基)-1-甲基-3-正丙基吡唑-5-甲酰胺
于0℃下,在搅拌着的4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺(3.0g,16.4mmol)、4-二甲氨基吡啶(0.02g,0.164mmol)和三乙胺(3.34g,33.0mmol)在二氯甲烷(50ml)中的溶液中,加入2-乙氧基苯甲酰氯(6.1g,33.0mmol)的二氯甲烷溶液(50ml)。使所得混合物温热至室温,再搅拌2小时。减压蒸发溶剂,将残余物溶于二氯甲烷和甲醇的19:1混合物(250ml)中,然后将该溶液用1N盐酸(100ml)洗涤,干燥(MgSO4)并减压蒸发。粗品在硅胶(200g)上进行层析,用二氯甲烷和甲醇的97:3混合物洗
脱,得到粉色固体,用乙酸乙酯-己烷结晶后得到浅粉色固体状的吡唑-5-甲酰胺(2.2g,40%),m.p.153-155℃。实验值:C,61.66;H,6.77;N,16.95。C17H22N4O3理论值:C,61.80;H,6.71;N,16.96%。
实施例7
5-(2-乙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
将氢氧化钠(54g,1.35mol)和30%过氧化氢溶液(224ml)溶于水(2000ml)中,向该溶液中分批加入4-(2-乙氧基苯甲酰氨基)-1-甲基-3-正丙基吡唑-5-甲酰胺(223g,0.676mol)。加入乙醇(700ml),所得混合物加热回流2.5小时,冷却,然后减压蒸发。所得固体在外部冷却的同时用2N盐酸(380ml)处理,该混合物用二氯甲烷萃取(1×700ml,3×200ml)。有机萃取液合并后依次用饱和碳酸钠水溶液(3×400ml)和盐水(300ml)洗涤,然后干燥(Na2SO4),减压蒸发。
残余物在硅胶(1000g)上进行层析,用甲醇的二氯甲烷溶液洗脱梯度(0-1%)进行洗脱,然后将粗品加乙醚(300ml)研磨,得到无色固体状的标题化合物(152.2g,72%),m.p.143-146℃。实验值:C,65.56;H,6.44;N,18.14;C17H20N4O2理论值:C,65.36;H,6.45;N,17.94%。
实施例8
5-(5-氯磺酰基-2-乙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
于0℃和氮气氛下,将5-(2-乙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮(10.0g,32.1mmol)分批加到氯磺酸(20ml)中。搅拌过夜后,将反应液小心地加到冰水中(150ml),将该含水混合物用二氯甲烷和甲醇的9∶1混合物(4×100ml)萃取。萃取液合并后干燥(Na2SO4),减压蒸发得到所要的白色固体状磺酰氯(12.8g,97%),m.p.179-181℃。实验值:C,50.07;H,4.71;N,13.29。C17H19ClN4O4S理论值:C,49.70;H,4.66;N,13.64%。
实施例9
5-〔2-乙氧基-5-(4-氨甲酰基哌啶基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
于室温下,于5-(5-氯磺酰基-2-乙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮(750mg,1.80mmol)在乙醇(50ml)中的搅拌悬浮液中,加入4-氨甲酰基哌啶(703mg,5.50mmol)。将所得混合物搅拌4天,然后减压蒸除溶剂。将残余物溶于二氯甲烷和甲醇的9∶1混合物(100ml)中,该溶液用饱和碳酸钠水溶液(100ml)洗涤。水相进一步用二氯甲烷-甲醇混合物(3×100ml)萃取,合并所有有机部分,干燥(MgSO4),减压蒸发得到固体物。用甲醇-二甲基甲酰胺的混合物结晶,得到灰白色固体状的标题磺酰胺(446mg,49%),m.p.274-276℃。实验值:C,55.36;H,6.01;N,16.65。C23H29N6O5S理
论值:C,55.08;H,5.83;N,16.75%。
实施例10-14
按实施例9的方法用适当的胺制备下列化合物。
实施例
产率 m.p. 元素分析(%)
(%) (℃) (括号内为理论值)
C H N
(54.77 6.13 18.25)
(54.75 6.39 16.65)
(55.68 6.37 17.71)
(57.35 6.82 16.72)
14
74 209-212 57.64 6.66 16.81
(57.35 6.82 16.72)
(50.85 5.63 18.87)
实施例16
5-{2-乙氧基-5-〔4-(甲硫基亚氨酰基)哌嗪基磺酰基〕苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮氢碘酸盐
将5-〔2-乙氧基-5-(4-硫代氨甲酰基哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮(0.78g,1.5mmol)、甲基碘(426mg,3.0mmol)和甲醇(20ml)的混合物搅拌回流2小时,然后使其冷却。滤出生成的白色固体,用乙酸乙酯-甲醇结晶,得到无色晶状标题化合物(0.70g,71%),m.p.227-228℃。实验值:C,41.43;H,4.79;N,14.42。
C23H31N7O4S2·HI理论值:C,41.75;H,4.88;N,14.82%。
实施例17
5-{2-乙氧基-5-〔4-(甲脒基)哌嗪基磺酰基〕苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮氢碘酸盐
将5-{2-乙氧基-5-〔4-(甲硫基亚氨酰基)哌嗪基磺酰基〕苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮氢碘酸盐(0.5g,0.75mmol)加到33%甲胺的乙醇溶液(20ml)中,将混合物于室温下搅拌18小时。将溶液减压蒸发,残余物加乙醚研磨。所得固体在硅胶(10g)上进行层析,用甲醇的二氯甲烷溶液进行梯度洗脱,洗脱梯度是9-4%,然后把粗产物加乙醚研磨,得到浅棕色粉末。用乙酸乙酯-甲醇结晶得到无色晶状的标题化合物(112mg,23%),m.p.253-255℃。实验值:C,42.90;H,5.09;N,17.41。C23H32N8O4S·HI理论值:C,42.86;H,5.16,N,17.39%。
实施例18
1-甲基-4-(2-正丙氧基苯甲酰氨基)-3-正丙基吡唑-5-甲酰胺
此酰胺按实施例6所述的方法由2-正丙氧基苯甲酰氯制备,得到粉红色固体(63%),m.p.148-149℃。实验值:C,62.97;H,7.00;N,16.29。C18H24N4O3理论值:C,62.77;H,7.02;N,16.27%。
实施例19
1-甲基-5-(2-正丙氧基苯基)-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
在30%过氧化氢溶液(1.0ml)、碳酸钾(0.54g,3.92mmol)、水(10ml)和乙醇(5ml)的搅拌混合物中,加入1-甲基-4-(2-正丙氧基苯甲酰氨基)-3-正丙基吡唑-5-甲酰胺(0.34g,0.99mmol)。将该混合物加热回流38小时,然后减压蒸发。将残余物悬浮于水(20ml)中,然后将该混合物用2N盐酸酸化,并用二氯甲烷(3×20ml)萃取。将萃取液合并,干燥(Na2SO4),减压蒸发。所得残余物在硅胶(6g)上进行层析,用甲醇的二氯甲烷溶液以洗脱梯度(0.0-1.0%)洗脱,得到一油状物,加乙醚连续研磨,得到所要的白色固体产物(0.19g,59%),m.p.111-114℃。实验值:C,66.26;H,6.92;N,17.15。C18H22N4O2理论值:C,66.23;H,6.80;N,17.17%。
实施例20
5-(5-氯磺酰基-2-正丙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
此磺酰氯按实施例8的方法由5-(2-正丙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮来制备,得到白色固体(92%)。实验值:C,51.26;H,5.02;N,12.90;C18H21ClN4O4S理论值:C,50.88;H,4.98;N,13.19%。
实施例21
1-甲基-5-〔5-(哌嗪基磺酰基)-2-正丙氧基苯基〕-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
此磺酰胺按实施例9的方法由哌嗪和5-(5-氯磺酰基-2-正丙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮来制备,得到白色固体(70%),m.p.185-186℃。实验值:C,56.17;H,6.38;N,17.65。C22H30N6O4S理论值:C,55.67;H,6.37;N,17.71%。
实施例22
5-{5-〔4-(2-羟基乙基)哌嗪基磺酰基〕-2-正丙氧基苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
此磺酰胺按实施例9的方法由N-(2-羟乙基)哌嗪和5-(5-氯磺酰基-2-正丙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮来制备,得到无色针状物(66%),m.p.158-159℃。实验值:C,55.83;H,6.58;N,16.13。C24H34N6O5S理论值:C,55.58;H,6.61;N,16.20%。
实施例23
4-(2-烯丙氧基苯甲酰氨基)-1-甲基-3-正丙基吡唑-5-甲酰胺
在搅拌着的4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺
(3.64g,0.02mol)的吡啶部分溶液(50ml)中,滴加2-烯丙氧基苯甲酰氯(3.93g,0.02mol)的二氯甲烷溶液(20ml),所得混合物在干燥气氛中于室温下搅拌过夜。减压蒸发溶剂,残余物在二氯甲烷(50ml)和饱和碳酸钠水溶液(50ml)之间分配。分出有机层,水层再用二氯甲烷进行极限萃取。有机溶液合并后用2M HCl(3×30ml)洗涤,然后用盐水(1×30ml)洗涤,干燥(Na2SO4)。过滤并将滤液减压蒸发,然后把粗产物用乙酸乙酯结晶,得到标题化合物(4.525g,66%),m.p.132-134℃。实验值:C,63.49;H,6.42;N,16.33。C18H22N4O3理论值:C,63.14;H,6.48;N,16.36%。
实施例24
5-(2-烯丙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
将4-(2-烯丙氧基苯甲酰胺基)-1-甲基-3-正丙基吡唑-5-甲酰胺(1.2g,0.0035mol)、氢氧化钠(0.70g,0.018mol)、水(34ml)和乙醇(8ml)的混合物回流5小时。冷却后,溶液用乙酸乙酯进行极限萃取。萃取液合并后用盐水(30ml)洗涤,干燥(Na2SO4),过滤,减压蒸发溶剂,得到粗产物,用乙酸乙酯/己烷结晶,得到标题化合物(0.476g,37%),m.p.116-119℃。实验值:C,67.00;H,6.21;N,17.23。C18H20N4O2理论值:C,66.65;H,6.21;N,17.27%。
实施例25
5-(2-羟基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
将5-(2-烯丙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮(0.25g,0.0008mol)、苯酚(0.145g,0.0015mol)、哌啶(0.131g,0.0015mol)和四(三苯膦)钯(O)(0.046g,0.00004mol)在无水乙醇(5ml)中的混合物在氮气中回流过夜。使该混合物冷却,减压蒸发溶剂,将残渣溶于乙酸乙酯(40ml)中。此溶液用水(3×10ml)、1M HCl(3×10ml)和盐水(1×10ml)洗涤。干燥(Na2SO4)和过滤后,将滤液减压蒸发得到粗产物。用乙醚研磨并用乙酸乙酯/戊烷结晶后,得到标题酚(0.021g,10%),m.p.233-238℃。实验值:C,63.17;H,5.65;N,19.52。C15H16N4O2理论值:C,63.36;H,5.67;N,19.71%。
实施例26
5-(5-氯磺酰基-2-羟基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
在氮气氛下,将5-(2-羟基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮(0.239g,0.00084mol)在搅拌下分批加到冷至0℃的氯磺酸(3ml)中,所得到的深红色溶液在室温下搅拌18小时。然后将反应混合物小心地滴加到搅拌着的冰水中,得到棕色固体。将后一混合物用二氯甲烷(3×30ml)萃取,萃取液合并后进行干燥
(Na2SO4)和过滤,将滤液减压蒸发后得到棕色固体(0.24g,75%),不经进一步纯化即用于下一步骤;Rf0.3(硅胶;二氯甲烷/甲醇95∶5)。
实施例27
5-〔2-羟基-5-(4-甲基哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
将5-(5-氯磺酰基-2-羟基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮(0.235g,0.0006mol)和N-甲基哌嗪(0.5ml,0.0045mol)的乙醇溶液(40ml)在室温下搅拌18小时。将该溶液减压蒸发,残余物在乙酸乙酯(40ml)和水(40ml)之间分配。滤出细沉淀颗粒,用水洗涤,再用乙酸乙酯洗涤,用乙酸乙酯/DMF结晶,得到灰白色粉末状标题化合物(0.260g,49%),m.p.283-284℃。实验值:C,53.53;H,5.89;N,18.40。C20H26N6O4S理论值:C,53.80;H,5.87;N,18.82%。
实施例28
5-〔2-烯丙氧基-5-(4-甲基哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
在5-〔2-羟基-5-(4-甲基哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮(0.103g,0.00023mol)和碳酸钾(0.032g,
0.00023mol)在2-丁酮(10ml)中的搅拌悬浮液中,加入烯丙基溴(0.02ml,0.00023mol),将该混合物加热回流8小时。冷却后,将该反应混合物减压蒸发,残余物悬浮于水(20ml)中。该水悬液用乙酸乙酯(3×20ml)萃取,萃取液合并后进行干燥(Na2SO4),过滤后减压蒸发得到油状物。在硅胶(2g)上进行柱层析,用甲醇的二氯甲烷溶液洗脱梯度(0-3%)洗脱,然后取适当的级分进行减压蒸发,得到半固体状物,将其溶于丙酮,将该溶液减压蒸发得到标题化合物(0.011g,10%),m.p.151-153℃,Rf0.5(硅胶;二氯甲烷/甲醇95∶5),m/e 487(M++1)。
实施例29
4-(2-乙氧基苯甲酰氨)-1,3-二甲基吡唑-5-甲酰胺
此酰胺按实施例6的方法由4-氨基-1,3-二甲基吡唑-5-甲酰胺(按J.Med.Chem.30:91,1987的方法制备)来制备,得到白色固体(81%),m.p.178-181℃。实验值:C,59.89;H,6.05;N,18.44。C15H18N4O3理论值:C,59.59;H,6.00;N,18.53%。
实施例30
5-(2-乙氧基苯基)-1,3-二甲基-1,6-二氢-7H-吡唑〔4,3-d〕嘧啶-7-酮
将4-(2-乙氧基苯甲酰氨基)-1,3-二甲基吡唑-5-甲酰胺(1.6g,5.29mmol)加到多磷酸(50g)中,将该混合物于140℃加热6小时。将该溶液冷却,倒入冰水(100ml)
中,然后将该混合物用10%氢氧化钠水溶液碱化,用二氯甲烷(3×100ml)萃取。合并有机萃取液,干燥(MgSO4),减压蒸发。残余物在硅胶上进行层析,用二氯甲烷和甲醇的97∶3混合物洗脱。粗产物用含水乙醇结晶,得到无色固体状的标题化合物,m.p.201-204℃。实验值:C,63.43;H,5.57;N,19.35。C15H16N4O2理论值:C,63.36;H,5.67;N,19.71%。
实施例31
5-(5-氯磺酰基-2-乙氧基苯基)-1,3-二甲基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
此磺酰氯按实施例8的方法由5-(2-乙氧基苯基)-1,3-二甲基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮来制备,以定量产率得到白色固体。Rf0.3(硅胶;乙醚)。不经进一步纯化即使用。
实施例32-34
按实施例9的方法由5-(5-氯磺酰基-2-乙氧基苯基)-1,3-二甲基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮和适当的胺来制备下列化合物。
实施例 m.p. 元素分析(%)
(%) C H N
(53.79 5.87 18.82)
(52.76 5.59 19.43)
(52.93 5.92 17.63)
实施例35
4-硝基-3-正丙基吡唑-5-甲酸
按实施例3的方法使3-正丙基吡唑-5-甲酸(按Chem.Pharm.Bull.32:1568,1984的方法制备)硝化,得到无色固体状的标题化合物(75%),m.p.169-173℃。实验值:C,42.35;H,4.56;N,21.07。C7H9N3O4理论值:C,42.21;H,4.55;N,21.10%。
实施例36
4-硝基-3-正丙基吡唑-5-甲酰胺
将4-硝基-3-正丙基吡唑-5-甲酸(7.8g,39.2mmol)和硫酰氯(35ml)的混合物加热回流3小时。减压蒸除溶剂,将固体残余物在0℃下分批加到氢氧化铵水溶液(40ml)中。然后将该混合物用水(60ml)稀释,用二氯甲烷和甲醇的9∶1混合物(3×100ml)萃取。合并有机部分,干燥(MgSO4)并减压蒸发,残余物用乙醇结晶,得到无色固体状的甲酰胺(1.0g,13%),m.p.202-206℃。实验值:C,42.35;H,5.01;N,28.38。C7H10N4O3理论值:C,42.42;H,5.09;N,28.27%。
实施例37
4-氨基-3-正丙基吡唑-5-甲酰胺
将4-硝基-3-正丙基吡唑-5-甲酰胺(198mg,1.0mmol)的甲醇溶液(5ml)滴加到硼氢化钠(113mg,2.97mmol)、10%钯/碳(5mg)和水(3ml)的混合物中。将该混合物于室温下搅拌3小时,过滤,减压蒸除溶剂。残余物用乙酸乙酯-甲醇重结晶,得到灰白色固体状的标题化合物(61mg,36%),m.p.196-201℃。Rf0.4(硅胶;二氯甲烷/甲醇/氢氧化铵90∶10∶1)。实验值:C,48.96;H,6.98;N,32.08。C7H12N4O理论值:C,49.98;H,7.19;N,33.31%。
实施例38
4-(2-乙氧基苯甲酰氨基)-3-正丙基吡唑-5-甲酰胺
该标题酰胺按实施例6的方法由4-氨基-3-正丙基吡唑-5-甲酰胺来制备,得到白色固体(64%),m.p.209-211℃。实验值:C,60.73;H,6.41;N,17.80。C16H20N4O3理论值:C,60.74;H,6.37;N,17.71%。
实施例39
5-(2-乙氧基苯基)-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
该标题化合物按实施例30的方法由4-(2-乙氧基苯甲酰氨基)-3-正丙基吡唑-5-甲酰胺来制备,得到白色固体(16%),m.p.199-201℃。实验值:C,64.44;H,6.19;N,18.44%。C16H18N4O2理论值:C,64.41;H,6.08;N,18.78%。
实施例40
5-(5-氯磺酰基-2-乙氧基苯基)-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
该标题磺酰氯按实施例8的方法由5-(2-乙氧基苯基)-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮来制备,得到白色固体(78%)。Rf0.25(硅胶;乙醚)。
该化合物不经进一步纯化即使用。
实施例41
5-〔2-乙氧基-5-(4-甲基哌嗪基)磺酰基苯基〕-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
该标题磺酰胺按实施例9的方法由5-(5-氯磺酰基-2-乙氧基苯基)-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕
嘧啶-7-酮来制备,得到白色固体(70%),m.p.236-239℃。实验值:C,54.84;H,6.27;N,18.10。C21H28N6O4S理论值:C,54.76;H,6.13;N,18.25%。
实施例42
3-溴甲基-5-氯-1-甲基-4-硝基吡唑
将N-溴丁二酰亚胺(10.7g,60.0mmol)加到5-氯-1,3-二甲基-4-硝基吡唑(8.78g,50.0mmol)的四氯化碳溶液(100ml)中,在用可见光(150W钨灯)照射的同时将溶液加热回流3天。在整个反应过程中以一定间隔加入一定量的过氧化苯甲酰(6×50mg)。减压蒸除溶剂,残余物在硅胶上进行层析,用二氯甲烷和己烷的1∶1混合物洗脱,得到灰白色固体状的溴化物(8.0g,63%),m.p.80-82℃。实验值:C,23.95;H,2.05;N,16.31。C5H5BrClN3O2理论值:C,23.60;H,1.98;N,16.51%。
实施例43
5-氯-3-甲氧基甲基-1-甲基-4-硝基吡唑
将3-溴甲基-5-氯-1-甲基-4-硝基吡唑(5.0g,19.6mmol)的甲醇溶液(50ml)用硝酸银(5.75g,33.8mmol)处理,并将该混合物加热回流2小时。将反应混合物冷却后过滤,滤液减压蒸发。使残余物在乙酸乙酯(100ml)和水(50ml)之间分配,水相再用一定量的乙酸乙酯(50ml)萃取。合并有机萃取液,干燥(MgSO4)并减压蒸发。在硅胶上进行层析,用二氯甲烷和甲醇的97∶3混合物洗脱,得到白色固体状的标题吡唑(1.6g,40%),m.p.59-63℃。实验值:C,
34.65;H,3.83;N,20.05。C6H8ClN3O3理论值:C,35.05;H,3.92;N,20.44%。
实施例44
5-氰基-3-甲氧基甲基-1-甲基-4-硝基吡唑
将5-氯-3-甲氧基甲基-1-甲基-4-硝基吡唑(205mg,1.0mmol)、氰化钾(130mg,2.0mmol)和18-冠醚-6-(10mg)的乙腈溶液(2ml)加热回流过夜。减压蒸发溶剂,残余物在乙酸乙酯(20ml)和水(20ml)之间分配。分出有机相,干燥(MgSO4),减压蒸发,然后残余物在硅胶上进行层析,用乙酸乙酯和戊烷的1∶1混合物洗脱。粗产物加乙醚研磨,得到黄色固体(30mg,19%),m.p.48-50℃。实验值:C,42.89;H,4.15;N,28.78。C7H8N4O3理论值:C,42.86;H,4.11;N,28.56%。
实施例45
4-氨基-5-氰基-3-甲氧基甲基-1-甲基吡唑
该标题化合物按实施例5的方法由5-氰基-3-甲氧基甲基-1-甲基-4-硝基吡唑来制备,得到灰白色固体(68%),m.p.82-84℃。实验值:C,50.81;H,6.13;N,33.94。C7H10N4O理论值:C,50.59;H,6.07;N,33.72%。
实施例46
5-氰基-4-(2-乙氧基苯甲酰氨基)-3-甲氧基甲基-1-甲基吡唑
该标题化合物按实施例6的方法由4-氨基-5-氰基-3-甲
氧基甲基-1-甲基吡唑来制备,得到灰白色固体(61%),m.p.103-105℃。实验值:C,61.21;H,5.98;N,17.80。C16H18N4O3理论值:C,61.13;H,5.77;N,17.83%。
实施例47
5-(2-乙氧基苯基)-3-甲氧基甲基-1-甲基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
该标题化合物按实施例7的方法,由5-氰基-4-(2-乙氧基苯甲酰氨基)-3-甲氧基甲基-1-甲基吡唑通过就地生成5-伯酰胺衍生物的中间过程来制备,得到白色固体(38%),m.p.160-161℃。实验值:C,61.35;H,5.75;N,17.98。C16H18N4O3理论值:C,61.13;H,5.77;N,17.83%。
实施例48
3-甲氧基甲基-1-甲基-5-〔5-(4-甲基哌嗪基磺酰基)-2-乙氧基苯基〕-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
于0℃下,将5-(2-乙氧基苯基)-3-甲氧基甲基-1-甲基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮(470mg,1.50mmol)溶于氯磺酸(3ml)中。将该溶液于室温下搅拌2小时,然后小心地加到冰水(50ml)中。所得溶液用饱和碳酸钠溶液中和,然后用二氯甲烷和甲醇的20∶1混合物萃取(2×50ml)。有机萃取液合并后减压蒸发,残余物溶于乙醇(5ml)中,将该溶液用N-甲基哌嗪(450mg,4.5mmol)处理。在室温下处理1小时后,减压蒸发溶剂,残余物在硅
胶上进行层析,用二氯甲烷、甲醇和氢氧化铵水溶液的混合物(体积比为90∶10∶1)洗脱。粗产物加乙酸乙酯研磨,得到白色固体状的标题化合物(49mg,7%),m.p.198-199℃。实验值:C,52.94;H,6.04;N,17.67。C21H28N6O5S理论值:C,52.93;H,5.92;N,17.64%。
层析和结晶后还从乙酸乙酯和甲醇的混合物中分离出了白色固体状的3-羟基甲基-1-甲基-5-〔5-(4-甲基哌嗪基磺酰基)-2-乙氧基苯基〕-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮(51mg,7%),m.p.209-210℃。实验值:C,51.94;H,5.77;N,18.05。C20H26N6O5S理论值:C,51.94;H,5.67;N,18.17%。
实施例49
1-乙基-3-正丙基吡唑-5-甲酸乙酯
此吡唑按实施例1所述的方法由3-正丙基吡唑-5-甲酸乙酯和硫酸二乙酯来制备,得到无色油状物(72%)。Rf0.5(硅胶;乙酸乙酯/己烷1∶1)。
实施例50
1-乙基-3-正丙基吡唑-5-甲酸
此羧酸按实施例2所述的方法由1-乙基-3-正丙基吡唑-5-甲酸乙酯来制备,得到浅棕色固体(89%),m.p.73-77℃。实验值:C,58.62;H,7.69;N,15.23。C9H14N2O2理论值:C,59.32;H,7.74;N,15.37%。
实施例51
1-乙基-4-硝基-3-正丙基吡唑-5-甲酸
此标题化合物按实施例3所述的方法由1-乙基-3-正丙基吡唑-5-甲酸来制备,得到无色固体(96%),m.p.120-123℃。实验值:C,47.61;H,5.81;N,18.54。C9H13N3O4理论值:C,47.57;H,5.77;N,18.49%。
实施例52
1-乙基-4-硝基-3-正丙基吡唑-5-甲酰胺
该标题酰胺按实施例4所述的方法由1-乙基-4-硝基-3-正丙基吡唑-5-甲酸来制备,得到灰白色固体(86%),m.p.119-120℃。实验值:C,47.38;H,6.18;N,24.34。C9H14N4O3理论值:C,47.78;H,6.24;N,24.77%。
实施例53
4-氨基-1-乙基-3-正丙基吡唑-5-甲酰胺
该标题化合物按实施例5所述的方法由1-乙基-4-硝基-3-正丙基吡唑-5-甲酰胺来制备,得到灰白色固体(100%),m.p.93-97℃。实验值:C,55.17;H,8.34;N,28.93。C9H16N4O理论值:C,55.08;H,8.22;N,28.55%。
实施例54
4-(2-乙氧基苯甲酰氨基)-1-乙基-3-正丙基吡唑-5-甲酰胺
该标题化合物按实施例6所述的方法由4-氨基-1-乙基-3-正丙基吡唑-5-甲酰胺和2-乙氧基苯甲酰氯来制备,得到无色固体(73%),m.p.139-141℃。实验值:C,63.03;
H,7.15;N,16.50。C18H24N4O3理论值:C,62.77;H,7.02;N,16.27%。
实施例55
5-(2-乙氧基苯基)-1-乙基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
该标题化合物按实施例7的方法由4-(2-乙氧基苯甲酰氨基)-1-乙基-3-正丙基吡唑-5-甲酰胺来制备,得到无色固体(46%),m.p.112-114℃。实验值:C,66.59;H,6.85;N,17.26。C18H22N4O2理论值:C,66.23;H,6.79;N,17.17%。
实施例56
5-(5-氯磺酰基-2-乙氧基苯基)-1-乙基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
该标题化合物按实施例8的方法由5-(2-乙氧基苯基)-1-乙基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮来制备,得到其二氯甲烷溶剂化物(86%),m.p.170-172℃。实验值:C,49.82;H,4.84;N,12.77。C18H21ClN4O4S·1/6CH2Cl2理论值:C,49.70;H,4.90;N,12.77%。
实施例57
5-〔2-乙氧基-5-(4-甲基哌嗪基磺酰基)苯基〕-1-乙基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
该标题化合物按实施例9的方法由5-(5-氯磺酰基-2-乙
氧基苯基)-1-乙基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮和N-甲基哌嗪来制备,得到无色固体(43%),m.p.160-162℃。实验值:C,57.24;H,6.17;N,16.83。C23H32N6O4S理论值:C,56.54;H,6.60;N,17.20%。Rf0.35(硅胶;二氯甲烷/甲醇9∶1)。
实施例58
5-{2-乙氧基-5-〔4-(2-羟乙基)哌嗪磺酰基〕苯基}-1-乙基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮
该标题磺酰胺按实施例9的方法由5-(5-氯磺酰基-2-乙氧基苯基)-1-乙基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮和N-(2-羟基乙基)哌嗪来制备,得到无色固体(88%),m.p.191-193℃。实验值:C,55.74;H,6.55;N,15.78。C24H34N6O5S理论值:C,55.58;H,6.61;N,16.20%。
Claims (6)
2、如权利要求1所述的方法,其中R1、R2、R4和R5如权利要求1所述,R3为H,在该方法之后接着进行苯酚的O-烷基化,并在需要时把所要的产物转化为可药用盐。
3、如权利要求1或2所述的方法,其中R1、R4和R5如权利要求1所述,R3如权利要求1或2所述,R2含有一个受乙酰基或苯甲酰基保护的羟基取代基,所述保护基在后续反应中用碱水解法脱除,然后再根据需要把所要的产物转化为可药用盐。
4、如权利要求1-3中任一项所述的方法,其中R1为H、甲基或乙基;R2为可被OH或甲氧基取代的C1-C3烷基;R3为C2-C3烷基或烯丙基;R4与它所连的氮原子一起构成哌啶子基或4-N-(R6)-哌嗪基;R5为H、NR7R8或CONR7R8;R6为H、C1-C3烷基、羟基C2-C3烷基、CSNR7R8或C(NH)NR7R8;R7和R8彼此独立地各为H或甲基。
5、如权利要求4所述的方法,其中R1为甲基;R2为正丙基;R3为乙基、正丙基或烯丙基;R4与其所连的氮原子一起构成4-N-(R6)-哌嗪基;R5为H;R6为H、C1-C3烷基或2-羟基乙基。
6、如权利要求5所述的方法,其中所制得的所述式(Ⅰ)化合物选自以下化合物及其可药用盐:
5-〔2-烯丙氧基-5-(4-甲基哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-〔2-乙氧基-5-(哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-〔2-乙氧基-5-(4-甲基哌嗪基磺酰基)苯基〕-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-{2-乙氧基-5-〔4-(2-丙基)哌嗪基磺酰基〕苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-{2-乙氧基-5-〔4-(2-羟基乙基)哌嗪基磺酰基〕苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
1-甲基-5-〔5-(哌嗪基磺酰基)-2-正丙氧基苯基〕-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮;
5-{5-〔4-(2-羟基乙基)哌嗪基磺酰基〕-2-正丙氧基苯基}-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并〔4,3-d〕嘧啶-7-酮。
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Cited By (3)
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CN102134242A (zh) * | 2011-01-21 | 2011-07-27 | 浙江大德药业集团有限公司 | 一种用于治疗阳痿的快速长效的新型化合物 |
CN102134242B (zh) * | 2011-01-21 | 2013-08-28 | 浙江大德药业集团有限公司 | 一种用于治疗阳痿的快速长效的化合物 |
CN105017255A (zh) * | 2014-04-25 | 2015-11-04 | 浙江泰康药业集团有限公司 | 西地那非制备工艺 |
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