CN1742731A - 治疗雌性性机能障碍的吡唑并嘧啶酮类 - Google Patents

治疗雌性性机能障碍的吡唑并嘧啶酮类 Download PDF

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CN1742731A
CN1742731A CNA011112603A CN01111260A CN1742731A CN 1742731 A CN1742731 A CN 1742731A CN A011112603 A CNA011112603 A CN A011112603A CN 01111260 A CN01111260 A CN 01111260A CN 1742731 A CN1742731 A CN 1742731A
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P·艾里士
N·K·特列特
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Abstract

公开了式(I)化合物或其药学上可接受的盐或含有它们中存在的药物组合物在制造用于治疗或预防包括人类在内的雌性动物性功能障碍的药物方面的应用，其中R1、R2、R3和R4的定义同说明书定义。

Description

治疗雌性性机能障碍的吡唑并嘧啶酮类
本申请是申请号为94192386.X的发明专利申请的分案申请。
本发明涉及使用一系列吡唑并[4，3-d]嘧啶-7-酮类治疗雌性性机能障碍。
阳萎照字义可以定义为雄性缺乏交配能力，包括阴茎不能勃起或射精，或二者兼有之。更具体地说，勃起不能或机能障碍可以定义为不能达到或坚持足以进行性交的勃起。它的发病率随年龄增加，据称在50岁以前的男性人口中占2-7％，在55至80岁之间则占18-75％。例如，单就美国而言，估计有高达1千万的阳萎患者，其中多数是器质性而不是精神性问题。
关于男性的控制良好的临床试验报告很少，而口服药物的效力很低。虽然有很多不同的药物显示出能诱发阴茎勃起，但它们只是在直接注射到阴茎内(例如尿道内或阴茎海绵体内注射)之后才有效，未被批准用于勃起机能障碍。现时的医疗方法是基于向阴茎海绵体内注射作用于血管的物质，据称用苯氧基苯甲胺、吩妥拉明、罂粟碱和前列腺素E1(单独使用或组合使用)已获得良好结果；但是，这些药剂中有一些在用阴茎海绵体内注射法用药时会引起阴茎疼痛、异常勃起及纤维变形。钾通道开通剂(KCO)和作用于血管的肠多肽(VIP)也显示出阴茎海绵体内具有活性，但是成本和稳定性问题会限制后者的发展。替代在阴茎海绵体内用药的另一途径是对阴茎涂敷三硝酸甘油酯(GTN)，它也显示出有效，但是对患者及配偶均有副作用。
作为对药物作用的一般性替代办法，曾使用各种阴茎假体来帮助实现勃起。短期成功率良好，但是存在感染和局部缺血问题，尤其是对于糖尿病患者，这使得此类治疗是最后的选择而不是最优良的疗法。
本发明的化合物是环状鸟嘌呤核苷3′，5′-单磷酸酯磷酸二酯酶(cGMP PDEs)的强抑制剂，与它们对环状腺嘌呤3′，5′-单磷酸酯磷酸二酯酶(cAMP PDEs)的抑制大不相同。这种选择性的酶抑制作用导致cGMP浓度的增高，从而为EP-A-0463756和EP-A-0526004中公开的所述化合物的应用提供了基础，即，治疗稳定的、不稳定的和变异的(Prinzmetal)咽峡炎，高血压，肺动脉高血压，充血性心力衰竭，动脉粥样硬化，血管开放降低的症状(例如经皮穿剌冠状动脉腔内成形术后的症状)，外围血管疾病，中风，支气管炎，过敏性哮喘，慢性哮喘，过敏性鼻炎，青光眼和以肠可动性失调为特征的疾病，例如应激性肠综合症(IBS)。
出乎意料的是，现已发现，所公开的这些化合物在治疗勃起机能障碍方面作用。另外，这些化合物可以口服，从而避免了在阴茎海绵体内用药的不便。因此，本发明涉及用式(I)化合物或其药学上可接受的盐或含有它们中存在的药物组合物制造用于治疗或预防雄性动物。包括人勃起机能障碍的药物，
其中R1是H，C1-C3烷基，C1-C3全氟烷基或C3-C5环烷基；
R2是H，可任选被C3-C6环烷基取代的C1-C6烷基，C1-C3全氟烷基或C3-C6环烷基；
R3是可任选被C3-C6环烷基取代的C1-C6烷基，C1-C6全氟烷基，C3-C5环烷基，C3-C6链烯基或C3-C6炔基；
R4是可任选被OH、NR5R6、CN、CONR5R6或CO2R7取代的C1-C4烷基，可任选被CN、CONR5R6或CO2R7取代的C2-C4链烯基，可任选被NR5R6取代的C2-C4烷酰基，可任选被NR5R6取代的(羟基)C2-C4烷基，可任选被OH或NR5R6取代的(C2-C3烷氧基)C1-C2烷基，CONR5R6、CO2R7、卤素、NR5R6、NHSO2NR5R6、NHSO2R8、SO2NR9R10；或是苯基、吡啶基、嘧啶基、咪唑基、噁唑基、噻唑基、噻吩基或三唑基，它们均可任选地被甲基取代；
R5和R6各自独立地为H或C1-C4烷基，或者与它们所连接的N原子一起形成一个吡咯烷基、哌啶子基、吗啉代、4-N(R11)哌嗪基或咪唑基，其中该基团可任选地被甲基或OH取代；
R7是氢或C1-C4烷基；
R8是可任选被NR5R6取代的C1-C3烷基；
R9和R10与它们所连接的N原子一起形成一个吡咯烷基、哌啶子基、吗啉代或4-N(R12)哌嗪基，其中该基团可任选地被C1-C4烷基、C1-C3烷氧基、NR13R14或CONR13R14取代；
R11是H，可任选被苯基取代的C1-C3烷基，(羟基)C2-C3烷基，或C1-C4烷酰基：
R12是H，C1-C6烷基，(C1-C3烷氧基)C2-C6烷基，(羟基)C2-C5烷基，(R12R14N)C2-C6烷基，(R13R14NOC)C1-C6烷基，CONR13R14、CSNR13R14或C(NH)NR13R14；
R13和R14各自独立地是H，C1-C4烷基，(C1-C3烷氧基)C2-C4烷基或(羟基)C2-C4烷基。
在以上的定义中，除非另外指明，有3个或更多碳原子的烷基、有4个或更多碳原子的链烯基的炔基、有3个碳原子的烷氧基和有4个碳原子的链烷酰基可以是直链或支链。卤素是指氟、氯、溴或碘。
式(I)化合物可以含一个或多个不对称中心，从而能以对映体或非对映体的形式存在。另外，某些含炔基的式(I)化合物可以以顺式或反式异构体的形式存在。在每种情形，本发明将混合物和分开的个别异构体都包括在内。
式(I)化合物也可以以互变异构体的形式存在，本发明将混合物和分开的个别互变异构体都包括在内。
含有碱性中心的式(I)化合物的药学上可接受的盐是例如与无机酸(如盐酸、氢溴酸、硫酸或磷酸)、有机羧酸或有机磺酸形成的无毒性的酸加成盐。式(I)化合物也可以与碱形成药学上可接受的金属盐，特别是无毒的碱金属盐。实例包括钠盐和钾盐。
优选的一组式(I)化合物是其中的R1是H、甲基或乙基；R2是C1-C3烷基；R3是C2-C3烷基或烯丙基；R4是任选被OH、NR5R6、CN、CONR5R6或CO2R7取代的C1-C2烷基，任选被NR5R6取代的乙酰基，任选被NR5R6取代的羟乙基，任选被OH或NR5R6取代的乙氧甲基，CH＝CHCN，CH＝CHCONR5R6，CH＝CHCO2R7，CONR5R6，CO2H，Br，NR5R6，NHSO2NR5R6，NHSO2R8，SO2NR9R10，或是均可任选地被甲基取代的吡啶或咪唑基；R5和R6各自独立地为H、甲基或乙基，或者与它们所连接的氮原子一起形成一个哌啶子基、吗啉代、4-N(R11)哌嗪基或咪唑基，其中该基团可任选地被甲基或OH取代；R7是H或叔丁基；R8是甲基或CH2CH2CH2NR5R6；R9和R10与它们所连接的氮原子一起形成一个哌啶子基或4-N(R12)哌嗪基，其中该基团可任选地被NR13R14或CONR13R14取代；R11是H，甲基、苄基、2-羟乙基或乙酰基；R12是H、C2-C3烷基、(羟基)C2-C3烷基、CSNR13R14或C(NH)NR13R14；R13和R14各自独立地是H或甲基。
一组更优选的式(I)化合物中，R1是甲基或乙基；R2是C1-C3烷基；R3是乙基、正丙基或烯丙基；R4是CH2NR5R6、COCH2NR5R6、CH(OH)CH2NR5R6、CH2OCH2CH3、CH2OCH2CH2OH、CH2OCH2CH2NR5R6、CH＝CHCON(CH3)2、CH＝CHCO2R7、CONR5R6、CO2H、Br、NHSO2NR5R6、NHSO2CH2CH2CH2NR5R6、SO2NR9R10、2-吡啶基、1-咪唑基或1-甲基-2-咪唑基；R5和R6与它们所连接的N原子一起形成一个哌啶子基、4-羟基哌啶子基、吗啉代、4-N(R11)哌嗪基或2-甲基-1-咪唑基；R7是H或叔丁基；R9和R10与它们所连接的N原子一起形成一个4-氨基甲酰哌啶子基或4-N(R12)哌嗪基；R11是H、甲基、苄基、2-羟乙基或乙酰基；R12是H、C1-C3烷基、2-羟乙基或CSNH2。
特别优选的式(I)化合物中，R1是甲基或乙基，R2是正丙基，R3是乙基、正丙基或烯丙基，R4是COCH2NR5R6、CONR5R6、SO2NR9R10或1-甲基-2-咪唑基，R5和R6与它们所连接的N原子一起形成一个吗啉代或4-N(R11)哌嗪基，R9和R10与它们所连接的氮原子一起形成一个4-N(R12)-哌嗪基，R11是甲基或乙酰基，R12是H、甲基、2-丙基或2-羟乙基。
特别优选的个别的本发明化合物包括：
5-(2-乙氧基-5-吗啉代乙酰苯基)-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮；
5-(5-吗啉代乙酰基-2-正丙氧苯基)-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-1-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-烯丙氧基-5-(4-甲基-1-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)-1-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-5-[4-(2-羟乙基)-1-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-{5-[4-(2-羟乙基)-1-哌嗪基磺酰基]-2-正丙氧苯基}-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-1-哌嗪基羰基)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-(1-甲基-2-咪唑基)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EP-A-0463756和EP-A-0526004中叙述了式(I)化合物及其药学上可接受的盐、它们的制备方法、测定它们的抑制cGMP PDE和cAMP PDE活性的体外试验法、它们的药物组合物及人类使用时的服药途径。
进行了预备性研究以便分离和鉴定人类阴茎海绵体的环状核苷酸PDE，海绵体的舒张导致了阴茎勃起。关于对底物的专一性、对活化剂的响应和抑制剂敏感性的研究已证实，人类阴茎海绵体含有三种明显不同的PDE酶。
方法
由IIAM(Pennsylvania)得到新鲜的冷冻人类阴茎。将组织在室温下解冻，从阴茎上分割下阴茎海绵体，得到约2-4g组织，按下述进行分离步骤。将组织在含250mM蔗糖，1mM EDTA、0.5mM PMSF(苯甲基磺酰氟化物)和20mM HEPES(N-羟乙基哌嗪-N′-2-乙烷磺酸酯)的冰冷的等渗缓冲液(pH7.2，35ml)中粗略地切碎，混合物用一台Silversen混合器/乳化剂进行短暂的(1分钟)处理。用带有聚四氟乙烯捣锤的均化器管制备均化物，在4℃和100,000xg下离心60分钟以得到可溶的级分。将10ml高速离心后的清液加在Pharmacia Mono Q阴离子交换柱(床体积1ml)上，该柱子用含1mMEDTA、0.5mM PMSF和20mM HEPES、pH为7.2的缓冲液(色谱缓冲液)平衡。然后用5倍床体积的色谱缓冲液洗柱子，接着用连续梯度的0-500mM NaCl(总体积35ml)洗脱PDEs，收集1ml各级分。
用500nM cGMP或500nM cAMP作为底物分析柱子各级分的PDE活性。还在1μM未标记的cGMP存在下测定cAMP PDE活性，在10mMCaCl2和10单位/ml牛脑调钙蛋白存在下确定所选级分的PDE活性。将合适的级分汇总，在研究期间于4℃贮存。
抑制作用研究一直采用浓度为500nM的底物进行。所有的抑制剂均溶在二甲基亚砜中，在3×10-10至1×10-4M的范围内按半对数增量构成浓度一响应曲线。用生物统计的S形曲线拟合算法计算出IC50值。
结果
人类阴茎海绵体可溶性PDEs被分离成三个活性明显不同的级分。第一个级分I(按洗脱的次序指定)代表所存在的主要的PDE，它对作为底物的cGMP有高度的选择性。发现这一级分对于钙/调钙蛋白的激发不敏感，将其分类为PDEv。级分II水解出cGMP和cAMP，后者的活性在cGMP存在下被激发，将其归入PDEII一类，而级分III有cAMP选择性，而且这一活性在cGMP存在下被抑制，与PDEIII的活性一致。
为了进一步鉴定组织中存在的PDE同功酶，用多种抑制剂进行了研究。用级分I和II进行的抑制剂研究采用cGMP作为底物，而级分III研究以cAMP为底物。这些研究证实，级分I相当于PDEv，而级分III显然与PDEIII相同；级分II(PDEII)对所试验的所有抑制剂均相对地不敏感。
总之，以上研究鉴别了人类阴茎海绵体组织内的三种PDE同功酶。占支配地位的PDE是对cGMP有专一性的PDEv，而cGMP激发的cAMPPDEII和cGMP抑制的cAMP PDEIII也存在。
本发明化合物已在体外作为试验并发现它们是对cGMP有专一性的PDEv的很强的选择性抑制剂。例如，本发明的一种特别优选的化合物对PDEv酶的IC50＝6+8nMV，但对于PDEII和PDEIII酶只显示很弱的抑制活性，IC50分别为≥100μm和34μm 。于是，阴茎海绵体组织的舒张和随之发生的阴茎勃起会由于该组织内的cGMP含量的增高而得到调节，而这又是本发明化合物对于几种PDE的抑制特点造成的。
另外，在鼠和狗内试验的本发明化合物，在最高达3mg/kg的静脉内(i.v.)和口服(p.o.)这两种情形，均未显示出任何不利的急性毒性的明显迹象。在小鼠的情形，在高达100mg/kg的剂量(i.v.)下未发生死亡。某些特别优选的化合物在以最高达10mg/kg的剂量对鼠和以高达20mg/kg的剂量对狗长期口服时，无毒性作用。
对于人，按一次剂量和多次剂量对志愿者口服试验了某些特别优选的化合物。另外，至今为止对患者进行的研究已证实，一种特别优选的化合物诱发了阳萎男性的阴茎勃起。
虽然本发明的化合物主要是设想用于治疗勃起机能障碍或男性性机能障碍，但它们也可以用来治疗女性性机能障碍，包括与阴蒂失调有关的性欲高潮机能障碍。
一般来说，对于人类，口服本发明化合物是优进的途径，它最为方便，而且避免了在阴茎海绵体内用药时遇到的不便。对于代表性的男人，优选的剂量范围是每日3次5至75mg化合物。在受体患者有吞咽障碍或口服后有药物吸收损伤时，可以非肠道用药，例如经舌下或经颊用药。
对于兽医使用，根据通常的兽医实践以合适的可接受的制剂形式施用式(I)化合物或其无毒性的盐，兽医师将决定最适合具体的雄性动物的剂量范围和用药途径。
因此，本发明包括一种用于治疗雄性动物，包括人勃起机能障碍的药物组合物，该组合物中含有一种式(I)化合物或其药学上可接受的盐，以及一种药学上可接受的稀释剂或载体。
还提供了一种制备用于治疗或预防雄性动物，包括人勃起机能障碍的药物组合物的方法，包括将式(I)化合物或其药学上可接受的盐与药学上可接受的稀释剂或载体一起配制。
本发明还提供了一种治疗或防止雄性动物，包括人勃起机能障碍的方法，该方法包括用有效数量的式(I)化合物或其药学上可接受的盐或含有它们中存在的药物组合物治疗雄性动物。
在另一方面，本发明还包括利用cGMP PDE抑制剂或其药学上可接受的盐或含有它们中存在的药物组合物来治疗雄性动物，包括人的勃起机能障碍。
本发明还包括一种治疗或预防雄性动物，包括人勃起机能障碍的方法，该方法包括用有效数量的cGMP PDE抑制剂或其药学上可接受的盐或含有它们中存在的药物组合物来治疗雄性动物。
另外，本发明还包括使用cGMP PDE抑制剂或其药学上可接受的盐或含有它们中存在的药物组合物来制造用于治疗或预防雄性动物，包括人勃起机能障碍的药物。

Claims (6)

1.式(I)化合物或其药学上可接受的盐或含有它们中任何一种的药物组合物在制造用于治疗或预防包括人在内的雌性动物性机能障碍的药物中的应用：
Figure A011112600002C1
其中R1是H，C1-C3烷基，C1-C3全氟烷基或C3-C5环烷基；
R2是H，可任选被C3-C6环烷基取代的C3-C6烷基，C1-C3全氟烷基或C3-C6环烷基；
R3是可任选被C3-C6环烷基取代的C1-C6烷基，C1-C6全氟烷基，C3-C5环烷基，C3-C6链烯基或C3-C5炔基；
R4是可任选被OH、NR5R6、CN、CONR5R6或CO2R7取代的C1-C4烷基，可任选被CN、CONR5R6或CO2R7取代的C2-C4链烯基，可任选被NR5R6取代的C2-C4烷酰基，可任选被NR5R6取代的(羟基)C2-C4烷基，可任选被OH或NR5R6取代的(C2-C3烷氧基)C1-C2烷基，CONR5R6、CO2R7、卤素、NR5R6、NHSO2NR5R6、NHSO2R8、SO2NR9R10；或是苯基、吡啶基、嘧啶基、咪唑基、噁唑基、噻唑基、噻吩基或三唑基，它们均可任选地被甲基取代；
R5和R6各自独立地为H或C1-C4烷基，或者与它们所连接的N原子一起形成一个吡咯烷基、哌啶子基、吗啉代、4-N(R11)哌嗪基或咪唑基，其中该基团可任选地被甲基或OH取代；
R7是氢或C1-C4烷基；
R8是可任选被NR5R6取代的C1-C3烷基；
R9和R10与它们所连接的N原子一起形成一个吡咯烷基、哌啶子基、吗啉代或4-N(R12)哌嗪基，其中该基团可任选地C1-C4烷基、C1-C3烷氧基、NR13R14或CONR13R14取代；
R11是H，可任选被苯基取代的C1-C3烷基，(羟基)C2-C3烷基，或C1-C4烷酰基；
R12是H，C1-C6烷基，(C1-C3烷氧基)C2-C6烷基，(羟基)C2-C6烷基，(R13R14N)C2-C6烷基，(R13R14NOC)C1-C6烷基，CONR13R14、CSNR13R14或C(NH)NR13R14；
R13和R14各自独立地是H，C1-C4烷基，(C1-C3烷氧基)C2-C4烷基或(羟基)C2-C4烷基。
2.根据权利要求1的应用，其中在式(I)化合物内R1是H、甲基或乙基；R2是C1-C3烷基；R3是C2-C3烷基或烯丙基；R4是任选被OH、NR5R6、CN、CONR5R6或CO2R7取代的C1-C2烷基，任选被NR5R6取代的乙酰基，任选被NR5R6取代的羟乙基，任选被OH或NR5R6取代的乙氧甲基，CH＝CHCN，CH＝CHCONR5R6，CH＝CHCO2R7，CONR5R6，CO2H，Br，NR5R6，NHSO2NR5R6，NHSO2R8，SO2NR9R10，或是均可任选地被甲基取代的吡啶基或咪唑基；R5和R6各自独立地为H、甲基或乙基，或者与它们所连接的氮原子一起形成一个哌啶子基、吗啉代、4-N(R11)哌嗪基或咪唑基，其中该基团可任选地被甲基或OH取代；R7是H或叔丁基；R8是甲基或CH2CH2CH2NR5R6；R9和R10与它们所连接的氮原子一起形成一个哌啶子基或4-N(R12)哌嗪基，其中该基团可任选地被NR13R14或CONR13R14取代；R11是H，甲基、苄基、2-羟乙基或乙酰基；R12是H、C1-C3烷基、(羟基)C2-C3烷基、CSNR13R14或C(NH)NR13R14；R13和R14各自独立地是H或甲基。
3.根据权利要求2的应用，其中在式(I)化合物中R1是甲基或乙基；R2是C1-C3烷基；R3是乙基、正丙基或烯丙基；R4是CH2NR5R6、COCH2NR5R6、CH(OH)CH2NR5R6、CH2OCH2CH3、CH2OCH2CH2OH、CH2OCH2CH2NR5R5、CH＝CHCON(CH3)2、CH＝CHCO2R7、CONR5R6、CO2H、Br、NHSO2NR5R6、NHSO2CH2CH2CH2NR5R6、SO2NR9R10、2-吡啶基、1-咪唑基或1-甲基-2-咪唑基；R5和R6与它们所连接的N原子一起形成一个哌啶子基、4-羟基哌啶子基、吗啉代、4-N(R11)哌嗪基或2-甲基-1-咪唑基；R7是H或叔丁基；R9和R10与它们所连接的N原子一起形成一个4-氨基甲酰哌啶子基或4-N(R12)哌嗪基；R11是H、甲基、苄基、2-羟乙基或乙酰基；R12是H、C1-C3烷基、2-羟乙基或CSNH2。
4.根据权利要求3的应用，其中在式(I)化合物中R1是甲基或乙基，R2是正丙基，R3是乙基、正丙基或烯丙基，R4是COCH2NR5R6、CONR5R6、SO2NR5R6或1-甲基-2-咪唑基，R9和R10与它们所连接的N原子一起形成一个吗啉代或4-N(R11)哌嗪基，R9和R10与它们所连接的氮原子一起形成一个4-N(R12)-哌嗪基，R11是甲基或乙酰基，R12是H、甲基、2-丙基或2-羟乙基。
5.根据权利要求4的应用，其中式(I)化合物选自：
5-(2-乙氧基-5-吗啉代乙酰苯基)-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮；
5-(5-吗啉代乙酰基-2-正丙氧苯基)-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-1-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-烯丙氧基-5-(4-甲基-1-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)-1-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-5-[4-(2-羟乙基)-1-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-{5-[4-(2-羟乙基)-1-哌嗪基磺酰基]-2-正丙氧苯基}-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-1-哌嗪基羰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮；和
5-[2-乙氧基-5-(1-甲基-1-咪唑基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮。
6.根据权利要求5的应用，其中式(I)化合物是5-[2-乙氧基-5-(4-甲基-1-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-酮或其药学上可接受的盐。
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