CN111747960A - 一种取代吡唑[3,4-d]嘧啶类化合物及其制备方法和应用 - Google Patents
一种取代吡唑[3,4-d]嘧啶类化合物及其制备方法和应用 Download PDFInfo
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- CN111747960A CN111747960A CN202010535423.9A CN202010535423A CN111747960A CN 111747960 A CN111747960 A CN 111747960A CN 202010535423 A CN202010535423 A CN 202010535423A CN 111747960 A CN111747960 A CN 111747960A
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- pyrimidine
- alkyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- -1 pyrazolo [3,4-d ] pyrimidine compound Chemical class 0.000 title claims description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
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- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims abstract description 18
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims abstract description 14
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 10
- 208000002815 pulmonary hypertension Diseases 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 150000003230 pyrimidines Chemical class 0.000 claims abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
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- 201000010099 disease Diseases 0.000 claims description 5
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- NLNGLCPAWPBRHX-UHFFFAOYSA-N 3-methyl-1,4-benzodioxine Chemical compound C1=CC=C2OC(C)=COC2=C1 NLNGLCPAWPBRHX-UHFFFAOYSA-N 0.000 claims description 4
- QENGPZGAWFQWCZ-UHFFFAOYSA-N Methylthiophene Natural products CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
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- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical class C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 claims 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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- Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract
Description
技术领域
本发明涉及医药技术领域,更具体地,涉及一种取代吡唑[3,4-d]嘧啶类化合物及其制备方法和应用。
背景技术
磷酸二酯酶(phosphodiesterase,PDE)是体内唯一能够降解cAMP和cGMP的一类超级酶家族,是许多疾病的治疗靶点,如肺动脉高压、特发性肺纤维化、阿尔茨海默症、糖尿病以及心功能不全。目前已有多个疗效显著的PDE抑制剂成功上市。PDE在体内广泛分布,其根据蛋白质的序列相似性、酶动力学特征、调节性质、细胞组织分布和药理学性质被分为11个同工酶家族(PDE1~PDE11);而这11个家族在体内又分别有着不同的分布区域,在不同的生理或病理过程其作用。在这11个家族中,PDE1被鉴定为Ca2+钙调素依赖性磷酸二酯酶(CaM-pde),其被Ca2+钙调素激活并被证明介导钙和环核苷酸信号通路。已知的三个CaM-PDE基因PDE1A、PDE1B和PDE1C均在中枢神经系统组织中表达。PDE1A在全脑表达,海马和小脑CA1和CA3层表达较高,纹状体表达较低。肺和心脏也表达PDE1A。PDE1B主要表达于纹状体、齿状回、嗅束和小脑,其表达与多巴胺能神经支配的脑区有关。虽然PDE1B主要在中枢神经系统中表达,但它可能在心脏中被检测到。PDE1C主要表达于嗅上皮、小脑颗粒细胞和纹状体。PDE1C也在心脏和血管平滑肌中表达。
Li,P.(J Med Chem 2016,59(3),1149-64)、Dyck,B(J Med Chem 2017,60(8),3472-3483)、McQuown,S.(Front Mol Neurosci 2019,12,21.)等已发表的文章研究表明,PDE1调节的信号通路的变化和中枢神经系统有所关联,可用于调节精神失常、运动障碍、认知功能和阿尔茨海默症等;Maurice,D.H.(Nat Rev Drug Discov 2014,13(4),290-314)、Hashimoto,T.(Circulation 2018,138(18),1974-1987.)、Humphrey,J.M.(J Med Chem2018,61(10),4635-4640.)等的研究表明PDE1与心功能不全有关,可用于调节心衰、心脏重塑和功能障碍等;Ren,L.(Exp Lung Res 2017,43(6-7),249-258.)、Xin,W.(Am J PhysiolRenal Physiol 2016,310(10),F994-9.)等的研究表明PDE1与肺、肾脏、血液学、胃肠道、肝脏、生育力、癌症和代谢紊乱等都有所关联。目前,Schermuly,R.T.(Circulation 2007,115(17),2331-9.)报道了PDE1抑制剂可作为抗肺动脉高压(PAH)的药物进行应用。然而,尚无PDE1抑制剂用于特发性肺纤维化(IPF)的治疗。现在对PDE1的研究还很有限,PDE1抑制剂主要用于中枢神经系统疾病,很少用于外周疾病。
发明内容
本发明的目的在于提供一种取代吡唑[3,4-d]嘧啶类化合物。本发明所述化合物磷酸二酯酶一型(PDE1)表现出良好的抑制作用,可作为PDE1抑制剂进行应用,从而可制备成为肺动脉高压、特发性肺纤维化药物进行应用,具有重要的药用价值和广阔的应用前景。
本发明的另一目的在于提供所述取代吡唑[3,4-d]嘧啶类化合物的制备方法。
本发明的再一目的在于提供所述取代吡唑[3,4-d]嘧啶类化合物的应用。
本发明的上述目的是通过以下方案予以实现的:
一种取代吡唑[3,4-d]嘧啶类化合物,所述化合物的结构如式(I)或式(Ⅱ)所示:
其中,R1为C1~8烷基、C1~8卤代烷基或C3~8环烷基、C3~8含氮环烷基或C3~8含氧环烷基;
R2和R3各自独立地为:氢、C1~4烷基、苯基、卤代苯基、C1~4烷基取代苯基、C1~4烷氧基取代苯基、苄基、卤代苄基、甲氧基苯基、卤代甲氧基苯基;
R4为C1~4烷基、苯基、取代的苯基、苄基、取代的苄基、甲基吡啶基、甲基噻吩、甲基吗啉或甲基苯并二噁英;
R5可与相连N原子成环或不成环;当R5与相连N成环时,所成环为:1-甲基异喹啉;
R5与相连N原子不成环时,R5为苯并环戊基或四氢萘。
优选地,所述R1为C1~8直链烷基、C1~8支链烷基、C1~8环烷基、C1~8卤代直链烷基、C1~8卤代支链烷基、C1~8卤代环烷基或C3~6含氧环烷基。
优选地,所述R1为C3~4直链烷基、C3~4支链烷基、C3~6环烷基、C3~4卤代直链烷基、C3~4卤代支链烷基、C3~6卤代环烷基或C3~6含氧环烷基。
优选地,R2和R3各自独立地为:氢、甲基、乙基、丙基、苯基、氟代苯基、二氟代苯基、氯代苯基、二氯代苯基、C1~4烷基取代苯基、C1~4烷氧基取代苯基、苄基、氟代苄基、二氟代苄基、氯代苄基、二氯代苄基、甲氧基苯基或卤代甲氧基苯基。
优选地,R4为甲基、乙基、异丙基、氟代苯基、二氟代苯基、氯代苯基、二氯代苯基、苄基、氟代苄基、二氟代苄基、氯代苄基、二氯代苄基、甲基吡啶基、甲基噻吩、甲基吗啉或甲基苯并二噁英。
所述R2和R3各自独立地为:氢、甲基、乙基、
所述R4为:甲基、乙基、异丙基、
更优选地,所述取代吡唑[3,4-d]嘧啶类化合物的结构如下结构式之一所示:
所述取代吡唑[3,4-d]嘧啶类化合物的制备方法也在本发明的保护范围内,包括如下步骤:
S1.嘧啶-2,4,6(1H,3H,5H)-三酮与三氯氧磷混溶,加热回流反应,得到式(1)所述化合物;
S2.式(1)所述化合物和R1NHN2·HCl在低温条件下,加入三乙胺保温2h,然后升温至室温反应,得到(2)所述化合物;
S3.式(2)所述化合物在碱性水溶液中,加热回流反应,得到式(3)所述化合物;
S4.式(3)所述化合物和R4Cl在碱性无机盐存在条件下反应,得到式(4)所述化合物;
S5.式(4)所述化合物和R2R3CHNH2或R5CHNH2加热回流反应,得到式(I)或式(Ⅱ)所述化合物;
其中式(1)、式(2)、式(3)和式(4)的结构如下所示:
优选地,步骤S1的反应在N,N-二甲基甲酰胺溶液中进行;加热回流的温度为120℃。
优选地,步骤S1中嘧啶-2,4,6(1H,3H,5H)-三酮和三氯氧磷的摩尔比为1:70。
优选地,步骤S2的反应在乙醇溶液中进行;所述低温条件为温度-78℃。
优选地,步骤S2中式(1)所述化合物和R1NHN2·HCl的摩尔比为1:1~1.5。
优选地,步骤S3中所述碱性水溶液为氢氧化钠的水溶液,其中氢氧化钠和水的质量比为20:1;所述加热回流的温度为60℃。
优选地,步骤S4反应在N,N-二甲基甲酰胺溶液中进行;所述碱性无机盐为碳酸钠。
优选地,步骤S4中式(3)所述化合物和R4Cl的摩尔比为1:1.2~1.5。
优选地,步骤S5反应在异丙醇和N,N-二异丙基乙胺溶液中进行;所述加热回流的温度为120℃。
优选地,步骤S5中式(4)所述化合物和R2R3CHNH2或R5CHNH2的摩尔比为1:1.2~1.5。
优选地,步骤S1的反应时间为16h;步骤S3的反应时间为3h;步骤S4的反应时间为2~16h;步骤S5的反应时间为16h。
本发明同时还保护所述取代吡唑[3,4-d]嘧啶类化合物作为磷酸二酯酶抑制剂的应用。
本发明同时还保护所述取代吡唑[3,4-d]嘧啶类化合物制备治疗磷酸二酯酶相关疾病的药物中的应用。
优选地,所述磷酸二酯酶为PDE1。
优选地,所述磷酸二酯酶相关疾病为肺动脉高压症和/或特发性肺纤维化症。
与现有技术相比,本发明具有以下有益效果:
本发明提供的化合物对磷酸二酯酶一型(PDE1)表现出良好的抑制作用,可作为磷酸二酯酶一型抑制剂应用;同时,由本发明所述化合物制备的药物对肺动脉高压和特发性肺纤维化具有较好的疗效;可见,本发明所述化合物在制备成为肺动脉高压和特发性肺纤维化药物具有重要的药用价值和广泛的应用前景。
另外,本发明所述化合物结构新颖,其制备方法简单,适用于大规模工业生产及应用。
附图说明
图1为SD大鼠呼吸参数测试数据。
图2为大鼠肺组织H&E染色和Masson染色结果。
图3为用Western blot法和免疫荧光染色法检测肺组织α-平滑肌肌动蛋白(a-SMA)水平结果。
具体实施方式
下面结合具体实施例对本发明做出进一步地详细阐述,所述实施例只用于解释本发明,并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
实施例1化合物1的制备
(1)化合物(1a)的制备:嘧啶-2,4,6(1H,3H,5H)-三酮(10g,78mmol)溶于N,N-二甲基甲酰胺(8mL),在120℃加热回流下分批加入三氯氧磷(50mL),反应过夜。反应结束后用冰水冷却至0℃,再缓慢将冰水加入体系中,搅拌逐渐析出黄色或棕红色固体,抽滤,减压干燥,最后得到黄色或棕红色固体(15g,产率为91%),即为化合物(1a),反应方程式为:
(2)化合物(1b)的制备:将化合物1a(15g,71mmol)和盐酸异丙肼(8.6g,78mmol)全部溶解于乙醇(100~150mL),在-78℃下缓慢滴加三乙胺(20mL),反应2小时后移至室温反应过夜。反应完全后,减压旋蒸除去溶剂,再加入乙酸乙酯,抽滤除去不溶物,滤液减压旋蒸除去溶剂,过柱纯化得到棕红色固体(6g,产率为36%),即为化合物(1b),反应方程式为:
(3)化合物(1c)的制备:化合物1b(6g,26mmol)溶于氢氧化钠溶液(519mL)中,在60℃下加热回流3小时。反应结束后,用2M盐酸调pH至中性,析出白色固体,抽滤干燥后得到白色固体(2.6g,产率为47%),即为化合物(1c),反应方程式为:
(4)化合物(1d)的制备:将化合物1c(100mg,0.47mmol)和碘甲烷(36μL,0.56mmol)溶于N,N-二甲基甲酰胺(1mL),再加入碳酸钾(100mg,0.94mmol),在室温反应2小时。反应结束后,加入适量水和乙酸乙酯,萃取乙酸乙酯层,用饱和碳酸氢钠水溶液洗涤三次。收集有机层,无水硫酸钠干燥,减压旋蒸除去溶剂,过柱纯化得到白色固体(80mg,产率为75%),即为化合物(1d),反应方程式为:
(5)化合物(1)的制备:将化合物(1d)(80g,0.35mmol)和(R)-1-(4-氯苯基)乙烷-1-胺(60μL,0.42mmol)溶于异丙醇(1mL)中,再加入N,N-二异丙基乙胺(83μL,0.7mmol),在120℃下加热回流过夜。反应结束后,过柱纯化得到白色固体(81mg,产率为53%),即为化合物(1),反应方程式为:
按照上述方法,将第(2)步中的盐酸异丙肼、第(4)步的碘甲烷和第(5)步的(R)-1-(4-氯苯基)乙烷-1-胺根据以下化合物中R1、R4、R2、R3或R5基团代替,制备得到化合物1~39。
化合物1~39的结构、外观和核磁数据
化合物1
1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.33(s,4H),5.26–5.19(m,1H),4.82(d,J=5.8Hz,1H),4.78–4.70(m,1H),3.45(s,4H),1.63(d,J=6.9Hz,3H),1.47(d,J=6.8Hz,3H),1.40(d,J=6.7Hz,3H).13C NMR(126MHz,CDCl3)δ158.19,151.38,150.78,142.00,134.70,133.20,128.80,127.61,99.94,51.32,48.84,26.86,22.30,21.64.HRMS(ESI-TOF)m/z[M-H]-called forC17H20ClN5O344.1284,found 344.1285.
化合物2
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.38(s,4H),7.25(s,2H),7.15(d,J=8.4Hz,2H),6.84(d,J=8.3Hz,2H),5.57(d,J=16.2Hz,1H),5.02(dd,J=18.7,11.7Hz,2H),4.86(d,J=6.5Hz,1H),4.76–4.68(m,1H),1.46(d,J=6.8Hz,3H),1.39(d,J=6.7Hz,3H),1.34(d,J=6.9Hz,3H).13C NMR(126MHz,CDCl3)δ158.49,151.39,150.90,142.05,135.61,134.98,132.81,129.58,128.48,127.17,126.74,99.84,51.27,48.85,43.80,22.38,21.65).HRMS(ESI-TOF)m/z[M-H]-called forC23H24ClN5O420.1597,found 420.1598.
化合物3
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.21(d,J=8.4Hz,2H),6.97(d,J=8.4Hz,2H),6.79(d,J=7.9Hz,1H),6.75–6.68(m,2H),5.99(d,J=2.0Hz,2H),5.39(d,J=16.1Hz,1H),5.04(d,J=6.6Hz,1H),5.02–4.95(m,2H),4.76–4.68(m,1H),1.46(d,J=6.7Hz,3H),1.40(d,J=6.5Hz,6H).13C NMR(126MHz,CDCl3)δ158.47,151.52,150.87,148.96,147.81,142.02,134.96,132.90,129.37,128.58×2,127.27×2,119.89,108.71,107.25,101.51,99.86,51.29,48.86,43.68,22.30,21.71,21.60.HRMS(ESI-TOF)m/z[M-H]-calcd forC24H24ClN5O3 464.1495,found 464.1496.
化合物4
1H NMR(400MHz,CDCl3)δ8.62(d,J=5.9Hz,2H),7.94(s,1H),7.27(s,1H),7.21(d,J=8.4Hz,2H),7.14(d,J=5.7Hz,2H),6.96(d,J=8.4Hz,2H),5.45(d,J=16.8Hz,1H),5.13(d,J=17.3Hz,1H),5.09–5.01(m,1H),4.80–4.71(m,1H),4.56(d,J=6.2Hz,1H),1.49(d,J=6.7Hz,3H),1.41(dd,J=10.6,6.8Hz,6H).
化合物5
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.40(dd,J=4.9,3.0Hz,1H),7.22(s,1H),7.20(d,J=2.2Hz,2H),6.99(d,J=5.0Hz,1H),6.96(d,J=8.4Hz,2H),5.48(d,J=16.2Hz,1H),5.11(d,J=16.1Hz,1H),5.04(d,J=6.1Hz,2H),4.76–4.68(m,1H),1.46(d,J=6.8Hz,3H),1.40(t,J=6.2Hz,6H).
化合物6
1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.35(d,J=8.3Hz,2H),7.30(s,2H),5.17–5.09(m,1H),4.87(dt,J=13.6,6.8Hz,1H),4.20(s,2H),4.02(d,J=7.9Hz,2H),3.43(t,J=11.4Hz,2H),1.75–1.65(m,2H),1.57(d,J=6.9Hz,3H),1.49(dd,J=12.2,6.8Hz,6H),1.31–1.27(m,2H).
化合物7
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.18–6.94(m,4H),5.31(s,1H),4.88(dt,J=13.4,6.7Hz,1H),4.31(t,J=5.0Hz,2H),3.98(dd,J=10.3,5.3Hz,2H),3.48(s,3H),1.53(d,J=6.7Hz,6H).
化合物8
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.08–6.91(m,3H),5.42(s,1H),4.85(dt,J=13.5,6.7Hz,1H),4.39(t,J=4.9Hz,2H),3.91(dd,J=10.0,5.2Hz,2H),3.51(s,3H),1.51(d,J=6.7Hz,6H).
化合物9
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.35–7.29(m,4H),6.97(dddd,J=21.2,15.9,7.8,4.3Hz,3H),5.30(s,2H),5.27(d,J=5.1Hz,1H),4.83(dt,J=13.4,6.7Hz,1H),4.22(t,J=5.0Hz,2H),3.74(dd,J=10.1,5.2Hz,2H),1.52(dd,J=12.8,6.8Hz,6H).
化合物10
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.08–6.90(m,3H),5.42(s,1H),5.04–4.95(m,1H),4.39(t,J=4.9Hz,2H),3.92(dd,J=10.0,5.1Hz,2H),3.51(s,3H),2.09(dd,J=12.9,5.6Hz,4H),1.96(dd,J=9.4,5.8Hz,2H),1.76–1.67(m,2H).
化合物11
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.32–7.28(m,4H),7.04–6.86(m,3H),5.30(s,2H),5.27(d,J=5.6Hz,1H),4.97(p,J=7.6Hz,1H),4.22(t,J=4.9Hz,2H),3.74(dd,J=10.1,5.1Hz,2H),2.08(dt,J=12.8,6.5Hz,4H),1.99–1.88(m,2H),1.74–1.63(m,2H).
化合物12
1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.33(s,4H),5.28–5.20(m,1H),4.92–4.83(m,1H),4.79(d,J=6.0Hz,1H),3.45(s,3H),2.06(d,J=7.0Hz,2H),1.93(d,J=16.1Hz,4H),1.67(d,J=4.8Hz,2H),1.63(d,J=6.9Hz,3H).13C NMR(126MHz,CDCl3)δ158.18,151.31,141.98,134.69,133.21,128.78,127.60,99.96,57.70,51.27,31.95,31.65,26.86,24.68,22.28.HRMS(ESI-TOF)m/z[M-H]-called forC19H22ClN5O370.1440,found370.1436.
化合物13
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.35(d,J=8.5Hz,2H),7.30(s,2H),5.32(d,J=6.6Hz,1H),5.19–5.11(m,1H),5.04–4.96(m,1H),4.42(d,J=7.1Hz,2H),2.11–2.02(m,4H),1.97–1.90(m,2H),1.74–1.66(m,2H),1.57(d,J=6.9Hz,3H),1.37(t,J=6.9Hz,3H).13C NMR(126MHz,CDCl3)δ163.78,159.78,156.49,143.81,132.37,131.11,128.45×3,127.46,97.63,62.19,57.54,50.77,31.92,31.76,24.70,24.69,22.95,14.41.HRMS(ESI-TOF)m/z[M-H]-calcd for C20H24ClN5O 384.1597,found 384.1600.
化合物14
1H NMR(400MHz,CDCl3)δ7.73(s,1H),7.33(d,J=8.5Hz,2H),7.29–7.26(m,2H),5.30(d,J=5.5Hz,1H),5.16–5.08(m,1H),5.03–4.93(m,1H),4.13–4.02(m,2H),2.05(dd,J=14.0,7.0Hz,4H),1.92(d,J=3.8Hz,2H),1.67(d,J=5.1Hz,2H),1.54(d,J=6.9Hz,3H),0.98(t,J=6.7Hz,6H).13C NMR(126MHz,CDCl3)δ164.04,159.77,156.48,143.84,132.36,131.08,128.44×3,,127.46,97.62,72.42,57.56,50.79,31.90,31.74,27.80,24.69,24.67,23.00,19.18.HRMS(ESI-TOF)m/z[M-H]-calcd for C22H28ClN5O 412.1910,found412.1915.
化合物15
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.38(s,3H),7.24(s,2H),7.16(d,J=8.3Hz,2H),6.84(d,J=8.3Hz,2H),5.56(d,J=16.3Hz,1H),5.05(d,J=12.2Hz,1H),5.01(d,J=9.0Hz,1H),4.85(dd,J=9.4,5.0Hz,2H),2.05(s,2H),1.98–1.88(m,4H),1.66(d,J=3.7Hz,2H),1.34(d,J=6.9Hz,3H).13C NMR(126MHz,CDCl3)δ158.47,151.38,142.06,135.62,134.95,132.79,129.55,128.45,127.17,126.73,99.85,77.31,77.06,76.80,57.69,51.23,43.75,31.98,31.69,24.71,22.37.HRMS(ESI-TOF)m/z[M-H]-calledforC25H26ClN5O446.1753,found 446.1747.
化合物16
1H NMR(500MHz,CDCl3)δ7.85(d,J=1.6Hz,1H),7.31(s,4H),5.18–5.11(m,1H),4.80(d,J=5.0Hz,1H),3.48(d,J=1.2Hz,3H),1.64(m,3H),1.58(d,J=1.3Hz,9H).13C NMR(101MHz,CDCl3)δ158.31,151.23,150.22,142.16,133.35,133.04,128.82,127.23,101.29,59.44,51.73,28.81,26.82,22.90.HRMS(ESI-TOF)m/z[M-H]-calledforC18H22ClN5O358.1440,found 358.1436.
化合物17
1H NMR(500MHz,CDCl3)δ7.90(s,1H),7.40(s,3H),7.30(s,2H),7.15(d,J=8.4Hz,2H),6.82(d,J=8.4Hz,2H),5.57(d,J=16.2Hz,1H),5.08(d,J=16.1Hz,1H),4.92(s,1H),4.86(s,1H),1.57(s,9H),1.33(d,J=6.8Hz,3H).13C NMR(126MHz,CDCl3)δ158.47,151.52,150.87,148.96,147.81,142.02,134.96,132.90,129.37,128.58,127.27,119.89,108.71,107.25,101.51,99.86,51.29,48.86,43.68,22.30,21.66.HRMS(ESI-TOF)m/z[M-H]-called forC24H26ClN5O434.1753,found 434.1755.
化合物18
1H NMR(400MHz,CDCl3)δ7.90(s,1H),7.43–7.36(m,3H),7.29(dd,J=6.2,1.6Hz,2H),7.20–7.11(m,2H),6.84(d,J=8.5Hz,2H),5.56(d,J=16.2Hz,1H),5.09(d,J=16.2Hz,1H),5.01–4.85(m,2H),1.58(s,9H),1.34(d,J=6.5Hz,3H).13C NMR(126MHz,CDCl3)δ158.64,151.44,150.20,142.32,135.61,133.56,132.61,129.52,128.54,128.38,126.84,101.17,59.54,51.64,43.68,28.87,22.89.HRMS(ESI-TOF)m/z[M-H]-calledforC24H26ClN5O434.1753,found 434.1748.
化合物19
1H NMR(400MHz,CDCl3)δ7.89(d,J=12.0Hz,1H),7.39(dt,J=9.9,2.7Hz,3H),7.29(dd,J=5.7,2.1Hz,2H),6.98–6.70(m,4H),5.55(d,J=16.2Hz,1H),5.10(d,J=16.2Hz,1H),4.95(d,J=6.3Hz,2H),1.59(s,9H),1.36(d,J=6.5Hz,3H).13C NMR(126MHz,CDCl3)δ162.71,160.76,158.68,151.51,150.24,139.43,135.62,133.57,129.49,128.35,127.07,126.82,115.31,115.14,101.16,59.54,51.56,43.72,28.88,22.95.HRMS(ESI-TOF)m/z[M-H]-called for C24H26FN5O 418.2049,found 418.2045.
化合物20
H NMR(400MHz,CDCl3)δ7.89(s,1H),7.20(d,J=8.4Hz,2H),6.96(d,J=8.4Hz,2H),6.78(dd,J=21.3,11.3Hz,3H),5.99(d,J=1.8Hz,2H),5.35(s,1H),5.04(d,J=16.0Hz,1H),4.94(s,2H),1.57(s,9H),1.39(d,J=6.4Hz,3H).13C NMR(126MHz,CDCl3)δ158.59,151.35,150.33,148.98,147.84,142.20,133.62,132.78,129.39,128.62,126.93,120.00,108.71,107.36,101.52,101.24,59.54,51.65,43.70,28.87,22.86.HRMS(ESI-TOF)m/z[M-H]-called for C24H26FN5O 418.2049,found 418.2042.
化合物21
1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.20(d,J=8.4Hz,2H),6.96(d,J=8.4Hz,2H),6.78(dd,J=21.3,11.3Hz,3H),5.99(d,J=1.8Hz,2H),5.37(d,J=16.0Hz,1H),5.04(d,J=16.0Hz,1H),4.95(d,J=10.6Hz,2H),1.57(s,9H),1.39(d,J=6.4Hz,3H).13C NMR(126MHz,CDCl3)δ158.59,151.35,150.33,148.98,147.84,142.20,133.62,132.78,129.39,128.82×2,126.93×2,120.00,108.71,107.36),101.52,101.24,59.54,51.65,43.70,28.87×3,22.86.HRMS(ESI-TOF)m/z[M+H]+calcd for C25H26ClN5O3 480.1797,found 480.1763.
化合物22
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.23(dd,J=11.8,6.8Hz,4H),7.07(t,J=8.6Hz,2H),6.99(d,J=8.4Hz,2H),5.27(s,2H),4.87(s,1H),4.50(d,J=5.3Hz,2H),1.68(s,9H).
化合物23
1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.27(d,J=8.7Hz,2H),7.19(d,J=8.4Hz,2H),7.09(d,J=8.5Hz,2H),6.93(d,J=8.4Hz,2H),5.44(d,J=16.2Hz,1H),5.13(d,J=16.2Hz,1H),4.99–4.93(m,1H),4.88(d,J=5.9Hz,1H),1.58(s,9H),1.38(d,J=6.8Hz,3H).13C NMR(126MHz,CDCl3)δ162.63(d,JC-F=248.0Hz),158.54,151.32,150.05,142.05,133.64,132.88,131.32,128.67×2,128.60,128.53,126.85×2,116.60,116.43,101.20,59.61,51.66,43.17,28.87×3,22.84.HRMS(ESI-TOF)m/z[M-H]-calcd for C24H25ClFN5O452.1659,found 452.1657.
化合物24
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.40(d,J=5.9Hz,2H),7.21(d,J=8.4Hz,2H),7.09(d,J=5.2Hz,2H),7.01(d,J=9.2Hz,1H),6.93(d,J=8.4Hz,2H),5.50(d,J=16.5Hz,1H),5.18(s,1H),5.00–4.94(m,1H),4.75(d,J=5.8Hz,1H),1.60(s,9H),1.39(d,J=6.9Hz,3H).13C NMR(126MHz,CDCl3)δ164.47,162.49,158.44,151.33,149.96,142.02,138.20,133.66,132.87,131.19,128.67,126.85,122.29,115.58,115.41,113.99,113.82,101.13,59.63,51.69,43.32,28.89,22.8.HRMS(ESI-TOF)m/z[M-H]-called forC24H25ClFN5O 452.1659,found 452.1655.
化合物25
1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.25(s,2H),7.17–7.13(m,3H),7.02(m,J=8.6Hz,2H),6.85(d,J=7.5Hz,1H),5.43(dd,J=14.1,6.7Hz,2H),4.98(d,J=16.3Hz,1H),4.73(d,J=6.4Hz,1H),2.89(m,2H),2.64(m,J=12.9,5.4Hz,1H),1.80–1.78(m,1H),1.74(s,9H).
化合物26
1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.25(d,J=5.9Hz,2H),7.22–7.10(m,3H),7.01(t,J=8.5Hz,2H),6.85(d,J=7.5Hz,1H),5.51–5.30(m,2H),4.98(d,J=16.3Hz,1H),4.74(d,J=6.4Hz,1H),2.89(s,2H),2.64(m,J=7.3Hz,1H),1.82–1.76(m,1H),1.74(s,9H).
化合物27
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.41(d,J=7.3Hz,1H),7.36–7.32(m,2H),7.29(s,1H),5.66(d,J=7.2Hz,1H),4.86(d,J=7.0Hz,1H),3.43(s,3H),3.14–3.06(m,1H),3.02(s,1H),2.83–2.74(m,1H),2.05–1.98(m,1H),1.76(s,9H).
化合物28
1H NMR(400MHz,CDCl3)δ7.90(s,1H),7.39(d,J=7.2Hz,1H),7.34–7.30(m,2H),7.28(s,1H),5.64(d,J=7.2Hz,1H),4.81(d,J=7.0Hz,1H),3.41(s,3H),3.08(ddd,J=16.0,8.9,4.3Hz,1H),3.00(s,1H),2.77(tdd,J=11.5,7.4,3.8Hz,1H),2.07–1.96(m,1H),1.74(s,9H).
化合物29
1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.31–7.27(m,2H),7.21(dt,J=6.6,5.7Hz,3H),7.09(t,J=8.6Hz,2H),6.98–6.93(m,2H),5.29(d,J=41.3Hz,2H),4.82(s,1H),4.76(d,J=6.7Hz,1H),1.70(dd,J=13.0,7.1Hz,2H),1.58(s,9H),0.74(t,J=7.4Hz,3H).
化合物30
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.31–7.25(m,3H),7.17(t,J=7.9Hz,1H),7.09(t,J=8.5Hz,2H),6.75(dd,J=8.1,2.2Hz,1H),6.58(dd,J=10.5,4.8Hz,2H),5.46(d,J=16.2Hz,1H),5.12(d,J=16.2Hz,1H),4.97(d,J=6.6Hz,1H),4.80(d,J=6.0Hz,1H),3.76(s,3H),1.63(s,9H),1.42(d,J=6.8Hz,3H).
化合物31
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.25(dd,J=8.5,5.3Hz,2H),7.08(t,J=8.6Hz,2H),6.94(d,J=8.6Hz,2H),6.78(d,J=8.7Hz,2H),5.44(d,J=16.3Hz,1H),5.09(d,J=16.2Hz,1H),5.02–4.94(m,1H),4.73(d,J=6.2Hz,1H),3.79(s,3H),1.66(s,9H),1.41(d,J=6.8Hz,3H).
化合物32
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.39(d,J=5.9Hz,1H),7.09(d,J=8.0Hz,2H),7.00(d,J=11.2Hz,2H),6.98–6.90(m,3H),5.49(d,J=16.4Hz,1H),5.15(d,J=16.4Hz,1H),4.99(s,1H),4.73(d,J=5.8Hz,1H),1.62(s,9H),1.40(d,J=6.9Hz,3H).
化合物33
1H NMR(400MHz,CDCl3)δ7.90(s,1H),7.26(dd,J=8.6,5.2Hz,2H),7.08(t,J=8.5Hz,2H),6.97–6.86(m,4H),5.43(d,J=16.2Hz,1H),5.11(d,J=16.1Hz,1H),4.95(d,J=6.5Hz,1H),4.75(d,J=5.8Hz,1H),1.59(s,9H),1.38(d,J=6.9Hz,3H).
化合物34
1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.14(dd,J=14.1,6.2Hz,2H),7.10(t,J=6.5Hz,2H),7.03(d,J=7.4Hz,1H),6.98(t,J=8.6Hz,2H),6.80(d,J=7.7Hz,1H),5.36(d,J=16.3Hz,1H),5.13(d,J=5.7Hz,1H),5.01(d,J=16.5Hz,1H),4.68(d,J=6.4Hz,1H),2.74(d,J=6.2Hz,2H),2.00(ddd,J=8.6,7.8,5.9Hz,2H),1.89(ddd,J=13.4,9.3,4.1Hz,1H),1.74(s,9H),1.30(s,2H).
化合物35
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.25–7.14(m,4H),7.12(m,J=4.5Hz,1H),6.96(dd,J=11.4,5.8Hz,3H),5.43(d,J=15.0Hz,1H),5.14(d,J=15.0Hz,1H),4.74(m,J=6.7Hz,1H),3.52(m,J=14.3Hz,1H),3.41(m,J=14.3Hz,1H),3.00(dt,J=15.6,4.7Hz,1H),2.86(dd,1H),1.69(s,9H),1.34(d,J=90.0,20.8,12.5Hz,3H).
化合物36
1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.22–7.19(m,4H),7.07(dd,J=11.8,5.2Hz,2H),6.94(d,J=8.4Hz,2H),5.45(d,J=16.2Hz,1H),5.06(dd,J=14.0,6.8Hz,2H),4.78(d,J=6.3Hz,1H),3.49(dq,J=11.2,3.8Hz,1H),1.38(d,J=6.9Hz,3H),1.18–1.08(m,2H),1.02–0.94(m,2H).
化合物37
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.26–7.20(m,4H),7.14–7.08(m,2H),6.94(dd,J=8.0,5.4Hz,2H),5.94(td,J=56.1,5.4Hz,1H),5.43(d,J=16.3Hz,1H),5.11(d,J=16.3Hz,1H),5.03(dd,J=13.5,6.8Hz,1H),4.86(d,J=6.3Hz,1H),4.84–4.76(m,1H),1.61(d,J=5.3Hz,3H),1.41(d,J=6.9Hz,3H).
化合物38
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.27–7.19(m,4H),7.10(t,J=8.5Hz,2H),6.95(d,J=8.4Hz,2H),5.39(d,J=16.4Hz,1H),5.15(d,J=16.0Hz,1H),5.07(dq,J=20.4,7.0Hz,2H),4.88(d,J=6.3Hz,1H),1.77(d,J=7.2Hz,3H),1.40(d,J=6.9Hz,3H).
化合物39
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.24–7.17(m,4H),7.12–7.05(m,2H),6.94–6.88(m,2H),5.43(d,J=16.3Hz,1H),5.08(d,J=16.4Hz,1H),5.05–4.97(m,1H),4.89(d,J=6.3Hz,1H),4.72–4.58(m,2H),1.38(d,J=6.9Hz,3H).
实施例2活性测试和结果
以上述实施例中制备的化合物为对象,测定其对磷酸二酯酶1型的抑制活性,测试浓度为100nM和10nM,测试化合物在这两种浓度条件下对PDE1B的抑制率,即指在化合物的100纳米摩尔或10纳米摩尔浓度下获得的PDE1B酶的抑制率。测得结果如表1所示。
表1化合物对磷酸二酯酶1型的抑制作用
“nd”表示“未测”
从表1中可知,大部分的化合物对于磷酸二酯酶1型均表现出一定的抑制作用,其中化合物1、2、3、9、16、17、18、19、21、22、23、24、30、31对磷酸二酯酶1型的抑制作用尤其明显,在100nM时的抑制率都大于80%;特别是1、2、17、23、31在10nM时的抑制率都大于50%,表现出对磷酸二酯酶1型的显著抑制作用。
1.动物实验及结果
鉴于动物实验过程中动物处理的过程,未对所有的化合物进行测试,仅选用化合物23为代表,进行试验,测定其在博来霉素(BLM)诱导的特发性肺纤维化大鼠(IPF)模型实验中的效果。
测试过程为:
IPF模型SD大鼠,体重180-220g,随机将大鼠随机分为4组:对照组、模型组、化合物23(10.0mg/kg)组和吡非尼酮阳性对照组(PFD,150mg/kg)。根据机构准则提供无菌食品和水。每次实验前,大鼠禁食一晚,并允许自由饮水。除对照组用生理盐水外,其余均用博来霉素单次气管内滴注5毫克/公斤,第二天开始治疗。大鼠口服药物载体(对照组和模型组)、化合物23(10.0mg/kg)或PFD(150mg/kg)4周。化合物23和PFD溶于0.5%羧甲基纤维素钠(CMC-Na)中,每100g体重口服0.4ml。观察并记录28天内体重、发色及呼吸状态的变化。给药28天后,测定各组大鼠的呼吸水平。腹腔注射4%戊巴比妥钠麻醉大鼠,取腹主动脉血5mL。大鼠安乐死后取左下肺缘,室温下4%多聚甲醛浸泡过夜,石蜡包埋切片,做H&E染色和Masson染色。各组肺组织提取蛋白做Western blot。
测试结果如图1所示。
图1中柱状图显示不同组大鼠的肺呼吸功能,在开始评估大鼠呼吸困难症状时,测试了吸气末暂停(EIP)、呼气末暂停(EEP)、呼气中流量(EF50)、吸气峰流量(PIF)、呼气峰流量(PEF)和增强暂停(PEH)。从图中可以看出,模型组大鼠上述参数均较对照组升高,说明模型成功。其中PFD(吡非尼酮,150mg/kg)和1921(10mg/kg)治疗28天后,上述指标均降至正常水平,说明PFD和化合物23均能调节博莱霉素诱导的呼吸功能障碍。
图2为大鼠肺组织H&E染色和Masson染色结果。
图2中,(A)分别为对照组(Con)、BLM治疗组(Mod)、BLM+PFD治疗组(PFD)、BLM+23治疗组(23)苏木精-伊红(H&E)染色切片,未染色为肺泡癌,蓝色为细胞核,红色为细胞质.
图2中,(B)分别为对照组(Con)、BLM治疗组(Mod)、BLM+PFD治疗组(PFD)、BLM+23治疗组(23)的Masson染色切片。未染色为肺泡癌,深蓝色为胶原,红色为细胞结构。
从图2中可以看出与对照组比较,模型组肺泡排列紊乱,肺泡壁破裂融合。模型组肺泡内可见炎性细胞浸润。给药化合物23(10mg/kg)可减轻肺结构损伤,减少纤维化病变,PFD(150mg/kg)也可减轻。胶原沉积是IPF的一个病理特征,其表达可通过Masson染色中的蓝色染色来表征。与对照组相比,模型组大面积胶原沉积于气管周围,细胞增生。化合物23和PFD几乎都能完全抑制胶原沉积到正常水平。
图3为用Western blot法和免疫荧光染色法检测肺组织α-平滑肌肌动蛋白(a-SMA)水平结果。
图3中,(A)为各组大鼠肺组织的Western blot图。
图3中,(B)为各组大鼠肺组织的免疫荧光染色图,α-SMA(绿色)和DAPI(蓝色)的代表性染色图像显示了免疫荧光显微镜下细胞核的位置(比例尺=10μm)
从图3中可知,与α-SMA上调的模型组相比,化合物23显著降低α-SMA水平。
以上结果表明,PDE1抑制剂化合物23对BLM诱导的肺纤维化有一定的改善作用。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,对于本领域的普通技术人员来说,在上述说明及思路的基础上还可以做出其它不同形式的变化或变动,这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明权利要求的保护范围之内。
Claims (10)
2.根据权利要求1所述取代吡唑[3,4-d]嘧啶类化合物,其特征在于,所述R1为C1~8直链烷基、C1~8支链烷基、C1~8环烷基、C1~8卤代直链烷基、C1~8卤代支链烷基、C1~8卤代环烷基或C3~6含氧环烷基;
R2和R3各自独立地为:氢、甲基、乙基、丙基、苯基、氟代苯基、二氟代苯基、氯代苯基、二氯代苯基、C1~4烷基取代苯基、C1~4烷氧基取代苯基、苄基、氟代苄基、二氟代苄基、氯代苄基、二氯代苄基、甲氧基苯基或卤代甲氧基苯基。
3.根据权利要求2所述取代吡唑[3,4-d]嘧啶类化合物,其特征在于,所述R1为C3~4直链烷基、C3~4支链烷基、C3~6环烷基、C3~4卤代直链烷基、C3~4卤代支链烷基、C3~6卤代环烷基或C3~6含氧环烷基。
4.根据权利要求1所述取代吡唑[3,4-d]嘧啶类化合物,其特征在于,R4为甲基、乙基、异丙基、氟代苯基、二氟代苯基、氯代苯基、二氯代苯基、苄基、氟代苄基、二氟代苄基、氯代苄基、二氯代苄基、甲基吡啶基、甲基噻吩、甲基吗啉或甲基苯并二噁英。
6.权利要求1至5任一所述取代吡唑[3,4-d]嘧啶类化合物的制备方法,其特征在于,包括如下步骤:
S1.嘧啶-2,4,6(1H,3H,5H)-三酮与三氯氧磷混溶,加热回流反应,得到式(1)所述化合物;
S2.式(1)所述化合物和R1NHN2·HCl在低温条件下,加入三乙胺保温2h,然后升温至室温反应,得到(2)所述化合物;
S3.式(2)所述化合物在碱性水溶液中,加热回流反应,得到式(3)所述化合物;
S4.式(3)所述化合物和R4Cl在碱性无机盐存在条件下反应,得到式(4)所述化合物;
S5.式(4)所述化合物和R2R3CHNH2或R5CHNH2加热回流反应,得到式(I)或式(Ⅱ)所述化合物;
其中式(1)、式(2)、式(3)和式(4)的结构如下所示:
7.权利要求1至5任一所述取代吡唑[3,4-d]嘧啶类化合物作为磷酸二酯酶抑制剂的应用。
8.权利要求1至5任一所述取代吡唑[3,4-d]嘧啶类化合物制备治疗磷酸二酯酶相关疾病的药物中的应用。
9.根据权利要求7或8所述应用,其特征在于,所述磷酸二酯酶为PDE1。
10.根据权利要求8所述应用,其特征在于,所述磷酸二酯酶相关疾病为肺动脉高压症和/或特发性肺纤维化症。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1213373A (zh) * | 1996-03-11 | 1999-04-07 | 诺瓦提斯公司 | 农药用嘧啶-4-酮衍生物 |
WO2017223086A1 (en) * | 2016-06-20 | 2017-12-28 | The Regents Of The University Of Michigan | Small molecule inhibitors of aldh and uses thereof |
US20190177327A1 (en) * | 2017-10-13 | 2019-06-13 | Dart Neuroscience, Llc | Substituted methyl pyrazolopyrimidinone and methyl imidazopyrazinone compounds as pde1 inhibitors |
CN111100128A (zh) * | 2018-10-26 | 2020-05-05 | 广安凯特制药有限公司 | 一种瑞博西尼中间产品的合成方法及其中间体化合物 |
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WO2017223086A1 (en) * | 2016-06-20 | 2017-12-28 | The Regents Of The University Of Michigan | Small molecule inhibitors of aldh and uses thereof |
US20190177327A1 (en) * | 2017-10-13 | 2019-06-13 | Dart Neuroscience, Llc | Substituted methyl pyrazolopyrimidinone and methyl imidazopyrazinone compounds as pde1 inhibitors |
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