CN104557938A - N-substituted pyrazolo[3,4-d]pyrimidinone compound and application thereof - Google Patents

N-substituted pyrazolo[3,4-d]pyrimidinone compound and application thereof Download PDF

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CN104557938A
CN104557938A CN201310517594.9A CN201310517594A CN104557938A CN 104557938 A CN104557938 A CN 104557938A CN 201310517594 A CN201310517594 A CN 201310517594A CN 104557938 A CN104557938 A CN 104557938A
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pyrimidinones
compound
triethylamine
substituted pyrazolecarboxylic
preparation
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CN104557938B (en
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罗海彬
万一千
黄漫娜
刘培庆
邵咏贤
朱新海
蔡颖红
刘雨果
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Sun Yat Sen University
National Sun Yat Sen University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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

Abstract

The invention discloses an N-substituted pyrazolo[3,4-d]pyrimidinone compound shown in formula (I) and an application of the N-substituted pyrazolo[3,4-d]pyrimidinone compound as an inhibitor of phosphodiesterase IX (PDEIX). Formula (I) is shown in the specification, wherein R' is isopropyl, cyclopentyl, isobutyl or o-chlorphenyl; when R' is equal to H, R is D/L-configuration CHCH3CONHR''', D/L-configuration CH2CONHR''' or D/L-configuration CH2CH2CONHR'''; and R''' is p-methoxyphenyl.

Description

Also [3,4-d] pyrimidinones and the application thereof of one class N-substituted pyrazolecarboxylic
Technical field
The present invention relates to the inhibitor of a class phosphodiesterase IX (PDEIX), be specifically related to also [3,4-d] pyrimidinones and the application thereof of the novel N-substituted pyrazolecarboxylic of a class.
Background technology:
Phosphodiesterase (PDEs) is a proteinoid enzyme, and second messenger's cyclic monophosphate (cAMP) important in body of optionally degrading and cyclic guanosine monophosphate (cGMP) play important physiological action to corresponding AMP.The phosphodiesterase reported so far has 11 families, and wherein phosphodiesterase IX (PDEIX) can be hydrolyzed cGMP with high specificity, and extensively distributes (JBioChem, 1998,273 (25): 15559-15564) in human body.PDEIX inhibitor can suppress PDEIX to the enzymolysis of cGMP, and the level of cGMP is improved, thus amplifies the effect of NO and Regular Insulin, produces expansion artery blood vessel, accelerates metabolism and study of anti-atherogenic effect (WO03037432).Research shows in addition, and important effect is played in the raising of cGMP to the cognitive ability of people.These features make phosphodiesterase IX can become the target spot of new generation for the treatment of diabetes, obesity, cardiovascular disorder and attention of improving, cognitive ability, learning and memory power.
2005, FrankWunder(MolPharmacol, 2005,68:1775-1781) report first PDEIX selective depressant BAY73-6691.This discovery facilitates the research that people are devoted to PDEIX selective depressant.The phosphodiesterase IX inhibitor of discovered in recent years can suppress phosphodiesterase IX preferably in human body and mouse body, and can obtain good pharmacologically active.It is PDEIX inhibitor of parent and preparation method thereof that international monopoly WO2003037899, WO2004096811, WO2012020022 disclose pyrazolopyrimidine ketone; It is PDEIX inhibitor of parent and preparation method thereof that WO2004113306 discloses cyanopyrimidine ketone; It is PDEIX inhibitor of parent and preparation method thereof that WO2004096811, WO2012040230 disclose imidazo three azepine ketone; It is PDEIX inhibitor of parent and preparation method thereof that WO2012004900 discloses pyrantel ketone; It is PDEIX inhibitor of parent and preparation method thereof that WO2012033101, WO2012033144 disclose imidazole quinoline ketone; WO2004096811 also discloses with other ketone compounds PDEIX inhibitor that is parent and preparation method thereof, comprises imidazoles pyrimidone, oxazole pyrimidone, thiazole pyrimidone.2011, the pyrazolopyrimidine ketone that our seminar also discloses 6 N-replacements was PDEIX inhibitor with better inhibit activities of parent and preparation method thereof (CN102260266A).
Summary of the invention:
The object of this invention is to provide Novel phosphoric acid diesterase Ⅸ inhibitor of a class high reactivity, highly selective, and provide pyrazolo [3,4-d] pyrimidinones that this N-replaces, its preparation method and application thereof.
The present invention is achieved by the following technical programs:
The invention provides N-substituted pyrazolecarboxylic also [3,4-d] pyrimidinones of structure as shown in formula I:
Wherein, R ' is selected from sec.-propyl or cyclopentyl, cyclohexyl, isobutyl-, Chloro-O-Phenyl;
During R ' '=H, R is selected from the CHCH of D or L configuration 3cONHR " ', the CH of D or L configuration 2cONHR " ', the CH of D or L configuration 2cH 2cONHR " '; Wherein R " ' be p-methoxyphenyl.Preferably, N-substituted pyrazolecarboxylic of the present invention also [3,4-d] pyrimidinones be selected from formula II, (III), (IV), (V), the compound shown in (VI):
The preparation method of compound N-substituted pyrazolecarboxylic of the present invention also [3,4-d] pyrimidinones, comprises the following steps:
(1) with 2,4,6-trichloropyrimidine formaldehyde and band substituent hydrazine for raw material, make alkali with triethylamine, with ethanol as solvent, be obtained by reacting compound (A) at-78 DEG C; The mol ratio of described 2,4,6-trichloropyrimidine formaldehyde, hydrazine and triethylamine is 1:1 ~ 1.1:2 ~ 3; The concentration of 2,4,6-trichloropyrimidine formaldehyde is 0.05-1.0mol/L.
(2) be hydrolyzed in the basic conditions by compd A, described alkaline condition comprises sodium hydroxide or potassium hydroxide, and the mol ratio of described A and alkali is 1:10 ~ 40, and the concentration of A is 0.05-0.5mol/L, obtains compound (B).
(3) reacted with aminated compounds under the condition being alkali with triethylamine by compd B, obtain target compound I, the mol ratio of described B, triethylamine and aminated compounds is the concentration of 1:1.3:1.2-3, B is 0.05-0.5mol/L.
Pyrazolo [3, the 4-d] pyrimidinones that N-of the present invention replaces has good restraining effect to phosphodiesterase IX, can be used as the selective depressant of phosphodiesterase.
N-substituted pyrazolecarboxylic of the present invention also [3,4-d] pyrimidinones can be used for treatment diabetes, obesity, cardiovascular disorder and attention of improving, cognitive ability, learning and memory power.
Preparation method provided by the present invention has fast, facilitate, low cost and other advantages.
Embodiment:
Below further illustrate of the present invention, instead of limitation of the present invention.
One, instrument and medicine
The AVANCE400 Instrument measuring that nuclear magnetic spectrum of the present invention (NMR) is produced by German Bruker company, solvent peak does interior mark; The LCMS-2010A(ESI source that mass spectrum of the present invention is produced by Japanese Shimadzu Corporation) measure; Chemical reagent purchased from Guangzhou Ai Erlu chemical company, J & K company, Alfar-Aser company, Aladdin chemical reagents corporation etc.; Column chromatography silica gel is purchased from Haiyang Chemical Plant, Qingdao.
Embodiment 1: structural formula is such as formula the synthesis of the compound M-1 shown in (M-1)
By 2,4,6-trichloropyrimidine formaldehyde (424mg, 2mmol), sec.-propyl hydrazine hydrochloride (221mg, 2mmol), triethylamine (505mg, 5mmol), under-78 DEG C of conditions, reacts 2 hours in ethanol (40mL), be raised to room temperature, react 8 hours, be spin-dried for solvent, be extracted with ethyl acetate, anhydrous sodium sulfate drying, decompression evaporates solvent, use rapid column chromatography separating-purifying, obtain white solid 323mg, yield 70%.MS(ESI +):m/z:231([M+H] +); 1HNMR(400MHz,CDCl 3)δ8.13(s,1H),5.16(hept,J=6.8Hz,1H),1.57(d,J=6.7Hz,6H)。
Embodiment 2: structural formula is such as formula the synthesis of the compound M-2 shown in (M-2)
Under 60 DEG C of conditions, by embodiment 1 compound M-1(231mg, 1mmol) join in the 20mL1mol/LNaOH aqueous solution, stir 1 hour.React complete, adjust PH=5-6 with Glacial acetic acid, separate out white solid, suction filtration, washing, dry, obtain white solid 162mg, yield 76%.MS(ESI -):m/z:211([M-H] -); 1HNMR(400MHz,CDCl 3)δ8.12(s,1H),5.01(hept,J=6.7Hz,1H),1.54(d,J=6.7Hz,6H)。
Embodiment 3: structural formula is such as formula the synthesis of the compound M-3 shown in (M-3)
Synthetic method as embodiment 1 compound M-1,2,4,6-trichloropyrimidine formaldehyde (424mg, 2mmol), cyclopentyl hydrazine hydrochloride (300mg, 2.2mmol), triethylamine (404mg, 4mmol), ethanol (2mL) separating-purifying obtains white solid 374mg, yield 73%.MS(ESI +):m/z:231([M+H] +); 1HNMR(400MHz,CDCl 3)δ8.14(s,1H),5.36–5.26(m,1H),2.25–2.07(m,4H),2.05–1.94(m,2H),1.82–1.71(m,2H)。
Embodiment 4: structural formula is such as formula the synthesis of the compound M-4 shown in (M-4)
Synthetic method as embodiment 2 compound M-2, compound M-3(257mg, 1mmol), the 2mL5mol/LNaOH aqueous solution, obtains white solid 410mg, yield 86%.MS(ESI -):m/z:237([M-H] -); 1HNMR(400MHz,CDCl 3)δ8.10(s,1H),5.15(p,J=7.5Hz,1H),2.20–2.04(m,4H),2.02–1.91(m,2H),1.72(ddd,J=11.2,7.8,3.2Hz,2H)。
Embodiment 5: the synthesis of compound M-7
Synthetic method as embodiment 1 compound M-1,2,4,6-trichloropyrimidine formaldehyde (424mg, 2mmol), isobutyl-hydrazine hydrochloride (249mg, 2mmol), triethylamine (505mg, 5mmol), ethanol (25mL) separating-purifying obtains brown solid 378mg, yield 77%.MS(ESI +):m/z:231([M+H] +); 1HNMR(400MHz,CDCl 3)δ8.14(s,1H),4.26(d,J=7.3Hz,2H),2.38(dp,J=13.8,6.9Hz,1H),0.93(d,J=6.7Hz,6H)。
Embodiment 6: the synthesis of compound M-8
Synthetic method as embodiment 2 compound M-2, compound M-7(245mg, 1mmol), the 10mL4mol/LNaOH aqueous solution obtains white solid 350mg, yield 77%.MS(ESI -):m/z:225([M-H] -); 1HNMR(400MHz,CDCl 3)δ12.45(brs,1H),8.11(s,1H),4.13(d,J=7.4Hz,2H),2.33(dp,J=13.8,6.9Hz,1H),0.92(d,J=6.7Hz,6H)。
Embodiment 7: the synthesis of compound M-11-D
By D-alanine (890mg, 10mmol), tert-Butyl dicarbonate (2616mg, 12mmol), triethylamine (1515mg, 15mmol) at ambient temperature, at the mixing solutions reaction response 8 hours of water and Isosorbide-5-Nitrae-dioxane, be spin-dried for solvent, be extracted with ethyl acetate, anhydrous sodium sulfate drying, decompression evaporates solvent, obtains lurid thick crude product, be not further purified, directly cast single step reaction.Add the DMF solution of P-nethoxyaniline (1230mg, 10mmol), 1-Methylimidazole (820mg, 10mmol), then under 0 DEG C of condition, in three-necked bottle, instill diethyl chloro-phosphate (1725mg, 10mmol).After dripping, be naturally warmed up to room temperature.Stopped reaction after monitoring reacts completely.Add saturated NaHCO 3the aqueous solution, until do not have bubble to produce, has solid to separate out.Filter, a small amount of water washing of solid, dry, obtain pale solid, it is dissolved in 30mL methyl alcohol, under condition of ice bath, pass into HCl gas, stopped reaction after monitoring reacts completely.Crude product column chromatography (DCM:MeOH=15:1) separating-purifying obtains colorless oil (400mg, 21%).MS(ESI +):m/z:195([M+H] +); 1HNMR(300MHz,DMSO)δ7.54(d,J=8.9Hz,2H),6.85(d,J=8.9Hz,2H),3.70(s,3H),3.42(dd,J=13.7,6.8Hz,1H),2.83(s,2H),1.22(d,J=6.9Hz,3H)。
Embodiment 8: the synthesis of compound WYQ-87-D.
Synthetic method: by embodiment 2 compound M-2(64mg, 0.3mmol), embodiment 11 compound M-11-D(116mg, 0.6mmol), triethylamine (40mg, 0.4mmol), Virahol (2mL) joins reaction tubes, tube sealing, under 100 DEG C of conditions, reacts 2 hours.React complete, be spin-dried for solvent, column chromatography for separation is purified (CH2Cl2:MeOH=20:1), obtains white solid (55mg, 50%).MS(ESI -):m/z:369([M-H] -); 1HNMR(400MHz,CDCl 3)δ7.87(s,1H),7.41(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),4.85–4.78(m,2H),4.70–4.62(m,1H),3.77(s,3H),1.58(d,J=7.0Hz,3H),1.45(dd,J=14.9,6.7Hz,6H).
Embodiment 9: the synthesis of compound WYQ-87-L.
Synthetic method is as WYQ-87-D, and separation and purification obtains white solid (50mg, 45%).MS(ESI -):m/z:369([M-H] -); 1HNMR(400MHz,DMSO)δ10.44(brs,1H),10.08(s,1H),7.75(s,1H),7.54–7.48(m,2H),6.92(d,J=6.9Hz,1H),6.91–6.86(m,2H),4.77–4.69(m,1H),4.59(p,J=6.8Hz,1H),3.72(s,3H),1.44(d,J=6.9Hz,3H),1.38(d,J=6.7Hz,3H),1.31(d,J=6.7Hz,3H).
Embodiment 10: the synthesis of compound WYQ-88.
Synthetic method: as WYQ-87-D, separation and purification obtains white solid (39mg, 37%).MS(ESI -):m/z:355([M-H] -); 1HNMR(400MHz,DMSO)δ10.72(s,1H),10.02(s,1H),7.75(s,1H),7.49(d,J=9.0Hz,2H),6.88m,3H),4.78–4.67(m,1H),4.14(d,J=5.1Hz,2H),3.72(s,3H),1.36(d,J=6.7Hz,6H).
Embodiment 11: the synthesis of compound WYQ-89.
Synthetic method: as WYQ-87-D, separation and purification obtains white solid (50mg, 45%).MS(ESI -):m/z:369([M-H] -); 1HNMR(400MHz,DMSO)δ10.25(s,1H),9.56(s,1H),7.66(s,1H),7.46(d,J=8.8Hz,2H),6.75(d,J=8.7Hz,2H),6.58(s,1H),4.80(dt,J=13.1,6.6Hz,1H),3.70(d,J=1.0Hz,3H),3.58(s,2H),2.59(t,J=5.3Hz,2H),1.41(dd,J=6.6,1.1Hz,6H).
Embodiment 12: the synthesis of compound WYQ-90-D.
Synthetic method: by embodiment 4 compound M-4(71mg, 0.3mmol), embodiment 11 compound M-11-D(116mg, 0.6mmol), triethylamine (40mg, 0.4mmol), Virahol (2mL) joins reaction tubes, tube sealing, under 100 DEG C of conditions, reacts 2 hours.React complete, be spin-dried for solvent, column chromatography for separation purification (CH 2cl 2: MeOH=20:1), separation and purification obtains white solid (45mg, 38%).MS(ESI -):m/z:395([M-H] -); 1HNMR(400MHz,CDCl 3)δ7.74(s,1H),7.47(d,J=9.0Hz,2H),6.86(d,J=9.1Hz,2H),4.86–4.77(m,1H),4.46(q,J=6.9Hz,1H),3.68(s,3H),1.92(dd,J=8.4,5.0Hz,2H),1.75(t,J=7.2Hz,4H),1.62–1.45(m,2H),1.40(d,J=7.0Hz,3H).
Embodiment 13: the synthesis of compound WYQ-90-L.
Synthetic method is as WYQ-90-D, and separation and purification obtains white solid (49mg, 42%).MS(ESI -):m/z:395([M-H] -); 1HNMR(400MHz,DMSO)δ10.44(s,1H),10.08(s,1H),7.75(s,1H),7.55–7.49(m,2H),6.93–6.86(m,3H),4.88(p,J=7.3Hz,1H),4.56(p,J=6.8Hz,1H),3.72(s,3H),2.02–1.92(m,2H),1.88–1.77(m,4H),1.63–1.51(m,2H),1.44(d,J=6.9Hz,3H).
Embodiment 14: the synthesis of compound WYQ-91.
Synthetic method is as WYQ-90-D, and separation and purification obtains white solid (39mg, 34%).
MS(ESI -):m/z:381([M-H] -); 1HNMR(400MHz,DMSO)δ10.02(s,1H),7.76(s,1H),7.50(d,J=9.0Hz,2H),6.92–6.84(m,3H),4.89(p,J=7.4Hz,1H),4.13(d,J=5.1Hz,2H),3.72(s,3H),1.99–1.87(m,4H),1.87–1.75(m,2H),1.65-1.52(m,2H).
Embodiment 15: the synthesis of compound WYQ-92.
Synthetic method is as WYQ-90-D, and separation and purification obtains white solid (43mg, 37%).
MS(ESI -):m/z:395([M-H] -); 1HNMR(400MHz,CDCl 3)δ10.16(s,1H),8.98(s,1H),7.67(s,1H),7.32(d,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),6.49(s,1H),4.86(p,J=7.5Hz,1H),3.67–3.61(m,2H),3.61(s,3H),2.54(t,J=5.8Hz,2H),1.97–1.84(m,4H),1.83–1.73(m,2H),1.58–1.47(m,2H).
Embodiment 16: the synthesis of compound WYQ-93-D.
Synthetic method: by embodiment 8 compound M-8(68mg, 0.3mmol), embodiment 11 compound M-11-D(116mg, 0.6mmol), triethylamine (40mg, 0.4mmol), Virahol (2mL) joins reaction tubes, tube sealing, under 100 DEG C of conditions, reacts 2 hours.React complete, be spin-dried for solvent, column chromatography for separation purification (CH 2cl 2: MeOH=20:1), separation and purification obtains white solid (43mg, 37%).
MS(ESI -):m/z:383([M-H] -); 1HNMR(400MHz,CDCl 3)δ7.75(s,1H),7.51–7.44(m,2H),6.88–6.82(m,2H),4.47(q,J=6.9Hz,1H),3.92–3.74(m,2H),3.68(s,3H),2.05(dp,J=13.6,6.8Hz,1H),1.40(d,J=7.0Hz,3H),0.69(d,J=6.7Hz,3H),0.63(d,J=6.7Hz,3H).
Embodiment 17: the synthesis of compound WYQ-94-D.
Synthetic method is as WYQ-93-D, and separation and purification obtains white solid (50mg, 38%).
MS(ESI -):m/z:437([M-H] -); 1HNMR(300MHz,CDCl 3)δ10.59(brs,1H),8.17(brs,1H),8.12(s,1H),7.53–7.45(m,2H),7.41–7.29(m,2H),7.09(d,J=8.9Hz,2H),7.00(d,J=5.0Hz,1H),6.77(d,J=8.9Hz,2H),4.50(p,J=6.8Hz,1H),3.76(s,3H),1.49(d,J=6.9Hz,3H).
Embodiment 18: the synthesis of compound WYQ-95.
Synthetic method is as WYQ-93-D, and separation and purification obtains white solid (43mg, 34%).
MS(ESI -):m/z:423([M-H] -); 1HNMR(400MHz,DMSO)δ10.87(brs,1H),9.93(s,1H),8.05(s,1H),7.66–7.62(m,1H),7.55–7.49(m,2H),7.47–7.38(m,3H),7.01(brs,1H),6.92–6.85(m,2H),3.98(d,J=4.7Hz,2H),3.72(s,3H).
Measure whole N-substituted pyrazolecarboxylic of the present invention also [3,4-d] pyrimidinones to the inhibit activities of phosphodiesterase IX, IC 50value is inhibitor concentration when inhibiting rate reaches 50%.Test result is as following table.Simultaneously and application number be the invention of 201210280123.6 whole N-substituted pyrazolecarboxylics also the inhibit activities of [3,4-d] pyrimidinones to phosphodiesterase IX compare.Found that: the N-substituted pyrazolecarboxylic that the present invention prepares also [3,4-d] pyrimidinones is obviously the N-substituted pyrazolecarboxylic also [3 of the invention of 201210280123.6 than application number to the inhibit activities of phosphodiesterase IX, 4-d] pyrimidinones will well a lot, and especially structural formula described in the embodiment of the present invention 12 is the more remarkable to the inhibit activities of phosphodiesterase IX of the compound of WYQ-90-D.
Also [3,4-d] pyrimidinones is inhibited to phosphodiesterase IX can to find out N-substituted pyrazolecarboxylic of the present invention by the above results, can be used as the inhibitor of phosphodiesterase IX, have broad application prospects.

Claims (6)

1. N-substituted pyrazolecarboxylic also [3,4-d] pyrimidinones of representing of formula (I):
Wherein, R ' is selected from sec.-propyl or cyclopentyl, cyclohexyl, isobutyl-, Chloro-O-Phenyl;
During R ' '=H, R is selected from the CHCH of D or L configuration 3the CH of CONHR ' ' ', D or L configuration 2the CH of CONHR ' ' ', D or L configuration 2cH 2cONHR ' ' '; Wherein R ' ' ' is p-methoxyphenyl.
2. N-substituted pyrazolecarboxylic according to claim 1 also [3,4-d] pyrimidinones, it is characterized in that, it is selected from formula II, (III), (IV), (V), the compound shown in (VI);
； ；
； ；
。
3. N-substituted pyrazolecarboxylic according to claim 1 also [3,4-d] pyrimidinones as the application of phosphodiesterase IX inhibitor.
4. the preparation method of N-substituted pyrazolecarboxylic according to claim 1 also [3,4-d] pyrimidinones, is characterized in that, be made up of following steps:
(1) with 2,4,6-trichloropyrimidine formaldehyde and hydrazine for raw material, make alkali with triethylamine, with ethanol as solvent, be obtained by reacting compd A at-78 DEG C, the mol ratio of described 2,4,6-trichloropyrimidine formaldehyde, hydrazine and triethylamine is 1:1 ~ 1.1:2 ~ 3; The concentration of 2,4,6-trichloropyrimidine formaldehyde is 0.05 ~ 1.0mol/L;
(2) be hydrolyzed in the basic conditions by compd A, the mol ratio of A and alkali is 1:10 ~ 40, and the concentration of A is 0.05-0.5mol/L, obtains compd B,
(3) reacted with aminated compounds under the condition being alkali with triethylamine by compd B, obtain target compound I, the mol ratio of described B, triethylamine and aminated compounds is the concentration of 1:1.3:1.2-3, B is 0.05-0.5mol/L;
5. the preparation method of N-substituted pyrazolecarboxylic also [3,4-d] pyrimidinones according to right 4, it is characterized in that, described step (2) alkali is selected from sodium hydroxide or potassium hydroxide.
6. the preparation method of N-substituted pyrazolecarboxylic also [3,4-d] pyrimidinones according to right 4, it is characterized in that, described step (3) adopts the method adding heat-sealing tube.
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CN108101910A (en) * 2017-12-12 2018-06-01 中山大学 A kind of N- substituted pyrazolecarboxylics simultaneously [3,4-d] pyrimidinones and its preparation method and application
CN109180679A (en) * 2018-07-31 2019-01-11 中山大学 A kind of N- substituted pyrazolecarboxylic simultaneously [3,4-d] pyrimidinones and its preparation method and application
CN112830929A (en) * 2019-11-22 2021-05-25 江苏恒瑞医药股份有限公司 Process for preparing pyrazoloateroaryl compounds
CN113429411A (en) * 2021-08-03 2021-09-24 韶远科技（上海)有限公司 Preparation method of 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008072778A1 (en) * 2006-12-13 2008-06-19 Aska Pharmaceutical Co., Ltd. Therapeutic agent for urinary tract disease
CN102260266A (en) * 2011-05-03 2011-11-30 中山大学 Pyrazolo[3,4-d]pyrimidone compounds and application thereof in preparation of phosphodiesterase IX inhibitor
CN102786525A (en) * 2012-08-08 2012-11-21 中山大学 N-substituted pyrazolo [3, 4-d] pyrimidine ketone compound and preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008072778A1 (en) * 2006-12-13 2008-06-19 Aska Pharmaceutical Co., Ltd. Therapeutic agent for urinary tract disease
CN102260266A (en) * 2011-05-03 2011-11-30 中山大学 Pyrazolo[3,4-d]pyrimidone compounds and application thereof in preparation of phosphodiesterase IX inhibitor
CN102786525A (en) * 2012-08-08 2012-11-21 中山大学 N-substituted pyrazolo [3, 4-d] pyrimidine ketone compound and preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FEI MENG，等: "Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106977518A (en) * 2017-03-06 2017-07-25 中山大学 A kind of simultaneously [3,4 d] pyrimidinones and preparation method and the application of N substituted pyrazolecarboxylics
CN106977518B (en) * 2017-03-06 2019-10-29 中山大学 A kind of N- substituted pyrazolecarboxylic simultaneously [3,4-d] pyrimidinones and preparation method and application
CN108101910A (en) * 2017-12-12 2018-06-01 中山大学 A kind of N- substituted pyrazolecarboxylics simultaneously [3,4-d] pyrimidinones and its preparation method and application
CN108101910B (en) * 2017-12-12 2020-01-10 中山大学 N-substituted pyrazolo [3,4-d ] pyrimidone compound and preparation method and application thereof
CN109180679A (en) * 2018-07-31 2019-01-11 中山大学 A kind of N- substituted pyrazolecarboxylic simultaneously [3,4-d] pyrimidinones and its preparation method and application
CN109180679B (en) * 2018-07-31 2021-05-14 中山大学 N-substituted pyrazolo [3,4-d ] pyrimidone compounds and preparation method and application thereof
CN112830929A (en) * 2019-11-22 2021-05-25 江苏恒瑞医药股份有限公司 Process for preparing pyrazoloateroaryl compounds
CN112830929B (en) * 2019-11-22 2022-09-16 江苏恒瑞医药股份有限公司 Process for preparing pyrazoloateroaryl compounds
CN113429411A (en) * 2021-08-03 2021-09-24 韶远科技（上海)有限公司 Preparation method of 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound

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