CN102260266A - Pyrazolo[3,4-d]pyrimidone compounds and application thereof in preparation of phosphodiesterase IX inhibitor - Google Patents

Pyrazolo[3,4-d]pyrimidone compounds and application thereof in preparation of phosphodiesterase IX inhibitor Download PDF

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CN102260266A
CN102260266A CN2011101128812A CN201110112881A CN102260266A CN 102260266 A CN102260266 A CN 102260266A CN 2011101128812 A CN2011101128812 A CN 2011101128812A CN 201110112881 A CN201110112881 A CN 201110112881A CN 102260266 A CN102260266 A CN 102260266A
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pyrazolo
pyrimidinones
phenyl
phosphodiesterase
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CN102260266B (en
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万一千
罗海彬
孟飞
刘培庆
朱新海
文丹
邵咏贤
张淳
黄杰辉
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National Sun Yat Sen University
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Abstract

The invention discloses pyrazolo[3,4-d]pyrimidone compounds and application thereof in preparation of a phosphodiesterase IX inhibitor. The structure of the compounds is shown as a formula (1); in the formula, when R' is 2-chlorophenyl, R refers to phenyl, substituted phenyl, benzyl, substituted benzyl, 3-methylpyridine, 1-phenylethyl, diphenylmethyl or CHCH3CONHR1, wherein R1 refers to phenyl or methyl, methoxyl, ethoxyl, isopropoxy, methylthio, NHCOCH3 or NCH3CH3 substituted phenyl; when R' is phenyl, R refers to CHCH3CONHR2, wherein R2 refers to methoxyl or ethoxyl substituted phenyl; and when R' is methyl, R refers to 4-methoxy-benzyl, diphenylmethyl or N-(2-amino-cyclohexyl)-4-methoxy-benzenesulfonamide. The pyrazolo[3,4-d]pyrimidone compounds have activity of inhibiting phosphodiesterase IX, can serve as the phosphodiesterase IX inhibitor, can be used for preparing the phosphodiesterase IX inhibitor, and have wide application prospect. The compounds are shown as the formula (1).

Description

Pyrazolo [3,4-d] pyrimidinones and the application in preparation phosphodiesterase IX inhibitor thereof
Technical field:
The present invention relates to a class phosphodiesterase IX inhibitor (PDEIX Inhibitors), be specifically related to pyrazolo [3,4-d] pyrimidinones and the application in preparation phosphodiesterase IX inhibitor thereof that 6 novel N-of a class replace.
Background technology:
Phosphodiesterase is a superfamily enzyme system that extensively exists in the organism, it is the important component part of cell signal path, important second messenger's cyclic monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in the degradation of cell optionally, thus bring into play the important physical effect.
Phosphodiesterase IX is the 9th member of phosphodiester enzyme family, and cGMP is had affinity highly, can narrow spectrum hydrolysis cGMP.In human body, extensively distribute, high expression is especially arranged in colon, kidney, small intestine, spleen, brain.Its messenger RNA(mRNA) all has the expression of height at starting point, hippocampus and the cerebellum of the forebrain of brain bottom, olfactory nerve, and these zones are with behavior, sense of smell, motion with learn relevant.There are some researches show that cGMP plays important effect to the raising of people's cognitive ability, and the hydrolysis cGMP that PDEIX can high specific.These characteristics show that all the expression of PDEIX is relevant with cognition, attention, memory and study.
Present studies show that selectivity phosphodiesterase 9 inhibitor can be used for the treatment of multiple diseases (WO 2010084438, WO 2003037899, WO2009068617, WO 2011018495, WO 2008139293) such as diabetes, central nervous system disorder, urinary system, cardiovascular disorder and obesity.Although it is clinical that the existing at present PDE9 inhibitor as senile dementia (AD) medicine enters the III phase, still there are many weak points in these inhibitor, contain hand shape as molecule, need asymmetric synthesis, and bioavailability is low etc.Therefore seek PDEIX inhibitor and still have crucial meaning with high reactivity, highly selective.
The present invention is under national 863 fund assistances, for designing the research that the synthetic novel phosphodiesterase IX inhibitor with independent intellectual property right of a class carries out.
Summary of the invention:
First purpose of the present invention provides a class to be had phosphodiesterase IX and suppresses active pyrazolo [3,4-d] pyrimidinones, and the structure of this compound as the formula (1).
For solving the problems of the technologies described above, the technical solution used in the present invention is:
Have phosphodiesterase IX and suppress active pyrazolo [3,4-d] pyrimidinones, its structure as the formula (1):
Figure BDA0000058962900000021
Formula (1)
Wherein when R ' was the 2-chloro-phenyl-, R represented phenyl, substituted phenyl, benzyl, substituted benzyl, 3-picoline, 1-phenylethyl, diphenyl methyl or CHCH 3CONHR 1, R wherein 1Represent phenyl or by methyl, methoxyl group, oxyethyl group, isopropoxy, methylthio group, NHCOCH 3, NCH 3CH 3The phenyl that replaces;
Wherein when R ' was phenyl, R represented CHCH 3CONHR 2, R wherein 2The phenyl that representative is replaced by methoxy or ethoxy;
Wherein when R ' was methyl, R represented 4-methoxy-benzyl, diphenyl methyl or N-(2-aminocyclohexyl)-4-methoxybenzenesulphoismide.
Preferably: described have structure that phosphodiesterase IX suppresses active pyrazolo [3,4-d] pyrimidinones as the formula (2):
Figure BDA0000058962900000031
Formula (2)
R wherein 3Be hydrogen, methyl, methoxyl group, 2,4-dimethoxy, oxyethyl group, 3,4-methylene-dioxy or chlorine.
Preferably: described have structure that phosphodiesterase IX suppresses active pyrazolo [3,4-d] pyrimidinones as the formula (3):
Figure BDA0000058962900000032
Formula (3)
R wherein 4Be hydrogen, methyl, methoxyl group, 3,4-methylene-dioxy, oxyethyl group or morpholinyl.
Preferably: described have structure that phosphodiesterase IX suppresses active pyrazolo [3,4-d] pyrimidinones as the formula (4):
Formula (4)
R wherein 5Be hydrogen, methyl, methoxyl group, 3,4-methylene-dioxy, oxyethyl group or morpholinyl.
Preferably: described have structure that phosphodiesterase IX suppresses active pyrazolo [3,4-d] pyrimidinones as the formula (5):
Figure BDA0000058962900000041
Formula (5)
R wherein 6Be methoxy or ethoxy.
Preferably, described have structure that phosphodiesterase IX suppresses active pyrazolo [3,4-d] pyrimidinones as the formula (18):
Formula (18)
R wherein 7Represent the 4-methoxy-benzyl, diphenyl methyl, N-(2-aminocyclohexyl)-4-methoxybenzenesulphoismide.
Test discovery through the inventor, pyrazolo of the present invention [3,4-d] pyrimidinones has the activity of inhibition to phosphodiesterase IX, can be as the inhibitor of phosphodiesterase IX.
Therefore second purpose of the present invention provides the application of pyrazolo [3,4-d] pyrimidinones in preparation phosphodiesterase IX inhibitor.
The preparation of compound of the present invention can be by following basic skills and principle preparation, and its used raw material all can be bought from the market, and those skilled in the art can be produced according to the present invention to any compound of the present invention.
Step 1: according to chemical equation
Figure BDA0000058962900000051
Reaction conditions: (a) EtOH, 60 ℃; (b) H 2O 2, NH 3.H 2O; (c) urea, 200 ℃; (d) PCl 5, POCl 3, reflux; (e) KOH, 60 ℃.
Step 2: according to chemical equation
Figure BDA0000058962900000052
In the b reaction system, after DECP dripped off, reaction was raised to room temperature by low temperature, continued reaction two hours, and monitoring reaction is the back termination reaction fully.Aftertreatment is fairly simple, with saturated NaHCO 3The pH value of conditioned reaction system has a large amount of products to separate out during to 7 left and right sides.In the c reaction system, make solvent, under condition of ice bath, feed HCl gas and get final product with methyl alcohol.
Figure BDA0000058962900000061
In this step building-up reactions, make solvent with acetonitrile, raw material 1, it is excessive that the 2-cyclohexanediamine needs, and the acetonitrile solution that at room temperature slowly drips the anisole SULPHURYL CHLORIDE gets final product then.
Step 3: according to chemical equation
Figure BDA0000058962900000062
In this step reaction, be solvent with the Virahol, reflux, monitoring reaction is the back termination reaction fully.
Pyrazolo [3, the 4-d] pyrimidinones that 6 N-of the present invention replace has good inhibitory effect to phosphodiesterase IX, can be used as the selective depressant of phosphodiesterase.
Preparation method provided by the present invention has simply, and is easy to operate, low cost and other advantages.
Pyrazolo of the present invention [3,4-d] pyrimidinones has the activity of inhibition to phosphodiesterase IX, can be used for preparing phosphodiesterase IX inhibitor as the inhibitor of phosphodiesterase IX, has broad application prospects.
Embodiment:
Following examples are further to explain the synthetic method of compound of the present invention and intermediate thereof, are not to limit the scope of the invention.
One, the preparation of pyrazolo [3,4-d] pyrimidinones:
Instrument and medicine
The Mercury-Plus 300M Instrument measuring that NMR is produced by U.S. VARIAN company, solvent peak is done interior mark; LCMS-2010A (ESI source) mensuration that mass spectrum is produced by the desk-top mass spectrograph of DSQ (EI source) and day island proper Tianjin company; Chemical reagent is fought east available from Guangzhou, Shen, Guangdong chemical company, Alfar-Aser company, Aladdin chemical reagents corporation; Column chromatography uses silica gel available from Haiyang Chemical Plant, Qingdao.
Embodiment one: compound W-1's is synthetic
Figure BDA0000058962900000071
Formula (6)
In the round-bottomed flask of 50mL, add Virahol (10mL) successively, 1-(2-chloro-phenyl-)-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.4mmol, 0.1g), 2-amino-N-Phenylpropionamide (0.48mmol, 0.08g), triethylamine (0.4mmol, 0.04g), reflux then, monitoring reaction be the back termination reaction fully.Concentrate behind the cool to room temperature, obtain water white oily matter, the crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.07g, productive rate 41%.
1H?NMR(300MHz，CDCl 3)δ：10.80(s，1H)，8.64(br?s，1H)，8.13(s，1H)，7.51-7.46(m，2H)，7.35-7.24(m，6H)，7.06(d，J＝6.3Hz，2H)，4.56-4.49(m，1H)，1.52(d，J＝7.3Hz，3H).ESI-MS：m/z＝407[M-H] -
Through identifying that its structure as the formula (6).
Embodiment two: compound W-2's is synthetic
Formula (7)
The same W-1 of synthetic method, raw material are Virahol (10mL), 1-(2-chloro-phenyl-)-6-chloro-pyrazolo [3,4-d] and pyrimidin-4-one (0.4mmol, 0.1g), 2-amino-N-(4-p-methoxy-phenyl) propionic acid amide (0.48mmol, 0.09g), triethylamine (0.4mmol, 0.04g).The crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.08g, productive rate 45%.
1H?NMR(300MHz，CDCl 3)δ：10.57(s，1H)，8.14(s，1H)，8.13(br?s，1H)，7.52-7.29(m，4H)，7.11-6.77(m，5H)，4.55-4.46(m，1H)，3.78(s，3H)，1.52(d，J＝6.9Hz，3H) 13C?ESI-MS：m/z＝437[M-H] -.
Through identifying that its structure as the formula (7).
Embodiment three: compound W-3's is synthetic
Figure BDA0000058962900000082
Formula (8)
The same W-1 of synthetic method, raw material are Virahol (10mL), and 1-phenyl-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.4mmol, 0.1g), 2-amino-N-(4-p-methoxy-phenyl) propionic acid amide (0.48mmol, 0.09g), triethylamine (0.4mmol, 0.04g).The crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.07g, productive rate 41%.
. 1H?NMR(300MHz，DMSO-d 6)δ：10.67(s，1H)，10.17(br?s，1H)，8.06(d，J＝6.3Hz，3H)，7.54(d，J＝9.0Hz，2H)，7.36-7.23(m，3H)，7.11(d，J＝6.3Hz，1H)，6.89(d，J＝9.0Hz，2H)，4.55-4.46(m，1H)，3.71(s，1H).ESI-MS：m/z＝403[M-H] -.
Through identifying that its structure as the formula (8).
Embodiment four: compound W-4's is synthetic
Figure BDA0000058962900000091
Formula (9)
The same W-1 of synthetic method, raw material are Virahol (10mL), 1-(2-chloro-phenyl-)-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.4mmol, 0.1g) 4-Methoxybenzylamine (0.48mmol, 0.07g), triethylamine (0.4mmol, 0.04g).The crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.11g, productive rate 69%.
1H?NMR(300MHz，CDCl 3)δ：10.98(s，1H)，7.58-7.39(m，6H)，7.51-7.48(m，1H)，7.23(s，1H)，7.04(br?s，1H)，6.86(d，J＝8.7Hz，2H)，4.46(d，J＝4.2Hz，2H)，3.79(s，1H).ESI-MS：m/z＝380[M-H] -.
Through identifying that its structure as the formula (9).
Embodiment five: compound W-5's is synthetic
Figure BDA0000058962900000092
Formula (10)
The same W-1 of synthetic method, raw material are Virahol (10mL), and 1-(2-chloro-phenyl-)-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.4mmol, 0.1g), the 3-aminomethyl-pyridine (0.48mmol, 0.05g), triethylamine (0.4mmol, 0.04g).The crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.06g, productive rate 43%.
1H?NMR(300MHz，Methanol-d 4)δ：8.39(d，J＝2.7Hz，2H)，8.01(s，1H)，7.71-7.60(m，2H)，7.54-7.42(m，3H)，7.33-7.29(m，1H)，4.43(s，2H).ESI-MS：m/z＝351[M-H] -.
Through identifying that its structure as the formula (10).
Embodiment six: compound W-6's is synthetic
Figure BDA0000058962900000101
Formula (11)
The same W-1 of synthetic method, raw material are Virahol (10mL), 1-(2-chloro-phenyl-)-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.4mmol, 0.1g) the 3-chlorobenzylamine (0.48mmol, 0.07g), triethylamine (0.4mmol, 0.04g).The crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.1g, productive rate 62%.
1H?NMR(300MHz，DMSO-d 6)δ：10.87(s，1H)，8.03(s，1H)，7.68-7.65(m，1H)，7.55-7.48(m，3H)，7.28-7.17(m，5H)，4.32(d，J＝5.4Hz，2H).ESI-MS：m/z＝384[M-H] -.
Through identifying that its structure as the formula (11).
Embodiment seven: compound W-7's is synthetic
Figure BDA0000058962900000111
Formula (12)
The same W-1 of synthetic method, raw material are Virahol (10mL), and 1-(2-chloro-phenyl-)-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.4mmol, 0.1g), the 2-chlorobenzylamine (0.48mmol, 0.07g), triethylamine (0.4mmol, 0.04g).The crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.09g, productive rate 58%.
1H?NMR(300MHz，CDCl 3)δ：10.98(s，1H)，7.68(s，1H)，7.61-7.58(m，1H)，7.50-7.40(m，3H)，7.37-7.30(m，3H)，7.23-7.12(m，2H)，4.62(d，J＝5.4Hz，2H).ESI-MS：m/z＝384[M-H] -.
Through identifying that its structure as the formula (12).
Embodiment eight: compound W-8's is synthetic
Formula (13)
The same W-1 of synthetic method, raw material are Virahol (10mL), and 1-(2-chloro-phenyl-)-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.4mmol, 0.1g), P-nethoxyaniline (0.48mmol, 0.06g), triethylamine (0.4mmol, 0.04g).The crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.07g, productive rate 45%.
1H?NMR(300MHz，CDCl 3)δ：8.54(br?s，1H)，8.09(s，1H)，7.61-7.57(m，1H)，7.52-7.37(m，5H)，6.84(d，J＝9.0Hz，2H)，3.79(s，3H).ESI-MS：m/z＝366[M-H] -.
Through identifying that its structure as the formula (13).
Embodiment nine: compound W-9's is synthetic
Figure BDA0000058962900000121
Formula (14)
The same W-1 of synthetic method, raw material are Virahol (10mL), and 1-(2-chloro-phenyl-)-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.4mmol, 0.1g), 4-(4-morpholinyl) aniline (0.48mmol, 0.09g), triethylamine (0.4mmol, 0.04g).The crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.07g, productive rate 44%.
1H?NMR(300MHz，CDCl 3)δ：10.53(s，1H)，8.69(br?s，1H)，8.09(s，1H)，7.60-7.57(m，1H)，7.52-7.37(m，5H)，6.87(d，J＝9.0Hz，2H)，3.88(d，J＝4.8Hz，4H)，3.14(d，J＝4.8Hz，4H).ESI-MS：m/z＝421[M-H] -.
Through identifying that its structure as the formula (14).
Embodiment ten: compound W-10's is synthetic
Formula (15)
The same W-1 of synthetic method, raw material are Virahol (10mL), and 1-methyl-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.5mmol, 0.1g), the phenylbenzene methylamine (0.6mmol, 0.11g), triethylamine (0.5mmol, 0.05g).The crude product column chromatography (DCM: MeOH=25: 1) separate purify white solid 0.07g, productive rate 43%.
1H?NMR(300MHz，CDCl 3)δ：7.35-7.29(m，11H)，7.25-7.21(m，1H)，6.43(d，J＝7.5Hz，2H)，3.74(s，3H). 13C?NMR(75MHz，CDCl 3)δ：159.9，154.6，152.1，143.7，141.4，128.6，127.5，126.8，99.5，58.4，33.6.ESI-MS：m/z＝330[M-H] -.
Through identifying that its structure as the formula (15).
Embodiment 11: compound W-11's is synthetic
Figure BDA0000058962900000131
Formula (16)
The same W-1 of synthetic method, raw material are Virahol (10mL), and 1-methyl-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.5mmol, 0.1g), N-(2-aminocyclohexyl)-4-methoxybenzenesulphoismide (0.6mmol, 0.17g), triethylamine (0.5mmol, 0.05g).The crude product column chromatography (DCM: MeOH=20: 1) separate purify white solid 0.08g, productive rate 37%.
1H?NMR(300MHz，CDCl 3)δ：10.44(s，1H)，7.78(s，1H)，7.66-7.62(m，2H)，7.01(br?s，1H)，6.85-6.82(m，2H)，5.82(s，1H)，5.30-5.29(m，1H)，3.77(s，6H)，3.18-3.15(m，1H)，2.14-1.99(m，2H)，1.74-1.70(m，2H)，1.44-1.22(m，4H).ESI-MS：m/z＝431[M-H] -.
Through identifying that its structure as the formula (16).
Embodiment 12: compound W-12's is synthetic
Figure BDA0000058962900000141
Formula (17)
The same W-1 of synthetic method, raw material are Virahol (10mL), and 1-methyl-6-chloro-pyrazolo [3,4-d] pyrimidin-4-one (0.5mmol, 0.1g), 2-amino-N-(4-dimethylamino) propionic acid amide (0.6mmol, 0.12g), triethylamine (0.5mmol, 0.05g).The crude product column chromatography (DCM: MeOH=20: 1) separate purify white solid 0.08g, productive rate 37%.
1H?NMR(300MHz，CH 3OD)δ：8.03(s，1H)，7.39-7.43(m，2H)，7.20-7.24(m，3H)，6.75(d，J＝8.7Hz，2H)，4.39(d，J＝6.9Hz，1H)，2.91(s，6H)，1.43(d，J＝6.9Hz，3H).ESI-MS：m/z＝450[M-H] -
Through identifying that its structure as the formula (17).
Two, active testing:
Measured part of the present invention suc as formula the pyrazolo [3 in shown in (1) structure, 4-d] pyrimidinones is to the inhibition activity of phosphodiesterase IX, test result be meant inhibitor when 100 μ M concentration to the active percent inhibition of phosphodiesterase IX, suppress activity and exceed at 50% o'clock, sift out IC routinely 50Value.The result is as shown in table 1:
Table 1: active testing result
Figure BDA0000058962900000151
Inhibited by pyrazolo [3, the 4-d] pyrimidinones that The above results 6 N-of the present invention as can be seen replace to phosphodiesterase IX, can have broad application prospects as the inhibitor of phosphodiesterase IX.

Claims (7)

1. the pyrazolo shown in the following formula (1) [3,4-d] pyrimidinones:
Figure FDA0000058962890000011
Formula (1)
Wherein when R ' was the 2-chloro-phenyl-, R represented phenyl, substituted phenyl, benzyl, substituted benzyl, 3-picoline, 1-phenylethyl, diphenyl methyl or CHCH 3CONHR 1, R wherein 1Represent phenyl or by methyl, methoxyl group, oxyethyl group, isopropoxy, methylthio group, NHCOCH 3, NCH 3CH 3The phenyl that replaces;
Wherein when R ' was phenyl, R represented CHCH 3CONHR 2, R wherein 2The phenyl that representative is replaced by methoxy or ethoxy;
Wherein when R ' was methyl, R represented 4-methoxy-benzyl, diphenyl methyl or N-(2-aminocyclohexyl)-4-methoxybenzenesulphoismide.
2. pyrazolo according to claim 1 [3,4-d] pyrimidinones is characterized in that, the structure of described pyrazolo [3,4-d] pyrimidinones as the formula (2):
Figure FDA0000058962890000012
Formula (2)
R wherein 3Be hydrogen, methyl, methoxyl group, 2,4-dimethoxy, oxyethyl group, 3,4-methylene-dioxy or chlorine.
3. pyrazolo according to claim 1 [3,4-d] pyrimidinones is characterized in that, the structure of described pyrazolo [3,4-d] pyrimidinones as the formula (3):
Formula (3)
R wherein 4Be hydrogen, methyl, methoxyl group, 3,4-methylene-dioxy, oxyethyl group or morpholinyl.
4. pyrazolo according to claim 1 [3,4-d] pyrimidinones is characterized in that, the structure of described pyrazolo [3,4-d] pyrimidinones as the formula (4):
Formula (4)
R wherein 5Be hydrogen, methyl, methoxyl group, 3,4-methylene-dioxy, oxyethyl group or morpholinyl.
5. pyrazolo according to claim 1 [3,4-d] pyrimidinones is characterized in that, the structure of described pyrazolo [3,4-d] pyrimidinones as the formula (5):
Figure FDA0000058962890000023
Formula (5)
R wherein 6Be methoxy or ethoxy.
6. pyrazolo according to claim 1 [3,4-d] pyrimidinones is characterized in that, the structure of described pyrazolo [3,4-d] pyrimidinones as the formula (18):
Figure FDA0000058962890000031
Formula (18)
R wherein 7Represent the 4-methoxy-benzyl, diphenyl methyl, N-(2-aminocyclohexyl)-4-methoxybenzenesulphoismide.
7. the application of the described pyrazolo of claim 1 [3,4-d] pyrimidinones in preparation phosphodiesterase IX inhibitor.
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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
CN104557938A (en) * 2013-10-28 2015-04-29 中山大学 N-substituted pyrazolo[3,4-d]pyrimidinone compound and application thereof
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
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