CN1177960A - 6-substituted pyrazolo (3, 4 -d) pyrimidin -4 ones and compositions and methods of use thereof - Google Patents
6-substituted pyrazolo (3, 4 -d) pyrimidin -4 ones and compositions and methods of use thereof Download PDFInfo
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Abstract
6-Substituted pyrazolo[3, 4-d] pyrimidin-4-one derivatives, pharmaceutical compositions containing them and methods for a) effecting c-GMP-phosphodiesterase inhibition, b) treating heart failure and hypertension, c) reversing or reducing nitrate-induced tolerance and d) treating angina pectoris, congestive heart disease and myocardial infarction utilizing them.
Description
Background of invention
(a) invention field
The present invention relates to the pyrazolo [3 that 6-replaces, 4-d] pyrimidin-4-one, relate to the pharmaceutical composition that contains them and use them a) to suppress the c-GMP-phosphodiesterase, b) treatment heart failure and/or hypertension, c) reverse or alleviate nitric ether inductive resistance and d) treatment stenocardia, the method for congestive heart disease and myocardial infarction.
(b) the open situation of reference
The U.S. patent that announce the January 12 nineteen sixty-five of Schmidt (Schmidt) etc., No.3,165,520 disclose as the following pyrazolo of the general formula of coronary dilation agent [3,4-d] pyrimidine:
Wherein:
R
1Expression hydrogen atom or alkyl, hydroxyalkyl, haloalkyl or oxa alkyl or cycloalkyl, cycloalkylalkyl, aralkyl or heterocyclic radical alkyl or in most of the cases be double-core aryl or heterocyclic radical;
R
3Expression hydrogen atom or low alkyl group;
R
9The expression aliphatic group, cyclic aliphatic group, cyclic aliphatic group-aliphatic group base, aryl aliphatic group or heterocyclic radical aliphatic group; And
R
6Expression aliphatic group or aralkyl or can substituted heterocyclic radical alkyl.
This patent more specifically discloses wherein R
1Expression hydrogen atom or low alkyl group or cycloalkyl.Hydroxyl low-grade alkyl or junior alkyl halides, the oxa-low alkyl group perhaps can be by halogen, alkoxyl group, alkyl, methylene-dioxy, trifluoromethyl, nitro, amino or pyridyl list-, two-, or the aryl of three-replacement; R
3Expression hydrogen atom or low alkyl group; R
5Expression low alkyl group or lower alkyl amino; And R
6The special value of the compound of expression low alkyl group or aralkyl.
It further discloses a series of 1-R of the intermediate that is used for synthetic final product
1-3-R
3-4-hydroxyl-6-R
6-pyrazolo [3,4-d] pyrimidine.1-cyclopentyl-4-hydroxyl-6-benzyl-pyrazolo [3,4-d] pyrimidine and 1-sec.-propyl-4-hydroxyl-6-m-methoxy-benzyl pyrazolo [3,4-d] pyrimidine is specifically disclosed in the mesosome in these.
The U.S. patent that announce the October 12 nineteen sixty-five of Schmidt (Schmidt) etc., No.3,211,731 disclose the following pyrazolo as the coronary dilation agent [3, the 4-d] pyrimidine of general formula:
Wherein,
R
1Expression hydrogen, alkyl, hydroxyalkyl, haloalkyl or oxa alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, heterocyclic radical alkyl or in most cases be double-core aryl or heterocyclic radical;
R
3Expression hydrogen, or secondly, be low alkyl group; And
R
6Substituted aralkyl or heterocyclic radical alkyl express possibility.
This patent more specifically discloses wherein R
1Expression hydrogen atom or low alkyl group, cycloalkyl, hydroxyl low-grade alkyl, junior alkyl halides, oxa-low alkyl group, or aryl; R
3Represent hydrogen atom or low alkyl group and R
6For replacing or the special value of the compound of unsubstituted aralkyl.In these compounds, 1-sec.-propyl-4-hydroxyl-6-(3 '-methoxyphenyl methyl) pyrazolo [3 is disclosed especially, 4-d] pyrimidine, 1-cyclopentyl-4-hydroxyl-6-benzyl pyrazole also [3,4-d] pyrimidine, 1-sec.-propyl-4-hydroxyl-6 (β-styroyl) pyrazolo [3,4-d] pyrimidine and 1-sec.-propyl-4-hydroxyl-6-(4-aminobenzyl) pyrazolo [3,4-d] pyrimidine.
The U.S. patent 3,211,732 that announce the October 12 nineteen sixty-five of Schmidt (Schmidt) etc. discloses as intermediate 1-R
1-3-R
3-6-R
6-4-hydroxyl-pyrazolo [3,4-d] pyrimidine, wherein:
R
1The expression hydrogen atom, the low alkyl group that replaces or replaced by hydroxyl or low alkyl group oxygen base, or cyclopentyl or cyclohexyl or phenyl or phenyl lower alkyl;
R
3Expression hydrogen atom or low alkyl group; And
R
6Expression replaces or unsubstituted phenyl lower alkyl.
Also [3,4-d] pyrimidine of 1-sec.-propyl-4-hydroxyl-6-benzyl pyrazole is disclosed especially.
1-R as intermediate is also disclosed
1-3-R
3-6-R
6-4-hydroxypyrazoles is [3,4-d] pyrimidine also, wherein:
R
1The expression hydrogen atom, lower alkoxy low alkyl group or hydroxyl low-grade alkyl, cyclopentyl or cyclohexyl or can substituted phenyl or phenyl lower alkyl;
R
3Definition as above; And
R
6Expression can substituted phenyl.Also [3,4-d] pyrimidine of 1-sec.-propyl-4-hydroxyl-6-phenylpyrazole is disclosed especially.
The U.S. patent that announce 8 days Mays in 1973 of Breuer (Bu Laoer) etc., No.3,732,225 disclose as the following pyrazolo of the general formula of hypoglycemia agent and anti-inflammatory agent [3,4-d] pyrimidine:
Wherein:
R is hydrogen or low alkyl group; R
1Be low alkyl group, cycloalkyl, phenyl or substituted-phenyl; R
2Be phenyl, substituted-phenyl or cycloalkyl; And R
3Be hydrogen, low alkyl group, cycloalkyl, phenyl or substituted-phenyl.1-methyl-6-phenyl and 1-methyl-6-(4-chloro-phenyl-) pyrazolo [3,4-d] pyrimidin-4-one is disclosed especially.
The U.S. patent that announce the 31 days October in 1967 of Burch (cloth is strange), No.3,350,397 disclose as the following pyrazolo of the general formula of antiseptic-germicide [3,4-d] pyrimidine:
Wherein:
R represents hydroxyl, chlorine or-N (X) (Y), wherein X represents hydrogen, (rudimentary) alkyl, hydroxyl (rudimentary) alkyl, (rudimentary) alkoxyl group (rudimentary) alkyl or amino; Y represents hydrogen, hydroxyl (rudimentary) alkyl, (rudimentary) alkoxyl group (rudimentary) alkyl or morpholinyl propyl; X and Y represent pyrrolidyl with N; And R
1Expression (rudimentary) alkyl or methoxyethyl.
This patent further discloses amino and 4-hydroxyl-1-R as the 4-of intermediate
1-6-(2-furyl)-1H-pyrazolo [3,4-d] pyrimidine.Burch is in J.Med.Chem.1968, and 11,79 have further exemplified the preparation of intermediate and the preparation and the biological test of final product.
English Patent 937,722 franchises that are disclosed on September 25th, 1963 disclose 1-sec.-propyl-4-hydroxyl-6-benzyl-pyrazolo [3, the 4-d] pyrimidine as the coronary dilation agent in CIBALIMITED.
The U.S. patent that announce 19 days Mays in 1987 of Hamilton (Hamilton), No.4,666,908 disclose following pyrazolo [4, the 3-d] pyrimidin-7-ones of general formula:
Wherein:
R
1Comprise a low alkyl group to six carbon atom, the low-grade alkylidene that comprises one to six carbon, the rudimentary hydroxyalkyl that comprises one to six carbon, the rudimentary hydroxy alkylidene that comprises two to six carbon, the rudimentary aminoalkyl that comprises one to six carbon, perhaps, comprise two rudimentary amino alkylidenyls to six carbon atom;
N is 0-4; And
Ar is R
2:
Or 2,3, or 4-pyrimidyl, X wherein, Y and Z respectively are (1) hydrogen; (2) comprise the low alkyl group of one to six carbon; (3) halogen; (4) hydroxyl; (5) comprise the lower alkoxy of one to six carbon; (6) nitro; (7) amino; (8) respectively do for oneself (a) hydrogen or (b) comprise the low alkyl group of one to six carbon of NR ' R " wherein R ' and R ", this alkyl can be non-imposedly by (i) amino, (ii) morpholino, or (iii) comprise the cycloalkyl substituted of five to seven carbon, (9) alkylsulfonyl or (10)-SO
2NR ' R ", wherein " definition is as above for R ' and R.
This patent more specifically discloses wherein, and Ar is R
2Preferred compound.These compounds can be used for treating cardiovascular disorder.
Miyashita equals Heterocycles (heterocycle) 1990., 31, and 1309-1341 discloses the preparation of following a series of pyrazolos [3, the 4-d] pyrimidine of general formula:
Wherein:
R is phenyl or methyl; And R
1Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, benzyl, Eufin or phenyl.Unexposed its purposes.
The PCT application WO88/00192 that is disclosed on January 14th, 1988 of Hamilton (Hamilton) discloses pyrazolo [4,3-d] the pyrimidin-7-ones derivative that a series of 5-replace, these compounds can be used as cardiotonic drug, CNS stimulant, anti-allergic agent, anti-asthmatic agent or identification activator.
The european patent application 0463756 that is disclosed on January 2nd, 1992 of Bell (Bel) etc. discloses a series of 5-(2, the dibasic phenyl of 5-) pyrazolo [4,3-d] pyrimidin-7-ones, and these compounds can be used for the treatment of cardiovascular disorder.
The U.S. patent of announcing the 12 days November in 1974 of Breuer and Treuner 3,847,908 discloses the compound of following formula:
Wherein:
R
1Be low alkyl group, ring low alkyl group, or phenyl-low alkyl group;
R
2Be hydrogen or low alkyl group; And
R
3Be hydrogen, low alkyl group, halogen, or trifluoromethyl.Specifically disclose 1,3-dimethyl-6-styryl-pyrazolo [3,4-d] pyrimidine, 1-cyclopentyl-6-(2-chloro-styrene base) pyrazolo [3,4-d] pyrimidine, 1-cyclohexyl-3-methyl-6-(styryl) pyrazolo [3,4-d] pyrimidine and 1,3-diethyl-6-(4-chloro-styrene base) pyrazolo [3,4-d] pyrimidine.It is said that this compound can be used as biocide and have anti-inflammatory and character that film is stable.
The U.S. patent of announcing the 7 days April in 1981 of Morrison etc. 4,260,758 discloses the preparation of following formula: compound:
R wherein
9Be selected from low alkyl group, phenyl, by the phenyl of one or more hydroxyls or lower alkoxy replacement, or pyridyl.The purposes of unexposed this compound.
The Canadian Patent 754 that announce the 14 days March in 1967 of Burch, 565 disclose that a series of 4-replace-1-alkyl-6-(2-furyl)-1H-pyrazolo [3,4-d] pyrimidine, it is said that this compound can be used as that 4-that preparation can bacteria growing inhibiting replaces-intermediate of 1-alkyl-6-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d] pyrimidine.
The U.S. patent of announcing the 13 days November in 1973 of Podesva etc. 3,772,294 discloses the preparation of formula I compound:
Wherein:
X represents halogen atom, the hydroxyl that dissociates or replace, and amino or sulfydryl and R represent hydrogen atom, or low alkyl group or replacement or unsubstituted aryl.The document discloses these compounds can be used to treat the hyperuricemia relevant with gout effectively, and in addition, wherein X represents that the compound of halogen atom can be used as the intermediate of synthetic other formulas I compound.The document also specifically discloses 4-hydroxyl-6-phenyl-1-pyrazolo [3,4-d] pyrimidine.
The U.S. patent of announcing the 24 days December in 1991 of Coates and Rawlings 5,075,310 (the series application No.370 that this patent was announced from June 23rd, 1989,494) open and claimed following formula: compound and pharmacy acceptable salt thereof;
Wherein:
Be following formula (a), (b) or (c) encircle:
X is oxygen or sulphur; And R
1Be C
1-C
6Alkyl, C
2-6Alkenyl, C
3-5Cycloalkyl-C
1-4Alkyl, or the C that replaces by 1 to 6 fluorine
1-4Alkyl.The document specifically discloses 6-(2-propoxy phenyl) pyrazolo [3,4-d] pyrimidines-4 (5H)-ketone.It is said that this compound can be used as bronchodilator and vasodilator.
Brief summary of the invention the present invention relates to formula I compound or its pharmaceutically-acceptable acid addition and/or hydrate:
Wherein:
R
1Be the tertiary butyl, or cyclopentyl;
R
3Be methyl, ethyl, or phenmethyl;
X is-CH
2-,-O-, or-NH-; And
R
6For phenyl (or by one to three, identical or different lower alkoxy, the hydroxyl of being selected from, halogen, carboxyl lower alkoxy, 4-morpholinyl lower alkoxy, 5-tetrazyl lower alkoxy, two elementary alkyl amido, trifluoromethyl, nitro, amino, the lower alkyl sulfonamido, two elementary alkyl amido-low alkyl group phenyl carbonyl oxygen base, and the phenyl of the substituting group of 1-imidazolyl replacement); Perhaps working as X is-CH
2-time, R
6Be 2-in addition, 3-, or 4-pyridyl, 1-pyrryl, 1-benzimidazolyl-, 1,2,3,4-tetrahydrochysene-2-isoquinolyl, 1,2,3,4-tetrahydrochysene-1-quinolyl, hydroxyl, 1-imidazolyl, 1-low alkyl group-2-, 3-, 4-, or 5-pyrryl, the 1-pyrazolyl, 3-, 4-, or 5-isoxazolyl (the perhaps 3-that on its any possible carbon atom, replaces by low alkyl group, 4-, or 5-isoxazolyl), 2-thienyl, or 3-thienyl.
Have been found that formula I compound has c-GMP-PDEV and suppresses active, therefore can be used for treating heart failure and/or hypertension.Found that also being used in combination formula I compound with nitric ether can be used for reversing or alleviating nitric ether inductive resistance, thereby can further be used to treat stenocardia, congestive heart disease and myocardial infarction.
Preferred formula I compound is for wherein
R
1, R
3Define as above with X, and
R
6For phenyl (or by one to three, identical or different, be selected from lower alkoxy, hydroxyl, carboxyl lower alkoxy, 4-morpholinyl lower alkoxy, 5-tetrazyl-lower alkoxy, two elementary alkyl amido, trifluoromethyl, nitro, amino, the low alkyl group sulfonamido, the phenyl that the substituting group of two lower alkyl aminos-low alkyl group phenyl carbonyl oxygen base and 1-imidazolyl replaces); Perhaps working as X is-CH
2-time, R
6Be 2-in addition, 3-, or 4-pyridyl, 1-pyrryl, the 1-benzimidazolyl-, 1,2,3,4-tetrahydrochysene-2-isoquinolyl, 1,2,3,4-tetrahydrochysene-1-quinolyl, hydroxyl, the 1-imidazolyl, 1-low alkyl group-2-pyrryl, 1-pyrazolyl, the 4-isoxazolyl that replaces by low alkyl group on any therein possible carbon atom), 2-thienyl, or the compound of 3-thienyl.
Particularly preferred formula I compound is for wherein:
R
1, R
3Define as above with X, and
R
6For phenyl (or by one to three, identical or different, be selected from methoxyl group, hydroxyl, carboxyl methoxyl group, 2-(4-morpholinyl) oxyethyl group, 1-(5-tetrazyl) methoxyl group, dimethylamino, trifluoromethyl, nitro, amino, sulfonyloxy methyl amino, the phenyl that the substituting group of diethylin aminomethyl phenyl carbonyl oxygen base and 1-imidazolyl replaces); Perhaps working as X is-CH
2-time, R
6Be 2-in addition, 3-, or 4-pyridyl, 1-pyrryl, the 1-benzimidazolyl-, 1,2,3,4-tetrahydrochysene-2-isoquinolyl, 1,2,3,4-tetrahydrochysene-1-quinolyl, hydroxyl, 1-imidazolyl, 1-methyl-2-pyrryl, 1-pyrazolyl, 3,5-dimethyl-4-isoxazolyl), 2-thienyl, or the compound of 3-thienyl.
More particularly preferred above-mentioned formula I compound is R wherein
1Be cyclopentyl; R
3Be ethyl; And X and R
6Definition compound as above.
The preferred particular compound of the present invention is:
1-cyclopentyl-3-ethyl-6-(4-mehtoxybenzyl) pyrazolo [3,4-d] pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-(4-hydroxybenzene methyl) pyrazolo [3,4-d] pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-(phenmethyl) pyrazolo [3,4-d] pyrimidin-4-one, and
1-cyclopentyl-3-ethyl-6-(4-amino-benzene methyl) pyrazolo [3,4-d] pyrimidin-4-one.
The invention still further relates to and comprise formula I compound and pharmaceutically acceptable carrier, auxiliary, thinner, or the pharmaceutical composition of vehicle.
The invention still further relates to the method that suppresses Mammals cGMP-phosphodiesterase, comprising the formula I compound that this animal is used significant quantity.
The invention still further relates to the in heart failure and/or hypertensive method of treatment Mammals, comprising the formula I compound that this animal is used significant quantity.
The invention still further relates to reverse or alleviate the chemical sproof method of nitric ether inductive that Mammals produces in the process of accepting the nitric ether treatment, comprising the formula I compound that this animal is used significant quantity.
The invention still further relates to treatment Mammals stenocardia, the method for congestive heart disease and myocardial infarction is comprising the formula I compound that this animal is used in combination significant quantity with nitric ether.
The detailed description of preferred preparation scheme
Formula I compound can with corresponding enol form:
Mode with tautomeric equilibrium exists, and it is believed that only the ketone form is dominant and all is expressed as this form, obviously the present invention includes these two kinds of forms and composition thereof.
Term lower alkyl used herein represents to have a straight or branched alkyl to about four carbon atom, comprises methyl, ethyl, and propyl group, sec.-propyl, normal-butyl, sec-butyl, etc.
It is one alkoxy substituted to the straight or branched of about four carbon atom that term lower alkoxy used herein is represented to have, and comprises methoxyl group, oxyethyl group, and propoxy-, isopropoxy, butoxy, sec-butoxy, etc.
Term halogen used herein, halogenide or halogen are represented bromine, chlorine, iodine or fluorine.
Wherein X is-CH
2-the synthetic of The compounds of this invention can be undertaken by shown in the flow process A: flow process A
Arrive under the temperature of about room temperature at about 0 ℃, at suitable alkali, under the existence as pyridine, non-imposedly at suitable solvent, under the existence as chloroform, with the excessive formula III acyl chlorides that replaces suitably, wherein X ' is a halogen, preferred chlorine is handled the formula II 5-amino-1H-pyrazoles-4-formonitrile HCN that replaces suitably, obtains formula IV carboxylic acid amides.Selectively, also can pass through at suitable solvent, in dimethyl formamide (DMF).Handle excessive formula R with formula II 5-amino-1H-pyrazoles-4-formonitrile HCN
6CH
2COOH acid or its acid salt and excess base, as sodium hydride, and excessive suitable coupler, as N, the mixture of N '-phosphinylidyne diimidazole and make formula IV carboxylic acid amides.Then can be at excess base, preferred sodium hydroxide, or under the existence of sodium methylate, at solvent such as water, low-level chain triacontanol, or in water/lower alkane alcohol mixture, when sodium methylate is used as alkali, preferred alcohol, when sodium hydroxide was used as alkali, preferably water/alcohol mixture was under the temperature of the boiling point that arrives solvent for use or solvent mixture with about 0 ℃, with excessive hydrogen peroxide treatment formula IV carboxylic acid amides, obtaining wherein, X is-CH
2-formula I compound.
Optionally, wherein X is-CH
2-formula I compound can shown in flow process B, prepare: flow process B
At the lower alkane alcoholic solvent, in the preferred alcohol, under the temperature of boiling point, use excess base, as basic metal lower alkane alcoholization thing from about room temperature to solvent for use, preferred alcohol sodium, with the excessive formula VI ester that replaces suitably, wherein R is a low alkyl group, preferable methyl or ethyl, handle the formula V 5-amino-1H-pyrazole-4-carboxamide that replaces suitably, obtaining wherein, X is-CH
2-formula I compound.
Wherein X is-O-, or-the formula I compound of NH-can prepare shown in flow process C: flow process C
From about 80 ℃ of boiling points to all solvents, preferred about 150 ℃ are arrived under about 160 ℃ temperature, in appropriate organic solvent, in the N-N-methyl-2-2-pyrrolidone N-, with excessive o-ethyl xanthate, handle the formula V 5-amino-1H-pyrazole-4-carboxamide that replaces suitably as sylvite, obtain formula V II6-sulfo-pyrazolo [3,4-d] pyrimidin-4-one.Then at excess base, as K
2CO
3Or under the existence of sodium hydride.In appropriate organic solvent, in dimethyl formamide, from about 0 ℃ under the temperature of about room temperature, with excessive suitable methylating reagent, handle formula VII compound as methyl-iodide or methyl-sulfate, obtain formula VII 6-(methylthio group) pyrazolo [3,4-d] pyrimidin-4-one.Can in chloroform, under the condition of about room temperature,, handle formula VIII compound at suitable solvent then, obtain formula IX 6-(methyl sulphonyl) pyrazolo [3,4-d] pyrimidin-4-one as the m-chloroperoxybenzoic acid with excessive suitable oxygenant.From about room temperature to about 190 ℃, preferably under about 170 ℃ to 190 ℃ temperature, at excess base, as sodium hydride, exist down non-imposedly, with the R of excessive formula X
6NH
2Derivative, or the R of excessive formula XI
6The OH derivative is handled formula IX derivative, obtain X wherein for-O-or-the formula I compound of NH-.
Can use be converted functional group's the variation of realization formula I compound of the known or conventional simple chemistry of chemical field technician.For example, the alkylation removal of aryl ester obtains corresponding amphyl, handles aryl derivatives with formaldehyde and two low-grade alkylamines and obtains corresponding two elementary alkyl amido methyl-derivatives, and handling wherein with methylsulfonyl chloride in the presence of alkali, X is-CH
2-and R
6For the formula I compound of OH obtains corresponding methanesulfonates, it is handled obtaining wherein X and be-CH with 1-acetyl imidazole or pyrazoles
2-and R
6Be the formula I compound of 1-imidazolyl or 1-pyrazolyl, the catalytic reduction nitro-derivative obtains corresponding amine, obtains corresponding low alkyl group sulphonamide with low alkyl group sulfonic acid halide sulfonated amine, and at coupler, for example, N, N '-phosphinylidyne diimidazole exists down to obtain corresponding ester with acid treatment phenol.
Both can use the formula I compound of free alkali form, and also can use the formula I compound of acid salt form, these two kinds of forms all belong to scope of the present invention.The acid salt form is the form of being more convenient for using; In fact, the purposes of salt form itself is equivalent to the purposes of alkali form.When the acid that can be used to prepare acid salt preferably includes those and combines with free alkali, produce the acid of pharmacy acceptable salt, promptly, the negatively charged ion of salt is harmless relatively to animal body under the pharmaceutical dosage of this salt, so that the beneficial property of free alkali itself can be not influential owing to anionic side effect.Form easy to use is the form or the hydrochloride of free alkali in enforcement of the present invention, fumarate, tosylate.Mesylate or maleate.But other suitable pharmacy acceptable salts can be formed by other mineral acids and organic acid in the scope of the invention.The acid salt of basic cpd can be by standard method preparation known in the art, comprising but be not limited to, free alkali is dissolved in the aqueous alcohol solutions that contains appropriate acid, and evaporating solns separated salt, or acid and free alkali are reacted, wherein direct separated salt, or with second kind of organic solvent deposit, maybe can obtain by concentrated solution.Although the medically acceptable salt of preferred basic cpd the present invention includes all acid salt.All acid salt all can be used as the source of free alkali form, even some special salt itself only is required as intermediate product, for example, and for purifying or evaluation and the salt that forms.Perhaps, as passing through, for example, ion exchange method prepares the salt of the intermediate of medically acceptable salt.
The formula II 5-amino that is replaced suitably-1H-pyrazoles-4-formonitrile HCN and the formula V 5-amino-1H-pyrazole-4-carboxamide that is replaced suitably all are known substances, therefore can prepare by means known in the art (referring to, for example, be published in the U.S. patent 5 on March 15th, 1994,294,612, its full content is adapted in this by reference), perhaps can be by the method preparation of describing among the embodiment hereinafter.The formula III acyl chlorides, formula VI ester, the R of formula X
6NH
2The R of derivative and formula XI
6The OH derivative both can obtain on market, also can prepare by means known in the art, also can be by the preparation of the method among the embodiment hereinafter.
The structure of The compounds of this invention can be passed through synthesis mode, and is selected from ultimate analysis by one or more, and is infrared, and nucleus magnetic resonance and mass spectral method confirm.The process of reaction and the identity and the homogeneity of product can be selected from thin-layer chromatography (TLC) by one or more, high pressure liquid chromatography (HPLC), or the method for gas-liquid chromatograph (GLC) is identified.
The following examples will further specify the present invention, but it does not limit the present invention.Given all fusing points (m.p.) all be degree centigrade (℃), proofread and correct.
Embodiment 1
(a)
In 20 minutes time, in ice bath, (10.6ml, (8.2g is 0.04mol) in the solution in pyridine (100ml) 0.08mol) to add the 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazoles-4-formonitrile HCN that is stirring with phenyllacetyl chloride.Reaction mixture was stirred 2 hours under this temperature, at room temperature stir then and spend the night.Solvent removed in vacuo, and residue is allocated between chloroform (200ml) and the water (200ml).Tell organic layer, vacuum concentration obtains oily matter, and it is passed through silica gel column chromatography, with hexane/ether (1/1) wash-out, with obtaining 8.3g (64%) white flakes shape 1-cyclopentyl-3-ethyl-4-cyano group-5-(phenmethyl carbonyl amino)-1H-pyrazoles behind the ether/hexane recrystallization.
(b) with 1-cyclopentyl-3-ethyl-4-cyano group-5-(phenmethyl carbonyl amino)-1H-pyrazoles (2.4g, 7.4mmol), ethanol (100ml), 30%H
2O
2(4.5ml, 40mmol), NaOH (0.3g, 7.5mmol) and the mixture of water (10ml) at room temperature stirred 1 hour, refluxed then 1 hour.Add a part of 30%H again
2O
2(2.5ml) also this mixture was refluxed 1 hour again.The vacuum concentration solvent, residue water (25ml) and acetate (3ml) are handled, formed yellow mercury oxide is filtered collect, wash and use the Virahol recrystallization with water, obtain the orange needle shape of 0.79g 1-cyclopentyl-3-ethyl-6-(phenmethyl)-pyrazolo [3,4-d] pyrimidin-4-one.m.p.175-176℃。
Optionally, this product also can be by following preparation: sodium (2.12g) is dissolved in the ethanol (145ml), add then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (10g, 45mmol).Then add Phenylacetic acid ethylester (2.8g) and reaction mixture refluxed is spent the night.Reaction mixture is cooled to room temperature, and stripping adds entry then in residue, then add 2N HCl.Filter and collect product, use re-crystallizing in ethyl acetate, obtain 10.52g (73%) 1-cyclopentyl-3-ethyl-6-(phenmethyl)-pyrazolo [3,4-d] pyrimidin-4-one.
Embodiment 2
(a)
In 20 minutes, under the ice bath cooling, (2.3ml is 17.2mol) at CHCl with phenyllacetyl chloride
31-cyclopentyl-3-phenmethyl-5-amino-1H-pyrazoles-4-formonitrile HCN that solution adding (10ml) is being stirred (2.3g, 8.6mmol), CHCl
3(50ml) and in the solution of pyridine (20ml).Reaction mixture was stirred in ice bath 3 hours, then stirring at room 2 hours.Solvent removed in vacuo, with residue at CHCl
3(100ml) and between the water (50ml) distribute, and tell organic layer, concentrated organic layer obtains the gumminess solid, and it is used the Virahol recrystallization, obtain the white needle shape of 1.1g (88%) 1-cyclopentyl-3-phenmethyl-4-cyano group-5-(phenmethyl carbonyl amino)-1H-pyrazoles, m.p.166-168 ℃.
(b)
(1.1g 2.8mmol) adds 30%H in the solution in ethanol (30ml) at ice-cooled 1-cyclopentyl-3-phenmethyl-4-cyano group-5-(phenmethyl carbonyl amino)-1H-pyrazoles
2O
2(2.5ml), then add the NaOH (100mg) of water-soluble (5ml), reaction mixture stirred 1 hour under this temperature, then stirring at room 1 hour, heating 3.5 hours in vapor bath then, at last with it in stirred overnight at room temperature.Reaction mixture is concentrated into dried, and is allocated in water (25ml) and CHCl
3(50ml).Tell organic layer, vacuum concentration with Virahol crystallization oily residue, obtains 234mg (22%) white solid 1-cyclopentyl-3-phenmethyl-6-(phenmethyl)-pyrazolo [3,4-d] pyrimidin-4-one, m.p.204-206 ℃.
Embodiment 3
(a)
With 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazoles-4-formonitrile HCN (4.50g, 0.022mol), pyridine (5.21g, 0.066mol), and CHCl
3Mixture (75ml) stirred in ice bath 0.5 hour, added CHCl then in 3 hours
3(25ml) 3, and 4-dimethoxy phenyllacetyl chloride (9.44g, 0.044mol).Reaction mixture at room temperature stirred spends the night, solvent removed in vacuo, with residue at CHCl
3(250ml) and between the water distribute.After the layering, use CH
2Cl
2(2 * 150ml) aqueous layer extracted and with the organic layer vacuum concentration that merges.Residue is dissolved in CHCl
3(20ml), use the ether wash-out, with hexane/CHCl also by silica gel chromatography
3(10/1) obtain white needle shape 1-cyclopentyl-3-ethyl-4-cyano group-5-[(3,4-dimethoxy phenmethyl behind the recrystallization) carbonyl amino]-the 1H-pyrazoles.
(b)
At 1-cyclopentyl-3-ethyl-4-cyano group-5-[(3,4-dimethoxy phenmethyl) carbonyl amino]-the 1H-pyrazoles (1.0g, 2.7mmol), ethanol (500ml) and NaOCH
3Add 30%H in the mixture (0.3g)
2O
2(4ml).Reaction mixture at room temperature stirred spend the night, add 30%H in addition
2O
2(3 equivalent) also refluxed reaction mixture 1 hour in vapor bath.Raw material still exists, so add 3 normal 30%H in addition
2O
2And with reaction mixture refluxed 4 hours.Reaction mixture is stripped to dried,, and is stripped to dried once more with acetate and Ethanol Treatment.The oily residue is dissolved in ethanol, adds entry, and cool off this solution with ice bath.Filter and collect the solid that generates,, obtain 0.3g (30%) faint yellow solid shape 1-cyclopentyl-3-ethyl-6-(3,4-dimethoxy phenmethyl)-pyrazolo [3,4-d] pyrimidin-4-one, 1/10 hydrate, m.p.148-149 ℃ 90 ℃ of dryings.
Embodiment 4
(a)
Ice bath cooling down, NaH (1.0g, 25mmol, the dispersed system in 60% mineral oil) is added the 4-pyridine acetic acid hydrochloride, and (4.3g is 25mmol) and in the mixture of DMF (50ml).The gained mixture was stirred 30 minutes, add N then, and N '-phosphinylidyne diimidazole (4.0g, 24.6mmol), after 30 minutes, adding 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazoles-4-formonitrile HCN (4.1g, 20mmol).Under identical temperature, reaction mixture was stirred 4 hours, at room temperature stirred then 2 days, in vapor bath, heated 2 hours at last.Reaction mixture is concentrated into dry doubling adds entry (50ml) and acetate (5ml).Use CH
2Cl
2(300ml) extract this mixture, with the organic layer vacuum concentration,, and pass through silica gel chromatography with the ether crystallization of gained oily matter, use the ether wash-out, obtain the sticking oily 1-cyclopentyl of 2.8g (35%)-3-ethyl-4-cyano group-5-[(4-pyridylmethyl) carbonyl amino]-the 1H-pyrazoles.
(b)
With 1-cyclopentyl-3-ethyl-4-cyano group-5-[(4-pyridylmethyl) carbonyl amino]-the 1H-pyrazoles (2.8g, 8.6mmol), ethanol (50ml), NaOCH
3(1.0g, 18mmol) and 30%H
2O
2Mixture (4.5ml) at room temperature stirred 20 minutes, and reflux is 3.5 hours then.Add 30%H in addition
2O
2(3ml), again with reaction mixture reflux 2 hours.With the reaction mixture vacuum concentration, with residue at CHCl
3(100ml) and 10%NaHCO
3Distribute between the aqueous solution (50ml), tell organic layer.With the organic layer vacuum concentration, with residue hexanaphthene crystallization, solid collected by filtration.Vacuum concentrated filtrate, residue is passed through silica gel chromatography, with the solvent systems wash-out of ether to 10% methanol, with products obtained therefrom ether recrystallization, obtain 420mg 1-cyclopentyl-3-ethyl-6-(4-pyridylmethyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.162-164 ℃.
Embodiment 5
Ice-cooled down, (1.0g 4.5mmol) is dissolved in the solution that benzene (10ml) forms and adds trimethyl aluminium (4.9ml, 2M is in methyl) to 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide.Reaction mixture was at room temperature stirred 1 hour, add 1-(ethoxycarbonylmethyl group) pyrroles (0.7g) who is dissolved in benzene (25ml) then and also this mixture backflow is spent the night.With the reaction mixture cooling, add 2N HCl and use CHCl
3(3x) extract this mixture.Organic layer is told, used MgSO
4Drying, and vacuum concentration.With residue with the ether digestion and from ether recrystallization, obtain 1-cyclopentyl-3-ethyl-6-(1-pyrryl methyl)-pyrazolo [3,4-d] pyrimidin-4-one, m.p.170-172 ℃.
Embodiment 6
Sodium ball (207mg) is dissolved in ethanol (15ml) and adds 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.0g), add subsequently 4-anisole yl acetate (1.62g, 9mmol).With reaction mixture refluxed 16 hours, the stripping solvent added entry in residue, and, use the ether recrystallization with product filtration collection, obtain 0.89g1-cyclopentyl-3-ethyl-6-(4-anisole ylmethyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.172-173 ℃.
Embodiment 7
(1.0g 2.8mmol) is dissolved in and adds 97% NaH (264mg) in the solution that DMF (25ml) forms, and adds propylmercaptan (0.65g) after 20 minutes to 1-cyclopentyl-3-ethyl-6-(4-anisole ylmethyl) pyrazolo [3,4-d] pyrimidin-4-one.With reaction mixture stirring at room 0.5 hour, heating 20 hours in vapor bath then, last heating 8 hours in 120 ℃ oil bath.Add again in addition 97%NaH (264mg) and propylmercaptan (0.77ml) and with reaction mixture 130 ℃ the heating 32 hours.Reaction mixture is added in the frozen water, add acetate and the sedimentation and filtration that forms is collected also drying, after re-crystallizing in ethyl acetate, obtain 0.69g 1-cyclopentyl-3-ethyl-6-(4-hydroxyphenyl methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.264-267 ℃ (dec.).
Embodiment 8
(a)
The solution of 4-hydroxyphenyl acetic acid methyl esters (10g, 0.06) in DMF (100ml) is added the 97%NaH that contains that places ice bath, and (1.78g is among DMF 0.072mol) (60ml).Reaction mixture was stirred 0.5 hour, add then and contain chloromethyl cyanide (5.44g, DMF 0.072mol) (50ml).With this reaction mixture stir about 2 days at room temperature, solvent removed in vacuo is distributed residue between water and ether.Organic layer is separated, use earlier saturated Na
2CO
3, use the salt water washing then, and use MgSO
4Drying is filtered, and vacuum concentration obtains 12.2g 4-(cyano group methoxyl group) phenylacetic acid methyl esters.
(b)
Sodium ball (600mg) is dissolved in the ethanol (15ml), adds 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.0g), add 4-(cyano group methoxyl group) phenylacetic acid ester (1.85g) then.Reaction mixture refluxed is spent the night, with the solvent stripping and add entry.Filter reaction mixture with 2N HCl acidifying, filters filtrate to collect product, uses re-crystallizing in ethyl acetate, obtains 1-cyclopentyl-3-ethyl-6-[4-(carboxymethoxyl) phenyl methyl] pyrazolo [3,4-d] pyrimidin-4-one, m.p.218-220 ℃.
Embodiment 9
Sodium Metal 99.5 (310mg) is dissolved in the ethanol (75ml), add then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.1g, 5mmol) and 2-pyridyl methyl acetate (1.52g, 10mmol).With reaction mixture reflux 28 hours, solvent removed in vacuo, with residue water-soluble (50ml) and use the acetate acidifying.Use CHCl
3(100ml) extract this mixture, remove and desolvate,, obtain the 0.85g crude product the hexanaphthene crystallization of oily residue.This product by silica gel chromatography, is used the ether wash-out, use the hexanaphthene recrystallization subsequently, obtain yellow crystal shape 1-cyclopentyl-3-ethyl-6-(2-pyridylmethyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.120-122 ℃.
Embodiment 10
(a)
NaH with 97% (3.56g, 0.14mol) be suspended among the DMF (100ml) and add 4-hydroxyphenyl methyl acetate (10g, 0.06mol).This reaction mixture was stirred 0.5 hour, add N-(2-chloroethyl) morpholine hydrochloride (11.2g) then and, heating 2 hours in vapor bath then this reaction mixture about 2 days in stirring at room.With reaction mixture cooling, filter and the filtrate stripping.Residue is distributed between water and ether, and the extracted with diethyl ether water layer is used in layering.Organic layer is merged, use the salt water washing, use MgSO
4Drying is filtered and is concentrated, and obtains 11.59g (69%) 4-[2-(4-morpholinyl) oxyethyl group] the phenylacetic acid methyl esters.
(b)
Be dissolved in sodium (414mg) in the ethanol (30ml) and add 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0g) and 4-[2-(4-morpholinyl) oxyethyl group] and the phenylacetic acid methyl esters (5.03g, 18mmol).Reaction mixture refluxed is spent the night, and the stripping solvent adds entry in residue, add subsequently capacity acetate with pH regulator to 8-9.Collect oily matter, water and saturated NaHCO by decantation
3Handle.With this mixture ethyl acetate extraction, water is used saturated NaHCO then
3(2x) washing.With water layer another part ethyl acetate extraction, with organic layer 2N NaOH and the salt water washing that merges.With organic layer MgSO
4Drying is filtered, and stripping obtains crude product with ether digestion and filtration.This crude product by acid/alkaline purification for several times, is used the ether recrystallization subsequently, obtains 1.67g 1-cyclopentyl-3-ethyl-6-[4-[2-(4-morpholinyl) oxyethyl group] phenyl methyl] pyrazolo [3,4-d] pyrimidin-4-one, m.p.136-137 ℃.
Embodiment 11
(a)
With 4-(cyano group methoxyl group) phenylacetic acid methyl esters (2.5g, 12mmol), NaN
3(0.87g), NH
4Cl (0.72g, 13mmol) and the mixture of DMF (20ml) 125 ℃ the heating 24 hours.With this reaction mixture cooling, add entry, and this mixture coupling vacuum stripping, but solution is not stripped to dried.Repeat this operation (2x) and add entry then, then add 2N HCl.The product that crystallization in the solution is gone out filters collection, washes with water, and dry air obtains 1.7g (60%) 4-(5-tetrazyl methoxyl group) phenylacetic acid methyl esters.
(b)
Sodium (0.253g) is dissolved in ethanol (15ml), add then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.813g, 3.7mmol) and 4-(5-tetrazyl methoxyl group) phenylacetic acid methyl esters (17g, 7.3mmol).With about 2 days of reaction mixture refluxed, cooling, solvent removed in vacuo then.With residue water and acetic acid treatment, with the sedimentation and filtration collection of formation and 60 ℃ of vacuum-dryings.This product is dissolved in ethyl acetate, uses Na
2CO
3(4 * 200ml) extractions are acidified to pH2.5 with water layer with dense HCl, use ethyl acetate (2 * 300ml) aqueous layer extracted, and with organic layer MgSO then
4Drying is filtered and vacuum concentration.With the solid residue re-crystallizing in ethyl acetate, obtain 0.21g 1-cyclopentyl-3-ethyl-6-[4-(5-tetrazyl methoxyl group) phenyl methyl] pyrazolo [3,4-d] pyrimidin-4-one, 2/5 hydrate, m.p.240-242 ℃.
Embodiment 12
(a)
NaH (3.0g with 97%, 0.12mol) suspension in DMF (100mL) stirred 0.5 hour, in 30 minutes, add then the benzoglyoxaline that is present among the DMF (50mL) (11.8g, 0.1mol), then add the bromoethyl acetate that is present among the DMF (50mL) (20g, 0.12mol).Reaction mixture at room temperature stirred spend the night, add NH
4Cl, and, in residue, add entry with the reaction mixture stripping, and it is used CH
2Cl
2(3 * 200mL) extractions.With organic layer MgSO
4Drying is filtered vacuum concentration.Residue is handled with ethyl acetate, filtered and collect white solid, vacuum concentrated filtrate with residue water recrystallization, obtains 8.0g1-(ethoxycarbonylmethyl group) benzoglyoxaline, mp.63-64 ℃.
(b)
Sodium (338mg) is dissolved in the ethanol (30mL), add 1-(ethoxycarbonylmethyl group) benzoglyoxaline (3.0g, 14.7mmol) and-1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.6g).Reaction mixture refluxed is spent the night stripping solvent and water and acetic acid treatment residue.Filter and collect formed precipitation, wash with water, obtain 1.96g (75%) 1-cyclopentyl-3-ethyl-6-[1-benzoglyoxaline ylmethyl] pyrazolo [3,4-d] pyrimidin-4-one, m.p.256-259 ℃.
Embodiment 13
(0.11g) is dissolved in ethanol with sodium, and (0.49g 2.21mmol), adds the 3-pyridyl ethyl acetate (0.73g) that is contained in the ethanol (2mL) again after 10 minutes to add 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide then.Reaction mixture refluxed is spent the night, add 3-pyridyl acetic ester (0.35g) again, reaction mixture is refluxed again spend the night.Reaction mixture is cooled to room temperature, the stripping solvent, and residue is water-soluble and with acetic acid treatment (to pH7).With this mixture CHCl
3(3 * 50mL) extractions merge organic layer, use MgSO
4Drying, stripping obtains light yellow oil.This oily matter is collected product by adding the ether crystallization, filtering,, obtains 0.4g 1-cyclopentyl-3-ethyl-6-[3-pyridylmethyl with the ether washing] pyrazolo [3,4-d] pyrimidin-4-one.
Embodiment 14
Formaldehyde with 37% (5mL) adds 1-cyclopentyl-3-ethyl-6-[4-hydroxybenzene methyl] (2.68g is 7.9mmol) and in the suspension of 40% diethylamine (5mL) in acetate (50mL) for pyrazolo [3,4-d] pyrimidin-4-one.Reaction mixture stirring at room 2 hours, is heated them 4 hours in 100 ℃ vapor bath then.The stripping solvent, in residue, add ethanol, stripping ethanol then, by preparation thin-layer chromatography purifying residue, launch with 5% Isopropylamine/ethyl acetate, will get product usefulness ether recrystallization after, obtain 0.79g 1-cyclopentyl-3-ethyl-6-[3,5-dimethylamino-4-hydroxybenzene methyl] pyrazolo [3,4-d] pyrimidin-4-one, m.p.164-166 ℃.
Embodiment 15
(a)
The solution of bromoethyl acetate (20.9g) in acetonitrile (30mL) is added K
2CO
3(27.6g, 0.2mol) with 1,2,3, (13.3g is 0.1mol) in the mixture in acetonitrile (220mL) for 4-tetrahydrochysene-2-isoquinoline 99.9.With reaction mixture stir about 2 days at room temperature, refluxed then 4 hours.Filter reaction mixture, vacuum concentrated filtrate distributes residue between ether and water.Ether layer is told, used MgSO
4Drying, vacuum concentration obtains a kind of fluent meterial, and it is dissolved in ether (200mL), cools off and uses Et
2OHCl handles, and obtains 12.5g (77%) 1, and 2,3,4-tetrahydrochysene-2-isoquinolyl ethyl acetate hydrochloride.
(b)
With 1,2,3,4-tetrahydrochysene-2-isoquinolyl ethyl acetate hydrochloride (3.63g) water-soluble (100mL) is used NaHCO
3Handle, use ether (3 * 75mL) extractions then.With the organic layer MgSO that merges
4Drying is filtered and stripping, obtains 3.02g light yellow liquid shape 1,2,3,4-tetrahydrochysene-2-isoquinolyl ethyl acetate.
(c)
With sodium (0.24g) be dissolved in ethanol (25mL) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.09g, 4.91mmol) in, add 1,2,3 subsequently, 4-tetrahydrochysene-2-isoquinolyl ethyl acetate (2.15g).With about 2 days of reaction mixture refluxed, stripping solvent, water and acetic acid treatment residue.Use CHCl
3(3 * 100ml) extract formed jelly, and with the organic layer MgSO that merges
4Drying is filtered and stripping, obtains yellow solid, and it is washed with ether, obtains crude product (0.6g).The crude product of this crude product with the experimental approach that comes self similarity merged, and this mixture is passed through silica gel chromatography, with ethyl acetate/hexane (1/1) wash-out.Another part product also can obtain from the concentrating of above-mentioned ether filtrate, and can be by the above-mentioned column chromatography purification that carries out.Product is flowed part precipitation and uses the ether recrystallization, obtain white solid 1-cyclopentyl-3-ethyl-6-(1,2,3,4-tetrahydrochysene-2-isoquinolyl methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.149-151 ℃.
Embodiment 16
(a)
Stir down, (8.4mL) splashes into K with bromoethyl acetate
2CO
3(20.7g, 150mmol) and 1,2,3,4-tetrahydrochysene-1-quinoline (10.0g, 75.08mmol) in the mixture in acetonitrile (150mL), and with this mixture stirring at room 48 hours.Reaction mixture is filtered, and vacuum concentrated filtrate distributes residue between ether and water.Organic layer is told, used the salt water washing, use MgSO
4Drying, evaporation obtains 15.0g (91%) amber color liquid shape 1,2,3,4-tetrahydrochysene-1-quinolyl ethyl acetate.
(b)
With sodium (0.33g) be dissolved in ethanol (30mL) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.54g, 6.94mmol) in, add 1,2,3 in the ethanol (5-10mL) subsequently, 4-tetrahydrochysene-1-quinolyl ethyl acetate (3.04g).With about two days of reaction mixture reflux, the stripping solvent neutralized gained oily residue with water treatment and with acetate.With formed precipitation CHCl
3Extract, use MgSO
4Drying, stripping obtains amber oil.Should pass through silica gel chromatography by oil,, use the acetonitrile recrystallization subsequently, obtain white crystalline solid shape 1-cyclopentyl-3-ethyl-6-(1,2,3,4-tetrahydrochysene-1-quinolyl methyl) pyrazolo [3,4-d] pyrimidin-4-one with ethyl acetate/hexane (1/1) wash-out.
Embodiment 17
(0.68g) is dissolved in the ethanol with sodium, successively add 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.0g, 13.5mmol), the glycolic acid ethyl ester (2.8g, 27mmol).Reaction mixture refluxed is spent the night,, in residue, successively add entry and 2N HCl the ethanol stripping.Filter and collect the precipitation that forms, successively use saturated NaHCO
3And water washing.Product is successively used ethyl acetate and ether recrystallization, obtain pyrimidin-4-one m.p.183-184 ℃ of 0.83g 1-cyclopentyl-3-ethyl-6-(methylol) pyrazolo [3,4-d].
Embodiment 18
(a)
Under-50 ℃, 1-cyclopentyl-3-ethyl-6-(methylol) pyrazolo [3,4-d] pyrimidin-4-one (1.0g, 3.8mmol), CH
2Cl
2(25mL) and triethylamine (0.77g adds CH in mixture 7.6mmol)
2Cl
2Methylsulfonyl chloride (5mL) (0.44g, 3.8mmol).Reaction mixture was stirred 1 hour, add CH
2Cl
2And water, tell organic layer, use MgSO
4Drying is filtered and vacuum concentration, obtains the 1.28g crude product.The product of crude product with the experimental approach that comes self similarity merged, and, obtain 1-cyclopentyl-3-ethyl-6-(methylsulfonyl oxygen methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.138-140 ℃ this mixture ether (2x) recrystallization.
(b)
With 1-cyclopentyl-3-ethyl-6-(methylsulfonyl oxygen methyl) pyrazolo [3,4-d] pyrimidin-4-one (1.8g, 15.3mmol), 1-(first carbonyl) imidazoles (640mg, 5.8mmol) and CH
3The mixture heating up of CN (36mL) refluxed 6 hours.With the solvent stripping, add frozen water and saturated NaHCO
3, and, use MgSO with this mixture ethyl acetate extraction
4Drying is filtered and stripping.The product of this product with the experimental approach that comes self similarity merged, and with this mixture re-crystallizing in ethyl acetate.This product is handled with 2N HCl, used ethyl acetate extraction, and use NaHCO
3In and water layer, use ethyl acetate extraction, use MgSO
4Drying is filtered and stripping.With the residue re-crystallizing in ethyl acetate, obtain 0.54g 1-cyclopentyl-3-ethyl-6-(1-imidazolyl methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.252-253 ℃.
Embodiment 19
Sodium (1.19g) is dissolved in the ethanol (85mL), and (5.7g is 26mmol) with 3-methoxyphenyl acetic acid ethyl ester (10g) successively to add 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide.Reaction mixture refluxed is spent the night, be cooled to room temperature, the stripping solvent.In residue, successively add entry and 2N HCl, filter and collect the precipitation that forms, and it is used re-crystallizing in ethyl acetate, obtain 5.08g 1-cyclopentyl-3-ethyl-6-(3-mehtoxybenzyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.148-150 ℃.
Embodiment 20 adds 1-cyclopentyl-3-ethyl-6-(3-mehtoxybenzyl) pyrazolo [3 with 97%NaH (1.26g), 4-d] (4.49g is 13mmol) in the solution in DMF (123mL), after 20 minutes for pyrimidin-4-one, the adding propylmercaptan (2.96g, 39mmol).Reaction mixture 130 ℃ of heated overnight, is cooled to room temperature, successively adds frozen water and acetate then.The precipitation that filter to collect forms use the ether recrystallization, and drying under 110 ℃ and 2mmHg obtains 2.72g 1-cyclopentyl-3-ethyl-6-(3-hydroxybenzene methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.195-197 ℃.
Embodiment 21
(a)
With the 3-hydroxyl phenylacetic acid (10g, 66mmol), HCl ethanolic soln (160mL) and H
2SO
4Mixture (1mL) refluxes and spends the night.The stripping solvent obtains 11.66g (98%) 3-hydroxyl phenylacetic acid ethyl ester.
(b)
With 97%NaH (1.75g, 0.07mol) suspension in DMF (50mL) stirred 15 minutes, add then 3-hydroxyl phenylacetic acid ethyl ester among the DMF (25mL) (5.4g, 0.03mol).Reaction mixture was stirred 0.5 hour, in ice bath, cool off then, and adding N-(2-chloroethyl) morpholine hydrochloride (5.6g, 0.03mol).Reaction mixture at room temperature placed spend the night, heating four hours in vapor bath then.The stripping solvent distributes residue between cold water and ether, tell organic layer, and uses the extracted with diethyl ether water layer.Organic layer is merged, use MgSO
4Drying is filtered and stripping, obtains crude product, and it by silica gel chromatography, is used eluent ethyl acetate, obtains 4.64g 3-[2-(4-morpholinyl) oxyethyl group] Phenylacetic acid ethylester.
(c)
Sodium (364mg) is dissolved in ethanol (30mL) adds 3-[2-(4-morpholinyl) oxyethyl group in 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.75g) and the ethanol (7mL) then successively] Phenylacetic acid ethylester (4.64g).With reaction mixture refluxed 2 days, the stripping solvent added entry and acetate successively in residue.With this mixture NaHCO
3Handle, (2 * 300mL) extractions merge organic layer and use saturated Na with ethyl acetate
2CO
3The salt water washing is used in washing then.With organic layer MgSO
4Drying is filtered and stripping, obtains the crude product of 2.89g.This crude product is passed through silica gel chromatography, use eluent ethyl acetate, use the ether recrystallization, after 75 ℃ and 0.2mmHg drying, obtain 1.21g 1-cyclopentyl-3-ethyl-6-[3-[2-(4-morpholinyl) oxyethyl group] phenmethyl] pyrazolo [3,4-d] pyrimidin-4-one.
Embodiment 22
With sodium grain (1.0g, 43.5mmol) under refluxing, be dissolved in the ethanol (50mL), add successively then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.2g, 10mmol) and the 1-methylpyrrole-2-methyl acetate in the ethanol (30ml) (3.06g, 20mmol).Reaction mixture is flow through night next time in argon atmospher, be cooled to room temperature, be evaporated to dried.Residue is water-soluble, cool off this solution and filter collection gained solid, the raw material that obtains reclaiming.Filtrate is freezing, filter and collect the solid that forms, the water pulping is with 2N HCl acidifying.With this mixture cooling, filter and collect product, 110 ℃ of vacuum-dryings, obtain 1.2g 1-cyclopentyl-3-ethyl-6-(1-methyl-2-pyrryl methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.214.5-216.5 ℃.By acetate acidifying filtrate, filter and collect product, use re-crystallizing in ethyl acetate, can obtain another part product (0.6g).
Embodiment 23
(a)
With 1-cyclopentyl-3-ethyl-6-(methylol) pyrazolo [3,4-d] pyrimidin-4-ones (5.15g) at CH
2Cl
2Solution in (1 20mL) is cooled to-50 ℃, adds triethylamine (4.7mL) successively, CH
2Cl
2Methylsulfonyl chloride (24mL) (2.09g, 18mmol).Reaction mixture is warmed to room temperature and stirred 3 hours.In reaction mixture, add entry and CH
2Cl
2, make its layering, use CH
2Cl
2Aqueous layer extracted.Organic layer is merged, use MgSO
4Drying is filtered and stripping.Residue is changed in the ether, drain isolated oil, use activated carbon treatment filtrate, filter vacuum concentration.Residue with ether recrystallization and dry under 75 ℃ and 0.2mmHg, is obtained 1.58g l-cyclopentyl-3-ethyl-4-methanesulfonamido-6-(methylsulfonyl oxygen methyl) pyrazolo [3,4-d] pyrimidine, m.p114-116 ℃.
(c)
97%NaH (0.158g) was stirred 15 minutes in DMF (25mL), add successively then pyrazoles (0.372g, 58mmol) and 1-cyclopentyl-3-ethyl-4-mesyloxy-6-(mesyloxy methyl) pyrazolo [3,4-d] and pyrimidine (1.22g, 2.9mmol).Reaction mixture was at room temperature stirred 2 hours, then heated overnight in vapor bath.In reaction mixture, add entry, then add capacity 2N HCl acidifying mixture.This mixture was placed 1.5 hours, and filtration is collected product and is washed with water.This product by preparation of silica gel thin-layer chromatography purifying, is launched with 50% ethyl acetate/hexane, use the ether recrystallization, under 75 ℃ and 0.2mmHg after the drying, obtain 0.26g 1-cyclopentyl-3-ethyl-6-(1-pyrazolyl methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.130-131 ℃.
Embodiment 24
(a)
With 4-trifluoromethyl phenylacetic acid (15g), HCl ethanolic soln (200mL) and H
2SO
4Mixture (1mL) refluxes and spends the night.The stripping solvent, with residue at ethyl acetate and saturated NaHCO
3Between distribute, tell organic layer, use the salt water washing, use MgSO
4Drying is filtered and is concentrated, and obtains 15.35g (90%) 4-trifluoromethyl phenylacetic acid ethyl ester.
(b)
Sodium (622mg) is dissolved in the ethanol (45mL), add successively then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.0g, 13.5mmol) and 4-trifluoromethyl phenylacetic acid ethyl ester (6.27g, 27mmol).Reaction mixture refluxed is spent the night, be cooled to room temperature, the stripping solvent.In residue, add entry and 2N HCl successively, filter and collect product, use the ether recrystallization, 110 ℃ and 0.2mmHg drying, obtain 3.03g 1-cyclopentyl-3-ethyl-6-(4-trifluoromethyl phenmethyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.212-213 ℃.
Embodiment 25
(a) and (b)
Under-10 to-15 ℃, to 90%HNO
3Adding 1-cyclopentyl-3-ethyl-6-(phenmethyl) pyrazolo [3,4-d] pyrimidin-4-one (95mL) (9.62g, 30mmol).Reaction mixture was stirred 1.5 hours under said temperature, be poured in the frozen water then.Filter and collect the precipitation that forms, use re-crystallizing in ethyl acetate, dry under 100 ℃ and 0.2mmHg, obtain 2.31g 1-cyclopentyl-3-ethyl-6-(4-oil of mirbane methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.221-223 ℃ [being labeled as embodiment 25 (a)].Mother liquor is merged, vacuum concentration, obtain the mixture [being labeled as embodiment 25 (b)] of 1-cyclopentyl-3 ethyls-6-(2-oil of mirbane methyl) pyrazolo [3,4-d] pyrimidin-4-one and 1-cyclopentyl-3-ethyl-6-(3-oil of mirbane methyl) pyrazolo [3,4-d] pyrimidine-4-.
Embodiment 26
Use 10% palladium charcoal (200mg) as catalyzer, and (the 4-oil of mirbane methyl) pyrazolo of the 1-cyclopentyl-3-ethyl-6-in 55psi hydrogenation DMF (50mL) [3,4-d] pyrimidin-4-one (2.12g, 5.8mmol).Reaction mixture is passed through SUPERCELL
Filter, vacuum concentrated filtrate with the residue re-crystallizing in ethyl acetate, after 100 ℃ and 0.2mmHg drying, obtains 1.28g 1-cyclopentyl-3-ethyl-6-(4-amino-benzene methyl) pyrazolo [3,4-d] pyrimidin-4-one 1/4 hydrate, m.p.198-199 ℃.
Embodiment 27
(a)
(25g 0.16mol) adds K in the solution in DMF (300mL) successively to 2-Hydroxyphenyl Acetic Acid
2CO
3(56.7g, 0.41mol) and methyl iodide (46.7g, 0.32mol).With reaction mixture stir about 3 days, filter stripping filtrate.Change residue over to ethyl acetate, use water saturation Na
2CO
3With the salt water washing, with organic layer MgSO
4Drying is filtered, and stripping obtains 26.4g (92%) 2-methoxyphenylacetic acid methyl esters.
(b)
Sodium (590mg) is dissolved in ethanol (45mL), add successively then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.65g, 12mmol) and 2-methoxyphenylacetic acid methyl esters (4.7g, 26mmol).Reaction mixture refluxed is spent the night, the stripping solvent, water and 2N HCl handle residue successively.Filter and collect product, use re-crystallizing in ethyl acetate, obtain 2.23g 1-cyclopentyl-3-ethyl-6-(2-mehtoxybenzyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.145-146 ℃.
Embodiment 28
(a)
With 3-ethanoyl-ethyl 4-oxopentanoate (37.24g, 0.2mol), hydroxy amine hydrochloric acid salt (1 4.6g, 0.21mol), NaOAc (17.23g, 0.21mol) and the mixture of ethanol (500mL) refluxed 4 hours.Reaction mixture is filtered, vacuum concentrated filtrate, and with residue (12.61g, heating is 6 to 6.5 hours 0.21mol) and in the toluene (300mL), with except that anhydrating at acetate.Filter reaction mixture, vacuum concentrated filtrate obtains brown yellow oil, with its crystallisation by cooling.Filter and collect product,, obtain 1.26g 3,5-dimethyl-4-isoxazolyl ethyl acetate, m.p.180-182 ℃ with the ether washing.By concentrating ether filtrate and will obtaining another part product at 69-81.5 ℃ and 0.05mmHg distillation leftover, 31.18g (85%) altogether.
(b)
Sodium grain (0.23g) is dissolved in the ethanol (50mL) of backflow, add successively then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.1g, 5mmol) and 3,5-dimethyl-4-isoxazolyl ethyl acetate (1.83g, 10mmol).Reaction mixture was refluxed 72 hours under argon atmospher, use the acetate acidifying, then vacuum concentration.Use the ether extraction residue, ether layer is washed with water, use MgSO
4Drying is filtered, and CH is used in evaporation
3CN/ ether recrystallization obtains 0.65g yellow crystal solid state 1-cyclopentyl-3-ethyl-6-(3,5-dimethyl-4-isoxazolyl methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.179.5-180 ℃.
Embodiment 29
Under the ice bath cooling, (0.54mL 3.8mmol) adds 1-cyclopentyl-3-ethyl-6-(4-amino-benzene methyl) pyrazolo [3 with triethylamine, 4-d] pyrimidin-4-one (1.3g, 3.8mmol) in the solution in pyridine (30mL), add then methylsulfonyl chloride (0.52g, 4.6mmol).Reaction mixture was stirred 3 hours under identical temperature, at room temperature stir then and spend the night.In reaction mixture, add entry, filter and collect crude product.Crude product is changed in the ethyl acetate, with 2N HCl washing, and with this mixture filtration.Filtrate is used MgSO
4Drying is filtered, and stripping use re-crystallizing in ethyl acetate, and drying under 110 ℃ and 0.2mmHg obtains 0.65g 1-cyclopentyl-3-ethyl-6-[4-(methanesulfonamido) phenmethyl] pyrazolo [3,4-d] pyrimidin-4-one, m.p.242-243 ℃.
Embodiment 30
With 1-cyclopentyl-3-ethyl-6-(2-mehtoxybenzyl) pyrazolo [3,4-d] pyrimidin-4-one (1.64g, 4.6mmol) solution in DMF (45ml) with 97%NaH (0.46g 19mmol) handles, add subsequently the 3-propylmercaptan (1.08g, 14mmol).Reaction mixture 130 ℃ of heated overnight, is cooled to room temperature.Add frozen water and acetate successively, filter and collect product, and wash with water.With the product re-crystallizing in ethyl acetate, dry under 100 ℃ and 0.2mmHg, obtain 1.27g (8.2%) 1-cyclopentyl-3-ethyl-6-(2-(2-hydroxybenzene methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.191-193 ℃.
Embodiment 31
Sodium (414mg) is dissolved in the ethanol (45mL), add successively 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2g, 9mmol), 3-thienyl ethyl acetate (3.1g, 18mmol).With about 2 days of reaction mixture refluxed, with the solvent stripping.Residue water successively and rare HCl are handled, filtered and collect product.With the product re-crystallizing in ethyl acetate, dry under 100 ℃ and 0.2mmHg, obtain 1.25g 1-cyclopentyl-3-ethyl-6-(3-thenyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.210-211
Embodiment 32
Sodium (414mg) is dissolved in the ethanol (45mL), add successively 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2g, 9mmol) and 2-thienyl ethyl acetate (3.1g, 18mmol).Reaction mixture refluxed is spent the night, be cooled to room temperature and the ethanol stripping.In residue, add entry and 2N HCl successively, filter and collect product, and wash with water, with the product re-crystallizing in ethyl acetate, dry under 90 ℃ and 0.2mmHg, obtain 119g 1-cyclopentyl-3-ethyl-6-(2-thenyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.173-174 ℃.
Embodiment 33
(a)
Under the ice bath cooling, in 20 minutes, (32.2g, (17.1g is 0.1mol) in the solution in ethanol (200ml) 0.44mol) to splash into the 4-chloromethyl benzoic acid with diethylamine.With reaction mixture refluxed 17 hours, be cooled to room temperature and with the solvent stripping.Residue is dissolved in 1NNaOH (50ml).With ether (50-100ml) extraction, water layer is acidified to pH3 with 2N HCl.The stripping water layer is used the Ethanol Treatment residue, filters, with the ethanol stripping.Residue with Virahol (3x) recrystallization, is obtained 13.54g 4-diethylin tolyl acid hydrochloride, m.p.189-191 ℃.
(b)
With 4-diethylin tolyl acid hydrochloride (360mg, 1.5mmol), N, N '-phosphinylidyne diimidazole (264mg, 1.5mmol) He the mixture of diox (20ml) in oil bath, heated 1 hour.Reaction mixture is cooled to room temperature, add 1-cyclopentyl-3-ethyl-6-(4-hydroxybenzene methyl) pyrazolo [3,4-d] pyrimidin-4-one (500mg, 105mmol) with diox (10ml), with this mixture 100 ℃ of heated overnight.With the reaction mixture cooling, the stripping solvent adds entry and ethyl acetate then.Tell ethyl acetate layer, with 2N HCl (4 * 150ml) washings.Water layer is merged, use dense NH
4OH handles, and uses ethyl acetate (2x) extraction then.With ethyl acetate layer salt water washing, use MgSO
4Drying is filtered and stripping, obtains crude product.With crude product with merge from the crude product of similar experiment approach, with this mixture ether recrystallization, obtain 0.46g 1-cyclopentyl-3-ethyl-6-[4-[4-(diethylin methyl) phenyl carbonyl oxygen base] phenmethyl] pyrazolo [3,4-d] pyrimidin-4-one, m.p.143-145 ℃.
Embodiment 34
In the presence of 10% palladium charcoal (700mg), hydrogenation 1-cyclopentyl-3-ethyl-6-under the pressure of 55psi (2-oil of mirbane methyl) pyrazolo [3,4-d] pyrimidin-4-one and 1-cyclopentyl-3-ethyl-6-(3-oil of mirbane methyl) pyrazolo [3,4-d] pyrimidin-4-one (7.1g, 19mmol) mixture in DMF (300mL) is used SUPERCELL
Filter reaction mixture with the filtrate stripping, obtains crude product.With this crude product to merge from the crude product of two other similar experimental approach, with this mixture re-crystallizing in ethyl acetate, then by the silica gel chromatography purifying, with 50% ethyl acetate/hexane wash-out, use re-crystallizing in ethyl acetate, obtain 111g 1-cyclopentyl-3-ethyl-6-(2-amino-benzene methyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.190-192 ℃.
Embodiment 35
(a)
With 4-dimethylamino toluylic acid (10g, 56mmol), the ethanolic soln of HCl (160mL) and dense H
2SO
4Mixture (1mL) (1mL) refluxes and spends the night.The stripping solvent adds ethyl acetate and rare NH in residue
4OH, and layering.With organic layer salt water washing, use MgSO
4Drying is filtered and stripping, obtains 8.32g (72%) 4-dimethylamino Phenylacetic acid ethylester.
(b)
Sodium (920mg) is dissolved in ethanol (67mL), add successively 4-dimethylamino Phenylacetic acid ethylester (8.32g, 40mmol) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (4.44g, 20mmol), with about 2 days of reaction mixture refluxed.Reaction mixture is cooled to room temperature, and stripping ethanol adds entry in residue.Filter to collect product, wash with water, dry under 100 ℃ and 0.2mmHg with ethyl acetate (2x) recrystallization, obtain 3.41g 1-cyclopentyl-3-ethyl-6-(4-dimethylamino phenmethyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.225-226 ℃.Embodiment 36
(a)
Use 40%TRITON
The methanol solution of B (3mL) handle 4-(1-imidazolyl) phenyl aldehyde (5.08g, 29.5mmol) and methyl (methylthio group) methyl sulfoxide (2.57g, 21mmol) mixture in THF (5mL).With reaction mixture refluxed 4 hours, add another part methyl (methylthio group) methyl sulfoxide (1.09g, 8.5mmol), again with reaction mixture refluxed 2 hours.Reaction mixture is cooled to room temperature, adds CH
2Cl
2,, use MgSO with organic layer water successively and salt water washing
4Drying is filtered and stripping.Change residue over to HCl ethanolic soln (180mL), refluxed 16 hours.Reaction mixture, stripping ethanol is handled residue water (200mL), and extracts with ethyl acetate (250mL).With the rare NH of water layer
4OH handles, with ethyl acetate (2x) extraction.Then organic layer is used the salt water washing, used MgSO
4Drying is filtered and stripping, obtains crude product.Change this crude product over to ethyl acetate, use 25% sodium bisulfite and salt solution jolting successively.With the water layer ethyl acetate extraction, with the organic layer that merges with using MgSO
4Drying is filtered and stripping, obtains 193g 4-(1-imidazolyl) Phenylacetic acid ethylester.
(b)
Sodium (193mg) is dissolved in ethanol (25mL), add successively 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.93g, 4.2mmol), and the 4-in the ethanol (7mL) (1-imidazolyl) Phenylacetic acid ethylester (1.93g, 8.4mmol).Reaction mixture refluxed is spent the night, and stripping ethanol adds entry in residue.Cool off this mixture, filter and collect crude product.Crude product and 1N HCl are stirred, filter the product of collecting hydrochloride form.With the rare NH of this hydrochloride
4OH handles, and filters and collects the gained precipitation, and it is used re-crystallizing in ethyl acetate, knows drying under the 0.2mmHg at 100 ℃, obtains 0.4g 1-cyclopentyl-3-ethyl-6-[4-(1-imidazolyl) phenmethyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.232-234 ℃.
Embodiment 37
(a)
(70mL, (68g, 0.5mol) (62.3g is 0.5mol) in the mixture in ethanol (500mL) with the tertiary butyl hydrazonium salt hydrochlorate 0.5mol) to add (1-oxyethyl group ethylidene) propane dinitrile with triethylamine.Reaction mixture was at room temperature stirred 2 hours, in ice, cool off then, filter and collect product and, obtain the 85.9g 1-tertiary butyl-3-methyl-5-amino-1H-pyrazoles-4-formonitrile HCN 2/3Et with the ether washing
3N-HCl.By concentrated mother liquor, residue can be obtained the required product of other 46.2g with ethyl alcohol recrystallization.
(b)
With the 1-tertiary butyl-3-methyl-5-amino-1H-pyrazoles-4-formonitrile HCN 2/3Et
3NHCl (38g, 0.12mol) and the mixture heating up to 85 of water (250mL) ℃.Filter and collect the product that from reaction mixture, is settled out, obtain 23.25g 1-tertiary butyl 3-methyl-5-amino-1H-pyrazoles-4-formonitrile HCN, m.p.156-157 ℃.
(c)
At 0 ℃, at water (200mL), (37g adds 30%H successively in mixture 0.56mol) for ethanol (120mL) and KOH
2O
2(89.1g, 0.786mol) and the 1-tertiary butyl-3-methyl-5-amino-1H-pyrazoles-4-formonitrile HCN (20.0g, 0.112mol), reaction mixture was stirred 4 hours, filter and collect product, wash drying with water, obtain the white needle shape of 20.64g (94%) the 1-tertiary butyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide, m.p.195-196 ℃.
(d)
With the 1-tertiary butyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide (1.0g, 5.1mmol), Phenylacetic acid ethylester (1.67g, 10.2mmol), NaOCH
3(1.74g, 31mmol) and the mixture of ethanol (50mL) refluxed about 3 days.Reaction mixture is stripped to dried,, uses the acetate acidifying then the residue water treatment.Filter and collect product, wash with water, drying obtains 0.53g (35%) the 1-tertiary butyl-3-methyl-6-(phenmethyl) pyrazolo [3,4-d] pyrimidin-4-one 1/5 hydrate, m.p.196-197 ℃.
Embodiment 38
(a)
(4.6g, 20.7mmol), (6.4g, 40mmol) mixture with N-N-methyl-2-2-pyrrolidone N-(15mL) heated 5 hours at 150-160 ℃ o-xanthogenic acid sylvite with 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide.Reaction mixture.Add entry, and this mixture is filtered.Use activated carbon treatment filtrate, use the acetate acidifying then.The precipitation that filter to collect forms washes with water and 90-95 ℃ of drying, obtains 4.7g 1-cyclopentyl-3-ethyl-6-(sulfo-) pyrazolo [3,4-d] pyrimidin-4-one, m.p.249-251 ℃.
(b)
With 1-cyclopentyl-3-ethyl-6-(sulfo-) pyrazolo [3,4-d] pyrimidin-4-one (5.2g, 19.6mmol), DMF (50mL) and K
2CO
3(2.76g, mixture 20mmol) at room temperature stirred 25 minutes, add then methyl-sulfate (3.88mL, 40mmol).Reaction mixture was stirred 2 hours, pour into then in the cold water, filter and collect product, wash with water, with hexanaphthene/ether recrystallization, 70-75 ℃ of vacuum-drying, obtain 4.6g1-cyclopentyl-3-ethyl-6-(methylthio group) pyrazolo [3,4-d] pyrimidin-4-one, m.p.200-202 ℃.
Optionally, this product also can be prepared as follows: under agitation, in 15 minutes, with NaH (4.0g, 0.1mol, dispersed system in 60% mineral oil) cyclopentyl-(23.4g is 0.09mol) in the mixture in DMF (250mL) for 3-ethyl-6-(sulfo-) pyrazolo [3,4-d] pyrimidin-4-one to add 1-.The gained mixture is cooled off in ice bath, and (6.3mL 0.1mol), and stirs the gained mixture 3 hours to add methyl-iodide then in 20 minutes.Reaction mixture is poured in the frozen water (400mL), filtered and collect the precipitation that forms, water and hexane wash successively, 80-85 ℃ of vacuum-drying, obtain 18.6g (74%) 1-cyclopentyl-3 ethyls-6-(methylthio group) pyrazolo [3,4-d] pyrimidin-4-one, m.p.203-205 ℃.
(c)
With 1-cyclopentyl-3-ethyl-6-(methylthio group) pyrazolo [3,4-d] pyrimidin-4-ones (4g), CHCl
3(100mL) spend the night with the mixture stirring of m-chloroperoxybenzoic acid (10.3g).With the saturated NaHCO of reaction mixture
3The aqueous solution (100mL) extraction is with CHCl
3Layer MgSO
4Drying filters and is concentrated into dried.Placement makes the crystallization of oily residue, uses the hexanaphthene recrystallization, 70-75 ℃ of vacuum-drying, obtains 1-cyclopentyl-3-ethyl-6-(methylsulfonyl) pyrazolo [3,4-d] pyrimidin-4-one, m.p.＞300 ℃.
(d)
1-cyclopentyl-3-ethyl-6-(methylsulfonyl) pyrazolo [3,4-d] pyrimidin-4-one (2.3g, 7.4mmol) and aniline (1.2g, mixture 13mmol) 180-190 ℃ the heating 3 hours.Reaction mixture is cooled to room temperature and at room temperature places and spend the night.In reaction mixture, add ether, filter and collect product,,, obtain crude product 80-85 ℃ of vacuum-drying with the ether washing.With the saturated NaHCO of crude product
3(25mL) handle, filter and collect insolubles, it is dissolved in hot Virahol, use activated carbon treatment, vacuum concentration.With residue ether crystallization,, obtain 0.58g (25%) 1-cyclopentyl-3-ethyl-6-(phenylamino) pyrazolo [3,4-d] pyrimidin-4-one 80-85 ℃ of vacuum-drying.
Embodiment 39
With 1-cyclopentyl-3-ethyl-6-(methylsulfonyl) pyrazolo [3,4-d] pyrimidin-4-one (3g, 9.6mmol), phenol (6g, 64mmol) and the mixture of NaH (O.5g, 12.8mmol, the dispersed system in 60% mineral oil) 170-175 ℃ the heating 5 hours.Reaction mixture is poured in the water (50mL), used CHCl
3(100mL) extraction.With CHCl
3Layer vacuum concentration by silica gel chromatography, with 10% ether/hexane wash-out, obtains 2.1g (68%) white solid 1-cyclopentyl-3-ethyl-6-(phenoxy group) pyrazolo [3,4-d] pyrimidin-4-one, m.p.175-177 ℃ with residue.
The biological test result
In the biological test step of standard, have been found that formula I compound has c-GMP-PDEV (being called as c-GMP-PDEI in the past) and suppresses active, therefore can be used to treat heart failure and hypertension.Have now found that, be used in combination formula I compound with nitric ether and can be used to reverse or reduce the tolerance that nitric ether causes, therefore can be used to treat stenocardia, congestive heart disease and myocardial infarction.
Many isozyme form of the cyclic nucleotide phosphodiesterase in the mammalian cell (PDE) is identified.That these isozyme are hydrolyzed to cyclic monophosphate (cAMP) and/or cyclic guanosine list phosphoric acid (cGMP) is may lifeless matter active 5 '-nucleoside phosphorylase.Intracellular cGMP in the vascular smooth muscle raises and causes that a series of variations cause alleviating of muscular tone.Renal tubular cell cGMP raises simultaneously stimulates natruresis and diuresis.Vascular smooth muscle and nephrocyte contain the phosphodiesterase isoenzyme that the cGMP hydrolysis is had low km (1 μ M), this isozyme has been called as cGMP-PDE or cGMP-PDE V (was called as cGMP-PD I in the past, because with concentration at the sodium acetate between the 150-200mM from the anionresin agarose resin during wash-out, it is in the active peak of first PDE).Therefore the inhibition of cGMP-PDE isozyme is a viable ubcellular mechanism, because the increase by cGMP, can produce reducing and the stimulation of natruresis and diuresis of total Peripheral resistance.The development of cGMP-PDE inhibitor is indicating will find can be used for the in heart failure and hypertensive medicament of treatment.For example, cGMP-PDE being had high inhibiting compound is considered to bring high blood pressure down and to induce natruresis and diuresis.
The cGMP-PDE V of typical compound of the present invention suppresses active may be proved by the following step.
CGMP-PDE and other PDE isozyme can be by Silver etc., Sec.Messeng.Phos.13:13-25, described in 1991, from various animal and humans' cardiovascular organization (heart and aorta), separate with affinity chromatography by negatively charged ion-exchange, have or not the PDE activity of test compound under existing basically by Thompson etc., the described mensuration of Adv Cyclic Nucleotide Res.10:69-92.In order to measure effectiveness and the selectivity of compound, can measure their influences when 10 μ M to the hydrolysis of ring-type nucleosides as the PDE inhibitor.If observe 〉=50% PDE maximum inhibition, will obtain IC
50Value (causing the active compound concentration that reduces of 50%PDE) and corresponding 95% believable interval.IC
50Can be by Tallarida and Murray, Manual of PharmacologicCalculations with Computer Programs, Procedure 8, Graded Dose-response, PP.14-19, Springer-Verlag, New York, the described method of 1981 (" computer program pharmacology calculates guide ") is calculated by corresponding concentration curve.
Following table has been summarized the result by typical compound test gained of the present invention.
With μ M or the IC that provides
50( nM ) cGMP-PDEV1 ( b ) 102 ( b ) 9％ ( 1μM ) 3 ( b ) 224 ( b ) 6505 3106 237 198 ( b ) 12009 54010 ( b ) 27011 ( b ) 31012 ( b ) 39％ ( 1μM ) 17％ ( 0.1μM ) 13 66014 77％ ( 10μM ) 28％ ( 1μM ) 15 ( c ) 177016 ( b ) 90％ ( 10μM ) 32％ ( 1μM ) 17 61％ ( 10μM ) 20％ ( 1μM ) 18 ( b ) 33％ ( 1μM ) 19 3320 8621 ( c ) 42022 30023 ( b ) 33％ ( 1μM ) 24 ( b ) 18025 ( a ) 7626 8.727 ( b ) 73％ ( 1μM ) 25％ ( 0.1μM ) 28 ( b ) 48％ ( 1μM ) 29 94％ ( 0.1μM ) 77％ ( 0.01μM ) 30 73％ ( 1μM ) 43％ ( 0.1μM )
With μ M or the IC that provides
50(nM) percent inhibition embodiment cGMP-PDEV31 3,032 89% of form (1 μ M) or 58% (0.1 μ M)
Or 24%, (0.01 μ M) 33, (b) 56%, (0.1 μ M) 34 78%, (1 μ M) or 45%, (0.1 μ M) 35 53%, (1 μ M) or 34%, (0.1 μ M) 36, (b) 62%, (1 μ M) or 26%, (0.1 μ M) 37, (d) 78%, (1 μ M) or 36%, (0.1 μ M) 38, (d) 27,039 74%, (1 μ M) or 33%, (0.1 μ M)
The antihypertensive active of typical compound of the present invention follows these steps to proof.
The rat (SHR) of spontaneously hypertensive is used vetanarcol, and (50mg/kg, ip) anesthesia are installed conduit to feed medicine and to write down arteriotony and heart rate respectively below Vena cava and aorta abdominalis.After the operative results 2 days, with 5 minutes intervals clear-headed SHR is made three baseline blood pressure and measure.(0.3-10mg host/kg) vein injection test compound or vehicle are used polygraph continuous recording arteriotony simultaneously in the mode relevant with dosage.Measured the mean blood pressure reaction at the test compound that feeds various dosage and after feeding next dosage in the integral dose mode in 5 minutes.With the reaction of calculating each dosetest compound with the difference of three base measurement mean values.
Following table has been summarized the result by typical compound test gained of the present invention.
SHR?iv
With given mg/kg or ED
25(mg/kg) percentage 1 (b)-15% (1mg/kg) that changes of the embodiment mean arterial blood pressure of expression or-29% (30mg/kg) 6 8.4 or-30% (10mg/kg) 7 4.610 (b)-17% (10mg/kg) 11 (b)-4% (10mg/kg) 19 11.0 or-21% (10mg/kg) 20 10.1 or-23% (10mg/kg) 24 (b)-8% (10mg/kg) 25 (a)-5% (10mg/kg) 26 4.2 or-46% (10mg/kg) or
-56% (10mg/kg, po) 33 (b) 9.3 or-27% (10mg/kg)
Typical compound of the present invention reverses or extenuates the chemical sproof activity of nitric ether inductive and can prove by following step:
Make spontaneous hypertensive rat (17-25 age in week) produce resistance by the pannonit (100mg/kg, s.c., 3 times/day, successive administration 3 days) of giving high dosage repeatedly to pannonit.In order further to confirm resistance,, write down the maximum of each dosage aspect mean arterial blood pressure (MAP) and change the pannonit intravenously administrable of 1-300 μ g/kg dosage range.Before the pannonit administration of booster dose 5-10 minute carried out the intravenously administrable pre-treatment with The compounds of this invention (resistance pretreated group) or with vehicle (0.05N NaOH) (resistance vehicle pretreated group) to the drug-fast rat of grouping.The pannonit that non-resistance rat (non-resistance group) is given booster dose causes the reduction of the MAP between relevant with dosage 10 to 40mmHg.The pannonit that resistance vehicle pretreated group is fed booster dose causes alleviating of tangible hyper tensive reactions.The pannonit that feeds booster dose with the pretreated resistance rat of The compounds of this invention (resistance pretreated group) is caused the rehabilitation in various degree of hyper tensive reactions.Calculate non-resistance group and resistance vehicle pretreated group and resistance pretreated group dosage-MAP area under a curve.The chemical sproof percentage reversion rate of phosphoric acid ester inductive is calculated as follows: percentage reversion rate=(AUC
Tol-pretreated-AUC
(tol-veh)/ (AUC
Nontol-AUC
Tol-veh) * 100 are wherein: AUC
Nontol=non-resistance group dosage-MAP area under a curve.
AUC
Tol-vehFace under=resistance vehicle pretreated group dosage-MAP curve
Long-pending
AUC
Tol-pretreated=resistance pretreated group dosage-MAP area under a curve 100% or bigger percentage reversion rate explanation reverse fully to the nitric ether inductive is chemical sproof, and the explanation of 0% percentage reversion rate does not reverse fully to the nitric ether inductive resistance that is produced.Following table has been summarized with typical compound of the present invention and has been tested resulting result.Embodiment dosage (mg/kg) is to the chemical sproof percentage reversion rate 6 1.0 69 7 3.0 140 of pannonit inductive
0.3 46
1.0 45
The compounds of this invention can be prepared into suitable medicinal pharmaceutical composition by conventional medicine method known in the art; Promptly comprise acceptable carrier on The compounds of this invention or its pharmacy acceptable salt and one or more physiology by preparation, auxiliary, the composition of thinner or vehicle, be prepared into the solid or the liquid form that are used for oral administration, be used for parenteral administration, surface administration or aerosol inhalation, etc.
The solids composition of oral administration comprises tablet agent, pill, powder and particle.In these solids compositions, active compound and at least a inert diluent such as starch, lime carbonate, sucrose or lactose mix.These compositions also can contain other materials beyond the thinner, for example, lubricant, as Magnesium Stearate, talcum etc.
The liquid composition of oral administration comprises pharmaceutically acceptable emulsion, solution, and suspension, syrup and elixir contain the inert diluent that is usually used in this area, as water and whiteruss in these preparations.Except that inert diluent, these compositions also can contain auxiliary, as wetting agent and suspension agent, and sweeting agent, perfume compound, spices and sanitas.According to the present invention, but be used for the capsule that oral compound also can be included in absorbing material such as gelatin, this capsule comprises above-mentioned active ingredient and can contain or can not contain other thinner or vehicle.
The preparation that is used for parenteral administration of the present invention comprises sterilized water, water-organic, and organic solution, suspension and emulsion.The example of organic solvent or suspension medium comprises propylene glycol, polyoxyethylene glycol, vegetables oil such as sweet oil and injection organic ester such as ethyl oleate.Also can contain auxiliary such as stablizer in these compositions, sanitas, wetting agent, emulsifying agent and dispersion agent.
Surperficial administration of the present invention or aerosol inhalation preparation comprise that The compounds of this invention is dissolved in or is scattered in pharmaceutically acceptable vehicle such as water, aqueous alcohol, ethylene glycol, the preparation in oil solution or the oil hydrosol etc.
If desired, can further The compounds of this invention be sneaked into slowly-releasing or target release system such as polymeric matrix, liposome, and microsphere.
Active ingredient can change at the per-cent of these compositions, so that obtain proper dosage.Dosage for particular patients ' can change according to clinician's judgement, and employed judging criterion has: route of administration, treatment cycle, patient's size and physical qualification, the effectiveness of active ingredient and patient's reaction.Therefore the effective dose of active ingredient can use him that the best of patient's performance is judged after the clinician has considered all standards, and decision easily.
Claims (36)
1. following formula: compound or its pharmaceutically-acceptable acid addition and/or hydrate:
Wherein:
R
1Be the tertiary butyl, or cyclopentyl;
R
3Be methyl, ethyl, or phenmethyl;
X is-CH
2-,-O-, or-NH-; And
R
6For phenyl (or by from one to three, identical or different, be selected from lower alkoxy, hydroxyl, halogen, carboxyl lower alkoxy, 4-morpholinyl lower alkoxy, 5-tetrazyl lower alkoxy, two elementary alkyl amido, trifluoromethyl, nitro, amino, low alkyl group sulfonamido, the phenyl that the substituting group of two elementary alkyl amido-low alkyl group phenyl carbonyl oxygen base and 1-imidazolyl replaces); Perhaps working as X is-CH
2-time, R
6Be 2-in addition, 3-, or 4-pyridyl, 1-pyrryl, 1-benzimidazolyl-, 1,2,3,4-tetrahydrochysene-2-isoquinolyl, 1,2,3,4-tetrahydrochysene-1-quinolyl, hydroxyl, 1-imidazolyl, 1-low alkyl group-2,3,4 or the 5-pyrryl, 1-pyrazolyl, 3-, 4-, or the 5-isoxazolyl (or on its any possible carbon atom by low alkyl group replace 3,4, or the 5-isoxazolyl), 2-thienyl or 3-thienyl.
2. according to the compound of claim 1, R wherein
6For phenyl (or by from one to three, identical or different, be selected from lower alkoxy, hydroxyl, carboxyl lower alkoxy, 4-morpholinyl-lower alkoxy, 5-tetrazyl-lower alkoxy, two elementary alkyl amido, trifluoromethyl, nitro, amino, the low alkyl group sulfonamido, the phenyl that the substituting group of two elementary alkyl amido-low alkyl group phenyl carbonyl oxygen base and 1-imidazolyl replaces); Perhaps working as X is-CH
2-time, R
6Be 2,3 in addition, or the 4-pyridyl, the 1-pyrryl, the 1-benzimidazolyl-, 1,2,3,4-tetrahydrochysene-2-isoquinolyl, 1,2,3,4-tetrahydrochysene-1-quinolyl, hydroxyl, the 1-imidazolyl, 1-low alkyl group-2-pyrryl, 1-pyrazolyl, the 4-isoxazolyl that on its any possible carbon atom, replaces), 2-thienyl, or 3-thienyl by low alkyl group.
3. according to the compound of claim 2, R wherein
6For phenyl (or from one to three, identical or different, be selected from methoxyl group, hydroxyl, carboxyl methoxyl group, 2-(4-morpholinyl) oxyethyl group, 1-(5-tetrazyl)-methoxyl group, dimethylamino, trifluoromethyl, nitro, amino, sulfonyloxy methyl amino, the phenyl that the substituting group of diethylin aminomethyl phenyl carbonyl oxygen base and 1-imidazolyl replaces); Perhaps working as X is-CH
2-time, R
6Be 2-in addition, 3-, or 4-pyridyl, 1-pyrryl, 1-benzimidazolyl-, 1,2,3,4-tetrahydrochysene-2-isoquinolyl, 1,2,3,4-tetrahydrochysene-1-quinolyl, hydroxyl, the 1-imidazolyl, 1-methyl-2-pyrryl, 1-pyrazolyl, 3,5-dimethyl-4-isoxazolyl), 2-thienyl, or 3-thienyl.
4. according to the compound of claim 3, R wherein
3Be methyl, or ethyl.
5. according to the compound of claim 4, R wherein
7Be cyclopentyl, and R
3Be ethyl.
6. according to the compound of claim 5, wherein be selected from:
1-cyclopentyl-3-ethyl-6-(4-methoxyphenyl methyl) pyrazolo [3,4-d] pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-(4-hydroxy phenyl methyl) pyrazolo [3,4-d] pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-(phenmethyl) pyrazolo [3,4-d] pyrimidin-4-one and
1-cyclopentyl-3-ethyl-6-(4-amino-benzene methyl) pyrazolo [3,4-d] pyrimidin-4-one.
7. pharmaceutical composition is comprising compound and the pharmaceutically acceptable carrier according to claim 1, auxiliary, thinner, or vehicle.
8. pharmaceutical composition is comprising compound and the pharmaceutically acceptable carrier according to claim 2, auxiliary, thinner, or vehicle.
9. pharmaceutical composition is comprising compound and the pharmaceutically acceptable carrier according to claim 3, auxiliary, thinner, or vehicle.
10. pharmaceutical composition is comprising compound and the pharmaceutically acceptable carrier according to claim 4, auxiliary, thinner, or vehicle.
11. a pharmaceutical composition is comprising compound and the pharmaceutically acceptable carrier according to claim 5, auxiliary, thinner, or vehicle.
12. a pharmaceutical composition is comprising compound and the pharmaceutically acceptable carrier according to claim 6, auxiliary, thinner, or vehicle.
13. a method that suppresses Mammals cGMP-phosphodiesterase is comprising the compound that this animal is used the claim 1 of significant quantity.
14. a method that suppresses Mammals cGMP-phosphodiesterase is comprising the compound that this animal is used the claim 2 of significant quantity.
15. a method that suppresses Mammals cGMP-phosphodiesterase is comprising the compound that this animal is used the claim 3 of significant quantity.
16. a method that suppresses Mammals cGMP-phosphodiesterase is comprising the compound that this animal is used the claim 4 of significant quantity.
17. a method that suppresses Mammals cGMP-phosphodiesterase is comprising the compound that this animal is used the claim 5 of significant quantity.
18. a method that suppresses Mammals cGMP-phosphodiesterase is comprising the compound that this animal is used the claim 6 of significant quantity.
19. the in heart failure and/or hypertensive method of treatment Mammals is comprising the compound that this animal is used the claim 1 of significant quantity.
20. the in heart failure and/or hypertensive method of treatment Mammals is comprising the compound that this animal is used the claim 2 of significant quantity.
21. the in heart failure and/or hypertensive method of treatment Mammals is comprising the compound that this animal is used the claim 3 of significant quantity.
22. the in heart failure and/or hypertensive method of treatment Mammals is comprising the compound that this animal is used the claim 4 of significant quantity.
23. the in heart failure and/or hypertensive method of treatment Mammals is comprising the compound that this animal is used the claim 5 of significant quantity.
24. the in heart failure and/or hypertensive method of treatment Mammals is comprising the compound that this animal is used the claim 6 of significant quantity.
25. one kind reverse or alleviate Mammals in accepting the process of nitric ether treatment by the chemical sproof method of nitric ether inductive, comprising the compound that this animal is used the claim 1 of significant quantity.
26. one kind reverse or alleviate Mammals in accepting the process of nitric ether treatment by the chemical sproof method of nitric ether inductive, comprising the compound that this animal is used the claim 2 of significant quantity.
27. one kind reverse or alleviate Mammals in accepting the process of nitric ether treatment by the chemical sproof method of nitric ether inductive, comprising the compound that this animal is used the claim 3 of significant quantity.
28. one kind reverse or alleviate Mammals in accepting the process of nitric ether treatment by the chemical sproof method of nitric ether inductive, comprising the compound that this animal is used the claim 4 of significant quantity.
29. one kind reverse or alleviate Mammals in accepting the process of nitric ether treatment by the chemical sproof method of nitric ether inductive, comprising the compound that this animal is used the claim 5 of significant quantity.
30. one kind reverse or alleviate Mammals in accepting the process of nitric ether treatment by the chemical sproof method of nitric ether inductive, comprising the compound that this animal is used the claim 6 of significant quantity.
31. a treatment Mammals stenocardia, the method for congestive heart disease and myocardial infarction is comprising the compound that this animal is used in combination the claim 1 of significant quantity with nitric ether.
32. a treatment Mammals stenocardia, the method for congestive heart disease and myocardial infarction is comprising the compound that this animal is used in combination the claim 2 of significant quantity with nitric ether.
33. a treatment Mammals stenocardia, the method for congestive heart disease and myocardial infarction is comprising the compound that this animal is used in combination the claim 3 of significant quantity with nitric ether.
34. a treatment Mammals stenocardia, the method for congestive heart disease and myocardial infarction is comprising the compound that this animal is used in combination the claim 4 of significant quantity with nitric ether.
35. a treatment Mammals stenocardia, the method for congestive heart disease and myocardial infarction is comprising the compound that this animal is used in combination the claim 5 of significant quantity with nitric ether.
36. a treatment Mammals stenocardia, the method for congestive heart disease and myocardial infarction is comprising the compound that this animal is used in combination the claim 6 of significant quantity with nitric ether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96192462 CN1177960A (en) | 1995-03-10 | 1996-03-05 | 6-substituted pyrazolo (3, 4 -d) pyrimidin -4 ones and compositions and methods of use thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/402,268 | 1995-03-10 | ||
| CN 96192462 CN1177960A (en) | 1995-03-10 | 1996-03-05 | 6-substituted pyrazolo (3, 4 -d) pyrimidin -4 ones and compositions and methods of use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1177960A true CN1177960A (en) | 1998-04-01 |
Family
ID=5128286
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 96192462 Pending CN1177960A (en) | 1995-03-10 | 1996-03-05 | 6-substituted pyrazolo (3, 4 -d) pyrimidin -4 ones and compositions and methods of use thereof |
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| Country | Link |
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| CN (1) | CN1177960A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102443031A (en) * | 2011-09-20 | 2012-05-09 | 山东大学 | Separation and purification method of c-di-GMP (cyclic diguanylate) |
| CN101573358B (en) * | 2006-09-15 | 2012-05-30 | 辉瑞产品公司 | Pyrido (2, 3-D) pyrimidinone compounds and their use as PI3 inhibitors |
| WO2014023191A1 (en) * | 2012-08-08 | 2014-02-13 | 中山大学 | N-substituted pyrazolo [3, 4-d] pyrimidine ketone compound and preparation method and application thereof |
| CN102292340B (en) * | 2009-01-26 | 2015-05-06 | 辉瑞大药厂 | Amino-heterocyclic compounds used as pde9 inhibitors |
-
1996
- 1996-03-05 CN CN 96192462 patent/CN1177960A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101573358B (en) * | 2006-09-15 | 2012-05-30 | 辉瑞产品公司 | Pyrido (2, 3-D) pyrimidinone compounds and their use as PI3 inhibitors |
| CN102292340B (en) * | 2009-01-26 | 2015-05-06 | 辉瑞大药厂 | Amino-heterocyclic compounds used as pde9 inhibitors |
| CN102443031A (en) * | 2011-09-20 | 2012-05-09 | 山东大学 | Separation and purification method of c-di-GMP (cyclic diguanylate) |
| CN102443031B (en) * | 2011-09-20 | 2014-03-05 | 山东大学 | Separation and purification method of c-di-GMP (cyclic diguanylate) |
| WO2014023191A1 (en) * | 2012-08-08 | 2014-02-13 | 中山大学 | N-substituted pyrazolo [3, 4-d] pyrimidine ketone compound and preparation method and application thereof |
| US9617269B2 (en) | 2012-08-08 | 2017-04-11 | Sun Yat-Sen University | N-substituted pyrazolo [3,4-D] pyrimidine ketone compound, and preparation process and use thereof |
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