MXPA97006878A

MXPA97006878A - Pirazolo [3,4-d] pyrimidin-4-onas 6-arilo and compositions and methods for your

Info

Publication number: MXPA97006878A
Application number: MXPA/A/1997/006878A
Authority: MX
Inventors: R Bacon Edward; Baldevsingh
Original assignee: Sanofi Winthrop Inc
Priority date: 1995-03-10
Filing date: 1997-09-09
Publication date: 1998-10-30

Abstract

Pyrazolo [3,4-d] pyrimidin-4-one-6-aryl derivatives, pharmaceutical compositions containing them and methods for effecting the inhibition of c-GMP-phosphodiesterase and for treating heart failure and / or hypertension

Description

PIRAZOLQ [3. 4 -dl PYRIMIDIN-4-ACONS 6 -ARILO AND COMPOSITIONS AND METHODS FOR USE DESCRIPTION OF THE INVENTION The invention relates to pyrazolo [3, 4 -d] -pyrimidin-4-ones 6-aryl, to pharmaceutical compositions containing them and to methods for effecting the inhibition of c-GMP-phosphodiesterase and to treat the failure of the heart and / or hypertension. Latent US Pat. No. 3,165,520 to Schmidt et al., Issued January 12, 1965, describes as agents that dilate the pyrazolo [3, 4-d] pyridine idolines of the general formula: wherein: R1 represents a hydrogen atom or an alkyl, hydroxyalkyl, halogen-alkyl or oxa-alkyl radical or a cycloalkyl, cycloalkyl-alkyl, aralkyl or heterocyclylalkyl radical or a higher or heterocyclic binuclear aryl radical; R3 represents a hydrogen atom or a lower alkyl radical; R5 represents an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic or heterocyclic-aliphatic radical; and R6 represents an aliphatic radical or an aralkyl or heterocyclyl-alkyl radical which can be substituted. The patent describes more specifically as particularly valuable compounds in which R 1 represents a hydrogen atom or a lower alkyl radical or a cycloalkyl radical, a hydroxy-lower alkyl radical or a halogeno-lower alkyl radical, an oxa-lower alkyl radical or a aryl radical which can be substituted or mono-, di- or tri-substituted by halogen, alkoxy, alkyl, methylenedioxy, trifluoromethyl, nitro, amino or a pyridyl radical; R3 represents a hydrogen atom or a lower alkyl radical; R ^ represents a lower alkyl radical or a lower alkylamino radical; and R6 represents a lower alkyl radical or an aralkyl radical. A series of l-R1-3-R3-4-hydroxy-6-R6-pyrazolo [3,4-d] pyrimidines are also described which may be useful as intermediates in the synthesis of the final products. Intermediates specifically describe l-cyclopentyl-4-hydroxy-6-benzyl-pyrazolo [3,4-d] -pyrimidine and l-isopropyl-4-hydroxy-6-m-methoxybenzyl-pyrazolo [3,4-d] ] pyrimidine.

U.S. Patent No. 3,211,731 of Schmidt et al., Issued October 12, 1965, describe pyrazolo [3, 4-d] pyrimidines of the general formula as agents that dilate the coronary: wherein: R1 represents hydrogen, an alkyl, hydroxy-alkyl, halogen-alkyl or oxa-alkyl radical, a cycloalkyl, cycloalkylalkyl, aralkyl, heterocyclyl-alkyl radical or a greater or heterocyclic binuclear radical; R3 means hydrogen, or secondly, for a lower alkyl radical; and R6 represents a possibly substituted aralkyl radical or heterocyclylalkyl. The patent describes more specifically as especially valuable compounds in which R1 represents a hydrogen atom or a lower alkyl, cycloalkyl, hydroxy-lower alkyl, halogen-lower alkyl, oxa-lower alkyl or an aryl group; R3 represents a hydrogen atom or lower alkyl and R6 represents a substituted or unsubstituted aralkyl. Among the compounds specifically described are 1-isopropyl-4-hydroxy-6- (3'-methoxyphenylmethyl) pyrazolo [3,4-d] pyrimidine, 1-cyclopentyl-4-hydroxy-6-benzylpyrazolo [3, 4-d] pyrimidine; l-iso-propyl-4-hydroxy-6- (β-phenylethyl) pyrazolo [3,4-d] pyrimidine and 1-iso-propyl-4-hydroxy-6- (4-aminobenzyl) pyrazolo [3, 4- d] pyrimidyria. U.S. Patent No. 3,211,732 to Schmidt et al., Issued October 12, 1965, describes, as intermediates, l-R1-3-R3-6-R6-4-hydroxy-pyrazolo- [3, 4 -d] pyrimidines in which: R 1 represents a hydrogen atom, a lower alkyl radical which is unsubstituted or substituted by a hydroxy group or a lower alkoxy group, or a cyclopentyl or cyclohexyl radical or a phenyl or lower phenyl radical- lower alkyl; R3 represents a hydrogen atom or a lower alkyl radical; and R6 means a substituted or unsubstituted phenyl lower alkyl radical. Specifically disclosed is 1-isopropyl-4-hydroxy-6-benzylpyrazolo [3,4-d] pyrimidine. Also described as intermediates are l-R 1 ^ -R 3 -6-R 6 -4-hydroxypyrazolo [3,4-d] pyrimidines in which: R 1 signifies a hydrogen atom, a lower alkoxy-lower alkyl radical or a hydroxy radical lower alkyl, a cyclopentyl or cyclohexyl radical or a phenyl or phenyl-lower alkyl radical which can be substituted; R3 has the meaning given in the above; and R * > means a phenyl radical which can be substituted. Specifically disclosed is l-isopropyl-4-hydroxy-6-phenylpyrazolo [3,4-d] pyrimidine. United States Patent No. 3,732,225 of Breuer et al., Issued May 8, 1973, describes pyrazolo [3, 4-d] pyrimidines of the formula as hypoglycemic agents and anti-inflammatory agents: wherein: R is hydrogen or a lower alkyl; R1 is lower alkyl, cycloalkyl, phenyl or substituted phenyl; R2 is phenyl, substituted phenyl or cycloalkyl; and R3 is hydrogen, lower alkyl, cycloalkyl, phenyl or substituted phenyl. Specifically described are l-methyl-6-phenyl and l-methyl-6- (4-chlorophenyl) pyrazolo [3,4-d] pyrimidin-4-ones. Patent 937,722 of British, published on September 25, 1963 for CIBA LIMITED, describes as an agent that dilates the coronary l-isopropyl-4-hydroxy-6-benzyl-pyrazolo [3,4 -d] -pyrimidine. U.S. Patent No. 4,666,908 to Hamilton, issued May 19, 1987, discloses pyrazolo [4, 3-d] pyrimidin-7-ones of the formula: wherein: R1 is lower alkyl of one to six carbons, inclusive, lower alkylene of one to six carbons, inclusive, lower hydroxyalkyl of one to six carbons, inclusive, lower hydroxyalkylene of two to six carbons, inclusive, aminoalkyl lower than one to six carbons, inclusive or lower aminoalkylene of two to six carbons, inclusive; n is 0-4; and Ar is R,: R, = or 2, 3 or 4 -pyridyl, wherein X, Y and Z are independently (1) hydrogen; (2) lower alkyl of one to six carbons; inclusive; (3) halogen; (4) hydroxyl; (5) lower alkoxy of one to six carbons, inclusive; (6) nitro; (7) amino; (8) NR'R ", wherein R 'and R" are each independently (a) hydrogen or (b) lower alkyl of one to six carbons, inclusive, optionally substituted by (i) amino, (ii) morpholino , or (iii) cycloalkyl of five to seven carbons, inclusive, (9) sulfonyl or (10 -S02 NR'R ", wherein R 'and R" are as defined above. Preferred compounds are those in which Ar is R. The compounds are established to be useful in the treatment of cardiovascular disorders Miyashita et al., Heterocycles 1990. 31, 1309-1314, describes the preparation of a series of pyrazolo [3, 4-d] pyrimidines of the general formula: in which : R is phenyl or methyl; and R1 is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, ethyl carboxylate or phenyl. No indication is described as useful. PCT Application WO 88/00192 of Hamilton, published on January 14, 1988, describes a series of 5-substituted pyrazolo [4, 3-d] pyrimidin-7-one derivatives which is established to be useful as agents cardiotonic, stimulators of CNS, antiallergic, antiasthmatic or that activate the knowledge. European Patent Application 0463756 to Bell et al., Published on January 2, 1992, describes a series of pyrazolo [4, 3-d] pyrimidin-7-ones 5- (2,5-disubstituted-phenyl), which are established to be useful in the treatment of cardiovascular disorders. United States Patent 3,772,294 of Podesva et al., Issued November 13, 1973, describe a process for preparing compounds of formula I: in which : X represents a halogen atom, a free or substituted hydroxyl group, - amino or mercapto and R represents a hydrogen atom or a lower alkyl radical or a substituted or unsubstituted aryl. The compounds are described as being potentially useful in the treatment of hyperuricaemia associated with gout and other conditions and additionally, compounds in which X represents a halogen atom which are to be useful as intermediates in the synthesis of other compounds having the Formula I. Specifically, 4-hydroxy-6-phenyl-1-pyrazolo [3,4-d] pyrimidine is described. United States Patent 5,075,310 of Coates and Rawlings, issued on December 24, 1991 of the application Serial No. 370,494 filed June 23, 1989, describes and claims compounds of the formula: and their pharmaceutically acceptable salts, wherein is a ring of sub-clause (a), (b) or (c) (•) () (c) X is oxygen or sulfur; and R1 is C ^ Cg alkyl, C2_6 alkenyl, C3_5 cycloalkyl C1-4 alkyl or C1_4 alkyl substituted by 1 to 6 fluoro groups. Specifically, 6- (2-propoxy-feniDpirazolo [3,4-d] pyrimidin-4 (5H) -one is described) The compounds are to be useful as bronchodilators and vasodilators U.S. Patent 5,294,612 to Bacon et al. ., issued March 15, 1994, of Application Serial No. 859,770 filed March 30, 1992, discloses a series of 6-heterocyclyl-pyrazolo [3,4-d] pyrimidin-4-ones, for example L-cyclopentyl-3-ethyl-6- (3-pyridyl) -pyrazolo [3,4-d] pyrimidin-4-one The compounds are described to be useful in the treatment of heart failure and hypertension. invention relates to compounds of the Formula I: wherein: R1 is tert-butyl or cyclopentyl; R3 is lower alkyl or phenyl-lower alkyl; and R6 is phenyl or phenyl substituted by one to three, same or different, substituents selected from the group consisting of lower alkoxy, lower alkyl, hydroxy, 1-imidazolyl, lower alkenyloxy, di-lower alkylamino-lower alkoxy, 4-morpholinyl- lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carboxy-lower alkoxy, trifluoromethyl, 1-piperidinyl-lower alkoxy, 1-pyrrolidinyl-lower alkoxy, nitro, halo, amino, - (CH2) 20-, lower alkylsulfonylamino, lower alkoxy-alkoxy lower, lower alkenyl, lower alkylamino, -OCH (CH3) CH2-, 4-morpholinylcarbonyl-lower alkoxy, 4-thiomorpholinyl-lower alkoxy, pyridinyl-lower alkoxy, 1-lower alkyl-3-hexahydroazepinyloxy and 1-lower alkyl -4-piperidinyloxy; or its pharmaceutically acceptable acid and / or hydrated addition salt. The compounds of Formula I have been found to possess inhibitory activity c-GmP-PDE V and are thus useful in the treatment of heart failure and / or hypertension. Particularly preferred compounds of Formula I above are those in which: R 1 is cyclopentyl; R3 is methyl or ethyl; and R6 is phenyl or phenyl substituted by one to two, same or different, substituents selected from the group consisting of methoxy, ethoxy, propoxy, methyl, hydroxy, 1-imidazolyl, CH2 = CHCH 0-, 2- (dimethylamino) ethoxy, 3- (di ethylamino) propoxy, 2- (4-morpholinyl) ethoxy, 3- (4-morpholinyl) propoxy, ethoxycarbonylmethoxy, carboxymethoxy, trifluoromethyl, 2- (1-piperidinyl) ethoxy, 2- (1-pyrrolidinyl) ethoxy, nitro, chloro, amino, - (CH2) 20-, methylsulfonylamino, 2- (methoxy) ethoxy, CH2 = CH2CH2-, diethylamino, -OCH (CH3) CH2-, 4-morpholinyl-carbonylmethoxy, 2- (4-thiomorpholinyl) ) ethoxy, 4-pyridinylmethoxy, l-methyl-3-hexahydroazepinyloxy and l-methyl-4-piperidinyloxy. The preferred species of the invention are: l-cyclopentyl-3-ethyl-6- (2-propoxyphenyl) -pyrazolo [3,4-d] pyrimidin-4-one, l-cyclopentyl-3-ethyl-6- [4 - (1-imidazolyl) phenyl] -pyrazolo [3,4-d] pyrimidin-4-one, l-cyclopentyl-3-ethyl-6- [3- (2- (4-morpholinyl) ethoxy) -phenyl] pyrazolo [3, 4-d] pyrimidin-4-one, l-cyclopentyl-3-ethyl-6- [2-ethoxy-4- (1-imidazolyl) -phenyl] pyrazolo [3,4-d] pyrimidine-4- ona, and l-cyclopentyl-3-ethyl-6- [2- (CH2 = CHCH20) phenyl] -pyrazolo [3,4-d] pyrimidin-4-one.

The invention further relates to pharmaceutical compositions which comprise compounds of Formula I together with a pharmaceutically acceptable carrier, adjuvant, diluent or carrier. The invention further relates to a method for effecting the inhibition of cGMP-phosphodiesterase in an animal organism which comprises administering to the organism an effective amount of a compound of Formula I. The invention is further related to a method for treating an attack to the heart and / or hypertension in an animal organism which comprises administering to the organism an effective amount of a compound of Formula I. The compounds of Formula I may exist in a tautoperic equilibrium with the corresponding enol form: While it is believed that the compounds are predominantly in the keto form and will be represented as such by this specification, it will be understood that the invention contemplates both forms and mixtures thereof. The term "lower alkyl" as used herein means linear or branched hydrocarbon chains having from one to about four carbon atoms and thus includes methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and the like. The term "lower alkoxy" as used herein means linear or branched alkoxy substituents having from one to about four carbon atoms and thus includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and the like. The term halogen, halide or halo as used herein means bromine, chlorine, iodine or fluorine. The term "lower alkenyl" as used herein means unsaturated, branched or unbranched hydrocarbon radicals of two to about four carbon atoms and thus includes 1-ethenyl, 1-propenyl, 2-propenyl, l-methyl-2- propenyl, isopropenyl, 2-butenyl, isobutenyl and the like. The synthesis of the compounds of the invention can be described as shown in Scheme A: An appropriately substituted 5-amino-lH-pyrazolo-4-carboxyamide (II) is reacted with an excess of an appropriately substituted aldehyde of the formula III, optionally in the presence of a suitable organic solvent, preferably xylenes or benzene, with or without the use of an acid catalyst, preferably p-toluenesulfonic acid, acetic acid or methanesulfonic acid, optionally in the presence of palladium on carbon, at a temperature in the range from about room temperature to the boiling point of the reaction mixture , preferably at the boiling point of the reaction mixture to produce the compounds of the formula I. Alternatively, a suitably substituted 5-amino-1H-pyrazole-4-carboxy-substituted (II) is treated with an excess of an ester of formula IV: R6C (0) OR, wherein R is lower alkyl, preferably ethyl , in the presence of a base, preferably sodium ethoxide, in an alcohol solvent, such as ethanol, at a temperature in the range from about room temperature to the boiling point of the solvent used, preferably at the boiling point of the solvent used, to produce the compounds of the formula I. The compounds of the formula I can also be synthesized as shown in Scheme B: VI An appropriately substituted 5-amino-1H-pyrazole-4-carboxamide of the formula II is treated with an excess of a nitrile of the formula V in a suitable organic solvent, preferably dimethylformamide (DMF) or dioxane, in the presence of an excess from a suitable base, preferably sodium hydride, at a temperature in the range from about room temperature to the boiling point of the solvent used, to produce either the compounds of formula I, directly or a mixture of the compounds of Formula I and the pyrazolo [3,4-d] irimidin-4-amines of the formula VI. This mixture can in turn be treated with an excess of sodium nitrite, in a water / acid l / 1 mixture, preferably a water / sulfuric acid l / 1 mixture, at a temperature in the range of about -10. ° C to about room temperature to produce the compounds of the formula I. Simple chemical transformations which are conventional and well known to those skilled in the art of chemistry can be used to effect changes in the functional groups of the compounds of formula I. For example, dialkylation of arylethers to produce the phenol derivatives corresponding, hydrolysis of esters to produce the corresponding acids, catalytic reduction of the nitro derivatives to produce the corresponding amines and sulfonylation of amines to produce the corresponding sulfonamide derivatives. The compounds of Formula I both are useful in the form of a free base in the form of acid addition salts and both are formed within the substance of the invention. Acid addition salts are frequently a more convenient way to be used; and in practice, the use of the salt forms inherently amounts to be used from the base form. The acids which can be used to prepare the acid addition salts preferably include those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are relatively harmless to the animal organism in pharmaceutical doses. of the salts, so the beneficial properties inherent in the free base are not vitiated by side effects attributable to the anions. In practice, the present invention is convenient for using the free base form or the hydrochloride, fumarate, toluenesulfonate, methanesulfonate or maleate salts. However, other pharmaceutically acceptable suitable salts within the scope of the invention are those derived from other mineral acids and organic acids. The acid addition salts of the basic compounds are prepared by standard procedures well known in the art, which include, but are not limited to, dissolving the free base in a solution of aqueous alcohol containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and an acid in an organic solvent, in which case, the salt is directly separated or precipitated with a second organic solvent or can be obtained by means of the concentration of the solution. Although medically acceptable salts of the basic compounds are preferred, all acid addition salts are within the scope of the present invention. All acid addition salts are useful as sources of the free base form even if the particular salt per se is only desired as an intermediate product, as, for example, when the salt is formed for purification or identification purposes or when used as an intermediary in preparing a medically acceptable salt by, for example, ion exchange procedures.

The appropriately substituted 5-amino-lH-pyrazole-4-carboxamides of the formula II are either known and thus can be prepared by known procedures (see, for example, U.S. Patent 5,294,612, issued on 15 March 1994, the complete contents of which are incorporated herein by reference) or can be prepared by the procedures described herein in the examples. The aldehydes of the formula III, the esters of the formula IV and the nitriles of the formula V are either commercially available or can be prepared by procedures known in the art or by the methods described herein in the examples. The structures of the compounds of the invention are established by the mode of synthesis and by one or more elemental analyzes and infrared nuclear magnetic resonance and mass spectroscopy. The course of the reactions and the identity and homogeneity of the products are determined by one or more of thin layer chromatography (TLC), high pressure liquid chromatography (CLAP) or gas-liquid chromatography (GLC). The following examples will further illustrate the invention, without limiting the same. All melting points (p.f.) are given in degrees centigrade (° C) and are not corrected.

Example 1 (a) A solution of salicylaldehyde (12.21 g, 0.1 mol) in DMF (65 ml) is cooled in an ice / water bath under argon and 60% sodium hydride in mineral oil (4.0 g, 0.1 mol) is add in several portions. The mixture is stirred for one hour and then iodopropane (16.99 g, 0.1 mol) is added at room temperature. The reaction mixture is stirred at room temperature overnight, it is poured into water (800 ml) and stirred. The mixture is extracted with chloroform (3X), the chloroform layer is concentrated in vacuo and the dark oil thus obtained is washed under vacuum (92-94 ° C to 1.15 mm Hg) to yield 12.68 g (77%) of 2- propoxybenzaldehyde. (b) A solution of KOH (12.16 g, 184.2 mmol) in water (150 ml) is cooled in an ice bath and then l-cyclopentyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrite (5.0 g, 26.3 mmol) is added, followed by 30% hydrogen peroxide. (13.5 mL, 131.6 mmol.) The reaction mixture is warmed to room temperature and stirred overnight.A precipitate is formed, which is collected by filtration and washed with ether to produce 1-cyclopentyl-3-methyl. -5-amino-lH-pyrazole-4-carboxamide as a white solid The additional product is obtained by concentration of the filtrate and the collection of the product by filtration to produce a total of 4.46 g of product.Alternatively, the carboxamide is prepared as follows: A concentrated sulfuric acid solution (50 ml) is cooled to -5 ° C and 1-cyclopentyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile (2.0 g, 10.5 mmol) is added. The mixture is stirred as such for 2 hours, then at room temperature overnight The reaction mixture is emptied into 400 ml of ice and NH 4 OH (100 ml) and stirred for 1 hour The product is precipitated and collected by filtration The additional product is obtained by acidification of the filtrate with acetic acid. ico to a pH of 5 and then extracted with chloroform. The chloroform layers are concentrated in vacuo and triturated with ether to produce, after filtration and drying at 100 ° C overnight, 1.67 g (76%) of 1-cyclopentyl-3-methyl-5-amino-1H- pyrazole-4-carboxamide. p.f. 191-192 ° C. A mixture of l-cyclopentyl-3-methyl-5-amino-lH-pyrazole-4-carboxamide (3.98 g, 0.019 mol), 2-propoxybenzaldehyde (6.35 g, 0.038 mol), xylene (150 ml) and methanesulfonic acid ( 0.5 ml) is heated to reflux for 39 hours with azeotropic removal of water. The reaction mixture is concentrated in vacuo and the residue is treated with 10% K2C03 and ether. The layers are separated, the aqueous layer is extracted with ether and the combined ether layers are concentrated in vacuo. Analysis of the reaction mixture by TLC indicates that the reaction is not yet completeThus, the mixture is heated to 180 ° C in an oil bath. The residue is dissolved in chloroform, and purified by column chromatography on silica gel eluting with hexane (100%) followed by ether (100%) to yield 2.67 g (41%) of 1-cyclopentyl-3-methyl-6- (2 -propoxyphenyl) -pyrazolo [3,4-d] pyrimidin-4-one, mp 130-132 ° C. Alternatively, the final product is prepared as follows: A mixture of l-cyclopentyl-3-methyl-5-amino-lH-pyrazole-4-carboxamide (1.0 g, 4.8 mmol) and 2-propoxybenzaldehyde (10.6 g, 10 mmol) it is heated at 160 ° C in an oil bath for 4 hours then at 170 ° C for 48 hours. The reaction mixture is cooled, chloroform (5 ml) is added and the solution is eluted on a column on silica gel with ether (100%) to produce, after recrystallization from cyclohexane, 0.16 g of 1-cyclopentyl. 3-methyl-6- (2-propoxyphenyl) -pyrazolo [3,4-d] pyrimidin-4-one. Example 2 A mixture of l-cyclopentyl-3-ethyl-5- (4-quinolinyl-CH = N-) -lH-pyrazole-4-carboxamide (6.34 g, 0.018 mol), benzaldehyde (0.96 g, 0.009 mol), xylenes (150 ml) and methanesulfonic acid (0.5 ml) are refluxed overnight. The reaction mixture is concentrated in vacuo, and the residue is treated with ethanol (200 ml) and azeotroped. The residue is then treated with 10% 2C03 (100 ml), triturated with ether, filtered and washed with water. The product is recrystallized from ethyl acetate and dried at 100 ° C to yield 2.68 g of unpurified product which is purified by column chromatography on silica gel to yield 0.603 g of 1-cyclopentyl-3-ethyl- 6-phenyl-pyrazolo [3,4-di-irimidin-4-one, mp 221-222 ° C. Alternatively, and preferably, the final product can be prepared from l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide and benzaldehyde following a procedure similar to that described in example 1 (c ). Example 3 A mixture of i-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9 mmol), o-tolualdehyde (2.16 g, 18 mmol), methanesulfonic acid (0.5 ml) and xylenes (50 ml), refluxed for 32 hours. The solvent is removed and the residue is treated with ethanol (100 ml) and then concentrated to dryness. The darkened residue is treated with 10% K2CO3 and chloroform, the organic layer is separated and the aqueous layer is extracted with chloroform (2 x 100 mL). The organic layers are combined, concentrated to approximately 20 ml and then added to silica gel (30 g). The pre-filled silica gel is placed on a column in silica gel and eluted with Et20 / hexanes (2/8) to (5/5) to produce, after drying at 70 ° C in vacuo, 1.10 g (40%) ) of l-cyclopentyl-3-ethyl-6- (2-methylphenyl) -pyrazolo [3,4-dl-irimidin-4-one]. p.f. 133-134 ° C. Example 4 A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (2.0 g, 9 mmol), o-ethoxybenzaldehyde (2.7 g, 18 mmol), methanesulfonic acid (5 drops), and xylenes (50 ml), it is refluxed for 48 hours. The reaction mixture is washed to dryness and treated with 10% K2C03 and CHC13 (100 mL). The layers are separated and the aqueous layer is extracted with chloroform (2 x 100 mL). The organic layers are combined, and concentrated in vacuo. The dark oil thus obtained is dissolved in CH2C12 (30 ml) and combined with silica gel (30 g). The pre-filled silica gel is placed on a column in silica gel and eluted with Et20 / hexanes (20/80) to Et20 (100%) to yield 1.41 g (45%) of 1-cyclopentyl-3-ethyl-6. - (2-ethoxyphenyl) -pyrazolo [3,4-d] pyrimidin-4-one. p.f. 146-147 ° C. Example 5 A mixture of l-cynylpentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (2.0 g, 9 mmol), anisaldehyde 2.45 g, 18 mmol, xylenes (50 ml) and p-toluenesulfonic acid ( 0.5 g) is refluxed for 32 hours. The reaction mixture is washed to dryness treated with ethanol (100 ml) and then concentrated again to dryness. The residue is treated with CHCl3 (100 mL) and 10% K2C03 and CHC13 (100 mL), the layers are separated and the aqueous layer extracted with chloroform (3 x 1T0 mL). The combined organic layers are concentrated to approximately 25 ml and then combined with silica gel (30 g). The pre-filled silica gel is placed on a column on silica gel and eluted with ether / hexanes (8/10) to ether (100%) to yield 1.25 g (41%) of 1-cyclopentyl-3-ethyl-6. - (2-methoxyphenyl) -pyrazolo [3,4-dl pyrimidin-4-one, mp. 135-136 ° C. Example 6 A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.0 g, 4.5 mmol), 2-propoxybenzaldehyde (1.5 g, 0. 9 mmol), p-toluenesulfonic acid (0.5 g) and xylenes (50 ml) are refluxed for 20 hours. The reaction mixture is washed to dryness, treated with ethanol and concentrated again to dryness. The residue is treated with CHC13 (100 mL) and washed with saturated NaHCO3. The organic layer is concentrated to a dark oil, which is dissolved in CH2Cl2 (30 mL) and combined with silica gel (50 g). The pre-filled silica gel is placed on a column on silica gel and eluted with 10% hexanes / ether to ether (10C%) to produce, after crystallization from hexanes, 0.492 g (30%) of 1 -cyclopentyl-3-ethyl-6- (2-propoxyphenyl) -pyrazolo-3,4-di-pyrimidin-4-one. p.f. 93-94 ° C.

Example 7 NaH (0.15 g, 3.75 mmol, 60% NaH in mineral oil) is added to a solution of l-cyclopentyl-3-ethyl-6- (2-methoxyphenyl) -pyrazolo [3,4-d] pyrimidine- 4-one (0.5 g, 1.5 mmol). The reaction mixture is stirred for 20 minutes, then propantiol (0.228 g, 3.0 mmol) is added and the mixture is stirred at room temperature for 4 hours, then at 110 ° C for 9 hours. The reaction mixture is washed to dryness and then water (15 ml) is added followed by acetic acid (1 ml). A precipitate is formed, which is collected by filtration, washed with water and recrystallized by DARC0R treatment from ethyl acetate to yield 0.28 g (58%) of l-cyclopentyl-3-ethyl-6- (2-hydroxyphenyl) ) -pyrazolo [3,4-di pyrimidin-4-one, pf 272-273 ° C, as white fibrous needles. EXAMPLE 8 (a) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (1.18 g, 5.32 mmol), 4- (1-imidazole, D-benzaldehyde (1.37 g) and xylenes (8 ml) ) is heated at 130 ° C for 30 minutes, then at 160 ° C for three days, the reaction mixture is cooled, and the product is collected by filtration and washed with Et20 to produce 1. 88 g of l-cyclopentyl-3-ethyl-6- [4- (1-imidazolyl) phenyl] -pyrazolo [3,4-d] pyrimidin-4-one as the 6,7-saturated derivative.

The derivative is mixed with ethanol (300 ml) and 30% H202 (3.0 ml) and refluxed overnight. 30% additional H202 (3 ml) is added and the mixture is refluxed for 8 hours. An additional 10 ml of 30% H202 is added and the mixture is refluxed overnight. The initial material is still present so that an additional 10 ml of 30% H202 is added and the mixture is refluxed for 4 hours and then 30% additional H202 (10 ml) is added and the reaction mixture is stirred for 1 hour, then let stand at room temperature overnight. The reaction mixture is washed to a yellow liquid and purified by column chromatography on silica gel eluting with ethyl acetate (100%), then 5% ethanol / ethyl acetate to produce, 0.4 g 1/2 l-cyclopentyl-3-ethyl-6- [4- (1-imidazolyl) -phenyl] -pirazolo hydrate [3 , 4-d] pyrimidin-4-one, mp > 3G0 ° C. (b) Alternatively, the product can be obtained as follows: To a mixture of imidazole (5.13 g, 75.35 mmol), K2CO3 (11.45 g and DMSO (50 ml) at room temperature is added to 4-fluorobenzonitrile (10.04 g) in a portion). The reaction mixture is stirred at room temperature for 1 hour and then heated in a steam bath for 2 hours. The reaction mixture is cooled to room temperature and emptied into cold water. A precipitate is formed, which is collected by filtration and washed with water and recrystallized from CHCl3 / hexane to yield 4.07 g of 4- (l-imidazolyl) benzonitrile, m.p. 146-148 ° C. To a mixture of 4- (1-imidazolyl) benzonitrile (0.9 g, 5.27 mmol), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.17 g) in DMF (20 ml) ) NaH (0.63 g, 60% dispersion in mineral oil) is added at room temperature. The reaction mixture is stirred at room temperature overnight, additional NaH (0.5 g) is added and the mixture is stirred at room temperature for about 2 days. The reaction mixture is poured into ice / water (500 ml), neutralized with acetic acid and the precipitate that forms is collected by filtration, washed with hexanes, dissolved in CHC13, dried over MgSO4, filtered and concentrated in vacuo The residue is crystallized from ethyl acetate, combined with the product obtained from two similar experimental runs and then recrystallized from CH3CN / CHCl3 to produce l-cyclopep-yl-3-ethyl-6- [4- (1-imidazoylyl) -phenyl] -pyrazolo [3,4-d] pyrimidin-4-one pf > 300 ° C.

Example 9 (ai To a solution of ethyl salicylate (100 g, 0.602 mol) in DMF (400 ml) is added K2CO3 (150 g), followed by the dropwise addition of allyl bromide (87.5 g, 0.723 mol). The reaction mixture is then heated in a steam bath for 2 hours, K2C03 is removed by filtration and the reaction mixture is poured into water and extracted with ethyl acetate (3 x 300 ml) .The organic layer is washed with brine, and dried over MgSO4, and the solvent is removed to yield 122 g (98%) of ethyl 2- (2-propenyloxy) benzoate. (b) Sodium spheres (207 mg) are dissolved in ethanol (15 ml). ) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1 g, 45 mmol) was added, followed by ethyl 2- (2-propenyloxy) benzoate (1.85 g, 9 mmol) The reaction mixture is refluxed overnight, cooled, the ethanol is stirred and water is added in. The pH is adjusted to about 7 and a solid is isolated by filtration The solid is extracted into ether, washed HCl dilution, dried over MgSO4, filtered and the solvent removed and the solid residue recrystallized from ether to yield 0.56 g of 1-cyclopentyl-3-ethyl-6-f2- (CT ^ CH-C ^ O) phenyl] -pyrazolo [3,4-dlpiritr.idin-4-one. p.f. 119-120 ° C.

Example 10 A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (2.03 g, 9.14 mmol), 4- [3- (dimethylamino) propoxy] benzaldehyde (2.76 ml), and xylenes it is heated at 120 ° C for 1 hour, then at 160 ° C for 6 hours. P-Toluenesulfonic acid (300 mg) is added and the mixture is heated to 160 ° C until the reaction is complete. The reaction mixture is cooled to room temperature, and a creamy white solid is formed, which is collected by filtration, washed with methanol and recrystallized from ethyl acetate to produce l-cyclopentyl-3-ethyl-6- [4- (3- (dimethylamino) propoxy] phenyl] pyrazolo [3,4-d] pyrimidin-4-one as a white solid, mp 175-178 ° C. Example 11 (a) To a solution of salicylaldehyde (2 ml) in acetonitrile (20 ml) is added K2 03 (5.71 g), followed by N- (2-chloroethyl) morpholine hydrochloride (3.5 g) and then the mixture is mixed. Stir at room temperature for 2 hours, then bring to reflux for the night. The reaction mixture is cooled to room temperature, filtered, and the filtrate concentrated in vacuo to yield 2- [2- (4-morpholinyl) ethoxy] benzaldehyde, run a yellow oil. (b) + (c) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (0.95 g, 4.28 mmol), 2- [2- (4-morpholinyl) ethoxy] benzaldehyde (1.51 g) and xylenes (15 ml) is heated at 120 ° C for 1 hour, then at 160 ° C until the reaction is complete. The reaction mixture is cooled to room temperature, the solvent is removed in vacuo, and the residue is purified by column chromatography on silica gel eluting with ethyl acetate (100%), followed by ethanol / ethyl acetate (l / l) to produce l-cyclopentyl-3-ethyl-6- [2- [2- (4-morpholinyl) ethoxy-1-phenyl] -pyrazolo [3,4-d] pyrimidin-4 -one (Example 11 (b)), as an oil. The free base is then converted to its hydrochloride salt, which is recrystallized from ethanol and dried at 110 ° C under high vacuum to yield 0.5 g of l-cyclopentyl-3-ethyl-6- [2- [2 - (4-morpholinyl) ethoxy] phenyl] pyrazolo [3,4-d] pyrimidin-4-one. as a whitish powder, m.p. 235-237 ° C, marked as in Example 11 (c). Example 12 (a) A mixture of 2-formylphenoxyacetic acid (9.01 g, 0.05 mol) ethanol (4.6 g), K2SO4 concentrate (0.4 ml) and toluene (40 ml) is heated to reflux with azeotropic removal of water for 1 hour . The reaction mixture is emptied into 10% KHC03 (100 mL), the layers are separated and the aqueous layer is extracted with ether (2 x 75 mL). The organic layers are combined, and concentrated in vacuo to yield 9.1 g, 95%) of 2- (ethoxycarbonylmethoxy) benzaldehyde. (b) A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (5.26 g, 23.7 mmol), 2- (ethoxycarbonylmethoxy) benzaldehyde (9.10 g, 47.3 mmol), p-acid toluenesulfonic (0.2 g) and xylenes (100 ml) is refluxed for 18 hours with the azeotropic removal of water. The solvent is removed in vacuo, and the residue is treated with ethanol and evaporated to dryness. The residue is partitioned between chloroform and 10% aqueous K2CO3, the layers are separated and the aqueous layer is extracted with chloroform (100 ml). The organic layers are combined and concentrated to dryness. The residue is preloaded on silica gel and then purified by column chromatography on silica gel eluting with hexanes (100%) to 20% ether / hexane to yield 3.74 g (38%) of 1-cyclopentyl-3-ethyl- 6- [2- (Ethoxycarbonylmethoxy) phenyl] -pyrazolo [3,4-dl pyrimidin-4-one. p.f. 116-117 ° C. Example 13 (a) To a solution of 3-Hydroxybenzaldehyde (3.05 g, 24.97 mmol) in acetonitrile (15 mL) is added K2CO3 (7.6 g), followed by N- (2-chloroethyl) morpholine hydrochloride (4.65 g). The reaction mixture is stirred at room temperature for 30 minutes, then brought to reflux overnight. Additional N- (2-chloroethyl) morpholine hydrochloride and K2CO3 (0.7 g) are added and the mixture is refluxed for an additional 6 hours. The reaction mixture is cooled to room temperature, filtered, and the filtrate concentrated in vacuo. The residue is divided between water and chloroform, the layers are separated and the aqueous layer is extracted with chloroform (2 x 75 ml). The organic layers are combined, washed with brine, dried over MgSO4, filtered and washed to yield 7.3 g of 3- [2- (4-morpholinyl) ethoxy] benzaldehyde, as an amber liquid. (b) A mixture of l-ciciopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (1.05 g, 4.73 mmol), 3- [2- (4-morpholinyl) ethoxy] benzaldehyde (1.67 g) and xylenes (7 ml) are heated at 160 ° C overnight. Additional aldehyde (0.4 g) is added and the mixture is heated to 160 ° C until the reaction is complete. The reaction mixture is cooled to room temperature and a solid is formed, which is collected by filtration and washed with ether. The filtrate is concentrated to dryness and the residue is combined with the solid and purified by column chromatography on silica gel eluting with ethyl acetate / ethanol (60/40). The solid product thus obtained is washed with ether again to produce l-cyclopentyl-3-ethyl-6- f3- [2- (4-morpholinyl) ethoxy] -phenyl] -pyrazolo [3 4-d] pyrimidin-4- ona p.f. 173-176 ° C. Example 14 A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (1.19 g, 5.38 mmole), 2-methoxy-4-carboxymethoxybenzaldehyde (1.13 g) and glacial acetic acid (25 ml) is heated at reflux for 4 days. The reaction mixture is cooled to room temperature and the solvent is washed to produce a suspension which is washed with methanol, collected by filtration and then washed with ether. The product is recrystallized from ethanol and washed with ether to produce l-cyclopentyl-3-ethyl-6- [(2-methoxy-4-carboxymethoxy) phenyl] pyrazolo [3,4-d] pyrimidin-4-one . Example 15 A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (0.59 g, 2.65 mmoies), 2-trifluoroethylbenzaldehyde (0.5 ml) and glacial acetic acid (25 ml) is refluxed overnight and then 0.5 equivalents of additional aldehyde are added and the mixture is brought to reflux for about 3 days. The reaction mixture is cooled to room temperature, the acetic acid is washed and the residue is cooled and rinsed with ether to give a white solid which is collected by filtration and recrystallized from tert-butyldimethyl ether / hexanes for produce l-cyclopentyl-3-ethyl-6- (2-trifluoromethylphenyl) -pyrazolof3.4-d] pyrimidin-4-one. p.f. 201-202 ° C. Example 16 A mixture of l-cyclopentyl-3-ethyl-6- [2- (ethoxycarbonylmethoxy) phenyl] pyrazolo [3,4-d] pyrimidin-4-one (3.0 g, 7.3 mmol), K2C03 (3.04 g), water (20 ml) and ethanol (50 ml) are refluxed for 1.5 hours. The reaction mixture is cooled, the solvent is removed in vacuo and the residue is stirred with water and acidified. A precipitate forms, which is collected by filtration, recrystallized from isopropanol and dried at 90 ° C. The solid is dissolved in 10% 2C03 (100 mL), treated with DARC0R, filtered and the filtrate acidified with acetic acid. A precipitate forms which is collected by filtration and dried at 110 ° C. The solid product is combined with the solid product obtained from a similar experimental run, shaken with 6N HCl (100 ml), filtered and dried with P2 ° 5 at 100 ° C under vacuum to yield 2.09 g of 1/2 hydrate. of l-cyclopentyl-3-ethyl-6- [2- (carboxymethoxy) phenyl-pyrazolo [3,4-d] irimidin-4-one, mp 208-209 ° C. Example 17 (a) To a water mixture 500 ml; and 85% KOH (37.91 g, at 0 ° C, 30% H20 is added (49.4 mL, 483 mmol), followed by l-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile (15.83 g, 96.5 mmol) The reaction mixture is stirred for four hours at 0 ° C and then at ambient temperature for 1 hour.A yellow precipitate has formed, which is collected by filtration and dried with air to yield 13.2 g ( 75%) of l-tert-butyl-5-amino-lH-pyrazole-4-carboxamide, mp 193-195 ° C. (b) A mixture of 2-propoxybenzaldehyde (3.0 g, 18.27 mmol), l-ter -butyl-5-amino-1H-pyrazole-4-carboxamide (2.5 g, 13.7 mmol), methanesulfonic acid (0.2 ml) and xylans (50 ml) are refluxed overnight, the reaction mixture is distilled to dryness treated with ethanol and distilled again to dryness The residue is partitioned between chloroform and 10% KHC03, the layers are separated, and the aqueous layer is extracted with chloroform (2 x 100 ml) .The organic layers are combined , and concentrate in vacuo and the residue is dis It is dissolved in CH2C12 (30 ml) and combined with silica gel (20 g). The pre-filled silica gel is placed on a column of silica gel and eluted with 70% ether / hexanes, followed by ether (100%) to yield 0.98 g (22%) of 1/100 hydrate of 1-tert. butyl-6- (2-propoxyphenyl) pyrazolo [3,4-d] pyrimidin-4-one. p.f. 130-131 ° C. (c) A mixture of 1/100 l-tert-butyl-6- (2-propoxyphenyl) -pyrazolo [3,4-d] pyrimidin-4-one hydrate (0.68 g, 2.1 mmol) and trifluoroacetic acid (50 mi) is heated in a steam bath for 3.5 hours. The reaction mixture is distilled to dryness and the residue is purified by column chromatography on silica gel eluting with ether to yield 0.45 g (79%) of 1/4 6- (2-propoxyphenyl) pyrazolohydrate [3, 4 -d] pyrimidin-4-one, p'.f. 170-171 ° C. Example 18 (a) To a solution of 4-hydrobenzaldehyde 84.04 g, 33.08 mmole) in acetonitrile (50 ml), 2C03 is added (10.1 g), followed by N- (2-chloroethyl) morpholine hydrochloride (6.16 g). The reaction mixture is refluxed overnight, and N- (2-chloroethyl) morpholine hydrochloride (0.6 g) and K2CO3 (0.5 g) are further added and the mixture is refluxed for an additional 3 hours. The reaction mixture is cooled to room temperature, filtered and the filtrate is treated with DARCOR, filtered and the solvent is distilled. The residue is partitioned between saturated NaHCO 3 (150 ml) and ethyl acetate (300 ml). The layers are separated and the organic layer is washed with IN NaOH, dried over MgSO4, filtered and distilled to yield, as an amber oil.

J of 4-I2- (4-morpholinyl) ethoxy] benzaldehyde. (b) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (2.19 g, 9.86 mmol), 4- [2- (4-morpholinyl) ethoxy] benzaldehyde (3.5 g) and xylans (10 ml) were • heated at 160 ° C at night. P-Toluenesulfonic acid (0.2 g) is added and the mixture is heated at 160 ° C overnight. The reaction mixture is cooled to room temperature, and the precipitate formed is stirred with methanol, collected by filtration and washed with methanol, and then with ether. The product is recrystallized from acetonitrile to produce l-cyclopentyl-3-ethyl-6- [4- [2- (4-orpholinyl) ethoxy] phenyl] pyrazolo [3,4-d] pyrimidin-4-one. Example 19 (a) To a mixture of 3-hydroxybenzaldehyde (5.42 g, 44.38 mmol), 2CO (13.5 g) and acetonitrile is added N- (2-chloroethyl) piperidine hydrochloride (9.8 g). The reaction mixture is refluxed overnight, cooled to room temperature and filtered. The filtrate is distilled to yield an oil which is divided between CHC13 (350 mL) and 1M NaOH (200 mL), treated with DARCOR, then with MgSO4, filtered and distilled to yield, as a dark liquid oil, 6.28 g of 3- [2- (1-piperidinyl) ethoxyl benzaldehyde. (b) A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.02 g, 9.09 mmol), 3- [2- (1-piperidinyl) ethoxy] benzaldehyde (3.18) g) and xylans (10 ml) are refluxed overnight. Additional aldehyde (0.5 g) is added and the mixture is heated at 160 ° C for 6 hours. The reaction is not yet complete so an additional 0.5 g of aldehyde is added and the mixture is brought to reflux for about 2 days. The reaction mixture is cooled, filtered and distilled to produce an oily residue. The residue is treated with acetonitrile and cooled and the precipitate that forms is collected by filtration and washed with ether. The product is purified by column chromatography on silica gel, eluting with ethyl acetate / hexanes (l / l), followed by recrystallization of acetonitrile to yield, as a white solid 1-cyclopentyl-3-ethyl-6- [3 - [2- (1-piperidinyl) -ethoxy] phenyl] pyrazolo [3,4-d] pyrimidin-4-one, mp 180 ° C. Example 20 (a) To a mixture of 3-hydroxybenzaldehyde 85.17 g, 42.34 mmoles) 2C03 (5.85 g) and acetone (50 ml) is added ethyl bromoacetate (5.2 ml). The reaction mixture is stirred at room temperature overnight, additional 2C03 (1 equivalent) is added, the mixture is stirred for one hour, then additional ethyl bromoacetate (5 equivalents) is added and the mixture is stirred at room temperature until that the reaction is complete. The reaction mixture is filtered, water is added to the filtrate and the solvent is removed. The residue is dissolved in ether, extracted with 1 M NaOH (2 x 100 mL) and the ether layer is dried over MgSO4 and distilled to yield, as a liquid, 7.89 g of 3- (ethoxycarbonylmethoxy) benzaldehyde. (b) A mixture of cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.54 g, 15.95 mmol), 3- (ethoxycarbonylmethoxy) benzaldehyde (4.3 g) and xylans (20 ml) is heated to 160 ° C at night. The reaction mixture is cooled to room temperature, a solid is formed which is collected by filtration and washed with methanol and then with ether. The product is recrystallized from acetonitrile to yield 2.48 g of l-cyclopentyl-3-ethyl-6- [3- (ethoxycarbonylmethoxy) phenyl] pyrazolo [3,4-p] pyrimidin-4-one. An additional 0.3 g of the product is also obtained from the recrystallization of the filtrate for a total of 2.78 g. Example 21 To a suspension of l-cyclopentyl-3-ethyl-6- [3- (ethoxycarbonylmethoxy) phenyl] pyrazolo [3,4-p] pyrimidin-4-one (1.23 g, 3.0 mmol) in ethanol (10 ml) water (100 ml) is added, followed by 85% KOH. The reaction mixture is heated on a steam bath for 3 hours, cooled to room temperature and filtered. The filtrate is cooled and acidified with acetic acid to produce a white precipitate, which is collected by filtration and washed with water, then with ethanol and finally with ether. The product is combined with the other product from the experimental run and then recrystallized from DMF / CH3CN to yield 0.98 g of l-cyclopentyl-3-ethyl-6- [3- (carboxymethoxy) phenyl] -pyrazolo [3, 4-dl pyrimidin-4-one, mp 299-300 ° C. Example 22 (a) To a mixture of 3-hydroxybenzaldehyde (4.15 g, 33.98 mmol), KOH (4.93 g) and DMSO (50 ml) is added N- (2-chloroethyl) pyrrolidine hydrochloride (6.94 g). The reaction mixture is stirred at room temperature overnight, then poured into water (750 ml) and ethyl acetate (350 ml) is added. The layers are separated, the aqueous layer is extracted with ethyl acetate and the combined organic layers are washed with water (2 x 1000 mL), dried over MgSO4, filtered and distilled to yield 7.12 g of 2- [2- (1-pyrrolidinyl) ethoxy] benzaldehyde. (b) A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazolo-4-carboxamide (232 g, 10.45 mmol), 3- [2- (1-pyrrolidinium-ethoxy] -benzaldehyde (2.98 g) and xylans (10 ml is heated at 160 ° C overnight.) Additional aldehyde (0.5 g) and p-toluenesulfonic acid (0.5 g) are added and heated continuously overnight, the reaction mixture is cooled, the solvent Distillate and the residue is purified by column chromatography on silica gel eluting with ethyl acetate (100%) then with ethanol / ethyl acetate (l / l), followed by recrystallization of the product from acetonitrile. obtained by preparative thin layer chromatography of the mother liquors from the recrystallization steps eluting with ethyl acetate to yield a total of 0.6 g of l-cyclopentyl-3-ethyl-6- [3- [2- (1-pyrrolidinyl) ethoxy] phenyl] pyrazolo [3, 4-p] pyrimidin-4 -one Example 23 (a) To a mixture of 3-hydroxybenzaldehyde (5.44 g, 44. 55 mmoles, K2C03 (13.6 g) and DMF (50 ml) are added in portions hydrochloride of 2-dimethylaminoethyl chloride (7.1 g). The reaction mixture is stirred at room temperature overnight, filtered and the filtrate distilled. The residue is diluted with IN HCl (300 mL) and extracted with ether and the ether layer is dried over MgSO4 and distilled. The aqueous layer is acidified and then treated with still basic 8N NaOH, then extracted with ether (3 x 150 ml). The ether layers are combined, dried over MgSO4, filtered and distilled to yield as an oily liquid, 1.43 g of 3- [2- (dimethylamino) ethoxyl benzaldehyde. (b) + (c) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (3.50 g, 15.74 mmol), 3- [2- (dimethylamino) ethoxy] benzaldehyde (3.95 g) and xylenes (10 ml) are heated at 160 ° C overnight. The reaction mixture is cooled to room temperature, the solvent is distilled, and the residue is partitioned between chloroform and water. The layers are separated, and the aqueous layer is extracted with chloroform. The organic layers are combined, washed with brine, dried over MgSO4, filtered and distilled to yield, as an oil, 1-cyclopentyl-3-ethyl-6- [3- (2- (dimethylamino) ethoxy] phenyl] pyrazolo [3,4-d] pyrimidin-4-one as marked in [Example 23 (b)]. The free base is treated with ethanolic HCl to produce the product as the hydrochloride salt [as marked in Example 23 (c)]. Example 24 (a) A mixture of 3-fluorobenzonutril 818 ml, 168.38 mmol), imidazole (11.46 g), K2CO3 (25.59 g), copper (1.75 g), potassium iodide (1.75 g) and DMF (125 ml) are It leads to reflux during the night. The reaction mixture is cooled to room temperature and poured into ice / water (600 ml). A precipitate forms, which is collected by filtration, washed with water, dissolved with ethanol (25 ml) / CHCl3 (500 ml) and filtered. The filtrate is divided in water, the organic layer is separated, dried over MgSO4 and distilled. The residue is combined with the product of the other experimental run and recrystallized from CHCl3 / hexanes to yield 13.4 g of 3- (l-imidazolyl) benzonitrile. (b) To a mixture of 3- (l-imidazolyl) benzonitrile (3.16 g), l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (3.77 g, 16.98 mmol) and DMF (75 mi) NaH is added (0.78 g, 60% dispersion in mineral oil). The reaction mixture is stirred at room temperature for about 2 days, then nitrile (0.1 equivalents) and NaH (0.2 equivalents) are added further and the mixture is stirred at room temperature overnight. The solvent is distilled and the residue is divided between chloroform (150 mi) and water (350 mi). The layers are separated, the aqueous layer is extracted with chloroform (2 x 100 mL) and the organic layers are combined, washed with brine, dried over MgSO4, filtered and distilled. The product is dissolved in hot ter-dibutyl methyl ether, filtered and distilled. The residue is treated with CH3CN and the solid that forms is collected by filtration to yield 2.10 g of 1 ^ -cyclopentyl-3-ethyl-6-3- (1-imidazole) phenyl] pyrazolo [3,4-d] pyrimidine. -4-amine. (OA solution of l-cyclopentyl-3-ethyl-6- [3- (1-imidazolyl) phenyl] pyrazolo [3,4-d] pyrimidin-4-amine 6.24 g 16.7 mmol), in 45 ml of H20 / H2SO4 (1: 1) in an EtOH / ice bath add sodium nitrite (5.77 g) in water (5 ml) in small portions over 1.5 hours. The reaction mixture is warmed to room temperature and stirred overnight. The reaction mixture is poured into ice / water (500 ml) and neutralized with NH 4 OH to produce a yellow precipitate which is collected by filtration, washed with water, then with ether. The product is recrystallized from EtOAc / MeOH, then with MeOH to produce l-cyclopentyl-3-ethyl-6- [3- (1-imidazolyl) phenyl] irazolo [3,4-d] pyrimidin-4-one. p.f. 264-265 ° C. Example 25 (a) To a mixture of 3,4-dihydroxybenzaldehyde 3.46 g, 25.05 mmol), K2CO3 (11.08 g) and DMF (50 ml) which is stirred at room temperature for 1 hour, N- (2-chloroethyl) morpholine hydrochloride (9.79 g) is added. The reaction mixture is stirred at room temperature overnight, then on a steam bath for 6 hours. The initial material is still present, in this way additional K2C03 (1.73 g) and N-2-chloroethylmofoline hydrochloride (4.66 g) are added and the mixture is heated on a steam bath overnight. The reaction mixture is filtered, the filtrate is diluted and the residue is extracted into 2N HCl (200 mL) and partitioned with CHC13 (100 mL). The aqueous layer is extracted with CHC13 (2 x 150 mL), and the organic layers are combined. The aqueous layer is cooled, then treated with concentrated NH4OH until neutral. The aqueous layer is then extracted with CHC13 (3 x 150 mL), and the organic aqueous layers are combined, washed with brine, dried over MgSO4, filtered and distilled to yield 3.4- [2- (4-morpholinyl ) ethoxy] benzaldehyde. • (b) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (2.09 g, 9.4 mmol), 3,4- [2- (4-orpholinyl) ethoxy] benzaldehyde ( 5.14 g) and xylan (25 ml) is heated at 160 ° C for about 2 days. The initial material is still present, in this way p-toluenesulfonic acid (6.0 g) is added and the mixture heated to 160 ° C overnight. The reaction mixture is cooled to room temperature, water and methanol are added and the mixture is distilled to produce an oily residue. The residue is partitioned between INN NaOH (300 mL) and EtOAc (100 mL), the layers separated and the aqueous layer extracted with EtOAc (1 x 150 mL). The organic layers are combined, washed with brine, dried over MgSO4, filtered and distilled. The solid product is recrystallized from EtOAc to yield 1.51 g of 1-cyclopentyl-3-ethyl-6- [3,4-f2- (4-morpholinyl) ethoxy] phenyl] -pyrazolo [3,4-d] pyrimidine. -4-one.

Example 26 (a) To a mixture of ethyl 2-hydroxybenzoate (2.4 ml, 16.38 mmol), K2CO3 (4.98 g) and DMF (30 ml) is added N- (3-chloropropyl) morpholine hydrochloride (3.93 g). The mixture is stirred at room temperature for 30 minutes, then heated on a steam bath overnight. The reaction mixture is cooled, filtered and distilled to yield a liquid which is partitioned between EtOAc (350 mL) and water. The organic layer is separated, washed with water (2 x 200 mL), dried over MgSO4 and distilled to yield ethyl 2- [3- (4-ortholinyl) propoxy] benzoate. (b) + (c) Sodium spheres (0.42 g) are dissolved in ethanol (20 ml) and then l-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.02 g, 9.10 g) is added. mmoles), followed by ethyl 2- [3- (4-morpholinyl) propoxy] benzoate (5.33 g). The reaction mixture is refluxed for 3 days, then stirred at room temperature, and then the solvent is distilled. The residue is dissolved in water (250 ml) acidified to a pH of about 7 with acetic acid and extracted with CHCl. The organic layers are washed with brine, dried over MgSO4 and distilled to produce an oil.

The oil is extracted into ether, filtered and the filtrate is distilled and purified by column chromatography on silica gel eluting with EtOAc (100%) followed by EtOAc / MeOH (80/20) to yield 2.71 g of l-cyclopentyl. 3-ethyl-6- [2- [3- (4-morpholinyl) propoxy] phenyl] pyrazolo [3,4-d] pyrimidin-4-one, as a solid [marked as in Example 26 (b)] . The free base is treated with EtOH-HCl and 1.14 g of the hydrochloride salt (labeled as in Example 26 (c)), m.p. 220-221 ° C. Example 27 (a) To a stirring solution of KOH (5.81 g) in DMSO (15 mL) imidazole is added (5.0 g, 73.4 mmol). The reaction mixture is stirred for 1 hour, then 2-fluorobenzonitrile (8.76 ml) in DMSO is added in drops over 20 minutes. The reaction mixture is stirred at room temperature overnight and the product is collected by filtration and washed with water to yield 10.91 g of 2- (1-imidazolyl) benzonitrile as a white solid. (b) To a mixture of 2- (1-imidazolyl) benzonitrile (3.14 g), l-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.75 g, 16.59 mmol) and DMF (75 ml), 60% NaH is added (0.78 g, 60% dispersion in mineral oil). The reaction mixture is stirred at room temperature overnight, poured into ice / water (600 ml) and treated with acetic acid until pH 7 is obtained. The product is collected by filtration, and recrystallized from EtOAc / hexane to yield 2.82 g of 1/4 hydrate of l-cyclopentyl-3-ethyl-6- [2- (1-imidazolyl) phenyl] pyrazolo [3,4-d] pyrimidin-4-amine. (c) To a solution of 1/4 hydrate of l-cyclopentyl-3-ethyl-6- [2- (1-imidazolyl) phenyl] pyrazolo [3,4-d] pyrimidin-4-amine (2.55 g, 6.837) mmoles) in 35 ml of H20 / H2SO4 (l / l) in an EtOH / ice bath was added dropwise NaN02 (2.36 g) in water (10 ml) for 2 hours. The reaction mixture is stirred overnight, poured into cold water (750 ml) and neutralized with NH 4 OH. A precipitate is formed which is collected by filtration and washed with water, then with ether to yield 0.75 g of the product. An additional 1.74 g of the filtrate product are extracted and these fractions of the combined product are recrystallized from EtOAc, and then dissolved in chloroform and distilled to yield, as a white solid 1.42 g of l-cyclopentyl-3-ethyl-6 - [2- (1-imidazole) phenyl] pyrazolo [3,4-d] pyrimidin-4-one. p.f. 192-194 ° C. Example 28 A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (2.0 g, 9 mmol), 4-nitrobenzaldehyde (2.04 g, 13.5 mmol), methanesulfonic acid (0.25 ml) and xylans (50 ml), is heated to reflux overnight, followed by an additional 6 hours. Ethanol (200 ml) is added to the reaction mixture, which is then brought to reflux and then treated with DARC0R. The reaction mixture is filtered, concentrate to 100 ml and then cool down. Yellow needles are formed, which are collected by filtration and washed with ether to yield 0.53 g (17%) of 1- 'cyclopentyl-3-ethyl-6- (4-nitrophenyl) -pyrazolo- [3,4- d ] pyrimidin-4-one, pf 321-323 ° C (dec). Example 29 (a) To a mixture of l-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (5.0 g, 22.5 mmol), ethyl 4-chloro-2-ethoxybenzoate (5.4 g, 23.6 g) mmoles) and DMF 850 ml) is cooled in an ice bath, NaH (3.9 g, 97.5 mmol, 60% dispersion in mineral oil) is added. The reaction mixture is stirred in an ice bath for 2 hours, then at room temperature overnight. The reaction mixture is then concentrated in vacuo, and the residue is treated with water (100 ml) and acidified with acetic acid. The mixture is extracted with CHC13 (2 x 150 mL), the organic layers are concentrated in vacuo and the oily residue is crystallized from ether. The product is collected by filtration and dried. Recrystallization of the isopropanol / ether product yields 6.2 g of 1-cyclopentyl-3-etii-5- (4-chloro-2-ethoxyphenylcarboxamido) -lH-pyrazole-4-carboxamide, m.p. 175- 177 ° C. (b) A mixture of l-cyclopentyl-3-ethyl-5- (4-chloro-2-ethoxyphenylcarboxa) -lH-pyrazole-4-carboxamide (1.0 g, 2.11 mmol) and N-methyl-2-pyrrolidinone ( 3 ml) is heated at 185 -190 ° C for 6 hours. The reaction mixture is cooled to room temperature and treated with water (25 ml) and the product is collected by filtration and recrystallized from isopropanol to produce l-cyclopentyl-3-ethyl-6- (-chloro-2 - ethoxyphenyl) pyrazolo [3,4-d] pyrimidin-4-one, mp 185-187 ° C. Example 30 A mixture of l-cyclopentyl-3-ethyl-5- (4-chloro-2-ethoxyphenylcarboxamido) -lH-pyrazole-4-carboxamide (4 g, 9.8 mmol), imidazole (5.0 g, 73.5 mmol), KF (4.5 g, 77.5 mmol) and N-methyl-2-pyrrolidinone (10 mL) is heated at 185-190 ° C for 2.5 hours, then at room temperature overnight. Water (20 ml) is added to the reaction mixture, and the mixture is acidified with acetic acid. A precipitate is formed which is collected by filtration, washed with water and dried to yield 2.8 g of l-cyclopentyl-3-ethyl-6- (4-chloro-2-hydroxyphenyl) pyrazolo [3,4-d] pyrimidin-4 -one, as needles, pf > 300 ° C. Example 31 To a mixture of l-cyclopentyl-3-ethyl-6- (4-nitrophenyl) pyrazolo [3,4-d] pyrimidin-4-one (1.38 g, 3.9 mmol), SnCl2-2H20 (2.64 g, 11.72 mmoles), ethanol (24 ml) and water (10 ml) were added concentrated HCl (14.5 ml). The reaction mixture is refluxed for 2 hours, cooled and the product is collected by filtration and dried in vacuo to yield 0.85 g (67%) of 1/3 of 1-cyclopentyl-3-ethyl-6-hydrate. - (4-aminophenyl) pyrazolo [3,4-d] pyrimidin-4 -one, mp 279 ° C (decomposition). Example 32 A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (2.0 g, 9.0 mmol), 2,3-dihydrobenzo [b] furan-5-carboxaldehyde (1.73 g, 11.7 mmoles), methanesulfonic acid (0.25 ml) and xylenes (50 ml) are brought to reflux for 20 hours and then allowed to stand for about 2 days. The reaction mixture is diluted with ether and the product is collected by filtration and dried to yield 1.65 g (52%) of 1/10 of l-cyclopentyl-3-ethyl-6- (2, 3-dihydrobenzo fb) hydrate. ] furan-5-yl) pyrazolo [3, 4-d] -pyrimidin-4-one, mp 253-254 ° C. Example 33 To a mixture of 1/3 hydrochloride hydrate of 1-cyclopentyl-3-ethyl-6- (4-aminophenyl) pyrazolo [3,4-d] pyrimidin-4-one (0.61 g, 1.7 mmole) in pyridine Dry (20 ml) in an ice bath is added methanesulfonyl chloride (0.49 g, 4.25 mmol). The reaction mixture is stirred at room temperature for about two days, the solvent is washed to dryness and the residue is treated with water. The product is collected by filtration and recrystallized from ethanol, after DARCOR treatment, to yield 0.49 g (72%) of l-cyclopentyl-3-ethyl-6- T4- (methylsulfonylamino) phenyl] pyrazolo [3, 4-d] pyrimidin-4-one, mp 325 ° C (decomposition). Example 34 (a) To a solution of 2-hydroxybenzaldehyde (6.11 g, 0.05 mol) in DMF (50 ml) under argon in an ice bath is added NaH (2.0 g, 0.05 mol), 60% dispersion in mineral oil ), followed 1 hour later by 2-chloroethylmethylether (4.73 g, 0.05 moles). The reaction mixture is allowed to stand for about 2 days, then heated at 70 ° C for 7 hours. The reaction mixture is washed to dryness, the residue is partitioned between water and CHC13, the layers are separated and the aqueous layer is extracted with CHC13 (2 x 75 mL). The product appears to be in both layers, in this way they were concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ether to yield 1.5 g of 2- [2- (methoxy) ethoxyl benzaldehyde. (b) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (1.07 g, 4.8 mmol), 2- [2- (methoxy) ethoxy] benzaldehyde (1.31 g, 7.2 mmol) ), xylenes (40 ml) and methanesulfonic acid (0.25 ml) are refluxed overnight. The reaction mixture is washed to dryness, the residue is partitioned between CH2Cl2 and water, the layers are separated and the aqueous layer is extracted with CH2C12 (2 x 100 mL). The organic layers are combined, concentrate in vacuo and combine with silica gel (30 g). The silica gel preload is placed on a column in silica gel and eluted with hexane / ether (l / l) to produce, after crystallization from hexane / tert-butyl methyl ether (25/1), 0.305 g (17%) of l-cyclopentyl-3-ethyl-6- [2- [2-. { methoxy) -ethoxy] phenyl] pyrazolo [3,4-d] pyrimidin-4 -one, m.p. 71-72 ° C. Example 35 (a) To a solution of 3-hydroxy-4-methoxybenzaldehyde (8.56 g, 56.26 mmol) in CH3CN (50 mL) is added K2C03 (17.1 g) with CH3CN (20 mL), followed 20 minutes later by CH2C3 hydrochloride. N- (2-chloroethyl) morpholine (11.52 g). The reaction mixture is refluxed overnight and then cooled to room temperature, filtered and the solvent washed to give, as an amber oil, 4-methoxy-3- (2- (4-morpholinyl) ethoxyl benzaldehyde. (b) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (1.25 g, 5.63 mmol), 4-methoxy-3- [2- (4-morpholinyl) ethoxy] benzaldehyde (1.64 g) and xylenes (12 ml) is heated at 160 ° C overnight. Additional aldehyde (0.5 g) is added and the mixture is refluxed to completion, then cooled to room temperature. The solvent is washed, the residue is suspended with EtOAc and the product is collected by filtration and combined with the product of a similar experimental run. The combined product is recrystallized from CH3CN to produce 1-cyclopentyl-3-ethyl-6- [4-methoxy-3- [2- (4-morpholinyl) ethoxyl-phenyl] pyrazolo [3,4-d] irimidin-4- ona, pf 205-206 ° C. Example 36 L-cyclopentyl-3-ethyl-6- [2- (CH2 = CH-CH20) phenyl] -pyrazolo [3,4-d] pyrimidin-4-one (5.84 g) is heated at 210 ° C for 2 hours. Ether is added and the mixture is filtered and the product is recrystallized from ethanol, then DMF to yield 3.42 g of l-cyclopentyl-3-ethyl-6- [2-hydroxy-3- (2-propenyl) pheny1] pyrazolo [3, 4-d] pyrimidin-4-one, mp >280 ° C. Example 37 (a) To a mixture of 2-hydroxy-4- (diethylamino) -benzaldehyde (10.0 g, 51.75 mmol), K2C03 (14.3 g) and DMF (150 ml) at room temperature is added ethyl iodide (4.1 ml). ). The reaction mixture is stirred for about two days, filtered and the filtrate concentrated in vacuo. The residue is partitioned between ether and saturated Na 2 CO 3, and the organic layer is separated, dried over MgSO 4, treated with charcoal, filtered and concentrated in vacuo. The solid product is recrystallized from hexane to yield as a pink crystalline solid, 9.8 g of 2-ethoxy-4- (diethylamino) benzaldehyde, m.p. 58-59 ° C. (b) A mixture of 2-ethoxy-4- (diethylamido) benzaldehyde (7.87 g, 35.56 mmol), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.95 g, 17.78 mmol) , p-toluenesulfonic acid monohydrate (0.05 g), 10% palladium on carbon (0.11 g) and benzene (150 ml) are refluxed overnight with the azeotropic removal of water. The catalyst is removed by filtration, and the filtrate is concentrated in vacuo. The residue is combined with that of the similar experimental run, and dissolved in CH2Cl2 and loaded onto a column on silica gel. Elution of the column with ether / hexane (60/40) produces a green foam which is triturated with refluxing hexane, and cooled and the product, as pale yellow needles, is collected by filtration to yield 1.19 g (8%) ) of l-cyclopentyl-3-ethyl-6- [2-ethoxy-4- (diethylamino) phenyl] pyrazolo [3,4-d] pyrimidin-4-one. p.f. 138-139 ° C. Example 38 (a) To a suspension of K2C03 (82.88 g, 0.6 moles) in CH3CN (300 ml) is added 3,5-dihydroxybenzoic acid (4.62 g, 0.03 mol), followed 10 minutes later by N- (2) hydrochloride. -chloroethyl) orfolin (18.42 g, 0.099 moles). The reaction mixture is refluxed overnight, cooled, filtered and the filtrate concentrated in vacuo. The oily residue is purified by column chromatography on silica gel eluting with acetone, followed by Kugelrohr distillation to > 195 ° C and 0.2 mm Hg to produce 7.45 g of 3, 5-di- [2- (4-morpholinyl) ethoxy] benzoate of 4-morpholinylethyl. (b) A mixture of 3-5-di- [2- (4-morpholinyl) ethoxy] -benzoic acid 4-morpholinylethyl ester (2.0 g, 4 mmol), 1-cyclopentyl-3-ethyl-5-amino-1H- pyrazole-4-carboxamide (0.45 g, 2 mmol), NaOCH3 (0.23 g, 4 mmol) and ethanol (50 mL) is refluxed for 96 hours. The reaction was incomplete so that the additional equivalent of benzoate and Na0CH3 were added and the mixture was refluxed for 48 hours. The reaction mixture is washed to dryness, and the residue is treated with water and acidified with acetic acid. The mixture is cooled and the product is isolated by filtration and dried at 90 ° C to yield 0.61 g (54%) of l-cyclopentyl-3-ethyl-6- [3,5-di [2- (4-morpholinyl ) ethoxy] phenyl] pyrazolo [3,4-d] pyrimidin-4-one, mp 182-183 ° C. Example 39 To a suspension of l-cyclopentyl-3-ethyl-6- [2-hydroxy-3- (2-propenyl) phenyl] pyrazolo [3,4-d] pyrimidin-4-one (1.0 g) in acetic acid (15 ml) sulfuric acid (15 ml) is added while cooling in an ice bath. The reaction mixture is warmed to room temperature and stirred overnight. The reaction mixture is poured into ice / water, a formed precipitate which is collected by filtration and washed with water. The product is purified by recrystallization from ether, followed by column chromatography on silica gel eluting with 25% EtOAc / hexane to yield 0.5 g of l-cyclopentyl-3-ethyl-6- [2-methyl-2]. , 3-dihydrobenzo [bl furan-5-yl] pyrazolo [3,4-d] pyrimidin-4 -one, mp 164-165 ° C. Example 40 (a) 3- (Ethoxycarbonylmethoxy) benzaldehyde (9.55 g, 45.91 mmol) is dissolved in ethanol (75 ml) and water (25 ml) and then KOH (3.02 g) is added. The reaction mixture is stirred at room temperature until the reaction is complete and then the product is collected by filtration and dried to yield, as a white powder, 3.78 g of the potassium salt of 3- (carboxymethoxy) benzaldehyde. (b) The potassium salt of 3- (carboxymethoxy) benzaldehyde is dissolved in water and treated with 9N HN03. A precipitate forms which is collected by filtration, washed with water and dried at 75 ° C under vacuum to yield 1.66 g of 3- (carboxymethoxy) benzaldehyde. (O 3- (carboxymethoxy) benzaldehyde (1.63 g, 9.05 mmol) is dissolved in p-dioxane (20 mL) and cooled in an ice bath and then N, N'-carbonyldiimidazole (1.9 g) is added in one portion. The reaction mixture is stirred for 30 minutes, then morpholine (0.8 ml) is added and the reaction mixture is warmed to room temperature and stirred until the reaction is complete.The solvent is removed in vacuo, the residue is divided. between CHC13 (100 mL) and 2N HCl (75 mL), the layers are separated, and the aqueous layer is extracted with CHC13 (2 x 75 mL) .The organic layers are combined, dried over MgSO4 and stirred to produce a oil which is combined with the product from an experimental run and purified by column chromatography on silica gel eluting with chloroform to yield 2.1 g of 3- [4-morpholinylcarbonylmethoxy] benzaldehyde. (d) A mixture of l- cyclopentyl-3-ethyl-5-amino-lH-zole-4-carboxamide (1.87 g), 3- [4-morpholinylcarbonyl-ethoxy] Benzaldehyde (2.1 g, 8.43 mmol) and xylenes (20 mL) is heated at 160 ° C for about 2 days. The solvent is removed, then methanol is added to the residue and the product is collected by filtration. The product of the filtrates is additionally obtained and the product fractions are concentrated and recrystallized from CH3CN / CHC13 to produce l-cyclopentyl-3-ethyl-6- [3- [4-morpholinylcarbonylmethoxy) phenyl] zolo [3.4 - d] midin-4 -one, pf 212-213 ° C. Example 41 (a) A mixture of 3-hydroxybenzaldehyde (5.17 g, 42.33 mmol), K2CO3 (58.5 g) and CH3CN (100 ml) is stirred at room temperature for 15 minutes, then dibromoethane (18.3 ml) is added. The reaction mixture is stirred at room temperature for 30 minutes, then brought to reflux for 3-4 hours. Additional dibromoethane is added and then the reaction mixture is refluxed overnight. The reaction mixture is cooled, filtered and the filtrate distilled to produce an oil. The oil is dissolved in ether (300 mL), washed with 5 N NaOH (2 x 75 mL) and the ether layer is dried over MgSO4 and distilled. The residue is purified by chromatography on silica gel eluting with 10% ethyl acetate / hexane to yield 5.23 g of 3- (2-bromoethoxy) benzaldehyde. (b) A mixture of 3- (2-bromoethoxy) benzaldehyde (3.91 g, 17.07 mmol) K2C03 (3.1 g), thiomorpholine (1.9 ml) and DMF (30 ml) is heated in a steam bath overnight. Additional K2C03 (0.7 g) and thio orpholine (1.0 ml) are added and the reaction mixture is heated in a steam bath overnight. The reaction mixture is cooled to room temperature, filtered and the filtrate distilled to produce an amber oil. The oil is combined with the product of a similar experimental run and purified by column chromatography on silica gel, eluting with EtOAc (100%) to produce, as an oil, 3- [2- (4-thiomorpholinyl) ethoxyl- benzaldehyde (c) A mixture of 3- [2- (4-thiomorpholinyl) ethoxy] -benzaldehyde (3.2 g, 12.75 mmol) l-cyclopentyl-3-ethyl-5-amino-1H-zole-4-carboxamide (2.55 g) and xylans (20 ml) are heated at 160 ° C overnight. The reaction mixture is cooled in an ice bath, and then the solvent is removed to produce an oil which is recrystallized during rest. The product is treated with MeOH / Et20, the mixture is cooled and the product is collected by filtration and washed with ether to yield 0.51 g of the desired product. The filtrate is concentrated in vacuo to yield 5.0 g of the 6,7-dihydro derivative, which is dissolved in xylans (25 ml), treated with palladium on charcoal and heated at 110 ° C for 3 hours. Palladium is added in additional charcoal (1.5 g) and heated continuously for 2 hours. The mixture is filtered through CELITER and the filtrate is distilled. The residue is treated with methanol and the product is collected by filtration and combined with 0.51 g of the product obtained above and the product obtained from the similar experimental run. The fractions of the combined product are recrystallized from EtOAc, washed with ether and dried at 100 ° C under vacuum to produce l-cyclopentyl-3-ethyl-6- [3- [2- (4-thiomorpholinyl) -ethoxy] phenyl] pyrazolo [3,4-d] pyrimidin-4 -one. Example 42 (a) To a mixture of 3-hydroxybenzonitrile (4.76 g, 0. 04 mmoles), K2C03 (16.6 g, 0.12 mmol) and DMF (100 ml) under an argon atmosphere was added 4-chloromethylpyridine hydrochloride (6.56 g, 0.04 mmol). The reaction mixture is stirred at room temperature for about two days, the solvent is evaporated and the residue is partitioned between water and CH2C12. The organic layer is washed with aqueous 2N NaOH (1 x 100 mL), brine, then dried over MgSO4. The solvent is removed in vacuo to yield, as an amber solid, 9.0 g of 3- (4-pyridinylmethoxy) benzonitrile. (b) A mixture of (3- (4-pyridinylmethoxy) benzonitrile (2.5 g, 0.012 mol) in 75% formic acid (35 ml) is treated with Raney nickel (2 g) and heated at reflux for 4 hours. The reaction mixture is filtered through SUPERCELL®, the filtrate is brought to a pH of 8-9 with 5N NaOH, extracted with EtOAc (3 x 150 mL) and the combined organic layers are dried over MgSO4, filtered and I know ~ distill. The residue is purified by column chromatography on silica gel eluting with EtOAc (100%) to yield 0.94 g (37%) of 3- (4-pyridinylmethoxy) -benzaldehyde. (c) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide (2.7 g, 0.124 mol), 3- (4-pyridinylmethoxy) benzaldehyde (3.95 g, 0.0185 mol) and xylan (100 ml) are refluxed overnight. Additional carboxamide (1 g) is added and the mixture is refluxed for another 2 days. Palladium in 10% carbon is added (1 g) and the mixture is refluxed for another 3 hours.

The catalyst is removed by filtration, the filtrate is concentrated in vacuo and the solid residue is collected by filtration. The additional product is obtained by concentration of the mother liquors and the fractions of the combined product are recrystallized from ethyl acetate to yield 1.66 g of l-cyclopentyl-3-ethyl-6- [3- [4-pyridinyl ethoxy] methoxy ] phenyl] pyrazolo [3,4-d] pyrimidin-4 -one, mp 230-232 ° C. Example 43 (a) A mixture of 3-hydroxybenzaldehyde (3.66 g, 0.03 mole), K2CO3 (12.43 g, 0.09 mole) and CH3CN (100 ml) is stirred at room temperature for 1/2 hour, then N- hydrochloride is added. methyl-2-chloromethylpiperidine (5.49 g, 0.03 mol). The reaction mixture is stirred until the reaction is complete, then the solvent is removed in vacuo and the residue is partitioned between CHC13 (3 x 100 mL) and the combined organic layers are concentrated in vacuo to yield 3- (1-methyl). 3-hexahydroazepinyloxy) benzaldehyde. (b) A mixture of 3- (1-methyl-3-hexahydroazepinyloxy) -benzaldehyde (0.79 g, 3.4 moles), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.5 g, 2.2 mmol), methanesulfonic acid (0.25 ml) and xylans (25 ml) are refluxed overnight. The solvent is distilled, the residue is dissolved in CH2C12 and purified by column chromatography on silica gel eluting with ether, then with acetone, then with 0.5% acetone / Et3N to yield 0.43 g (45%) of l-cyclopentyl. 3-ethyl-6- [3- (1-methyl-3-hexahydroazepinyl-oxy) phenyl] pyrazolo [3, 4-d] pyrimidin-4-one. p.f. 195-196 ° C. Example 44 To a mixture of l-cyclopentyl-3-ethyl-6- [3- [4-pyridinylmethoxyphenyl] pyrazolo [3,4-d] pyrimidin-4-one, (11 g) in acetic acid (100 ml) / water (50 mi) is added Pt20 (200 mg). The mixture is hydrogenated at 50 psi with heating (varying the setting to 40) for four hours. The catalyst is removed by filtration, the filtrate is concentrated and the residue is partitioned between NH 4 OH and ethyl acetate. The organic layer is separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography on silica gel, eluting with ethyl acetate followed by preparative thin layer chromatography eluting with ethyl acetate to produce, then recrystallized with EtOAc, 64 mg of 1-cyclopentyl-3-ethyl. -6- (3-hydroxyphenyl) pyrazolo [3,4-d] -pyrimidin-4-one, mp 275-278 ° C (dec). Example 45 (a) To a stirred solution of 3-hydroxybenzaldehyde (8 g, 65 mmol), l-methyl-4-piperidinol (7.5 g, 65 mmol), triphenylphosphine (13.1 g, 65 mmol) and THF (100 mL) was added diethylazodicarboxylate (11.4 g, 65 mmol) in THF (20 mL) over a period of 35 minutes. The reaction mixture is stirred in an ice bath for 3 hours, then at room temperature for 5 days. The reaction mixture is concentrated in vacuo and partitioned between CHC13 (300 mL) and 3 N HCl (300 mL). The aqueous layer is concentrated in vacuo, the residue is treated with 10% K2CO3 and extracted with CHC2 (2 x 10 mL). The solvent is removed in vacuo to yield 7.4 g of the crude 3- (1-methyl-4-piperidinyloxy) -benzaldehyde. (b) A mixture of 3- (1-methyl-4-piperidinyloxy) -benzaldehyde (7.4 g) 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2 g) and xylans (200) mi) is refluxed for 31 hours and then stirred at room temperature for several days. The solvent is removed in vacuo, and the residue is purified by column chromatography on silica gel eluting with ether (100%), ether / 10% methanol to produce, after recrystallization from isopropanol, 2.3 g of 1/4 l-cyclopentyl-3-ethyl-6- [3- (1-methy1-4-piperidinyloxy) phenyl] pyrazolo [3,4-d] pyrimidinone-hydrate. Example 46 (a) To a stirring solution of 2,4-fluorobenzonitrile (25 g, 0.18 mol) in p-dioxane (250 ml) in an ice bath is added sodium ethoxide (15 g, 0.22 mol) during 45 minutes. The reaction mixture is stirred for 2 hours, then at room temperature for 18 hours. The solvent is concentrated in vacuo and the residue is partitioned between water (200 ml) and CH2C12 (400 ml) and acidified with acetic acid. The organic layer is separated, dried over MgSO4 and concentrated in vacuo to yield, as a yellow oil, 26.7 g of a mixture of 2-ethoxy-4-fluorobenzonitrile and 4-ethoxy-2-fluorobenzonitrile. (b) To a mixture of the benzonitriles of Example 46 (a) (26.5 g, 0.16 moles), imidazole (11.5 g, 0.17 moles) and p-dioxane (150 ml) cooled in an ice bath is added NaH ( 6.8 g, 60% dispersion in mineral oil) for a period of 30 minutes. The reaction mixture is stirred for 1 hour, then at room temperature for 24 hours, followed by standing at room temperature for 24 hours. The solvent is removed in vacuo, the residue is partitioned between CH2Cl2 (2 x 300 mL) and water (100 mL). The CH2C12 extracts are combined, concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with ether (100%), ether / 10% methanol to yield 10.1 g of 4- (1-imidazolyl) ) -2-ethoxy-benzonitrile. p.f. 134-136 ° C. (c) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide 81.5 g, 6.3 mmol), 4 - (1-imidazolyl) -2-ethoxy-benzonitrile (1.5 g, 7 mmol) , NaH (0.84 g, 21 mmol, 60% dispersion in mineral oil) and p-dioxane (75 ml) is heated on a steam bath for 12 hours, then stirred at room temperature overnight. The reaction mixture is acidified with acetic acid, concentrated in vacuo and water is added to the residue. A sticky solid is formed which is collected, washed with water, dried and purified by column chromatography on silica gel eluting with ether (100%) to ether / 15% methanol to produce after recrystallization of acetonitrile , 0.78 g, 36%) of l-cyclopentyl-3-ethyl-6- [4- (1-imidazolyl) -2-ethoxyphenyl] irazolo [3,4-d] pyrimidin-4-one, mp. 204-206 ° C. Example 47 Following a procedure similar to that described in Example 1 (c), but substituting l-tert-butyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamide for l-cyclopentyl-3-ethyl -5-amino-lH-pyrazole-4-carboxamide and 2,4,6-trimethylbenzaldehyde by 2-propoxybenzaldehyde, it is contemplated that l-tert-butyl-3-ethyl-6- [2, 4,6-trimethylphenyl] -pyrazolo-3,4-d] pyrimidin-4-one. Example 48 Following a procedure similar to that described in Examples 1 (b) and 1 (c), but substituting 1-cyclopentyl-3-phenylmethyl-5-amino-1H-pyrazole-4-carbonitrile for l-cyclopentyl-3 -ethyl-5-amino-1H-pyrazole-4-carbonitrile in part 1 (b), it is contemplated that it can be prepared: (a) 1-cyclopentyl-3-phenylmethyl-5-amino-1H-pyrazole-4-carboxamide . (b) l-Cyclopentyl-3-phenylmethyl-6- (2-propoxyphenyl) -pyrazolo [3,4-d] pyrimidin-4-one. Biological Test Results In standard biological test procedures, it is found that the compounds of Formula I possess an inhibitory activity of c-GMP-PDE V (formally named as c-GMP-PDE I) and thus are useful in the treatment of heart failure and hypertension. It has also been found that in the compounds of the formula I, together with nitrates, are useful in reducing or reversing nitrate-induced tolerance and thus may be useful in the treatment of angina pectoris, congestive heart disease and myocardial infarction. The multiple isozyme forms of the cyclic nucleotide phosphodiesterase (PDE) have been identified in mammalian cells. These isozymes hydrolyse cyclic adenosine monophosphate (cAMP) and / or cyclic guanosine monophosphates (cGMP) to inactive 5'-nucleotide phosphates in biologically presumable form. The intracellular elevation of cGMP in uniform vascular muscle causes a cascade of events that leads to a reduction in muscle tone while the elevations of cGMP in the renal tubule cells stimulate natriuresis and diuresis. The vascular uniform muscle and renal cells contain an isozyme of phosphodiesterase which has a low Km (1 μM) for the hydrolysis of cGMP. This isozyme has been referred to as cGMP-PDE or cGMP-PDE V (formally named as cGMP-PDE I since it elutes from an anion exchange sepharose resin in the first peak of PDE activity at a concentration of sodium between 150-200 mM). In this way, the inhibition of the cGMP-PDE isozyme is a viable subcellular mechanism in which the increase in cGMP can produce a reduction in total peripheral resistance and a stimulation of natriuresis and diuresis. The development of cGMP-PDE inhibitors represents a method for the discovery of useful agents for the treatment of heart failure and hypertension. For example, compounds that have high inhibitory potency for cGMP-PDE are expected for low blood pressures and induce natriuresis and diuresis. The inhibitory activity of cGMP-PDE of the representative compounds of the invention has been demonstrated by the following procedure. The cGMP-PDE isozymes and other PDEs are isolated from cardiovascular tissues (heart and aorta) of various animal and human species by affinity and anion exchange chromatography as described in Silver et al., Sec. Messeng. Phos. 13: 13-25, 1991; the activity of the PDE is determined, in the presence and absence of test compounds essentially as described by Thompson et al., Adv. Cyclic Nucleotide Res. 10: 69-92. To determine the potency and selectivity of compounds as PDE inhibitors, the compounds are screened for their effect in the hydrolysis of cyclic nucleotides at 10 μM. If observed = 50% inhibition of PDE activity, an IC50 value (concentration of the compound causing 50% reduction in PDE activity) is generated and corresponds to 95% confidence intervals. The IC50 values are calculated from the concentration response curves as described by Tallarida and Murray, Manual of Pharmacologic Calculations with Computer Programs, Procedure 8, Graded Dose-response, pp. 14-19, Springer-Verlag, New York, 1981. The following table summarizes the results obtained from the tests of the representative compounds of the invention.

Example No. Percent inhibition at μM given or CI5Q (nM) cGMP-PDE V 1 (C) 7/3 * 2 250 3 200 4 5.8 5 87 6 1.6 7 51% (10 μM) or 20%: i μM) cía! 41C / 430 * S (b) 701 il μK) or 32% .'0.1 μM) 9 (b) 4.9 10 851 (10 μM) or 15% ¡1M) 11 (c 2700/4500 * 12 (b) 74 % (1 μM) or 301 ci μM) 14 810 15 500 16 68% (10 μM) or 19% μM) or 780 nM Example No. Percent inhibition to uM dice or CI5Q (nM) cGMP-PDE V 17 (c) 14% (0.1 μM) or 19% (1 μM) or 39% (10 μM) 18 (b) 370 19 (b) 73 20 (b) 94 21 93 22 (b) 140 23 (C) 540 24 (O 130 25 (b) 14/51 * 26 (c) 28% (1 μM) 27 < c > 73% (1 μM) or 21% (0.1 μM.) 28 40% (1 μM) 29 (b) 7.4 / 8.4 * 30 53%; l μM) or 9% (Cl μM) 31 61%: l μM) or 31% Í0.1 μM) 32 47% (1 μM) or 23% (0.1 μM) 33 56% (1 μM) or 21% (0.1 μM) 34 (b 56% (Cl μM) or 28% (0.01 μM¡ 35 (b) 58% (0.1 μM) or 13% (0.01 μM) 36 0% (0.1 μM) or 4% (1 μM) 27 (b 73% (1 μM) or 31% (0.1 μM) 38 (f 63% (Cl μM) or 11% 10.01 μM) 39 65% (0.1 μM) or 24% (0.01 μM) 40 (d) 74% (1 μM) or 47% (0.1 μM) 41 (c) 56% (1 μM) or 46% (0.1 μM) 42 (c: 56% (Cl μM) or 25% (0.01 μM) 43 (b! 75% (1 μM) or 41 * ( 0.1 μM) 44 56%; i μM) OR 29% (Cl μM) 46 fc í 26% (Cl μM) OR 76%: 1 μM) or?: • *: 10 μM) or 18 nM * The numbers represent the IC50 values (nM) for experimental separate runs The antihypertensive activity of the representative compounds of the invention is demonstrated by the following procedure. all spontaneously hypertensive rats (SHR) with sodium pentobarbital (50 mg / kg, ip) and instrumented with catheters placed in the inferior vena cava and the abdominal aorta for administration of the drug and record of blood pressure and heart ratio, respectively . After 2 days of recovery from surgery, three baseline blood pressure measurements are performed at 5 minute intervals in conscious SHR. The compounds to be tested or vehicles are then administered intravenously in a dose-dependent manner (0.3-10 mg base / kg) while blood pressure is continuously recorded in a polygraph. The response of the mean arterial pressure is measured 5 minutes after the administration of each dose of the test compound and the next dose in a cumulative dose mode. The response is calculated for each dose of the test compound as the difference from the average of the three baseline measurements. The following table summarizes the results obtained from the test of the representative compounds of the invention.

SHR iv% change in mean blood pressure to mg / kg Example No. given: 6 (mg / kg) l (c) -5% (1 mg / kg) 3 -7% (1 mg / kg) 8 (at 5.7 o -35% (10 mg / kg) or -20% (3 rag / kg) or -81% (30 mg / kg, po) 9 (b) -19% (10 mg / kg) 13 (b) 9.5 or -58% (30 mg / kg, po) or -19% (3 mg / kg) or -14% .1 mg / kg) or -11% (0.3 mg / kg) 19 (bl 12.5 or -19% (10 g / kg 21 -1% (10 mg / kg) 22 (b) 17.9 or -18% (10 mg / kg) 24 (c) 12.7 or -21% (10 mg / kg) or -13% (3 mg / kg) 25 ib) 4.5 or -36% (10 mg / kgi or -27 * (3 mg / kg) or -18% (1 mg / kg) or -18% (10 mg) / kg, po: The activity of representative compounds of the invention in the inversion or reduction of nitrate-induced tolerance is demonstrated by the following procedure. They became tolerant to nitroglycerin spontaneously hypertensive rats (17-25 weeks of age) by repeated administration of high doses of nitroglycerin (100 mg / kg, each, 3 times / day for 3 consecutive days). To confirm the doses of tolerance result of nitroglycerin, a dose range of 1-300 μg / kg is administered intravenously and the maximum change in mean arterial pressure (MAP) is recorded for each dose. Groups of rats tolerant to the compounds of the invention (tolerant pretreated group) with vehicle (0.05 N NaOH) (pretreated group with tolerant vehicle) are intratreated intravenously 5-10 minutes before the administration of the exposure doses of nitroglycerin. The administration of exposure doses of nitroglycerin to non-tolerant rats, (non-tolerant group) causes a decrease depending on the MAP dose of between 10 to 40 mm Hg. The administration of exposure doses of nitroglycerin to the group pretreated with tolerant vehicles results in a significant decrease in the hypotensive response. The administration of exposure doses of nitroglycerin to tolerant rats which are pretreated with the compounds of the invention (a tolerant pretreated group) results in various degrees of restoration of the hypotensive response. The area below the dose-MAP curve is calculated by the non-tolerant group and for the pretreated group with tolerant vehicle and the tolerant pretreated group. The percent inversion of tolerance induced by nitrate is calculated as follows: Percentage of investment = (AUCtol-pretreated - AUCtol-veh) / (AUC-nontol-AUCtol-veh) x 100 where: AUCnontol = to the area below the MAP dose curve for the non-tolerant group. AUCtol-veh = to the area under the dose-MAP curve for the group pretreated with tolerant vehicle.

AUCtol-pretreated "to the area below the dose-MAP curve for the tolerant pretreated group. An inverse percentage of 100% or greater reflects a complete reversal of nitrate-induced tolerance, while an inversion percentage of 0% indicates that no reversal of nitrate-induced tolerance occurs. The following table summarizes the results obtained from the tests of the representative compounds of the invention. Percentage (%) of tolerance inversion Example Dose (mg / kg) induced by nitroglycerin 6 1.0 49 8 (a) 0.3 5 13 (b! 0.3 58 The compounds of the invention can be prepared for pharmaceuticals useful for conventional pharmaceutical procedures which are well known in the art; that is, by formulating a pharmaceutical composition which comprises compounds of the invention or their pharmaceutically acceptable salts together with one or more physiologically acceptable carriers, adjuvants, diluents or vehicles, for oral administration in solid or liquid form, parenteral administration, topical administration or administration. by inhalation of aerosol and the like.

Solid compositions for oral administration include compressed tablets, lozenges, powders and granules. In such solid compositions, the active compound is mixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions may also contain additional substances other than inert diluents, for example lubricating agents, such as magnesium stearate, talc and the like. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Together with the inert diluents such compositions may also contain adjuvants, such as wetting and suspending agents, and sweeteners,. flavors, perfuming agents and preservatives. According to the invention, the compounds for oral administration also include capsules of absorbent material, such as gelatin, which contains the active component with or without the addition of diluents or excipients. Preparations according to the invention for parenteral administration include sterile aqueous, organic-aqueous and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilization, preservation, emulsification, wetting and dispersing agents. The preparations according to the invention for topical administration or administration by. aerosol inhalation includes dissolving or suspending a compound of the invention in a pharmaceutically acceptable carrier such as water, aqueous alcohol, liquor, oil solution or oil in water emulsion and the like. If desired, the compounds of the invention can be further incorporated into slow delivery or target delivery systems such as polymer matrices, liposomes and microspheres. The percentage of the active compound in such compositions may vary such that a suitable dose is obtained. The dose administered to a particular patient varies depending on the judgment of the doctor using as criteria: the route of administration, the duration of treatment, the size and physical condition of the patient, the potency of the active component, and the patient's response to it. An effective amount of the dose of the active component can thus be easily determined by the physician after a consideration of all the criteria and using his best judgment on the improvement of the patient.

Claims

CLAIMS 1. A compound of the formula characterized in that: R1 is tert-butyl or cyclopentyl; R3 is lower alkyl or phenyl-lower alkyl; Y R6 is phenyl or phenyl substituted by one to three, the same or different, substituents selected from the group consisting of lower alkoxy, lower alkyl, hydroxy,

1-imidazolyl, lower alkenyloxy, lower alkylamino-lower alkoxy, 4-morpholinyl-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carboxy-lower alkoxy, trifluoromethyl, 1-piperidinyl-lower alkoxy, 1-pyrrolidinyl-lower alkoxy, nitro , halo, amino, - (CH ^)? ^ - lower alkylsulfonylamino, lower alkoxy-lower alkoxy, lower alkenyl, lower alkylamino, -OCH (CH3) CH

2-, 4-morpholinylcarbonyl-lower alkoxy, 4-thiomorpholinyl-alkoxy lower, pyridinyl-lower alkoxy, 1-lower alkyl-

3-hexahydroazepinyloxy and l-lower alkyl-

4-piperidinyloxy; or its pharmaceutically acceptable acid and / or hydrated addition salt. 2. The compound according to claim 1, characterized in that R1 is cyclopentyl; and R3 is lower alkyl. 3. The compound according to claim 2, characterized in that R3 is methyl or ethyl. 4. The compound according to claim 3, characterized in that R6 is phenyl or phenyl substituted by one to two, same or different, substituents selected from the group consisting of lower alkoxy-lower alkyl, hydroxy, 1-imidazolyl, lower alkenyloxy, di-lower alkylamino-lower alkoxy, 4-morpholinyl-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carboxy-lower alkoxy, trifluoromethyl, 1-piperidinyl-lower alkoxy, 1-pyrrolidinyl-lower alkoxy, nitro, halo, amino, - ( CH2) 20"'lower alkylsulfonylamino, lower alkoxy-lower alkoxy, lower alkenyl, lower dialkylamino, -OCH (CH3) CH2-, 4-morpholinylcarbonyl-lower alkoxy, 4-thiomorpholinyl-lower alkoxy, pyridinyl-lower alkoxy, l-alkyl lower-3-hexahydroazepinyloxy and l-lower alkyl-4-piperidinyloxy 5. The compound according to claim 4, characterized in that R6 is phenyl or phenyl substituted by one to two, the same or different, substituents s selected from the group consisting of methoxy, ethoxy, propoxy, methyl, hydroxy, 1-imidazolyl, CH2 = CHCH20-, 2- (dimethylamino) ethoxy, 3- (dimethylamino) propoxy, 2- (4-morpholinyl) ethoxy, 3- (4-morpholinyl) propoxy, ethoxycarbonyl-methoxy, carboxymethoxy, trifluoro-ethyl, 2- (1-piperidinyl) -ethoxy, 2- (1-pyrrolidinyl) ethoxy, nitro, chloro, amino, - (CH2) 20-, methylsulfonylamino, 2- (methoxy) ethoxy, CH2 = CH2CH2-, diethylamino, -OCH (CH3) CH2-, 4-morpholinyl-carbonylmethoxy, 2- (4-thiomorpholinyl) ethoxy, 4-pyridinylmethoxy, l-methyl-3-hexahydroazepinyloxy and l-methyl-4-piperidinyloxy. 6. The compound according to claim 5, characterized in that it is selected from the group consisting of: l-cyclopentyl-3-ethyl-6- (2-propoxyphenyl) -pyrazolo [3,4-d] pyrimidin-4 -one , l-cyclopentyl-3-ethyl-6- [4- (1-imidazolyl) phenyl] -pyrazolo [3,4-d] pyrimidin-4-one, l-cyclopentyl-3-ethyl-6- [3- ( 2- (4-morpholinyl) ethoxy) -phenyl] pyrazolo [3,4-d] pyrimidin-4-one, l-cyclopentyl-3-ethyl-6- [2-ethoxy-4- (1-imidazolyl) -phenyl) ] pyrazolo [3,4-d] pyrimidin-4-one, and l-cyclopentyl-3-ethyl-6- [2- (CH2 = CHCH20) phenyl] -pyrazolo [3,4-d] pyrimidin-4 -one . 7. The pharmaceutical composition characterized in that it comprises a compound according to claim 1, together with a pharmaceutically acceptable carrier, adjuvant, diluent or carrier. 8. The pharmaceutical composition characterized in that it comprises a compound according to claim 2, together with a pharmaceutically acceptable carrier, adjuvant, diluent or carrier. 9. The pharmaceutical composition characterized in that it comprises a compound according to claim 3, together with a pharmaceutically acceptable carrier, adjuvant, diluent or carrier. 10. The pharmaceutical composition characterized in that it comprises a compound according to claim 4, together with a pharmaceutically acceptable carrier, adjuvant, diluent or carrier. 11. The pharmaceutical composition characterized in that it comprises a compound according to claim 5, together with a pharmaceutically acceptable carrier, adjuvant, diluent or carrier. 12. The pharmaceutical composition characterized in that it comprises a compound according to claim 6, together with a pharmaceutically acceptable carrier, adjuvant, diluent or carrier. 13. The method for effecting cGMP-phosphodiesterase inhibition in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound according to claim 1. 14. The method for effecting cGMP-phosphodiesterase inhibition in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound according to claim 2. 15. The method for effecting cGMP-phosphodiesterase inhibition in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound in accordance with claim 3. The method for effecting cGMP-phosphodiesterase inhibition in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound according to claim 4. 17. The method for effecting cGMP-phosphodiesterase inhibition in a animal organism characterized p or which comprises administering to the organism an effective amount of a compound according to claim 5. 18. The method for effecting the cGMP-phosphodiesterase inhibition in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound according to the claim 6. The method for treating a heart failure and / or hypertension in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound according to claim 1. 20. The method for treating a heart failure and / or hypertension in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound according to claim 2. 21. The method for treating a heart failure and / or hypertension in an animal organism characterized in that it comprises administering to the organism an effective amount of a compliant compound c in claim 3. 22. The method for treating a heart failure and / or hypertension in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound according to claim 4. 23. The method for treating a fault of the heart and / or hypertension in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound according to claim 5. 24. The method for treating a heart failure and / or hypertension in an animal organism characterized in that it comprises administering to the organism an effective amount of a compound according to claim 6.