6-ARYL PYRAZOLO[3,4-d]PYRIMIDIN-4-ONES AND COMPOSITIONS AND METHODS OF USE THEREOF

Abstract: 6-Aryl pyrazolo[3,4-d]pyrimidin-4-one derivatives, pharmaceutical compositions containing them and methods for effecting c-GMP-phosphodiesterase inhibition and for treating heart failure and/or hypertension.

Description: 6-ARYL PYRAZO θn.4-dlPYRIMIDIN-4-O ΞS AND COMPOSITIONS AND METHODS OF USE THEREOF BACKGROUND OF THE INVENTION (a) Field of the Invention: The invention relates to 6-aryl pyrazolo [3 , 4-d] -pyrimidm- 4-ones, to pharmaceutical compositions containing them and to methods for effecting c-GMP-phosphodiesterase inhibition, and treating heart failure and/or hypertension. (b) Information Disclosure Statement .- Schmidt et al . , U.S. Pat. No. 3,165, 520, issued January 12, 1965, disclose as coronary dilating agents p razolo- [3 , 4-d]pyrιmιdmes of general formula: R 1 wherein: R 1 represents a hydrogen atom or an alkyl, -, halogen-alkyl or oxa-alkyl radical or a cycloalkyl, .- alkyl, aralkyl or heterocyclylalky1 radical or an at iv, r ~ t bmuclear aryl cr heterocyclic radical; R 3 represents a hydrogen atom or a lower-alky1 radical; R 5 represents an aliphatic, cycloaliphatIC , cyci - aliphatic-aliphatic , araliphatic or heterocyc1Ic-aliphat -c radical; and R δ represents an aliphatic radical or an aralkyl >r heterocyclyl-alkyl radical which may be substituted. The patent more specifically discloses as especially valuable the compounds in which R 1 represents a hydrogen atom oi a lower-alky1 radical cr a cycloalkyl radical, α hydroxy-lower- lI-./I radical or halogen-lower-alky1 radical, an oxa-lower-alkyl , cr m aryl radical • . ■ :nιcn may be unsubstltuted c: mono-, di-, cr r: : - substituted by halogen, alkoxy, alkyl, methylenediox , trifluoromethyl, nitro, amino, or a pyridyl radical; R 3 represents a hydrogen atom or a lower-alkyl radical; R 5 represents a lower- alkyl radical or a lower-alkylamino radical; and R 6 represents a lower-alkyl radical or an aralkyl radical. Further disclosed are a series of l-R 1 -3-R 3 -4-hydroxy-6- R 6 -pyrazolo [3 , -d]pyrimidines which are said to be useful as intermediates in the synthesis of final products. Among the intermediates specifically disclosed are l-cyclopentyl-4-hydrox - 6-benzyl-pyrazolo[3 , 4-d]pyrimidine and 1-isopropyl- -hydroxy-6-ιn- methoxybenzylpyrazolo [3 , 4-d]pyrimidine. Schmidt et al . , U.S. Pat. No. 3,211,731, issued October 12, 1965, disclose as coronary dilating agents pyrazoio- [3 , 4-d]pyrimidines of general formula: wherein: R 1 represents hydrogen, an alkyl, hydroxy-alkyl , halogen-alky1 or oxa-alkyl radical, a cyclo-alkyl, cycio- alkylalkyl, aralkyl, heterocyclyl-alkyl radical cr an at most binuclear aryl or heterocyclic radical; P. 3 stands for hydrogen, or in the second place, for a lower-alkyl radical; and R 5 represents a possibly substituted aralkyl or heterocyclylalkyl radical. The patent more specifically discloses as especially valuable the compounds in which R 1 represents a hydrogen atom or a lower-alkyl group, cycloalkyl, hydroxy-lower-alkyl , halogen-iower- alkyl, oxa-lower-alkyl , or an aryl; R 3 represents a hydrogen atom or lower-alkyl and R 6 a substituted or unsubstituted aralkyl. Among the compounds specifically disclosed are 1-isopropyl-4- hydroxy-6- 2 ' -me hoxyphenylme hyl ) pyra olo ( 3 , -d] pyrimidine , 1- cyclopentyl-4-hydroxy-6-benzylpyrazolo [3 , 4-d] pyrimidine, 1-iso- propyl-4-hydroxy-6- (β-phenylethyl)pyrazolo[3 , 4-d]pyrimidine, and l-isopropyl-4-hydroxy-6- (4-aminobenzyl)pyrazolo[3 , 4-d]pyrimidine. Schmidt et al . , U.S. Patent 3,211,732, issued October 12, 1965, disclose, as intermediates, l-R 1 -3 -R 3 -6-R 6 -4- hydroxy-pyrazolo[3 , 4-d]pyrimidines wherein: 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 phenyl lower-alkyl radical; R 3 represents a hydrogen atom or a lower-alkyl radical; and R 6 stands for a substituted or unsubstituted phenyl lower-alkyl radical. Specifically disclosed is 1-isopropyl-4-hydroxy-6- benzylpyrazolo[3 , 4-d]pyrimidine. Also disclosed, as intermediates, are l-R 1 -3-R 3 -6-R 6 - - hydroxypyrazolo [3 , 4-d]pyrιmidmes wherein: R 1 stands for a hydrogen atom, a lower-alkoxy-lower- alkyl radical or a hydroxy-lower-alkyl radical, a cyclopentyl or cyclohexyl radical or a phenyl or phenyl-lower-alkyl radical which may be substituted; R 3 has the meanings given above; and R 6 stands for a phenyl radical which may be substituted. Specifically disclosed is l-ιsopropyl-4-hydroxy-6-phenylpyrazolo- [3 , 4-d]pyrimidine. Breuer et al . , U.S. Pat. No. 3,732,225, issued May 8, 1973, disclose as hypoglycemic agents and an 1-inflammatory agents pyrazolo [3 , 4-d]pyrιmιdmes of formula: wherein: R is hydrogen or lower-alkyl; R 1 is lower-alkyl, cycloalkyl, phenyl or substituted phenyl; R 2 is phenyl, substituted phenyl or cycloalkyl; and R 3 is hydrogen, lower-alkyl, cycloalkyl, phenyl or substituted phenyl. Specifically disclosed are 1-methyl-6-phenyl and l-methyl-6- (4-chlorophenyl)pyrazolo [3 , 4- d]pyrimidin-4-ones. British Patent 937,722, published September 25, 1963, to CIBA LIMITED, discloses as a coronary dilating agent 1-isopropyl- 4-hydroxy-6-benzyl-pyrazolo[ , 4-d]pyrimidine. Hamilton, U.S. Pat. No. 4,666,908, issued May 19, 1987, discloses pyrazolo[4, 3-d]pyrιmidine-7-ones of formula: wherein: R 1 is lower-alkyl of from one to six carbons, inclusive, lower-alkylene of from one to six carbon, inclusive, lower- hydroxyalkyl of from one to six carbons, inclusive, lower- hydroxyalkylene of from two to six carbons, inclusive, lower- aminoalkyl of from one to six carbons, inclusive, or lower- aminoalkylene of from two to six carbons, inclusive; n is 0-4; and or 2 , 3 or 4 -pyridyl wherein X, Y and Z are independently (1) hydrogen; (2) lower-alkyl of from one to six carbons, inclusive; (3) halogen; (4) hydroxyl; (5) lower-alkoxy of from 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 from one to six carbons, inclusive, optionally substituted by (i) amino, (ii) morpholino, or (iii) cycloalkyl of from five to seven carbons, inclusive, (9) sulfonyl or (10) -S02 NR'R" wherein R' and R" are as defined above. The patent more specifically discloses as preferred compounds those wherein Ar is R 2 . The compounds are stated to be useful in the treatment of cardiovascular disorders. Miyashita et al., Heterocycles 1990. 31, 1309-1314, describe the preparation of a series of pyrazolo[3 , 4-d]pyrimidines of general formula: wherein: R is phenyl or methyl; and R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, ethyl carboxylate or phenyl. No indication of utility is disclosed. Hamilton, PCT Application 00192, published January 14, 1988, discloses a series of 5 - subs t i u ted pyrazolo [4 , 3-d] pyrimidin-7-one derivatives which are stated to be useful as cardiotonic, CNS stimulative, antiallergy, antiasthma or cognition activating agents. Bell et al., European Patent Application 0463756, published January 2, 1992, disclose a series of 5- (2, 5- disubsti tut ed -phenyl )pyrazolo[4,3-d] pyrιmidm-7 -ones which are stated to be useful in the treatment of cardiovascular disorders. Podesva et al., U.S. patent 3,772,294, issued November 13, 19 ~ 3, disclose a process for preparing compounds of the formula I : I wherein: X represents a halogen atom, a free or substituted hydroxyl, amino or mercapto group and R represents a hydrogen atom, or a lower-alkyl or a substituted or unsubstituted aryl radical. The compounds are disclosed as being potentially useful in the treatment of hyperuricemia associated with gout and other conditions and additionally, the compounds v/herein X represents a halogen atom are said to be useful as intermediates in the synthesis of other compounds having the formula I. Specifically disclosed is 4-hydroxy-6-phenyl-l-pyrazolo[3 , 4-d]pyrimidine. Coates and Rawlmgs, U.S. Patent 5,075,310, issued December 24, 1991 from application Serial No. 370,494 filed June 23, 1989, disclose and claim compounds of the formula: and pharmaceutically acceptable salts thereof, wherein c is a ring of sub-formula (al or (c) H (a) ) (c) X is oxygen or sulphur; and R 1 is Ci-C δ alkyl, C 2 - 6 alkenyl, C 3 - 5 cycloalkyl-Cι- 4 alkyl, or C 1 - 4 alkyl substituted by 1 to 6 fluoro groups. Specifically disclosed is 6- (2-propoxyphenyl ) pyrazolo [3 , 4-d] pyrιmιdιn-4 ( 5H) -one. The compounds are said to be useful as bronchodilators and vasodilators. Bacon et al, U.S. Patent 5,294,612 issued March 15, 1994 from Application Serial No. 859,770 filed March 30, 1992, discloses a series of 6-heterocyclyl-pyrazolo[3 , 4-d]pyrιmιdm-4-ones, e.g., 1- cyclopentyl-3-ethy1-6- (3-pyridyl)pyrazolo [3 , -d]pyrιmιdιn-4-one. The compounds are disclosed to be useful in treating heart failure and hypertension. SUMMARY OF THE INVENTION The invention relates to compounds of the Formula I: I wherein: P 1 is tert-butyl, or cyclopentyl; R 3 is lower-alkyl, or phenyl-lower-alkyl; and R 6 is phenyl, or phenyl substituted by from one to three, the same or different, substituents selected from the group consisting of lower-alkoxy, lower-alkyl, hydroxy, 1-ιmιdazolyl , lower-alkenyloxy, di lower -alkyl ammo -lower -alkoxy, 4 -morphol my 1- lower-alkoxy , lower-alkoxycarbonyl -lower-alkoxy , carboxylower- alkoxy, t ri f luoromethyl , 1 -piperidinyl - lower-alkoxy , 1- pyrrolidinyl-lower-alkoxy, nitro, halo, amino, -(CH2)2θ-, lower- alkylsulf onylamino, lower-alkoxy-lower-alkoxy , lower-alkenyl , dilower-alkylamino, -OCH (CH3 ) CH2- , 4-morpholmylcarbonyl-lower- alkoxy, 4-thιomorpholmyl-lower-alkoxy , pyridinyl-lower-alkoxy , 1- lower-alky 1 -3 -hexahydroazepmy loxy , and 1 -lower-alky 1 - 4 - piperidinyl oxy; or a pharmaceutically acceptable acid-addition salt and/or hydrate thereof. The compounds of the Formula I have been found to possess c-GmP-PDE V inhibitory activity and are thus useful in the treatment of heart failure and/or hypertension. Particularly preferred compounds of Formula I above are those wherein: R 1 is cyclopentyl; R3 IS methyl, or ethyl; and R 6 is phenyl, or phenyl substituted by from one to two, the same or different, substituents selected from the group consisting of methoxy, ethoxy, propoxy, methyl, hydroxy, 1- lmidazolyl, CH2=CHCH2θ-, 2 - ( dimethy lammo ) ethoxy , 3- ( imethylamino ) propoxy , 2 - ( 4 -morphol my 1 ) e thoxy , 3- (4- morpholmyl ) propoxy , ethoxycarbonyl methoxy, carboxymethoxy , trif luoromethyl , 2- (l-pιper dιnyl etnoxy, 2 - ( 1 - pyrrol ldinyl ethoxy , nitro, chloro, amino, - {CE2 ) 20- , methylsulf onylamino, 2 - (methoxy ) ethoxy , CH2 = CH2CH2-, diethylammo, - OCH ( CH3 ) CH2 - , 4 -morphol my 1 - carbony lmet hoxy , 2- (4- thiomorpholinyl 1 ethoxy, 4 -pyndmy , l-methyl-3- hexahydroazepinyloxy , and l-methyl-4-pιperιdmyloxy . Particularly preferred species of the invention are: 1- cyclopentyl-3-ethyl-6- ( 2-propoxypheny pyrazolo [ 3 , 4-d] pyrimmdm- 4 -one , 1- cyclopentyl- 3 -ethyl-6- [4- ( 1-ιmιdazolyl ) pnenyl ] pyrazolo [ 3 , 4-d] pyrιmιndιn-4-one , l-cyclopentyl-3-ethyl-6- [3- (2- (4-morpholmyl ) ethoxy) phenyl ] pyrazolo [ 3 , -d] pyrιmιndιn-4 -one, l-cyclopentyl-3-ethyl-6- [2-ethoxy-4- (1-ιmιdazolyl)phenyl] pyrazolo [3 , 4-d]pynmιndιn-4-one, and l-cyclopentyl-3-ethyl-6- [2- (CH2=CHCH2θ)phenyl]pyrazolo [3, 4-d] pyrιmmdιn-4-one. The invention further relates to pharmaceutical compositions which comprise compounds of Formula I together with a pharmaceutically acceptable carrier, adjuvant, diluent, or vehicle. The invention further relates to a method for effecting cGMP-phosphodiesterase inhibition in a mammalian organism which comprises administering to said organism an effective amount of a compound of Formula I. The invention further relates to a method for treating heart failure and/or hypertension in a mammalian organism which comprises administering to said organism an effective amount of a compound of the Formula I. DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS The compounds of Formula I may exist in tautomeric equilibrium with the corresponding enol form: While the compounds are believed to be predominantly in the keto form and will be represented as such throughout this specification, it is to 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 tne like. The term lower-alkoxy as used herein means linear or branched alkyloxy substituents having from one to about four _Q _ 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 branched or unbranched unsaturated hydrocarbon radicals of from two to about four carbon atoms and thus includes 1-ethenyl, 1-propenyl, 2- propenyl, 1-methyl-2-propenyl , isopropenyl, 2-butenyl, isobutenyl, and the like. The synthesis of compounds of the invention may be outlined as shown in Scheme A: Scheme A A suitably substituted 5-ammo-lH-pyrazolo- -carbcxamide :il' is reacted with an excess of an appropriately substituted aldehyde of the formula III, optionally m the presence of a suitable organic solvent, preferably xyleneε, or benzene, with or v;ιthout the use of an acid catalyst, preferably p-toluenesulfonic acid, acetic acid, or methanesulfonic acid, optionally m the presence of palladium on carbon, at a temperature m the range of about room temperature up to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to afford the compounds of the formula I. Alternatively, a suitably substituted 5-amιno-lH- pyrazole-4-carboxamιde (II) is treated with an excess of an ester of the formula IV: R^C(0)OR wherein R is lower-alkyl, preferably ethyl, m the presence of a base, preferably sodium ethoxide, n an alcoholic solvent, such as ethanol, at a temperature in the range of about room temperature up to the boiling point of the solvent used, preferably at the boiling point of the solvent used, to afford the compounds of the formula I. The compounds of the formula I can also be synthesized as shown in Scheme B: Scheme B VI A suitably substituted 5-amιno-lH-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, the presence of an excess of a suitable base, preferably sodium hydride, at a temperature in the range cf about room temperature up to the boiling point of the solvent used, to afford either the compounds of the formula I directly, or a mixture of the compounds of the formula I and the pyrazolo [3 , 4- d] pyr midin-4-amines of the formula VI. This mixture can in turn be treated with an excess of sodium nitrite, a 1/1 water/acid mixture, preferably a 1/1 water/sulfuric acid mixture, at a temperature in the range of about -10°C up to about room temperature to afford 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 for effecting changes in the fuctional groups of the compounds of the formula I. For example, dealkylation of aryl ethers to afford the corresponding phenol derivatives, hydrolysis cf esters to afford the corresponding acids, catalytic reduction of nitro derivatives to afford the corresponding amines, and sulfonylation of amines to afford the corresponding sulfonamide derivatives . The compounds of Formula I are useful both m the free base form and in the form of acid-addition salts, and, both forms are within the purview of the invention. The acid-addition salts are often a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the base form. The acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, pharmaceutically-acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmaceu ical doses of the salts, so that the beneficial properties inherent m the free base are not vitiated by side effects ascπbable to the anions. In practicing the present invention it is convenient to use the free base form or the hydrochloride, fumarate, toluenesulfonate, methanesulfonate or maleate salts. However, other appropriate pharmaceutically acceptable 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 m the art which include, but are not limited thereto, dissolving the free base an aqueous alcohol solution containing the appropriate acid and isolating the salt by evaporating tne solution, or by reacting trie free base and an acid an organic solvent, in which case the salt separates directly, or is precipitated with a second organic solvent, or can be obtained by concentration of the solution. Although medicinally 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 desired only as an intermediate product, as, for example, wnen tne salt is formed for purposes of purification or identification, or when it is used as an intermediate in preparing a medicinally acceptable salt by, for example, ion exchange procedures. The appropriately substituted 5-amιno-lH-pyrazole-4- carboxamides of tne formula II are either -:novτ. and thus can be prepared by known procedures (see, for example, U.S. Patent 5,294,612, issued March 15, 1994, the entire contents of which is incorporated herein by reference) , or they can be prepared by the procedures described herembelow 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, cr they can be prepared by procedures known in the art, or by the procedures described hereinbelow in the examples. The structures of the compounds of the invention were established by the mode of synthesis, and by one or more of elemental analysis, and infrared, nuclear magnetic resonance and mass spectroscopy . The course of the reactions and the icentity and homogenity of the products were assessed by one or more of thin layer chromatography (TLC) , high pressure liquid chromatography (HPLC) , or gas-liquid chromatography (GLC) . The following examples will further illustrate the invention without, however, limiting it thereto. All melting points (m.p. ) are given in degrees centigrade ( * C) and are uncorrected. Example 1 (a) A solution of salicylaldehyde (12.21 g, 0.1 mol) DMF (65 ml) was cooled in an ice/water bath under argon and 60% sodium hydride mineral oil (4.0 g, 0.1 mol) was added in several portions. The mixture was stirred for one hour and then lodopropane (16.99 g, 0.1 mol) was added at room temperature. The reaction mixture was stirred at room temperature overnight, poured into water (800 ml) and stirred. The mixture was extracted with chloroform (3X), the chloroform layer was concentrated m vacuo and the dark oil thus obtained v/as distilled under vacuum ,?2-94°C at 1.15 mm Hg) to afford 12.68 g (77 %) of 2-propoxybenzalάehvd . (b) A solution of KOH (12.16 g, 184.2 mmol) water 150 ml) was cooled in an ice-bath and then l-cyclopentyl-3-methyl-5-ammo- lH-pyrazole-4-carbonιtrιte (5.0 g, 26.3 mmol) , followed by 30% hydrogen peroxide (13.5 ml, 131.6 mmol) were added. The reaction mixture was warmed to room temperature and stirred overnight. A precipitate formed which was collected by filtration and washed with ether to afford l-cvclopentyl-3-methyl-5-amιno-lH-pyrazole-4- carboxamid . as a white solid. Additional product was obtained by concentration of the filtrate and collection of the product by filtration to afford a total of 4.46 g of product. Alternatively, the carboxamide was prepared as fellows: A solut-.on of concentrated sulfuric acid (50 rnl j was cooled to -5°C and 1 -cyclopentyl-3-methyl-5-amιno-lH-pyrazole-4-carbonιtrιie 2 .0 g, 10.5 mmol was added. The mixture was stirred as sucπ for 2 hours, tnen at room temperature overnight. The reaction mixture was poured into 400 ml of ice and NH4OH (100 ml) and was stirred for 1 hour. The product precipitated and was collected by filtration. Additional product was obtained by acidifying the filtrate w th acetic acid to a pH of 5 and then extracting with chloroform". The chloroform layers were concentrated m vacuo and titurated with ether to afford, after filtration and drying at 100°C overnignt, 1.67 g (76%) of 1-cvclooentyl-3-methyl-5-a-^ιno- lH-pyra ole- -carboxamide, m.p. 191-192°C. (c) A mixture of l-cyclopentyl-3-methyl-5-amιno-lH-pyrazole-4- carboxamide (3.98 g, 0.019 mol) , 2-propoxybenzaldehyde (6.35 g, 0.038 mol), xylenes (150 ml) and methanesulfonic acid (0.5 ml) v/as heated at reflux for 39 hours with azeotropic removal of water. The reaction mixture was concentrated in vacuo and the residue was treated with 10% K2CO3 and ether. The layers were separated, the aqueous layer was extracted with ether and the combined ether layers were concentrated in vacuo. Analysis of the reaction mixture by TLC indicated that the reaction was not yet complete, therefore, the mixture was heated at 180°C on an oil bath. The residue was dissolved in chloroform, and purified by column chromatography on silica gel eluting with hexane '100%) followed by ether (100%) to afford 2.67 g (41%) of 1-cvclooentyl-^ -methyl- 6- (2-DroDθxynhenyl )-pyrazolof3,4-d1pyrιmιdιn-4-one. m.p. 130- 132°C. Alternatively, the final product was prepared as follows: A mixture of 1-cyclopentyl -3 -methy1 -5-amino-lH-pyrazole-4 - carboxamide (1.0 g, 4.8 mmol) and 2-propoxybenzaldehyde (10.6 g, 10 mmol) was heated at 160°C on an oil bath for 4 hours then at 170°C for 48 hours. The reaction mixture was cooled, chloroform (5 ml) was added and the solution was eluted on a silica gel column with ether (100 %) to afford, after recrystallization from cyclohexane, 0.16 g of pyrazolo [3 , 4-dl pyrιmιdιn- -one. Example 2 A mixture of l-cyclopentyl-3-ethy1-5- (4-quιnolmyl-CH=N- ) lH-pyrazole-4-carboxamιde (6.34 g, 0.018 mol) , benzaldehyde '0.96 g, 0.009 mol), xylenes (150 ml) and methanesulfonic acid (0.5 ml) was refluxed overnight. The reaction mixture was concentrated vacuo, and the residue was treated with ethanol (200 ml 1 and azeotroped. The residue was then treated with 10% K2CO3 (100 ml) , titurated with ether, filtered and washed v/ith water. The product was recrystallized from ethyl acetate and dried at 100°C to afforα 2.68 g of crude product which was purified by column chromatography on silica gel to afford 0.603 g of 1-cvclopen yl-3 - ethyl- -phenyl-nyrazolo f 3 , 4-dipyrιmιdm-4-one, m.p. 221-222°C. Alternatively , and pref erably , the f inal product can be prepared f rom 1 - cyc lopenty l - 3 - ethyl - 5 -amino - lH -pyrazol e - 4 - carboxamide and benzaldehyde following a procedure similar to that described in example 1 ( c ) . Example 3 A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4- carboxamide (2.0 g, 9 mmol) , o-tolualdehyde (2.16 g, 18 mmol) , methanesulfonic acid (0.5 ml) and xylenes (50 ml) was refluxed for 32 hours. The solvent was removed and the residue was treated with ethanol (100 ml) and then concentrated to dryness. The dark residue was treated with 10% K2CO3 and chloroform, the organic layer was separated and the aqueous layer was extracted with chloroform (2 x 100 ml) . The organic layers were combined, concentrated to approximately 20 ml and then added to silica gel ( 30 g) . The preloaded silica gel was placed on a silica gel column and eluted with Et2θ/hexanes (2/8) to (5/5) to afford, after drying at 70°C in vacuo, 1.10 g (40%) of l-cvclooentyl-3-ethyl-6- Example 4 A mixture of l-cyclopentyl-3-ethyl- -ammo-lH-pyrazole-4- carboxamide (2.0 g, 9 mmol) , o-ethoxybenzaldehyde (2.7 g, 18 mmol) , methanesulfonic acid (5 drops) , and xylenes (50 ml) was refluxed for 48 hours. The reaction mixture was stripped to dryness, and treated with 10% K2CO3 and CHCI3 (100 ml) . The layers were separated and the aqueous layer was extracted with chloroform (2 x 100 ml) . The organic layers were combined, and concentrated in vacuo. The dark oil thus obtained was dissolved in CH2CI2 (30 ml) and combined with silica gel (30 g) . The preloaded silica gel was placed on a silica gel column and eluted with Et2θ/hexanes (20/80) to Et20 (100%) to afford 1.41 g (45%) of l-cvclopentyl- - ethyl-6- (2-ethoxyphenyl ^ -pyrazolo f3 , 4-d1Pyrιmidin-4-one, m.p. 146- 147°C. Example 5 A mixture of 1-cyclopentyl-3-ethy1-5-amιr.o-lH-pyrazole-4 - carboxamide (2.0 g, ? mmol) , anisaldehyde i 2 . 5 g, 18 mmol) , xylenes (50 ml) and p-toluenesulfonic acid (0.5 g > was refluxed for 32 hours. The reaction mixture was stripped to dryness, treated with ethanol (100 ml) and then again concentrated to dryness. The residue was treated with CHCI3 (100 ml and 10% K2CO3 (100 ml), the layers were separated and the aqueous layer was extracted with chloroform (3 x 100 ml) . The combined organic layers were concentrated to approximately 25 ml and then combined with silica gel (30 g) . The preloaded silica was placed on a silica gel column and eluted with ether/hexaneε 3/10) to ether (100%) to afford 1.25 g (41%) of 1-cvclopentyl- ?. -ethyl-6- (2- methoxyphenyl ) -pyrazolor3 , 4-d1pyrιmιdm-4-one, r.p. 135-136°C, after recrystallization from cyclohexane. Example 6 A mixture of l-cyclopentyl-3-ethyl -5-ammo-lH-pyra?ole-4- carboxamide (1.0 g, 4.5 mmol), 2-propoxybenzaldenyde (1.5 g, 9 mmol), p-toluenesulfonic acid (0.5 g) and xylenes (50 ml) was refluxed for 20 hours. The reaction mixture was stripped to dryness, treated with ethanol and again concentrated to dryness. The residue was treated with CHCI3 (100 ml) and washed with saturated NaHCC . The organic layer was concentrated to a dark oil which was dissolved in CH2CI2 (30 ml j and combined "lth silica gel (50 g) . The preloaded silica gel was placed on a silica gel column and eluted with 10% hexanes/ether to ether (100%) to afford, after crystallization from hexanes, 0.492 g (30 %) of 1- cvclopentyl -3 - ethyl -6- (2-propoxyphenyl ? -pyrazolo f 3 , 4 -d 1 pyrιmιdιn---one . m.p. 93- 94°C. Example 7 To a solution of 1-cyc1openty1-3 -ethy1 -6- ( 2 - methoxyphenyl) -pyrazolo[3, 4-d]pyπmιdm-4-one (0.5 g, 1.5 mmol) DMF (10 ml) was added NaH (0.15 g, 3.75 mmol, 60% NaH in mineral oil). The reaction mixture was stirred for 20 minutes, then propanethiol (0.228 g, 3.0 mmol) was added and the mixture was stirred at room temperature for 4 hours, then at 110°C for 9 hours. The reaction mixture was stripped to dryness and then water (15 ml) followed by acetic acid (1 ml) were added. A precipitate formed whicn was collected by filtration, washed with water and recrystallized DARCO® treatment from ethyl acetate to afford 0.28 g (58%) of l- yrlonenryl-. , !-qr.hyl-g- '2 -hvdroxyphenv1 > - pyrazolo f 3.4-dl Pyrιmιdm-4-one , m.p. 272-273°C, as white fibrous needles . Example 8 (a) A mixture of l-cyclopentyl-3-ethyl-5-ammo-lH-pyrazole-4- carboxamide (1.18 g, 5.32 mmol) , 4- (1-ιmιdazolyl ) benzaldehyde (1.37 g) and xylenes (8 ml) was warmed to 130°C for 30 minutes, then to 160°C for three days. The reaction mixture was cooled, and the product was collected by filtration and washed with Et2θ to afford 1.88 g of l-cyclopentyl-3-ethyl-6- [4- (1-ιmιdazolylJphenyl] pyrazolo [3 , -d]pyrιmιdιn-4-one as the 6 , 7-saturated derivative. This derivative was mixed with ethanol (300 ml) and 30% H2O2 (3.0 ml) and refluxed overnight. Additional 30% H2O2 '3 ml) was added and the mixture was refluxed for 8 hours. An additional 10 ml of 30% H2O2 was added and the mixture was refluxed overnight. Starting material was still present so an additional 10 ml of 30% H2O2 was added and the mixture was refluxed for 4 hours and then additional 30% H2O2 (10 ml) was added and the mixture was stirred for 1 hour, then was allowed to stand at room temperature overnight . The reaction mixture was stripped to a yellow liquid and purified by column chromatography on silica gel eluting with ethyl acetate (100%) , then 5% methanol ethyl acetate to afford 0.4 g of 1-cvciopent.yl-3-ethyl-6- (4- (1-ιmιdazolyl Innenyll - pyrazolo '3 , 4-di pyrιmιdm-4-one 1 ' 2 hvdrate, m.p. - 300°C. (b) alternatively, the product can be obtained as follows: To a mixture of lmidazole (5.13 g, 75.35 mmol) , K2CO3 (11.45 g and DMSO (50 ml) at room temperature was added to 4- fluorobenzon tπle (10.04 g) in one portion. The reaction mixture was stirred at room temperature for 1 hour, and then v/as warmeα on a steam for 2 hours. The reaction mixture was cooled to room temperature, and poured into cold water. A precipitate formed which was collected by filtration and washed v/ith water and recrystallized from CHCl3/hexane to afford 4.07 g of 4-(l- 1) benzonitrile, m.p. 146-148°C. To a mixture of 4- ( 1 ) benzonitrile (0.9 g, 5.27 mmol ) , l-cyciopentyi-3-ethyl-5-amιno-lH-pyrazole-4 -carboxamide (1.17 g) in DMF (20 ml) at room temperature was added NaH (0.63 g, 60% dispersion in mineral oil) . The reaction mixture was stirred at room temperature overnight, additional NaH (0.5 g) was added and the mixture was stirred at room temperature for about 2 days. The reaction mixture was poured into ice/water (500 ml) , neutralized with acetic acid and the precipitate which formed was collected by filtration, washed with hexanes, dissolved in CHCI3, dried over MgSθ4, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate, combined with the product obtained from two similar experimental runs and then recrystallized from CH3CN/CHCI3 to afford l-cvclo p entyl-3-ethyl-6- f4- (l-ιmidazolyl)phenvHpyrazoler3,4-d1pyrimidin-4-one. m.p. >300°C. Example 9 (a) To a solution of ethyl salicylate (100 g, 0.602 mol) m DMF (400 ml) was added K2CO3 (150 g) , followed by the dropwise addition of allyl bromide (87.5 g, 0.723 mol) . The reaction mixture was then heated on a steam bath for 2 hours, the K2CO3 was removed by filtration and the reaction mixture was poured into water and extracted with ethyl acetate (3 x 300 ml) . The organic layer was washed v/ith brine, and dried over MgS04, and the solvent was removed to afford 122 g (98%) of ethyl 2 - f 2 - propenyloxy)benzoate. (b) Sodium spheres (207 mg) was dissolved in ethanol (15 ml) and l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4-carboxamιde (1 g, 45 mmol) was added, followed by ethyl 2- (2-propenyloxy) benzoate (1.85 g, 9 mmol) . The reaction mixture was refluxed overnight, cooled, the ethanol was stripped and water was added. The pH was adjusted to about 7 and a solid was isolated by filtration. The solid was taken up in ether, washed with dilute HCl, dried over MgS04 , filtered and the solvent was removed and the solid residue was recrystallized from ether to afford 0.56 g of 1-cvclopentyl-? - m.p. 119-120°C. Fxamole 10 -10- A mixture of l-cyclopentyl-3-ethyl-5-ammo-lH-pyrazole-4- carboxamide (2.03 g, 9.14 mmol) , 4- [3 - (dimethylamino)propoxy] benzaldehyde (2.76 ml), and xylenes was heated at 120°C for 1 hour, then at 160°C for 6 hours. p-Toluenesulfonic acid (300 mg) was added and the mixture was heated at 160°C until the reaction was complete. The reaction mixture was cooled to room temperature, and a creamy white solid formed, which was collected by filtration, washed with methanol and recrystallized from ethyl acetate to afford l-cvclopentyl-3 -ethyl- 6- r 4 - r 3 - (dimer.hylammo) nronoxvlPhenvl1 nvrazolofl .4-dlPvnmιdm-4-one . as a white solid, m.p. 1 " 5-178°C. Example 11 (a) To a solution of salicylaldehyde (2 ml) in acetonitrile (20 ml) was added K2CO3 (5.71 g) , followed by U-(2- chloroethyl) morpholine hydrochloride (3.5 gj and then the mixture was stirred at room temperature for 2 hours, then at reflux overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to afford 2- \ 2 - (4-morpholιnyl ) ethoxylbenzaldehyde. as a yellow oil. (b) + (c) A mixture of 1-cyclopentyl-3-ethyl-5-amιno-lH-pyrazole-4- carboxamide '0.95 g, 4.28 mmol , 2- [2 - (4-morpholiny1 ) ethoxy] benzaldehyαe 1.51 g) and xylenes (15 ml) was heated to 120°C for 1 hour, then to 160°C until the reaction was complete. The reaction mixture was then cooled to room temperature, the solvent was removed m vacuo, and the residue was purified by silica gel chromatography eluting with ethyl acetate ιl00%) , followed by ethanol/ethyl acetate (1 1) to afford \ 2 - (4-morpholmyl ethoxy1phenyl1pyrazolof3.4-d 1ryrιmιdm-4-one (Example 11 [ y as an oil. The free base was tnen converted into its hydrochloride salt, which was recrystallized from ethanol and dried at 110°C under high vacuum to afford 0.5 g of 1-cvclopentyl- 3-ethyl-6- f2- f2- ( -morphol yl ) ethoxylphenyl1pyra olo r 3 , 4-dl Pyrιmιdιn-4-one monohvdrochloride , as an off-wnite powder, m.p. 235-237°C, labelled as Example 11 (c) . Example 12 A mixture of 2-formylphenoxyacetic acid (9.01 g, 0.05 mol) , ethanol (4.6 g) , concentrated H2SO4 (0.4 ml) and toluene (40 ml) was heated to reflux with azeotropic removal of water for 1 hour. The reaction mixture was poured into 10% KHCO3 (100 ml) , the layers were separated and the aqueous layer was extracted with ether (2 x 75 ml ) . The organic layers were combined, and concentrated in vacuo to afford 9.1 g ,95 %) of 2 - (ethoxvoarbonvlmethoxv) benzaldehyde. (b) A mixture of l-cyclopentyl-3-ethyl-5-amir.o-lH-pyrazole-4- carboxamide !5.26 g, 23.7 mmol) , 2- (ethoxycarbonylmethoxy ) benzaldehyde '9.10 g, 47.3 mmol) , p-toluenesulfcr. c acid .0.2 g) and xylenes : 00 ml) v/as refluxed for 18 hours w th the azeotropic removal cf water. The solvent was removed in vacuo, and the residue was treated with ethanol and evaporated to dryness. The residue was partitioned between chloroform and 1C% aqueous K2CO3 , the layers were separated and the aqueous layer was extracted with chloroform (100 ml) . The organic layers were combined, and concentrated to dryness. The residue was preloaded on silica gel and then was purified by column chromatography on silica gel eluting with hexanes (100%) to 20% ether/hexane to afford 3.74 g v c l o o e n t v r 2 - (ethoxycarbon-.-lmethoxy lohenv11 pyrazolo (3 , 4-d1c--nmidin-4-one, m.p. 116-117°C. Example 13 (a) To a solution of 3-Hydroxybenzaldehyde 3.05 g, 24.97 mmol) in acetcnitrile (15 ml) was added K2CO3 (7.6 g), followed by N- (2-chloroethyl ) morpholine hydrochloride (4.65 g) . The reaction mixture was stirred at room temperature for 30 minutes, then at reflux overnight. Additional N- ( 2 -chloroethyl ) morpholine hydrochloride (0.93 g) and K2CO3 (0.7 g) were added and the mixture was refluxed for an additional 6 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between water and chloroform, the layers were separated and the aqueous layer was extracted with chloroform (2 x 75 ml) . The organic layers were combined, washed with brine, dried over gS04 , filtered and stripped to afford 7.3 g of 3 - r 2 - ( 4 - morpholinyl ) ethoxylbenzaldehyde, as an amber liquid. (b) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4- carboxamide (1.05 g, 4.73 mmol) , 3 - [2- (4-morphol yl ) ethoxy] benzaldehyde (1.67 g) and xylenes (7 ml) was heated to 160°C overnight. Additional aldehyde (0.4 g) was added and the mixture was heated at 160°C until the reaction was complete. The reaction mixture was cooled to room temperature and a solid formed which was collected by filtration and washed .with ether. The filtrate was concentrated to dryness and the residue was combined with the solid and was purified by column chromatography on silica gel eluting with ethyl acetate/ethanol (60/40) . The solid product thus obtained was washed with ether, recrystallized from ethyl acetate and then v/ashed with ether again to afford l-cvclopentyl-3-e hyl- 6- (3- (2- (4-morpholinyl ) ethoxylphenyll -pyrazolof3 , 4-dl oyrιmιάm-4- one. m.p. 173-176°C. Example 14 A mixture of l-cyclopentyl-3-ethyl-5-amιno-lH-pyrazole-4- carboxamide (1.19 g, 5.38 mmol) , 2-metho y-4- carboxy ethoxybenzaldehyde '1.13 gj and glacial acetic acid (25 ml) was • ■-armed to reflux for 4 days. The reaction mixture v/as cooleα to room temperature and the solvent was stripped tc afford a slurry v/hich was washed with methanol, collected by filtration and then v/ashed with ether. The product was recrystallized from ethanol and v/ashed with ether to afford 1-cvclopentyl-3-e r.--l-6- f (2-m hoxy-4-carboxymethoxy)phenyllpyrazolof3.4-dlpyrιmιdm- - one. Example 15 A mixture of 1-cyclopentyl-3-ethyl-5-amιno-lH-pyrazoie- - carboxamide !0.59 g, 2.65 mmol) , 2-trifluoromethylbenzaldehyde (0.5 ml and glacial acetic acid (25 ml) was refluxed overnight and then 0.5 equivalents of additional aldehyde was added and the mixture was refluxed for about 3 days. The reaction mixture was cooled to room temperature, the acetic acid was stripped and the residue was cooled and rinsed with ether to give a white solid which was collected by filtration and recrystallized from tert- butyl dimethyl ether/hexanes to afford l-cvclopentyl-3-ethyl-6- (2- trifluoromethylohenyl ) -pyrazolo L3.4-dlpvr mιdm-4-one. m.p. 201- 202 °C. Example 16 A mixture of 1 - cyc 1 openty1 - 3 - ethy1 - 6 - [ 2 - (ethoxycarbonylmethoxy) pheny] pyrazolo [3 , 4-d]pyrιmιdm-4-one (3.0 g, 7.3 mmol) , K2CO3 (3.04 g) , water (20 ml) and ethanol (50 ml) was refluxed for 1.5 hours. The reaction mixture v/as cooled, the solvent was removed in vacuo and the residue was slurried with water and acidified. A precipitate formed which was collected by filtration, recrystallized from isopropanol and dried at 90°C. The solid was dissolved m 10% K2CO3 (100 ml) , treated with DARCO® ' filtered and the filtrate was acidified with acetic acid. A precipitate formed which was collected by filtration and dried at 110°C. The solid product was combined with the solid product obtained from a similar experimental run, stirred with 6N HCL (100 ml) , filtered and dried with P2O5 at 100°C under vacuum to afford 2.09 g of l-cvclooentyl-3-ethyl-6- \ 2 - (carboxymethoxy) phenyl 1 pyrazolon.4-dlpyr mιdm-4-one 1/2 hvdrate, m.p. 208-209°C. Example 17 (a) To a mixture of water 500 mi and 85% KOH 37.91 g) at 0 °C was added 30% H2O2 '49.4 m_. , 483 mmol) , followed by 1-tert- butyl-5-ammo-lH-pyrazole-4-carDonιtrιle '15.83 g, 96.5 mmol 1 . The reaction mixture was stirred for four hours at 0°C and then at room temperature for 1 hour. A yellow precipitate had formed which was collected by filtration and air dried to afford 13.2 g (75%) of 1-tert-butyl-5-ammo-lH-oyrazole-4-carboxamide. m.p. 193-195°C. (b) A mixture of 2-propcxyoenzaldehyde (3.0 g, 18.27 mmol), 1- tert-butyl-5-ammo-lH-pyrazole-4-carboxamide (2.5 g, 13.7 mmol , methanesulfonic acid (0.2 ml) and xylenes (50 ml; was refluxed overnight. The reaction mixture was stripped to dryness, treated with ethanol and again stripped to dryness. The residue v/as partitioned between chloroform and 10% KHCO3 , the layers were separated, and the aqueous layer was extracted with chloroform (2 x 100 ml) . The organic layers were combined, and concentrated in vacuo and the residue was dissolved in CH2CI2 (30 ml) and combined with silica gel (20 g) . The preloaded silica gel was placed on a silica gel column and eluted with 70% ether/hexanes, followed by ether (100%) to afford 0.98 g (22%) of 1 -1ert -butyl- 6 - (?.- propoxvphenyl)pyrazolof . -dlpyrimidin-4-one 1/100 hvdrate. m.p. 130-131°C. (c) A mixture of l-tert-butyl-6- (2-propoxyphenyl)pyrazolo[3 , 4- d] pyrimidin-4 -one 1/100 hydrate (0.68 g, 2.1 mmol) and trifluoroacetic acid (50 ml) was heated on a steam bath for 3.5 hours. The reaction mixture was stripped to dryness and the residue was purified by column chromatography on silica gel eluting with ether to afford 0.45 g (79%) of 6 - * 2 - propoxyphenyl ) yrazolo (3 , 4-dl pyrimidin-4-one- 1/4 hvdrate, m.p. 170-171°C. Example 18 (a) To a solution of 4-hydroxybenzaldehyde (4.04 g, 33.08 mmol) , in acetonitrile (50 ml) v/as added K2CO3 (10.1 g) , followed by N- (2-chloroethyl ) morpholine hydrochloride (6.16 g) . The reaction mixture was heated to reflux overnight, additional N- ;2- chloroethyl ) morpholine hydrochloride (0.6 g) and K2CO3 (0.5 g) were added and the mixture was refluxed for another 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was treated with DARCO®, filtered and the solvent was stripped. The residue v/as partitioned betv/een saturated NaHCC3 (150 ml) and ethyl acetate (300 ml) . The layers were separated and the organic layer was v/ashed with IN NaOH, dried over MgSC-j , filtered and stripped to afford, as an amber oil, 6.41 g of 4- ' 2- (4-morpholinyl) ethoxy 1 benzaldehyde. (b) A mixture of 1 -cyclopentyl -3 -ethyi-5-ammo-lH-pyrazole- - carboxamide ( 2.19 g , 9.86 mmol ) , 4- [ 2 - ' 4 - morpholinyl ) ethoxy j benzaldehyde '3.5 g; and xylenes '10 ml- was heated at 160°C overnight. p-Toluenesulfonic acid (0.2 g) was added and the mixture was heated at 160°C overnight. The reaction mixture was cooled to room temperature, and the precipitate which formed was slurried with methanol, collected by filtration and washed with methanol, and then ether. The product was recrystallized from acetonitrile to afford l-cvclopentyl-3-ethyl- 6- f4-f2- ( -morpholinvl) ethoxvlphenvll pyrazolo L3.4-dlcvrimidin-4- one. Example 19 (a) To a mixture of 3 -hydroxybenzaldehyde 5.42 g, 44.38 mmol) , K2CO3 (13.5 g) and acetonitrile was added N- (2- chloroethyl)piperidine hydrochloride (9.8 g) . The reaction mixture was refluxed overnight, cooled to room temperature and filtered. The filtrate was stripped to give an oil which was partitioned between CHCI3 (350 ml) and IM NaOH (200 ml) . The organic layer was separated, washed with IM NaOH (2 x 200 ml) , treated with DARCO®, then MgS04 , filtered, and stripped to afford, as a dark oily liquid, 6.28 g of 3- \ 2 - (1-pjperdinyl) ethoxylbenzaldehvde. (b) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole- - carboxamide ,2.02 g, 9.09 mmol) , 3- [2- (1-piperidmyl ) ] ethoxy] benzaldehyde (3.18 g) and xylenes (10 ml) was refluxed overnight. Additional aldehyde (0.5 g) was added and the mixture was heated at 160°C for 6 hours. The reaction was still not complete so an additional 0.5 g of aldehyde was added and the mixture was refluxed for about 2 days. The reaction mixture was cooled, filtered and stripped to afford an oily residue. The residue was treated with acetonitrile and chilled and the precipitate which formed was collected by filtration and washed with ether. The product was purified by column chromatography en silica gel eluting with ethyl acetate/hexanes (1/1) , followed by recrystallization from acetonitrile to afford, as a white solid, l-cvclonencr.--- t.hyl-6-r3-f2-q- piperidmvl ) ethoxvl phenvll pyrazolo f 3 , 4-dl Pvrιmιdm-4-one . m.p. 180°C Example 20 (a) To a mixture of 3-hydroxybenzaldehyde (5.17 g, 42.34 mmol) , K2CO3 (5.85 g) and acetone (50 ml) was added ethyl bromoacetate (5.2 ml) . The reaction mixture was stirred at room temperature overnight, additional K2CO3 (1 equivalent) -'/as added, the mixture was stirred for one hour, then additional ethyl bromoacetate (0.5 equivalents) was added and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was filtered, water was added to the filtrate and the solvent was removed. The residue was dissolved m ether, extracted with IM NaOH (2 x 100 ml) , and the ether layer was dried over MgSθ4 and stripped to afford, as a liquid, 7.89 g of 3 - (ethoxycarbonylmethoxy) benzaldehyde. (b) A mixture of l-cyclopentyl-3-ethyl-5-amιno-lH-pyrazole-4- carboxamide (3.54 g, 15.95 mmol) , 3 -(ethoxycarbonylmethoxy) benzaldehyde (4.3 g) and xylenes (20 ml) was heated at 160°C overnight. The reaction mixture was cooled to room temperature, a solid formed which was collected Oy filtration and --ashed with methanol and then ether. The product was recrystallized from acetonitri.e to afford 2.48 g of 1 -rvcloπentyl -3-et. n ."l- fi - r " - (ethoxycaroonylmethoxy)phenyl1 pyrazolo f 3 , 4-dlpyrιmιdm-4-one. An addit ional 0.3 g of product was also obtained from the recrystallization of the filtrate for a total of 2.78 g. Example 21 Tc a slurry of 1 -cyc 1open y1 - 3 - e ny1 - 6 - [ 3 - (ethoxycaroonylmethoxy)phenyl]pyrazolo[3 , 4-d]pyrιmιdm-4-one (1.23 g, 3.0 mmol) in ethanol (10 ml) was added water (100 ml) , followed by 85% KOH (0.4 g) . The reaction mixture was heated on a steam bath for 3 hours, cooled to room temperature and filtered. The filtrate was chilled and acidified with acetic acid to afford a white precipitate, v/hich was collected by filtration and washed with water, then ethanol, and finally ether. The product was combined with the product from another experimental run and then was recrystallized from DMF/CH3CN to afford 0.98 g of 1 - cvclopentvl-3-ethvl-6-L3- fcarboxv ethoxv)phenvllpyrazolo f3.4- dlpvrιm dιn-4-one. m.p. 299-300°C. Exam le 22 (a) To a mixture of 3-hydroxybenzaldehyde (4.15 g, 33.98 mmol, , KOH (4.93 g) and DMSO (50 ml) was added N- (2-chloroethyl) pyrrolidine hydrochloride (6.94 g) . The reaction mixture was stirred at room temperature overnight, then was poured into water (750 ml) and ethyl acetate (350 ml) was added. The layers were separated, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water (2 x 1000 ml) , drieα over MgSθ4 , filtered and stripped to afford 7.12 g of 3- f2- ( 1-r'rrolιdιnyl) ethoxyl benzaldehyde. (b) A mixture of l-cyclopentyl-3-ethyl-5-amιno-lH-pyrazolo-4- carboxamide (2.32 g, 10.45 mmol) , 3- [2- (1-pyrrolιdmyl) ethoxy] benzaldeyde (2.98 g) , and xylenes (10 ml) was heated at 160°C overnight. Additional aldehyde (0.5 g) , and p-toluenesulfonic acid (0.5 g) were added and the heating was continued at 160°C overnight. The reaction mixture was cooled, the solvent was stripped and the residue was purified by column chromatography on silica gel eluting with ethyl acetate (100%) then ethanol/ ethyl acetate (1 7 1 , followed by recrystallization of the product from acetonitrile. Additional product v/as obtained by preparative thin layer chromatography of the mother liquors from the recrystallization steps eluting with ethyl acetate to afford a total of 0.6 g (14 %) of pvrr~1 idinyl) ethoxylohenyl1pyrazolor3.4-dlPvrιmιdm-4-one. Example 23 (a) To a mixture of 3-hydroxybenzaldehyde (5.44 g, 44.55 mmol , K2CO3 (13.6 g) and DMF (50 ml) was added in portions 2- dimethylaminoethylchloride hydrochloride (7.1 g) . The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was stripped. The residue was diluted witn IN HCl (300 ml) , and extracted with ether, and the ether layer was dried over MgSθ4 and stripped. The acidic aqueous layer was cooled and then treated with 8N NaOH till basic, then it was extracted with ether (3 x 150 ml) . The ether layers were combined, dried over MgS04, filtered and stripped to afford, as an oily liquid, 1.43 g of 3- r2- (dimethvlam o) ethoxv1benza1dehvde. (b) + (c) A mixture of l-cyclopentyl-3-ethyl-5-amιno-lH-pyrazole-4- carboxamide (3.50 g, 15.74 mmol) , 3 - [2- (dimethylamino) ethoxy] benzaldehyde (3.95 g) and xylenes (10 ml) was heated at 160°C overnight. The reaction mixture was cooled to room temperature, the solvent was stripped, and the residue was partitioned between chloroform and water. The layers were separated, and the aqueous layer was extracted v/ith chloroform. The organic layers v/ere combined, washed with brine, dried over MgS04 , filtered and stripped to afford, as an oil, -cvclooent^ 1 -3 -ethr'l-6- H - I 2 - (dimethylamino) ethoxylphenyl1 pyrazolo f , 4-dlpyrιmιdιn-4-one labelled as [Example 23 (b) ] . The free base was treated with ethanolic HCl to afford the product as the hydrocnioride salt [labelled as Example 23 (c)] . Example 24 (a) A mixture of 3-fluorobenzonitπle (18 ml, 168.38 mmol) , lmidazole (11.46 g; , K2CO3 (25.59 g) , copper '1.75 g , potassium iodide (1.75 g) and DMF (125 mi was refluxed overnight. The reaction mixture was cooled to room temperature and poured into ice/water (600 ml) . A precipitate formed, which was collected by filtration, washed with water, dissolved in ethanol (25 ml)/CHCl3 (500 ml) and filtered. The filtrates were partitioned in water, the organic layer was separated, dried over MgS04 and stripped. The residue was combined witn the product from another experimental run and was recrystallized from CHCI3 hexaneε to afford 13.4 g of 3- 1-lmidazol" 1 )benzonitrile. (b) To a mixture of 3- ( 1-ιmιdazolyl ) benzonitrile '3.16 g , i- cyclopentyl-3-ethyl-5-ammo-lH-pyrazole-4-carooxamιde (3.77 g, 16.98 mmol) and DMF (75 ml) was added NaH (0.78 g, 60% dispersion in mineral oil) . The reaction mixture v/as stirred at room temperature for about 2 days, then additional nitrile (0.1 equivalents) and NaH (0.2 equivalents) were added and the mixture was stirred at room temperature overnight. The solvent was stripped, and the residue was partitioned between chloroform (150 ml) and water (350 ml) . The layers were separated, the aqueous layer was extracted with chlorform (2 x 100 ml), and the organic layers were combined, washed with brine, dried over MgSO i , filtered and stripped. The product was dissolved in hot tert- butyldimethyl ether, filtered and stripped. The residue • .• ■ as treated with CH3CN and the solid which formed was collected by filtration to afford 2.10 g of 1-cvclooentyl-3 -ethyl-6- \ 3 - ' L- imidazolyl )phenyl1pyrazolo \ 2 , 4-dl yrimidin-4-amine. (c) To a solution of 1 -cyclopentyl - 3 -etr.yl-6 - [ 3 - ■ , 1- imidazolyl ) phenyl]pyrazolo [3 , 4-d] yrimidm-4-amine 6.24 g, 1 * .7 mmol) , in 45 ml of H2O/H2SO4 (1:1) in an EtOH/ice bath was added sodium nitrite (5.77 g) in water (5 ml ) in small portions over 1.5 hours. The reaction mixture was warmed to room temperature ,-.nd stirred overnight. The reaction mixture v/as poured into ice/v/arer (500 ml) and neutralized with NH4OH to afford a yellcv: precipit :te which was cellected by filtration, washed with water, then ethe . The product was recrystallized from EtOAc/MeOH, then MeOH to afford l - c v ^ l o o e n t v l - ? - e h y l - - " - ( 3 - ' 1 - imidazolyl^ohenyl 1 pyra olof .4-dl yrιmιdin-4-one, m.p. 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 was stirred at 1 c om temperature for 1 hour, was added N- (2-chloroethyl ) morphol : ne hydrochloride (9.79 g) . The reaction mixture was stirred at rr om temperature overnight, then on a steam bath for 6 hours. Starting material was still present so additional K2CO3 (1.73 g) and N--2- chloroethyl , orpholine hydrochloride ι .66 gi were added and r e mixture was heated on a steam bath overnight. The reaction mixture was filtered, the filtrate was stripped and the residue was t -.en up in 2N HCl (200 ml) and partitioned with CHCI3 (100 ml) . Tne aqueous layer v/as extracted with CH I3 .2 x 150 mi) , and • ne organic layers were combined. The aqueous layer was chilled, tl.en treated with concentrated NH4OH until neutral. The aqueous layer was then extracted with CHCI3 (3 x 150 ml) , and the organic layers were combined, washed with brine, dried over MgS04 , filtered --md stripped to afford 3.4- f2- (4-morpholinyl) ethoxylbenzaldehyde. (b) A mixture of l-cyclopentyl-3-ethyl-5-amino-lH-pyrazole-4- carboxamide (2.09 g, 9.4 mmol) , 3 , 4- [2- (4-morpholinyl) ethoxy] benzaldehyde (5.14 g) and xylenes (25 ml) was heated at 160°C for about 2 days. Starting material was still present so p- toluenesulfonic acid (6.0 g) was added and the mixture was heated at 160°C overnight. The reaction mixture was cooled to room temperature, water and methanol were added and the mixture was stripped to afford an oily residue. The residue v/as partitic ed between IN NaOH (300 ml) and EtOAc (100 ml) , the layers v re separated, and the aqueous layer was extracted with EtOAc (1 x -50 ml) . The organic layers were combined, v/ashed with brine, dried over MgSθ4 , filtered and stripped. The solid product •■■ as recrystallized from EtOAc to afford 1.51 g of l-cvclopentyl-3- ethyl-6- r3. - r2- (4-morpholinyl )ethoxy1ohenyl1pyrazolo[3.4- dlPvrimidin-4-one. Example 26 (a) To ≤ mixture of ethyl 2-hydroxybenzoate (2.4 mi, 16.38 mmol! K2CC3 (4.98 g) , and DMF (30 ml) was added N- .3- chloropropyi , morpholine hydrochloride (3.93 g) . The mixture ' -as stirred at room temperature for 30 minutes, then was warmed cr a steam bath overnight. The reaction mixture was cooled, filtered and stripped to afford a liquid which was partitioned betw e en EtOAc (350 mi) and water. The organic layer was separated, wasted with water '2 x 200 ml) , dried over MgSθ4 and stripped to affo rd ethyl 2- [3- ' -morpholinyl )proooxy 1 benzoate. (b)+(c) Sodium spheres (0.42 g) were dissolved in ethanol (20 v1) and then 1-cyclopentyl-3-ethyl-5-amιno-lH-pyrazole-4-carboxam:de (2.02 g, 9.10 mmol) was added, followed by ethyl 2-[3- 4- morpholmyi propoxy] benzoate (5.33 g) . The reaction mixture ' as refluxed for 3 days, then stirred at room temperature, and then the solvent was stripped. The residue was dissolved in water (250 ml) , acidified to a pH of about 7 with acetic acid and extracted with CHCI3. The organic layers were washed with brine, dried over MgS04 and stripped to afford an oil. The oil was taken up m ether, filtered and the filtrate was stripped and purified by column chromatography on silica eluting with EtOAc (100%) followed by EtOAc/MeOH (80/20) to afford 2.71 g of l-cyclopentyl-3-ethyl-6- [2- [3- (4-morphol yl)propoxy]phenyl]pyrazolo [3 , 4-d]pynmιdm-4- one, as a liquid [labelled as Example 26 (b) ] . The free base was treated with EtOH-HCl and 1.14 g of the hydrochloride salt (labelled as Example 26 (c) ) was obtained, m.p. 220-221°C. Example 2"? (a) To a stirred solution of KOH (5.81 g) in DMSO (15 mL) was added lmidazole (5.0 g, 73.4 mmol) . The mixture was stirred for 1 hour, then 2-fluorobenzonitrile (8.76 mL) in DMSO (10 mLi was added dropwise over 20 minutes. The reaction mixture was stirred at room temperature overnight and the product was collected by filtration and washed with water to afford 10.91 g of 2 - ( 1- lmidazolyl)benzonitrile as a white solid. (b) To a mixture of 2- ( 1-ιmιdazolyl ) benzonitrile (3.14 g) , 1- cyclopentyl-3-ethyl-5-amιno-lH-pyrazole-4-carboxamιde (3.75 g, 16.59 mmol) and DMF (75 ml) was added 60% NaH (0.78 g, 60% dispersion in mineral oil) . The reaction mixture was stirred at room temperature overnight, poured into ice/water (600 ml) and treated with acetic acid until a pH of 7 was obtained. The product was collected by filtration, and recrystallized from EtOAc/hexane to afford 2.82 g of 1-cvclnnentyl -1-et.hyl -^- f 2- 1 - imidazolvDphenyl l yrazolor3.4 -dl pvrιmι ιn-4 -amine - 1 hvdrate. (c) To a solution of 1 -cyclopentyl -3 -ethy1 - 6 - [ 2 - \ 1 - lmidazolyl)phenyl]pyrazolo [3 , -d]pyrιmιdm-4-amine 1/4 hydrate (2.55 g, 6.837 mmol) in 35 ml of H2OΗ2SO (1/1) m an EtOH/ice bath was added dropwise NaN02 (2.36 g) water (10 ml) over 2 nours. The reaction mixture was stirred ovenigh , poured into ice water (750 ml) and neutralized with NH4OH. A precipitate formed which was collected by filtration, and washed with water, then ether to afford 0.75 g of the product. An additional 1.74 g of product was extracted from the filtrate and these combined product fractions were recrystallized from EtOAc, and then were dissolved in chloroform and stripped to afford, as a white powder, 1.42 g of l-cvclopentyl-3-ethvl-6- \ 2 - (1-ιm dazolvl)nhenvl1pyrazolo 3. - dlPyrιmιdm-4-one, m.p. 192-194°C. Example 28 A mixture of l-cyclopentyl-3-ethyl-5-ammo-lH-pyrazole-4- carboxamide (2.0 g, 9 mmol) , 4-nitrobenzaldehyde (2.04 g, 13.5 mmol) , methanesulfonic acid (0.25 ml) and xylenes (50 ml) was heated at reflux overnight, followed by an additional 6 hours. Ethanol (200 ml) was added to the reaction mixture, which was then refluxed and then treated with DARCO®. The reaction mixture was filtered, concentrated to 100 ml and then cooled. Yellow needles formed, which were collected by filtration ana washed with ether to afford 0.53 g (17%) of l-evclopen yl-3-ethyl-6- f 4 - nitrophenyl )pyrazolo (3.4-diPyrιmιdm-4-one, m.p. 321-323°C (dec. , . Example 29 (a) To a mixture of l-cyclopentyl-3-ethyl-5-ammo-lH-pyrazole- 4-carboxamιde (5.0 g, 22.5 mmol) , ethyl 4-chloro-2-ethoxybenzoate (5.4 g, 23.6 mmol) and DMF (50 ml) cooled an ice bath was added NaH (3.9 g, 97.5 mmol, 60% dispersion in mineral oil) . The reaction mixture was stirred in the ice bath tor 2 hours, then at room temperature overnight The reaction mixture was then concentrated in vacuo, and the residue was treated with water (100 ml) and acidified with acetic acid. The mixture was extracted with CHCI3 (2 x 150 ml), the organic layers were concentrated vacuo and the oily residue was crystallized from ether. The product was collected by filtration and dried. Recrystallization of the product from isopropanol/ ether afforded 6.2 g of 1-cvclopentv1-3 - ethyl-5- '4-chloro-2-e noxyphenylcarboxamιdo! 1 -lH-pyrazole-4- carboxarmd . m.p. 1 ~ 5-177°C. (b) ■ n . A mixture of 1-cyclopentyl-3 -ethy1-5 - ( 4-chloro-2- ethoxyphenylcarboxamido) -lH-pyrazole-4-carboxamide (1.0 g, 2.11 mmol) and N-methyl-2-pyrrolidinone (3 ml) was heated at 185 - 190° C for 6 hours. The reaction mixture was cooled to room temperature, and treated with water (25 ml) and the product was collected by filtration and recrystallized from isopropanol to afford l - cv c l open tv l - 3 - e t hv l - 6 - ( 4 - c h l oro - 2 - ethoxvphenvl)pyrazolof3.4-dlpvrimidin-4-one, m.p. 185-187°C. Example 30 A mixture of 1-cyclopentyl-3 -ethyl -5 - ( 4-chloro-2 - ethoxyphenylcarboxamido ) -lH-pyrazole-4-carboxamide (4 g, 9.8 mmol) , lmidazole (5.0 g, 73.5 mmol) , KF (4.5 g, 7 " .5 mmol) and N- methyl-2-pyrroiιdmone (10 ml) was heated at 185 - 190 °C for 2.5 hours, then at room temperature overnight. Water (23 ml) was added to the reaction mixture, and the mixture was acidified with acetic acid. A precipitate formed which was collected oy filtration, washed with water and dried to afford 2.8 g of l-cvclopentyl-3- ethyl-6- (4-chloro-2-hvdroxyphenyl)pyrazolo f3 , 4-dlpyπnιdin-4-one. as white needles, m.p.> 300°C. Example 31 To a mixture of l-cyclopentyl-3-ethyl-6- (4- nitrophenyl )pyrazolo [3 , 4-d] pyrιmιdin-4-one (1.38 g, 3.9 mmol) , SnCl2-2H2θ '2.64 g, 11.72 mmol) , ethanol (24 ml) and water (10 ml) was added concentrated HCl (14.5 ml) . The reacticn mixture was refluxed for 2 hours, cooled, and the product v/as collected by filtration and dried vacuo to afford 0.85 g (67%) of 1 - cvclopentyl-3-ethyl-6- '4-ammophenyl ) y razolo (3 , 4-d 'cyrιmιdιn-4- one hydrochloride 1 3 hydrate, m.p. 279°C (dec ) . Example 32 A mixture of l-cyclopentyl-3-ethyl-5-ammo-iH-pyrazole-4- carboxamide !2.0 g, 9.0 mmol) , 2 , 3-dihydrobenzo [b] furan-5 - carboxaldehyde (1.73 g, 11.7 mmol) , methanesulfonic acid (0.25 ml) and xylenes (50 ml) was refluxed for 2C hours and then allowed to stand for about 2 days. The reaction mixture was diluted v/ith ether and the product was collected by filtration and dried to afford 1.65 g (52%) of l -cvclopen yl -3-e hyl- - ' 2.2 - -_>-> dihvdrobenzo [bl furaπ-5-yl ) pyrazolo [ 3 , 4-d1pyrimidm-4-one 1/10 hvdrate. m.p. 253-254°C. Example 33 To a mixture of 1 -cyclopenty1 - 3 -ethy1 - 6 - ( 4 - aminophenyl ) pyrazolo [3 , 4-d] pyrιmιdιn-4-one hydrochloride 1/3 hydrate (0.61 g, 1.7 mmol) in dry pyridme (20 ml) in an ice bath was added methanesulfonyl chloride (0.49 g, 4.25 mmol) . The reaction mixture was stirred at room temperature for about two days, the solvent was stripped to dryness and the residue was treated with water. The product was collected by filtration and recrystallized from ethanol, after DARCO® treatment, to afford 0.49 g '72%) of l - cv c l open v l - 3 - e hv l - 6 - f 4 - (methylsulfonylamino) phenyll pyrazolo [ 3. -dl pyrιmιdιn-4-one, m.p. 325°C (dec. , . 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 v/as added NaH (2.0 g, 0.05 mol, 60% dispersion in mineral oil) , followed 1 hour later by 2-chloroethylmethyl ether (4.73 g, 0.05 mol) . The reaction mixture was allowed to stand for about 2 days, then v/as heated at 70°C for 7 hours. The reaction mixture was stripped to dryness, the residue was partitioned between water and CHCI3 , the layers were separated and the aqueous layer was extracted with CHCI3 (2 x 75 ml) . The product appeared to be m both layers, thus they were concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting v/ith ether to afford 1.5 g of 2 - f 2 - (methoxy) ethoxylbenzaldehyde. (b) A mixture of l-cyclopentyl-3-ethyl-5-ammo-lH-pyrazole- - 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) was refluxed overnight. The reaction mixture was stripped to dryness, the residue was partitioned between CH2CI2 and water, the layers were separateα and the aqueous layer was extracted with CH2CI2 (2 x 100 ml) . The organic layers were combined, concentrated in vacuo and combined with silica gel (30 g) . The preloaded silica gel was placed on a silica gel column and eluted with hexane/ether (1/1) to afford, after crystallization from hexane/tert-butylmethyl ether (25/1) , 0.305 g (17%) of ^_ cvclopentyl-3-ethyl-6- f2- [2- (methoxy) ethoxylphenyllpyrazolo[3 , 4- dlpyrιmidin-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) was added K2CO3 (17.1 g) with CH3CN (20 ml) , followed 20 minutes later by N- (2-chloroethyl)morpholine hydrochloride (11.52 g) . The reaction mixture was refluxed overnight, and then was cooled to room temperature, filtered, and the solvent was stripped to give, as an amber oil, 4-methoxy-3- [2- (4-morphol mvl ) ethoxylbenzaldehyde. (b) A mixture of l-cyclopentyl-3-ethyl-5-ammo-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) was heated at 160°C overnight. Additional aldehyde (0.5 g) was added and the mixture was refluxed until complete, then cooled to room temperature. The solvent was stripped, the residue was slurried with EtOAc and the product was collected by filtration and combined with the product from a similar experimental run. The combined product was recrystallized from CH3CN to afford 1 - cvclopentv1- -ethyl -6- [4-methoxv-3- \ 2 - (4- morpholinyl )ethoxylphenyllpyrazolo[3,4-dlpyrιmιdιn-4-one, m.p. 205-206°C. Example 36 l-cyclopentyl-3-ethyl-6- [2- (CH2=CH-CH2θ)phenyl]pyrazolo [3 , 4-d]pyrιmιdιn-4-one (5.84 g) was heated at 210°C for 2 hours. Ether was added and the mixture was filtered and the product was recrystallized from ethanol, then DMF to afford 3.42 g of 1 - cvciopentyl - -ethyl-6- \2-hvdroxy-3- ( 2- propenyl)phenyllpyrazolo f ~*> , -d1oyrιmιdιn-4-one, m.p. > 280°C. Example 37 (a) To a mixture of 2-hydroxy-4- (diethylam o)benzaldehyde (10.0 g, 51.75 mmol) , K2CO3 (14.3 g) and DMF (150 ml) at room temperature was added ethyl iodide (4.1 ml) . The reaction mixture was stirred for about two days, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ether and saturated Na2C03 , and the organic layer was separated, dried over MgS0 , treated with charcoal, filtered and concentrated in vacuo. The solid product was recrystallized from hexane to afford, as a pink crystalline solid, 9.8 g of 2 - e t ho xy - 4 - (diethylammo)benzaldehyde. m.p. 58-59°C. (b) A mixture of 2-ethoxy-4-(diethylammo> benzaldehyde (7.87 g, 35.56 mmol) , 1-cyclopentyl-3 -ethy1-5-am o-lH-pyrazole-4- carboxamide (3.95 g, 17.78 mmol) , p-toluenesul onic acid monohydrate (0.05 g), 10% palladium on carbon (0.11 g) and benzene (150 ml) was refluxed overnight with the azeotropic removal of water. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was combined with that from a similar experimental run, and dissolved in CH2CI2 , and loaded onto a silica gel column. Elution of the column with ether/hexane (60/40) afforded a green foam v/hich was titurated with refluxmg hexane, and cooled and the product, as pale yellow needles, was collected by filtration to afford 1.19 g (8%) of l-cyclooentyl-3- ethyl-6- [2-ethoxy-4- (diethylammo) phenyl1pyrazolo [3 , 4-dipyrimidm- 4-one. m.p. 138-139°C. Example 38 (a) To a suspension of K2CO3 (82.88 g, 0 6 mol) in CH3CN (300 ml) was added 3 , 5-dιhydroxybenzoιc acid (4.62 g, 0.03 mol 1 , followed 10 minutes later by U- ( 2 -chloroethyl ) orpholine hydrochloride (18.42 g, 0.099 mol) . The reaction mixture was refluxed overnight, cooled, filtered and the filtrate was concentrated m vacuo The oily residue was purified by column chromatography on silica gel eiutmσ with acetone, followed by -j c- Kugelrohr distillation at > 195°C and 0.2 mm Hg to afford 7.45 g of 4-morpholinvl thyl 3.5-di-f2- (4-morpholinvl) ethoxvlbenzoate. (b) A mixture of 4 -morpholinylethyl 3 , 5 -di- [2 - ( 4 - morpholinyl ) ethoxy]benzoate (2.0 g, 4 mmol) , l-cyclopentyl-3- ethyl-5-ammo-lH-pyrazole-4-carboxamide (0.45 g, 2 mmol) , NaOCH3 (0.23 g, 4 mmol) and ethanol (50 ml) was refluxed for 96 hours. The reaction was incomplete so an additional equivalent of the benzoate and NaOCH3 were added and the mixture was reluxed for 48 hours. The reaction mixture was stripped to dryness, and the residue was treated with water and acidified with acetic acid. The mixture was cooled and the product was isolated by filtration and dried at 90°C to afford 0.61 g (54%) of l-cvclopentyl-3-ethyl-6- [3 , 5-di [2- '4-morpholinyl ) ethoxylphenyl1pyrazolo [3 , -dipyrιmιdιn-4- one. m.p. 182-183°C. Example 39 To a suspension of l-cyclopentyl-3-ethyl-6- [2-hydroxy-3- (2-propenyl )phenyl]pyrazolo [3 , 4-d]pyrιmιdin-4-one (1.0 g) in acetic acid (15 ml) was added sulfuπc acid (15 ml! while cooling in an ice bath. The reaction mixture was • •-armed to room temperature and stirred overnight. The reaction mixture was poured into ice/water, a precipitate formed which was collected by filtration and washed v/ith water. The product was purified by recrystallization from ether, followed by column chromatography on silica gel eluting with 25% EtOAc/hexane to afford 0.5 g of 1 - cvclopentyl-3-ethyl-6- [2-methyl-2. -dihvdrobenzofbl furan-5- yllpyrazolo [3 , 4-dlpyrιmιdm-4-one, m.p. 164-165°C. Example 40 (a) 3- (Ethcxycarbonylmethoxy)benzaldehyde (9.55 g, 45.91 mmol) was dissolved ethanol (75 ml) and water (25 ml) and then KOH (3.02 g) was added. The reaction mixture was stirred at room temperature until the reaction was complete and then the product was collected by filtration and dried to afford, as a white -3"- powder, 3.78 g of he potassium sal of 3 - (carboxvmethoxv)benzaldehyd . (b) The potassium salt of 3- (carboxymethoxy) benzaldehyde was dissolved m water and treated with 9N HNO3. A precipitate formed which was collected by filtration, washed with water and dried at 75°C under high vacuum to afford 1.66 g of 3- (carboxymethoxy) benzaldehyde. (c) 3- (Carboxymethoxy)benzaldehyde (1.63 g, 9.05 mmol! was dissolved p-dioxane (20 ml) and cooled in an ice bath and then N,N' -carbonyldiimidazole (1.9 g) was added in one portion. The reaction mixture was stirred for 30 minutes, then morpholine (0.8 ml) was added and the mixture was warmed to room temperature and stirred until the reaction was complete. The solvent was removed in vacuo, the residue was partitioned between CHCI3 (100 ml) and 2N HCl (75 ml) , the layers were separated, and the aqueous layer was extracted with CHCI3 (2 x 75 ml) . The organic layers were combined, dried over MgSθ4 and stripped to afford an oil which was combined with the product from a similar experimental run and purified by column chromatography on silica gel eluting with chloroform to afford 2.1 g of 3 - ^ 4 - morpholinylcarbonylmethoxylbenzaldehyde. (d) A mixture of l-cyclopentyl-3-ethyl-5-ammo-lH-pyrazole-4- carboxamide (1.87 g), 3- [4-morpholmylcarbonylmethoxy]benzaldehyde (2.1 g, 8.43 mmol) and xylenes (20 ml) was heated at 160°C for about 2 days. The solvent was removed, then methanol was added to the residue and the product was collected by filtration. Additional product was obtained from the filtrates and the product fractions '-/ere pooled and recrystallized from CH3CN/CHC1 to afford l - c v c l o p e n t v l - 3 - e t h v l - 6 - [ 3 - ' 4 - morpholinylcarbonylmethoxy)phenyll pyrazolo[3 , 4-dlpyrimidir---one. m.p. 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) was stirred at room temperature for 15 minutes, then dibromoethane (18.3 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes, then at reflux for 3-4 hours. Additional dibromoethane was added and then the reaction mixture was refluxed overnight. The reaction mixture was cooled, filtered, and the filtrate was stripped to afford an oil. The oil was dissolved m ether (300 ml), washed with 5N NaOH (2 x 75 ml) and the ether layer was dried over MgSθ4 and stripped. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 5.23 g of 3- (2-brornoethoxy)benzaldehyde. (b) A mixture of 3-(2-bromoethoxy) benzaldehyde (3.91 g, 17.07 mmol) , K2CO3 (3.1 g) , thiomorpholine (1.9 ml) and DMF (30 ml) was warmed on a steambath overnight. Additional K2CO3 (0.7 g) and thiomorpholine (1.0 ml) were added and the reaction mixture was warmed on a steam bath overnight. The reaction mixture was cooled to room temperature, filtered and the filtrate was stripped to afford an amber oil. The oil was combined with the product from a similar experimental run and purified by column chromatography on silica gel eluting with EtOAc (100%) to afford, as an oil, ? - f2 - '4-thιornorpholιnyl ) ethoxyl benzaldehyde. (c) A mixture of 3- [2- (4-thιomorpholmyl ) ethoxy] benzaldehyde (3.2 g, 12.75 mmol) , l-cyclopentyl-3-ethyl-5-ammo-lH-pyrazole-4- carboxamide (2.55 g) and xylenes (20 ml) was heated at 160°C overnight. The reaction mixture was cooled in an ice bath, and then the solvent was removed to afford an oil which crystallized on standing. The product was treated with hot MeOH/Et2θ, the mixture was cooled, and the product v/as collected by filtration and washed with ether to afford 0.51 g of desired product. The filtrate was concentrated in vacuo to afford 5.0 g of the 6,7- dihydro derivative which was dissolved in xylenes (25 ml) , treated with palladium on carbon and heated at 110°C for 3 hours. Additional palladium on carbon (1.5 g) was added and heating was continued for 2 hours. The mixture was filtered through CELITE® and the filtrate was stripped. The residue was treated with methanol and the product was collected by filtration and combined with the 0.51 g of product obtained above and the product obtained from a similar experimental run. The combined product fractions were recrystallized from EtOAc, v/ashed with ether and dried at 100°C under high vacuum to afford l-cvclopentyl-3-ethyl-6- [3- r2- (4-thιomorphol nyl) ethoxvlohenvl1 pyrazolof3.4-dlPvrιmιdm-4-one. Example 42 (a) To a mixture of 3-hydroxybenzonitπle (4.76 g, 0.04 mol) , K2CO3 (16.6 g, 0.12 mol) and DMF (100 ml) under argon v/as added 4- chloromethylpyridme hydrochloride (6.56 g, ^ 04 mol) . The reaction mixture was stirred at room temperature tor about two days, the solvent was evaporated and the residue was partitioned between water and CH2CI2 • The organic layer was washed with 2N aqueous NaOH (1 x 100 ml) , brine, then was dried over MgS04. The solvent was removed in vacuo to afford, as an amber solid, 9.0 g of 3- (4-Pyrιdιnylmethoxy)benzonitrile. (b) A mixture of 3 -( 4-pyrid yimethoxy) benzonitrile '2.5 g, 0.012 mol m 75% formic acid '35 ml) was treated with raney nickel (2 g) and heated to reflux for 4 hours The reaction mixture was filtered through SUPEPCELL®, the filtrate was brought to a pH of 8-9 with 5N NaOH, extracted with EtOAc (3 x 150 ml) and the combined organic layers were dried over MgS04 , filtered and stripped. The residue was purified by column chromatography on silica gel eluting with EtOAc (100%) to afford 0.94 g (37%) of 3- (4-Pyrιdmyl ethoxλ benzaldehyde. (c) A mixture of l -cyclopentyl - 3 -ethyl - 5 -amιno- lH-pyrazole- 4 - carboxamide ( 2 . 7 g , 0 . 124 mol ) , 3 - ( 4 -pyridmyimethoxy ) benzaldehyde ( 3 . 95 g , 0 . 0185 mol ) and xylenes 100 ml ) was ref luxed overnight . Addi t ional carboxamide ' 1 g 1 v/as added and t e mixture was refluxed for another 2 days. 10% palladium on carbon (1 g) was added and the mixture was refluxed for another 3 hours. The catalyst was removed by filtration, the filtrate v/as concentrated in vacuo and the solid residue was collected by filtration. Additional product was obtained by concentration of the mother liquors and the combined product fractions were recrystallized from ethyl acetate to afford 1.66 g of l-cvclθDentyl-3-ethyl-6- [3- f4-pvridinvlmethoxvlphenvll pyrazolo[3 , 4-d1Pyrimidin-4-one, m.p. 230-232°C. Example 43 (a) A mixture of 3-hydroxybenzaldehyde (3.66 g, 0.03 mol) , K2CO3 (12.43 g, 0.09 mol) , and CH3CN (100 ml) was stirred at room temperature for 1/2 hour, then N-methyl-2-chloromethyipiperidine hydrochloride 5.49 g, 0.03 mol) was added. The reaction mixture was stirred until the reaction was complete, then the solvent was removed in vacuo and the residue v/as partitioned between CHCI3 and water. The aqueous layer was extracted with CHCI3 ; x 100 ml) and the combined organic layers were concentrated in vacuo to afford 3- (1-methyl-3-hexahvdroazepinyloxy)benzaldehyde. (b) A mixture of 3 - ( 1 -met hy 1 - 3 - hexahy droazepiny loxy ) benzaldehyde (0.79 g, 3.4 mol), l-cyciopentyl-3-ethyl -5-ammo-lH- pyrazole-4 -carboxamide (0.5 g, 2.2 mmol), methanesulfonic acid (0.25 ml) and xylenes (25 ml) was refluxed overnight. The solvent was stripped, the residue was dissolved in CH2CI2 and purified by column chromatography on silica gel eluting with ether, then acetone, then 0.5% Et3N/acetone to afford 0.43 g (45%) of 1 - cvclopentyl-3-ethyl-6- f 3- ( 1 -methyl -3 -hexahvdroazepinyloxy) phenyl 1 pyrazolo[ . -dloyrimidin-4-one. m.p. 195-196°C. Example 44 To a mixture of 1 -cyclopenty1 - 3 - ethy1 - 6 - [ 3 - [ 4 - pyridinylmethoxy1phenyl ]pyrazolo[ 3 , 4 -a yrimidin- -one (1.1 g) in acetic acid (100 ml) /water (50 ml) was added P 2C (200 mg ) . The mixture was hydrogenated at 50 psi with heating ivanac set at 40) for four hours. The catalyst v/as removed by filtration, the filtrate was concentrated and the residue was partitioned between NH4OH and ethyl acetate. The organic layer was separated, v/ashed with brine, dried over MgS04 , filtered and concentrated. The residue was purified by column chromatography on silica gel- eluting with ethyl acetate, followed by preparative thm layer chromatography eluting with ethyl acetate to afford, after recrystallization from EtOAc, 64 mg of l-cvclopentyl-3-ethyl-6- (3- hvdroxvphenvl) pyrazolo f .4-d1 πvrlmidm-4-one . m.p. 275-278°C (dec. ) . Example 45 (a) To a stirred solution of 3-hydroxybenzaldehyde (8 g, 65 mmol) , l-methyl-4-pιperιdmol (7.5 g, 65 mmol), triphenylphosphine (13.1 g, 65 mmol) and THF (100 ml) was added diethyiazodicarboxylate (11.4 g, 65 mmol) m THF (20 ml) over a 35 minute period. The reaction mixture was stirred in an ice bath for 3 hours, then at room temperature for 5 days. The reaction mixture was concentrated m vacuo, and partitioned between CHCI3 (300 ml) and 3N HCl 300 ml) . The aqueous layer was concentrated in vacuo, the residue '-/as treated with 10% K2CO3 and extracted with CHCI3 (2 x 100 ml) . The solvent was removed in vacuo to afford 7.4 g of crude 3- l-methyl-4-piperιdmyloxy)benzaldehyde. (b) -. mixture of 3 -! 1 -methyl -4 -piper ldinyloxy ) benzaldehyde (7.4 g , l-cyclopentyi-3-ethyl-5-ammo-lH-pyrazole-4-carboxamιde (2 g) and xylenes (200 ml) was refluxed for 31 hours and then was stirred at room temperature for several days. The solvent was removed m vacuo, and the residue was purified by column chromatography on silica gel eluting with ether (100%) to 10% methantl /ether to afford, after recrystallization from isopropanol, 2.3 g of 1-cvclnnentyl -3-ethyl-6- (3- '1 -methyl -4 - pipencir.ylcxy' phenyll pyrazolo [ 3 , 4-dl pynmιdm-4 -one 1/4 hydrate. Example 46 (a) To a stirred solution of 2 , 4-dιf luorobenzonitrile 25 g, 0.18 mcl p-dioxane (250 ml) in an ice-bath was added sodium ethoxide (15 g, 0.22 mol) over 45 minutes. The reaction mixture was stirred as such for 2 hours, then at room temperature for 18 hours. The solvent was concentrated in vacuo and the residue was partitioned between water (200 ml) and CH2CI2 (400 ml) and acidified with acetic acid. The organic layer was separated, dried over MgS04 and concentrated in vacuo to afford, as a yellow oil, 26.7 g of a mixture of 2-ethoxy-4-fluorobenzonitrile and 4-ethoxv- 2-fluorobenzonιtrιle. (b) To a mixture of the benzomtriles from Example 46 (a) (26.5 g, 0.16 mol) , lmidazole '11.5 g, 0.17 mol) , and p-dioxane (150 ml) cooled in an ice bath was added NaH (6.8 g, 60% dispersion m mineral oil) over a 30 minute period. The reaction mixture v/as stirred for 1 hour as such, then at room temperature for 24 hours, followed by standing at room temperature for 24 hours. The solvent was removed in vacuo, the residue was partitioned between CH2CI2 (2 x 300 ml) and water (100 ml) . The CH2CI2 extracts were combined, concentrated in vacuo and the residue was purified by column chromatography on silica eluting with ether (100%) to 10% methanol/ether to afford 10.1 g of 4- (1- lmidazolyl) -2-ethoxy benzonitrile, m.p. 134-136°C. (c) A mixture of l-cycιopentyl-3-ethyl-5-ammo-lH-pyrazole-4- carboxamide (1.5 g, 6.3 mmol) , 4 - ( 1-lmidazoly1 ) - 2 - ethoxybenzonitrile (1.5 g, 7 mmol) , NaH (.0.84 g, 21 mmol, 60% dispersion m mineral oil and p-dioxane (75 ml) was heated on a steam bath for 12 hours, then v/as stirred at room temperature overnight. The reaction mixture was acidified with acetic acid, concentrated in vacuo, and water was added to the residue. A gummy solid formed which was collected, washed with water, dried and purified by column chromatography on silica gel eluting with etner (100%) to 15% methanol/ether to afford, after recrystallization from acetonitrile, 0.78 g 36%) of l-cvclopentyl-3-ethyl-6- f4- (1- lmidazolyl) - 2-e ho^ypher.'- 1 pyrazolo[3 , 4-dlpyrιmιdιn-4 -one . m.p. 204-206°C. Ex fl mpl-e 47 Following a procedure similar to that described in Example 1 (c) , but substituting l-tert-butyl-3-ethyl-5-ammo-lH-pyrazole- 4-carboxamide for l-cyclopentyl-3 -ethyl-5-ammo-lH-pyrazole-4- carboxamide and 2 , , 6 - tr imethy lbenzaldehyde for 2- propoxybenzaldehyde, it is contemplated that there can be prepared l-tert-butvl-3-ethvl-6-r2.4.6-trimethvlphenvllPvrazolor3.4- dlpvrimidin-4-one. Example 48 Following procedures similar to those described in Examples 1 (b) and 1 (c), but substituting l-cyclopentyl-3 - phenylmethyl-5-amιno-lH-pyrazole-4-carbonιtrιle for 1 -cyclopentyl - 3 -ethyl-5-amιno-lH-pyrazole-4-carbonιtrιle m part 1 (b) , it is contemplated that there can be prepared: (a) l-Cvclopentyl-3-phenylmethyl-5-ammo-lH-oyrazole-4- carboxamidp. (b) l-Cvclopentyl-3-phenylmethyl-6- (2-propoxyphenyl )pyrazolo [3 , 4-dlpyrιmιdin-4-one. Biological Test Results In standard biological test procedures, the compounds of Formula I have been found to possess c-GMP-PDE V (formerly named as c-GMP-PDE I) inhibitory activity and are thus useful in the treatment of heart failure and hypertension. The compounds of Formula I, m combination with nitrates, have also been found to be useful in reversing or reducing nitrate- auced tolerance and thus would be useful in the treatment of angina pectoris, congestive heart disease and myocardial infarction. Multiple lsozymic forms of cyclic nucleotide phosphodiesterase (PDE) have been identified mammalian cells. These isozymes hydrolyze cyclic adenosine monophosphate (cAMP) and/or cyclic guanosme monophosphate (cGMP) to the presumably biologically inactive 5 ' -nucleotide phosphates. Elevation of mtracellular cGMP in vascular smooth muscle triggers a cascade of events that leads to a reduction in muscle tone while elevations in renal tubule cell cGMP stimulates natriuresis and diuresis. Vascular smooth muscle and renal cells contain a phosphodiesterase isozyme that has a low Km (1 μM) for the hydrolysis of cGMP. This isozyme has been referred to as the cGMP-PDE cr cGMP-PDE V (formerly named as cGMP-PDE I since it eluted from an anion- exchange sepharose resin in the first peak of PDE activity at a sodium acetate concentration between 150-200 mM) . Thus inhibition of the cGMP-PDE isozyme is a viable subcellular mecr.amsm by which increases in cGMP can produce a reduction in total peripheral resistance and a stimulation of natriuresis and diuresis . The development of cGMP-PDE inhibitors represents an approach for the discovery of agents useful for treating heart failure and hypertension. For example, compounds having hign inhibitory potency for the cGMP-PDE are expected to lower bleed pressure and induce natriuresis and diuresis. The c-GMP-PDE V inhibitory activity of representative compounds of the invention was demonstrated by the following procedure. The cGMP-PDE and other PDE lsozymes were isolated from cardiovascular tissues (heart and aorta) of various animal species and man by anion-exchange and affinity chromatograpny as described by Silver et al . , Sec. Messeng . Phos . 13:13-25, 1991; PDE activity, the presence and absence of test tompounds was determined 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, compounds are screened for their effect on cyclic nucleotide hydrolysis at 10 μM. If > 50% inhibition of PDE activity is observed, an IC 50 value (concentration of compound causing 50% reduction in PDE activity) and corresponding 95% confidence intervals are generated. The IC 50 values are calculated from concentration-response curves as described oy Tallarida and Murray, Manual of Pnarmacologic 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 testing of representative compounds of the invention. Percent Inhibition at Given μM or IC50 (nM) Percent Inhibition at Given μM or IC50 (nM) Example No, 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(c) 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 30 53% (1 μM) or 9% (0. 1 μM) 31 61% (1 μM) or 31% (0.1 μM) 32 47% (1 μM) or 23% (0.1 μM) 33 56% (1 μM) or 21% (0.1 μM) 34(b) 56% (0.1 μM) or 28% (0.01 μM) 35(b) 58% 1 μM) or 13% (0.01 μM) 36 0% 1 μM) or 4% ( 1 μM) 37(b) 73% (1 μM) or 31% (0.1 μM) 38(b) 63% (0.1 μM) or 11% (0.01 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) cr 46% (0.1 μM) 42(c) 56% (0.1 μM) or 25% (0.01 μM) 43(b) 75% (1 μM) or 41% (0.1 μM) 44 56% (1 μM) or 29% (0.1 μM) 46(c) 26% (0.1 μM) or 76% ,1 μM o 90% (10 μM) or 18 nM *The numbers represent IC ,;. (nM) values for separate experimental runs . -4 ' The antihypertensive activity of representative compounds of the invention was demonstrated by the following procedure. Spontaneously hypertensive rats (ΞHR) were anesthetized with sodium pentobarbital (50 mg/kg, lp) and instrumented with catheters positioned in the inferior vena cava and abdominal aorta for administration of drug and recording of arterial pressure and heart rate, respectively. After a 2 day recovery from surgery, three baseline blood pressure measurements were made at 5 mm intervals in conscious SHR. Compounds to be tested or vehicle were then administered intravenously in a dose-dependent manner (0.3-10 mg base/kg) while arterial pressure was recorded continuously on a polygraph. The mean arterial pressure response was measured 5 minutes after the administration of each dose of the test compound and the next dose given a cumulative dose fashion. The response to each dose of the test compound was calculated as the difference from the mean of the three baseline measurements. The following table summarizes the results obtained from the testing of representative compounds of the invention. SHR lv % change in mean arterial pressure Example No. at Given mg/kg or ED ? - (mg/kg) -5% (1 mg/kg) -7% (1 mg/kg) -13% (10 mg/kg) -8% (1 mg/kg) -1% (10 mg/kg) 5.7 or 35% (10 mg/kg) or -20% (3 mg/kg) or -81% (30 mg/kg, po! -19% (10 mg/kg) 9.5 or -58% (30 mg/kg, po) or -19% (3 mg/kg) or -14% 1 mg/kg) or -11% (0 3 mg/kg) 12.5 or -19% (10 mg/kg) 17.9 or -18% (10 mg/kg) 12.7 or -21% (10 mg/kg) -13% (3 mg/kg! 4.5 or (10 mg/kg) tr -27% ''3 mg/kg) or -18% mg kg) or The activity of representative compounds of the invention m reversing or reducing nitrate-induced tolerance was demonstrated by the following procedure: Spontaneously hypertensive rats (17-25 weeks of age) were made nitroglycerm tolerant by repeated administration of high doses of nitroglycerm (100 mg/kg, s.c , 3 times/day for 3 consecutive days) . To confirm tolerance challenge doses of nitroglycerm were administered intravenously at doses ranging from 1-300 μg/kg and the maximum change in mean arterial pressure (MAP) for each dose was recorded. Groups of tolerant rats were pretreated --'lth the compounds of the invention (tolerant pretreated group) or with vehicle (0.05 N NaOH) (tolerant vehicle pretreated group) intravenously 5-10 minutes prior to administration of challenge doses of nitroglycer . The administration of challenge doses of nitroglycerm to non-tolerant rats (the non-tolerant group) caused a dose-dependent decrease in MAP of between 10 to 40 mm Hg. The administration of challenge doses of nitroglycerm to the tolerant vehicle pretreated group resulted m a significant reduction of the hypotensive response. The administration of challenge doses of nitroglycerm to tolerant rats which were pretreated with the compounds of the invention (tolerant pretreated group) resulted m varying degrees of restoration of the hypotensive response. The area unαer the dose- MAP curve was calculated for the non-tolerant group and for the tolerant vehicle pretreated group and the tolerant pretreated group. The percent reversal of nitrate-induced tolerance was calculated as fellows. Percent Reversal = ( AUC to l-pretreated - AUC to l-veh ) / ( UC nθ ntol - AUCtol-veh ) x 100 wherein: AUC n ontol = the area under the dose-MAP curve for the non- tolerant group. AUCtc_-veh = the area under the dose-MAP cur'e for the tolerant vehicle pretreated group. AUCtc.-pretreated = the area under the dose-MAP curve for the tolerant pretreated group. A percent reversal of 100% or greater reflects complete reversal of nitrate-induced tolerance, whereas a percent reversal of 0% indicates that no reversal of nitrate-induced tolerance occurred. The following table summarizes the results obtained from the testing of representative compounds of the invention. Percent (%) Reversal of Example Dose (mg/kg) Nitroσlycerm-mduced Tolerance 6 1.0 49 8(a) 0.3 5 13 (b) 0.3 58 The compounds of the invention can be prepared for pharmaceutical use by conventional pharmaceutical procedures that are v/ell known in the art; that is, by formulating a pharmaceutical composition which comprises compounds of the invention or their pharmaceutically acceptable salts togetner with one or more physiologically acceptable carriers, adjuvants, diluents or vehicles, for oral administration m solid or liquid form, parenteral administration, topical administration or aerosol inhalation administration, and the like. Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, the active compound is admixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactcse. These compositions may also contain additional substances other than inert diluents, e g. , 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 the art, such as water and liquid paraffin Besides inert diluents sucn compositions may also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfuming and preserving agents. According to the invention, the compounds for oral administration also include capsules of absorbable material, such as gelatin, containing said active component with or without the addition of diluents or excipients. Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, 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 can also contain adjuvants such as stabilizing, preserving, wetting, emulsifying and dispersing agents. Preparations according to the invention for topical administration or aerosol inhalation administration include dissolving or suspending a compound of the invention a pharmaceutically acceptable vehicle such as water, aqueous alcohol, glycol, oil solution or oil-water emulsion, and the like. If desired, the compounds of the invention can further be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres . The percentage of active component such compositions may be varied so that a suitable dosage is obtained. The dosage administered to a particular patient is variable depending upon the clinician's judgment 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 tnereto. An effective dosage amount of the active component can thus readily be determined by the clinician after a consideration of all criteria and using his best judgment on the patient's behalf

Claims: We claim: A compound of the formula: wherein R 1 is tert-butyl, or cyclopentyl; R 3 is lower-alkyl, or phenyl-lower-alkyl ; and R 6 is phenyl, or phenyl substituted by from one to three, the same or different, substituents selected from the group consisting of lower-alkoxy, lower-alkyl, hydroxy, 1-ιmidazolyl , lower-alkenyloxy, dilower-alkylammo-lower-alkoxy, 4 -morphol inyl - lower-alkoxy , lower-alkoxycarbonyl -lower-alkoxy , carboxylower- alkoxy, t ri f luoromethyl , 1 -piperidinyl - lower-alkoxy , 1- pyrrolidinyl-lower-alkoxy , nitro, halo, amino, -(CH2) 2 θ-, lower- alkylsul f onylamino , lower-alkoxy-lower-alkoxy , lower-alkenyl , dilower-alkylamino, -OCH (CH 3 ) CH 2 - , 4-morpholmyicarbonyl-lower- alkoxy, 4-thιomorpholmyl-lower-alkoxy , pyridinyl-lower-alkoxy, 1- lower-alky 1 - 3 -hexahydroazepiny loxy , and 1 - lower- alky 1 - 4 - piperidinyl oxy; or a pharmaceutically acceptable acid-addi tion salt and/or hydrate thereof. 2. A compound according to Claim 1 wherein P. 1 is cyclopentyl; and R 3 is lower-alkyl. 3. A compound according to Claim 2 wherein R^ is methyl or ethyl . 4. A compound according to Claim 3 wherein R 6 is phenyl, or phenyl substituted by from one to two, the same or different, substituents selected from the group consisting cf lower-alkoxy, lower-alkyl, hydroxy, 1 - lmidazolyl , lower-alkenyloxy, dilower- alkylamino- lower -al koxy , 4 -morphol y 1 - lower-al koxy , lower- alkoxycarbonyl -lower-alkoxy, carboxylower -alkoxy, t if luoromethyl, 1-piperidinyl-lower-alkoxy, 1-pyrrolidinyl-lower-alkoxy , nitro, halo, amino, -(CH2)2θ-- lower-alkylsulf onylamino, lower-alkoxy - lower-alkoxy, lower-alkenyl, dilower-alkylamino, -OCH (CH3 ) CH2- , 4- orphol inyl carbonyl- lower-alkoxy, 4 - thiomorphol inyl -lower-alkoxy , pyridinyl-lower-alkoxy, l-lower-alkyl-3-hexahydroazepinyloxy , and l-lower-alkyl-4-piperidinyloxy . 5. A compound according to Claim 4 wherein R 6 is phenyl, or phenyl substituted by from one to two, the same or different, substituents selected from the group consisting of methoxy, ethoxy, propoxy, methyl, hydroxy, 1-imidazolyl , CH2=CHCH2θ-, 2- ( dimethylamino ) ethoxy , 3 -( dime thy lami no ) propoxy , 2-(4- morpholinyl ) ethoxy, 3- (4-morpholιn l ) propoxy, ethoxycarbony lmethoxy , carboxymethoxy, rif luoromethyl , 2-(l- piperidinyl ) ethoxy , 2 -( 1-pyrrolidinyl ) ethoxy , nitro, chloro, amino, -(CH 2 ) 2 θ-, methylsulf onylamino , 2 - (methoxy ) ethoxy , CH2=CH2CH 2 ~, diethy lamino , -OCH ( CH3 ) CH2 - , 4 -morphol inyl - carbonylmethoxy , 2- (4-thiomorphol inyl ) ethoxy , 4 -pyridmyimethoxy , l-methyl-3-hexahydroazepinyloxy , and l-methyl-4-pipendinyloxy . 6. A compound according to Claim 5 selected from the group consisting of: 1- cyclopentyl -3 -ethyl -6- (2 -propoxyphenyl ) yrazolo [3 , 4-d] pyrimindin-4-one, l-cyclopentyl-3-ethyl-6- [4- (1-imidazolyl) phenyl] pyrazolo [3 , 4-d] pyrimindin-4-one, l-cyclopentyl-3-ethyl-6- [3- (2- (4 -morphol inyl ! ethoxy) phenyl ] pyrazolo [3 , 4-d] pyrimindin-4-one, 1 -cyclopentyl -3 -ethyl -6- [2-ethoxy-4- ( 1-imidazolyl ) phenyl ] pyrazolo [3,4-d]pyrimindin-4 -one, and l-cyclopentyl-3-ethyl-6- [2- (CH 2 =CHCH2θ) phenyl ] pyrazolo [3, 4-d] pynmindin-4-one . 7. A pharmaceutical composition which comprises a compound according tc claim 1 together with a pharmaceutically acceptable carrier, adjuvant, diluent, or vehicle. 8. A pharmaceutical composition which comprises a compound according to claim 2 together with a pharmaceutically acceptable carrier, adjuvant, diluent, or vehicle. 9. A pharmaceutical composition which comprises a compound according to claim 3 together with a pharmaceutically acceptable carrier, adjuvant, diluent, or vehicle. 10. A pharmaceutical composition which comprises a compound according to claim 4 together with a pharmaceutically acceptable carrier, adjuvant, diluent, or vehicle. 11. A pnarmaceutical composition which comprises a compound according to claim 5 together with a pharmaceutically acceptable carrier, adjuvant, diluent, or vehicle. 12. A pharmaceutical composition which comprises a compound according to claim 6 together with a pharmaceutically acceptable carrier, adjuvant, diluent, or vehicle. 13. A method for effecting cGMP-phosphodiesterase inhibition in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 1. 14. A method for effecting cGMP-phosphodiesterase inhibition in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 2. 15. A method for effecting cGMP-phosphodiesterase inhibition in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 3. 16. A method for effecting cGMP-phosphodiesterase inhibition in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 4. 17. A method for effecting cGMP-phosphodiesterase inhibition in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 5. 18. A method for effecting cGMP-phosphodiesterase inhibition in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 6. 19. A method for treating heart failure and/or hypertension in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 1. 20. A method for treating heart failure and/or hypertension in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 2. 21. A method for treating heart failure and/or hypertension in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 3. 22. A method for treating heart failure and/or hypertension in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 4. 23. A method for treating heart failure and/or hypertension in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 5. 24. A method for treating heart failure and/or hypertension in a mammalian organism which comprises administering to said organism an effective amount of a compound according to claim 6.

Inventors: BACON EDWARD R, SINGH BALDEV, BACON, EDWARD, R., SINGH, BALDEV
Applicants: SANOFI WINTHROP INC, SANOFI WINTHROP, INC.
Application year: 1996
Main classification: C07D487
IPC codes: A61K31, A61P9, C07D487