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WO1993006104A1 - Agents antiangineux a pyrazolopyrimidinone - Google Patents

Agents antiangineux a pyrazolopyrimidinone Download PDF

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Publication number
WO1993006104A1
WO1993006104A1 PCT/EP1992/002068 EP9202068W WO9306104A1 WO 1993006104 A1 WO1993006104 A1 WO 1993006104A1 EP 9202068 W EP9202068 W EP 9202068W WO 9306104 A1 WO9306104 A1 WO 9306104A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
ethyl
formula
methyl
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1992/002068
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English (en)
Inventor
David Brown
Nicholas Kenneth Terrett
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Original Assignee
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Corp Belgium, Pfizer Ltd Great Britain, Pfizer Corp SRL filed Critical Pfizer Corp Belgium
Publication of WO1993006104A1 publication Critical patent/WO1993006104A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to a group of pyrazolo[4,3- d]-pyrimidin-7-ones, which are potent and selective inhibitors of cyclic guanosine 3', 5'-monophosphate phosphodiesterase (cGMP PDE) , having utility in a variety of therapeutic areas including the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.
  • cGMP PDE cyclic guanosine 3', 5'-monophosphate phosphodiesterase
  • the compounds of the invention exhibit selectivity for inhibition of cGMP PDEs rather than cyclic adenosine 3',5'-monophosphate phospodiesterases (cAMP PDEs) and, as a consequence of this selective PDE inhibition, cGMP levels are elevated, which in turn can give rise to beneficial anti-platelet, anti-neutrophil, anti-vasospastic and vasodilatory activity, as well as potentiation of the effects of endothelium-derived relaxing factor (EDRF) and nitrovasodilators.
  • cAMP PDEs cyclic adenosine 3',5'-monophosphate phospodiesterases
  • the compounds have utility in the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension,, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA) , peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS) .
  • IBS irritable bowel syndrome
  • Certain pyrazolo[4,3-d]pyrimidin-7-ones are disclosed in European patent application EP-A-0201188, where they are described as adenosine receptor antagonists and PDE inhibitors, useful in the treatment of cardiovascular disorders such as heart failure or cardiac insufficiency.
  • EP-A-0201188 European patent application
  • the compounds specifically exemplified therein are neither particularly potent PDE inhibitors, nor are they claimed to be selective inhibitors of cGMP PDE.
  • the compounds of the present invention have the formula (I) :
  • R 1 is methyl or ethyl
  • R 2 is ethyl or n-propyl; and R 3 and R 4 are each independently H, or C x - C 6 alkyl optionally substituted with C 5 -C 7 cycloalkyl or with morphorino; and pharmaceutically acceptable salts thereof.
  • alkyl groups having three or more carbon atoms may be straight chain or branched chain;
  • the compounds of formula (I) may contain one or more asymmetric centres and consequently can exist as enantiomers or diastereoisomers; the invention includes both mixtures and separate individual isomers.
  • the compounds of formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
  • radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
  • the pharmaceutically acceptable salts of the compounds of formula (I) which contain a basic centre are acid addition salts formed with pharmaceutically acceptable acids.
  • examples include the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, furmarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p- toluenesulphonate salts.
  • Compounds of the formula (I) can also provide pharmaceutically acceptable metal salts, in particular alkali metal salts, with bases. Examples include the sodium and potassium salts.
  • a preferred group of compounds of formula (I) is that wherein R 3 is H, methyl or ethyl; R 4 is C 1 -C 6 alkyl optionally substituted with cyclohexyl or with morpholino; and R 1 and R 2 are as previously defined.
  • Particularly preferred individual compounds of the invention are:
  • R 1 and R 2 are as previously defined and Y is fluoro, chloro or bromo, preferably chloro, with a compound of formula (III) :
  • reaction is generally carried out at room temperature, preferably in the presence of a solvent, for example a C,-C 3 alkanol, using an excess of (III) to scavenge the acid by-product (HY) .
  • a solvent for example a C,-C 3 alkanol
  • R 1 and R 2 are as previously defined, by the application of known methods for the introduction of a S0 2 Y group, wherein Y is as previously defined, into an aromatic ring; for example, when Y is chloro, by the action of chlorosulphonic acid at or near 0°C.
  • the cyclisation may be effected by the treatment of (V) with a base such as sodium hydroxide or potassium carbonate, optionally in the presence of hydrogen peroxide, in an ethanol-water medium at reflux temperature for 2-40 hours.
  • a base such as sodium hydroxide or potassium carbonate
  • hydrogen peroxide hydrogen peroxide
  • compounds of formula (IV) may be obtained by treatment of (V) with polyphosphoric acid at or near 140°C for 6-18 hours.
  • R 2 and -Y are as previously defined.
  • the reaction is generally carried out using an excess of (IX) in the presence of an excess of a tertiary amine such as triethylamine or pyridine to act as scavenger for the acid by-product (HY) , optionally in the presence of a catalyst such as 4- dimethylaminopyridine, in an inert solvent such as dichloromethane at from about 0 to 25°C for 2-6 hours.
  • a catalyst such as 4- dimethylaminopyridine
  • pyridine may also be used as co- solvent.
  • the amines of formula (III) , the aminopyrazoles of formulae (VII) and (VIII) , the acyl halides of formula (IX) , and the various reagents required for the process hereinbefore disclosed, when neither commercially available nor subsequently described, can be obtained by conventional synthetic procedures, in accordance with literature precedent, from readily accessible starting materials using appropriate reagents and reaction conditions.
  • the pharmaceutically acceptable acid addition salts of the compounds of formula (I) which contain a basic centre may also be prepared in a conventional manner.
  • a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula (I) with the appropriate base. Both types of salt may be formed or ulcererconverted using ion-exchange resin techniques.
  • Compound affinities for cGMP and cAMP PDEs are assessed by determination of their IC 50 values (the concentration of inhibitor required for 50% inhibition of enzyme activity) .
  • the PDE enzymes are isolated from rabbit platelets and rat kidney, essentially by the method of W. J. Thompson et _al. (Biochem. , 1971, 10. 311).
  • the calcium/calmodulin (Ca/CAM)-independent cGMP PDE and the cGMP-inhibited cAMP PDE enzymes are obtained from rabbit platelets whilst, of the four major PDE enzymes of the rat kidney, the Ca/CAM- dependent cGMP PDE (fraction I) is isolated.
  • Assays are performed using a modification of the "batch" method of W. J. Thompson and M. M. Appleman (Biochem. , 1979, 18_, 5228). Results from these tests show that the compounds of the present invention are potent and selective inhibitors of both cGMP PDEs. Platelet anti-aqqre
  • Washed platelets are prepared essentially by the method of J. F. Mustard et al. (Methods in Enzymol., 1989, 169. 3) and aggregation is determined using standard turbidimetric techniques as described by G. V. R. Born, (J. Physiol. (Lond) , 1962, 162. 67P) . Antihypertensive activity
  • oral dosages of the compounds will generally be in the range of from 4-800 mg daily for an average adult patient (70 kg) .
  • individual tablets or capsules contain from 2-400 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier, for administration in single or multiple doses, once or • several times per day.
  • Dosages for intravenous, buccal or sublingual administration will typically be within the range of from 1-400 mg per single dose as required.
  • the physician will determine the actual dosing regimen which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case but there can be individual instances in which higher or lower dosage ranges may be merited, and such are within the scope of this invention.
  • the compounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they may be administered orally, b ⁇ ccally or sublingually, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents.
  • the compounds may also be injected parenterally, for example intravenously, intramuscularly, subcutaneously or intracoronarily.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example salts, or monosaccharides such as mannitol or glucose, to make the solution isotonic with blood.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a compound of formula (I) , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for use in medicine.
  • the invention further provides the use of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, e.g. post-PTCA, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma, or diseases characterised by disorders of gut otility, e.g. IBS.
  • stable, unstable and variant (Prinzmetal) angina hypertension
  • pulmonary hypertension congestive heart failure
  • atherosclerosis stroke
  • peripheral vascular disease conditions of reduced blood vessel patency, e.g. post-PTCA, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma
  • diseases characterised by disorders of gut otility e.g.
  • the invention provides a method of treating or preventing stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel potency e.g. post- . PTCA, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma, or diseases characterised by disorders of gut motility, e.g. IBS, in a mammal (including a human being) which comprises administering to said mammal a therapeutically effective amount of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.
  • stable, unstable and variant (Prinzmetal) angina e.g. post- . PTCA
  • chronic asthma bronchitis
  • allergic asthma allergic rhinitis
  • glaucoma glaucoma
  • diseases characterised by disorders of gut motility e.g. IBS
  • the invention also includes any novel intermediates of formulae (II) and (IV) disclosed herein.
  • N-(3-Aminopropyl)morpholine (0.943 g, 0.0066 mol) was added dropwise to a stirred suspension of 5-(5- chlorosulphonyl-2-ethoxyphenyl)-1,3-dimethyl-1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.626 g, 0.00164 mol) in ethanol (40 ml). After 1 hour at room temperature, when tic analysis showed no remaining starting material, the solvent was removed by evaporation under vacuum.
  • Example 2 Following the procedure of Example 1, the title compound was prepared from 5-(5-chlorosulphonyl-2-n- propoxyphenyl)-l-ethyl-3-methyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (0.7 g, 0.0017 mol) and N-methylcyclohexylmethylamine (0.433 g, 0.0034 mol) (prepared by borane:dimethylsulphide mediated reduction of N-formylcyclohexylmethylamine) . After crystallisation from EtOAc-hexane, the product was obtained as colourless crystals (0.668 g, 78%), m.p. 190-192°C. Found: C,60.03; H,7.07; N,13.96. C ⁇ H JS N J O ⁇ requires C,59.86; H,7.03; N,13.96%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés répondant à la formule (I), et leurs sels pharmaceutiquement acceptables. Dans ladite formule (I), R1 représente méthyle ou éthyle; R2 représente éthyle ou n-propyle; et R3 et R4, indépendamment l'un de l'autre, représentent H ou alkyle C¿1-6? éventuellement substitué par cycloalkyle C5-7 ou par morpholino. Lesdits composés sont des inhibiteurs sélectifs des cGMP PDE et sont utilisés dans le traitement des troubles cardio-vasculaires tels que l'angine, l'hypertension, l'insuffisance cardiaque et l'athérosclérose.
PCT/EP1992/002068 1991-09-14 1992-09-04 Agents antiangineux a pyrazolopyrimidinone Ceased WO1993006104A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9119704.6 1991-09-14
GB919119704A GB9119704D0 (en) 1991-09-14 1991-09-14 Therapeutic agents

Publications (1)

Publication Number Publication Date
WO1993006104A1 true WO1993006104A1 (fr) 1993-04-01

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Application Number Title Priority Date Filing Date
PCT/EP1992/002068 Ceased WO1993006104A1 (fr) 1991-09-14 1992-09-04 Agents antiangineux a pyrazolopyrimidinone

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GB (1) GB9119704D0 (fr)
PT (1) PT100862A (fr)
WO (1) WO1993006104A1 (fr)

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996016657A1 (fr) * 1994-11-26 1996-06-06 Pfizer Limited Composes heterocycliques bicycliques destines au traitement de l'impuissance
US5541187A (en) * 1992-03-30 1996-07-30 Sterling Winthrop Inc. 6-heterocycyclyl pyrazolo[3,4-d]pyrimidin-4-ones and compositions and method of use thereof
EP0743304A1 (fr) * 1995-05-17 1996-11-20 MERCK PATENT GmbH 4-(Arylaminométhylène)-2,4-dihydro-pyrazole-3-ones
WO1999024433A1 (fr) * 1997-11-12 1999-05-20 Bayer Aktiengesellschaft Imidazotriazinones a substitution 2-phenyle utilisees comme inhibiteurs des phosphodiesterases
WO2000027848A1 (fr) * 1998-11-11 2000-05-18 Dong A Pharm. Co., Ltd. Derives de pyrazolopyrimidinone utiles pour traiter l'impuissance
US6133272A (en) * 1996-11-01 2000-10-17 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
WO2000068208A1 (fr) * 1999-05-05 2000-11-16 Smithkline Beecham Plc Derives pyrimidinones destines au traitement de l'atherosclerose
US6225315B1 (en) 1998-11-30 2001-05-01 Pfizer Inc Method of treating nitrate-induced tolerance
US6235742B1 (en) 1997-10-24 2001-05-22 Pfizer Inc. 5-substituted pyrazolo[4,3-D]pyrimidin-7-ones
US6251904B1 (en) 1998-04-20 2001-06-26 Pfizer Inc. Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction
WO2001047929A1 (fr) * 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Triazolotriazinones et leur utilisation
US6300335B1 (en) 1994-11-26 2001-10-09 Pfizer Inc. 4-aminoquinazoline derivative cGMP-PDE inhibitors for the treatment of erectile dysfunction
US6333330B1 (en) 1998-10-23 2001-12-25 Pfizer Inc. Pyrazolopyrimidinone CGMP PDE5 inhibitors for the treatment of sexual dysfunction
WO2001098304A1 (fr) * 2000-06-23 2001-12-27 Dong A Pharm. Co., Ltd. Procede de preparation de derives de pyrazolopyrimidinone utiles pour traiter l'impuissance
US6407114B1 (en) 1998-10-23 2002-06-18 Pfizer Inc. Pyrazolopyrimidinone CGMP PDE5 inhibitors for the treatment of sexual dysfunction
US6472425B1 (en) 1997-10-31 2002-10-29 Nitromed, Inc. Methods for treating female sexual dysfunctions
US6548508B2 (en) 2000-10-20 2003-04-15 Pfizer, Inc. Use of PDE V inhibitors for improved fecundity in mammals
WO2003053923A2 (fr) 2001-12-20 2003-07-03 Applied Research Systems Ars Holding N.V. Derives de pyrrolidine utilises en tant que modulateurs de la prostaglandine
WO2003064402A1 (fr) 2002-01-31 2003-08-07 Pfizer Limited Traitement de troubles fonctionnels sexuels masculins
EP1365806A2 (fr) * 2000-04-19 2003-12-03 Johns Hopkins University Utilzation d'activators de no pour le traitement et la prevention des troubles gastrointestinaux
RU2220145C2 (ru) * 1998-11-11 2003-12-27 Донг А Фарм. Ко., Лтд. Производные пиразолопиримидинона для лечения импотенции и способ их получения
US6670366B1 (en) 1998-10-23 2003-12-30 Pfizer Inc Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction
US6677335B1 (en) 1999-10-11 2004-01-13 Pfizer Inc Pharmaceutically active compounds
US6723719B1 (en) 1997-04-25 2004-04-20 Pfizer Inc Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3′,5′—monophosphate phosphodiesterase (cGMP PDE5) for the treatment of sexual dysfunction
US6756373B1 (en) 1999-10-11 2004-06-29 Pfizer Inc. Pharmaceutically active compounds
US6914160B1 (en) 2002-08-28 2005-07-05 Pfizer Inc Oxytocin inhibitors
RU2271359C2 (ru) * 2000-06-29 2006-03-10 Мерк Патент Гмбх 5-аминоалкилпиразоло[4,3-d]пиримидины
WO2007056955A1 (fr) * 2005-11-17 2007-05-24 Topharman Shanghai Co., Ltd. Derives de la pirazolopyrimidinone, leur preparation et leur utilisation
US7235625B2 (en) 1999-06-29 2007-06-26 Palatin Technologies, Inc. Multiple agent therapy for sexual dysfunction
US7262192B2 (en) 2003-04-29 2007-08-28 Pfizer Inc. Substituted pyrazolo[4,3-d]pyrimidines and their use as PDE-5 inhibitors
US7323462B2 (en) 2002-12-10 2008-01-29 Pfizer Inc. Morpholine dopamine agonists
US7449462B2 (en) 2004-01-22 2008-11-11 Pfizer, Inc. Triazole derivatives which inhibit vasopressin antagonistic activity
US7569572B2 (en) 2004-04-07 2009-08-04 Pfizer Inc Pyrazolo[4,3-D]pyrimidines
US7572799B2 (en) 2003-11-24 2009-08-11 Pfizer Inc Pyrazolo[4,3-d]pyrimidines as Phosphodiesterase Inhibitors
US8227475B2 (en) 2005-05-12 2012-07-24 Pfizer Inc. Anhydrous crystalline forms of N-[1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-methylpyridin-2-yl-amino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]methanesulfonamide
US8273876B2 (en) 2002-07-16 2012-09-25 Bayer Intellectual Property Gmbh Medicaments containing vardenafil hydrochloride trihydrate
WO2013067309A1 (fr) 2011-11-04 2013-05-10 Xion Pharmaceutical Corporation Procédés et compositions pour l'administration orale de composés agonistes d'un récepteur de la mélanocortine
US8613950B2 (en) 2005-03-01 2013-12-24 Bayer Intellectual Property Gmbh Pharmaceutical forms with improved pharmacokinetic properties

Citations (2)

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EP0463756A1 (fr) * 1990-06-20 1992-01-02 Pfizer Limited Pyrazolopyrimidones comme agents antiangineux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0201188A2 (fr) * 1985-04-05 1986-12-17 Warner-Lambert Company Pyrazolo[4,3-d]pyrimidine-7-ones substituées en 5, leur procédé de préparation et compositions pharmaceutiques les contenant
EP0463756A1 (fr) * 1990-06-20 1992-01-02 Pfizer Limited Pyrazolopyrimidones comme agents antiangineux

Cited By (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5541187A (en) * 1992-03-30 1996-07-30 Sterling Winthrop Inc. 6-heterocycyclyl pyrazolo[3,4-d]pyrimidin-4-ones and compositions and method of use thereof
US6656945B2 (en) 1994-11-26 2003-12-02 Pfizer Inc 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-one cGMP-PDE inhibitors for the treatment of erectile dysfunction
WO1996016657A1 (fr) * 1994-11-26 1996-06-06 Pfizer Limited Composes heterocycliques bicycliques destines au traitement de l'impuissance
US6100270A (en) * 1994-11-26 2000-08-08 Pfizer Inc. Bicyclic heterocyclic compounds for the treatment of impotence
US6300335B1 (en) 1994-11-26 2001-10-09 Pfizer Inc. 4-aminoquinazoline derivative cGMP-PDE inhibitors for the treatment of erectile dysfunction
US6534511B1 (en) 1994-11-26 2003-03-18 Pfizer Inc. Bicyclic heterocyclic compounds for the treatment of impotence
EP0743304A1 (fr) * 1995-05-17 1996-11-20 MERCK PATENT GmbH 4-(Arylaminométhylène)-2,4-dihydro-pyrazole-3-ones
US5869516A (en) * 1995-05-17 1999-02-09 Merck Patent Gesellschaft Mit Beschrankter Haftung 4-(arylaminomethylene)-2,4-dihydro-3-pyrazolones
US6133272A (en) * 1996-11-01 2000-10-17 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6232321B1 (en) 1996-11-01 2001-05-15 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6723719B1 (en) 1997-04-25 2004-04-20 Pfizer Inc Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3′,5′—monophosphate phosphodiesterase (cGMP PDE5) for the treatment of sexual dysfunction
US6916927B2 (en) 1997-04-25 2005-07-12 Pfizer Inc. Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterase (cGMP-PDE5) for the treatment of sexual dysfunction
US6235742B1 (en) 1997-10-24 2001-05-22 Pfizer Inc. 5-substituted pyrazolo[4,3-D]pyrimidin-7-ones
US6472425B1 (en) 1997-10-31 2002-10-29 Nitromed, Inc. Methods for treating female sexual dysfunctions
US6566360B1 (en) 1997-11-12 2003-05-20 Bayer Aktiengesellschaft 2-phenyl substituted imidatriazinones as phosphodiesterase inhibitors
HRP20020585B1 (hr) * 1997-11-12 2013-02-28 Bayer Schering Pharma Aktiengesellschaft 2-fenil supstituirani imidazotriazinoni kao inhibitori fosfodiesteraze
GB2346877B (en) * 1997-11-12 2001-12-05 Bayer Ag 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
WO1999024433A1 (fr) * 1997-11-12 1999-05-20 Bayer Aktiengesellschaft Imidazotriazinones a substitution 2-phenyle utilisees comme inhibiteurs des phosphodiesterases
US7704999B2 (en) 1997-11-12 2010-04-27 Bayer Schering Pharma Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
EP1174431A3 (fr) * 1997-11-12 2002-01-30 Bayer Aktiengesellschaft 2-Phényl-substitués Imidazotriazinone comme inhibiteurs de la phoshodiesterase
US6362178B1 (en) 1997-11-12 2002-03-26 Bayer Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
ES2194567A1 (es) * 1997-11-12 2003-11-16 Bayer Ag Imidazotriazinonas 2-fenil sustituidas como inhibidores de fosfodiesterasas
US7122540B2 (en) 1997-11-12 2006-10-17 Bayer Healthcare Ag 2-Phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US7314871B2 (en) 1997-11-12 2008-01-01 Bayer Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors, for treatment of hypertension
US6890922B2 (en) 1997-11-12 2005-05-10 Bayer Healthcare Ag 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US7696206B2 (en) 1997-11-12 2010-04-13 Bayer Schering Pharma Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
GB2346877A (en) * 1997-11-12 2000-08-23 Bayer Ag 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
ES2194567B1 (es) * 1997-11-12 2005-03-01 Bayer Healthcare Ag. Imidazotriazinonas 2-fenil sustituidas como inhibidores de fosfodiesterasas.
US6251904B1 (en) 1998-04-20 2001-06-26 Pfizer Inc. Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction
US6458951B2 (en) * 1998-04-20 2002-10-01 Pfizer Inc Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction
US6407114B1 (en) 1998-10-23 2002-06-18 Pfizer Inc. Pyrazolopyrimidinone CGMP PDE5 inhibitors for the treatment of sexual dysfunction
US6670366B1 (en) 1998-10-23 2003-12-30 Pfizer Inc Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction
US6333330B1 (en) 1998-10-23 2001-12-25 Pfizer Inc. Pyrazolopyrimidinone CGMP PDE5 inhibitors for the treatment of sexual dysfunction
RU2220145C2 (ru) * 1998-11-11 2003-12-27 Донг А Фарм. Ко., Лтд. Производные пиразолопиримидинона для лечения импотенции и способ их получения
AU760422B2 (en) * 1998-11-11 2003-05-15 Dong-A Pharm. Co., Ltd. Pyrazolopyrimidinone derivatives for the treatment of impotence
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