WO1993006104A1 - Pyrazolopyrimidinone antianginal agents - Google Patents
Pyrazolopyrimidinone antianginal agents Download PDFInfo
- 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
Links
- 0 Cc1n[n](*)c(*)c1N Chemical compound Cc1n[n](*)c(*)c1N 0.000 description 2
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%.
Abstract
Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R1 is methyl or ethyl; R2 is ethyl or n-propyl; and R?3 and R4¿ are each independently H, or C¿1?-C6 alkyl optionally substituted with C5-C7 cycloalkyl or with morpholino; are selective cGMP PDE inhibitors useful in the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.
Description
PYRAZOLOPYRIMIDINONE ANTIANGINAL AGENTS
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.
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. Thus 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) .
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. However the compounds specifically exemplified therein are neither particularly potent PDE inhibitors, nor are they claimed to be selective inhibitors of cGMP PDE.
It has now been discovered that 1,3-dialkyl-5- (disubstituted phenyl)-1,6-dihydro-7H-pyrazolo[ ,3- d]pyrimidin-7-ones, in which the two phenyl substituents are in a 2,5 relative disposition, possess unexpectedly high levels of both cGMP PDE inhibitory potency and, as stated above, selectivity for inhibition of cGMP PDEs over that of cAMP PDEs. These compounds are neither specifically disclosed nor exemplified in EP-A-0201188.
The compounds of the present invention have the formula (I) :
wherein R1 is methyl or ethyl;
R2 is ethyl or n-propyl; and R3 and R4 are each independently H, or Cx- C6 alkyl optionally substituted with C5-C7 cycloalkyl or with morphorino; and pharmaceutically acceptable salts thereof. In the above definition, unless otherwise indicated, alkyl groups having three or more carbon atoms may be straight chain or branched chain; Thus 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.
Also included in the invention are 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 R3 is H, methyl or ethyl; R4 is C1-C6 alkyl optionally substituted with cyclohexyl or with morpholino; and R1 and R2 are as previously defined.
Particularly preferred individual compounds of the invention are:
5-[2-ethoxy-5-(3-morpholinopropylsulphamoyl)- phenyl]-1,3-dimethyl-l,6-dihydro-7H-pyrazolo[4,3-d]- pyrimidin-7-one; l-ethyl-5-[5-(n-hexylsulphamoyl)-2-n-propoxy- phenyl]-3-methyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one; l-ethyl-5-(5-diethylsulphamoyl-2-n-propoxy- phenyl)-3-methyl-l,6-dihydro-7H-pyrazolo[4,3-d]- pyrimidin-7-ohe; and 5-[5-(N-cyclohexylmethyl-N-methylsulphamoyl)-2- n-propoxypheny1]-l-ethyl-3-methyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one.
The compounds of formula (I) may be prepared by the reaction of a compound of formula (II) :
wherein R1 and R2 are as previously defined and Y is fluoro, chloro or bromo, preferably chloro, with a compound of formula (III) :
HNR3R4 (HI)
wherein R3 and R4 are as previously defined. The reaction is generally carried out at room temperature, preferably in the presence of a solvent, for example a C,-C3 alkanol, using an excess of (III) to scavenge the acid by-product (HY) .
Compounds of formula (II) may be prepared from compounds of formula (IV) :
(IV)
wherein R1 and R2 are as previously defined, by the application of known methods for the introduction of a S02Y 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.
Compounds of formula (IV) may be prepared from compounds of formula (V) :
(V) (VI)
wherein R1 and R2 are as previously defined, by the application of known cyclisation methods for pyrimidinone ring formation. Thus, for example, 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. Under these conditions the related nitrile of formula (VI) , wherein R1 and R2 are as previously defined, may also be employed as the precursor to (IV) .
In an alternative cyclisation procedure, compounds of formula (IV) may be obtained by treatment of (V) with polyphosphoric acid at or near 140°C for 6-18 hours.
Compounds of formulae (V) and (VI) may be prepared
from compounds of formulae (VII) and (VIII) respectively:
(VII) (VIII)
wherein Rl is as previously defined, by reaction with a compound of general formula (IX) :
wherein R2 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. For convenience, 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. For example 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 iriterconverted using ion-exchange resin techniques.
All of the above reactions are entirely conventional and the necessary reagents and conditions for their performance can readily be established by reference to standard textbooks and to the Examples and Preparations provided hereafter. Alternatives and variations will also be evident to persons skilled in the art to enable all the compounds defined by formula (I) to be prepared.
The biological activities of the compounds of the present invention were determined by the following test methods. Phosphodiesterase activity
Compound affinities for cGMP and cAMP PDEs are assessed by determination of their IC50 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-aqqreqatorv activity
This is assessed by the determination of a compound's ability to inhibit platelet aggregation in vitro induced by platelet activating factor (PAF) , and to potentiate the platelet antiaggregatory action in vitro of activators of guanylate cyclase such as nitroprusside and EDRF. 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
This is assessed following intravenous or oral administration of a compound to spontaneously hypertensive rats. Blood pressure is recorded via a cannula implanted in the carotid artery of either conscious or.anaesthetised animals.
For administration to man in the curative or prophylactic treatment of angina, hypertension or . congestive heart failure, oral dosages of the compounds will generally be in the range of from 4-800 mg daily
for an average adult patient (70 kg) . Thus for a typical adult patient, 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. In practice 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.
For human use, 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. For example, they may be administered orally, bύccally 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. For 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.
Thus the invention provides 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.
In a.further aspect, 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.
The invention also includes any novel intermediates of formulae (II) and (IV) disclosed herein.
The syntheses of the compounds of the invention and of the intermediates for use therein are
illustrated by the following Examples and Preparations. The purity of the compounds was routinely monitored by thin layer chromatography (tic) using Merck Kieselgel 60 F254 plates." Η-Nuclear magnetic resonance spectra were recorded using either a Nicolet QE-300 or a Bruker AC-300 spectrometer and were in all cases consistent with the proposed structures.
EXAMPLE 1 5-r2-Ethoxy-5-f3-morpholinopropylsulphamoyl)phenyl1- 1f3-dimethyl-l.6-dihvdro-7H-pyrazolo[4.3-d]pyrimidin-7- one
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. The residue was partitioned between saturated aqueous sodium bicarbonate solution (30 ml) and dichloromethane (30 ml) , then the organic phase removed and the aqueous phase further extracted with dichloromethane (3 x 30 ml) . The combined organic solutions were dried (Na2S04) and the solvent removed by evaporation under vacuum. The residue was purified by column chromatography (Si02, 5% MeOH in CH2C12) followed by crystallisation of the resulting solid from ethyl acetate-methanol, to afford the title compound as white crystals (0.568 g, 73%) , m.p. 193- 195°C. Found: C,54.05; H,6.00; N,17.18.
requires C,53.86; H,6.16; N,17.13%.
EXAMPLE 2 l-Ethyl-5-.5- ( -hexylsulphamo ll-2-n-propoxyphenyl]-3- methyl-1.6-dihvdro-7H-pyrazolo[ .3-d.pyrimidin-7-one Following the procedure of Example 1, the title compound was prepared from 5-(5-chlorosulphon l-2-n- propoxyphenyl)-l-ethyl-3-methyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (0.5 g, 0.0012 mol) and hexylamine (0.49 g, 0.0048 mol). After crystallisation from EtOAc-hexane, the product was obtained as a white solid (0.328 g, 57%), m.p. 172-174°C. Found: C,58.02;
H,6.98; N,14.85. ^11331.3045 requires C,58.08; H,6.9.9; N,14.73%.
EXAMPLE 3 5-r5-.N-Cvclohexylmethyl-N-methylsulphamoyl. -2-n- propoxyphenyll-l-ethyl-3-methyl-l.6-dihvdro-7H- pyrazolo[4,,3-dlpyrimidin-7-one
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^HJSNJO^ requires C,59.86; H,7.03; N,13.96%.
EXAMPLE 4 1-Ethy1-5-if5-diethylsulphamoy1-2-n-propoxypheny1. -3- methyl-1.6-dihvdro-7H-pyrazolo[4.3-d]pyrimidin-7-one
Following the procedure of Example 1, the title compound was prepared from 5-(5-chlorosuiphonyl-2-n- propoxyphenyl)-1-ethy1-3-methyl-1,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (0.5 g, 0.0012 mol) and diethylamine (0.5 ml, 0.356 g, 0.0048 mol). After crystallisation from EtOAc-hexane, the product was obtained as white crystals (0.379 g, 70%), m.p. 181- 183°C. Found: C,56.47; H,6.42; N,15.62. C^H^N^S requires C,56.36; H,6.53; N,15.65%.
PREPARATION 1 4-f2-Ethoxybenzamido)-1,3-dimethylpyrazole-5- carboxamide
A solution of 2-ethoxybenzoyl chloride (14.42 g, 0.078 mol) in dichloromethane (50 ml) was added dropwise to a stirred solution of 4-amino-l,3- dimethylpyrazole-5-carboxamide (12.0 g, 0.078 mol) (prepared by the method of J. Med. Chem. , 1987, J3p_, 91 in pyridine (150 ml) and the resulting mixture stirred at room temperature overnight in a dry nitrogen atmosphere. The solvent was removed by evaporation under vacuum and the residue partitioned between ethyl acetate (100 ml) and saturated aqueous sodium carbonate solution (100 ml) . The organic phase was separated and the aqueous phase exhaustively extracted with ethyl acetate. The combined organic solutions were dried (Na2S04) and evaporated under vacuum. The solid thus obtained was triturated with diethyl ether (100 ml) , then dried, to give the product as a white solid (19.24 g, 82%) , m.p. (after crystallisation from ethyl acetate) 178-181°C. Found: C,59.89; H,6.05; N,18.44. C,5H1gN403 requires C,59.59; H,6.00; N,18.53%.
PREPARATION 2 5-f2-Ethoxyphenyl. -1.3-dimethyl-l.6-dihydro-7H- pyrazolof4.3-d.pyrimidin-7-one
4-(2-Ethoxybenzamido)-1,3-dimethylpyrazole-5- carboxamide (1.6 g, 0.0053 mol) was added to polyphosphoric acid (50 g) and the mixture heated at about 140°C for 6 hours. The cool reaction mixture was poured onto ice/water (100 g) , then the resulting solution basified with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 100 ml) . The combined organic extracts were dried (MgS04) and evaporated under vacuum to give the crude product. After purification by column chromatography (Si02, 3%
MeOH in CH2C12) , followed by crystallisation from aqueous ethanol, the title compound was obtained as colourless crystals (0.26 g, 17%), m.p. 201-204°C. Found: C,63.43; H,5.57; N,19.3.5. C,5H16N402 requires C,63.36; H,5.67; N,19.71%.
PREPARATION 3 5- (5-Chlorosulphonyl-2-ethoχyphenyl.-1.3-dimethyl-l.6- dihydro-7H-pyrazolor4.3-dlpyrimidin-7-one 5-(2-Ethoxyphenyl)-1,3-dimethyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (1.0 g, 0.0032 mol) was added portionwise to cold (0°C) chlorosulphonic acid (6 ml) and the resulting solution stirred at room temperature for 12 hours. The reaction mixture was added dropwise to ice/water (50 g) and the resulting aqueous solution extracted with dichloromethane (4 x 50 ml). The combined extracts were dried (Na2S04) and the solvent removed by evaporation under vacuum to give a white solid which, on trituration with diethyl ether provided the title compound (1.21 g, 100%) , m.p. 233- 235°C. Found: C,47.24; H,3.73; N,14.54. C,5Hι5ClN404S requires C,47.06; H,3.95; N,14.64%.
PREPARATION 4 l-Ethyl-3-methyl-4-.2-n-propoxybenzamido. yrazole-5- carboxamide
Following the procedure of Preparation 1, the title compound was prepared from 2-n-propoxybenzoyl chloride (2.16 g, 0.0109 mol) and 4-amino-l-ethyl-3- methylpyrazole-5-carboxamide (0.916 g, 0.0055 mol) (prepared by the method of EP-A-0095289) . The product was obtained as a white solid (1.63 g, 91%), m.p. (after crystallisation from ethyl acetate-hexane) 150- 152°C. Found: C,61.87; H,6.46; N,17.16. CπH^ ^ requires C,61.80; H,6.71; N,16.96%.
PREPARATION 5 l-Ethyl-3-methyl-5-f2-n-propoxyphenyl.-1.6-dihvdro-7H- pyrazolo.4.3-dlpyrimidin-7-one l-Ethyl-3-methyl-4-(2-n-propoxybenzamido)pyrazole- 5-carboxamide (8.0 g, 0.024 mol) was added to a stirred solution of sodium hydroxide (4.84 g, 0.121 mol) in water (180 ml) and ethanol (50 ml) and the mixture heated under reflux for 12 hours. The solution was allowed to cool and extracted with dichloromethane (6 x 60 ml) ; the combined extracts were then dried (Na2S04) and the solvent removed by evaporation under vacuum. Crystallisation of the resulting solid from EtOAc- hexane gave the title compound as white crystals (5.0 g, 66%), m.p. 149-151°C. Found: C,65.53; H,6.59; N,18.02. C17H20N4O2 requires C,65.37; H,6.45; N,17.94%.
PREPARATION 6 5- (5-Chlorosulphonyl-2-n-propoxyphenyl)-l-ethyl-3- methyl-1.6-dihydro-7H-pyrazolo[4P3-d.pyrimidin-7-one
Following the procedure of Preparation 3, the title compound was prepared from l-ethyl-3-methyl-5-(2- n-propoxyphenyl)-1,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (2.5 g, 0.008 mol) and chlorosulphonic acid (8 ml) . The product was obtained as a white solid (3.17 g, 96%), m.p. 155-158°C. Found:- C,49.19; H,4.50; N,13.38. C17H19C1N404S requires C,49.70; H,4.66; N,13.64%.
In vitro inhibitory activity and selectivity against the Ca/ CAM- independent cGMP PDE and the cGMP-inhibited cAMP PDE enzymes
Claims
CLAIMS 1. A compound of formula :
or a pharmaceutically acceptable salt thereof, wherein R1 is methyl or ethyl;
R2 is ethyl or n-propyl; and R3 and R4 are each indepdendently H, or C,-C6 alkyl optionally substituted with C5-C7 cycloalkyl or with morpholino.
2. A compound as claimed in claim 1 wherein R3 is H, methyl or ethyl; and R4 is Cj-C6 alkyl optionally substituted with cyclohexyl or with morpholino.
3. A compound as claimed in claim 2 wherein the said compound is selected from:
5-[2-ethoxy-5-(3-morpholinopropylsulphamoyl)- phenyl]-1,3-dimethyl-l,6-dihydro-7H-pyrazolo[4,3-d]- pyrimidin-7-one; l-ethyl-5-[5-(n-hexylsulphamoyl)-2-n-propoxy- phenyl]-3-methyl-l,6÷dihydro-7H-pyrazoIo[4,3- d]pyrimidin-7-one; l-ethyl-5-(5-diethylsulphamoyl-2-n-propoxy- phenyl)-3-methyl-l,6-dihydro-7H-pyrazolo[4,3-d]- pyrimidin-7-one; and 5-[5-(N-cyclohexylmethyl-N-methylsulphamoyl)-2-n- propoxypheny1]-1-ethy1-3-methyl-1,6-dihydro-7H- pyrazolo[4 ,3-d]pyrimidin-7-one; and pharmaceutically acceptable salts thereof.
4. A pharmaceutical composition comprising a compound of formula (I) , or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, together with a pharmaceutically acceptable diluent or carrier.
5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, as claimed in any one of claims 1 to 4, for use in medicine.
6. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, as claimed in any one of claims 1 to 4, 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, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility.
7. 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 patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility, in a mammal (including a human being) , which comprises administering to said mammal an effective amount of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, as claimed in any one of claims 1 to 4.
8. A process for the preparation of a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein R1 is methyl or ethyl;
R2 is ethyl or n-propyl; and R3 and R4 are each independently H, or Ci-Cg alkyl optionally substituted with C5-C7 cycloalkyl or with morpholino; which comprises reacting a compound of formula:
wherein Y is fluoro, chloro or bromo, and R1 and R2 are as previously defined in this claim, with a compound of formula: HNR3R4 (III)
wherein R3 and R4 are as previously defined in this claim, followed by optional isolation as, or formation of, a pharmaceutically acceptable salt of the product.
9. A process as claimed in claim 8 wherein R3 is H, methyl or ethyl; and R4 is Ct-C6 alkyl optionally substituted with cyclohexyl or with morpholino.
10. A process as claimed in claim 9 wherein the said compound of formula (I) produced is selected from:
5-[2-ethoxy-5-(3-morpholinopropylsulphamoyl)- phenyl]-1,3-dimethyl-l,6-dihydro-7H-pyrazolo[4,3-d]- pyrimidin-7-one; l-ethyl-5-[5-(n-hexylsulphamoyl)-2-n-propoxy- phenyl]-3-methyl-l,6-dihydro-7H-pyrazolo[4,3-d]- pyrimidin-7-one; l-ethyl-5-(5-diethylsulphamoyl-2-n-propoxy- phenyl)-3-methyl-l,6-dihydro-7H-pyrazolo[4,3-d]- pyrimidin-7-one; and 5-[5-(N-cyclohexylmethyl-N-methylsulphamoyl)-2- n-propoxyphenyl]-1-ethy1-3-methyl-1,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one; and pharmaceutically acceptable salts thereof.
11. A process as claimed in any one of claims 8 to 10 wherein Y is chloro.
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 (en) | 1993-04-01 |
Family
ID=10701447
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1992/002068 WO1993006104A1 (en) | 1991-09-14 | 1992-09-04 | Pyrazolopyrimidinone antianginal agents |
Country Status (3)
Country | Link |
---|---|
GB (1) | GB9119704D0 (en) |
PT (1) | PT100862A (en) |
WO (1) | WO1993006104A1 (en) |
Cited By (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996016657A1 (en) * | 1994-11-26 | 1996-06-06 | Pfizer Limited | Bicyclic heterocyclic compounds for the treatment of impotence |
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 (en) * | 1995-05-17 | 1996-11-20 | MERCK PATENT GmbH | 4-(Arylaminomethylene)-2,4-dihydro-pyrazol-3-ones |
WO1999024433A1 (en) * | 1997-11-12 | 1999-05-20 | Bayer Aktiengesellschaft | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
WO2000027848A1 (en) * | 1998-11-11 | 2000-05-18 | Dong A Pharm. Co., Ltd. | Pyrazolopyrimidinone derivatives for the treatment of impotence |
US6133272A (en) * | 1996-11-01 | 2000-10-17 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses |
WO2000068208A1 (en) * | 1999-05-05 | 2000-11-16 | Smithkline Beecham Plc | Pyrimidinones derivatives for the treatment of atherosclerosis |
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 (en) * | 1999-12-24 | 2001-07-05 | Bayer Aktiengesellschaft | Triazolotriazinones and the use thereof |
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 (en) * | 2000-06-23 | 2001-12-27 | Dong A Pharm. Co., Ltd. | A process for preparing pyrazolopyrimidinone derivatives for the treatment of impotence |
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 (en) | 2001-12-20 | 2003-07-03 | Applied Research Systems Ars Holding N.V. | Pyrrolidine derivatives as prostaglandin modulators |
WO2003064402A1 (en) | 2002-01-31 | 2003-08-07 | Pfizer Limited | Treatment of male sexual dysfunction |
EP1365806A2 (en) * | 2000-04-19 | 2003-12-03 | Johns Hopkins University | Use of no acttivators for treatment and prevention of gastrointestinal disorders |
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 |
WO2007056955A1 (en) * | 2005-11-17 | 2007-05-24 | Topharman Shanghai Co., Ltd. | Pyrazolopyrimidinone derivatives, their preparation and their use |
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 |
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 (en) | 2011-11-04 | 2013-05-10 | Xion Pharmaceutical Corporation | Methods and compositions for oral administration of melanocortin receptor agonist compounds |
US8613950B2 (en) | 2005-03-01 | 2013-12-24 | Bayer Intellectual Property Gmbh | Pharmaceutical forms with improved pharmacokinetic properties |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0201188A2 (en) * | 1985-04-05 | 1986-12-17 | Warner-Lambert Company | 5-Substituted pyrazolo[4,3-d] pyrimidine-7-ones, process for preparing the compounds and pharmaceutical compositions comprising the compounds |
EP0463756A1 (en) * | 1990-06-20 | 1992-01-02 | Pfizer Limited | Pyrazolopyrimidinone antianginal agents |
-
1991
- 1991-09-14 GB GB919119704A patent/GB9119704D0/en active Pending
-
1992
- 1992-09-04 WO PCT/EP1992/002068 patent/WO1993006104A1/en active Application Filing
- 1992-09-11 PT PT10086292A patent/PT100862A/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0201188A2 (en) * | 1985-04-05 | 1986-12-17 | Warner-Lambert Company | 5-Substituted pyrazolo[4,3-d] pyrimidine-7-ones, process for preparing the compounds and pharmaceutical compositions comprising the compounds |
EP0463756A1 (en) * | 1990-06-20 | 1992-01-02 | Pfizer Limited | Pyrazolopyrimidinone antianginal agents |
Cited By (71)
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 |
US6100270A (en) * | 1994-11-26 | 2000-08-08 | Pfizer Inc. | Bicyclic heterocyclic compounds for the treatment of impotence |
WO1996016657A1 (en) * | 1994-11-26 | 1996-06-06 | Pfizer Limited | 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 (en) * | 1995-05-17 | 1996-11-20 | MERCK PATENT GmbH | 4-(Arylaminomethylene)-2,4-dihydro-pyrazol-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 |
US7696206B2 (en) | 1997-11-12 | 2010-04-13 | Bayer Schering Pharma Aktiengesellschaft | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
GB2346877B (en) * | 1997-11-12 | 2001-12-05 | Bayer Ag | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
WO1999024433A1 (en) * | 1997-11-12 | 1999-05-20 | Bayer Aktiengesellschaft | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
US7704999B2 (en) | 1997-11-12 | 2010-04-27 | Bayer Schering Pharma Aktiengesellschaft | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
EP1174431A3 (en) * | 1997-11-12 | 2002-01-30 | Bayer Aktiengesellschaft | 2-Phenyl-substituited Imidazotriazinones as Phoshodiesterase Inhibitors |
US6362178B1 (en) | 1997-11-12 | 2002-03-26 | Bayer 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 |
US7122540B2 (en) | 1997-11-12 | 2006-10-17 | Bayer Healthcare Ag | 2-Phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
ES2194567A1 (en) * | 1997-11-12 | 2003-11-16 | Bayer 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 |
HRP20020585B1 (en) * | 1997-11-12 | 2013-02-28 | Bayer Schering Pharma Aktiengesellschaft | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
US6890922B2 (en) | 1997-11-12 | 2005-05-10 | Bayer Healthcare Ag | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
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 |
US6670366B1 (en) | 1998-10-23 | 2003-12-30 | 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 |
US6333330B1 (en) | 1998-10-23 | 2001-12-25 | Pfizer Inc. | Pyrazolopyrimidinone CGMP PDE5 inhibitors for the treatment of sexual dysfunction |
AU760422B2 (en) * | 1998-11-11 | 2003-05-15 | Dong-A Pharm. Co., Ltd. | Pyrazolopyrimidinone derivatives for the treatment of impotence |
WO2000027848A1 (en) * | 1998-11-11 | 2000-05-18 | Dong A Pharm. Co., Ltd. | Pyrazolopyrimidinone derivatives for the treatment of impotence |
US6225315B1 (en) | 1998-11-30 | 2001-05-01 | Pfizer Inc | Method of treating nitrate-induced tolerance |
WO2000068208A1 (en) * | 1999-05-05 | 2000-11-16 | Smithkline Beecham Plc | Pyrimidinones derivatives for the treatment of atherosclerosis |
US7235625B2 (en) | 1999-06-29 | 2007-06-26 | Palatin Technologies, Inc. | Multiple agent therapy for sexual dysfunction |
US6677335B1 (en) | 1999-10-11 | 2004-01-13 | Pfizer Inc | Pharmaceutically active compounds |
US6756373B1 (en) | 1999-10-11 | 2004-06-29 | Pfizer Inc. | Pharmaceutically active compounds |
US7176311B2 (en) | 1999-10-11 | 2007-02-13 | Pfizer Inc. | Process for preparing pharmaceutically active compounds |
WO2001047929A1 (en) * | 1999-12-24 | 2001-07-05 | Bayer Aktiengesellschaft | Triazolotriazinones and the use thereof |
US6683081B2 (en) | 1999-12-24 | 2004-01-27 | Bayer Aktiengesellschaft | Triazolotriazinones and the use thereof |
EP1365806A2 (en) * | 2000-04-19 | 2003-12-03 | Johns Hopkins University | Use of no acttivators for treatment and prevention of gastrointestinal disorders |
US6844436B2 (en) | 2000-06-23 | 2005-01-18 | Dong A. Pharm. Co., Ltd. | Preparing pyrazolopyrimidinone derivatives for the treatment of impotence |
AU2001258896B2 (en) * | 2000-06-23 | 2005-12-08 | Dong A Pharm. Co., Ltd. | A process for preparing pyrazolopyrimidinone derivatives for the treatment of impotence |
WO2001098304A1 (en) * | 2000-06-23 | 2001-12-27 | Dong A Pharm. Co., Ltd. | A process for preparing pyrazolopyrimidinone derivatives for the treatment of impotence |
US6548508B2 (en) | 2000-10-20 | 2003-04-15 | Pfizer, Inc. | Use of PDE V inhibitors for improved fecundity in mammals |
US7335680B2 (en) | 2001-12-20 | 2008-02-26 | Laboratoires Serono Sa | Pyrrolidine derivatives as prostaglandin modulators |
WO2003053923A2 (en) | 2001-12-20 | 2003-07-03 | Applied Research Systems Ars Holding N.V. | Pyrrolidine derivatives as prostaglandin modulators |
US7635713B2 (en) | 2001-12-20 | 2009-12-22 | Laboratoires Serono Sa | Pyrrolidine derivatives as prostaglandin modulators |
US8058305B2 (en) | 2001-12-20 | 2011-11-15 | Merck Serono Sa | Pyrrolidine derivatives as prostaglandin modulators |
WO2003064402A1 (en) | 2002-01-31 | 2003-08-07 | Pfizer Limited | Treatment of male sexual dysfunction |
US8273876B2 (en) | 2002-07-16 | 2012-09-25 | Bayer Intellectual Property Gmbh | Medicaments containing vardenafil hydrochloride trihydrate |
US8841446B2 (en) | 2002-07-16 | 2014-09-23 | Bayer Intellectual Property Gmbh | Medicaments containing vardenafil hydrochloride trihydrate |
US6914160B1 (en) | 2002-08-28 | 2005-07-05 | Pfizer Inc | Oxytocin inhibitors |
US7576081B2 (en) | 2002-12-10 | 2009-08-18 | Pfizer Inc. | Morpholine dopamine agonists |
US7902188B2 (en) | 2002-12-10 | 2011-03-08 | Pfizer Inc. | Morpholine dopamine agonists |
US7323462B2 (en) | 2002-12-10 | 2008-01-29 | Pfizer Inc. | Morpholine dopamine agonists |
US7262192B2 (en) | 2003-04-29 | 2007-08-28 | Pfizer Inc. | Substituted pyrazolo[4,3-d]pyrimidines and their use as PDE-5 inhibitors |
US8097621B2 (en) | 2003-11-24 | 2012-01-17 | Pfizer Inc. | Pyrazolo[4,3-d]pyrimidines as phosphodiesterase inhibitors |
US7572799B2 (en) | 2003-11-24 | 2009-08-11 | Pfizer Inc | Pyrazolo[4,3-d]pyrimidines as Phosphodiesterase Inhibitors |
US7569572B2 (en) | 2004-04-07 | 2009-08-04 | Pfizer Inc | Pyrazolo[4,3-D]pyrimidines |
US8613950B2 (en) | 2005-03-01 | 2013-12-24 | Bayer Intellectual Property Gmbh | Pharmaceutical forms with improved pharmacokinetic properties |
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 |
US8796287B2 (en) | 2005-05-12 | 2014-08-05 | 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 |
US8796288B2 (en) | 2005-05-12 | 2014-08-05 | 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 |
EP2253632A1 (en) * | 2005-11-17 | 2010-11-24 | Topharman Shanghai Co., Ltd. | Pyrazolopyramidinone derivatives, their preparation and their use |
JP2009515911A (en) * | 2005-11-17 | 2009-04-16 | トップハーマン シャンハイ カンパニー リミテッド | Pyrazolopyrimidinone derivatives and methods for their preparation and uses |
CN102002045B (en) * | 2005-11-17 | 2012-11-28 | 上海特化医药科技有限公司 | Pyrazolopyrimidinone derivatives as well as preparation method and application thereof |
WO2007056955A1 (en) * | 2005-11-17 | 2007-05-24 | Topharman Shanghai Co., Ltd. | Pyrazolopyrimidinone derivatives, their preparation and their use |
WO2013067309A1 (en) | 2011-11-04 | 2013-05-10 | Xion Pharmaceutical Corporation | Methods and compositions for oral administration of melanocortin receptor agonist compounds |
Also Published As
Publication number | Publication date |
---|---|
GB9119704D0 (en) | 1991-10-30 |
PT100862A (en) | 1993-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1993006104A1 (en) | Pyrazolopyrimidinone antianginal agents | |
EP0647227B1 (en) | Purinone antianginal agents | |
US5250534A (en) | Pyrazolopyrimidinone antianginal agents | |
US5591742A (en) | Pyridopyrimidinone antianginal agents | |
EP0463756B1 (en) | Pyrazolopyrimidinone antianginal agents | |
AU636816B2 (en) | Pyrazolopyrimidinone antianginal agents | |
US5734053A (en) | Purinone antianginal agents | |
EP1689751B1 (en) | 5,7-diaminopyrazolo[4,3-d]pyrimidines with pde-5 inhibiting activity | |
US6218397B1 (en) | Pyrazolopyrimidines as CRF antagonists | |
WO1993007149A1 (en) | Pyrazolopyrimidinone antianginal agents | |
EP0636626A1 (en) | Pyrazolopyrimidine Derivatives | |
US20040220186A1 (en) | PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease | |
EP1689752B1 (en) | Pyrazolopyrimidines | |
US20050130983A1 (en) | Pyrrolopyrimidinone derivatives, process for preparation thereof, and method of using and composition comprising them | |
EP1362858A1 (en) | Pyrrolopyrimidinone derivates, process of preparation and use | |
JPS61207385A (en) | Novel oxadiazolylimidazobenzodiazepine derivative and manufacture |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA FI JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2373/MUMNP/2009 Country of ref document: IN |