WO1993007149A1 - Agents anti-angineux derives de la pyrazolopyrimidinone - Google Patents

Agents anti-angineux derives de la pyrazolopyrimidinone Download PDF

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Publication number
WO1993007149A1
WO1993007149A1 PCT/EP1992/002237 EP9202237W WO9307149A1 WO 1993007149 A1 WO1993007149 A1 WO 1993007149A1 EP 9202237 W EP9202237 W EP 9202237W WO 9307149 A1 WO9307149 A1 WO 9307149A1
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Prior art keywords
formula
alkyl
methyl
propyl
reaction
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PCT/EP1992/002237
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English (en)
Inventor
Andrew Simon Bell
Nicholas Kenneth Terrett
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Pfizer Ltd Great Britain
Pfizer Inc
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Pfizer Ltd Great Britain
Pfizer Inc
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Publication of WO1993007149A1 publication Critical patent/WO1993007149A1/fr
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    • 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 series of
  • pyrazolo[3,4-d]pyrimidin-4-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
  • cAMP PDEs adenosine 3' ,5'-monophosphate phosphodiesterases
  • EDRF endothelium-derived relaxing factor
  • 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 rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
  • post-PTCA post-percutaneous transluminal coronary angioplasty
  • peripheral vascular disease e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA)
  • stroke bronchitis
  • chronic asthma e.g. chronic asthma
  • allergic rhinitis glaucoma
  • glaucoma irritable bowel syndrome
  • European patent application EP-A-0349239 discloses a group of 1-unsubstituted pyrazolo[3,4-d]pyrimidin-4-ones as cGMP PDE inhibitors with bronchodilator and vasodilator activity of value in combatting asthma, bronchitis, angina, hypertension and congestive heart failure.
  • EP-A-0201188 discloses certain pyrazolo[4,3-d]pyrimidin-7-ones as adenosine receptor antagonists and PDE inhibitors, useful in the treatment of cardiovascular disorders such as heart failure or cardiac insufficiency. However these compounds are neither particularly potent PDE
  • the compounds of the present invention have the formula (I):
  • R 1 is C 1 -C 6 alkyl
  • R 2 is H, methyl or ethyl
  • R 3 is C 2 -C 4 alkyl
  • R 4 is C r -C 4 alkyl optionally substituted with NR 5 R 6 , CN, CONR 5 R 6 or CO 2 R 7 ; C 2 -C 4 alkenyl optionally substituted with CN, CONR 5 R 6 or CO 2 R 7 ; C 2 -C 4 alkanoyl optionally substituted with NR 5 R 6 ; SO 2 NR 5 R 6 ; CONR 5 R 6 ; CO 2 R 7 ; or halo; R 5 and R 6 are each independently H or C 1 -C 4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, 4-(NR 8 )-1-piperazinyl or 1-imidazolyl group wherein said group is optionally substituted by one or two C 1 -C 4 alkyl groups;
  • R 7 is H or C 1 -C 4 alkyl
  • R 8 is H, C 1 -C 3 alkyl or hydroxy C 2 -C 3 alkyl; and pharmaceutically acceptable salts thereof.
  • alkyl and alkoxy groups having three or more carbon atoms may be straight chain or branched chain.
  • alkenyl and alkanoyl groups having four carbon atoms may be straight chain or branched chain.
  • Halo means fluoro, chloro, bromo or iodo.
  • the compounds of formula (I) may contain one or more asymmetric centres and thus they can exist as enantiomers or diastereoisomers. Furthermore certain compounds of formula (I) which contain alkenyl groups may exist as cis- or trans-isomers. In each instance, 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, fumarate, maleate, lactate, citrate, tartrate,
  • 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 1 is n-propyl; R 2 is H or methyl; R 3 is ethyl or n-propyl; R 4 is ethyl substituted with CONR 5 R 6 or CO 2 R 7 ; vinyl substituted with CONR 5 R 6 or CO 2 R 7 ; acetyl substituted with NR 5 R 6 ; SO 2 NR 5 R 6 ; CONR 5 R 6 ; CO 2 R 7 ; or bromo; R 5 and R 6 together with the nitrogen atom to which they are attached form a morpholino, 4-(NR 8 )-1- piperazinyl or 2, 4-dimethyl-1-imidazolyl group; R 7 is H or t-butyl; and R 8 is methyl or 2-hydroxyethyl.
  • Particularly preferred individual compounds of the invention include:
  • the compounds of formula (I) may be prepared by a variety of methods from a compound of formula (II):
  • R 1 , R 2 and R 3 are as previously defined for formula (I).
  • R 4 is C 2 -C 4 alkanoyl
  • the required product is obtainable by conventional Friedel-Crafts acylation whereby (II) is reacted with about a 2-fold excess of an acyl halide of formula (C 1 - C 3 alkyl) COY, wherein Y is halo, preferably chloro or bromo, in the presence of about a 3-fold excess of a Lewis acid such as aluminium chloride or aluminium bromide, in a suitable solvent, e.g. dichloromethane, at from about 0°C to the reflux temperature of the reaction medium.
  • a suitable solvent e.g. dichloromethane
  • R 4 is C 2 -C 4 alkanoyl substituted with NR 5 R 6 , wherein R 5 and R 6 are as previously defined
  • the product is obtained from (II) via the intermediacy of the corresponding haloketone, i.e. a compound of formula (I) wherein R 4 is CO(C 1 -C 3 alkylene)X and X is halo, preferably chloro or bromo, by reaction of the appropriate haloketone with the required amine of formula R 5 R 6 NH in the presence of at least one
  • the base may be an
  • inorganic salt such as anhydrous potassium carbonate, a tertiary amine such as triethylamine, or excess
  • protecting group e.g. benzyl which can be subsequently removed by catalytic hydrogenation.
  • R 5 and R 6 are H
  • the potassium salt of the non-basic aminating reagent is used for reaction with the haloketone; deprotection is effected by acidolysis using, for example, hydrogen chloride, which allows convenient isolation of the desired aminoketone as its hydrochloric salt.
  • the intermediate haloketone is also obtained via Friedel-Crafts chemistry, as described above, in this case between (II) and the appropriate haloacyl halide of formula X(C 1 -C 3 alkylene)COY, wherein X and Y are as previously defined.
  • the primary amines are obtained by nitration of (II) using, e.g. a conventional
  • (II), i.e. compounds of formula (III), may also be, prepared directly from compounds of formula (II) by bromination in a suitable solvent. This may be
  • the reaction is generally carried out with about a 50% excess of both the alkene reagent and a tertiary amine such as triethylamine, in the presence of about 0.1 equivalents of a tertiary
  • arylphosphine preferably tri-o-tolylphosphine, and about 0.05 equivalents of palladium(II) acetate, in a suitable solvent such as acetonitrile, at the reflux temperature of the reaction medium.
  • a suitable solvent such as acetonitrile
  • the resulting acrylic esters may be hydrolysed if desired, e.g. using aqueous sodium hydroxide solution, with methanol as co-solvent, to afford the corresponding cinnamic acids.
  • these cinnamic acids may be used as an
  • paraformaldehyde and concentrated hydrochloric acid at from about room temperature to about 120°C.
  • the desired alkenes (and derived alkanes via catalytic hydrogenation) may be obtained using a Wittig-Horner strategy in which an aldehyde of formula (I), wherein R 4 is CHO and R 1 , R 2 and R 3 are as previously defined, is reacted with the appropriate phosphonium salt or phosphonate in the presence of a suitable base.
  • the aldehyde itself is obtainable by formylation, e.g. using DMF, of the aryllithium
  • the chloromethyl intermediates of formula (IV) may also be used for the preparation of compounds of formula (I), wherein R 4 is CH 2 NR 5 R 6 and R 1 , R 2 , R 3 , R 5 and R 6 are as previously defined, by reaction with the appropriate amine of formula HNR 5 R 6 (or protected version thereof - vide supra). Preferably the reaction is carried out with about a 3-fold excess of amine in a suitable solvent, e.g. 2-butanone, at from about 0°C to the reflux temperature of the reaction medium.
  • a suitable solvent e.g. 2-butanone
  • compounds of formula (I) wherein R 4 is (C 2 -C 4 alkylene)NR 5 R 6 may be conveniently obtained from, e.g., the appropriate chloro, bromo, iodo or mesyloxy
  • the C 2 -alcohol (R 4 is CH 2 CH 2 OH) may be obtained by reaction of the above-mentioned aryllithium
  • aryllithium intermediates are also useful in the preparation of compounds of formula (I) wherein R 4 is CONR 5 R 6 or CO 2 R 7 and R 1 , R 2 , R 3 , R 5 , R 6 and R 7 are as previously defined.
  • R 4 is CONR 5 R 6 or CO 2 R 7 and R 1 , R 2 , R 3 , R 5 , R 6 and R 7 are as previously defined.
  • lithiation of (III) in dry tetrahydrofuran (THF) at about -78°C using about a 2 to 3-fold excess of a solution of n-butyllithium in hexane, quenching of the resulting aryllithium with carbon dioxide at from about -70 to 0°C, and aqueous acidic work-up at about room temperature furnishes the corresponding benzoic acid derivative.
  • the acid may be activated under mild conditions, such as those
  • R 1 , R 2 and R 3 are as previously defined for formula (IV), and Z is fluoro, chloro or bromo, preferably chloro, with a compound of formula (VI):
  • reaction is generally carried out at room temperature, preferably in the presence of a solvent, for example a C 1 -C 3 alkanol, using a 2 to 5-fold excess of (VI) to scavenge the acid by-product (HZ).
  • a solvent for example a C 1 -C 3 alkanol
  • the cyclisation may be effected by the treatment of (VII) with a base such as sodium hydroxide or potassium carbonate, optionally in the presence of hydrogen peroxide, in an ethanol-water medium at reflux
  • compounds of the formula (II) may be obtained by treatment of (VII) with polyphosphoric acid at about 140°C.
  • R 3 and Y are as previously defined.
  • the reaction is generally carried out using about a 20% excess of (X) 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-dimethylamino-pyridine, in an inert solvent such as dichloromethane at from about 0 to about 25°C for 2-24 hours.
  • a catalyst such as 4-dimethylamino-pyridine
  • an inert solvent such as dichloromethane at from about 0 to about 25°C for 2-24 hours.
  • pyridine may also be used as solvent.
  • aminopyrazole carboxamides of formula (VIII) may be obtained by acid hydrolysis of the corresponding nitriles of formula (IX), whilst the latter, the acyl halides of formulae (X) and (XI), and the intermediates employed for introduction of the various R 4
  • 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 interconverted using ion-exchange resin techniques.
  • the biological activities of the compounds of the present invention were determined by the following test methods.
  • 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
  • Washed platelets are prepared essentially by the method of J.F. Mustard et al.
  • 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
  • dosages for intravenous, buccal or sublingual administration will typically be within the range of from 1-400 mg per single dose as required.
  • 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
  • compositions for example, they may be administered orally, buccally 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 may also be injected parenterally, for example intravenously, intramuscularly, subcutaneously or intracoronarily.
  • a sterile aqueous solution which may
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a compound of the 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 the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical
  • 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 patency 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
  • composition containing either entity.
  • the invention also includes any novel
  • Morpholine (0.175 g, 0.002 mol) was added to a stirred suspension of 6-(5-bromoacetyl-2-ethoxyphenyl)- 1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4- one (Preparation 4; 0.70 g, 0.0017 mol) and anhydrous potassium carbonate (0.461 g, 0.0033 mol) in
  • Aluminium trichloride (1.34 g, 0.010 mol) was added portionwise to a stirred solution of 6-(2-ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 1; 1.0 g, 0.0034 mol) and bromoacetyl bromide (1.35, 0.0067 mol) in
  • Example 3 has been tested at therapeutic doses of up to 1 mg/Kg i.v. in rabbit with no signs of adverse acute toxicity being observed.

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

Abstract

Dans les composés de formule (I), et leurs sels pharmaceutiquement acceptables, R1 représente C¿1?-C6 alkyle; R?2¿ représente H, méthyle ou éthyle; R3 représente C¿2?-C4 alkyle; R?4¿ représente C¿1?-C4 alkyle éventuellement substitué par NR?5R6¿, CN, CONR5R6 ou CO¿2R?7; C2-C4 alcényle éventuellement substitué par CN, CONR5R6 ou CO¿2R?7; C2-C4 alkanoyle éventuellement substitué par NR5R6; SO2NR?5R6; CONR5R6; CO¿2R7; ou halo; R5 et R6 représentent chacun indépendemment H ou C¿1?-C4 alkyle, ou bien avec l'atome d'azote auquel ils sont liés, ils forment un groupe pyrrolidino, pipéridino, morpholino, 4-(NR?8¿)-1-pipérazinyle ou 1-imidazolyle, groupe éventuellement substitué par un ou deux groupes C¿1?-C4 alkyle; R?7¿ représente H ou C¿1?-C4 alkyle; et R?8¿ représente H, C¿1?-C3 alkyle ou hydroxy C2-C3 alkyle. Ils constitutent des inhibiteurs sélectifs de la cGMP PDE, utiles dans le traitement de troubles cardiovasculaires tels que l'angine de poitrine, l'hypertension, les arrêts cardiaques et l'athérosclérose.
PCT/EP1992/002237 1991-10-03 1992-09-24 Agents anti-angineux derives de la pyrazolopyrimidinone Ceased WO1993007149A1 (fr)

Applications Claiming Priority (2)

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GB9121028.6 1991-10-03
GB919121028A GB9121028D0 (en) 1991-10-03 1991-10-03 Therapeutic agents

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WO1993007149A1 true WO1993007149A1 (fr) 1993-04-15

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PT (1) PT100915A (fr)
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