WO1994003453A1 - Derives de pyrazolopyridine utiles comme antagonistes de l'angiotensine ii - Google Patents

Derives de pyrazolopyridine utiles comme antagonistes de l'angiotensine ii Download PDF

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WO1994003453A1
WO1994003453A1 PCT/GB1993/001635 GB9301635W WO9403453A1 WO 1994003453 A1 WO1994003453 A1 WO 1994003453A1 GB 9301635 W GB9301635 W GB 9301635W WO 9403453 A1 WO9403453 A1 WO 9403453A1
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formula
group
alkyl
compound
methyl
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PCT/GB1993/001635
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English (en)
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Arnold Harry Ratcliffe
Brian Bernard Masek
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Zeneca Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention concerns novel heterocyclic derivatives and, more particularly, novel pyrazolopyridine derivatives which possess pharmacologically useful properties in antagonising at least in part one or more of the actions of the substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "All").
  • the invention also concerns pharmaceutical compositions of the novel compounds for use in treating diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the
  • the invention also includes processes for the manufacture of the novel compounds and their use in treating one of the
  • the angiotensins are key mediators of the renin-angiotensin-aldosterone system, which is involved in the control of homeostasis and fluid/electrolyte balance in many warm-blooded animals, including man.
  • the angiotensin known as All is produced by the action of angiotensin converting enzyme (ACE) on angiotensin I, itself produced by the action of the enzyme renin on the blood plasma protein angiotensinogen. All is a potent spasmogen especially in the vasculature and is known to increase vascular resistance and blood pressure.
  • the angiotensins are known to stimulate the release of aldosterone and hence result in vascular congestion and hypertension via sodium and fluid retention mechanisms. Hitherto there have been a number of different approaches to pharmacological intervention in the renin-angiotensin-aldosterone system for
  • R 1 is hydrogen, ( 1-8C)alkyl, (3-8C) cycloalkyl, phenyl or substituted (1-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, (1-4C)alkoxy or phenyl substituent;
  • R 2 is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, carboxy, (1-4C)alkoxycarbonyl,
  • R 3 is selected from halogeno, (1-4C)alkoxy, hydroxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and any of the values defined for R 1 ;
  • R 4 is selected from (1-4C)alkoxy, halogeno, hydroxy(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyi, (3-6C)alkenyloxycarbonyl, cyano, nitro, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, (1-4C)alkanoyl, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, phenylthio, phenylsulphinyl, phenyl
  • B is a direct bond or is phenylene optionally bearing a substituent selected from (1-4C)alkyl,
  • B 2 is oxygen, sulphur or a group of the formula -NR 5 - in which R 5 is hydrogen or (1-4C)alkyl;
  • Zb has any of the values defined above for Za;
  • B 3 is phenyl optionally bearing one or two substituents independently selected from (1-4C)alkyl,
  • Rb and Rc are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy and halogeno;
  • Zc is 1H-tetrazol-5-yl, carboxy or in vivo hydrolysable ester thereof or a group of the formula CF 3 SO 2 NH-;
  • Rd is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno,
  • alkyl include both straight and branched chain variants when the carbon numbers permit.
  • branched chain variants such as “isopropyl” being specifically named where intended. The same convention applies to other radicals.
  • R 1 , R 3 or R 4 include, by way of example, for alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl and hexyl; for cycloalkyl: cyclopropyl, cyclopentyl and cyclohexyl; for alkyl bearing one or more fluoro substitutents: fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and
  • R 2 , R 3 or R 4 when it is halogeno is, for example, fluoro, chloro, bromo or iodo; and when it is alkoxy is, for example, methoxy or ethoxy;
  • R 2 or R 4 include, by way of example, for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and
  • R 2 or R 3 are, by way of example, for alkylamino: methylamino, ethylamino or butylamino; and for
  • dialkylamino dimethylamino, diethylamino or dipropylamino.
  • R 2 include, by way of example, for alkanoylamino: formamido, acetamido and propanamido; and for
  • 3-alkylureido 3-methylureido, 3-ethylureido and 3-propylureido.
  • R 4 include, by way of example, for hydroxyalkyl: hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; for alkylthio: methylthio and ethylthio; for alkylsulphinyl:
  • R 2 , R 5 or R 6 when it is alkyl is, for example, methyl, ethyl or propyl.
  • a particular value for an alkanoyl substituent on B 1 when it is phenylene is, for example, formyl, acetyl or propionyl.
  • Za, Zb, or Zc when it is an in vivo hydrolysable ester is, for example an ester derived from a
  • (1-6C)alkanol such as methanol or ethanol, or phenol, glycerol or the like.
  • R 8 when it is alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl; and when it is cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 7 includes, by way of example, for alkyl: methyl and ethyl;
  • alkyl containing one or more fluoro substitutents fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl;
  • N-alkylcarbamoyl N-methyl and N-ethylcarbamoyl
  • halogeno fluoro, ehloro, bromo or iodo
  • alkoxycarbonyl methoxycarbonyl or ethoxycarbonyl
  • alkanoyl formyl, acetyl or propionyl.
  • phenyl moieties include, by way of example, for halogeno: fluoro, ehloro and bromo; for alkyl: methyl and ethyl; and for alkoxy: methoxy and ethoxy.
  • R 1 or R 3 is, for example, (1-4C)alkyl such as methyl or ethyl.
  • a preferred value for R 2 is, for example, hydrogen.
  • a preferred value for R 4 is, for example, phenyl.
  • a preferred value for A 1 is, for example, a group of partial formula Ila.
  • a preferred value for B 1 is, for example, a p-phenylene group.
  • Za, Zb or Zc is, for example, carboxy or 1H-tetrazol-5-yl.
  • Za is 1H-tetrazol-5-yl is particularly preferred
  • a preferred value for B 2 is, for example, oxygen.
  • a particularly preferred combination of values is, for example, when R 1 and R 1 are both alkyl.
  • Particular groups of compounds of the invention include, for example,
  • Zb is tetrazolyl or carboxy
  • R 1 - R 4 , Rb, Rc and B 3 have any of the meanings defined above;
  • a preferred group of compounds of the formula I comprises those compounds of the formula la wherein R 1 , R 2 , R 3 and R 4 have any of the meanings defined above; R 9 and R 10 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro; and Z is 1H-tetrazol-5-yl or carboxy; and the non-toxic salts thereof.
  • a preferred sub-group of compounds of the formula la comprises those compounds in which R 1 is (1-4C)alkyl; R 2 , R 9 and R 1 0 are all hydrogen; R 3 is (1-4C)alkyl; R 4 is phenyl optionally bearing a halogeno, (1-4C)alkoxy or (1-4C)alkyl substituent; and the non-toxic salts thereof.
  • Compounds of the invention which are of particular interest include, for example, the specific embodiments set out hereinafter in the accompanying Examples and these are provided as a further feature of the invention.
  • Particularly suitable non-toxic salts for such compounds therefore also include, for example, salts with bases affording physiologically acceptable cations, for example, alkali metal (such as sodium and potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts, as well as salts with suitable organic bases, such as with ethanolamine, methylamine, diethylamine or triethylamine, as well as salts with acids forming physiologically acceptable anions, such as salts with mineral acids, for example with hydrogen- halides (such as hydrogen chloride and hydrogen bromide), sulphuric and phosphoric acid, and with strong organic acids, for example with p-toluenesulphonic and methanesulphonic acids.
  • bases affording physiologically acceptable cations for example, alkali metal (such as sodium and potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts, as well as salts with suitable organic bases, such as with ethanolamine, methylamine, diethyl
  • the compounds of formula I may be obtained by standard procedures of organic chemistry well known in the art for the production of structurally analogous compounds. Such procedures are provided as a further feature of the invention and include, by way of example, the following procedures in which the generic radicals have any of the values given above, unless stated otherwise: a) For those compounds in which A is a group of partial formula IIa, IIb or IIc in which Za, Zb and Zc respectively are carboxy, a carboxylic acid derivative of the formula Ilia, Illb or IIIc in which Qa, Qb and Qc respectively are protected carboxy groups selected from (1-6C)alkoxycarbonyl (especially methoxy-, ethoxy-, propoxy- or t-butoxy-carbonyl), phenoxycarbonyl, benzyloxyearbonyl and carbamoyl, is converted to carboxy.
  • A is a group of partial formula IIa, IIb or IIc in which Za, Zb and Zc respectively are carboxy
  • the conversion may be carried out, for example by hydrolysis, conveniently in the presence of a suitable base such as an alkali metal hydroxide, for example, lithium, sodium or potassium hydroxide.
  • a suitable aqueous solvent or diluent for example in an aqueous (1-4C)alkanol, such as aqueous methanol or ethanol.
  • aqueous (1-4C)alkanol such as aqueous methanol or ethanol.
  • it may also be performed in a mixture of an aqueous and non-aqueous solvent such as water and toluene using a conventional quaternary ammonium phase transfer catalyst.
  • the hydrolysis is generally performed at a temperature in the range, for example, 0 - 120°C, depending on the reactivity of the group Q.
  • Q is carbamoyl
  • temperatures in the range, for example, 40 - 120°C are required to effect the hydrolysis.
  • the conversion may also be performed by hydrogenolysis, for example using hydrogen at 1-3 bar in the presence of a suitable catalyst, such as palladium on charcoal or on calcium sulphate, in a suitable solvent or diluent such as a (1-4C)alkanol (typically ethanol or 2-propanol) and at a temperature in the range, for example, 0 - 40°C.
  • a suitable catalyst such as palladium on charcoal or on calcium sulphate
  • a suitable solvent or diluent such as a (1-4C)alkanol (typically ethanol or 2-propanol) and at a temperature in the range, for example, 0 - 40°C.
  • the conversion may also be carried out by hydrolysis at a temperature in the range, for example, 0 - 100°C, in the presence of a strong acid catalyst, such as trifluoroacetic acid.
  • a strong acid catalyst such as trifluoroacetic acid.
  • the hydrolysis may either be performed in an excess of the acid or in the presence of a suitable diluent such as tetrahydrofuran, t-butyl methyl ether or
  • tetrazolyl a compound of the formula IVa, IVb or IVc in which La, Lb and Lc respectively are suitable protecting group, such as trityl, benzhydryl, trialkyltin (for example trimethyltin or tributyltin) or triphenyltin, affixed to a nitrogen of the tetrazolyl moiety, is deprotected.
  • suitable protecting group such as trityl, benzhydryl, trialkyltin (for example trimethyltin or tributyltin) or triphenyltin
  • reaction conditions used to carry out the deprotection necessarily depend on the nature of the group La, Lb or Lc. As an illustration, when it is trityl, benzhydryl, trialkyltin or
  • the decomposition conditions include, for example, acid catalysed hydrolysis in a mineral acid (such as aqueous hydrochloric acid), conveniently in an aqueous solvent (such as aqueous dioxan or 2-propanol).
  • a trityl or benzhydryl group may be removed by hydrogenolysis, for example as described in (a) above for conversion of a benzyloxyearbonyl to a carboxy.
  • Compounds of the formula IVa, IVb or IVc wherein La, Lb and Lc respectively are trialkyltin or triphenyltin may be obtained, for example, by reaction of a nitrile of the formula Villa, Vlllb or VIIIc with a trialkyltin azide, such as tributyltin azide, or triphenyltin azide respectively.
  • the reaction is conveniently carried out in a suitable solvent or diluent, such as toluene or xylene, and at a temperature in the range, for example, 50-150°C.
  • the tetrazolyl group may be generated directly by in situ removal of the trialkyltin or triphenyltin group without prior isolation of the intermediate, for example by the addition of aqueous mineral acid or gaseous hydrogen chloride to the reaction mixture.
  • the nitriles of the formula Villa, Vlllb or VIIIc may be obtained, for example, by alkylation of a compound of the formula V with a nitrile of the formula IXa, IXb or IXc respectively wherein Hal. stands for a suitable leaving group such as ehloro, bromo, iodo,
  • Trialkyltin azides and triphenyltin azides are either commercially available or may be prepared by standard procedures well known in the art, such as by reaction of a trialkyltin halide with an alkali metal azide.
  • a compound of the formula V is alkylated with a compound of the formula VIa, VIb or VIc wherein Hal. stands for a suitable leaving group such as ehloro, bromo, iodo, methanesulphonyloxy or
  • the reaction is generally carried out in the presence of a suitable base, for example, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide or an alkali metal hydride such as sodium hydride or an alkali metal carbonate such as sodium or potassium carbonate, or an organic base such as diisopropylethylamine and in a suitable solvent or diluent, for example, a (1-4C)alkanol such as methanol or ethanol when an alkali metal alkoxide is used, or in a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10 - 100°C.
  • a suitable base for example, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide or an alkali metal hydride such as sodium hydride or an alkali metal carbonate such as sodium or potassium carbonate, or an organic base such as diisoprop
  • quaternary ammonium hydroxide may be used in a mixture of an aqueous and non-aqueous solvent such as water and dichloromethane.
  • an aqueous and non-aqueous solvent such as water and dichloromethane.
  • Procedure (c) is particularly suitable for the production of those compounds of the formula I in which Za, Zb or Zc is an ester group for example wherein Za, Zb or Zc is an (1-6C)alkyl, benzyl or phenyl ester, which compounds are also starting materials of formula IIIa, Illb and IIIc respectively for the reaction described in (a) above.
  • Za, Zb or Zc is an (1-6C)alkyl, benzyl or phenyl ester
  • formula IIIa, Illb and IIIc respectively for the reaction described in (a) above.
  • the starting materials of the formula IVa, IVb or IVc respectively may be obtained for procedure (b).
  • the reaction is preferably carried out in the presence of a base, such as triethylamine, and conveniently in a suitable solvent or diluent, for example dichloromethane, and at a temperature in the range of -78oC to ambient temperature.
  • a base such as triethylamine
  • a suitable solvent or diluent for example dichloromethane
  • the compounds of the formula X may be obtained by alkylation of a compound of formula V with a compound of the formula XI (itself obtained using analogous procedures to those described in EPA 429257 and 430709) using similar conditions to those of process (c) above, followed by reduction of the nitro group in the intermediate obtained, for example by conventional catalytic hydrogenation.
  • those compounds of formula I wherein Za, Zb or Zc is 1H-tetrazol-5-yl may be obtained by stepwise conversion of a compound of the formula I wherein Za, Zb or Zc is a carboxylic acid or ester group respectively into the corresponding nitrile under standard conditions, followed by reaction of the nitrile with an azide such as an alkali metal azide, preferably in the presence of an ammonium halide, and preferably in the presence of a suitable polar solvent such as N,N-dimethylformamide and at a temperature in the range, for example, 50 to 160°C.
  • an azide such as an alkali metal azide
  • an ammonium halide preferably in the presence of an ammonium halide
  • a suitable polar solvent such as N,N-dimethylformamide
  • -CO.NH.SO 2 R 8 or an ester group may be obtained, for example, by reacting a corresponding carboxylic acid of the formula I in which Za,
  • Zb or Zc is carboxy (or a reactive derivative of said acid) with
  • Suitable reactive derivatives include, for example the chloride, bromide, azide, anhydride and mixed anhydride with formic or acetic acid of the carboxylic acid of formula I as defined above.
  • the reaction is generally carried out in the presence of a suitable dehydrating agent such as dicyclohexycarbodiimide or 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide in the presence of a base such as triethylamine, pyridine or 4-dimethylaminopyridine.
  • a suitable dehydrating agent such as dicyclohexycarbodiimide or 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide
  • a base such as triethylamine, pyridine or 4-dimethylaminopyridine.
  • Za, Zb or Zc is a group of the formula -CO.NH.SO 2 R 8 or an ester group
  • the sulphonamide or hydroxy compound is used in the form of a salt, such as its alkali metal salt (in particular the lithium, sodium or potassium salt thereof).
  • a salt such as its alkali metal salt (in particular the lithium, sodium or potassium salt thereof).
  • a suitable diluent or solvent such as dioxan, t-butyl methyl ether or tetrahydrofuran and at a temperature in the range, for example, 0 - 60°C.
  • Suitable oxidising agents include those well known in the art for the conversion of nitrogen heterocycles to their corresponding N-oxide derivatives, for example, hydrogen peroxide or an organic peracid such as m-chloropterbenzoic acid or peracetic acid.
  • the oxidation is preferrably carried out in a suitable conventional solvent or diluent for such oxidations, for example dichloromethane, chloroform or acetic acid, and at a temperature in the general range, for example 0 to 80oC.
  • a non-toxic salt of a compound of formula I when required, it may be obtained, for example, by reaction with the appropriate base affording a physiologically acceptable cation, or with the appropriate acid affording a physiologically acceptable anion, or by any other conventional salt formation procedure.
  • an optically active form of a compound of formula I when required, one of the aforesaid processes may be carried out using an optically active starting material.
  • the racemic form of a compound of formula I in which Za, Zb or Zc is an acidic group may be resolved, for example by reaction with an optically active form of a suitable organic base, for example, ephedrine, N,N,N-trimethyl(1-phenylethyl)ammonium hydroxide or
  • B is p--henylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano and nitro, and R 1 , R 2 , R 3 , R 4 and Ra, have any of the meanings defined hereinbefore; which comprises reaction of a compound of the formula XII wherein P is an electron-deficient phenyl group; Re is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno,
  • (1-4C)alkanoyl trifluoromethyl, cyano or nitro
  • R 1 , R 2 , R 3 , R 4 and Ra have any of the values defined above with a base selected from an alkali metal hydroxide, (1-12C)alkanolate, (1-12C)alkanethiolate, phenolate, thiophenolate or diphenylphosphide, wherein any phenyl ring of the latter three groups may optionally bear a (1-4C)alkyl,
  • a particular value for P includes, for example, a phenyl group bearing 1, 2 or 3 electron-withdrawing groups independently selected from nitro, cyano and trifluoromethyl.
  • a particular value for Re when it is alkyl is, for example, methyl or ethyl; when it is alkoxy is, for example, methoxy or ethoxy; when it is alkanoyl is, for example, formyl, acetyl or propionyl; and when it is halogeno is, for example, fluoro, ehloro, bromo or iodo.
  • a particular value for a base includes the following by way of example:- for an alkali metal hydroxide: sodium or potassium hydroxide;
  • an alkali metal alkanolate for example an alkali metal (1-8C)alkanolate, for example an alkali metal (1-4C)alkoxide, such as sodium or potassium methoxide, ethoxide, propoxide or butoxide;
  • (1-8C)alkanethiolate for example an alkali metal (1-4C)alkanethiolate such as sodium or potassium methanethiolate, ethanethiolate, propanethiolate or butanethiolate.
  • alkali metal (1-4C)alkanethiolate such as sodium or potassium methanethiolate, ethanethiolate, propanethiolate or butanethiolate.
  • diphenylphosphide when it is alkyl is, for example, methyl or ethyl; when it is alkoxy is, for example, methoxy or ethoxy; and when it is halogeno is, for example, fluoro, ehloro or bromo.
  • a preferred value for P is, for example, a nitrophenyl group, especially 4-nitrophenyl.
  • a particularly preferred base is an alkali metal
  • alkanethiolate such as sodium or potassium propanethiolate
  • an alkali metal alkanolate such as sodium or potassium ethoxide or methoxide
  • an alkali metal thiophenolate such as sodium or potassium
  • the base is an alkali metal alkanolate, alkanethiolate, phenolate, thiophenolate or
  • diphenylphosphide it may be generated in situ from the corresponding alkanol, alkanethiol, phenol, thiophenol or diphenylphosphine with a suitable alkali metal base such as an alkali metal hydride, for example, lithium, potassium or sodium hydride.
  • a suitable alkali metal base such as an alkali metal hydride, for example, lithium, potassium or sodium hydride.
  • the process of the invention is particularly useful for the preparation of compounds of the formula I wherein the tetrazolyl group is at the ortho position relative to the adjacent phenyl group.
  • reaction is conveniently carried out in a suitable inert organic solvent or diluent, for example, a polar solvent such as
  • N,N-dimethylformamide or N-methylpyrrolidone Alternatively, an alkanol such as methanol or ethanol may be used, for example, when an alkali metal hydroxide or alkoxide such as sodium or potassium hydroxide, methoxide or ethoxide is employed.
  • the reaction is generally carried out at a temperature in the range, for example, -30°C to 50°C. It will be appreciated that the choice of temperature will depend on the nature of the base employed. For example, when an alkali metal alkanethiolate or alkanolate is used, a temperature in the range of 0°C to ambient temperature is preferred.
  • Compounds of the formula XII may be obtained by reaction of a boronic acid of the formula XIII with a compound of the formula XIV wherein P 1 is an electron-deficient phenyl group having any of the meanings defined above and W is a bromo, iodo or trifluoromethane sulphonyloxy group, in the presence of a palladium(O) or palladium(II) catalyst, such as tetrakis(triphenylphosphine)palladium(O) or
  • the reaction is preferably carried out in the presence of a base, such as sodium or potassium carbonate, in an inert solvent or diluent, for example, a hydrocarbon such as toluene or xylene, an ether, such as dioxan or tetrahydrofuran, an inert solvent or diluent, for example, a hydrocarbon such as toluene or xylene, an ether, such as dioxan or tetrahydrofuran, an inert solvent or diluent, for example, a hydrocarbon such as toluene or xylene, an ether, such as dioxan or tetrahydrofuran, an inert solvent or diluent, for example, a hydrocarbon such as toluene or xylene, an ether, such as dioxan or tetrahydrofuran, an inert solvent or diluent, for example, a hydrocarbon such as to
  • (1-4C)alkanol such as methanol or ethanol, water, or mixture thereof, for example a mixture of water, methanol and toluene, and at a temperature in the range of, for example, 50°C to 150°C, and conveniently at or about the reflux temperature of the solvent or mixture of solvents used.
  • Compounds of the formula XIII may be obtained, for example, by heating at reflux a 4-methylphenylboronic acid in a solvent such as methyl chloroform with azeotropic removal of water, followed by radical bromination of the product which may be carried out in situ, for example with bromine or N-bromosuccinimide in the presence of azo(bisisobutyronitrile).
  • the resultant 4-bromomethylphenylboronic acid anhydride may then be used to alkylate a compound of the formula V (using similar alkylation conditions to those used in process (c) described above), followed by subsequent acidic hydrolysis, to give a formula XIII compound.
  • the product from the alkylation step prior to hydrolysis may be isolated and reacted directly with a compound of the formula XIV under similar conditions to those described above to obtain a formula XII compound directly.
  • a 4-methylphenylboronic acid and an appropriate alkanediol for example 2,2-dimethylpropan-1,3-diol
  • a solvent such as cyclohexane
  • the resultant bromomethyl compound may then be reacted using analogous procedures to those described above for the 4-bromomethylphenylboronic acid anhydride to obtain a formula XIII compound or a compound of the formula XII directly.
  • Compounds of the formula XIV may be obtained, for example, by reaction of an appropriately substituted benzoyl chloride with a amine of formula P 1 .NH 2 under standard conditions.
  • the resultant amide is then, for example, reacted with thionyl chloride in the presence of triethylamine and N,N-dimethylformamide in acetonitrile at about ambient temperature to form the corresponding imidazoyl chloride, which is reacted in situ with triethylamine, sodium azide and tetrabutylamraonium bromide at 10-30°C to give the formula XIV compound.
  • the compounds of formula I will have beneficial pharmacological effects in warm-blooded animals (including man) in diseases and medical conditions where amelioration of the vasoconstrifctor and fluid retaining properties of the renin-angiotensin-aldosterone system is desirable, at least in part by antagonism of one or more of the physiological actions of All.
  • the compounds of the invention will thus be useful in the treatment of diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role.
  • the compounds of the invention may also be useful for the treatment of ocular hypertension, glaucoma, cognitive disorders (such as Alzheimer's disease, amnesia, senile dementia and learning disorders), as well as other diseases such as renal failure, cardiac insufficiency, post-myocardial infarction, cerebrovascular disorders, anxiety, depression and certain mental illnesses such as
  • antagonism of one or more of the physiological actions of All and, in particular, the antagonism of the interaction of All with the receptors which mediate its effects on a target tissue may be assessed using one or more of the following, routine laboratory procedures:
  • Test A This in vitro procedure involves the incubation of the test compound initially at a concentration of 100 micromolar (or less) in a buffered mixture containing fixed concentrations of radiolabelled All and a cell surface membrane fraction prepared from a suitable angiotensin target tissue.
  • the source of cell surface membranes is the guinea pig adrenal gland which is well known to respond to All.
  • concentrations of the test compound are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate IC 50 , which latter is subsequently determined from a plot of percentage displacement against concentration of the test compound.
  • acidic compounds of formula I as defined above show significant inhibition in Test A at a concentration of about 50 micromolar or much less.
  • Test B This in vitro test involves the measurement of the
  • Test C This in vivo test involves using terminally-anaesthetised or conscious rats in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure. The All antagonistic effects of the test compound following oral or parenteral administration, are assessed against angiotensin II-induced pressor responses. To ensure that the effect is specific, the effect of the test compound on vasopressin-induced pressor responses may also be determined in the same preparation.
  • the compounds of formula I generally show specific All-antagonist properties in Test C at a dose of about 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.
  • Test D This in vivo test involves the stimulation of endogenous All biosynthesis in a variety of species including rat, marmoset and dog by introducing a diet of low sodium content and giving appropriate daily doses of a saluretic known as frusemide. The test compound is then administered orally or parenterally to the animal in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure.
  • test A an IC 50 of 1.51 ⁇ 10 -8 M;
  • test C ED 50 of 0.45 mg/kg (i.v. administration).
  • the compounds of formula I will generally be administered for therapeutic or prophylactic purposes to warm-blooded animals (including man) requiring such treatment in the form of a
  • compositions as is well known in the pharmaceutical art.
  • a pharmaceutical composition comprising a compound of formula I, or a salt or N-oxide thereof as defined above, together with a pharmaceutically acceptable diluent or carrier.
  • Such compositions will conveniently be in a form suitable for oral administration (e.g. as a tablet, capsule, solution, suspension or emulsion) or parenteral administration (e.g. as an injectable aqueous or oily solution, or injectable emulsion).
  • the compounds of formula I may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinab ⁇ ve, such as a beta-adrenergic blocker (for example atenolol), a calcium channel blocker (for example nifedipine), an angiotensin converting enzyme (ACE) inhibitor (for example lisinopril) or- a diuretic (for example furosemide or hydrochlorothiazide).
  • ACE angiotensin converting enzyme
  • a diuretic for example furosemide or hydrochlorothiazide
  • a compound of formula I (or a pharmaceutically acceptable salt thereof as appropriate) will generally be administered to man so that, for example, a daily oral dose of up to 50 mg/kg body weight (and preferably of up to 10 mg/kg) or a daily parenteral dose of up to 5 mg/kg body weight (and preferably of up to 1 mg/kg) is received, given in divided doses as necessary, the precise amount of compound (or salt) administered and the route and form of
  • the compounds of the formula I will generally be administered in an analogous amount and manner to those described above for administration to humans.
  • the compounds of formula I are also of value as pharmacological tools in the
  • the starting material (A) was obtained as follows:- (i) 3-benzoyl-1,4-dihydro-2,6-dimethyl-4-oxopyridine (1.0 g) (obtained as described in Monatshefte fur Chemie, 1969, 100, 132) was added to phosphorus oxychloride (30 ml) and the mixture was heated at reflux for 3 hours. The mixture was cooled to ambient temperature and volatile material was removed by evaporation. The residue was added to crushed ice (50 g) and the mixture was basified with 4M sodium hydroxide solution. The mixture was then extracted with
  • the starting material A was obtained as follows:- (i) A mixture of 3-araino-1-phenyl-2-buten-1-one (2.3 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.0 g) was heated at 120°C for 1 hour. The mixture was cooled to ambient temperature and the residue was purified by flash chromatography, eluting with dichloromethane/methanol (19:1 v/v), to give
  • the compounds of the invention may be administered for therapeutic or prophylactic use to warm-blooded animals such as man in the form of conventional pharmaceutical compositions, typical examples of which include the following:- a) Capsule (for oral administration)
  • the active ingredient * may typically be an Example described hereinbefore and will conveniently be present as a pharmaceutically acceptable acid-addition salt, such as the hydrochloride salt.
  • Tablets and capsules formulations may be coated in conventional manner in order to modify or sustain dissolution of the active ingredient.
  • they may be coated with a conventional enterically digestible coating.

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

Abstract

L'invention concerne des composés de la formule (I) dans laquelle A1 représente un groupe de la formule partielle IIa, IIb ou IIc, Za et Zb représentent 1H^_-tétrazol-5-yl, un goupe carboxy ou un ester hydrolysable in vivo de celui-ci, -CO.NH.(1H^_-tétrazol-5-yl), ou un groupe de la formule -CO.NH.CO¿2R?8 et Zc représente 1H^_-tétrazol-5-yl, carboxy ou un ester hydrolysable in vivo de celui-ci ou un groupe de la formule CF¿3?SO2NH-. Les nouveaux composés ont une efficacité dans le traitement d'états tels que l'hypertension et l'insuffisance cardiaque congestive.
PCT/GB1993/001635 1992-08-07 1993-08-03 Derives de pyrazolopyridine utiles comme antagonistes de l'angiotensine ii WO1994003453A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47203/93A AU4720393A (en) 1992-08-07 1993-08-03 Pyrazolopyridine derivatives as angiotensin ii antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929216783A GB9216783D0 (en) 1992-08-07 1992-08-07 Heterocyclic derivatives
GB9216783.2 1992-08-07

Publications (1)

Publication Number Publication Date
WO1994003453A1 true WO1994003453A1 (fr) 1994-02-17

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Country Status (3)

Country Link
AU (1) AU4720393A (fr)
GB (1) GB9216783D0 (fr)
WO (1) WO1994003453A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011141756A1 (fr) * 2010-05-14 2011-11-17 Medical Research Council Technology Pyrazolopyridines en tant qu'inhibiteurs de la kinase lrrk2

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5264576A (en) * 1992-10-22 1993-11-23 Hoechst-Roussel Pharmaceuticals Incorporated Pyrazolo[4,3-c]pyridines which are intermediates

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399731A1 (fr) * 1989-05-23 1990-11-28 Zeneca Limited Azaindènes
EP0497516A1 (fr) * 1991-01-30 1992-08-05 Merck & Co. Inc. Antagonistes d'angiotensine II du type pyrrolo condensé à un hétérocycle à 6 chaînons substitués

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399731A1 (fr) * 1989-05-23 1990-11-28 Zeneca Limited Azaindènes
EP0497516A1 (fr) * 1991-01-30 1992-08-05 Merck & Co. Inc. Antagonistes d'angiotensine II du type pyrrolo condensé à un hétérocycle à 6 chaînons substitués

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011141756A1 (fr) * 2010-05-14 2011-11-17 Medical Research Council Technology Pyrazolopyridines en tant qu'inhibiteurs de la kinase lrrk2

Also Published As

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AU4720393A (en) 1994-03-03
GB9216783D0 (en) 1992-09-23

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