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WO1994011379A1 - Composes heterocycliques utilises comme antagonistes d'angiotensine - Google Patents

Composes heterocycliques utilises comme antagonistes d'angiotensine Download PDF

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Publication number
WO1994011379A1
WO1994011379A1 PCT/GB1993/002282 GB9302282W WO9411379A1 WO 1994011379 A1 WO1994011379 A1 WO 1994011379A1 GB 9302282 W GB9302282 W GB 9302282W WO 9411379 A1 WO9411379 A1 WO 9411379A1
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Prior art keywords
formula
compound
alkyl
group
hydrogen
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PCT/GB1993/002282
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English (en)
Inventor
Arnold Harry Ratcliffe
Keith Hopkinson Gibson
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Zeneca Limited
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Priority to AU53761/94A priority Critical patent/AU5376194A/en
Publication of WO1994011379A1 publication Critical patent/WO1994011379A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This invention concerns novel heterocyclic compounds and, more particularly, novel heterocyclic compounds 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
  • Rb is hydrogen or (1-4C)alkyl
  • R 4 is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno,
  • X is phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno,
  • R 1 or R 3 when it is alkyl includes, for example, (1-6C)alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl and hexyl; and when it is
  • cycloalkyl includes, for example, cyclopropyl, cyclopentyl and cyclohexyl.
  • a particular value for R 1 or R 3 when it is alkyl containing one or more fluoro substitutents includes, for example, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl; and when it is alkyl bearing a cycloalkyl, (1-4C)alkoxy or phenyl substituent includes, for example, cyclopropylmethyl, cyclopentylmethyl,
  • R 2 when it is alkyl includes, for example, methyl, ethyl, propyl, isopropyl and butyl; when it is alkoxycarbonyl includes, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; when it is alkenyloxycarbonyl includes, for example, allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl and
  • R 2 or R 3 include, by way of example, for alkylamino: methylamino, ethylamino and butylamino; for
  • dialkylamino dimethylamino, diethylamino and dipropylamino; for halogeno: fluoro, chloro, bromo and iodo; and for alkoxy: methoxy and ethoxy.
  • Particular values for R 2 include, by way of example, for
  • N-alkylcarbamoyl N-methyl and N-ethylcarbamoyl; for
  • di(N-alkyl)carbamoyl N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl; for alkanoylamino: formamido, acetamido and propanamido; and for
  • 3-alkylureido 3-methylureido, 3-ethylureido and 3-propylureido
  • Ra include, by way of example, for alkyl: methyl, ethyl and propyl; for alkyl containing one or more fluoro substitutents or bearing a cycloalkyl, alkoxy or phenyl substituent: fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl, cyclopropylmethyl, cyclopentylmethyl,
  • cyclohexylmethyl 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl and 2-phenylethyl; for cycloalkyl: cyclopropyl, cyclopentyl and cyclohexyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; and for alkenyloxycarbonyl: allyloxycarbonyl,
  • Rb when it is alkyl includes, by way of example, methyl and ethyl.
  • a particular value for R 4 when it is alkyl includes, for example, methyl and ethyl; when it is halogeno includes, for example, fluoro, chloro, bromo and iodo; and when it is alkoxy includes, for example, methoxy and ethoxy.
  • a particular value for R 5 when it is a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol includes, for example, a residue derived from a (1-6C)alkanol (such as methanol and ethanol), phenol, glycerol and the like.
  • R 6 when it is alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl and pentyl; and when it is cycloalkyl includes, for example, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 7 when it is alkyl includes, for example, methyl and ethyl; when it is alkanoyl includes, for example, formyl, acetyl and propionyl; and when it is -CO.NH. (1-4C)alkyl includes, for example, -CONHCH 3 and -CONHC 2 H 5 .
  • Particular values for optional substituents which may be present on phenyl moieties, or for an optional substituent which may be present when X is phenylene, or for an optional additional substituent on Z when it is a 2-carboxybenzamido, 2-sulfobenzamido or 2-carboxybenzyloxy group include, by way of example, for halogeno: fluoro, chloro and bromo; for alkyl: methyl and ethyl; and for alkoxy: methoxy and ethoxy.
  • a particular value for an optional alkanoyl substituent on X which may be present when X is phenylene includes, for example, formyl, acetyl and propionyl.
  • a particular combination of values for Ra and Rb of interest includes, for example, for when one or both are hydrogen.
  • a specific value for X which is of particular interest includes, for example, p-phenylene.
  • a preferred value for R 1 includes, for example, (1-4C)alkyl such as methyl, ethyl and propyl.
  • a preferred value for R 2 includes, for example, hydrogen.
  • a preferred value for R 3 includes, for example, (1-4C)alkyl such as methyl and ethyl.
  • a preferred value for R 4 or R 5 includes, for example, hydrogen.
  • a preferred value for Ra or Rb includes, for example, hydrogen.
  • a preferred combination of values for R 1 and R 3 includes, for example, when they are both alkyl; and for Ra and Rb includes, for example, when they are both hydrogen.
  • a preferred value for Z includes, for example,
  • a particular group of compounds of the formula I which are of interest comprises compounds of the formula I wherein R 1 , R 2 , R 3 , R 4 , Ra, Rb and X have any of the meanings defined above and Z is
  • R 5 is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol
  • R 6 is (1-6C)alkyl, (3-8C)cycloalkyl or phenyl; or an
  • a preferred group of compounds of the formula I comprises compounds of the formula la wherein R 1 , R 2 , R 3 , R 4 , Ra and Rb have any of the meanings defined above; and Z is carboxy or 1H-tetrazol-5-yl; and the non-toxic salts thereof.
  • R 1 and R 3 are both (1-4C)alkyl and Z 1 is 1H-tetrazol-5-yl are particularly preferred.
  • a compound of the invention which is of particular interest includes, for example, the specific embodiment set out hereinafter in the accompanying Example, and this compound, or a non-toxic salt thereof, is provided as a further feature of the invention.
  • salts with bases can form salts with bases as well as with acids.
  • 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
  • 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 Z is carboxy (that is in which Z is a group of the formula -CO.OR 5 in which R 5 is hydrogen), a carboxylic acid derivative of the formula II, in which Q is a protected carboxy group selected from (1-6C)alkoxycarbonyl (especially methoxy-, ethoxy-, propoxy- or t-butoxy-carbonyl), phenoxycarbonyl, benzyloxycarbonyl and carbamoyl, is converted to 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 may be carried out under acidic conditions, for example, using a suitable mineral acid, such as hydrochloric acid, and conveniently in the presence of a suitable solvent or diluent, such as dioxan.
  • a suitable mineral acid such as hydrochloric acid
  • a suitable solvent or diluent such as dioxan.
  • the hydrolysis is generally performed at a temperature in the range, for example, 0 - 120°C, depending on the reactivity of the group Q.
  • 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 1,2-dimethoxyethane.
  • reaction conditions used to carry out the deprotection necessarily depend on the nature of the group L.
  • 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
  • a trityl or benzhydryl group may be removed by hydrogenolysis, for example as described in (a) above for conversion of a benzyloxycarbonyl to a carboxy.
  • Compounds of the formula III wherein L is trialkyltin or triphenyltin may be obtained, for example, by reaction of a nitrile of the formula VII with a trialkyltin azide, such as tributyltin azide, or triphenyltin azide respectively.
  • a nitrile of the formula VII 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.
  • a formula I compound wherein Z is tetrazolyl may be obtained directly by in situ removal of the trialkyltin or triphenyltin group without prior isolation of the formula III compound, for example by the addition of aqueous mineral acid or gaseous hydrogen chloride to the reaction mixture.
  • the nitriles of the formula VII may be obtained, for example, by alkylation of a compound of the formula IV with a nitrile of the formula VIII wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p-toluenesulphonyloxy, using similar conditions to those used in process (c) described hereinafter.
  • the necessary compounds of formula VIII may be made by standard procedures such as that illustrated in Scheme 1, using methods of organic chemistry well known in the art.
  • the nitriles of the formula VII may be obtained from stepwise conversion of a compound of formula I wherein Z is a group of the formula -CO. O R 5 under standard conditions.
  • 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 IV is alkylated with a compound of the formula V wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p-toluenesulphonyloxy.
  • 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
  • a 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 Z is a group of the formula
  • Compounds of the formula IV can be made using standard procedures of organic cheeistry well known in the art, for example as described in standard works of heterocyclic chemistry such as those edited by Elderfield or Wiessberger, or as illustrated in Scheme 2 by ring closure of an appropriately substituted 4-amino-3-hydroxymethyl- pyridine or protected derivative thereof. It will be appreciated that a compound of the formula IV can be converted into another compound of the formula IV by functional group interconversion using procedures well known in the art. For example, carboxylic acids or their esters may be converted to amides or nitriles under standard conditions.
  • the necessary compounds of the formula V (and also of formula VI) may be made by standard procedures such as those which are illustrated in Scheme 1 for compounds in which X is phenylene.
  • Compounds of the formula VI wherein X is phenylene may also be conveniently obtained by. reaction of a Grignard reagent, formed from a suitably substituted 4-bromotoluene, with a trialkyltin halide, such as tributyltin chloride, followed by reaction of the resulting (substituted)phenyltrialkyltin compound with a bromobenzonitrile in the presence of a palladium(O) catalyst, such as
  • suitably substituted 4'-methylbiphenylcarbonitriles may be obtained by reaction of 4-methylphenylboronic acid with an appropriately substituted bromobenzonitrile in the presence of a suitable palladium catalyst, such as palladium (II)chloride or tetrakis(triphenylphosphine)palladium, and azo(bisisobutyronitrile).
  • a suitable palladium catalyst such as palladium (II)chloride or tetrakis(triphenylphosphine)palladium, and azo(bisisobutyronitrile).
  • the compounds of formula XII wherein X is a direct bond may be obtained, for example, by alkylation of a compound of the formula IV with an unsubstituted or appropriately substituted nitrobenzyl halide, using analogous conditions to those described in process (c) above, followed by reduction of the nitro group under standard conditions, for example by catalytic hydrogenation over platinum oxide in a suitable solvent, such as a (1-4C)alcohol (typically ethanol or 2-propanol) or ether (for example, dioxan or tetrahydrofuran), and at a temperature in the range, for example, 0-40°C.
  • a suitable solvent such as a (1-4C)alcohol (typically ethanol or 2-propanol) or ether (for example, dioxan or tetrahydrofuran), and at a temperature in the range, for example, 0-40°C.
  • a suitable solvent such as a (1-4C)alcohol (typically ethanol or 2-
  • reaction is generally carried out in a suitable solvent or diluent, for example a chlorinated hydrocarbon such as
  • a compound of the formula IV is alkylated with a compound of the formula XV wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p-toluenesulphonyloxy.
  • the reaction is generally carried out using similar conditions to those described for procedure (c).
  • the compounds of formula XV may be obtained by standard procedures such as those described in EPA 400974 for compounds in which X is phenylene, or by analogy therewith.
  • a compound of the formula X is reacted with a compound of the formula XIV wherein W 1 is a bromo, iodo or trifluoromethanesulphonyloxy group.
  • the reaction may be carried out using similar conditions to those described hereinafter for the reaction of a compound of formula X with a compound of formula XI.
  • the compounds of formula XIV may be obtained by standard procedures well known in the art.
  • a compound of the formula I wherein Z is -SO 2 NH 2 may also be obtained by acid hydrolysis of a compound of the formula I wherein Z is a group of the formula -SO 2 NHR 7 in which R 7 is a tert-butyl group.
  • the hydrolysis is generally carried out in the presence of a strong acid, such as trifluoroacetic acid.
  • the acid may be used in excess or in the presence of a suitable diluent such as tetrahydrofuran, t-butyl methyl ether or 1,2-dimethoxyethane, and at a temperature in the range, for example, 0-100°C.
  • a suitable diluent such as tetrahydrofuran, t-butyl methyl ether or 1,2-dimethoxyethane
  • compounds of the formula I wherein Z is -SO 2 NHR 7 may be obtained from the corresponding compound in which Z is -SO 2 NH 2 , for example, by alkylation, acylation (such as with an appropriate acid chloride, acid anhydride or other acylating agent) or reaction with an alkyl isocyanate, using standard conditions.
  • X is p-phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano and nitro, a compound of the formula IX, wherein P 1 is an electron-deficient phenyl group or a pyridyl or pyrimidyl group and Ry is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano or nitro, is reacted with a base selected from an alkali metal hydroxide,
  • (1-12C)alkanolatej (1-12C)alkanethiolate, phenolate, thiophenolate and diphenylphosphide, wherein any phenyl ring of the latter three groups may optionally bear a (1-4C)alkyl, (1-4C)alkoxy or halogeno group.
  • the 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.
  • a suitable inert organic solvent or diluent for example, a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone.
  • 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.
  • Particular bases which may be used in the reaction are, for example, sodium or potassium hydroxide, an alkali metal (1-4C)alkoxide (such as sodium or potassium methoxide, ethoxide, propoxide or butoxide or an alkali metal (1-4C)alkanethiolate (such as sodium or potassium
  • methanethiolate, ethanethiolate, propanethiolate or butanethiolate methanethiolate, ethanethiolate, propanethiolate or butanethiolate.
  • a temperature in the range of 0°C to ambient temperature is preferred.
  • P 1 includes, for example, a phenyl group bearing 1, 2 or 3 electron-withdrawing groups independently selected from nitro, cyano and trifluoromethyl, p-nitrophenyl being particularly preferred.
  • Compounds of the formula IX may be obtained by reaction of a boronic acid of the formula X with a compound of the formula XI wherein P 1 is an electron-deficient phenyl group or a pyridyl or pyrimidyl group and W is a bromo, iodo or trifluoromethanesulphonyloxy group, in the presence of a palladium(O) catalyst, such as
  • 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 (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.
  • a base such as sodium or potassium carbonate
  • an inert solvent or diluent for example, a hydrocarbon such as toluene or xylene, an ether, such as dioxan or tetrahydrofuran, an (1-4C)alkanol such as methanol or ethanol, water, or mixture thereof, for example a mixture of water,
  • Compounds of the formula X 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 IV (using similar alkylation conditions to those used in process (c) described above), followed by subsequent acidic hydrolysis, to give a formula X compound.
  • the product from the alkylation step prior to hydrolysis may be isolated and reacted directly with a compound of the formula XI under similar conditions to those described above to obtain a formula IX compound directly.
  • a 4-methylphenylboronic acid and an appropriate alkanediol for example 2,2-dimethylpropan-1,3-diol, may be heated at reflux in a solvent (such as cyclohexane) with azeotropic removal of water followed by free radical bromination of the product, which may be carried out in situ.
  • 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 X compound or a compound of the formula IX directly.
  • Compounds of the formula XI may be obtained, for example, as shown in EPA 495626.
  • compounds of the formula IX may be obtained, for example, by alkylation of a compound of the formula IV with a compound of formula XVI in which P 1 , Ry and Hal. have any of the meanings defined above.
  • the reaction is conveniently carried out using similar conditions to those described for procedure (c).
  • the compounds of formula XVI may be obtained, for example, as described in EPA 495626.
  • reactive or labile groups may be protected in a conventional manner and subsequently deprotected, using conventional protecting groups and deprotection procedures, for example, as described in "Protective Groups in Organic Synthesis” by Theodora Green (John Wiley and Sons Inc, 1981).
  • 1H-tetrazol-5-yl may be obtained by stepwise conversion of a compound of the formula I wherein Z is a group of the formula -CO.OR 5 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. (1H-tetrazol-5-yl), a group of the formula -CO.NH.SO 2 R 6 or a group of the formula -CO.OR 5 in which R 5 is other than hydrogen, may be obtained, for example, by reacting a carboxylic acid of the formula
  • 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.
  • reaction is generally carried out in the presence of a suitable dehydrating agent such as
  • 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 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-chloroperbenzoic 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 80°C.
  • 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 Z 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 1-phenylethylamine, followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, for example by fractional crystallisation from a suitable solvent, for example a (1-4C)alkanol, whereafter the optically active form of said compound of formula I may be liberated by treatment with acid using a conventional procedure, for example using an aqueous mineral acid such as dilute hydrochloric acid.
  • a suitable organic base for example, ephedrine, N,N,N-trimethyl- (1-phenylethyl)ammoni
  • 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 vasoconstrictor 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.
  • Interaction of the radiolabelled All with its receptors is antagonized by compounds which also bind to the membrane receptor sites and the degree of antagonism (observed in the test as displacement of membrane-bound radioactivity) is determined.
  • 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 cinaesthesia 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.
  • the compound of Example 1 gave a IC50 of 6 x 10 -9 M. in test A.
  • 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, or a non-toxic salt thereof 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 hereinabove, 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
  • a beta-adrenergic blocker for example atenolol
  • a calcium channel blocker for example nifedipine
  • an angiotensin converting enzyme (ACE) inhibitor for example lisinopril
  • a diuretic for example furosemide or
  • 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) Di-tert-butyl dicarbonate (0.24 g) was added to a solution of methyl 4-amino-2,6-diethylpyridine-3-carboxylate (0.21 g) (obtained as described in European patent application, publication number
  • Lithium borohydride (1.07 g) was added to a solution of compound B (1.0 g) in tetrahydrofuran (THF) (15 ml) and the mixture was stirred for 7 days and then heated at reflux for 60 hours. The mixture was cooled to ambient temperature, water (100 ml) was added and the mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried (MgSO 4 ) and solvent was
  • 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.
  • Reagents a) BuLi/THF; ZnCl 2 /Et 2 O; Pd(Ph 3 P) 4
  • R' lower alkyl
  • R lower alkoxy, phenoxy, N-imidazolyl, N-triazolyl or halogeno
  • Reagents a) LiBH 4 or LiAlH 4 , THF
  • step (i) (tert-BuOCO) 2 O, pyridine; (ii) as for step (a) d) (i) as for step (c), part (i); (ii) as for step (b) e) THF, heat

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

Abstract

L'invention se rapporte à des composés pharmaceutiquement utiles, répondant à la formule (I), dans laquelle R?1, R2, R3, R4¿, Ra, X et Z ont les différentes notations définies dans le descriptif, ainsi qu'à leurs sels non toxiques et à des compositions pharmaceutiques les contenant. Les nouveaux composés peuvent être utilisés pour le traitement d'états tels que l'hypertension et l'insuffisance cardiaque congestive. L'invention se rapporte en outre à des procédés de fabrication des nouveaux composés et à leur utilisation dans un traitement médical.
PCT/GB1993/002282 1992-11-06 1993-11-04 Composes heterocycliques utilises comme antagonistes d'angiotensine WO1994011379A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53761/94A AU5376194A (en) 1992-11-06 1993-11-04 Heterocyclic compounds as angiotensin ii antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929223371A GB9223371D0 (en) 1992-11-06 1992-11-06 Heterocyclic compounds
GB9223371.7 1992-11-06

Publications (1)

Publication Number Publication Date
WO1994011379A1 true WO1994011379A1 (fr) 1994-05-26

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/002282 WO1994011379A1 (fr) 1992-11-06 1993-11-04 Composes heterocycliques utilises comme antagonistes d'angiotensine

Country Status (3)

Country Link
AU (1) AU5376194A (fr)
GB (1) GB9223371D0 (fr)
WO (1) WO1994011379A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8067418B2 (en) 2005-04-12 2011-11-29 Vicore Pharma Ab Tricyclic angiotensin II agonists
US8080571B2 (en) 2005-04-12 2011-12-20 Vicore Pharma Ab Tricyclic angiotensin II agonists
US8357710B2 (en) 2005-04-12 2013-01-22 Vicore Pharma Ab Bicyclic angiotensin II agonists

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0468258A1 (fr) * 1990-07-21 1992-01-29 Bayer Ag Pyrido-oxazines substituées
EP0501892A1 (fr) * 1991-03-01 1992-09-02 Sanofi Dérivés hétérocycliques diazotés N-substitués par un groupement biphénylméthyle, leur préparation, les compositions pharmaceutiques en contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0468258A1 (fr) * 1990-07-21 1992-01-29 Bayer Ag Pyrido-oxazines substituées
EP0501892A1 (fr) * 1991-03-01 1992-09-02 Sanofi Dérivés hétérocycliques diazotés N-substitués par un groupement biphénylméthyle, leur préparation, les compositions pharmaceutiques en contenant

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8067418B2 (en) 2005-04-12 2011-11-29 Vicore Pharma Ab Tricyclic angiotensin II agonists
US8080571B2 (en) 2005-04-12 2011-12-20 Vicore Pharma Ab Tricyclic angiotensin II agonists
US8357710B2 (en) 2005-04-12 2013-01-22 Vicore Pharma Ab Bicyclic angiotensin II agonists

Also Published As

Publication number Publication date
GB9223371D0 (en) 1992-12-23
AU5376194A (en) 1994-06-08

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