WO1993024487A1 - Composes heterocycliques contenant de l'azote utiles comme antagonistes de l'angiotensine ii - Google Patents

Composes heterocycliques contenant de l'azote utiles comme antagonistes de l'angiotensine ii Download PDF

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WO1993024487A1
WO1993024487A1 PCT/GB1993/001057 GB9301057W WO9324487A1 WO 1993024487 A1 WO1993024487 A1 WO 1993024487A1 GB 9301057 W GB9301057 W GB 9301057W WO 9324487 A1 WO9324487 A1 WO 9324487A1
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alkyl
methyl
formula
group
ethyl
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PCT/GB1993/001057
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English (en)
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Keith Hopkinson Gibson
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4

Definitions

  • This invention concerns novel nitrogen compounds and, more particularly, novel nitrogen 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 renin-angiotensin-aldosterone system plays a significant causative role.
  • the invention also includes processes for the manufacture of the novel compounds and their use in treating one of the afore-mentioned diseases or medical conditions and for the production of novel pharmaceuticals for use in such medical treatments.
  • 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
  • ACE angiotensin converting enzyme
  • angiotensinogen All is a potent spasmogen especially in the
  • vasculature and is known to increase vascular resistance and blood pressure.
  • 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
  • Q is selected from a group of the partial structural formula Ila, IIb, IIc, IId, or IIe in which
  • ring B of formula IIa completes a benzene or pyridine ring
  • R 1 , T 1 and F 1 are independently selected from (1-8C)alkyl
  • R 2 , T 2 and F 2 are independently selected from hydrogen, (1-8C)alkyl,
  • R 3 and R 4 are optional substituents on ring B independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano, nitro, fluoro(1-4C)alkoxy, hydroxy or hydroxy(1-4C)alkyl;
  • T 3 is selected from halogeno, (1-4C)alkoxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms and any of the values defined for
  • T 4 and F 3 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkyl containing one or more fluoro substituents, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, halogeno, cyano, nitro, carbamoyl, (1-4C)alkanoyl, N-alkylcarbamoyl and
  • a 1 is (1-6C)alkylene, a carbonyl group or a direct bond and B is
  • a 5 or 6-membered saturated or unsaturated heterocyclic ring optionally bearing a (1-4C)alkyl group and containing a single heteroatom selected from oxygen, sulphur and nitrogen or containing two heteroatoms one of which is nitrogen and the other is oxygen, sulphur or nitrogen;
  • T 3 and T 4 together form an (3-6C)alkenylene group, an
  • T 2 is additionally selected from any of the previous values defined for T 4 ;
  • Y is oxygen or a group of the formula -NRb- wherein Rb is hydrogen
  • -CO-CH CH-, -CO-CH 2 -CH 2 -, -CH 2 -CH 2 -CO, -CH 2 ⁇ C0 and -CO-CH 2 -;
  • E 1 is hydrogen, (1-8C)alkyl or trifluoromethyl
  • E 2 is hydrogen, (1-8C)alkyl, halogeno, (1-4C)alkoxy, trifluoromethyl, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro,
  • E 3 is hydrogen,, (1-8C)alkyl, (1-4C)alkoxy, halogeno or
  • E 4 and E 5 are optional substituents on linking group A independently selected from (1-4C)alkyl, substituted (1-4C)alkyl containing one or more fluoro substituents, phenyl, pyridyl, alkoxy, halogeno, cyano, nitro, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, carbamoyl, N-alkylcarbamoyl and di- (N-alkyl)carbamoyl of up to 7 carbon atoms, (1-4C)alkylthio, (1-4C)alkylsulphinyl,
  • L 1 is (1-8C)alkyl
  • L 2 and L 3 are independently selected from hydrogen and (1-4C)alkyl;
  • F 4 is hydrogen or (1-4C)alkyl;
  • linking group A 2 which is selected from
  • linking group A optionally bears one or two substituents independently selected from any of the values defined for E 4 or E 5 ;
  • Rm and Rn are independently selected from hydrogen, (1-4C)alkyl,
  • any of said phenyl moieties of R 1 , R 2 , T 1 , T 2 , T 3 , E 2 , E 4 , E 5 , F 1 or F 2 may be unsubstituted or bear one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof; or a non-toxic metabolically labile ester thereof.
  • alkyl methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl and hexyl;
  • cycloalkyl cyclopropyl, cyclopentyl and cyclohexyl
  • fluoromethyl trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl
  • cycloalkyl-alkyl cyclopropylmethyl, cyclopentylmethyl
  • phenylalkyl benzyl, 1-phenylethyl and 2-phenylethyl;
  • alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl and
  • alkenyloxycarbonyl allyloxycarbonyl
  • a particular value for T 3 , T 4 , F 3 or for T 2 when it is selected from a value for T 4 includes, by way of example,
  • alkyl methyl, ethyl and propyl; for alkoxycarbonyl:
  • alkenyloxycarbonyl allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl; for halogeno: fluoro, chloro, bromo and iodo; for alkoxy: methoxy, ethoxy and propoxy; for alkyl
  • a particular value for A when it is alkylene is, for example, methylene, ethylene or propylene.
  • alkyl methyl and ethyl
  • alkoxy methoxy and ethoxy
  • halogeno chloro, bromo and iodo
  • alkanoylamino formamido, acetamido and propanamido
  • alkanoyl formyl, acetyl and butyryl
  • fluoroalkoxy trifluoromethoxy, 2-fluoroethoxy
  • N-ethylsulphamoyl for di(N-alkylsulphamoyl: N,N-dimethylsulphamoyl and N,N-diethylsulphamoyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkanesulphonamido:
  • methanesulphonamido and ethanesulphonamido for alkylthio: methylthio and ethylthio; for alkylsulphinyl; methylsulphinyl and ethylsulphinyl; and for alkylsulphonyl: methylsulphonyl and ethylsulphonyl.
  • a particular value for B when it is a 5 or 6-membered saturated or unsaturated heterocyclic ring containing a single hetero atom selected from oxygen, sulphur or nitrogen includes, for example, a thienyl, furyl, pyrrolyl, pyrrolidinyl, pyridyl and piperidyl ring.
  • a particular value for B when it is a 5 or 6-membered saturated or unsaturated heterocyclic ring containing two heteroatoms one of which is nitrogen and the other is oxygen, sulphur or nitrogen includes, for example, an imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, oxazolyl, oxazolidinyl,
  • pyrimidinyl pyrazinyl, pyridazinyl, piperazinyl, morpholinyl and thiomorpholinyl ring.
  • a particular value for an alkyl group which may be present on B when it is a saturated or unsaturated heterocyclic ring is, for example, methyl or ethyl.
  • T 3 and T 4 when together they form (3-6C)alkylene is, for example, trimethylene, tetramethylene or pentamethylene; when together they form (3-6C)alkylene
  • (3-6C)alkenylene is, for example, 1-propenylene, 2-propenylene,
  • Rb when it is alkyl is, for example, methyl or ethyl; and when it is alkanoyl is, for example, formyl, acetyl or propanoyl.
  • a particular value for E 1 , E 2 , E 3 or L 1 when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl.
  • a particular value for E 2 or E 3 when it is halogeno is, for example, fluoro, chloro, bromo or iodo; and when it is alkoxy is, for example, methoxy, ethoxy or propoxy.
  • a particular value for E 1 when it is alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; when it is alkenyloxycarbonyl is, for example, allyloxycarbonyl,
  • E 4 or E 5 or for an optional substituent on linking group A 2 include, by way of example, for alkyl: methyl and ethyl; for alkyl containing one or more fluoro
  • N,N-diethylcarbamoyl for alkylthio: methylthio and ethylthio; for alkylsulphinyl: methylsulphinyl and ethylsulphinyl; and for
  • alkylsulphonyl methylsulphonyl and ethylsulphonyl.
  • a particular value for L 2 , L 3 or F 4 when it is alkyl is, for example, methyl or ethyl.
  • Rm, Rn or for an optional substituent which may be present on a phenyl moiety of R 1 , R 2 , T 1 , T 2 , T 3 , E 2 , E 4 , E 5 , F 1 or F 2 include, by way of example, for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; and for halogeno: chloro, bromo and iodo.
  • a metabolically labile ester of a compound of the formula I is, for example, a (1-6C)alkyl (such as methyl or ethyl), phenyl or benzyl ester.
  • a value for R 1 , T 1 , T 3 , F 1 or F 2 of particular interest is, for example, methyl, ethyl or propyl
  • a value for R 2 of particular interest is, for example, hydrogen.
  • T 2 of particular interest is, for example, hydrogen or alkoxycarbonyl or, when T 3 and T 4 form alkylene is, for example, halogeno
  • a value for T 4 of particular interest is, for example, alkoxycarbonyl or halogeno.
  • a value of particular interest for T 3 and T 4 , or F 2 and F 3 , when together they form alkylene is, for example, trimethylene or tetramethylene.
  • a value for Y of particular interest is, for example, oxygen or a group of the formula -NRb- in which Rb is hydrogen.
  • a value of particular interest for E 1 is, for example, methyl, ethyl or propyl; for E 2 is, for example, hydrogen; for E 3 is, for example, methyl, ethyl or halogeno; for E 4 or E 5 is, for example, hydrogen, alkyl, halogeno, phenyl, pyridvl, alkoxycarbonyl, carbamoyl, N-N-dialkylcarbamoyl, cyano, hydroxy, phenylthio or phenylsulphinyl.
  • a value of particular interest for F 3 is, for example, hydrogen or halogeno.
  • a value of particular interest for L 1 is, for example,
  • (1-4C)alkyl such as ethyl, propyl or butyl
  • L 2 and L 3 is, for example, methyl
  • Rm or Rn is, for example, hydrogen.
  • a combination of values of special interest is, for example, when R 1 and R 3 are both alkyl, when T 1 and T 3 are both alkyl; when T 1 is alkyl and T 3 together with T 4 form alkylene; or when E 4 and E 5 are both hydrogen.
  • Particular groups of compounds of the invention comprise those compounds of the formula I in which Q constitutes:-
  • Sub-groups of compounds of the invention of special interest from within the groups of compounds of particular interest (1) to (4) above comprise those compounds of the formula I in which Q
  • linking group A together with the nitrogen atom and pyridine ring to which it is attached constitutes a 1,6-naphthyridin-2(1H)-one ring or a 1,2,3,4-tetrahydronaphthyridin-2-one ring;
  • group (e) is of particular interest.
  • the formula I compounds can form salts with suitable acids or bases.
  • suitable non-toxic salts for such compounds 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
  • 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, die
  • 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) A carboxylic acid derivative of the formula III, in which G is a protected carboxy group selected from (1-6C)alkoxycarbonyl
  • 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 base such as an alkali metal hydroxide, for example, lithium, sodium or potassium hydroxide.
  • the hydrolysis is generally carried out in the presence of a suitable aqueous solvent or diluent, for example in an aqueous
  • (1-4C)alkanol such as methanol or ethanol
  • aqueous dioxan such as tetrahydrofuran, or 1,2-dimethoxyethane.
  • the hydrolysis is generally performed at a temperature in the range, for example, 0 - 120oC, depending on the reactivity of the group G .
  • the conversion may also be carried out, for example, with trimethylsilyl bromide or iodide in a suitable solvent, such as dichloromethane, and at a temperature in the range, for example, 0 to 60°C.
  • a suitable solvent such as dichloromethane
  • 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.
  • the compounds of formula III may be obtained, for example, by coupling a carboxylic acid of formula V (or a reactive derivative of said acid) with an amine of formula IV.
  • Suitable reactive derivatives of the carboxylic acid of formula V include, for example, the chloride, bromide, anhydride or mixed anhydride with formic or acetic acid.
  • the reaction may be carried out in the presence of a suitable dehydrating agent such as dicyclohexylcarbodiimide or 3-(3-dimethylaminopropyl)-1- ethylcarbodiimide in the presence of a base such as triethylamine, pyridine or 4-dimethylaminopyridine.
  • reaction is generally carried out in the presence of a base such as mentioned above.
  • a suitable solvent or diluent such as dioxan, t-butyl methyl ether or tetrahydrofuran and at a temperature in the range, for example, 0-60°C.
  • the compounds of formula V may be obtained, for example, by standard procedures known in the art, such as ring opening of an anhydride of the formula VI with an appropriate alcohol or phenol. It will be appreciated that such a ring-opening reaction may give rise to a mixture of positional isomers dependent on the alcohol or phenol used, from which the formula V compound may be separated using conventional techniques.
  • the amines of formula IV may be obtained by conventional procedures, such as by alkylation of a compound of formula Q.H (or a tautomer thereof) with a 4-nitrobenzyl halide, followed by reduction of the nitro group of the product to amino, for example using catalytic hydrogenation.
  • Anhydrides of formula VI are already known and the remainder can be made by analogy therewith using standard procedures of organic chemistry well known in the art.
  • compounds of formula III are metabolically labile esters of the compounds of formula I and that procedure (a) may be carried out with a compound of the formula III in which one or more functional groups of Q are protected with suitable protecting groups.
  • the protecting groups may be removed either during the carrying out of procedure (a) dependent on the conditions employed, or subsequent thereto using conventional techniques.
  • a compound of the formula IV is reacted with an anhydride of formula VI.
  • the reaction is generally carried out in a suitable solvent or diluent, for example, an ether such as tetrahydrofuran, dioxan, t-butyl methyl ether or 1,2-dimethoxyethane and at a temperature in the range, for example, 10 - 100°C, and conveniently at or about ambient temperature.
  • a suitable solvent or diluent for example, an ether such as tetrahydrofuran, dioxan, t-butyl methyl ether or 1,2-dimethoxyethane and at a temperature in the range, for example, 10 - 100°C, and conveniently at or about ambient temperature.
  • 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 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
  • 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 AII.
  • 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 AII and, in particular, the antagonism of the interaction of AII 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 AII 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 AII.
  • Interaction of the radiolabelled AII 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 readily by comparing the receptor-bound radioactivity in the presence of the test compound at the specified test concentration with a control value determined in the absence of the test compound. Using this procedure compounds showing at least 50% displacement of radiolabelled AII binding at a concentration of 10 -4 M are retested at lower concentrations to determine their potency. For determination of the IC 50 (concentration for 50% displacement of radiolabelled AII binding), 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.
  • the compounds of formula I as defined above show significant inhibition in Test A at a concentration of about 50 micromolar or much less.
  • the compound of Example 1 shows an IC 50 of 3.58 ⁇ 10 -7 M.
  • Test B This in vitro test involves the measurement of the
  • the compounds of formula I as defined above show significant inhibition in Test B at a final concentration of about 50 micromolar or much less.
  • 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 AII 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 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
  • composition as is well known in the pharmaceutical art. According to a further feature of the invention there is provided a pharmaceutical composition comprising a compound of formula I, or a salt thereof, as defined above, together with a
  • 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 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 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) A solution of tin tetrachloride (24 ml) in toluene (70 ml) was added to a stirred solution of 3-amino-2-pentenenitrile (10 g) (obtained as described in J. Het. Chem., 1989, 26 , 1575) and methyl propionylacetate (13.4 g) in toluene (150 ml). The mixture was heated at reflux for 6 hours and then stirred at ambient temperature for 16 hours. Saturated sodium carbonate solution was added to the stirred mixture until the aqueous phase was basic (pH > 9).
  • Ether 200 ml was added to the mixture and the precipitated tin salts removed by filtration through diatomaceous earth. The organic phase of the filtrate was separated, washed with sodium chloride solution and dried (MgSO 4 ). Solvent was remvoed by evaporation and the residue was extracted with hot hexane (3 ⁇ 50 ml). The combined hexane extracts were evaporated and the residue was dissolved in minimum of hot hexane. The solution was then cooled at 4°C for 16 hours when a yellow solid crystallised. The solid (7.3 g) was collected by filtration and purified by flash chromatography eluting with
  • Methyl 4-amino-2,6-diethylpyridine-3-carboxylate (B) (3.94 g) was added to a mixture of 2M sodium hydroxide solution (9.5 ml) and methanol (40 ml) and the mixture was heated at reflux for 16 hours. The solution was cooled to ambient temperature and volatile material was removed by evaporation. The residue was partitioned between ethyl acetate and a mixture of 2M hydrochloric acid (9.5 ml) and water (20 ml). The aqueous phase was separated, water was removed by
  • 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.
  • Rx and Ry are optional substituents
  • Ph phenyl
  • R' lower alkyl
  • Reagents a) NaOH, methanol, water, reflux
  • Reagents a) SnCl 4 , toluene, reflux
  • Reagents a) hydrogen, Pd on C or PtO 2
  • Reagents a) 1-(tert-butyl.CO)imidazole, toluene, heat
  • Reagents (a) polyphosphoric acid, acetic acid
  • R' lower alkyl
  • Rx and Ry are optional substituents
  • Reagents a) sodium ethoxide, ethanol, ambient temperature

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Abstract

L'invention concerne des composés pharmaceutiquement utiles de la formule (I) dans laquelle Q, Rm et Rn possédent les diverses significations définies, et leurs sels non toxiques et esters métaboliquement labiles, ainsi que les compositions pharmaceutiques les contenant. Les nouveaux composés sont valables dans le traitement de certains états tels que l'hypertension et l'insuffisance cardiaque congestive. L'invention se rapporte également à des procédés de fabrication de ces nouveaux composés et à leur utilisation dans un traitement médical. Q est sélectionné dans la formule (I) parmi le groupe de la formule structurelle partielle (IIA, IIb, IIc, IId, ou IIe).
PCT/GB1993/001057 1992-05-28 1993-05-21 Composes heterocycliques contenant de l'azote utiles comme antagonistes de l'angiotensine ii WO1993024487A1 (fr)

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GB9211270.5 1992-05-28
GB929211270A GB9211270D0 (en) 1992-05-28 1992-05-28 Nitrogen compounds

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WO1993024487A1 true WO1993024487A1 (fr) 1993-12-09

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PCT/GB1993/001057 WO1993024487A1 (fr) 1992-05-28 1993-05-21 Composes heterocycliques contenant de l'azote utiles comme antagonistes de l'angiotensine ii

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AU (1) AU4083493A (fr)
GB (1) GB9211270D0 (fr)
WO (1) WO1993024487A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991007404A1 (fr) * 1989-11-20 1991-05-30 Imperial Chemical Industries Plc Derives de diazine
EP0516392A2 (fr) * 1991-05-31 1992-12-02 Zeneca Limited Dérivés de la naphthyridine comme inhibiteurs de l'angiotensine II

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991007404A1 (fr) * 1989-11-20 1991-05-30 Imperial Chemical Industries Plc Derives de diazine
EP0516392A2 (fr) * 1991-05-31 1992-12-02 Zeneca Limited Dérivés de la naphthyridine comme inhibiteurs de l'angiotensine II

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GB9211270D0 (en) 1992-07-15
AU4083493A (en) 1993-12-30

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