WO1993024501A1 - Phosphorus containing heterocyclic compounds as angiotensins antagonists - Google Patents

Phosphorus containing heterocyclic compounds as angiotensins antagonists Download PDF

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Publication number
WO1993024501A1
WO1993024501A1 PCT/GB1993/001068 GB9301068W WO9324501A1 WO 1993024501 A1 WO1993024501 A1 WO 1993024501A1 GB 9301068 W GB9301068 W GB 9301068W WO 9324501 A1 WO9324501 A1 WO 9324501A1
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alkyl
methyl
group
formula
ethyl
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PCT/GB1993/001068
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French (fr)
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Keith Hopkinson Gibson
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Zeneca Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3229—Esters of aromatic acids (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3241—Esters of arylalkanephosphinic acids

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 cingiotensin 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.
  • ACE angiotensin converting enzyme
  • 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 IIa, IIb, IIe, 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 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 di-(N-alkyl)carbamoyl of up to 7 carbon atoms, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and a group of the formula
  • a 1 is (1-6C)alkylene, a carbonyl group or a direct bond and B 1 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, (1-4C)alkyl, (1-4C)alkanoyl or benzoyl;
  • -CO-CH CH-, -CO-CH 2 -CH 2 -, -CH 2 -CH 2 -CO, -CH 2 -CO 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 ;
  • X is methylene or a direct bond
  • 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
  • alkyl containing one or more fluoro substituents 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 L 4 includes, by way of example,
  • alkyl methyl, ethyl and propyl; for alkoxycarbonyl:
  • methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl for 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 1 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 of the phosphinic acid group present
  • 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, pyridyl, alkoxycarbonyl, carbamoyl,
  • a value of particular interest for F 3 is , for example , hydrogen or halogeno.
  • L 1 is, for example, (1-4C)alkyl such as ethyl, propyl or butyl; and for L 2 and L 3 is, for example, methyl.
  • a preferred valued for X is, for example, a direct bond.
  • 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 phosphinic acid derivative of the formula III, in which G is a (1-6C)alkyl (such as methyl, ethyl, propyl or t-butyl), phenyl or benzyl group, is converted to a phosphinic acid.
  • G a (1-6C)alkyl (such as methyl, ethyl, propyl or t-butyl), phenyl or benzyl group
  • the conversion may be carried out, for example, by hydrolysis, conveniently in the presence of a suitable acid such as a mineral acid, for example, aqueous hydrochloric acid.
  • a suitable acid such as a mineral acid, for example, aqueous hydrochloric acid.
  • the hydrolysis may also be carried out under basic conditions, conveniently in the presence of 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) or in aqueous dioxan, tetrahydrofuran, or
  • the hydrolysis is generally performed at a temperature in the range, for example, 0 - 120°C.
  • the conversion may also be carried out, for example, with trimethylsilyl bromide or iodide in a suitable solvent, such as dichloromethane, and at a temperture in the range, for example, 0 to 60°C.
  • a suitable solvent such as dichloromethane
  • G 1 is a benzyl group
  • 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
  • G 1 is a t-butyl group
  • 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.
  • 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 reaction of a compound of formula VI with a compound of formula VII or VIII, by analogy with the procedures illustrated in Scheme 12.
  • 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 Q.H (or a tautomer thereof) is alkylated with a compound of the formula IV wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo,
  • the reaction is preferably carried out in the presence of a suitable base, for example, an alkali metal alkoxide such as sodium or potassium methoxide, ethoxide or tert-butoxide, 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
  • reaction is conveniently carried out in a suitable solvent or diluent, for example, a (1-4C)alkanol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxan, or a polar solvent such as
  • N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10 - 100°C.
  • a temperature in the range, for example, 10 - 100°C.
  • about two molecular equivalents of a suitable base is generally required.
  • procedure (b) it will be necessary to carry out procedure (b) with a starting material of formula IV and/or Q.H in which one or more functional groups present are protected with suitable protecting groups which can subsequently be removed. It will also be appreciated that procedure (b) is suitable for the production of the starting materials of formula III for the reaction described in (a) above if a compound of the formula V is used in place of a formula IV compound.
  • the compound of formula IV and V may be obtained, for example, as illustrated in Scheme 12, or by analogy thereof.
  • 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 (1-4C)alkanol, whereafter the optically active form of said compound of formula I may be liberated by treatment with acid using 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,
  • 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, cerebrobacsular 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.
  • 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 gave an IC 50 of 7 ⁇ 10 -8 M.
  • 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.
  • 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
  • a pharmaceutical co isition 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 system (ACE) inhibitor (for example lisinopril) or a diuretic (for example furosemide or hydrochlorothiazide).
  • ACE angiotensin converting system
  • 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 mixture of 4-iodotoluene (7.5 g), ethyl phenylphosphinate (3 g), tetrakis(triphenylphosphine)palladium (0) (1.95 g),
  • N-Bromosuccinimide (1.24 g) and ⁇ , ⁇ '-azobisisobutyronitrile (20 mg) was added to a solution of compound B (1.81 g) in carbon tetrachloride (110 ml). The mixture was heated at reflux and irradiated with a 275 Watt photoflood bulb for 1 hour.
  • Methyl 4-amino-2,6,diethylpyridine-3-carboxylate (B) (3.94 g) was added to a mixture of the 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 evaporation and the residue was extracted with ethyl acetate/methanol (1:1 v/v). The combined organic extracts were filtered and solvent was removed from the filtrate by evaporation to give
  • the starting material A was obtained as follows :- (i) A solution of dimethyl phenylphosphonite (0.85 g) in toluene (10 ml) was added dropwise to a stirred and refluxing solution of ⁇ , ⁇ '-dibromo-p-xylene (5.25 g) in toluene (100 ml) under an atmosphere of argon. When the addition was complete, the reaction mixture was heated at reflux for a further 16 hours. Volatile material was then removed by evaporation and the residue was purified by flash
  • 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.
  • Ph phenyl
  • R' lower alkyl
  • Reagents a) NaOH, methanol, water, reflux
  • Reagents : a) SnCl,, toluene, reflux
  • Et ethyl
  • Ph phenyl
  • R' lower alkyl
  • EtOH EtOH
  • piperidme reflux
  • Reagents a) hydrogen, Pd on C or PtO 2
  • Reagents a) 1-(tert-butyl.CO) imidazole, toluene, heat
  • R lower alkyl
  • Tos p-toluenesulphonyl (tosyl)
  • Reagents (a) polyphosphoric acid, acetic acid
  • R' lower alkyl
  • Rx and Ry are optional substituents
  • Reagents a) sodium ethoxide, ethanol, ambient temperature
  • R 1 alkyl, phenyl or benzyl

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Abstract

The invention concerns pharmaceutically useful compounds of formula (I) wherein Q is selected from a group of the partial structural formula (IIa, IIb, IIc, IId, or IIe) and their non-toxic salts and metabolically labile esters, and pharmaceutical compositions containing them. The novel compounds are of value in treating such conditions such as hypertension and congestive heart failure. The invention further concerns processes for the manufacture of the novel compounds and the use of the compounds in medical treatment.

Description

PHOSPHORUS CONTAINING HETEROCYCLIC COMPOUNDS
AS ANGIOTENSINS ANTAGONISTS
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
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 cingiotensin 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. In addition, 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
therapeutic control of blood pressure and/or fluid/electrolyte balance, including, for example, inhibiting the actions of renin or ACE. However, there remains a continuing need for an alternative approach because of the side-effects and/or idiosyncratic reactions associated with any particular therapeutic approach. In our published co-pending European Patent Applications, Publication Nos. 399731, 412848, 454831, 453210, 511791 and 516392 there are respectively disclosed certain imidazopyridine, quinoline, naphthyridine, pyridine, pyrrolopyridine and naphthyridone derivatives which have All antagonist activity. In European Patent Application, publication no. 475206 certain pyrimidine derivatives are also described as having All antagonist activity.
We have now discovered that the compounds of the invention (set out below) surprisingly antagonise one or more of the actions of the substances known as angiotensins (and in particular of All) and thus minimise the physiological effects associated with their presence in warm-blooded animals (including man) and this is the basis of the invention.
According to the invention there is provided a heterocyclic compound of the formula I (set out hereinafter, together with the other chemical formulae identified by Roman numerals) wherein
Q is selected from a group of the partial structural formula IIa, IIb, IIe, IId, or IIe in which
ring B of formula IIa completes a benzene or pyridine ring;
R1, T1 and F1 are independently selected from (1-8C)alkyl,
(3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, phenyl,
phenyl(1-4C)alkyl or substituted (1-4C)alkyl, the latter containing one or more fluoro substituents or bearing an (1-4C)alkoxy
substituent;
R2, T2 and F2 are independently selected from hydrogen, (1-8C)alkyl,
(3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy,
(1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl;
R3 and R4 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;
3
T is selected from halogeno, (1-4C)alkoxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms and any of the values defined for
T1.
T4 and F3 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 di-(N-alkyl)carbamoyl of up to 7 carbon atoms, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and a group of the formula
-A1.B1 wherein A1 is (1-6C)alkylene, a carbonyl group or a direct bond and B1 is
(1) an unsubstituted phenyl or phenyl bearing one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano, trifluoromethyl, nitro, hydroxy, carboxy,
(1-4C)alkanoylamino, (1-4C)alkanoyl, fluoro(1-4C)alkoxy,
hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, carbamoyl, N-alkyl or di-(N-alkyl)carbamoyl of up to 7 carbon atoms, sulphamoyl, N-alkyl or di-(N-alkyl)sulphamoyl of up to 6 carbon atoms, (1-4C)alkoxycarbonyl, (1-4C)alkanesulphonamido, (1-4C)alkyl.S(O)n- [in which n is zero, 1 or
2] and 1H-tetrazol-5-yl; or B1 is
(2) 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;
or T3 and T4 together form an (3-6C)alkenylene group, an
(3-6C)alkylene group or an (3-6C)alkylene group in which a methylene is replaced by carbonyl, provided that when T3 and T4 together form one of said latter three groups then T2 is additionally selected from any of the previous values defined for T4;
Y is oxygen or a group of the formula -NRb- wherein Rb is hydrogen, (1-4C)alkyl, (1-4C)alkanoyl or benzoyl;
linking group A of formula IIc is selected from -CH=CH-, -CH=CH-CO-,
-CO-CH=CH-, -CO-CH2-CH2-, -CH2-CH2-CO, -CH2-CO and -CO-CH2-;
E1 is hydrogen, (1-8C)alkyl or trifluoromethyl;
E2 is hydrogen, (1-8C)alkyl, halogeno, (1-4C)alkoxy, trifluoromethyl, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro,
(1-4C)alkanoyl, (1-4C)alkyl.S(O)m- [in which m is zero, 1 or 2] or phenylsulphonyl;
E3 is hydrogen, (1-8C)alkyl, (1-4C)alkoxy, halogeno or
trifluoromethyl; E4 and E5 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,
(1-4C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl and (1-4C)alkanoyl;
L1 is (1-8C)alkyl;
L2 and L3 are independently selected from hydrogen and (1-4C)alkyl; F4 is hydrogen or (1-4C)alkyl;
or F2 and F3 together complete a benzene ring, said benzene ring optionally bearing one or two substituents independently selected from any of the previous values defined for F3;
or F2 and F3 together form an (3-6C)alkenylene group, an
(3-6C)alkylene group or an (3-6C)alkylene group in which a methylene is replaced by carbonyl;
or F3 and F4 together form a linking group A2 which is selected from
-CH2-CH2-, -CH2-CH2-CH2-, -CO-CH2-, -CH2-CO-, -CO-CH2-CH2-,
-CH2-CH2-CO-, -CO-CH=CH- and -CH=CH-CO-, and wherein said linking group A optionally bears one or two substituents independently selected from any of the values defined for E4 or E5;
X is methylene or a direct bond;
Rm and Rn are independently selected from hydrogen, (1-4C)alkyl,
(1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro;
and wherein any of said phenyl moieties of R1, R2, T1, T2, T3, E2, E4, E5, F1 or F2 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.
It will be appreciated that the letter P used in formula I (and in any other chemical formulae referred to herein) is the chemical symbol for phosphorus.
It will appreciated that, depending on the nature of the substituents, certain of the formula I compounds may possess one or more chiral centres and may be isolated in one or more racemic or optically active forms. It is to be understood that this invention concerns any form of such a compound of formula I which possesses the afore-mentioned useful pharmacological properties, it being well known how to make optically active forms, for example by synthesis from suitable chiral intermediates, and how to determine their
pharmacological properties, for example by use of the standard tests described hereinafter.
It is to be understood that generic terms such as "alkyl" include both straight and branched chain variants when the carbon numbers permit. However, when a particular radical such as "propyl" is given, it is specific to the straight chain variant, branched chain variants such as "isopropyl" being specifically named where intended. The same convention applies to other radicals. A particular value for R1, R2, T1, T2, F1 or F2 where appropriate, include, by way of example,
for alkyl: methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl and hexyl;
for cycloalkyl: cyclopropyl, cyclopentyl and cyclohexyl;
for alkyl containing one or more fluoro substituents : fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl;
for alkyl bearing an (1-4C)alkoxy substituent: 2-methoxyethyl and
2-ethoxyethyl;
for cycloalkyl-alkyl: cyclopropylmethyl, cyclopentylmethyl,
cyclohexylmethyl and 2-cyclopentyl-ethyl;
for phenylalkyl: benzyl, 1-phenylethyl and 2-phenylethyl;
for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and
propoxycarbonyl; and
for alkenyloxycarbonyl: allyloxycarbonyl,
2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl .
A particular value for T3, T4, F3 or for T2 when it is selected from a value for L4, where appropriate, includes, by way of example,
for alkyl: methyl, ethyl and propyl; for alkoxycarbonyl:
methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for 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
containing one or more fluoro substituents: fluoromethyl,
trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl; for alkanoyl: formyl, acetyl and butyryl; for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; for di(N-alkyl) carbamoyl: N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl; for alkylamino: methylamino, ethylamino and butylamino; and for dialkylamino: dimethylamino, diethylamino and dipropylamino.
A particular value for A1 when it is alkylene is, for example, methylene, ethylene or propylene.
Particular values for R3, R4 or an optional substituent on B1 when it is phenyl bearing one or two substituents, where
appropriate, include, by way of example,
for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; for halogeno: chloro, bromo and iodo; for alkanoylamino : formamido, acetamido and propanamido; for alkanoyl: formyl, acetyl and butyryl; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy,
2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy; for hydroxyalkyl: hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; for alkoxyalkyl:
2-methoxyethyl and 2-ethoxyethyl; for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl; for N-alkylsulphamoyl: N-methyl and
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.
A particular value for T3 and T4, or for F2 and F3, when together they form (3-6C)alkylene is, for example, trimethylene, tetramethylene or pentamethylene; when together they form
(3-6C)alkenylene is, for example, 1-propenylene, 2-propenylene,
1-butenylene, 2-butenylene or 3-butenylene; and when together they form (3-6C)alkylene wherein one of the methylene groups is replaced by a carbonyl group is, for example, 1-oxopropylidene, 3-oxopropylidene,
1-oxobutylidene or 4-oxobutylidene.
A particular value for 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 E1, E2, E3 or L1 when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl.
A particular value for E2 or E3 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 E1 when it is alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; when it is alkenyloxycarbonyl is, for example, allyloxycarbonyl,
2-methyl-2-propenyloxycarbonyl or 3-methyl-3-butenyloxycarbonyl; when it is alkanoyl is, for example, formyl, acetyl or butyryl; when it is alkylthio is, for example, methylthio or ethylthio; when it is alkylsulphinyl is, for example, methylsulphinyl or ethylsulphinyl; and when it is alkylsulphonyl is, for example, methylsulphonyl or ethylsulphonyl.
Particular values for E4 or E5 or for an optional substituent on linking group A2 include, by way of example, for alkyl: methyl and ethyl; for alkyl containing one or more fluoro
substituents: fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl; for alkoxy: methoxy and ethoxy; for halogeno:
chloro, bromo and iodo; for alkoxycarbonyl: methoxycarbonyl,
ethoxycarbonyl and propoxycarbonyl; for alkenyloxycarbonyl:
allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl and
3-methyl-3-butenyloxycarbonyl; and for alkanoyl: formyl, acetyl or butyryl; for N-alkylcarbamoyl: N-methylcarbamoyl and N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and
N,N-diethylcarbamoyl; for alkylthio: methylthio and ethylthio; for alkylsulphinyl: methylsulphinyl and ethylsulphinyl; and for
alkylsulphonyl: methylsulphonyl and ethylsulphonyl.
A particular value for L2, L3 or F4 when it is alkyl is, for example, methyl or ethyl.
A particular value for Rm, Rn or for an optional substituent which may be present on a phenyl moiety of R1, R2, T1, T2, T3, E2, E4, E5, F1 or F2 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 of the phosphinic acid group present
A value for R1, T1, T3, F1 or F2 of particular interest is, for example, methyl, ethyl or propyl
A value for R2 of particular interest is, for example, hydrogen
A value for T2 of particular interest is, for example, hydrogen or alkoxycarbonyl or, when T3 and T4 form alkylene is, for example, halogeno
A value for T4 of particular interest is, for example, alkoxycarbonyl or halogeno.
A value of particular interest for T3 and T4, or F2 and F3, 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 for linking group A of formula IIe of particular interest is, for example, an optionally substituted group of the formula -CH=CH-, -CH=CH-CO- or -CH2-CH2-CO-. A value of particular interest for E1 is, for example, methyl, ethyl or propyl; for E2 is, for example, hydrogen; for E3 is, for example, methyl, ethyl or halogeno; for E4 or E5 is, for example, hydrogen, alkyl, halogeno, phenyl, pyridyl, alkoxycarbonyl, carbamoyl,
N-N-dialkylcarbamoyl, cyano, hydroxy, phenylthio or phenylsulphinyl.
A value of particular interest for F3 is , for example , hydrogen or halogeno.
A value of particular interest for F3 and F4 when together they form linking group A2 is, for example, -CH=CH-CO-, -CH2-CH2-CH2- or -CH2-CH2-CO-.
A value of particular interest for L1 is, for example, (1-4C)alkyl such as ethyl, propyl or butyl; and for L2 and L3 is, for example, methyl.
A preferred valued for X is, for example, a direct bond.
A preferred value for Rm or Rn is, for example, hydrogen.
A combination of values of special interest is, for example, when R1 and R3 are both alkyl, when T1 and T3 are both alkyl; when T1 is alkyl and T3 together with T4 form alkylene; or when E4 and E5 are both hydrogen.
Particular groups of compounds of the invention comprise those compounds of the formula I in which Q constitutes:-
(1) a group of the partial structural formula IIa in which ring B, R1, R2, R3 and R4 have any of the values defined hereinbefore;
(2) a group of the partial structural formula IIb in which T1, T2, T3, T4 and Y have any of the values defined hereinbefore;
(3) a group of the partial structural formula IIc in which E1, E2, E3, E4, E5 and linking group A have any of the values defined hereinbefore;
(4) a group of the partial structural formula IId in which L1, L2 and L3 have any of the values defined hereinbefore; and
(5) a group of the partial structural formula IIe in which F1, F2, F3 and F4 have any of the values defined hereinbefore;
and wherein in each of said groups the variables X, Rm or Rn have any of the values defined hereinbefore; together with the non-toxic salts thereof.
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
constitutes:-
(a) a group of the partial structural formula IIa wherein ring B together with the pyridine ring to which it is attached constitutes a quinoline ring;
(b) a group of the partial structural formula IIa wherein ring B together with the pyridine ring to which it is attached constitutes a pyrido-pyridine ring (that is a naphthyridine);
(c) a group of the partial structural formula IIb wherein Y is an oxygen atom;
(d) a group of the partial structural formula IIb wherein Y is a group of the formula -NH-;
(e) a group of the partial structural formula IIe wherein 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; and
(f) a group of the partial structural formula IIe wherein linking group A together with the nitrogen atom and pyridine ring to which it is attached constitutes a 1H-pyrrolo[3,2-c]pyridine ring; and wherein in each of said groups R1, R2, R3, R4, T1, T2, T3, T4, E1, E2, E3, E4 and E5, where present have any of the values defined above and the variables X, Rm or Rn have any of the values defined
hereinbefore; together with the non-toxic salts thereof and the non-toxic metabolically labile esters thereof.
Of groups (a) to (f), group (e) is of particular interest.
It will be appreciated that the formula I compounds can form salts with suitable acids or bases. Particularly 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
methanesulphonic acids.
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 phosphinic acid derivative of the formula III, in which G is a (1-6C)alkyl (such as methyl, ethyl, propyl or t-butyl), phenyl or benzyl group, is converted to a phosphinic acid.
The conversion may be carried out, for example, by hydrolysis, conveniently in the presence of a suitable acid such as a mineral acid, for example, aqueous hydrochloric acid. The hydrolysis may also be carried out under basic conditions, conveniently in the presence of 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) or in aqueous dioxan, tetrahydrofuran, or
1,2-dimethoxyethane. The hydrolysis is generally performed at a temperature in the range, for example, 0 - 120°C.
The conversion may also be carried out, for example, with trimethylsilyl bromide or iodide in a suitable solvent, such as dichloromethane, and at a temperture in the range, for example, 0 to 60°C.
Alternatively, when G1 is a benzyl group 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.
Further, when G1 is a t-butyl group, 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. 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 reaction of a compound of formula VI with a compound of formula VII or VIII, by analogy with the procedures illustrated in Scheme 12.
It will be appreciated that 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. b) A compound of the formula Q.H (or a tautomer thereof) is alkylated with a compound of the formula IV wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo,
methanesulphonyloxy or p-toluenesulphonyloxy.
The reaction is preferably carried out in the presence of a suitable base, for example, an alkali metal alkoxide such as sodium or potassium methoxide, ethoxide or tert-butoxide, 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 or 4-dimethylaminopyridine. The reaction is conveniently carried out in a suitable solvent or diluent, for example, a (1-4C)alkanol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxan, or a polar solvent such as
N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10 - 100°C. In carrying out process (b), about two molecular equivalents of a suitable base is generally required.
It will be appreciated that it may be necessary to carry out procedure (b) with a starting material of formula IV and/or Q.H in which one or more functional groups present are protected with suitable protecting groups which can subsequently be removed. It will also be appreciated that procedure (b) is suitable for the production of the starting materials of formula III for the reaction described in (a) above if a compound of the formula V is used in place of a formula IV compound. The compound of formula IV and V may be obtained, for example, as illustrated in Scheme 12, or by analogy thereof.
Many of the compounds of formula Q.H (or the tautomers thereof) are already known and the remainder can be made by analogy therewith using standard procedures of organic chemistry well known in the art, for example as described in standard works of heterocyclic chemistry such as that edited by Elderfield. Certain 4-quinolones are described in EPA, Publication No. 412848 and certain 4-naphthyridones are described in International Patent Application No. PCT/GB90/01776. Certain 4-pyridones are described in Monatshefte fur Chemie, 1969, 100, 132; J. Chem. Soc. (B), 1968, 866; Liebigs Ann. Chem., 1882, 1656; Heterocycles, 1982, 13, 239; and J. Am. Chem. Soc, 1974, 96(4), 1152. Certain 4-aminopyridines may be obtained as described in Tet. Lett., 1990, 3485 from intermediates obtainable as described in J. Het. Chem., 1989, 26, 1575 or European Patent No. 129408. Certain imidazo[4,5-b]pyridines are described in EPA 399731 and EPA 400974. Other compounds of the formula Q.H may be obtained as illustrated in Schemes 1 to 11, or by analogy therewith.
Whereafter when a metabolically labile ester of a compound of formula I is required, it may be obtained by esterification with the appropriate alcohol or phenol using conventional procedures.
Whereafter, when a non-toxic salt of a compound of formula I is 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.
Further, when an optically active form of a compound of formula I is required, one of the aforesaid processes may be carried out using an optically active starting material. Alternatively, 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 (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.
Certain of the intermediates defined herein are novel, for example the compounds of the formula V and are provided as a further feature of the invention.
As stated above, 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, cerebrobacsular disorders, anxiety, depression and certain mental illnesses such as
schizophrenia.
The 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. In this test, 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 (assessed as radiolabel bound to the particulate membrane fraction following removal of unbound radiolabel by a rapid filtration procedure such as is standard in such studies) 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 All binding at a concentration of 10-4 M are retested at lower concentrations to determine their potency. For determination of the IC50 (concentration for 50% displacement of radiolabelled All binding), concentrations of the test compound are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate IC50, which latter is subsequently determined from a plot of percentage displacement against concentration of the test compound.
In general, the compounds of formula I as defined above show significant inhibition in Test A at a concentration of about 50 micromolar or much less. For example, the compound of Example 1 gave an IC50 of 7×10-8M.
Test B: This in vitro test involves the measurement of the
antagonistic effects of the test compound against All-induced contractions of isolated rabbit aorta, maintained in a physiological salt solution at 37°C. In order to ensure that the effect of the compound is specific to antagonism of All, the effect of the test compound on noradrenaline-induced contractions may also be determined in the same preparation.
In general, 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 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.
In general compounds of formula I will show All-antagonist properties in Test D as demonstrated by a significant reduction in blood pressure at a dose of about 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.
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
pharmaceutical composition, as is well known in the pharmaceutical art. According to a further feature of the invention there is provided a pharmaceutical co isition comprising a compound of formula I, or a salt 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 hereinabove, such as a beta-adrenergic blocker (for example atenolol), a calcium channel blocker (for example nifedipine), an angiotensin converting system (ACE) inhibitor (for example lisinopril) or a diuretic (for example furosemide or hydrochlorothiazide). It is to be understood that such combination therapy constitutes a further aspect of the invention.
In general 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
administration depending on size, age and sex of the person being treated and on the particular disease or medical condition being treated according to principles well known in the medical arts.
In addition to their aforesaid use in therapeutic medicine in humans, the compounds of formula I are also useful in the
veterinary treatment of similar conditions affecting commercially valuable warm-blooded animals, such as dogs, cats, horses and cattle. In general for such treatment, 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
development and standardisation of test systems for the evaluation of the effects of All in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the continuing search for new and improved therapeutic agents.
The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated:- (i) concentrations and evaporations were carried out by rotary evaporation in vacuo;
(ii) operations were carried out at room temperature, that is in the range 18-26°C;
(iii) flash column chromatography was performed on Merck Kieselgel
60 (Art. no. 9385) obtained from E Merck, Darmstadt, Germany;
(iv) yields, where given, are intended for the assistance of the reader only and are not necessarily the maximum attainable by diligent process development;
(v) 1H NMR spectra were normally determined at 200 MHz in CDCl3 or using tetramethylsilane (TMS) as an internal standard, and are expressed as chemical shifts (delta values) in parts per million relative to TMS using conventional abbreviations for designation of major peaks: s, singlet; m, multiplet; t, triplet; br, broad; d, doublet; and
(vi) all end-products had satisfactory microanalyses.
EXAMPLE 1
Ethyl (4-[5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1- ylmethyl]phenyl) (phenyl)phosphinate (A) (0.27 g) was added to a mixture of dioxan (13.5 ml), water (2.7 ml) and concentrated
hydrochloric acid (5 ml) and the mixture was heated at reflux for 7.5 hours. Volatile material was removed by evaporation and toluene was added to the residue. Volatile material was again removed by evaporation and the residue was dissolved in a minimum of ethanol. Ether was added to precipitate a solid. The solid was collected by filtration and purified by reprecipitation from ethanolic solution by the addition of ether to give (4-[5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-ylmethyl]phenyl)(phenyl)phosphinic acid hydrochloride as a white amorphous solid (0.1 g), m.p. 160-180°C; NMR (d6-DMSO): 1.16(t, 3H), 1.27(t, 3H), 2.82(q, 2H) , 3.2(q, 2H) , 5.55(s, 2H), 6.85(d, 1H), 7.2-7.8(complex m, 10H), 8.32(d, 1H); mass spectrum (positive fast atom bombardment (+ve FAB)): 433 (M + H)+;
microanalysis, found: C, 61.6; H, 5.9; N, 5.8%; C25H25N2O3P.HCl.H2O requires: C, 61.6; H, 5.7; N, 5.7%. The starting material A was obtained as follows :- (i) A mixture of 4-iodotoluene (7.5 g), ethyl phenylphosphinate (3 g), tetrakis(triphenylphosphine)palladium (0) (1.95 g),
triethylamine (15.6 ml) and toluene (6 ml) was heated at reflux for 4.5 hours under an atmosphere of argon. The mixture was then poured into water and extracted twice with ethyl acetate. The combined extracts were washed successively with water, dilute hydrochloric acid, saturated sodium chloride solution and then dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/petroleum ether (2:3 v/v increasing to 1:0 v/v), to give ethyl (p-tolyl) (phenyl)phosphinate (B) as a brown oil (1.81 g); NMR (CDCl3): 1.32(t, 3H), 2.33(s, 3H), 4.05(dq, 2H), 7.2(dd, 2H) , 7.3-7.5(complex m, 3H) , 7.6-7.85(complex m, 4H); mass spectrum (chemical ionisation (CI)): 261 (M+H)+.
(ii) N-Bromosuccinimide (1.24 g) and α,α'-azobisisobutyronitrile (20 mg) was added to a solution of compound B (1.81 g) in carbon tetrachloride (110 ml). The mixture was heated at reflux and irradiated with a 275 Watt photoflood bulb for 1 hour. Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate, to give ethyl (4-bromomethylphenyl) (phenyl)phosphinate (C), as a yellow oil (2.6 g); NMR (CDCl3): 1.36(t, 3H), 2.71(s, 3H), 4.11(dq, 2H) , 4.45(s, 2H), 7.2-7.9(complex m, 9H) ; mass spectrum (CI): 239 (M+H)+.
(iii) Sodium hydride (50% dispersion in oil; 0.42 g) was added to a solution of 5,7-diethyl-1,6-naphthyridin-2(1H)-one (1.43 g) in DMF (15 ml) and the mixture was stirred until effervescence ceased. A solution of compound C (2.6 g) in DMF (10 ml) was then added and the mixture was stirred for 16 hours under an atmosphere of argon.
Potassium carbonate (2 g) and potassium iodide (0.3 g) were added and the mixture was heated at 50°C for 2.5 hours. The reaction mixture was then poured into water and extracted twice with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried (MgSO4) and solvent was removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/methanol (1:0 v/v, increasing to 19:1 v/v) to give ethyl (4-[5,7-diethyl-2-oxo-l,2-dihydro-1,6-naphthyridin-1-ylmethyl]phenyl) (phenyl)phosphinate (A) as a yellow oil (0.5 g); NMR (CDCl3): 1.18(t, 3H) , 1.34(dt, 6H), 2.75(q, 2H), 3.1(q, 2H) , 4.1(dq, 2H), 5.5(s, 2H) , 6.75(d + s, 2H), 7.2-7.85 (complex m, 9H), 8.0(d, 1H); mass spectrum (CI): 461 (M+H)+
5,7-Diethyl-1,6-naphthyridin-2(1H)-one, used in step (iii) above, was obtained using Procedure 1 or 2 as follows:
Procedure 1:
(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 (MgSO4). 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
dichloromethane/methanol (1:19 v/v) to give methyl
4-amino-2,6-diethylpyridine-3-carboxylate (B) (6 g) as a light yellow solid, m.p. 75°C; NMR (CDCl3): 1.25(t,6H), 2.65(q,2H), 2.95(q,2H), 3.9(s,3H), 5.65(broad s,2H), 6.25(s,1H); mass spectrum (chemical ionisation (CI), ammonia): 239(M+H)+.
(ii) Methyl 4-amino-2,6,diethylpyridine-3-carboxylate (B) (3.94 g) was added to a mixture of the 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 evaporation and the residue was extracted with ethyl acetate/methanol (1:1 v/v). The combined organic extracts were filtered and solvent was removed from the filtrate by evaporation to give
4-amino-2,6-diethylpyridine-3-carboxylic acid (C) (3.46 g) as a yellow-brown foam; NMR (d6-DMSO): 1.18(m,6H), 2.64(q,2H), 3.12(q,2H), 6.49(s,lH), 8.28(broad s,2H); mass spectrum (chemical ionisation, ammonia): 195(M+H)+.
(iii) 4-Amino-2,6-diethylpyridine-3-carboxylic acid (C) (3.26 g) was heated at 220°C for 50 minutes. The residue was cooled to ambient temperature and purified by flash chromatography eluting with concentrated aqueous ammonia solution/dichloromethane/methanol
(1:85:15 v/v) to give 4-amino-2,6-diethylpyridine (D) (1.94 g) as a solid, m.p. 133-137°C; NMR (CDCl3/d6-DMSO): 1.24(t,6H), 2.68(q,4H), 4.48(broad s,2H), 6.27(s,2H); mass spectrum (chemical ionisation, ammonia): 151(M+H)+.
(iv) 4-Amino-2,6-diethylpyridine (D) (1.8 g) was added to a solution of iodine (3.1 g) and [bis(trifluoroacetoxy)iodo] benzene (5.7 g) in a mixture of dichloromethane (70 ml) and methanol (20 ml) and the mixture was stirred for 16 hours. Solvent was removed by evaporation and the residue was partitioned between ethyl acetate and a mixture of saturated sodium metabisulphite solution (50 ml) and saturated sodium carbonate solution (150 ml). The organic phase was separated, washed with saturated sodium chloride solution and dried (MgSO4). Solvent was removed by evaporation and the residue was purified by flash chromatography eluting with dichloromethane/methanol (97:3 v/v) to give 4-amino-2,6-diethyl-3-iodopyridine (E) (1.33 g) as a solid, m.p. 72-74°C; NMR (CDCl3): 1.25(m,6H), 2.65(q,2H),
2.96(q,2H), 4.59(broad s,2H), 6.30(s,1H); mass spectrum (chemical ionisation, ammonia): 277(M+H)+.
(v) Palladium (II) acetate (50 mg) and tri(2-methylphenyl)-phosphine (50 mg) were added to a solution of 4-amino-2,6-diethyl-3-iodopyridine (E) (1.3 g), ethyl acrylate (1.2 ml) and triethylamine (1.2 ml) in DMF (25 ml). The mixture was heated at 130°C for 2 hours and then allowed to cool. Volatile material was removed by
evaporation and the residue was purified by flash chromatography, eluting with aqueous ammonia (density 0.88g/ml)/dichloromethane/ methanol (1:200:20, v/v/v) to give ethyl-3-[(4-amino-2,6-diethyl) pyridin-3-yl] acrylate (G), as an oil; NMR (CDCl3): 1.15-1.45(m,9H), 2.7(q,2H), 2.8(q,2H), 4.25(q,2H), 4.5(broad s,2H), 6.25(d,2H),
7.75(d,2H); mass spectrum (chemical ionisation, ammonia): 249 (M+H)+. (vi) A solution of ethyl-3-[(4-amino-2,6-diethyl)pyridin-3-yl]acrylate (G) (600 mg) in dry methanol (10 ml) was added to a solution of sodium methoxide, prepared from sodium (500 mg) and dry methanol (30 ml), and the mixture was heated at reflux under an atmosphere of argon for 3 hours. Solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic solutions were washed with saturated sodium chloride solution and then dried (MgSO4). The solvent was removed by
evaporation and the residue was triturated with ether to give
5,7-diethyl-1,6-naphthyridin-2(lH)-one (H) (310 mg), as a solid, m.p. 170-171°C; NMR (CDCl3): 1.45(m,6H), 2.85(q,2H), 3.1(q,2H), 6.7(d,1H), 6.95(s,1H), 8.05(d,1H), 12.05(broad s,1H): mass spectrum (chemical ionisation, ammonia): 203(M+H)+.
Procedure 2:
(i) A mixture of methyl 3-aminopentenoate (7.3 g) and
5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (23.0 g) (obtained as described in J. Org. Chem., 1978, 43, 2087) was heated at 120°C for 2 hours. The mixture was cooled to ambient temperature and triturated with ether (50 ml). The product was collected by
filtration to give methyl 2,6-diethyl-4-oxo-1,4-dihydropyridine-3-carboxylate (5.2 g) as a solid, m.p. 124-127°C; NMR (d6-DMSO): 1.2(t, 6H), 2.3-2.6(m, 4H), 3.7(s, 3H), 5.9(s, 1H), 11.2(s, 1H); mass spectrum (CI, ammonia): 210 (M+H)+; microanalysis, found: C, 63.1; H, 7.5; N, 6.7%; C11H15NO3 requires: C, 63.1; H, 7.2; N, 6.7%.
(ii) Tosyl isocyanate (39.12 g) was added to a stirred suspension of methyl 2,6-diethyl-4-oxo-1,4-dihydropyridine-3-carboxylate (25.0 g) in acetonitrile (300 ml). After the initial exotherm had subsided the mixture was heated at reflux for 2 hours. The mixture was cooled to ambient temperature and the suspended solid was collected by
filtration to give methyl 2,6-diethyl-4-(4-tosylamino)pyridine-3-carboxylate (37.12 g) as a solid, m.p. 185-187°C; NMR (d4-methanol): 1.22(t, 6H), 2.38(s, 3H), 2.62(two q, 4H), 3.88(s, 3H), 7.1(s, 1H), 7.28(d, 2H), 7.75(d, 2H) ; mass spectrum: (CI, ammonia): 363 (M+H)+; microanalysis, found: C, 59.3; H, 6.1; N, 7.8%; C18H22N2SO4 requires C, 59.6; H, 6.12; N, 7.73%.
(iii) 2,6-Diethyl-4-(4-tosylamino)pyridine-3-carboxylate (36.4 g) was dissolved in concentrated sulphuric acid (50 ml) and the mixture was stirred at 50°C for 1 hour. The mixture was cooled to ambient temperature and poured onto ice. The mixture was then adjusted to pH 8 with solid sodium bicarbonate and the suspended solid was collected by filtration to give methyl 4-amino-2,6-diethylpyridine-3-carboxylate (18.23 g) as a white solid, m.p. 82.5-84.5°C; NMR (d6-DMSO): 1.13(two t, 6H), 2.51(q, 2H), 2.72(q, 2H) , 3.80(s, 3H), 6.37(s, 1H) , 6.45(s, 2H); mass spectrum (CI, ammonia): 209 (M+H)+ ; microanalysis, found: C, 62.8; H, 7.8; N, 13.5%; C11H16N2O2.0.1H2O requires: C, 62.9; H, 7.7; N, 13.3%.
(iv) A solution of methyl 4-amino-2,6-diethyl-pyridine-3-carboxylate (25 g) in THF (125 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (6.5 g) in anhydrous ether (500 ml) over 1 hour. The reaction mixture was then stirred and heated under reflux for 2 hours. The reaction mixture was cooled in . an ice-bath and water (6.5 ml) was added cautiously. 2M Aqueous sodium hydroxide solution (6.5 ml) was then added cautiously, followed by water (20 ml), and the resulting mixture was stirred for 1 hour. THF (150 ml) was added and the mixture was stirred for a further hour. Insoluble material was removed by filtration and washed with ethyl acetate (500 ml). The combined filtrates were dried (MgSO4) and volatile material was removed by evaporation to give 4-amino-2,6-diethyl-3-hydroxymethylpyridine as a solid (21.5 g), m.p. 135-137°C (after recrystallisation from ethyl acetate/petroleum ether); NMR (CDCl3 + d6-DMSO): 1.19(t, 3H), 1.21(t, 3H), 2.58(q, 2H), 2.75(q, 2H), 4.62(s, 2H), 5.12(s, 2H), 6.33(s, 1H) ; mass spectrum (CI): 181 (M+H)+; microanalysis, found: C, 66.6; H, 9.0; N, 15.5%; C10H16N2O requires: C, 66.6; H, 8.95; N, 15.5%.
(v) A mixture of 4-amino-2,6-diethyl-3-hydroxymethylpyridine (21.5 g) and activated manganese dioxide (21.0 g) in toluene (500 ml) was stirred and heated at reflux for 3 hours. The hot reaction mixture was filtered and the solid washed with ethyl acetate (500 ml). The combined filtrates were concentrated by evaporation to give 4-amino-2,6-diethylpyridine-3-carbaldehyde (B) as a yellow solid (20.3 g), m.p. 92-94°C (after recrystallisation from petroleum ether);
NMR (CDCl3): 1.25(t, 3H), 1.33(t, 3H) , 2.65(q, 2H), 3.03(q, 2H), 6.24(s, 1H), 10.35(s, 1H); mass spectrum (CI): 179 (M+H)+;
microanalysis, found: C, 67.0; H, 7.9; N, 15.7%; C 1 0H 1 4N2O requires: C, 67.4; H, 7.9; N, 15.7%.
(vi) A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (40 g) and (carbethoxymethylene)triphenylphosphorane (82.5 g) in toluene (1 1) was stirred and heated at reflux for 3 hours. The solution was cooled and the solvent was removed by evaporation. A solution of sodium (20 g) in methanol (800 ml) was added to the residue and the resulting solution was heated at reflux for 4 hours. Methanol was removed by evaporation and water (500 ml) was added. The mixture was acidified to pH 1-2 by addition of concentrated hydrochloric acid. The mixture was then extracted with ethyl acetate (2 × 500 ml) and ether (1 × 500) and the extracts were discarded. The aqueous phase was then basified by addition of solid potassium carbonate and the solid which crystallised was collected by filtration and washed with water. The solid was recrystallised from acetone to give
5,7-diethyl-l16-naphthyridin-2(1H)-one (34.6 g), m.p. 168-169°C;
NMR (d6-DMSO): 1.24(dt, 6H), 2.72(q, 2H) , 3.0(q, 2H), 6.46(d, 1H), 6.9(s, 1H), 8.07(d, 1H); mass spectrum (CI): 203 (M+H)+;
microanalysis, found: C, 70.9; H, 6.9; N, 13.8%; C 1 2H 1 4N2O requires: C, 71.3; H, 6.98; N, 13.9%.
EXAMPLE 2
Using an analogous procedure to that described in Example 1, but starting from methyl (4-[5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-ylmethyl]benzyl)(phenyl)phosphinate (A), there was thus obtained (4- [5,7-diethyl-2-oxo-1,2-dihydro-l,6-naphthyridin-1-ylmethyl]benzyl)(phenyl)phosphinate (A) as an amorphous solid, in 56% yield; NMR (dg-DMSO): 1.20(t, 3H) , 1.28(t, 3H), 2.87(q, 2H), 3.18(d, 2H), 3.20(broad q, 2H), 5.47(s, 2H), 6.86(d, 1H), 7.0-7.2(m, 4H), 7.3-7.7 (complex m, 6H), 8.30(d, 1H); mass spectrum (+ve FAB): 447 (M+H)+; microanalysis, found: C, 64.9; H, 5.8; N, 5.7%; C26H27N2O3P requires: C, 64.7; H, 5.8; N, 5.8%. The starting material A was obtained as follows :- (i) A solution of dimethyl phenylphosphonite (0.85 g) in toluene (10 ml) was added dropwise to a stirred and refluxing solution of α,α'-dibromo-p-xylene (5.25 g) in toluene (100 ml) under an atmosphere of argon. When the addition was complete, the reaction mixture was heated at reflux for a further 16 hours. Volatile material was then removed by evaporation and the residue was purified by flash
chromatography, eluting first with ethyl acetate/dichloromethane (1:1 v/v) and then with neat ethyl acetate, to give methyl
(4-bromomethylbenzyl) (phenyl)phosphinate (B) (0.9 g) after
recrystallisation from ethyl acetate/petroleum ether; m.p. 92-94°C; NMR (CDCl3): 3.28(d, 2H), 3.63(d, 3H), 4.44(s, 2H), 7.07(dd, 2H), 7.24(d, 3H), 7.35-7.65 (complex m, 4H); mass spectrum (CI): 339 (M+H)+; (ii) Sodium hydride (50% dispersion in oil; 0.105 g) was added to a stirred solution of 5,7-diethyl-1,6-naphthyridin-2(lH)-one (0.4 g) in DMF (7.5 ml) and the mixture was stirred until effervesence ceased. Compound B (0.7 g) was added and the mixture was stirred under argon for 4 hours. The mixture was then poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried (MgSO4) and solvent was removed by evaporation. The residue was purified by flash
chromatography, eluting first with ethyl acetate and then with ethyl acetate/THF (4:1 v/v), to give methyl (4-[5,7-diethyl-2-oxo-1,2-dihydro-l,6-naphthyridin-1-ylmethyl]benzyl)(phenyl)phosphinate (A) (0.4 g) as an oil; NMR (d6-DMSO): 1.13(t, 3H), 1.25(t, 3H), 2.68(q, 2H), 3.05(q, 2H), 3.47(d, 3H), 5.41(s, 2H), 6.69(d, 1H),
6.95-7.1(broad s, 5H), 7.35-7.65 (complex m, 5H), 8.21(d, 1H); mass spectrum (+ve FAB); 461 (M+H)+; microanalysis, found: C, 70.1; H, 6.8; N, 5.4%; C27H29N2O3P.0.25H2O requires: C, 69.8; H, 6.4; N, 6.0%.
EXAMPLE 3
(Note: all parts by weight)
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)
Active ingredient * 20
Lactose powder 578.5
Magnesium stearate 1.5 b) Tablet (for oral administration)
Active ingredient * 50
Microcrystalline cellulose 400
Starch (pregelatinised) 47.5
Magnesium stearate 2.5 c) Injectable Solution (for intravenous administration)
Active ingredient * 0.05 - 1.0
Propylene glycol 5.0
Polyethylene glycol (300) 3.0 - 5.0
Purified water to 100% d) Injectable Suspension (for intramuscular administration)
Active ingredient * 0.05 - 1,0
Methylcellulose 0.5
Tween 80 0.05
Benzyl alcohol 0.9
Benzalkonium chloride 0.1
Purified water to 100%
Note: 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. Thus, for example, they may be coated with a conventional enterically digestible coating.
HS36985
07MAY93
Figure imgf000029_0001
Scheme 1
Figure imgf000030_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Note: T1 = T3 = methyl or ethyl; Rx and Ry are optional substituents;
Ph = phenyl; R' = lower alkyl
Reagents: a) NaOH, methanol, water, reflux
b) Sublimation at 250°C
c) Iodine, NaOH, water
d) C6H5CH2Cl, NaH, DMF, 50°C
e) Product from (d) added to (Rx)(Ry)PhCH2ZnBr in THF (from activated zinc, (Rx) (Ry)PhCH2Br in THF), then (Ph3P)4Pd f) hydrogenation over palladium on carbon, methanol g) (Ph3P)4Pd, methanol, aq. NaHCO3, toluene, reflux h) ammonium formate, 10% palladium on carbon, methanol i) tert-ButylLi/pentane; trimethyl borate/THF/-78°C; aq. HCl Scheme 2
Figure imgf000031_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: R' = lower alkyl
Reagents: a) R,OCH=C(CO2R')2, 110°C
b) hydrogen, Pd on C or PtO2
c) Ph-Ph/Ph-O-Ph mixture, reflux
d) (i) NaOH; (ii) as for step (c) Scheme 3
Figure imgf000032_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: R' = lower alkyl; R" = lower alkyl
Reagents: : a) SnCl,, toluene, reflux
b) aqu. NaOH, methanol, reflux; then HCl
c) heat, 220°C
d) I2, [bis(trifluoroacetoxy)iodo]benzene, CH2Cl2, methanol e) Pα(II)acetate, tri(2-methylphenyl)phosphine, Et3N, DMF, 130°C, CH2=CHCO2R"
f) NaOCH,, methanol, reflux
h) hydrogen, palladium on carbon, acetic acid/ethanol, 20 atmospheres, 70°C Scheme 4
Figure imgf000033_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: Et = ethyl; Ph = phenyl; R' = lower alkyl
Reagents: a) diethyl malonate, NaOEt, EtOH, 150°C, autoclave
b) Ph3P=C(Rb)CO2Et, xylene or toluene , reflux
c) RbCH2CO2Et (e.g. Rb = CO2Et, Ph, Pyridyl, CN, SPh) , EtOH, piperidme, reflux
d) aqu.HCl, dioxan, reflux Scheme 5
Figure imgf000034_0002
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: R' = lower alkyl
Reagents: a) hydrogen, Pd on C or PtO2
b) heat
Scheme 6
Figure imgf000034_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Reagents: a) 1-(tert-butyl.CO) imidazole, toluene, heat
b) (i) tert-butyllithium (2 equivalents), -78°C, THF;
(ii) iodomethane
c) as (b)(i); then carbon dioxide
d) aqueous HCl, heat Scheme 7
Figure imgf000035_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: R' and R" = lower alkyl;
Reagents: (a) NaOMe, heat
(b) (i) NaOH (ii) HCl (iii) heat
(c) hydrazine hydrate, 2-ethoxyethanol, reflux; then
acetone, reflux
(d) Ph-Ph/Ph-O-Ph mixture, reflux
(e) POCl3, PCI5, heat
(f) POCl3 (freshly distilled), reflux
(g) (CH3)3OBF4, dichloromethane Scheme 8
Figure imgf000036_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: Ph = phenyl
Reagents: (a) POCl3/DHF
(b) Catalytic hydrogenation over palladium on carbon
(c) N-Chlorosuccinimide, dichloromethane
(d) (i) n-BuLi, THF/hexane, -78 to 0°C
(ii) PhSO2Cl, THF, -78 to ambient
(e) Nal, aqueous HI, methyl ethyl ketone, reflux
(f) Cul, KF, triethyl(trifluoromethyl)silane, DHF/NMP, 80ºC
(g) NaOH, aqu. methanol, reflux Scheme 9
Figure imgf000037_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: R" = lower alkyl; Tos = p-toluenesulphonyl (tosyl)
Reagents: (a) Heat, 120ºC
(b) p-Toluenesulphonyl isocyanate, acetonitrile, reflux
(c) Lithium aluminium hydride, THF, reflux
(d) Activated MnO2, toluene, reflux
(e) NaH, DMF, BrCH2CO2CH3, 0°C
(f) (i) NaN(SiMe3)2, THF, 0°C; (ii) Pyridine, SOCl2, 0°C
(g) NaN(SiMe3)2, THF
(h) NaH, DHF; BrCH2CN, 0°C Scheme 10
Figure imgf000038_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: Rw and Rx are optional substituents
Reagents: (a) polyphosphoric acid, acetic acid
(b) (i) boron trifluoride, acetic anhydride
(ii) NaH or (isopropyl)-NLi, ethyl acetate
(iii) benzene, PTSA, heat or cone. H2SO4, ambient temp.
(c) acetic acid, 0-50°C
(d) heat, 120°C
(e) ethanolic ammonia, 120°C, sealed tube
(f) heat
(g) ethanolic ammonia
Figure imgf000039_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: R' = lower alkyl; Rx and Ry are optional substituents
Reagents: a) sodium ethoxide, ethanol, ambient temperature
b) p-Toluenesulphonic acid, benzene, reflux with azeotropic removal of water; heat
c) POCl3, reflux
d) R4NH2, EtOH, ambient to 180°C
e) bis(trifluoroacetoxy)iodobenzene, I2, CH2Cl2/MeOH f) tetrakis(triphenylphosphine)palladium, triethylamine, dimethoxyethane
g) ethyl acrylate, Pd(II)acetate, Et3N, 120°C, DMF
h) sodium ethoxide, ethanol, reflux
i) hydrogenation, palladium on carbon Scheme 12
Figure imgf000040_0001
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Note: R1 = alkyl, phenyl or benzyl
Reagents: (a) toluene, reflux
(b) (Ph3P)4Pd, triethylamine, toluene, reflux
(c) N-bromosucciniraide, azo(bisisobutyronitrile), CCl4, reflux
(d) (isopropyl)2NLi, THF

Claims

What we claim is :
A heterocyclic compound of the formula I
Figure imgf000041_0002
wherein
Q is selected from a group of the partial structural formula IIa, IIb, IIc, IId, or IIe
Figure imgf000041_0001
ring B of formula IIa completes a benzene or pyridine ring;
R1, T1 and F1 are independently selected from (1-8C)alkyl,
(3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, phenyl,
phenyl(1-4C)alkyl or substituted (1-4C)alkyl, the latter containing one or more fluoro substituents or bearing an (1-4C)alkoxy
substituent;
R2, T2 and F2 are independently selected from hydrogen, (1-8C)alkyl,
(3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy,
(1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, phenyl or phenyl (1-4C)alkyl;
R3 and R4 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;
T3 is selected from halogeno, (1-4C)alkoxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms and any of the values defined for T1;
T4 and F3 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 di-(N-alkyl)carbamoyl of up to 7 carbon atoms, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and a group of the formula
-A1.B1 wherein A1 is (1-6C)alkylene, a carbonyl group or a direct bond and B is
(1) an unsubstituted phenyl or phenyl bearing one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano, trifluoromethyl, nitro, hydroxy, carboxy,
(1-4C)alkanoylamino, (1-4C)alkanoyl, fluoro(1-4C)alkoxy,
hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, carbamoyl, N-alkyl or di- (N-alkyl)carbamoyl of up to 7 carbon atoms, sulphamoyl, N-alkyl or di- (N-alkyl)sulphamoyl of up to 6 carbon atoms, (1-4C)alkoxycarbonyl, (1-4C)alkanesulphonamido, (1-4C)alkyl.S(O)n- [in which n is zero, 1 or
2] and 1H-tetrazol-5-yl; or B1 is
(2) 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;
or T3 and T4 together form an (3-6C)alkenylene group, an
(3-6C)alkylene group or an (3-6C)alkylene group in which a methylene is replaced by carbonyl, provided that when T3 and T4 together form one of said latter three groups then T2 is additionally selected from any of the previous values defined for T4;
Y is oxygen or a group of the formula -NRb- wherein Rb is hydrogen, (1-4C)alkyl, (1-4C)alkanoyl or benzoyl;
linking group A of formula He is selected from -CH=CH-, -CH=CH-CO-,
-CO-CH=CH-, -CO-CH2-CH2-, -CH2-CH2-CO, -CH2-CO and -CO-CH2-;
E1 is hydrogen, ( 1-8C)alkyl or trifluoromethyl;
E2 is hydrogen, ( 1-8C)alkyl, halogeno, ( 1-4C)alkoxy, trifluoromethyl , carboxy, J l-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl , cyano , nitro , (1-4C)alkanoyl, (1-4C)alkyl.S(O)m- [in which m is zero, 1 or 2] or phenylsulphonyl; R3 is hydrogen, (1-8C)alkyl, (1-4C)alkoxy, halogeno or
trifluoromethyl;
E4 and E5 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,
(1-4C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl and (1-4C)alkanoyl;
L1 is (1-8C)alkyl;
L2 and L3 are independently selected from hydrogen and (1-4C)alkyl; F4 is hydrogen or (1-4C)alkyl;
or F2 and F3 together complete a benzene ring, said benzene ring optionally bearing one or two substituents independently selected from any of the previous values defined for R3;
or F2 and F2 together form an (3-6C)alkenylene group, an
(3-6C)alkylene group or an (3-6C)alkylene group in which a methylene is replaced by carbonyl;
or F3 and F4 together form a linking group A2 which is selected from
-CH2-CH2-, -CH2-CH2-CH2-, -C0-CH2-, -CH2-CO-, -CO-CH2-CH2-,
-CH2-CH2-CO-, -CO-CH=CH- and -CH=CH-CO-, and wherein said linking group A optionally bears one or two substituents independently selected from any of the values defined for E4 or E5;
X is methylene or a direct bond;
Rm and Rn are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro;
and wherein any of said phenyl moieties of R1, R2, T1, T2, T3, E2, E4, E5, F1 or F2 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.
2. A compound as claimed in claim 1 wherein
R1, T1 and F1 are independently selected from methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentyl-ethyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,
2-methoxyethyl and 2-ethoxyethyl;
R2, T2 and F2 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentyl-ethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl,
2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl, cyano, nitro, phenyl, benzyl, 1-phenylethyl and 2-phenylethyl;
R3 and R4 are optional substituents on ring B independently selected from methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo,
trifluoromethyl, cyano, nitro, trifluoromethoxy, 2-fluoroethoxy,
2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, hydroxy, hydroxymethyl,
1-hydroxyethyl and 2-hydroxyethyl;
T3 is selected from methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,
2-cyclopentyl-ethyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,
2-methoxyethyl, 2-ethoxyethyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, amino, methylamino, ethylamino, butylamino,
dimethylamino, diethylamino and dipropylamino;
T4 and F3 are independently selected from hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl,
2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl, fluoro, chloro, bromo, iodo, cyano, nitro, carbamoyl, formyl, acetyl, butyryl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, amino, methylamino, ethylamino, butylamino, dimethylamino, diethylamino, dipropylamino, and a group of the formula -A1.B1 wherein A1 is methylene, ethylene, propylene, a carbonyl group or a direct bond and B1 is
(1) an unsubstituted phenyl or phenyl bearing one or two substituents independently selected from methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo, cyano, trifluoromethyl, nitro, hydroxy, carboxy, formamido, acetamido, propanamido, formyl, acetyl, butyryl,
trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy,
3,3,3-trifluoropropoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, carbamoyl, N-methylcarbamoyl and
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, sulphamoyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methanesulphonamido,
ethanesulphonamido, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, methylsulphonyl, ethylsulphonyl and 1H-tetrazol-5-yl; or B1 is
(2) a heterocyclic ring selected from thienyl, furyl, pyrrolyl, pyrrolidinyl, pyridyl, piperidyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl and thiomorpholinyl, said ring optionally bearing a methyl or ethyl group;
or T3 and T4 together form a trimethylene, tetramethylene,
pentamethylene, 1-propenylene, 2-propenylene, 1-butenylene,
2-butenylene, 3-butenylene, 1-oxopropylidene, 3-oxopropylidene,
1-oxobutylidene or 4-oxobutylidene group, provided that when T3 and T4 together form one of said latter twelve groups then T2 is additionally selected from any of the previous values defined for T4;
Y is oxygen or a group of the formula -NRb- wherein Rb is hydrogen, methyl, ethyl, formyl, acetyl, propanoyl or benzoyl;
E1 is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl or trifluoromethyl;
E2 is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, trifluoromethyl, carboxy, methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl,
3-methyl-3-butenyloxycarbonyl, cyano, nitro, formyl, acetyl, butyryl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl,
methylsulphonyl, ethylsulphonyl or phenylsulphonyl;
E3 is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy or trifluoromethyl; E4 and E5 are optional substituents on linking group A independently selected from methyl, ethyl, fluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, phenyl, pyridyl, methoxy, ethoxy, chloro, bromo, iodo, cyano, nitro, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl,
2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethylsulphonyl, phenylthio,
phenylsulphinyl, phenylsulphonyl, formyl, acetyl and butyryl;
L1 is methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl;
L2 and L3 are independently selected from hydrogen, methyl and ethyl; F4 is hydrogen, methyl or ethyl;
or F2 and F3 together complete a benzene ring, said benzene ring optionally bearing one or two substituents independently selected from any of the values defined above for F3;
or F2 and F3 together form trimethylene, tetramethylene,
pentamethylene, 1-propenylene, 2-propenylene, 1-butenylene,
2-butenylene, 3-butenylene, 1-oxopropylidene, 3-oxopropylidene,
1-oxobutylidene or 4-oxobutylidene;
or F3 and F4 together form a linking group A2 which is selected from
-CH2-CH2-, -CH2-CH2-CH2-, -CO-CH2-, -CH2-CO-, -CO-CH2-CH2-,
-CH2-CH2-CO-, -CO-CH=CH- and -CH=CH-CO-, and wherein said linking group A optionally bears one or two substituents independently selected from any of the values defined above for E4 or E5;
Rm and Rn are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo, trifluoromethyl, cyano and nitro; and wherein any of said phenyl moieties of R1, R2, T1, T2, T3, E2, E4, E5, F1 or F2 may be unsubstituted or bear one or two
substituents independently selected from methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo, cyano and trifluoromethyl; or a non-toxic salt thereof; or a metabolically labile ester thereof.
3. A compound as claimed in claim 1 or 2 wherein Q is a group of partial structural formula IIc.
4. A compound as claimed in claim 1, 2 or 3 wherein Q is a group of partial structural formula IIc in which 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-tetrahydro-1,6-naphthyridin-2-one ring.
5. A compound as claimed in any preceding claim wherein X is a direct bond.
6. The compound (4-[5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-ylmethyl]phenyl)(phenyl)phosphinic acid as claimed in any preceding claim; or a non-toxic salt thereof; or a non-toxic metabolically labile ester thereof.
7. A salt as claimed in any one preceding claim which is selected from salts with acids forming physiologically acceptable anions and salts with bases forming physiologically acceptable cations.
8. A process for the manufacture of a compound of the formula I, or a non-toxic salt thereof, as claimed in claim 1, which is characterised in that:-
(a) A phosphinic acid derivative of the formula III
Figure imgf000047_0001
in which G is an (1-6C)alkyl, phenyl or benzyl group, is converted to a phosphinic acid; or
(b) A compound of the formula Q.H (or a tautomer thereof) is alkylated with a compound of the formula IV
Figure imgf000047_0002
wherein Hal. stands for a suitable leaving group. and whereafter: if necessary, any protecting group present is removed; when a metabolically labile ester of a compound of formula I is required it is obtained by esterification with an appropriate alcohol or phenol using conventional procedures;
when a non-toxic salt is required it is obtained by reaction with the appropriate acid or base affording a physiologically acceptable ion, or by any other conventional salt formation procedure; and
when an optically active form of a compound of the formula I is required, one of the aforesaid processes (a) or (b) is carried out with an optically active starting material, or the racemic form of a compound of formula I is resolved by reaction with an optically active form of a suitable organic base followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, and liberation of the required optically active form of said compound of formula I by conventional treatment with acid;
and wherein Q, X, Rm and Rn have any of the meanings defined in any of claims 1 to 5 unless otherwise stated.
9. A pharmaceutical composition which comprises a compound of the formula I, or a non-toxic salt thereof, as claimed in any of claims 1 to 7, together with a pharmaceutically acceptable diluent or carrier.
10. A compound of the formula V
Figure imgf000048_0001
wherein Hal. is a suitable leaving group, G is an (1-6C)alkyl, phenyl or benzyl group and X, Rm and Rn have any of the meanings defined in any of claims 1 to 5.
PCT/GB1993/001068 1992-05-28 1993-05-24 Phosphorus containing heterocyclic compounds as angiotensins antagonists WO1993024501A1 (en)

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Publication number Priority date Publication date Assignee Title
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2116559A (en) * 1982-03-15 1983-09-28 Squibb & Sons Inc Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors
EP0475206A2 (en) * 1990-09-10 1992-03-18 Abbott Laboratories Angiotensin II receptor antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2116559A (en) * 1982-03-15 1983-09-28 Squibb & Sons Inc Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors
EP0475206A2 (en) * 1990-09-10 1992-03-18 Abbott Laboratories Angiotensin II receptor antagonists

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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