WO1994000450A1 - Derives de chromane utilises comme antagonistes d'angiotensine ii - Google Patents

Derives de chromane utilises comme antagonistes d'angiotensine ii Download PDF

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Publication number
WO1994000450A1
WO1994000450A1 PCT/GB1993/001294 GB9301294W WO9400450A1 WO 1994000450 A1 WO1994000450 A1 WO 1994000450A1 GB 9301294 W GB9301294 W GB 9301294W WO 9400450 A1 WO9400450 A1 WO 9400450A1
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Prior art keywords
alkyl
formula
group
methyl
independently selected
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PCT/GB1993/001294
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English (en)
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Andrew Peter Thomas
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Zeneca Limited
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Priority claimed from GB929213474A external-priority patent/GB9213474D0/en
Priority claimed from GB929216779A external-priority patent/GB9216779D0/en
Application filed by Zeneca Limited filed Critical Zeneca Limited
Priority to AU43485/93A priority Critical patent/AU4348593A/en
Publication of WO1994000450A1 publication Critical patent/WO1994000450A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention concerns novel nitrogen derivatives and, more particularly, novel nitrogen derivatives which possess pharmacologically useful properties in antagonising at least in part one or more of the actions of the substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "All").
  • the invention also concerns pharmaceutical compositions of the novel compounds for use in treating diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role.
  • the invention also includes processes for the manufacture of the novel compounds and their use in treating one of the afore-mentioned diseases or medical conditions and for the production of novel pharmaceuticals for use in such medical treatments.
  • the angiotensins are key mediators of the renin-angiotensin- aldosterone system, which is involved in the control of homeostasis and fluid/electrolyte balance in many warm-blooded animals, including man.
  • the angiotensin known as All is produced by the action of angiotensin converting enzyme (ACE) on angiotensin I, itself produced by the action of the enzyme renin on the blood plasma protein angiotensinogen. All is a potent spasmogen especially in the vasculature and is known to increase vascular resistance and blood pressure.
  • ACE angiotensin converting enzyme
  • All is a potent spasmogen especially in the vasculature and is known to increase vascular resistance and blood pressure.
  • the angiotensins are known to stimulate the release of aldosterone and hence result in vascular congestion and hypertension via sodium and fluid retention mechanisms.
  • R , T and F are independently selected from (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, phenyl, phenyl(1-4C)alkyl or substituted (l-4C)alkyl, the latter containing one or more fluoro substituents or bearing an (l-4C)alkoxy substituent;
  • R , T and F are independently selected from hydrogen, (l-8C)alkyl,
  • R and R are optional substituents on ring B independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano, nitro, fluoro(l-4C)alkoxy, hydroxy or hydroxy(l-4C)alkyl;
  • T is selected from halogeno, (l-4C)alkoxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms and any of the values defined for
  • T and F are independently selected from hydrogen, (l-4C)alkyl,
  • A is (l-6C)alkylene, a carbonyl group or a direct bond and B is
  • T 3 and T4 together form an (3-6C)alkenylene group, an
  • T is additionally selected from any of the previous values defined for T ;
  • Y is oxygen or a group of the formula -NRb- wherein Rb is hydrogen
  • -C0-CH CH-, -CO-CH 2 -CH 2 -, -CH.--CH 2 -C0, -CH 2 -C0 and -C0-CH 2 -;
  • E is hydrogen, (l-8C)alkyl or trifluoromethyl
  • 2 E is hydrogen, (l- ⁇ C)alkyl, halogeno, (l-4C)alkoxy, trifluoromethyl, carboxy, (l-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, ( (ll--44CC))aallkkaannooyyll,, (l-4C)alkyl.S(0) m - [in which m is zero, 1 or 2] or pheennyyllssuullpphhoonnyyll;;
  • X is CH or a nitrogen atom
  • L 1 is (l-8C)alkyl or (l- ⁇ C)alkoxy
  • 2 3 L and L are independently selected from hydrogen, (l-4C)alkyl and carboxy or a non-toxic metabolically labile ester thereof;
  • 4 F is hydrogen or (1-4C)alkyl
  • linking group A optionally bears one or two substituents independently
  • M , M , M and M have any of the values defined above for E , E , E and , E4 respectively;
  • Rm and Rn are independently selected from hydrogen, (l-4C)alkyl,
  • Z is carboxy or non-toxic metabolically labile ester thereof, lH-tetrazol-5-yl, -CO.NH. (lH-tetrazol-5-yl) or a group of the formula
  • G 1 is (l-6C)alkyl, (3- ⁇ C)cycloalkyl or phenyl;
  • E , F , F , M , M or G may be unsubstituted or bear one or two substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof.
  • alkyl include both straight and branched chain variants when the carbon numbers permit.
  • branched chain variants such as “isopropyl” being specifically named where intended.
  • R , R , T , T , F or F 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 (l-4C)alkoxy substituent: 2-methoxyethyl and
  • T 3 2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl.
  • T 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, eth ⁇ xy-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;
  • a particular value for A when it is alkylene is, for example, methylene, ethylene or propylene.
  • B when it is phenyl bearing one or two substituents 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,
  • N-ethylcarbamoyl N,N-dimethylcarbamoyl
  • 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 T 3 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,
  • 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 , E , E , M , r_ , M or L when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl.
  • a particular value for L when it is alkoxy is, for example,
  • (1-4C)alkoxy such as methoxy, ethoxy or propoxy.
  • E , E , M or M 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 E2 or M when it is alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; when it is alkenyloxycarbonyl is, for example, allyloxycarbonyl,
  • substituent on linking group A include, by way of example, for alkyl: methyl and ethyl; for alkyl containing one or more fluoro substituents: fluoromethy , 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)carb
  • E , F , F , M or M include, by way of example, for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; and for halogeno: chloro, bromo and iodo.
  • a particular value for G when it is alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl; and when it is cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.
  • 2 L includes, for example, an (l-6C)alkyl (such as methyl or ethyl), alkenyl (such as vinyl), alkynyl (such as ethynyl), alkoxyalkyl (such as methoxymethyl) , alkanoyloxyalkyl (such as pivaloyloxymethyl) , alkoxycarbonyloxyalkyl (such as 1-(ethoxycarbonyloxy)ethyl) , cycloalkyloxycarbonyloxyalkyl (such as l-(cyclohexyloxycarbonyloxy)- ethyl), phenyl or benzyl ester.
  • an (l-6C)alkyl such as methyl or ethyl
  • alkenyl such as vinyl
  • alkynyl such as ethynyl
  • alkoxyalkyl such as methoxymethyl
  • alkanoyloxyalkyl such as pivaloyloxymethyl
  • 1 1 11 3 1 2 AA vvaalluuee ffoorr RR ,, TT ,, TT , F or F of particular interest is, for example, methyl, ethyl or propyl.
  • R of particular interest is, for example, hydrogen
  • T of particular interest is, for example, hydrogen or alkoxycarbonyl or, when T 3 and T4 form alkylene is, for example, halogeno.
  • AA vvaalluuee for T of particular interest is, for example, alkoxycarbonyl or halogeno
  • 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 is, for example,
  • E 4 5 for example, methyl, ethyl or halogeno; for E or E is, for example, hydrogen, alkyl, halogeno, phenyl, pyridyl, alkoxycarbonyl, carbamoyl,
  • a value of particular interest for M or H is, for example,
  • H is, for example, hydrogen
  • M is, for example, substituted or unsubstituted phenyl.
  • AA vvaalluuee ooff particular interest for F is, for example, hydrogen or halogeno.
  • a value of particular interest for L is, for example,
  • a value of particular interest for Z is carboxy or lH-tetrazol-5-yl, the latter being preferred.
  • Rm or Rn is, for example, hydrogen.
  • a combination of values of special interest is, for example,
  • a particular group of compounds of the invention which is of interest comprises those compounds of the formula I in which Q is a group of the formula Ha, lib, He or He having any of the values defined above or Q is a group of the formula Hd in which X is a
  • L is (1- ⁇ C)alkyl; and L and L are independently selected from hydrogen and (l-4C)alkyl; or a non-toxic salt thereof.
  • 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 Ha in which ring
  • 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:-
  • linking group A together with the nitrogen atom and pyridine ring to which it is attached constitutes a l,6-naphthyridin-2(lH)-one ring or a l,2,3,4-tetrahydronaphthyridin-2-one ring;
  • group (g) is of particular interest.
  • salts with suitable acids or bases 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 methanesulphonic acids.
  • bases affording physiologically acceptable cations for example, alkali metal (such as sodium and potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts, as well as salts with suitable organic bases,
  • 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 carboxylic acid derivative of the formula HI in which V is a protected carboxy group selected from (1-6C)alkoxycarbonyl (especially methoxy-, ethoxy-, propoxy- or t-butoxy-carbonyl), phenoxycarbonyl, benzyloxyearbonyl and carbamoyl, is converted to carboxy.
  • the conversion may be carried out, for example by hydrolysis, conveniently in the presence of a suitable base such as an alkali metal hydroxide, for example, lithium, sodium or potassium hydroxide.
  • a suitable aqueous solvent or diluent for example in an aqueous (l-4C)alkanol, such as aqueous methanol or ethanol.
  • aqueous (l-4C)alkanol such as aqueous methanol or ethanol.
  • it may also be performed in a mixture of an aqueous and non-aqueous solvent such as water and toluene using a conventional quaternary ammonium phase transfer catalyst.
  • the hydrolysis may be carried out under acidic conditions, for example, using a suitable mineral acid, such as hydrochloric acid, and conveniently in the presence of a suitable solvent or diluent, such as dioxan.
  • a suitable mineral acid such as hydrochloric acid
  • a suitable solvent or diluent such as dioxan.
  • the hydrolysis is generally performed at a temperature in the range, for example, 0 - 120°C, depending on the reactivity of the group W. In general, when W is carbamoyl, temperatures in the range, for example, 40 - 120°C are required to effect the hydrolysis.
  • W is benzyloxyearbonyl
  • 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 (l-4C)alkanol (typically ethanol or 2-propanol) and at a temperature in the range, for example, 0 - 40°C.
  • a suitable catalyst such as palladium on charcoal or on calcium sulphate
  • a suitable solvent or diluent such as a (l-4C)alkanol (typically ethanol or 2-propanol) and at a temperature in the range, for example, 0 - 40°C.
  • the conversion may also be carried out by hydrolysis at a temperature in the range, for example, 0 - 100°C, in the presence of a strong acid catalyst, such as trifluoroacetic acid.
  • a strong acid catalyst such as trifluoroacetic acid.
  • the hydrolysis may either be performed in an excess of the acid or in the presence of a suitable diluent such as tetrahydrofuran, t-butyl methyl ether or 1,2-dimethoxyethane.
  • reaction conditions used to carry out the deprotection necessarily depend on the nature of*the group P .
  • the decomposition conditions include, for example, acid catalysed hydrolysis in a mineral acid (such as-aqueous hydrochloric acid), conveniently in an aqueous solvent (such as aqueous dioxan or 2-propanol).
  • a trityl or benzhydryl group may be removed by hydrogenolysis, for example as described in (a) above for conversion of a benzyloxyearbonyl to a carboxy.
  • Compounds of the formula IV wherein P is trialkyltin or triphenyltin may be obtained, for example, by reaction of a nitrile of the formula VII with a trialkyltin azide, such as tributyltin azide, or triphenyltin azide respectively.
  • a nitrile of the formula VII with a trialkyltin azide, such as tributyltin azide, or triphenyltin azide respectively.
  • the reaction is conveniently carried out in a suitable solvent or diluent, such as toluene or xylene, and at a temperature in the range, for example, 50-150°C.
  • a formula I compound wherein Z is tetrazolyl may be obtained directly by in situ removal of the trialkyltin or triphenyltin group without prior isolation of the formula IV compound, for example by the addition of aqueous mineral acid or gaseous hydrogen chloride to the reaction mixture.
  • the nitriles of the formula VII may be obtained, for example, by alkylation of a compound of the formula Q.H with a nitrile of the formula VIII wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p_-toluenesulphonyloxy, using similar conditions to those used in process (c) described hereinafter.
  • the necessary compounds of formula VIII may be made by standard procedures such as that illustrated in Scheme 12, using methods of organic chemistry well known in the art.
  • the nitriles of the formula VII may be obtained from stepwise conversion of a compound of formula I wherein Z is carboxy or an ester thereof under standard conditions.
  • Trialkyltin azides and triphenyltin azides are either commercially available or may be prepared by standard procedures well known in the art, such as by reaction of a trialkyltin halide with an alkali metal azide.
  • a compound of the formula Q.H is alkylated with a compound of the formula V wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p_-toluenesulphonyloxy.
  • the reaction is generally carried out in the presence of a suitable base, for example, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide or an alkali metal hydride such as sodium hydride or an alkali metal carbonate such as sodium or potassium carbonate, or an organic base such as diisopropylethylamine and in a suitable solvent or diluent, for example, a (l-4C)alkanol such- as methanol or ethanol when an alkali metal alkoxide is used, or in a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10 - 100°C.
  • a suitable base for example, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide or an alkali metal hydride such as sodium hydride or an alkali metal carbonate such as sodium or potassium carbonate, or an organic base such as diis
  • a quaternary ammonium hydroxide may be used in a mixture of an aqueous and non-aqueous solvent such as water and dichloromethane.
  • an aqueous and non-aqueous solvent such as water and dichloromethane.
  • Procedure (c) is particularly suitable for the production of those compounds of the formula I in which Z is a metabolically labile ester group, for example wherein Z is an (l-6C)alkyl, benzyl or phenyl ester, which compounds are also starting materials of formula HI for the reaction described in (a) above.
  • Z is a metabolically labile ester group
  • Z is an (l-6C)alkyl, benzyl or phenyl ester
  • the starting materials of the formula IV may be obtained for procedure (b).
  • the compounds of formula V and VI may be obtained, for example, as illustrated in Scheme 13, or by analogy therewith.
  • those compounds of formula I wherein Z is lH-tetrazol-5-yl may be obtained by stepwise conversion of a compound of the formula I wherein Z is carboxy, or a metabolically labile ester thereof, into the corresponding nitrile under standard conditions, followed by reaction of the nitrile with an azide such as an alkali metal azide, preferably in the presence of an ammonium halide, and preferably in the presence of a suitable polar solvent such as N,N-dimethylformamide and at a temperature in the range, for example, 50 to 160°C.
  • an azide such as an alkali metal azide
  • an ammonium halide preferably in the presence of an ammonium halide
  • a suitable polar solvent such as N,N-dimethylformamide
  • those compounds of the formula I wherein Z is -CO.NH. (lH-tetrazol-5-yl), a group of the formula -CO.NH.SO.,.G or a metabolically labile ester group may be obtained, for example, by reacting a carboxylic acid of the formula I in which Z is carboxy (or a reactive derivative of said acid) with 5-aminotetrazole, a sulphonamide of the formula NH ? .SO ? .G or a salt thereof (for example, an alkali metal salt), or an appropriate alcohol or phenol or a salt thereof (for example an alkali metal salt).
  • Suitable reactive derivatives include, for example the chloride, bromide, azide, anhydride and mixed anhydride with formic or acetic acid of the carboxylic acid of formula I as defined above.
  • the reaction is generally carried out in the presence of a suitable dehydrating agent such as dicyclohexycarbodiimide or 3-(3-dimethylaminopropyl)-l-ethylcarbodiimide in the presence of a base such as triethylamine, pyridine or 4-dimethylaminopyridine.
  • a reactive derivative When a reactive derivative is used, either the reaction is carried out in the presence of a base such as mentioned above, or, for the preparation of a compound of the formula I wherein Z is a group of the formula -C0.NH.S0RAT.G or a metabolically labile ester group, the sulphonamide or alcohol or phenol is used in the form of a salt, such as its alkali metal salt (in particular the lithium, sodium or potassium salt thereof).
  • the reaction is generally performed in the presence of a suitable diluent or solvent such as dioxan, t-butyl methyl ether or tetrahydrofuran and at a temperature in the range, for example, 0 - 60°C.
  • 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(l-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 (l-4C)alkanol, whereafter the optically active form of said compound of formula I may be liberated by treatment with acid using a conventional procedure, for example using an aqueous mineral acid such as dilute hydrochloric acid.
  • a suitable organic base for example, ephedrine, N,N,N-trimethyl(l-phenylethyl)ammonium__ hydrox
  • 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 AH.
  • 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 hyperaldosteronis in warm-blooded animals (including man) , as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role.
  • the compounds of the invention may also be useful for the treatment of ocular hypertension, glaucoma, cognitive disorders (such as Alzheimer's disease, amnesia, senile dementia and learning disorders), as well as other diseases such as renal failure, cardiac insufficiency, post-myocardial infarction, cerebrovascular disorders, anxiety, depression and certain mental illnesses such as schizophrenia.
  • cognitive disorders such as Alzheimer's disease, amnesia, senile dementia and learning disorders
  • other diseases such as renal failure, cardiac insufficiency, post-myocardial infarction, cerebrovascular disorders, anxiety, depression and certain mental illnesses such as schizophrenia.
  • the antagonism of one or more of the physiological actions of AH and, in particular, the antagonism of the interaction of AH 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 AH 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 AH.
  • concentrations of the test compound are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate IC cn , 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 7xl0 "9 M.
  • 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 AH, the effect of the test compound on noradrenaline-induced contractions may also be determined in the same preparation.
  • 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 AH antagonistic effects of the test compound following oral or parenteral administration are assessed against angiotensin H-induced pressor responses.
  • 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 AH 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.
  • compositions 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 enzyme (ACE) inhibitor (for example lisinopril) or a diuretic (for example furosemide or hydrochlorothiazide) .
  • ACE angiotensin converting enzyme
  • a diuretic for example furosemide or hydrochlorothiazide
  • a compound of formula I (or a pharmaceutically acceptable salt thereof as appropriate) will generally be administered to man so that, for example, a daily oral dose of up to 50 mg/kg body weight (and preferably of up to 10 mg/kg) or a daily parenteral dose of up to 5 mg/kg body weight (and preferably of up to 1 mg/kg) is received, given in divided doses as necessary, the precise amount of compound (or salt) administered and the route and form of 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.
  • 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.
  • 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 AH 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 starting material A was obtained as follows:- (i) A solution of 6-methylcoumarin (64. ⁇ g) in ethanol (800 ml) was hydrogenated at 40 psi and 60°C over 6 g of 10% palladium on carbon catalyst until hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated by evaporation. Toluene (1 litre) and p_-toluenesulphonic acid monohydrate (0.5 g) were added, and half the solvent volume was removed from the mixture by distillation. The remaining mixture was cooled and ether (500 ml) was added. The mixture was then washed with saturated sodium bicarbonate solution (100 ml) and water (100 ml).
  • Trimethylsilyl cyanide (3.3 ml) was added to a stirred solution of compound E (2.25 g) in acetonitrile (100 ml) under an atmosphere of argon. Titanium tetrachloride (0.1 ml) was added dropwise and the mixture was stirred for 65 hours. A further amount of titanium tetrachloride (0.1 ml) was added and the mixture stirred a further l ⁇ hours. Methanol (10 ml) was added dropwise, followed by water (500 ml) and the mixture was extracted with ethyl acetate (3 x 200 ml).
  • N-Bromosuccinimide (1.25 g) and azobisisobutyronitrile (125 mg) were added to a stirred, degassed solution of compound F (1.6 g) in carbon tetrachloride (30 ml) under an atmosphere of argon. The mixture was refluxed for 4 hours, then cooled to 40°C and filtered. The filtered solid was washed with carbon tetrachloride (30 ml). The filtrate was concentrated by evaporation to give crude 6-bromomethyl-2-phenylchroman-2-carbonitrile (1.9 g).
  • 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:-
  • 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.
  • Rx and Ry are optional substituents
  • R' lower alkyl
  • R" lower alkyl
  • Reagents: a) SnCl,, toluene, reflux b) aqu. NaOH, methanol, reflux; then HCl c) heat, 220°C d) I ⁇ , [bis(trifluoroacetoxy)iodo]benzene, CH-Cl.., methano! e) Pd(II)acetate, tri(2-methylphenyl)phosphine, Et-N, DMF, 130°C, CH 2 CHC0 2 R n f) NaOCH , methanol, reflux h) hydrogen, palladium on carbon, acetic acid/ethanol, 20 atmospheres, 70°C Scheme 4
  • Et ethyl
  • Ph phenyl
  • R' lower alkyl
  • R' lower alkyl Reagents: a) hydrogen, Pd on C or PtOont b) heat
  • Reagents a) l-(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
  • Ph phenyl Reagents: (a) P0C1-/DMF
  • Rw and Rx are optional substituents
  • Reagents (a) polyphosphoric acid, acetic acid
  • R' lower alkyl
  • Rx and Ry are optional substituents
  • Reagents a) sodium ethoxide, ethanol, ambient temperature b) jj-Toluenesulphonic acid, benzene, reflux with azeotropic removal of water; heat c) P0C1 3 , reflux d) NH O .
  • R lower alkyl
  • Tr triphenylmethyl (trityl) Reagents: a) hydrogenation over palladium on carbon, ethanol b) [(CH ) 2 CHCH ] A1H, hexane/CH Cl 2 , -75°C c) (Rn)PhHgBr, ether, 0°C to am ⁇ ient d) (i) Jones reagent (chromic acid and sulphuric acid in water), acetone, 0-5°C (ii) trimethyl orthoformate, p_-toluenesulphonic acid e) trimethylsilyl cyanide, acetonitrile, TiCl, f) tributyltin azide, toluene; HCl, toluene g) Tr.Cl, triethylamine, CH 2 Cl 2 h) N-bromosuccinimide, bisisobutyronitrile, CC1, i) ROH,

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Abstract

L'invention se rapporte à des composés pharmaceutiquement utiles de la formule (I) dans laquelle Q est choisi entre (IIa), (IIb), (IIc), (IId), (IIe), (IIf), Z représente carboxy ou un ester labile métaboliquement non toxique de celui-ci, 1H^_-tétrazol-5-yle, -CO.NH. (1H^_-tétrazol-5-yle) ou un groupe de la formule -CO.NH.SO2.G1 dans laquelle G1 représente alkyle, cycloalkyle ou phényle. Ces nouveaux composés peuvent être utilisés pour traiter des états tel que l'hypertension et l'insuffisance cardiaque congestive. L'invention se rapporte également à des procédés de fabrication de ces nouveaux composés, ainsi qu'à leur utilisation dans un traitement médical.
PCT/GB1993/001294 1992-06-25 1993-06-18 Derives de chromane utilises comme antagonistes d'angiotensine ii WO1994000450A1 (fr)

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AU43485/93A AU4348593A (en) 1992-06-25 1993-06-18 Chromanderivatives as angiotensin ii antagonists

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GB929213474A GB9213474D0 (en) 1992-06-25 1992-06-25 Nitrogen derivatives
GB9213474.1 1992-06-25
GB9216779.0 1992-08-07
GB929216779A GB9216779D0 (en) 1992-08-07 1992-08-07 Heterocyclic compounds

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
EP3325471A1 (fr) * 2015-07-20 2018-05-30 Genzyme Corporation Inhibiteurs du récepteur de facteur-1 de stimulation de colonies (csf-1r)
US11530216B2 (en) 2020-12-23 2022-12-20 Genzyme Corporation Deuterated colony stimulating factor-1 receptor (CSF-1R) inhibitors
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
WO1991011999A1 (fr) * 1990-02-13 1991-08-22 Merck & Co., Inc. Antagonistes d'angiotensine ii incorporant un element benzylique substitue
EP0543491A2 (fr) * 1991-10-07 1993-05-26 Merck & Co. Inc. Antagonistes d'angiotensin II avec 1,3-benzodioxole substitué ou 1,3-benzodithiole substitué

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011999A1 (fr) * 1990-02-13 1991-08-22 Merck & Co., Inc. Antagonistes d'angiotensine ii incorporant un element benzylique substitue
EP0543491A2 (fr) * 1991-10-07 1993-05-26 Merck & Co. Inc. Antagonistes d'angiotensin II avec 1,3-benzodioxole substitué ou 1,3-benzodithiole substitué

Cited By (10)

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EP3325471A1 (fr) * 2015-07-20 2018-05-30 Genzyme Corporation Inhibiteurs du récepteur de facteur-1 de stimulation de colonies (csf-1r)
JP2018524381A (ja) * 2015-07-20 2018-08-30 ジェンザイム・コーポレーション コロニー刺激因子−１受容体（ｃｓｆ−１ｒ）阻害剤
US20190016707A1 (en) * 2015-07-20 2019-01-17 Genzyme Corporation Colony stimulating factor-1 receptor (csf-1r) inhibitors
AU2016297558B2 (en) * 2015-07-20 2021-03-25 Genzyme Corporation Colony stimulating factor-1 receptor (CSF-1R) inhibitors
JP2021107414A (ja) * 2015-07-20 2021-07-29 ジェンザイム・コーポレーション コロニー刺激因子−１受容体（ｃｓｆ−１ｒ）阻害剤
US11274108B2 (en) * 2015-07-20 2022-03-15 Genzyme Corporation Colony stimulating factor-1 receptor (CSF-1R) inhibitors
IL276292B1 (en) * 2015-07-20 2023-10-01 Genzyme Corp CSF–1R receptor antagonists
IL276292B2 (en) * 2015-07-20 2024-02-01 Genzyme Corp CSF–1R receptor antagonists
US11530216B2 (en) 2020-12-23 2022-12-20 Genzyme Corporation Deuterated colony stimulating factor-1 receptor (CSF-1R) inhibitors
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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