Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
  • C07D215/22—Oxygen atoms attached in position 2 or 4
  • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This invention concerns a novel process for the production of novel quinoline derivatives which possess pharmacologically useful properties in antagonising at least in part one or more of the actions of substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "All").
• the invention also concerns various quinoline derivatives which are valuable chemical intermediates, for example for use in the abovementioned process.
• 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 an.
• the angiotensin known as All is produced by the action of giotensin erting enzyme (ACE) from angiotensin I, itself produced by action of the enzyme renin from 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 giotensin erting 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 flu retention mechanisms.
• AII renin erting enzyme
• AII inhibitors are useful for the reduction or prevention of these effects produced by the action of AII.
• AII inhibitors and processes for tneir preparation are known, for example certain substituted imidazoles described in European Patent Application, Publication No. (EPA) 253310 and EPA 324377, certain benzimidazoles described in U.S. Patent no. 4880804 and certain pyrroles, pyrazoles and described in EPA 323841, there remains a continuing need for alternative inhibitors and for effective synthetic procedures for their production such as those provided by this invention.
• Certain quinoline derivatives which are structurally related to the novel quinoline derivatives obtainable by the process of the present invention are described in EPA 348155 as having leukotriene D4 antagonist activity.
• (1-4C)alkyl the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (1-4C)alkoxy or phenyl
• R 2 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl,
• R 3 and R 4 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, fluoro(1-4C)alkoxy, halogeno, hydroxy, trifluoromethyl, cyano, nitro, amino,
• (1-4C)alkyl bearing an amino, hydroxy or (1-4C)alkoxy substituent; or R 3 and R 4 together form (1-4C)alkylenedioxy attachteedd to adjacent carbon atoms of the benzene moiety of formula I;
• Ra and R 5 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano or nitro;
• A is methylene;
• X is phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, or X is a direct bond between the adjacent phenyl group and moiety A;
• Z is 1H-tetrazol-5-yl, -CO.NH.
• alkyl include both straight and branched chain variants when the carbon numbers permit.
• 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.
• R 1 or R 2 when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl; and when it is cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.
• R 1 when it is alkyl bearing one or more fluoro substitutents is, for example, fluoromethyl
• R 2 when it is cycloalkyl-alkyl is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or
• R 3 , R 4 , R 5 , or Ra, or for an optional substituent which may be present when X is phenylene, as defined above, include by way of example:- for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy; for halogeno: fluoro, chloro, bromo and iodo; for alkanoylamino: formamido, acetamido and propanamido; for alkylamino: methylamino, ethylamino and butylamino; for dialky
• di(N-alkyl)carbamoyl N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and
• alkylthio methylthio, ethylthio and butylthio
• alkylsulphinyl methylsulphinyl, ethylsulphinyl and
• alkyl bearing an amino, hydroxy or alkoxy substituent: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, 2-methoxyethyl and 2-ethoxyethyl; and alkylenedioxy: methylenedioxy and ethylenedioxy.
• a particular value for R 6 when it is a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol is, for example, a residue derived from a (1-6C)alkanol such as methanol or ethanol, or phenol, glycerol or the like.
• R 7 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.
• substituents which may be present on one or more phenyl moieties include, by way of example, for halogeno: fluoro, chloro and bromo; for alkyl: methyl and ethyl; and for alkoxy: methoxy and ethoxy.
• a specific value for X which is of particular interest is, for example, p-phenylene.
• a preferred value for R 1 or R 1 is, for example, hydrogen and for R is, for example, methyl, ethyl or propyl.
• a preferred group of compounds described in our co-pending application comprises those compounds of the formula la (set out hereinafter) wherein R 1 , R 2 , R 3 , R 4 and R 5 have any of their meanings as defined above and Z 1 is carboxy, 1H-tetrazol-5-yl or
• benzenesulphonamido the latter optionally containing one or two substituents independently selected from halogeno (such as fluoro, chloro or bromo), (1-4C)alkyl (such as methyl or ethyl), (1-4C)alkoxy (such as methoxy or ethoxy), cyano, nitro and trifluoromethyl;
• halogeno such as fluoro, chloro or bromo
• (1-4C)alkyl such as methyl or ethyl
• 1-4C)alkoxy such as methoxy or ethoxy
• cyano nitro and trifluoromethyl
• a preferred value for Z or Z is, for example, carboxy or 1H-tetrazol-5-yl, which latter is especially preferred and, in particular, when it is attacheed ortho to the group X.
• a particularly preferred combination of values in any of the above definitions is wherein the quinoline moiety together with the attached substituents R 1 , R 2 , R 3 and R 4 , and Ra when present, has any of the following values:- 2-methylquinoline, 2-ethylquinoline,
• 2-ethyl-6-methoxyquinoline 6,7-dimethoxy-2-ethylquinoline, 2-ethyl-5 , 6,7-trimethoxyquinoline, 2-ethyl-6-hydroxyquinoline, 2-ethyl-6-methylthioquinoline, 2-ethyl-6-hydroxymethylquinoline, 2-ethyl-6-(2-fluoroethoxy)quinoline, 2-ethyl-6-(2,2,2-trifluoroethoxy)-quinoline, 2-ethyl-6-carboxamidoquinoline, 2-ethyl-6-fluoroquinoline, 2-ethyl-6-isopropoxyquinoline or 6-aminomethyl-2-ethylquinoline; and in which the substituent O.A.X- is attached at the 4-position of the quinoline ring.
• Particularly suitable non-toxic salts for such compounds therefore also include, for example, salts with bases affording physiologically acceptable cations, for example, alkali metal (such as sodium and potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts, as well as salts with suitable organic bases, such as with ethanolamine, methylamine, diethylamine or triethylamine, as well as salts with acids forming physiologically acceptable anions, such as salts with mineral acids, for example with hydrogen halides (such as hydrogen chloride and hydrogen bromide), sulphuric and phosphoric acid, and with strong organic acids, for example with p-toluenesulphonic and methanesulphonic acids.
• bases affording physiologically acceptable cations for example, alkali metal (such as sodium and potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts, as well as salts with suitable organic bases, such as with ethanolamine, methylamine, diethylamine
• R 1 , R 2 , R 3 , R 4 , R 5 and Ra have any of the values defined hereinbefore and Rb is hydrogen or a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, which comprises removal of a trisubstituted tin moiety of the formula Sn(Q) 3 from a compound of the formula IV wherein R 1 , R 2 , R 3 , R 4 , R 5 , Ra and Rb have any of the meanings as defined hereinbefore and Q is a (1-6C)alkyl or phenyl group, the latter optionally substituted by an (1-4C)alkyl,
• Q is, for example, (1-4C)alkyl such as methyl, ethyl, propyl or butyl, of which butyl is preferred.
• Rb or for an optional substituent on Q when it is phenyl, when it is alkyl is, for example, methyl or ethyl; when it is halogeno is, for example, fluoro, chloro or bromo; and when it is alkoxy is, for example, methoxy or ethoxy.
• the process is particularly suitable for the manufacture of compounds of the formula III wherein the tetrazolyl group is in a position ortho to the adjacent phenyl group.
• the trisubstituted tin moiety Sn(Q) 3 may be removed, for example, by acid or base hydrolysis.
• the reaction is conveniently carried out, for example, by treatment of the compound of formula IV with mineral acid, such as aqueous hydrochloric acid, in the presence of a suitable solvent or diluent.
• a suitable solvent or diluent is, for example, a hydrocarbon such as toluene or xylene, an ether such as dioxan or tetrahydrofuran, or water, or mixtures thereof.
• the reaction is generally carried out at a temperature in the range, for example, 0-50°C, and conveniently at or about ambient temperature.
• azo(bisisobutyronitrile) in a solvent such as chlorobenzene or carbon tetrachloride and the alkylation is generally carried out in the presence of a base, for example, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate, or an alkali metal hydride such as sodium hydride and in a solvent or diluent, for example, a (1-4C)alkanol such as methanol or ethanol when an alkali metal alkoxide is used, or in a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10-100°C.
• a quaternary ammonium hydroxide may be used in a mixture of an aqueous or non-aqueous solvent such as water and dichloromethane.
• Compounds of the formula VII may be obtained, for example, by the procedure described in European Patent Application, Publication no. 0253310 A2. Alternatively, they may be obtained, for example, by reaction of a Grignard reagent, formed from an unsubstituted or substituted 4-bromotoluene in a solvent such as tetrahydrofuran, with a trialkyltin halide, such as tributyltin chloride, at a temperature of 0-25°C, followed by reaction of the resulting
• formula VII compounds are by reaction of an unsubstituted or substituted 4-bromotoluene with an alkali metal alkane, such as butyllithium, and zinc chloride followed by reaction with a suitably substituted bromobenzonitrile in the presence of tetrakis(triphenylphosphine)palladium.
• an alkali metal alkane such as butyllithium
• a compound of the formula IV as defined above is generated in situ from a compound of the formula V as defined above by reaction with an azid e of the formula VI as defined above.
• trisubstituted tin moiety Sn(Q) 3 present may then be removed without isolation of the compound of the formula IV, for example, by addition of aqueous mineral acid to the reaction mixture.
• a mixture of sodium nitrite and hydrochloric acid may be used to acidify the reaction mixture, thereby conveniently destroying any excess azide present.
• the azides of formula VI are either commercially available or may be prepared oy standard procedures well known in the art, such as by reaction of a trialkyltin halide with an alkali metal azide.
• a non-toxic salt of a compound of formula II 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,
• antagonism of one or more of the physiological actions of All and, in particular, the antagonism of the interaction of AII with the receptors which mediate its effects on a target tissue may be assessed using one or more of the following, routine laboratory procedures:
• Test A This in vitro procedure involves the incubation of the test compound initially at a concentration of 100 micromolar (or less) in a buffered mixture containing fixed concentrations of radiolabelled AII and a cell surface membrane fraction prepared from a suitable angiotensin target tissue.
• the source, of cell surface membranes is the guinea pig adrenal gland which is well known to respond to 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.
• 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 AII antagonistic effects of the test compound following oral or parenteral administration are assessed against angiotensin II-induced pressor responses. To ensure that the effect is specific, the effect of the test compound on vasopressin-induced pressor responses may also be determined in the same preparation.
• the compounds of formula III generally show specific AII-antagonist properties in Test C at a dose of 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 AII biosynthesis in a variety of species including rat, marmoset and dog by introducing a diet of low sodium content and giving appropriate daily doses of a saluretic known as frusemide. The test compound is then administered orally or parenterally to the animal in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure.
• test B an average pA 2 of 8.95;
• test C ED 50 of 0.5 mg/kg (i.v. administration).
• the starting material A was obtained as follows:-
• N-bromosuccinimide (0.3 g) and azo(bisisobutyronitrile) (0.05 g) was added and the mixture was heated for another 15 minutes. Heating was stopped and the mixture stirred for 16 hours at ambient temperature. Water (50 ml) was added and the mixture stirred for 30 minutes and filtered. The organic phase was separated, washed with water (f ml) and dried (MgSO 4 ). The solvent was removed by evaporation and the resultant solid recrystallised from cyclohexane to give

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• 1990
  • 1990-08-09 GB GB909017479A patent/GB9017479D0/en active Pending
• 1991
  • 1991-07-09 IE IE240691A patent/IE912406A1/en unknown
  • 1991-07-15 IL IL98833A patent/IL98833A0/xx unknown
  • 1991-07-16 ZA ZA915567A patent/ZA915567B/xx unknown
  • 1991-07-16 GB GB919115250A patent/GB9115250D0/en active Pending
  • 1991-07-17 CA CA002047249A patent/CA2047249A1/en not_active Abandoned
  • 1991-07-24 CN CN91105053A patent/CN1058965A/zh active Pending
  • 1991-07-30 WO PCT/GB1991/001287 patent/WO1992002508A1/en not_active Ceased
  • 1991-07-30 AU AU83090/91A patent/AU8309091A/en not_active Abandoned
  • 1991-07-30 JP JP3513216A patent/JPH05501728A/ja active Pending
  • 1991-07-30 EP EP91914106A patent/EP0495948A1/en not_active Withdrawn
  • 1991-07-30 FI FI921319A patent/FI921319A7/fi not_active Application Discontinuation
  • 1991-07-30 KR KR1019920700813A patent/KR920702357A/ko not_active Withdrawn
  • 1991-07-30 HU HU92933A patent/HUT60490A/hu unknown
  • 1991-08-08 PT PT98607A patent/PT98607A/pt not_active Application Discontinuation
• 1992
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