WO2004043930A1 - Quinoline derivatives which enhance cognition via the gaba-a receptor - Google Patents

Quinoline derivatives which enhance cognition via the gaba-a receptor Download PDF

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Publication number
WO2004043930A1
WO2004043930A1 PCT/GB2003/004845 GB0304845W WO2004043930A1 WO 2004043930 A1 WO2004043930 A1 WO 2004043930A1 GB 0304845 W GB0304845 W GB 0304845W WO 2004043930 A1 WO2004043930 A1 WO 2004043930A1
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fluoro
alkyl
represents hydrogen
phenyl
formula
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PCT/GB2003/004845
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French (fr)
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William Robert Carling
Kevin William Moore
Leslie Joseph Street
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Merck Sharp & Dohme Limited
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Priority to AU2003282222A priority Critical patent/AU2003282222A1/en
Publication of WO2004043930A1 publication Critical patent/WO2004043930A1/en

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    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • 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
    • C07D215/18—Halogen atoms or nitro radicals

Definitions

  • the present invention relates to a class of substituted quinoline derivatives and to their use in therapy. More particularly, this invention is concerned with 8-fluoroquinoline analogues which are substituted in the 4-position by a substituted phenyl ring. These compounds are ligands for GABAA receptors and are therefore useful in the therapy of deleterious neurological complaints.
  • the technical background to the present invention is disclosed on pages 1-4 of WO-A-02074773.
  • the present invention provides a class of quinoline derivatives which possess desirable binding properties at various GABAA receptor subtypes.
  • the compounds in accordance with the present invention have good affinity as ligands for the ⁇ 2 and/or ⁇ 3 and/or ⁇ .5 subunit of the human GABAA receptor.
  • the compounds of this invention may interact more favourably with the ⁇ 2 and/or ⁇ 3 subunit than with the ⁇ l subunit; and or may interact more favourably with the ⁇ 5 subunit than with the ⁇ l subunit.
  • the compounds of the present invention are GABA A receptor subtype ligands having a binding affinity (Ki) for the ⁇ 2 and/or ⁇ 3 and/or ⁇ 5 subunit, as measured in the assay described hereinbelow, of 200 nM or less, typically of 100 nM or less, and ideally of 20 nM or less.
  • the compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the ⁇ 2 and/or ⁇ 3 and/or ⁇ subunit relative to the ⁇ l subunit.
  • compounds which are not selective in terms of their binding affinity for the ⁇ 2 and/or ⁇ 3 and/or ⁇ 5 subunit relative to the ⁇ l subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of zero or weak (positive or negative) efficacy at the ⁇ l subunit and (i) a full or partial agonist profile at the ⁇ 2 and/or ⁇ 3 subunit, and/or (ii) an inverse agonist profile at the ⁇ 5 subunit.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof:
  • X 1 represents hydrogen, halogen, Ci-e alkyl, trifluoromethyl or Ci- ⁇ alkoxy;
  • X 2 represents hydrogen or halogen
  • Y represents a chemical bond, an oxygen atom, or a -NH- linkage;
  • Z represents an optionally substituted aryl or heteroaryl group;
  • R a and R b independently represent hydrogen, hydrocarbon or a heterocyclic group.
  • the aryl or heteroaryl group Z in the compounds of formula I above may be unsubstituted, or substituted by one or more substituents. Typically, the group Z will be unsubstituted, or substituted by one or two substituents. Suitably, the group Z is unsubstituted or monosubstituted.
  • hydrocarbon and the expression "a heterocyclic group” suitable alkyl, alkenyl, alkynyl and cycloalkyl groups, typical C3-7cycloalkyl(C ⁇ - ⁇ )alkyl groups, particular indanyl, aryl and aryl(C ⁇ -6)alkyl groups, suitable heterocycloalkyl and heteroaryl groups, the expression “hetero(C ⁇ -6)alkyl”, optional substituents on hydrocarbon and heterocyclic groups, the term “halogen” and asymmetric compounds can be found on pages 6 to 9 of WO-A-02074773.
  • Suitable values for the X 1 substituent include hydrogen, fluoro, chloro, methyl, trifluoromethyl and methoxy; in particular hydrogen or fluoro; and especially fluoro.
  • Typical values of X 2 include hydrogen and fluoro, especially hydrogen.
  • Y represents a chemical bond. In another embodiment, Y represents an oxygen atom. In a further embodiment, Y represents a -NH- linkage.
  • Selected values for the substituent Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl, any of which groups may be optionally substituted by one or more substituents.
  • Z represents an optionally substituted phenyl group, in particular monosubstituted or disubstituted phenyl.
  • Z represents optionally substituted pyridinyl, especially unsubstituted, monosubstituted or disubstituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.
  • substituents on the group Z include fluoro, trifluoromethyl, cyano and carboxamido.
  • Detailed values of Z include trifluoromethyl-phenyl, cyanophenyl,
  • Z include trifluoromethyl-phenyl, cyanophenyl, (cyano) (fluorophenyl, (carboxamido) (fluorophenyl, pyridinyl, carboxamido-pyridinyl and pyrimidinyl.
  • R a examples include hydrogen and C1.-6 alkyl.
  • R a represents hydrogen or methyl.
  • R b examples include hydrogen, Ci- ⁇ alkyl, hydroxy (Ci- ⁇ ) alkyl and di(C ⁇ -6)alkylamino(C ⁇ -6)alkyl.
  • R b represents hydrogen, methyl, ethyl, hydroxyethyl or dimethyla inoethyl.
  • Particular values of R b include hydrogen, hydroxyethyl and dimethylaminoethyl, especially hydrogen or dimethylaminoethyl.
  • R 1 Representative values of R 1 include hydrogen, Ci- ⁇ alkyl, halo(C ⁇ -6)alkyl, hydroxy(C ⁇ - ⁇ )alkyl and trifluoromethyl. Individual values of R 1 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1 -hydroxyethyl), fluoroethyl (especially
  • -CR 2 NOR 3 , in which R 2 represents hydrogen or methyl, and R 3 represents hydrogen, hydroxyethyl or dimethylaminoethyl.
  • R 1 represents hydrogen. In a favoured embodiment, R 1 represents 2 _ hydroxyprop-2-yl. In another embodiment,
  • R 1 represents 2-fluoroprop-2-yl. In an additional embodiment, R 1 represents trifluoromethyl. In a further embodiment, R 1 represents methyl.
  • R 2 is hydrogen.
  • R 3 represents hydrogen or dimethylaminoethyl, especially hydrogen.
  • a particular sub-class of compounds according to the invention is represented by the compounds of formula HA, and pharmaceutically acceptable salts thereof:
  • Z is as defined above;
  • X 11 represents hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy;
  • X 12 represents hydrogen or fluoro
  • R 4 represents hydrogen or Ci- ⁇ alkyl
  • R 5 represents hydrogen, Ci-e alkyl, hydroxy (C ⁇ -6)alkyl or di(C ⁇ -6)alkylamino(C ⁇ -6) alkyl.
  • Suitable values of X 11 include hydrogen and fluoro, especially fluoro.
  • X 12 represents hydrogen. In another embodiment, X 12 represents fluoro.
  • R 4 represents hydrogen or methyl, especially hydrogen.
  • R 5 represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of R 5 include hydrogen, hydroxyethyl and dimethylaminoethyl. Typically, R 5 represents hydrogen or dimethylaminoethyl, especially hydrogen. Where R 11 represents heteroaryl, this group is suitably pyridinyl, furyl, thienyl or oxazolyl.
  • R 11 represents Ci- ⁇ alkyl-heteroaryl
  • this group is suitably methylthiazolyl (e.g. 2-methylthiazol-5-yl) or methyloxadiazolyl (e.g. 3- methyl- [1,2, 4]oxadiazol-5-yl).
  • R n represents heteroaryl(C ⁇ -6)alkyl
  • this group is suitably imidazolylmethyl or triazolylmethyl.
  • R 11 include hydrogen, Ci- ⁇ alkyl, hydroxy(C ⁇ - ⁇ ) alkyl, fluoro(C ⁇ -6)alkyl and trifluoromethyl.
  • Individual values of R 11 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1 -hydroxyethyl), fluoroethyl (especially 1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1 -dimethox ethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), dihydroxypropyl (especially l,2-dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), cyanopropyl (especially 2- cyanoprop-2-yl), methoxycarbonylpropyl (especially 2- me
  • R 11 represents hydrogen. In a favoured embodiment, R u represents 2-hydroxyprop-2-yl. In another embodiment, R 11 represents 2-fluoroprop-2-yl. In an additional embodiment, R 11 represents trifluoromethyl. In a further embodiment, R 11 represents methyl.
  • R 6 represents hydrogen or fluoro.
  • R 6 is hydrogen
  • R 6 is fluoro, in which case the fluorine atom R 6 is favourably attached to the phenyl ring at the 4-, 5- or 6-position (relative to the cyano group at position 2).
  • R 7 represents hydrogen, fluoro, cyano or carboxamido. In one embodiment, R 7 is hydrogen.
  • R 7 is fluoro
  • R 7 is cyano
  • R 7 is carboxamido
  • R 8 represents hydrogen or fluoro.
  • R 8 represents hydrogen
  • R 8 represents fluoro
  • Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.
  • a method for the treatment and/or prevention of convulsions e.g. in a patient suffering from epilepsy or a related disorder
  • convulsions e.g. in a patient suffering from epilepsy or a related disorder
  • the present invention provides a method for the treatment and/or prevention of cognitive disorders, including dementing conditions such as Alzheimer's disease, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.
  • Cognition enhancement can be shown by testing the compounds in the Morris watermaze as reported by McNamara and Skelton, Psychobiology, 1993, 21, 101-108. Further details of relevant methodology are described in WO 96/25948.
  • Cognitive disorders for which the compounds of the present invention may be of benefit include delirium, dementia, amnestic disorders, and cognition deficits, including age-related memory deficits, due to traumatic injury, stroke, Parkinson's disease and Down Syndrome. Any of these conditions may be attributable to substance abuse or withdrawal.
  • dementia include dementia of the Alzheimer's type with early or late onset, and vascular dementia, any of which may be uncomplicated or accompanied by delirium, delusions or depressed mood; and dementia due to HIV disease, head trauma, Parkinson's disease or Creutzfeld- Jakob disease.
  • the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called "blood-brain barrier".
  • the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.
  • Unit dosage forms of the present invention contain from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • a suitable dosage level is about 0.01 to 250 mg kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • the compounds in accordance with the present invention may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV:
  • L 1 represents a suitable leaving group
  • M 1 represents a boronic acid moiety -B(OH) 2 or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol, or M 1 represents -Sn(Alk)3 in which Alk represents a C ⁇ -6 alkyl group, typically /rbutyl; in the presence of a transition metal catalyst.
  • the leaving group L 1 is typically a halogen atom, e.g. chloro or bromo.
  • the transition metal catalyst of use in the reaction between compounds III and TV is suitably tetrakis(triphenylphosphine) _ palladium( ⁇ ).
  • the reaction is conveniently carried out at an elevated temperature in a solvent such as ⁇ '-dimethylacetamide, 1,2- dimethoxyethane, 1,4-dioxane or tetrahydrofuran, advantageously in the presence of potassium phosphate, copperCD iodide, sodium carbonate, cesium carbonate or sodium hydrogencarbonate.
  • the transition metal catalyst employed may be dichloro[l,l'-bis(diphenyl- phosphino)ferrocene]palladium(II), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as N,N- dimethylformamide, advantageously in the presence of potassium phosphate.
  • the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula V with a compound of formula VI-
  • X 1 , X 2 , Y, Z, R 1 , L 1 and M 1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and TV.
  • the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula VII with a compound of formula VIII:
  • X 1 , X 2 , Z, R 1 , 1 and M 1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.
  • the leaving group L 1 is typically trifluoromethanesulfonyloxy (triflyloxy); or a halogen atom, e.g. bromo.
  • the transition metal catalyst employed is suitably dichlorobis(triphenylphosphine)- palladiumdl), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,2-dimethoxyethane, advantageously in the presence of sodium carbonate.
  • the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula IX with a compound of formula X:
  • X 1 , X 2 , Z, R 1 , L 1 and M 1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.
  • the compounds according to the present invention in which Y represents an oxygen atom may be prepared by a process which comprises reacting a compound of formula X as defined above with a compound of formula XI:
  • reaction is conveniently carried out under basic conditions, e.g. using sodium hydride in a solvent such as A ⁇ imethylformamide, typically at an elevated temperature which may be in the region of 120°C.
  • a solvent such as A ⁇ imethylformamide
  • the compounds according to the present invention in which Y represents a -NH- linkage may be prepared by a process which comprises reacting a compound of formula X as defined above with a compound of formula XII:
  • X 1 , X 2 and R 1 are as defined above.
  • the leaving group 1 in the compounds of formula X may suitably represent fluoro.
  • the reaction between compounds X and XII is conveniently carried out by heating the reactants, typically at a temperature in the region of 120°C, in a solvent such as A ⁇ ⁇ imethylformamide.
  • M 1 in the intermediates of formula TV and IX above represents a boronic acid moiety -B(OH) 2 or a cyclic ester thereof formed with pinacol or neopentyl glycol
  • the relevant compound TV or IX may be prepared by reacting bis(pinacolato)diboron or bis(neopentyl glycolato)diborane respectively with a compound of formula VI or VII as defined above; in the presence of a transition metal catalyst.
  • the transition metal catalyst of use in the reaction between bis(pinacolato)diboron or bis (neopentyl glycolato)diborane and compound VI or VII is suitably dichloro[l,l'-bis(diphenylphosphino)ferrocene]- palladiumdl).
  • the reaction is conveniently carried out at an elevated temperature in a solvent such as 1,4-dioxane, optionally in admixture with dimethylsulfoxide, typically in the presence of 1,1'- bis(diphenylphosphino)ferrocene and/or potassium acetate.
  • the relevant compound VII may be prepared by reacting the appropriate compound of formula XI as defined above with triflic anhydride, typically in the presence of pyridine; or with N- phenyltriflylimide, typically in the presence of triethylamine and an optional solvent such as dichloromethane. Analogous conditions may be utilised for preparing a compound of formula VI wherein L 1 represents triflyloxy from the corresponding hydroxy precursor.
  • the intermediates of formula XI above may suitably be prepared from the appropriate methoxy- substituted precursor of formula XIII:
  • X 1 , X 2 and R 1 are as defined above; by treatment with boron tribromide, typically in chloroform or dichloromethane; or with hydrogen bromide, typically in acetic acid at reflux.
  • X 1 , X 2 and M 1 are as defined above, and Y 1 represents amino or methoxy; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.
  • the transition metal catalyst of use in the reaction between compounds III and XIV is suitably tetrakis(triphenylphosphine)- palladium( ⁇ ), in which case the reaction is conveniently carried out at an elevated temperature in a solvent such as aqueous 1,2-dimethoxyethane, advantageously in the presence of sodium carbonate.
  • M 1 in the intermediates of formula V above represents
  • this compound may be prepared by reacting a compound of formula III as defined above with a reagent of formula (Alk)3Sn-Hal, in which Hal represents a halogen atom, typically chloro.
  • a reagent of formula (Alk)3Sn-Hal in which Hal represents a halogen atom, typically chloro.
  • the reaction is conveniently effected by treating compound III with isopropylmagnesium chloride, typically in a solvent such as tetrahydrofuran, with subsequent addition of the stannyl reagent (Alk) 3 Sn-Hal.
  • the intermediates of formula XV may be prepared by reacting a compound of formula XVI with a compound of formula XVII:
  • R 1 is as defined above, and Alk 1 represents Ci- ⁇ alkyl, typically ethyl; followed by saponification and decarboxylation.
  • reaction between compounds XVI and XVII is conveniently effected at an elevated temperature, for example in 1,4-dioxane at 100°C followed by Dowtherm at reflux.
  • Saponification of the compound thereby obtained may conveniently be effected by heating, typically at reflux, in a basic medium such as aqueous potassium hydroxide.
  • the subsequent decarboxylation step can conveniently be accomplished by heating in Dowtherm at reflux.
  • the compounds according to the present invention wherein R 1 represents an aryl or heteroaryl moiety may be prepared by a process which comprises reacting a compound of formula XVIII with a compound of formula XIX:
  • R la represents an aryl or heteroaryl moiety
  • L 2 represents a suitable leaving group; in the presence of a transition metal catalyst.
  • the leaving group L 2 is typically a halogen atom, e.g. chloro.
  • the transition metal catalyst of use in the reaction between compounds XVIII and XIX is suitably tetrakis(triphenylphosphine)- palladium( ⁇ ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as A ⁇ A ⁇ -dimethylacetamide, typically in the presence of potassium phosphate or in the presence of lithium chloride and copperOO iodide.
  • the transition metal catalyst may suitably be tris(dibenzylideneacetone)dipalladium( ⁇ ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of tri-t ⁇ r ⁇ butylphosphine and cesium carbonate.
  • L 2 in the compounds of formula XIX above represents a halogen atom
  • these compounds correspond to compounds of formula I as defined above wherein R 1 represents halogen, and they may therefore be prepared by any of the methods described above for the preparation of the compounds according to the invention.
  • the compounds according to the invention in which Y represents a chemical bond and Z represents pyrrol- 1-yl may be prepared by reacting a compound of formula XII as defined above with 2,5-dimethoxy- tetrahydrofuran. The reaction is conveniently accomplished at an elevated temperature in a solvent such as acetic acid.
  • the starting materials of formula VIII, X, XIV, XVI, XVTI and XVTII may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
  • a compound of formula I wherein Z is substituted with cyano may be converted into the corresponding compound wherein Z is substituted with carboxamido by hydrolysis.
  • Other standard interconversions are described on pages 40-42 of WO-A-02074773.
  • the title compound was prepared by heating a mixture of 4-chloro- 8-fluoroquinoline (50 mg), 2'-fluoro-5'-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (prepared as described in WO 02/074773) (116 mg) and tetrakis(triphenylphosphine) ⁇ alladium( ⁇ ) (6.5 mg) in 1,2-dimethoxyethane (3 ml) and 2M sodium carbonate solution (0.5 ml) in a sealed tube at 150°C for 10 min using a Smith Microwave.
  • reaction mixture was partitioned between water (3 ml) and dichloromethane (3 ml) and this solution was passed through a phase separation cartridge.
  • the organic phase was concentrated in vacuo and the residue purified by silica gel chromatography eluting with dichloromethane on a gradient of methanol (1-3%).
  • the solid obtained was recrystallized from a mixture of ethyl acetate and isohexane to yield the title compound as a white sohd (19 mg), m.p.
  • a flask containing Dowtherm (30 ml) was heated to 240°C under nitrogen and the above product (1.2 g, 4.40 mmol) added portionwise over a period of 5 min. This mixture was heated at 240°C for a further 1.5 h and then allowed to cool to ambient temperature. The reaction was treated with a mixture of diethyl ether and isohexane (l ' -l, 200 ml) and the resulting precipitate collected by filtration.
  • the title compound was prepared in a similar manner as described in Example 1. Following work-up, the residue was purified by silica gel chromatography eluting with dichloromethane on a gradient of methanol (0-5%). The solid obtained was recrystallized from a mixture of ethyl acetate and isohexane to yield the title compound (38 mg, 46%), m.p.
  • EXAMPLE 8 8-Fluoro-4- r2-fluoro-3-(pyridin-3-yl)phenyll -7-trifluoro methylq uinoline
  • the title compound was prepared using 3-[2-fluoro-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-pyridine to give a pale yellow solid (47 mg, 60%): ⁇ H (360 MHz, CDCI3) 7.41-7.49 (3H, ), 7.61-7.69 (4H, m), 7.92 (IH, d, 7.8 Hz), 8.68 (lH, br s), 8.90 (lH, br s), 9.14 (lH, d, ⁇ 74.3 Hz); m/z (ES + ) 387 ( + +H).
  • the reaction was allowed to cool to ambient temperature and the solid removed from the reaction by 30 filtration.
  • the filtration cake was washed with diethyl ether (lOO ml) and then the filtrates were combined and concentrated in vacuo.
  • the residue was stirred with 2N sodium hydroxide solution (500 ml) for 45 min and the solid removed by filtration.
  • the aqueous component was cooled (0°C) and treated with 36% hydrochloric acid in a drop wise manner to pH 5 over a 15 min period.
  • the precipitate was allowed to stand at 0°C for 2 h and then filtered.

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Abstract

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X1 represents hydrogen, halogen, C1-6 alkyl, trifluoromethyl or C1-6 alkoxy; X2 represents hydrogen or halogen; Y represents a chemical bond, an oxygen atom, or a -NH- linkage; Z represents an optionally substituted aryl or heteroaryl group; R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra, -CONRaRb or -CRa=NORb; and Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group;a pharmaceutical composition comprising it, its use in therapy; use of it for manufacturing a medicament; and methods using it to treat or prevent anxiety, convulsions or cognitive disorders.

Description

QUINOLINE DER ATIVES WHICH ENHANCE COGNITION VIA THE
GABA-A RECEPTOR
The present invention relates to a class of substituted quinoline derivatives and to their use in therapy. More particularly, this invention is concerned with 8-fluoroquinoline analogues which are substituted in the 4-position by a substituted phenyl ring. These compounds are ligands for GABAA receptors and are therefore useful in the therapy of deleterious neurological complaints. The technical background to the present invention is disclosed on pages 1-4 of WO-A-02074773.
The present invention provides a class of quinoline derivatives which possess desirable binding properties at various GABAA receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the α2 and/or α3 and/or α.5 subunit of the human GABAA receptor. The compounds of this invention may interact more favourably with the α2 and/or α3 subunit than with the αl subunit; and or may interact more favourably with the α5 subunit than with the αl subunit. The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the α2 and/or α3 and/or α5 subunit, as measured in the assay described hereinbelow, of 200 nM or less, typically of 100 nM or less, and ideally of 20 nM or less. The compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the α2 and/or α3 and/or αδ subunit relative to the αl subunit. However, compounds which are not selective in terms of their binding affinity for the α2 and/or α3 and/or α5 subunit relative to the αl subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of zero or weak (positive or negative) efficacy at the αl subunit and (i) a full or partial agonist profile at the α2 and/or α3 subunit, and/or (ii) an inverse agonist profile at the α5 subunit.
The present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
(I)
wherein X1 represents hydrogen, halogen, Ci-e alkyl, trifluoromethyl or Ci-β alkoxy;
X2 represents hydrogen or halogen;
Y represents a chemical bond, an oxygen atom, or a -NH- linkage; Z represents an optionally substituted aryl or heteroaryl group; R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SR , -SORa, -SO2Ra, "SO2NRaR , -NRaRb, -NRaCORb, -NRaCO Rb, -CORa, -CO2Ra, -CONRaRb or -CRa=NORb; and
Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.
The aryl or heteroaryl group Z in the compounds of formula I above may be unsubstituted, or substituted by one or more substituents. Typically, the group Z will be unsubstituted, or substituted by one or two substituents. Suitably, the group Z is unsubstituted or monosubstituted. Typical substituents on the group Z include halogen, trifluoromethyl, cyano, carboxamido, nitro, Ci-β alkyl, hydroxy, Ci-β alkoxy, oxy, Ci-β alkylsulphonyl, amino, aminocarbonyl, formyl, C2-6 alkoxycarbonyl and -CRa=NORb, wherein Ra and Rb are as defined above.
Information about salts useful in the present invention, definitions of the term "hydrocarbon" and the expression "a heterocyclic group", suitable alkyl, alkenyl, alkynyl and cycloalkyl groups, typical C3-7cycloalkyl(Cι-β)alkyl groups, particular indanyl, aryl and aryl(Cι-6)alkyl groups, suitable heterocycloalkyl and heteroaryl groups, the expression "hetero(Cι-6)alkyl", optional substituents on hydrocarbon and heterocyclic groups, the term "halogen" and asymmetric compounds can be found on pages 6 to 9 of WO-A-02074773.
Suitable values for the X1 substituent include hydrogen, fluoro, chloro, methyl, trifluoromethyl and methoxy; in particular hydrogen or fluoro; and especially fluoro. Typical values of X2 include hydrogen and fluoro, especially hydrogen.
In a preferred embodiment, Y represents a chemical bond. In another embodiment, Y represents an oxygen atom. In a further embodiment, Y represents a -NH- linkage. Selected values for the substituent Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl, any of which groups may be optionally substituted by one or more substituents. In one favoured embodiment, Z represents an optionally substituted phenyl group, in particular monosubstituted or disubstituted phenyl. In another favoured embodiment, Z represents optionally substituted pyridinyl, especially unsubstituted, monosubstituted or disubstituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl. Examples of suitable substituents on the group Z include fluoro, chloro, trifluoromethyl, cyano, carboxamido, nitro, methyl, hydroxy, methoxy, oxy, methanesulphonyl, amino, aminocarbonyl, formyl, methoxycarbonyl and -CH=NOH.
Examples of particular substituents on the group Z include fluoro, trifluoromethyl, cyano and carboxamido. Detailed values of Z include trifluoromethyl-phenyl, cyanophenyl,
(cyano) (fluorophenyl, (chloro) (cyano)phenyl, (carboxamido) (fluorophenyl, nitrophenyl, methoxyphenyl, methanesulphonyl-phenyl, pyridinyl, fluoro- pyridin l, difluoro-pyridinyl, (amino) (chloro)pyridinyl, cyano-pyridinyl, carboxamido-pyridinyl, methyl-pyridinyl, hydroxy-pyridinyl, methoxy- pyridinyl, oxy-pyridinyl, aminocarbonyl-pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyano-thienyl, aminocarbonyl-thienyl, formyl- thienyl, methoxycarbonyl-thienyl, thienyl-CH=NOH, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and methyl-tetrazolyl.
Specific values of Z include trifluoromethyl-phenyl, cyanophenyl, (cyano) (fluorophenyl, (carboxamido) (fluorophenyl, pyridinyl, carboxamido-pyridinyl and pyrimidinyl.
Typically, R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, -CORa, -CO2Ra or -CRa=NORb.
Typical values of Ra include hydrogen and C1.-6 alkyl. Suitably, Ra represents hydrogen or methyl.
Typical values of Rb include hydrogen, Ci-β alkyl, hydroxy (Ci-β) alkyl and di(Cι-6)alkylamino(Cι-6)alkyl. Suitably, Rb represents hydrogen, methyl, ethyl, hydroxyethyl or dimethyla inoethyl. Particular values of Rb include hydrogen, hydroxyethyl and dimethylaminoethyl, especially hydrogen or dimethylaminoethyl.
Suitable values of R1 include hydrogen, C1-6 alkyl, halo(Cι-6)alkyl, dihalo(Cι-β)alkyl, hydroxy(Cι-6)alkyl, dihydroxy(Cι-β)alkyl, Cι-6 alkoxy(Cι-6) alkyl, di(Cι-6)alkoxy(Cι-6)alkyl, cyano(Cι-β)alkyl, C2-6 alkoxycarbonyl(Cι-6)alkyl, C3-7 cycloalkyl, heteroaryl, Ci-6 alkyl-heteroaryl, heteroaryl(Cι-6)alkyl, halogen, cyano, trifluoromethyl, formyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl and -CRa=NORb, in which Ra and Rb are as defined above.
Representative values of R1 include hydrogen, Ci-β alkyl, halo(Cι-6)alkyl, hydroxy(Cι-β)alkyl and trifluoromethyl. Individual values of R1 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1 -hydroxyethyl), fluoroethyl (especially
1-fludroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl
(especially 1,1 -dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop_2-yl), dihydroxypropyl (especially l,2-dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), cyanopropyl (especially 2- cyanoprop-2-yl), methoxycarbonylpropyl (especially 2- methoxycarbonylprop-2-yl), tertrbutyl, hydroxybutyl (especially 1-hydroxy-
2-methylprop-2-yl), cyclopropyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, formyl, acetyl, methoxycarbonyl and
-CR2=NOR3, in which R2 represents hydrogen or methyl, and R3 represents hydrogen, hydroxyethyl or dimethylaminoethyl.
In one embodiment, R1 represents hydrogen. In a favoured embodiment, R1 represents 2_hydroxyprop-2-yl. In another embodiment,
R1 represents 2-fluoroprop-2-yl. In an additional embodiment, R1 represents trifluoromethyl. In a further embodiment, R1 represents methyl.
Suitably, R2 is hydrogen. Suitably, R3 represents hydrogen or dimethylaminoethyl, especially hydrogen.
A particular sub-class of compounds according to the invention is represented by the compounds of formula HA, and pharmaceutically acceptable salts thereof:
Figure imgf000007_0001
12
X
(UA)
wherein
Z is as defined above; X11 represents hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy;
X12 represents hydrogen or fluoro;
RH represents hydrogen, Ci-β alkyl, halo(Ci-6)alkyl, dihalo(Cι-β)alkyl, hydroxy(Ci-6)alkyl, dihydroxy(Cι-6)alkyl, Ci-β alkoxy(Cι-6)alkyl, di(Cι-6)alkoxy(Cι-6)alkyl, cyano(Cι-β)alkyl, C2-e alkoxycarbonyl(Cι-6)alkyl, C3-7 cycloalkyl, heteroaryl, Ci-β alkyl-heteroaryl, heteroaryl(Cι-6)alkyl, halogen, cyano, trifluoromethyl, formyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl or -CR4=NOR5;
R4 represents hydrogen or Ci-β alkyl; and R5 represents hydrogen, Ci-e alkyl, hydroxy (Cι-6)alkyl or di(Cι-6)alkylamino(Cι-6) alkyl.
Suitable values of X11 include hydrogen and fluoro, especially fluoro.
In a favoured embodiment, X12 represents hydrogen. In another embodiment, X12 represents fluoro. Suitably, R4 represents hydrogen or methyl, especially hydrogen.
Suitably, R5 represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of R5 include hydrogen, hydroxyethyl and dimethylaminoethyl. Typically, R5 represents hydrogen or dimethylaminoethyl, especially hydrogen. Where R11 represents heteroaryl, this group is suitably pyridinyl, furyl, thienyl or oxazolyl.
Where R11 represents Ci-β alkyl-heteroaryl, this group is suitably methylthiazolyl (e.g. 2-methylthiazol-5-yl) or methyloxadiazolyl (e.g. 3- methyl- [1,2, 4]oxadiazol-5-yl).
Where Rn represents heteroaryl(Cι-6)alkyl, this group is suitably imidazolylmethyl or triazolylmethyl.
Representative values of R11 include hydrogen, Ci-β alkyl, hydroxy(Cι-β) alkyl, fluoro(Cι-6)alkyl and trifluoromethyl. Individual values of R11 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1 -hydroxyethyl), fluoroethyl (especially 1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1 -dimethox ethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), dihydroxypropyl (especially l,2-dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), cyanopropyl (especially 2- cyanoprop-2-yl), methoxycarbonylpropyl (especially 2- methoxycarbonylprop-2-yl), tertrhutyl, hydroxybutyl (especially 1-hydroxy- 2-methylprop-2-yl), cyclopropyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, formyl, acetyl, methoxycarbonyl and -CR2=NOR3, in which R2 and R3 are as defined above.
In one embodiment, R11 represents hydrogen. In a favoured embodiment, Ru represents 2-hydroxyprop-2-yl. In another embodiment, R11 represents 2-fluoroprop-2-yl. In an additional embodiment, R11 represents trifluoromethyl. In a further embodiment, R11 represents methyl.
One representative subset of the compounds of formula IIA above is represented by the compounds of formula IIB, and pharmaceutically acceptable salts thereof
Figure imgf000009_0001
(IIB)
wherein X11, X12 and R11 are as defined above; and
R6 represents hydrogen or fluoro.
In one embodiment, R6 is hydrogen.
In another embodiment, R6 is fluoro, in which case the fluorine atom R6 is favourably attached to the phenyl ring at the 4-, 5- or 6-position (relative to the cyano group at position 2).
Another representative subset of the compounds of formula HA above is represented by the compounds of formula IIC, and pharmaceutically acceptable salts thereof
Figure imgf000009_0002
(IIC)
wherein X11, X12 and R11 are as defined above; and
R7 represents hydrogen, fluoro, cyano or carboxamido. In one embodiment, R7 is hydrogen.
In an additional embodiment, R7 is fluoro.
In another embodiment, R7 is cyano.
In a further embodiment, R7 is carboxamido.
A further representative subset of the compounds of formula IIA above is represented by the compounds of formula IID, and pharmaceutically acceptable salts thereof
Figure imgf000010_0001
(IID)
wherein X11, X12, R7 and R11 are as defined above; and
R8 represents hydrogen or fluoro.
Suitably, R8 represents hydrogen.
In another embodiment, R8 represents fluoro.
Specific compounds within the scope of the present invention include:
2'-fluoro-5'-(8-fluoroquinolin-4-yl)biphenyl-2-carbonitrile; 2'-fluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-2- carbonitrile;
2'-fluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-3- carbonitrile;
4,2'-difluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-2- carbonitrile; 4,2'-difluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-2- carboxylic acid amide;
4-[2,4-difluoro-3-(pyridin-3-yl)phenyl]-8-fluoro-7-trifluoromethylquinoline;
8-fluoro-4-[4-fluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylquinoline; 8-fluoro-4" [2-fluoro-3-(pyridin-2-yl)phenyl] -7-trifluoromethylquinoline;
8-fluoro-4-[2-fluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylquinoline;
8-fluoro-4-[2-fluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylquinoline;
4-[2,4-difluoro-3-(pyridin-4-yl)phenyl]-8-fluoro-7-trifluoromethylquinoline;
8-fluoro-4-[4-fluoro-3-(pyrimidin-4-yl)phenyl]-7-trifluoromethylquinoline; 2-[2-fluoro-5-(8-fluoro-7-trifluoromethylquinolin-4-yl)phenyl]nicotinamide;
2'-fluoro-3'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-2- carbonitrile;
8- fluoro- 4- (2 -fluoro- 2 ' -trifluoromethylbiphenyl- 5 -yl) - 7 - trifluoromethyl- quinoline; and pharmaceutically acceptable salts thereof.
Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof. Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof. Details of the binding affinity, functional efficacy, and anxiolytic and anticonvulsant activity of the present compounds can be found on pages 27 and 28 of WO-A-02074773.
In another aspect, the present invention provides a method for the treatment and/or prevention of cognitive disorders, including dementing conditions such as Alzheimer's disease, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.
Cognition enhancement can be shown by testing the compounds in the Morris watermaze as reported by McNamara and Skelton, Psychobiology, 1993, 21, 101-108. Further details of relevant methodology are described in WO 96/25948.
Cognitive disorders for which the compounds of the present invention may be of benefit include delirium, dementia, amnestic disorders, and cognition deficits, including age-related memory deficits, due to traumatic injury, stroke, Parkinson's disease and Down Syndrome. Any of these conditions may be attributable to substance abuse or withdrawal. Examples of dementia include dementia of the Alzheimer's type with early or late onset, and vascular dementia, any of which may be uncomplicated or accompanied by delirium, delusions or depressed mood; and dementia due to HIV disease, head trauma, Parkinson's disease or Creutzfeld- Jakob disease.
In order to elicit their behavioural effects, the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called "blood-brain barrier". Preferably, the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.
Details of pharmaceutical formulations of use in the present invention can be found on pages 29 and 30 of WO-A-02074773.
Unit dosage forms of the present invention contain from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
In the treatment of neurological disorders, a suitable dosage level is about 0.01 to 250 mg kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day. The compounds in accordance with the present invention may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV:
Figure imgf000013_0001
(ill) (IV)
wherein X1, X2, Y, Z and R1 are as defined above, L1 represents a suitable leaving group, and M1 represents a boronic acid moiety -B(OH)2 or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol, or M1 represents -Sn(Alk)3 in which Alk represents a Cι-6 alkyl group, typically /rbutyl; in the presence of a transition metal catalyst.
The leaving group L1 is typically a halogen atom, e.g. chloro or bromo. The transition metal catalyst of use in the reaction between compounds III and TV is suitably tetrakis(triphenylphosphine)_ palladium(θ). The reaction is conveniently carried out at an elevated temperature in a solvent such as Λ^Λ'-dimethylacetamide, 1,2- dimethoxyethane, 1,4-dioxane or tetrahydrofuran, advantageously in the presence of potassium phosphate, copperCD iodide, sodium carbonate, cesium carbonate or sodium hydrogencarbonate. Alternatively, the transition metal catalyst employed may be dichloro[l,l'-bis(diphenyl- phosphino)ferrocene]palladium(II), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as N,N- dimethylformamide, advantageously in the presence of potassium phosphate. In an alternative procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula V with a compound of formula VI-
Figure imgf000014_0001
(V) (VI)
wherein X1, X2, Y, Z, R1, L1 and M1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and TV. In another procedure, the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula VII with a compound of formula VIII:
Figure imgf000014_0002
wherein X1, X2, Z, R1, 1 and M1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV. In the compounds of formula VI and VII above, the leaving group L1 is typically trifluoromethanesulfonyloxy (triflyloxy); or a halogen atom, e.g. bromo.
In the reaction between compounds VII and VIII, the transition metal catalyst employed is suitably dichlorobis(triphenylphosphine)- palladiumdl), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,2-dimethoxyethane, advantageously in the presence of sodium carbonate.
Alternatively, the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula IX with a compound of formula X:
Figure imgf000015_0001
(IX) (X)
wherein X1, X2, Z, R1, L1 and M1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.
In an additional procedure, the compounds according to the present invention in which Y represents an oxygen atom may be prepared by a process which comprises reacting a compound of formula X as defined above with a compound of formula XI:
Figure imgf000016_0001
wherein X1, X2 and R1 are as defined above.
The reaction is conveniently carried out under basic conditions, e.g. using sodium hydride in a solvent such as AζΛ imethylformamide, typically at an elevated temperature which may be in the region of 120°C.
In a further procedure, the compounds according to the present invention in which Y represents a -NH- linkage may be prepared by a process which comprises reacting a compound of formula X as defined above with a compound of formula XII:
Figure imgf000016_0002
(XII)
wherein X1, X2 and R1 are as defined above. In relation to the reaction between compounds X and XII, the leaving group 1 in the compounds of formula X may suitably represent fluoro. The reaction between compounds X and XII is conveniently carried out by heating the reactants, typically at a temperature in the region of 120°C, in a solvent such as Aζ Λ imethylformamide.
Where M1 in the intermediates of formula TV and IX above represents a boronic acid moiety -B(OH)2 or a cyclic ester thereof formed with pinacol or neopentyl glycol, the relevant compound TV or IX may be prepared by reacting bis(pinacolato)diboron or bis(neopentyl glycolato)diborane respectively with a compound of formula VI or VII as defined above; in the presence of a transition metal catalyst. The transition metal catalyst of use in the reaction between bis(pinacolato)diboron or bis (neopentyl glycolato)diborane and compound VI or VII is suitably dichloro[l,l'-bis(diphenylphosphino)ferrocene]- palladiumdl). The reaction is conveniently carried out at an elevated temperature in a solvent such as 1,4-dioxane, optionally in admixture with dimethylsulfoxide, typically in the presence of 1,1'- bis(diphenylphosphino)ferrocene and/or potassium acetate.
Where L1 in the intermediates of formula VTI above represents triflyloxy, the relevant compound VII may be prepared by reacting the appropriate compound of formula XI as defined above with triflic anhydride, typically in the presence of pyridine; or with N- phenyltriflylimide, typically in the presence of triethylamine and an optional solvent such as dichloromethane. Analogous conditions may be utilised for preparing a compound of formula VI wherein L1 represents triflyloxy from the corresponding hydroxy precursor. The intermediates of formula XI above may suitably be prepared from the appropriate methoxy- substituted precursor of formula XIII:
Figure imgf000018_0001
wherein X1, X2 and R1 are as defined above; by treatment with boron tribromide, typically in chloroform or dichloromethane; or with hydrogen bromide, typically in acetic acid at reflux.
The intermediates of formula XII and XIII above may be prepared by reacting a compound of formula III as defined above with the appropriate compound of formula XIV: '
Figure imgf000018_0002
(XIV)
wherein X1, X2 and M1 are as defined above, and Y1 represents amino or methoxy; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV. In particular, the transition metal catalyst of use in the reaction between compounds III and XIV is suitably tetrakis(triphenylphosphine)- palladium(θ), in which case the reaction is conveniently carried out at an elevated temperature in a solvent such as aqueous 1,2-dimethoxyethane, advantageously in the presence of sodium carbonate. Where M1 in the intermediates of formula V above represents
-Sn(Alk)3 and Alk is as defined above, this compound may be prepared by reacting a compound of formula III as defined above with a reagent of formula (Alk)3Sn-Hal, in which Hal represents a halogen atom, typically chloro. The reaction is conveniently effected by treating compound III with isopropylmagnesium chloride, typically in a solvent such as tetrahydrofuran, with subsequent addition of the stannyl reagent (Alk)3Sn-Hal.
Where L1 in the intermediates of formula III above represents chloro, this compound may be prepared by treatment of the corresponding compound of formula XV:
Figure imgf000019_0001
(XV) wherein R1 is as defined above; with phosphorus oxychloride, typically by stirring the reactants at ambient temperature.
The intermediates of formula XV may be prepared by reacting a compound of formula XVI with a compound of formula XVII:
Figure imgf000019_0002
wherein R1 is as defined above, and Alk1 represents Ci-β alkyl, typically ethyl; followed by saponification and decarboxylation.
The reaction between compounds XVI and XVII is conveniently effected at an elevated temperature, for example in 1,4-dioxane at 100°C followed by Dowtherm at reflux. Saponification of the compound thereby obtained may conveniently be effected by heating, typically at reflux, in a basic medium such as aqueous potassium hydroxide. The subsequent decarboxylation step can conveniently be accomplished by heating in Dowtherm at reflux.
In a yet further procedure, the compounds according to the present invention wherein R1 represents an aryl or heteroaryl moiety may be prepared by a process which comprises reacting a compound of formula XVIII with a compound of formula XIX:
Figure imgf000020_0001
xΛ
(XVIII)
(XIX)
wherein X1, X2, Y, Z and M1 are as defined above, Rla represents an aryl or heteroaryl moiety, and L2 represents a suitable leaving group; in the presence of a transition metal catalyst. The leaving group L2 is typically a halogen atom, e.g. chloro.
The transition metal catalyst of use in the reaction between compounds XVIII and XIX is suitably tetrakis(triphenylphosphine)- palladium(θ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as A^A^-dimethylacetamide, typically in the presence of potassium phosphate or in the presence of lithium chloride and copperOO iodide. Alternatively, the transition metal catalyst may suitably be tris(dibenzylideneacetone)dipalladium(θ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of tri-tør^butylphosphine and cesium carbonate.
Where L2 in the compounds of formula XIX above represents a halogen atom, these compounds correspond to compounds of formula I as defined above wherein R1 represents halogen, and they may therefore be prepared by any of the methods described above for the preparation of the compounds according to the invention.
The compounds according to the invention in which Y represents a chemical bond and Z represents pyrrol- 1-yl may be prepared by reacting a compound of formula XII as defined above with 2,5-dimethoxy- tetrahydrofuran. The reaction is conveniently accomplished at an elevated temperature in a solvent such as acetic acid.
Where they are not commercially available, the starting materials of formula VIII, X, XIV, XVI, XVTI and XVTII may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
A compound of formula I wherein Z is substituted with cyano may be converted into the corresponding compound wherein Z is substituted with carboxamido by hydrolysis. Other standard interconversions are described on pages 40-42 of WO-A-02074773.
Standard methods for purifying, resolving and protecting compounds are described on pages 42 to 43 of WO-A-02074773.
Assays for testing the present compounds are described on pages 43 and 44 of WO-A-02074773. The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [3H]-flumazenil from the α2 and/or α3 and/or α5 subunit of the human GABAA receptor of 100 nM or less.
The following Examples illustrate the preparation of compounds according to the invention. EXAMPLE 1 2'-Fluoro-5'-(8-fluoroαuinolin-4-yl)bipheny1-2-carbonitrile
The title compound was prepared by heating a mixture of 4-chloro- 8-fluoroquinoline (50 mg), 2'-fluoro-5'-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (prepared as described in WO 02/074773) (116 mg) and tetrakis(triphenylphosphine)ρalladium(θ) (6.5 mg) in 1,2-dimethoxyethane (3 ml) and 2M sodium carbonate solution (0.5 ml) in a sealed tube at 150°C for 10 min using a Smith Microwave. The reaction mixture was partitioned between water (3 ml) and dichloromethane (3 ml) and this solution was passed through a phase separation cartridge. The organic phase was concentrated in vacuo and the residue purified by silica gel chromatography eluting with dichloromethane on a gradient of methanol (1-3%). The solid obtained was recrystallized from a mixture of ethyl acetate and isohexane to yield the title compound as a white sohd (19 mg), m.p. 177-178°C: δH (400 MHz, CDC13) 7.38-7.53 (4H, m), 7.58-7.61 (4H, m), 7.67 (lH, t, Jl.l Hz), 7.80 (2H, t, J1.2 Hz), 9.01 (lH, s); m/z (ES+) 343 (M++H); Anal. Found: C, 77.03; H, 3.37; N, 8.03%. C22H12F2N2 requires: C, 77.18; H, 3.53; N, 8.18%.
EXAMPLE 2 2'-Fluoro-5'-(8-fluoro-7-trifluoromethylαuinolin-4- yl)biphenyl- 2-carbonitrile
a) 2- [(2-Fluoro-3-trifluoromethylphenylamino)methylene] malonic acid diethyl ester A mixture of 3-amino-2-fluorobenzotrifluoride (2 g, 15.5 mmol) and ethoxymethylenemalonic acid diethyl ester (2.4 g, 11.1 mmol) in 1,4- dioxane (20 ml) was heated at 100°C for 18 h. The reaction was cooled to ambient temperature and then concentrated in vacuo to give the title compound as a crude residue (3.75g, 98%): m/z (Ε.S+) 350 (M++H). b) 8-Fluoro-7-trifluoromethyl-lH-quinolin-4-one-3-carboxylic acid ethyl ester
A vessel containing Dowtherm (30 ml) and equipped with an internal thermometer was heated to 220°C under nitrogen. The above product (2.74 g, 7.85 mmol) was added portionwise over a period of 10 min. This mixture was heated at 250°C for a further 2.5 h and then allowed to cool to ambient temperature. The reaction mixture was treated with diethyl ether (ca. 200 ml) and the resulting precipitate collected by filtration. The solid was washed with diethyl ether (2 x 100 ml) and dried under vacuum at 40°C for 16 h to afford the title compound (2.21 g, 93%): δH (400 MHz, DMSO) 1.29 (3H, t, JQ. Hz), 4.24 (2H, q, J7.0 Hz), 7.71 (1H, t, J6.6 Hz), 8.11 (lH, J8.7 Hz), 8.46 (lH, s); m/z (ES+) 304 (M++H).
c) 8-Fluoro-7-trifluoromethyl-lH-quinolin-4-one-3-carboxylic acid To a solution of potassium hydroxide (2.33 g, 41.5 mmol) in water
(10 ml) was added the above product (2.1 g, 6.9 mmol) and the mixture was heated at reflux for 2 h. The resulting aqueous solution was allowed to cool to ambient temperature prior to acidification with hydrochloric acid (lM) to pH 4. The resulting precipitate was collected by filtration, washed with water (2 x 50 ml), diethyl ether (l x 50 ml) and then dried under vacuum over phosphorus pentoxide to afford the title compound (1.3 g, 69%): δH (400 MHz, DMSO) 7.87 (lH, t, =76.6 Hz), 8.25 (lH, d, J8.6 Hz), 8.75 (1H, s), 14.00 (2H, br s); m/z (ES+) 276 (M++H).
d) 8-Fluoro-7-trifluoromethyl-lH-quinohn-4-one
A flask containing Dowtherm (30 ml) was heated to 240°C under nitrogen and the above product (1.2 g, 4.40 mmol) added portionwise over a period of 5 min. This mixture was heated at 240°C for a further 1.5 h and then allowed to cool to ambient temperature. The reaction was treated with a mixture of diethyl ether and isohexane (l'-l, 200 ml) and the resulting precipitate collected by filtration. The solid was washed with a mixture of diethyl ether and isohexane (i:i, 50 ml) and dried under vacuum to give the title compound (1.01 g, 99.5%): δH (400 MHz, DMSO) 6.10 (1H, d, J1A Hz), 7.60 (lH, t, J6.9 Hz), 7.97 (lH, t, -77.0 Hz), 8.05 (1H, d, -78.5 Hz), 12.21 (lH, s); /z (ES+) 232 (M++H).
e) 4- Chloro- 8-fluoro- 7-trifluoromethylquinoline
The above product (l.O g, 4.33 mmol) was added with care to a vessel previously charged with phosphorus oxychloride in a portionwise manner over 5 min. This mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was carefully partitioned between dichloromethane (50 ml) and saturated aqueous sodium hydrogencarbonate (50 ml). The aqueous component was extracted with dichloromethane (3 x 25 ml) and the combined organic extracts washed with brine (3 x 50 ml) before drying over MgS0 and filtering off the drying agent. The filtrate was concentrated in vacuo to give the title compound (0.98 g, 91%): δH (400 MHz, CDC13) 7.67 (lH, d, J4..6 Hz), 7.80 (1H, t, ,76.4 Hz), 8.13 (lH, d, J9.0 Hz), 8.94 (lH, s); mlz(E8+) 250, 252 (M++H).
f) 2'-Fluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-2- carbonitrile
The title compound was prepared in a similar manner as described in Example 1. Following work-up, the residue was purified by silica gel chromatography eluting with dichloromethane on a gradient of methanol (0-5%). The solid obtained was recrystallized from a mixture of ethyl acetate and isohexane to yield the title compound (38 mg, 46%), m.p. 182- 3°C: δH (400 MHz, CDCI3) 7.44 (lH, t, -79.4 Hz), 7.52-7.62 (5H, m), 7.70 (2H, t, J8.8 Hz), 7.83 (lH, d, Jl.8 Hz), 7.93 (lH, d, -78.9 Hz), 9.01 (lH, s); ^ ES -) 411 (M++H). The following compounds were made in the same way as Example 2 with the indicated starting materials in part f).
EXAMPLE 3 2'-Fluoro-5'-(8-fluoro-7-trifluoromethylαuinolin-4- yl)biphenyl-3-carbonitrile
The title compound was prepared using 5'-(5,5-dimethyl- [l,3,2]dioxaborinan-2-yl)-2'-fluorobiphenyl-3-carbonitrile (prepared as described in WO 02/074773) to give a white sohd (55 mg, 67%): δH (360 MHz, CDC13) 7.41 (IH, dd, 8.2, 1.7 Hz), 7.50-7.62 (4H, m), 7.66-7.72 (2H, m), 7.79 (IH, d, J9.0 Hz), 7.85 (lH, dd, -76.7, 1.3 Hz), 7.90 (lH, d, -71.3 Hz), 9.11 (IH, d, J4Λ Hz); /z (ES+) 411 (M++H).
EXAMPLE 4 4.2'-Difluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4- yl)biphenyl-2-carbonitrile and 4,2'-Difluoro-5'-(8-fluoro-7- trifluoromethylquinolin-4-yl)biphenyl-2-carboxylic acid amide The title carbonitrile was prepared using 4,2'-difluoro-5'-(5,5- dimethyl-[l,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile (prepared as described in WO 02/074773) to give a pale yellow solid (34 mg, 40%): δH (360 MHz, CDCI3) 7.40-7.47 (2H, m), 7.53-7.62 (5H, m), 7.70 (lH, dd, J6.6, 2.3 Hz), 7.91 (IH, d, J8.9 Hz), 9.10 (IH, d, -74.3 Hz); m/z (ES+) 429 (M++H).
The title amide was also formed in the same reaction mixture as a result of hydrolysis of a proportion of the carbonitrile title compound. This was isolated by flash chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-5%) to yield a pale cream solid (28 mg, 32%): δH (360 MHz, CDCI3) 5.69 (2H, br s), 7.23-7.36 (3H, m), 7.42-7.52 (3H, m), 7.54 (lH, d, 74.3 Hz), 7.68 (lH, dd, JQ.l, 2.3 Hz), 7.85 (IH, d, 9.0 Hz), 9.08 (lH, d, -74.3 Hz); m/z (ES+) 447 (M++H). EXAMPLE 5 4-r2.4-Difluoro-3-(pyridin-3-yl)phenyll-8-fluoro-7-trifluoro methylquinoline The title compound was prepared using 3-[2,6-difluoro-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]pyridine to give a yellow solid (26 mg, 32%): δH (360 MHz, CDC13) 7.24-7.28 (lH, t, -79.3 Hz), 7.40-7.46 (2H, m), 7.49-7.61 (2H, m), 7.68 (lH, dd, -76.3, 2.4 Hz), 7.87 (lH, d, Jl.9 Hz), 8.68 (IH, d, -72.9 Hz), 8.80 (lH, s), 9.14 (lH, d, -74.3 Hz); mlz(ES+) 405 (M++H).
EXAMPLE 6 8-Fluoro-4-r4-fluoro-3-(pyridin-2-yl)phenyll-7-trifluoro methylquinoline The title compound was prepared using 2-[2-fluoro-5-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-pyridine to give a pale cream solid (30 mg, 38%): δH (360 MHz, CDCI3) 7.29-7.40 (2H, m), 7.48-7.52 (lH, m), 7.57 (lH, d, -74.3 Hz), 7.65 (lH, dd, -76.6, 2.3 Hz), 7.79 (lH, d, Jl.l Hz), 7.82 (IH, d, J9.1 Hz), 7.91 (lH, d, -78.0 Hz), 8.19 (lH, dd, 2.3, 5.0 Hz), 8.71 (IH, d, -74.6 Hz), 9.09 (lH, d, J4.3 Hz); mlz (ES+) 387 (M++H).
EXAMPLE 7 8-Fluoro-4- [2-fluoro-3-(pyridin-2-yl)phenyll -7-trifluoro methylquinoline
The title compound was prepared using 2-[2-fluoro-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-pyridine to give a pale yellow sohd (59 mg, 76%): δH (360 MHz, CDCI3) 7.29-7.35 (lH, m), 7.40-7.50 (2H, m), 7.61-7.67 (3H, m), 7.75-7.79 (2H, m), 8.17 (lH, dt, Jl.9, 5.6 Hz), 8.78 (IH, d, J4.6 Hz), 9.14 (lH, d, -74.3 Hz); m/z (ES+) 387 (M++H).
EXAMPLE 8 8-Fluoro-4- r2-fluoro-3-(pyridin-3-yl)phenyll -7-trifluoro methylq uinoline The title compound was prepared using 3-[2-fluoro-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-pyridine to give a pale yellow solid (47 mg, 60%): δH (360 MHz, CDCI3) 7.41-7.49 (3H, ), 7.61-7.69 (4H, m), 7.92 (IH, d, 7.8 Hz), 8.68 (lH, br s), 8.90 (lH, br s), 9.14 (lH, d, <74.3 Hz); m/z (ES+) 387 ( ++H).
EXAMPLE 9 8-Fluoro-4- r2-fluoro-3-(pyridin-4-yl)phenvn -7-trifluoro methylquinohne
The title compound was prepared using 4-[2-fluoro-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-pyridine to give a white solid (38 mg, 49%): δH (360 MHz, CDC13) 7.44-7.50 (2H, m), 7.53 (2H, d, -74.6 Hz), 7.65-7.71 (2H, d, -74.6 Hz), 8.73 (2H, br s), 9.14 (lH, d, J4.S Hz); m/z (ES+) 387 (M++H).
EXAMPLE 10 4-[2.4-Difluoro-3-(pyridin-4-yl)phenyl1-8-fluoro-7-trifluoro methylquinoline The title compound was prepared using 4-[2,6-difluoro-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]pyridine to give a white solid (34 mg, 42%): δH (360 MHz, CDCI3) 7.24-7.29 (lH, dd, -71.2, 8.4 Hz), 7.42- 7.47 (3H, m), 7.57-7.59 (2H, m), 7.68 (2H, dd, J6.4, 2.4 Hz), 8.75 (2H, br s), 9.14 (IH, d, 4.3 Hz); m/z (ES+) 405 (M++H).
EXAMPLE 11 8-Fluoro-4- [4-fluoro-3-(pyrimidin-4-yl)phenvn -7-trifluoro methylquinoline The title compound was prepared using 4-[2-fluoro-5-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-pyrimidine to give a white solid (35 mg, 45%): δH (400 MHz, CDCI3) 7.41 (lH, dd, -72.6, 8.5 Hz), 7.57- 7.63 (2H, m), 7.67 (lH, dd, -72.5, 6.5 Hz), 7.78 (lH, d, -79.0 Hz), 7.95-7.97 (IH, m), 8.38 (lH, dd, J2Λ, 4.8 Hz), 8.85 (IH, s), 9.11 (lH, d, <74.4 Hz), 9.30 (IH, d, J1.3 Hz); /z (ES+) 388 (M++H). EXAMPLE 12 2-[2-Fluoro-5-(8-fluoro-7-trifluoromethylquinolin-4- vQphenyll nicotinamide The title compound was prepared using 2-[2-fluoro-5-(4,4,5,5" tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl] -nicotinamide to give a pale yellow solid (45 mg, 52%): δH (360 MHz, CDC13) 5.74 (2H, br s), 7.33 (lH, t, -78.6 Hz), 7.44 (lH, dd, -74.8, 3.0 Hz), 7.54-7.59 (2H, m), 7.67 (lH, dd, J 6.6, 2.4 Hz), 7.80 (lH, dd, J2.3, 4.6 Hz), 7.87 (lH, d, J8.9 Hz), 8.07 (lH, dd, J1.6, 6.2 Hz), 8.80 (lH, s), 9.08 (lH, d, J4.3 Hz); m/z (ES+) 430 (M++H).
10
EXAMPLE 13 2'-Fluoro-3'-(8-fluoro-7-trifluoromethylquinolin-4- yl)biphenyl-2-carbonitrile The title compound was prepared using 2'-fluoro-3'-(4,4,5,5- tetramethyl- [1,3,2] dioxaborolan-2-yl)biphenyl-3-carbonitrile to give a 15 white solid (23 mg, 28%): δH (360 MHz, CDCI3) 7.46-7.62 (6H, m), 7.68-7.74 (2H, m), 7.78 (lH, d, J9.2 Hz), 7.81 (lH, d, 7.8 Hz), 9.14 (lH, d, -74.4 Hz); m/z (ES+) 411 (M++H).
EXAMPLE 14 8-Fluoro-4-(2-fluoro-2'-trifluoromethylbiphenyl-5-yl)-7- 20 trifluoromethyl-quinoline
a) 2-(4-Fluoro-3-methoχyphenyl)-4,4,5,5-tetramethyI-[l,3,2]dioxaborolane ■ A mixture of 4-bromo-l-fluoro-2-methoxybenzene (5.0 g, 24.4 mmol), potassium acetate (4.79 g, 48.8 mmol), bis(pinacolato)diboron (7.12 g, 28.0 25 mmol) and dichloro[l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (l.OO g, 1.22 mmol) in 1,4-dioxane (50 ml) containing 4.5 ml of dimethylsulphoxide was degassed with nitrogen for 45 min and then heated at 90°C for 16 h. The reaction was allowed to cool to ambient temperature and the solid removed from the reaction by 30 filtration. The filtration cake was washed with diethyl ether (lOO ml) and then the filtrates were combined and concentrated in vacuo. The residue was stirred with 2N sodium hydroxide solution (500 ml) for 45 min and the solid removed by filtration. The aqueous component was cooled (0°C) and treated with 36% hydrochloric acid in a drop wise manner to pH 5 over a 15 min period. The precipitate was allowed to stand at 0°C for 2 h and then filtered. The resulting solid was washed with ice-cold water (100 ml) and dried at 40°C under high vacuum to give the title compound (5.52 g, 90%): δH (400 MHz, CDCls) 1-34 (12H, s), 3.92 (3H, s), 7.03-7.09 (lH, m), 7.37- 7.39 (2H, m).
b) 8-Fluoro-4-(4-fluoro-3-methoxyphenyl)-7-trifluoromethylquinoline
A mixture of 4-chloro-8-fluoro-7-trifluoromethylquinoline (0.25 g, 1.00 mmol) and the above product (0.33 g, 1.31 mmol) in ethylene glycol dimethyl ether (15 ml) and 2M aqueous sodium carbonate (2.51 ml, 5.02 mmol) was degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)-palladium(θ) (93 mg, 0.08 mmol) was then added and the mixture heated at 70°C for 14 h. The reaction was cooled to ambient temperature, poured onto 0.5N sodium hydroxide solution (50 ml) and stirred for 15 min at room temperature. The aqueous component was extracted with ethyl acetate (3 x 100 ml) and the combined organic extracts were dried over sodium sulphate. The drying agent was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica eluting with ethyl acetate to give the title compound (0.32 g, 94%): δH (360 MHz, CDCI3) 3.94 (3H, s), 6.99-7.07 (2H, m), 7.26 (lH, dd, J8.1, 2.2 Hz), 7.51 (lH, d, J4.3 Hz), 7.65 (IH, dd, -76.6, 2.4 Hz), 7.78 (lH, d, -79.0 Hz), 9.08 (lH, d, J Λ Hz); m/z (ES+) 340 (M++H).
c) 2-Fluoro-5-(8-fluoro-7-trifluoromethylquinolin-4-yl)phenol
To a solution of the above product (0.32 g, 0.94 mmol) in dichloromethane (7 ml) was added a 2M solution of boron tribromide (1.42 ml, 2.83 mmol) in a dropwise manner at 0°C. Stirring of the mixture was continued at this temperature for 5 h before cautious addition of methanol (2 ml) at 0°C to the reaction vessel. Water (50 ml) was added and then the aqueous phase was washed with dichloromethane (2 x 50 ml). The aqueous component was re-acidified to pH 1 with 5N hydrochloric acid and then extracted with dichloromethane (3 x 200 ml). The combined organic extracts were dried over sodium sulphate followed by removal of the drying agent by filtration. The filtrate was concentrated in vacuo to give the title compound (297 mg, 97%): δH (360 MHz, DMSO) 6.97-7.01 (lH, m), 7.12 (IH, dd, J2.2, 6.2 Hz), 7.38 (lH, dd, -78.3, 2.9 Hz), 7.72 (lH, d, <74.4 Hz), 7.87 (2H, dd, -79.0, 5.3 Hz), 9.12 (lH, d, J4Λ Hz), 10.28 (lH, s); m/z (ES+) 326 (M++H).
d) Trifluoromethanesulphonic acid 2-fluoro-5-(8-fluoro-7-trifluoromethyl- quinolin-4-yl)phenyl ester The above product (0.27 g, 0.84 mmol), A^phenyltrifluoromethane sulphonimide (0.36 g, 1.0 mmol) and triethylamine (0.11 g, 1.1 mmol) were stirred together at room temperature for 16 h under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo and the residue purified by flash column chromatography on silica eluting with dichloromethane to give the title compound (0.38 g, 100%): δH (400 MHz, CDC13) 7.28-7.34 (IH, m), 7.47-7.55 (3H, m), 7.67-7.74 (2H, m), 9.12 (lH, d, =74.4 Hz); m/z (ES+) 458 (M++H).
e) 8-Fluoro-4-(2-fluoro-2'-trifluoromethylbiphenyl-5-yl)-7-trifluoromethyl- quinoline
The title compound was prepared in a similar manner as described in Example 2 using trifluoromethanesulphonic acid 2-fluoro-5-(8-fluoro-7- trifluoromethylquinolin-4-yl)phenyl ester (100 mg, 0.22 mmol) and 2- trifluoromethyl-benzeneboronic acid (54 mg, 0.28 mmol). The residue was purified by preparative thin-layer chromatography on silica eluting with dichloromethane to give τηε τiτλε χoμπoυvδ (8.0 μγ, 8%): δH (360 MHz, CDCI3) 7.33-7.44 (3H, m), 7.50-7.58 (3H, m), 7.61-7.69 (2H, m), 7.81 (lH, d, -78.4 Hz), 9.09 (lH, d, J4.3 Hz); /z (ES+) 454 (M++H).

Claims

CLAJMS:
1. A compound of formula I, or a pharmaceutically acceptable salt thereof
Figure imgf000032_0001
(I)
wherein X1 represents hydrogen, halogen, Ci-β alkyl, trifluoromethyl or Ci-e alkoxy!
X2 represents hydrogen or halogen;
Y represents a chemical bond, an oxygen atom, or a -NH- linkage; Z represents an optionally substituted aryl or heteroaryl group; R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -S02Ra, -S02NRaR , -NRaRb, -NRaCOR , -NRaC02Rb, -CORa, -C02Ra, -CONRaRb or -CRa=NOR ; and
Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.
A compound according to claim 1 of formula IIA:
Figure imgf000033_0001
12
X
(IIA)
wherein
Z is as defined in claim l;
Xu represents hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy!
X12 represents hydrogen or fluoro;
R11 represents hydrogen, Ci-β alkyl, halo(Cι-6)alkyl, dihalo(Cχ-6)alkyl, hydroxy(Cι-6)alkyl, dihydroxy(Cχ-β)alkyl, Ci-β alkoxy(Cι-β) alkyl, di(Cχ-6)alkoxy(Cι-6)alkyl, cyano(Cι-β)alkyl, C2-e alkoxycarbonyl(Cι-6)alkyl, C3-7 cycloalkyl, heteroaryl, Cχ-β alkyl-heteroaryl, heteroaryl(Cι-β) alkyl, halogen, cyano, trifluoromethyl, formyl, C2-6 alkylcarbonyl, C2-β alkoxycarbonyl or -CR4=NOR5;
R4 represents hydrogen or Ci-β alkyl; and
R5 represents hydrogen, Ci-β alkyl, hydroxy(Cι-6)alkyl or di(C1-6)alkylamino(C1-6) alkyl.
A compound according to claiml or 2 of formula IIB:
Figure imgf000034_0001
(IIB)
wherein X11, X12 and R11 are as defined in claim l; and R6 represents hydrogen or fluoro.
4. A compound according to claim 1 or 2 of formula IIC-'
Figure imgf000034_0002
(IIC)
wherein X11, X12 and R11 are as defined in claim l; and
R7 represents hydrogen, fluoro, cyano or carboxamido.
5. A compound according to claim 1 or 2 of formula IID:
Figure imgf000035_0001
(IID)
wherein X11, X12, R7 and R11 are as defined in claim V, and R8 represents hydrogen or fluoro. Suitably, R8 represents hydrogen.
6. A compound according to claim 1 which is:
2'-fluoro-5'-(8-fluoroquinoUn-4-yl)biphenyl-2-carbonitrile;
2'-fluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-2- carbonitrile;
2'-fluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-3- carbonitrile;
4,2'-difluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-2- carbonitrile; 4,2'- difluoro" 5 ' - (8-fluoro- 7-trifluoromethylquinolin-4-yl)biphenyl- 2- carboxylic acid amide;
4-[2,4-difluoro-3-(pyridin-3-yl)phenyl]-8-fluoro-7-trifluoromethylquinoline;
8-fluoro-4-[4-fluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylquinoline;
8-fluoro-4-[2-fluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylquinoline; 8-fluoro-4-[2-fluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylquinoline;
8-fluoro-4-[2-fluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylquinoline;
4- [2,4-difluoro-3-(pyridin-4-yl)phenyl] -8-fluoro-7-trifluoromethylquinoline;
8-fluoro-4-[4-fluoro-3-(pyrimidin-4-yl)phenyl]-7-trifluoromethylquinoline; 2-[2-fluoro-5-(8-fluoro-7-trifluoromethylquinolin-4-yl)phenyl] nicotinamide; 2'-fluoro-3'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-2- carbonitrile! or
8-fluoro-4-(2-fluoro-2'-trifluoromethylbiphenyl-5-yl)-7-trifluoromethyl- quinoline; or a pharmaceutically acceptable salts thereof.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
8. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human body by therapy.
9. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of anxiety, convulsions or cognitive disorders.
10. A method for the treatment and/or prevention of anxiety, convulsions or cognitive disorders, which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
PCT/GB2003/004845 2002-11-13 2003-11-10 Quinoline derivatives which enhance cognition via the gaba-a receptor WO2004043930A1 (en)

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US7425556B2 (en) 2005-12-20 2008-09-16 Astrazeneca Ab Compounds and uses thereof
US7465795B2 (en) 2005-12-20 2008-12-16 Astrazeneca Ab Compounds and uses thereof
US7728142B2 (en) 2005-06-02 2010-06-01 Hoffmann-La Roche Inc. 3-methanesulfonylquinolines as GABAB enhancers
WO2013120438A1 (en) 2012-02-14 2013-08-22 中国科学院上海生命科学研究院 Substance for treatment or relief of pain

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WO2000058303A1 (en) * 1999-03-29 2000-10-05 Neurogen Corporation 4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands
WO2002074773A1 (en) * 2001-03-21 2002-09-26 Merck Sharp & Dohme Limited Imidazo-pyrimidine derivatives as ligands for gaba receptors

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006048146A1 (en) * 2004-11-01 2006-05-11 F. Hoffmann-La Roche Ag Quinoline as allosteric enhancers of the gaba-b receptors
US7576217B2 (en) 2004-11-01 2009-08-18 Hoffman-La Roche Inc. Quinolines as allosteric enhancers of the GABAB receptors
US7728142B2 (en) 2005-06-02 2010-06-01 Hoffmann-La Roche Inc. 3-methanesulfonylquinolines as GABAB enhancers
US7425556B2 (en) 2005-12-20 2008-09-16 Astrazeneca Ab Compounds and uses thereof
US7465795B2 (en) 2005-12-20 2008-12-16 Astrazeneca Ab Compounds and uses thereof
WO2013120438A1 (en) 2012-02-14 2013-08-22 中国科学院上海生命科学研究院 Substance for treatment or relief of pain

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