EP0126087A1 - Derives d'amino-azabicycloalkyle utilises en tant qu'antagonistes de la dopamine - Google Patents

Derives d'amino-azabicycloalkyle utilises en tant qu'antagonistes de la dopamine

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Publication number
EP0126087A1
EP0126087A1 EP19830903004 EP83903004A EP0126087A1 EP 0126087 A1 EP0126087 A1 EP 0126087A1 EP 19830903004 EP19830903004 EP 19830903004 EP 83903004 A EP83903004 A EP 83903004A EP 0126087 A1 EP0126087 A1 EP 0126087A1
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EP
European Patent Office
Prior art keywords
alkyl
formula
amino
compound
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19830903004
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German (de)
English (en)
Inventor
Francis David King
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
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Beecham Group PLC
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Filing date
Publication date
Priority claimed from GB838301782A external-priority patent/GB8301782D0/en
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0126087A1 publication Critical patent/EP0126087A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/08—Bridged systems

Definitions

  • Amino-azabicycloalkyl derivatives as dopamine antagonists are Amino-azabicycloalkyl derivatives as dopamine antagonists.
  • This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
  • EP.13 138 and EP.41 817 disclose benzamides having a bicyclic side chain and possessing dopamine antagonist activity.
  • heteroarylamines and heteroaryl- eneimines having a bicyclic heteroalkyl N-substituent have been discovered. Such compounds have dopamine antagonist activity.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, or N-oxide thereof, or a solvent adduct of any of the foregoing:
  • A is a group :
  • p and q each independently are 0 to 2 ;
  • R 5 is C 1-7 alkyl, - (CH 2 ) s R 10 , s being 0 to 2 and R 10 being C 3-8 cycloalkyl, -CH 2 ) t R 11 , t being 1 or 2 and R 11 being thienyl or phenyl optionally substituted by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy and C 1-4 alkyl optionally substituted by hydroxy, C 1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy.
  • R 3 and R 4 include hydrogen, chloro, bromo, CF 3 , formyl, acetyl, propionyl, n- and iso-butyryl; formylamino, acetylamino, propionylamino, n- and iso-butyrylamino; methylsulphonylamino, ethylsulphonylamino, n- and iso-propylsulphonylamino, methyl, ethyl and n- and iso-propylsulphone, -sulphinyl or -thia; nitro ; methoxy, ethoxy and n- and iso-propoxy; hydroxy; amino, aminocarbonyl aminosulphonyl and aminosulphonamido and amino, aminocarbonyl, aminosulphonyl and aminosulphonamido substituted by one or two methyl, ethyl, n- or iso-propyl
  • R 3 and R 5 taken together are methylenedioxy or ethylenedioxy, they are most suitably ethylenedioxy.
  • R 3 and R 4 are generally independent groups.
  • R 3 and R 4 groups include hydrogen, halogen amino, and methoxy, and acylamino and nitro, which can conveniently be converted to the corresponding amino groups.
  • R 3 is in the 4-position as numbered in formula (I) .
  • R 4 is in the 5-position.
  • R 3 groups include 4-amino and
  • R 3 is 4-amino.
  • R 4 groups include 5-halo, such 5-chloro.
  • R 3 is hydrogen, or 4-halo (eg chloro) , or -amino ; and R 4 is 5-C 1-6 alkyl S (O) n (such as 5-methylsulphonyl , -sulphinyl or -thio) or 5-optionally substituted aminosulphonyl.
  • group G and the heterobicycle nitrogen atom are separated by 2 or 3 carbon atoms, preferably 3.
  • the C-G. moiety is preferably in an equatorial orientation to the heterobicycle ring.
  • a preferred value of A is of formula (II).
  • A is a group of formula (II) as defined, p is suitably 0 or 1 , preferably 1 , and q is suitably 0 or 1.
  • A is a group of formula (III) as defined Z is 0 or S, preferably 0.
  • the most preferred is methyl.
  • R 5 C 1-4 alkyl examples include methyl, ethyl and n-and isopropyl.
  • C 4-7 alkyl are of interest, especially those of the form (CH 2 ) u R 16 wherein u is 1 or 2 and R 16 is a secondary or tertiary C 3-6 alkyl group or a C 3-8 cycloalkyl group.
  • R 5 examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, tert--butylmethyl, iso-propylmethyl, iso-propylethyl and tert-butylethyl.
  • R 5 is cyclopropylmethyl, cyclohexylmethyl, iso-propyl ⁇ .ethyl, tert-butylmethyl or iso-propylethyl, preferably tert-butyImethyl.
  • R 5 when -(CH 2 ) t R 11 , are thosewherein t is 1.
  • R 11 may be 2- or 3-thaenyl or preferably is phenyl optionally substituted by one of C 1-4 alkoxy, trifluoromethyl, halogen, carboxy, esterified carboxy or C 1-4 alkyl optionally substituted by hydroxy, C 1-4 alkoxy, carboxy, esterified carboxy and in vivo hydrolysable acyloxy.
  • C 1-4 alkyl When phenyl is substituted by optionally substituted C 1-4 alkyl, examples of C 1-4 alkyl include methyl, ethyl, n- and iso-propyl, and n-, iso-, sec- and tert- butyl; methyl however is preferred. Examples of substituents of such alkyl groups include hydroxy, methoxy, ethoxy, n- and iso- propoxy, carboxy, esterified carboxy, and in vivo hydrolysable acyloxy. The substitution preferably occurs on a terminal carbon atom of the alkyl group.
  • esterified carboxy groups include C 1 _ 4 alkoxycarbonyl, such as methoxy-, ethoxy-, n- and iso- propoxy-carbonyl, phenoxycarbonyl or benzyloxycarbonyl, either being optionally substituted in the phenyl ring by one or two s ⁇ bstituents selected from C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, halogen or nitro.
  • in vivo hydrolysable acyloxy groups inclnde C 1-6 alkanoyloxy for example aceioxy, propionoxy, n- and iss-butyroxy, and 2,3 dimethylpropanyloxy, benzyl oxy or benzcnesulphonyloxy either being optionally substituted in the phenyl ring by one or two substit ⁇ ents selected from C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, halogen or nitro, or other sulphonyloxy groups, for example C 1-6 alkanesulphonyloxy group, such as methanesulphonyloxy.
  • R 5 when -(CH 2 ) t R 11 , are those wherein t is 1 and R 11 is unsubstituted phenyl or monosubstituted phenyl in particular mono-p-substitutedphenyl
  • preferred p-substituents include methyl, trifluoromethyl, fluoro, chloro and bromo, especially fluoro.
  • Unsubstituted benzyl, p-fluorobenzyl , p-chlorobenzyl and p-methylbenzyl are especially preferred examples of R 5 .
  • the pharmaceutically acceptable salts of the compound of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric phosphoric, sulphuric and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto gluraric, ⁇ -glycerophosphoric, and glucose-1-phosphoric; and quarternary ammonium salts.
  • the acid addition salt is a hemisuccinate, hydrochloride, ⁇ -ketoglutarate, ⁇ -glycerophosphate or glucose-1-phosphate, in particular the hydrochloride salt.
  • quarternary ammonium salts include such compounds quarternised by compounds such as R 9 - E wherein R 9 is C 1-6 alkyl, phenyl-C 1-6 alkyl or C 5-7 cycloalkyl, and E is a radical corresponding to an anion of an acid.
  • R 9 include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl.
  • Suitable E include halide such as chloride, bromide and iodide.
  • the compounds of formula (I) may also form pharmaceutically acceptable N-oxides.
  • the compounds of the formula (I) and their pharmaceutically acceptable salts and N-oxides may also form solvent adducts.
  • the pharmaceutically acceptable salts of the compounds of the formula as hereinafter defined consist mainly of acid addition salts with conventional acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.
  • the invention extends to each of these stereoisomeric forms, and to mixtures thereof (including racemates).
  • the differsnt stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. From the aforesaid it will be seen that suitably the moiety of formula may be of formulae :
  • a group of compounds within those of formula (I), are those of formula (VI) :
  • R 5 in formula (VI) include those listed under formula (I) for R 5 .
  • Particularly preferred examples of R 5 include benzyl optionally substituted in the phenyl ring as defined under formula (I) ⁇ nsubstituted benzyl, 4-methyl, 4-fluoro-and 4-chlorobenzyl are included in preferred R 5 .
  • a sub-group of compounds within those of formula (VI) are those of the formula (VIII):
  • aminoquinazoline moiety is in ⁇ -orientation to the nortropane ring, that is as follows:
  • Benzyl, 4-methylbenzyl, 4-chlorobenzyl and 4-fluorobenzyl are preferred values.
  • aminoquinazoline moiety is in the ⁇ -orientation to the nortropane ring.
  • a third sub-group within formula (VIII) is of the formula (IX):
  • aminoquinazoline is in the B-orientation to the granatane ring, the ⁇ -orientation being the same as in the nortropane hereinbefore depicted.
  • a fourth sub-group of compounds within those of formula (VI) is of formula (X):
  • aminoquinazoline moiety isin the B-orientation to the granatane ring.
  • the present invention also provides a process for the preparation of a compound of formula (I), which process comprises reacting a compound of formula (XI):
  • Q 2 is NH 2 and E is A as defined;
  • Q 1 is -NH 2 ;
  • Q 2 is a monovalent leaving group , o xo or thiooxo ; and E is of one of formulae (XIII) , (XIV) or (XV) :
  • the leaving group Q 1 is a group that is readily displaceable by a nucleophile
  • examples of such groups are C 1-4 alkoxy, C 1-4 alkylthio, halogen such as chloro and bromo and acyloxy such as C 1-4 alkanoyloxy.
  • examples of s ⁇ ch groups are halogen such as chloro or bromo, and labile s ⁇ lphonyloxy such as raesylate or tosylate.
  • a leaving group is C 1-4 alkoxy, C 1-4 alkylthio or acyloxy
  • the reaction is preferably carried out in an inert non-hydroxylic solvent, such as benzene, toluene or diethyl ether.
  • the reaction may be carried out at a non-extreme temperature such as -10 to 100°C, for example 0 to 80°C.
  • a leaving group is a halide, or labile sulphonyloxy, or Q 1 is dihalo
  • the reaction is preferably carried out at a non-extreme temperature in an inert non- hydroxylic solvent, such as benzene, toluene or diethyl ether. It is also preferably carried out in the presence of an acid acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or picoline, which base can also function as the solvent.
  • the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate.
  • Q 1 is halogen such as chloro and Q 2 is NH 2 .
  • condensation eliminates water it is preferable to carry out the reaction in the presence of a dehydrating agent, for example molecular sieves.
  • a dehydrating agent for example molecular sieves.
  • a non-aqueous acid catalyst can be advantageous, for example hydrogen chloride or p-toluencsol- phonic acid.
  • an acid addition salt of the compound of formula (XI) or (XII) may be used.
  • the product compound must be reduced to give a compound of formula (I). This is conveniently effected in situ, and most conveniently simultaneously with the condensation.
  • the reduction of the product compound is conveniently simultaneously effected with a mild reducing agent, such as a mild inorganic complex hydride, for example sodium cyanoborohydride.
  • a mild reducing agent such as a mild inorganic complex hydride, for example sodium cyanoborohydride.
  • the reaction is generally carried out in a dry, inert polar solvent, such as dry ethanol, maintained at neutral or acid pH, for example pH 5-7, with for example hydrogen chloride when less than 7.
  • a dry, inert polar solvent such as dry ethanol
  • Non-extreme temperatures at about ambient are generally suitable.
  • the reduction may be effected sequentially, optionally with isolation of the condensation product compound by reduction with tin/hydrochloric acid at a non-extreme temperature.
  • an amino substituent is convertible to a carboxylic C 1-4 acylamino substituent by acylation; with a carboxylic acid derivative;
  • a hydrogen substituent is convertibl e to a halogen substituent by halogenation
  • a C 1-6 alkylthio or C 1-6 alkylsulphinyl substituent is convertible to a C 1-6 alkyl sulphinyl or a C 1-6 alkylsulphonyl substituent respectively by oxidation;
  • an amino, aminocarbonyl, aminosulphonyl, aminosulphonyl amino or N-(aminosulphonyl)- C 1-4 alkylamino substituent is convertible to a corresponding substituent substituted by one or two groups selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-4 alkyl or phenyl C 1-6 alkyl groups any of which phenyl groups may be substituted by one or more groups selected from halogen, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxy and nitio, or substituted by C 4-5 polymet hylene, by N-alkylation (h) an amino substituent is convertible to a C 1-6 alkylsulphonylamino group or an aminosulphonylamino group optionally N-substituted as defined by acylation with a C 1-4 alkylsulphonic acid or optionally N-substituted carb
  • a C 1-4 alkylamino substituent group is convertible to a N-(C 1-6 alkylsulphonyl) C 1-4 alkylamino group or an N-(amino sulphonyl)- C 1-4 alkylamino group optionally N-substituted as defined by acylation with a C 1-6 alkylsulphonic acid or optionally N-substituted carbamic acid derivative.
  • the reduction is carried out with a reagent suitable for reducing nitroanisole to aminoanisole.
  • deacylation is carried out by treatment with a base, such as an alkali metal hydroxide.
  • acylation is carried out with an acylating agent, such as the corresponding acid or acid chloride.
  • acylating agent such as the corresponding acid or acid chloride.
  • Formylation is carried out with the free acid.
  • halogenation is carried out with conventional halogenating agents.
  • oxidation is carried out at below ambient temperatures in a non-agueous solvent, such as a chlorinated hydrocarbon, in the presence of an organic peracid, such as 3-chloroperbenzoic acid, or in water in the presence of a soluble strong inorganic oxidant, such as an alkali metal permanganate or in aqueous hydrogen peroxide.
  • a non-agueous solvent such as a chlorinated hydrocarbon
  • an organic peracid such as 3-chloroperbenzoic acid
  • a soluble strong inorganic oxidant such as an alkali metal permanganate or in aqueous hydrogen peroxide.
  • alkylation is carried out with a corresponding alkylating agent such as the chloride or bromide under conventional conditions.
  • R 5 optionally substituted benzyl as hereinbefore defined may be replaced by other R 5 .
  • Such R 5 benzyl groups may for example be removed, when R 3 or R 4 is not halogen by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (XVI) :
  • a 1 is of the formula :
  • This invention also provides third process for the preparation of a compound of the formula (I) which comprises the reaction of a corresponding compound of the formula (XVI) as hereinbefore defined with a compound Q 5 R 5 wherein R 5 is as defined in formula (I) and Q 5 is a leaving group, and optionally forming a pharmaceutically acceptable salt or N-oxide of the resulting compound of the formula (I).
  • Suitable values for Q 5 include groups readily displaced by nucleophiles such as Cl , Br, I, OSO 2 CH 3 or OSO 2 C 6 H 4 pCH 3 .
  • Favoured values for Q 5 include Cl , Br and I.
  • the reaction may be carried out under conventional alkylation conditions for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at non-extreme temperature such as at ambient or slightly above.
  • Inter-converting R 5 in the compound of the formula (XI) before coupling with the compound of the formula (XII) is preferred. Such interconversions are effected conveniently under the above conditions. It is desirable to protect any amine function with a group readily removable by acidolysis, such as a C 2-7 alkanoyl group, before R 5 interconversion.
  • an esterified carboxy C 1-4 alkyl substituent is convertible to a carboxy C 1-4 alkyl substituent by deesterification
  • an C 1-4 alkoxy C 1-4 alkyl substituent or an in vivo hydrolysable C 2-4 acyloxy C 1-4 alkyl substituent is convertible to an hydroxy C 1-4 alkyl substituent by deetherification;
  • an optionally esterified carboxy or carboxy C 1-3 alkyl substituent is convertible to an hydroxymethyl or hydroxy C 2-4 alkyl substituent by reduction;
  • a hydroxy C 1-4 alkyl substituent is convertible to C 1-4 alkoxy C 1-4 alkyl by O-alkylation or to in vivo hydrolysable C 1-4 acyloxy C 1-4 alkyl by O-acylation.
  • a C 1-4 alkoxy C 1-4 alkyl substituent is convertible to an hydroxy C 1-4 alkyl substituent by conventional methods, such as. warming with aqueous hydrobromic acid or by treatment with pyridine hydrochloride, boron tribromide, boron triodide or iodotrimethylsilane.
  • An in vivo hydrolysable C 2-4 acyloxy C 1-4 alkyl substituent is convertible to an hydroxy C 1-4 alkyl substituent by acid or base hydrolysis.
  • O-alkylation is carried out under conventional conditions in an inert solvent at a non-extreme temperature such as ambient temperature or slightly above or at reflux temperature.
  • the C 1-4 alkylating agent has a leaving group that is readily displaceable by a nucleophile.
  • leaving groups include halide, such as chloride, bromide or iodide, or labile acyloxy groups, such as mesyl and tosyl.
  • O-acylation is carried out under conventional conditions with an acylating agent which has an acyl group capable of forming an in vivo hydrolysable acyloxy group and a leaving group, such as halide,. for example chloride and bromide, and hydrogen.
  • a leaving group such as halide,. for example chloride and bromide
  • the reaction is generally carried out in the presence of a base.
  • a dehydrating agent such as a s dicyclohexylcarbodiimide
  • inert solvent at non-extreme temperature, such as ambient temperature or slightly above, or reflux temperature.
  • O-alkylation and O-acylation may also produce N-alkylated and N-acylated products rescpect i vely unless the nitronen atom(s) in (arc) previously protected.
  • This may be conveniently achieved by carrying out the alkylation or acylation reaction in a strong acid, such as trifluoroacetic acid, which protonates, and thereby protects, the nitrogen atom(s).
  • the compounds of formula (XVIII) are known or are preparable analogously to or routinely from known compounds.
  • the compound, wherein Q 1 is bromo can be prepared by reacting a compound of formula (XX) :
  • R 3 , R 4 , X, Y and Z are as hereinbefore defined; with a brominating agent, such as PBr 5 .
  • Compounds of formula (XI) are either known compounds or are preparable analogously to or routinely derivable from known compounds.
  • X, Y and Z are each CR 1 , as defined and Q 1 is -NH 2
  • the compound may be prepared by the Hofmann degradation of the corresponding compound where Q 1 is -CONH 2 or by the Schmidt reaction of the corresponding compound where Q 1 is -CO 2 H.
  • the compound may be prepared by Chichibabin amination. It will be realised that in the compound of the fomula (1) the -G-C-linkage may have an ⁇ or ⁇ orientation with respect to the ring of the bicyclic moiety to which it is attached.
  • a mixtuie of ⁇ and ⁇ isomers of the compound of the formula (I) may be synthesized non-steieospeci f i c a l l y and the desired isoiaer separated conventionally therefrom e.g. by chromatography; or alternatively the ⁇ and ⁇ isomer may if desired by synthesised from the corresponding ⁇ or ⁇ form of the compound of the formula (XII).
  • the ⁇ or ⁇ form of the compound of the formula (XIX) may if desired be prepared by known stereospecific processes. such as those leading to the ⁇ or ⁇ isomers of the compound of the formula (XI) depicted in the Scheme and described in the Descriptions hereinafter.
  • N-oxides of the nitrogen atom of the bicyclic ring system are produced by reaction of a compound of formula (I) with an organic peracid, such as m-chloroperbenzoic acid in, for example, a chlorinated hydrocarbon solvent at below ambient temperature.
  • an organic peracid such as m-chloroperbenzoic acid in, for example, a chlorinated hydrocarbon solvent at below ambient temperature.
  • Quaternary ammonium salts may be prepared by reaction of a compound of the present invention with the appropriate alkyl, aryl, aralkyl, chloride, bromide or iodide. This reaction may be carried out in a solvent, such as acetone, methanol, ethanol, dimethylformamide at ambient or elevated temperature with or without pressure.
  • a solvent such as acetone, methanol, ethanol, dimethylformamide
  • the compounds of the present invention are dopamine antagonists and may generally be used in the treatment of ernesis. Depending on their balance between peripheral and central action on the nervous system, they may also be used in the treatment of disorders relating to impaired gastro-intestinal motility, such as retarded gastric emptying dyspepsia, flatulence, oesophagal reflux and peptic ulcer and/or in the treatment of disorders of the central nervous system, such as psychosis.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) , or a pharmaceutically acceptable salt thereof, or N-oxide thereof, or a solvent adduct of any of the foregoing and a pharmaceutically acceptable carrier.
  • Such compositions are prepared by admixture and are suitably adapted for oral or parental administration, and as s ⁇ ch may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Orally administerable compositions are preferred, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, manitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium sterate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate,
  • Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
  • the oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in the vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • the invention further provides a method of treatment of emesis, disojders relating to impaired castro-intestinal motality and of disorders of the central nervous system in majunals, such as humans, which comprises the administration of an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or N-oxide thereof, or a solvent adduct of any of the foregoing as hereinbefore defined, to the sufferer.
  • a unit dose will normally contain 0-1 to 20m ⁇ for example 0.5 to 10mg, of the compound of the invention.
  • Unit doses will normally be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day such that the total daily dose is normally in the range 0.03 to 10mq/kg per day.
  • the compounds of the present invention have the ability to potentiate the effect of conventional analgesics in migraine treatment when administeredconcomitantly with the analgesic. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the present invention and an analgesic.
  • the effective amount of each component of the composition will depend in the usual way on a number of factors such as the nature and severity of the malady to be treated, the weight of the sufferer, and the actual compound used.
  • the compound of the present invention and the analgesic such as aspirin or paracetamol, are present in unit doses of the composition in amounts generally similar to their usual effective dose.
  • the composition can be a combination product, for example a tablet or capsule containing both a compound of the invention and an analgesic for oral administration, or a twin pack comprising the two active ingredients made up for separate administration.
  • the invention accordingly provides a method of treatment of migraine comprising the administration of an effective amount of a compound of the invention and an analgesic.
  • the invention also provides a compound of formula (I), for use in the treatment of emesis, disorders relating to impaired gastro-intestinal motility and/or of disorders of the central nervous system.
  • This present invention also provides a method of treating inflammatory conditions in mammals which comprises administering per day from 50 to 4000 mg of a compound of formula (VI) or a pharmaceutically acceptable salt thereof and more usually from 100 to 3000 mg for example from 200 to 1500 of a compound of formula (VI).
  • Mammals which may be thus treated include humans and domestic animals such as dogs, cats or horses.
  • the medicament will be administered orally as 2 , 3 or 4 doses per day at the dose level previously indicated.
  • the invention further provides a method of treatment of hypertension in mammals including humans comprising the administration to the sufferer of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the "effective amount" will depend in the usual way on a number of factors such as the nature and severity of the malady to be treated, the weight of the sufferer, and the actual compound used.
  • the compositions of this invention are in the form of a unit-dose. Suitable unit dose forms include tablets, capsule and powders in sachets or vials. Such unit dose forms aptly contain 1 to 100 mg of the compound of this invention and more usually from 2 to 50 mg, for example 5 to 25 mg such as 6, 10, 15 or 20 mg.
  • Such compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from 5 to 200 mg for a 70 kg human adult and more aptly from 10 to 100 mg.
  • Shaped oral dosage compositions are favoured.
  • compositions may contain further active agents such as other anti-hypertensive agents, diuretics and ⁇ -blocking agents.
  • Intragastric pressure changes were recorded from previously starved conscious but restrained rats using a saline filled catheter inserted into the lumen of the stomach via a permanent gastric fistula.
  • the catheter was connected to a physiological pressure transducer and pressure changes recorded on a hot wire pen recorder.
  • An index of activity was obtained by measuring the average height of pressure waves during 10 minute periods. Values for 4 such periods were obtained during assessment of spontaneous activity and for 40 minute period after administration of compound. Student's"t" test was applied to the difference in average values obtained for spontaneous and post compound activity.
  • Compound 5 significantly increased the index of activity post administration at a dose level of 0.2mg/kg s.c.
  • Apomorphine 1 mg/kg s.c. induces mice to climb the wall of a wire cage (inverted food hopper - 11 x 7.5 x 18 cm high). Mice acclimatised in their home cages in groups of 5 are placed under the hoppers immediately after the injection of apomorphine 1mg/kg s.c. At 10, 20 and 30 minutes after injection climbing behaviour is scored. The mice are observed for 30 seconds and scored according to the position they spend the majority of time in, score 0 - four paws on floor of cage; score 1 - fore paws only on walls; score 2 - all paws on wall of cage. The scores at all 3 times and for each mouse are summed and mice drug treated orally compared to mice receiving apomorphine only. A saline only treated group is also included and any score, generally >5% of maximum taken into account.
  • Dopamine receptors were labelled using methods similar to those previously reported [see S. Lazareno and S.R. Nahorski, Communication presented to Brit. Pharm. Soc, Bradford, 74, (1981), and P. Greengrass and R. Bremner, E ⁇ r. J. Pharmacol 55, 323 (1979)].
  • the compounds showed displacement of 3H-Spiperone, indicating interaction with dopamine receptors.
  • Systolic blood pressures were recorded by a modification of the tail cuff method described by I.M. Claxton, M.G. Palfreyman, R.H. Poyser, R.L. Whiting, European Journal of Pharmacology, 37 , 179 (1976).
  • W+W BP recorder model 8005
  • Compound (1) was active at 100mg/kg p.o.

Abstract

Composés de formule (I) et N-oxydes, solvants d'addition et sels pharmaceutiquement acceptables de l'un quelconque de ces composés, où G représente -N = ou -NR; X, Y et Z représentent chacun indépendamment -CR1 ==, -N == ou -NR2, ou bien un élément parmi X, Y et Z est égal à C:B, où B représente O ou S et les deux autres représentent chacun indépendamment -CR1, -N= ou -NR2; A est un groupe représenté par les formules (II), (III) ou (IV), où p et q valent indépendamment l'un de l'autre de 0 à 2; Z2 représente O ou S; n vaut 0 ou 1. Ces composés présentent une activité antagoniste de la dopamine. Leur procédé de préparation et leur utilisation en tant que produits pharmaceutiques sont également décrits.
EP19830903004 1982-09-24 1983-09-22 Derives d'amino-azabicycloalkyle utilises en tant qu'antagonistes de la dopamine Withdrawn EP0126087A1 (fr)

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GB8227300 1982-09-24
GB8227300 1982-09-24
GB838301782A GB8301782D0 (en) 1983-01-22 1983-01-22 Compounds
GB8301782 1983-01-22

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EP0315390B1 (fr) * 1987-11-04 1994-07-20 Beecham Group Plc Composés nouveaux de 4-oxobenzotriazine et 4-oxoquinazoline
IT1228293B (it) * 1989-02-06 1991-06-07 Angeli Inst Spa Benzoderivati di composti eterociclici contenenti azoto.
GB9009542D0 (en) * 1990-04-27 1990-06-20 Beecham Group Plc Novel compounds
JP3122671B2 (ja) * 1990-05-23 2001-01-09 協和醗酵工業株式会社 複素環式化合物
IL112249A (en) * 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
IL112248A0 (en) 1994-01-25 1995-03-30 Warner Lambert Co Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them
US5658902A (en) * 1994-12-22 1997-08-19 Warner-Lambert Company Quinazolines as inhibitors of endothelin converting enzyme
US7217716B2 (en) * 2001-02-23 2007-05-15 Merck & Co., Inc. N-substituted nonaryl-heterocyclic NMDA/NR2B antagonists
MXPA03011083A (es) 2001-06-11 2004-07-08 Biovitrum Ab Compuestos de sulfonamida sustituida, procedimiento para su preparacion, y su uso como medicamento para el tratamiento de trastornos del sistema nervioso central. obesidad y diabetes tipo ii.
US7943639B2 (en) 2002-06-20 2011-05-17 Proximagen Limited Compounds
NZ542236A (en) * 2003-03-31 2008-05-30 Predix Pharmaceuticals Holding New piperidinylamino-thieno[2,3-d]pyrimidine compounds
EP1838705A2 (fr) 2005-01-13 2007-10-03 Neurosearch A/S Nouveaux derives de 8-aza-bicyclo[3.2.1]octane et leur utilisation comme inhibiteurs du recaptage du neurotransmetteur monoamine
FR2891829A1 (fr) * 2005-10-12 2007-04-13 Sanofi Aventis Sa Derives de la 4-amino-quinazoline, leur preparation et leur application en therapeutique
KR102392896B1 (ko) * 2020-04-07 2022-05-03 충북대학교 산학협력단 신규한 3-((1-벤질-1h-1,2,3-트리아졸-4-일)메틸)퀴나졸린-4(3h)-원 및 n-(1-벤질피페리딘-4-일)퀴나졸린-4-아민 및 이의 용도

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FR2476088A2 (fr) * 1979-01-16 1981-08-21 Delalande Sa Nouveaux derives du nor-tropane, leur procede de preparation et leur application en therapeutique
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