EP0135545A1 - Derives anylides et benzamides d'azabicycloalkyle - Google Patents

Derives anylides et benzamides d'azabicycloalkyle

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Publication number
EP0135545A1
EP0135545A1 EP84900862A EP84900862A EP0135545A1 EP 0135545 A1 EP0135545 A1 EP 0135545A1 EP 84900862 A EP84900862 A EP 84900862A EP 84900862 A EP84900862 A EP 84900862A EP 0135545 A1 EP0135545 A1 EP 0135545A1
Authority
EP
European Patent Office
Prior art keywords
formula
alkyl
hydrogen
compound
alkoxy
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Withdrawn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
EP84900862A
Other languages
German (de)
English (en)
Inventor
Christine Summers
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
Original Assignee
Beecham Group PLC
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Filing date
Publication date
Priority claimed from GB838304648A external-priority patent/GB8304648D0/en
Priority claimed from GB838328550A external-priority patent/GB8328550D0/en
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0135545A1 publication Critical patent/EP0135545A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel compounds, to a process for their preparation and their use.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt and/or N-oxide and/or a solvate thereof:
  • one of X and Y is CO and the other is NH;
  • E is O, S or NR wherein R is hydrogen, C 1-6 alkyl or a protecting group and A is C 2-4 alkylene or C 2-4 alkenylene or E and A together with the phenyl to which they are attached form a quinoline nucleus;
  • R 4 is a group:
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 and R 3 are the same or different and are hydrogen, halogen, trifluoromethyl, C 1-6 alkoxy, C 1-6 alkylthio, carboxylic C 1-7 acyl, carboxylic C 1-7 acylamino, C 1-6 alkylsulphonyl, C 1-6 alkylsulphinyl, nitro or NR 12 R 13 , NR 12 R 13 CO, NR 12 R 13 SO 2 , or C 1-6 alkyl-SO 2 NR 14 , NR 12 R 13 SO 2 NR 14 wherein R 12 and R 13 are the same or different and are hydrogen C 1-6 alkyl, phenyl or phenyl C 1-4 alkyl groups any of which phenyl moieties may be substituted by one or more halogen, trifluoromethyl, C 1-6 alkoxy or nitro groups, or R 12 and R 13 together form C 4-5 polymethylene, and R 14 is hydrogen or C 1-6 alkyl.
  • X is CO and Y is NH.
  • Suitable values for E-A include the following:
  • E 1 is O, S or NR' wherein R'is hydrogen, methyl or acetyl
  • Preferred values for E-A include a) wherein E 1 is O or NH, and c) wherein E 1 is 0 or NH.
  • R 4 is of formula (II).
  • R 4 is a group of formula (II) as defined, p is suitably 0 or 1, and q is suitably 0 or 1.
  • the group Y and the heterobicycle nitrogen atom are separated by 2 or 3 carbon atoms preferably 3.
  • the X.Y. moiety is preferably in an equatorial orientation to the heterobicycle ring.
  • R 4 is a group of formula (III) as defined Z is O or S, preferably O.
  • R 5 when C 1-7 alkyl include methyl, ethyl and n-and iso-propyl.
  • C 4-7 alkyl are of interest, especially those of the formula (CH 2 ) u R 16 wherein u is 1 or 2 and R 16 is a secondary or tertiary C 3 -6 alkyl group.
  • Examples of 04.7 alkyl include n-,sec- and tert-butyl, n-pentyl, n-heptyl, and especially iso-butyl, 3-methylbutyl, 2,2-dimethylpropyl and 3,3-dimethylbutyl.
  • R 5 when -(CH 2 )s R 10 are those wherein s is 1 or 2, in particular those wherein R 10 is C 5-8 cycloalkyl, such as cyclohexyl, and cyclopropyl.
  • R 5 when -(CH 2 )tR 11 , are those wherein t is 1.
  • R 11 may be 2- or 3-thienyl 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 the terminal carbon atom of the alkyl group.
  • esterified carboxy groups include C 1-4 alkoxycarbonyl, such as methoxy-, ethoxy-, n- and iso-propoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, either being optionally substituted in the phenyl ring by one or two substituents selected from C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, halogen or nitro.
  • Examples of in vivo hydrolysable acyloxy groups include C 1-6 alkanoyloxy, for example acetoxy, propionoxy, n- and iso- butyroxy, and 2,3-dimethylpropanyloxy, benzyloxy or benzenesulphonyloxy either being optionally substituted in the phenyl ring by one or two substituents selected from C 1-4 alkyl, C 1-4 trifluoromethyl, halogen or nitro, or other sulphonyloxy groups, for example C 1-6 alkanesulphonyloxy group, such as methanesulphonyloxy .
  • R 5 when -(CH 2 )tR 11 , are those wherein t is 1 and R 11 is unsubstituted phenyl or monosubsti tuted phenyl in particular mono-p-substituted phenyl.
  • preferred p-substitutents 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 .
  • Suitable examples of R 1 include hydrogen, methyl, ethyl, n- and iso-propyl.
  • R 1 is hydrogen or methyl.
  • R 1 is preferably attached at the 2-position, i.e. at the carbon atom adjacent to E.
  • R 2 and R 3 include the following groups: hydrogen, chloro, bromo,CF 3 , methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and iso- propylthio, nitro, amino, C 1-4 alkanoylamino such as formylamino, acetylamino, propionylamino, n- and iso-butyrylamino, aminosulphonyl ; and amino, aminosulphonyl and aminosulphonylamino N-substi tuted by one or two methyl, ethyl, n- or iso-propyl n-, sec-, or tert-butyl; cyclopropyl, cyclopentyl, cyclohexyl, phenyl or benzyl groups or N-disubstituted by C 4 or C 5 polymethylene; or aminosulphonyla
  • R 2 and R 3 are independently hydrogen, chloro, amino or optionally substituted aminosulphonyl, as defined.
  • R 2 and R 3 are other than C 1-6 alkoxy or C 1-6 alkylthio, R 2 is preferably in the 4-position with respect to X as the 1-position; R 3 is then preferably in the 5-position similarly defined.
  • the compounds of the formula (I) have chiral or prochiral centres, and thus are capable of existing in a number of stereoispmeric forms.
  • the invention extends to each of these stereoisomeric forms, and to mixtures thereof (including racemates).
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by sterospecific or asymmetric synthesis.
  • R 1 3 is aminosulphonyl optionally substituted as defined and R 1 and E 1 are as hereinbefore defined.
  • variable groups are as hereinbefore defined.
  • Suitable values for R 1 3 N-substituents are as described under formula (I).
  • R 1 3 is aminosulphonyl optionally substituted by one or two methyl groups.
  • Suitable and preferred values for R 1 and E 1 are as so described under formula (I). More suitably p is 0 or 1, it is believed preferably 0.
  • R 1 5 is C 4-7 alkyl or -(CH 2 ) s R 10 where s is 0 to 2 and R 10 is C 5-8 cycloalkyl; and the remaining variables are as defined in formula (V).
  • Suitable and preferred R 1 3 are as so described under formula (I) for corresponding R 3 .
  • a group of compounds within those of. formula (VII) is that wherein R 1 5 is (CH 2 ) u R 16 as defined or (CH 2 ) u R 10 where u and R 10 are as defined.
  • R 1 5 in these compounds examples include iso-butyl, 3-methylbutyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl and cyclopropylethyl.
  • CONH moiety is in the ⁇ -orientation to the nortropane ring.
  • a sub-group of compounds wi thi n those of formula (VI ) is of the formula (VIII ) :
  • R 2 5 is thienylmethyl or -(CH 2 )tR 11 , t being 1 or 2, and R 11 being phenyl optionally subsituted by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen, carboxy, esterified carboxy, and C 1-4 alkyl optionally substituted by hydroxy, C 1-4 alkoxy, carboxy esterified carboxy or i n vivo hydrolysable acyloxy.
  • Particularly preferred compounds are those wherein R 2 5 is benzyl optionally substituted in the phenyl ring by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen and C 1-4 alkyl.
  • phenyl ring is unsubstituted.
  • Suitable and preferred R 1 3 are as so described under formula (V) . It is preferred that the CONH moiety is in the ⁇ -orientation to the nortropane moiety.
  • a third sub-group of compounds within those of formula (VI) is of formula (IX):
  • R 1 5 is as defined in formula (VII).
  • R 2 5 is as defined in formula (VIII)
  • Preferred compounds are those wherein R 2 5 is optionally substituted benzyl as defined under formula (VIII). It is especially preferred that the phenyl ring is mono-substituted and/or that the substitution is in the para-position and/or that the substituent is chloro, fluoro or methyl.
  • Suitable and preferred R 1 3 are as so described under formula (VIII).
  • a second group of compounds within those of formula (I) is of formula (XI):
  • Z is O, and the CONH moiety is in the ⁇ -orientation.
  • R 1 2 and R 2 3 are the same or different and are hydrogen, halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, trifluoromethyl, amino or C 1-7 acylamino;
  • R 1 and E are as hereinbefore defined.
  • variable groups are as hereinbefore defined.
  • R 1 2 and R 2 3 are as so described for the relevant R 2 and R 3 under formula (I).
  • a sub-group of compounds within those of formula (XIII) are those of formula (XIV): wherein the variable groups are as hereinbefore defined.
  • R 1 2 and R 2 3 are as so described under formula (I) for corresponding R 2 and R 3 . Often, R 1 2 and R 2 3 are both hydrogen.
  • a group of compounds within those of formula (XIV) is that wherein R 1 5 is (CH 2 ) u R 10 where u and R 10 are as defined.
  • R 1 5 in these compounds examples include iso-butyl, 3-methylbutyl, 2,2-dimethylpropyl and cyclopropylethyl.
  • CONH moiety is in the ⁇ -orientation to the nortropane ring.
  • variable groups are as hereinbefore defined.
  • Particularly preferred compounds are those wherein R 2 5 is benzyl optionally substituted in the phenyl ring by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen and C 1-4 alkyl.
  • Suitable and preferred R 1 2 and R 2 3 are as so described under formula (XII).
  • CONH moiety is in the ⁇ -orientation to the nortr ⁇ pane moiety.
  • a third sub-group of compounds within those of formula (XIII) is of formula (XVI):
  • variable groups are as hereinbefore defined under formula (XIV).
  • R 2 5 is as defined in formula (VIII).
  • Preferred compounds are those wherein R 2 5 is optionally substituted benzyl as defined under formula (VIII).
  • the phenyl ring is mono-substituted and/or that the substitution is in the para-position and/or that the substituent is chloro, fluoro or methyl.
  • Suitable and preferred R 1 2 and R 2 3 are as so described under formula (XII).
  • R 1 1 is halogen or C 1-6 alkyl
  • R 3 3 is halogen
  • R 21 is hydrogen or C 1-4 alkanoyl
  • the invention also provides a process for the preparation of a compound of the formula (I), which process comprises reacting a compound of the formula (XIX):
  • One of J and L is COQ, where Q is a leaving group, and the other is -NH 2 ; and the remaining variable groups are as defined in formula (I), with the proviso that when J is -NH 2 , R 2 or R 3 is other than amino, and thereafter optionally converting R, R 1 , R 2 or R 3 to another R, R 1 , R 2 or R 3 respectively; as necessary converting R 5 to other R 5 ; and optionally forming a pharmaceutically acceptable salt of the resultant compound of the formula ( I ) .
  • the leaving group Q is a group that is readily displaceable by a nucleophile.
  • examples of such groups are hydroxy, halogen such as chloro and bromo, acyloxy such as C 1-4 alkanoyloxy, C 1-4 alkoxycarbonyloxy and activiated hydrocarbyloxy such as pentachlorophenoxy.
  • Another example of an acyloxy group Q is when Q is joined to E 1 to form -O-CO-N'-.
  • the reaction is preferably carried out in an inert non-hydroxylic solvent, such as benzene, toluene or diethyl ether in the presence of a dehydrating catalyst, such as a carbodiimide, for example dicyclohexylcarbodiimide.
  • a dehydrating catalyst such as a carbodiimide, for example dicyclohexylcarbodiimide.
  • the reaction may be carried out at a non-extreme temperature such as -10 to 100oC, for example 0 to 80oC.
  • 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, some of which can also function as the solvent.
  • an acid acceptor such as an organic base, in particular a tertiary amine such as triethylamine, trimethylamine, pyridine or picoline, some of which can also function as the solvent.
  • the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate.
  • the reaction is preferably carried in substantially the same manner as if the leaving group were hydroxy.
  • Suitable examples of acyloxy leaving groups include C 1-4 alkanoyloxy, mesyloxy, tosyloxy and triflate; and when E 1 is NH, and X-Y is CO-N'.
  • the reaction is preferably carried out in an inert solvent, such as methylene chloride, at a non-extreme temperature in the presence of an acid acceptor, such as triethylamine.
  • an inert solvent such as methylene chloride
  • the reaction is preferably carried out in an inert polar solvent, such as dimethylformamide. It is also preferred that the activated hydrocarbyloxy group is pentachlorophenyl ester and that the reaction is carried out at ambient temperature.
  • Q is halogen, such as chloro.
  • the compounds of formula (XIX) and (XX) are either known compounds or can be prepared analogously to the preparation of structurally similar known compounds.
  • Compounds of formula (XIX) wherein R 3 is aminosulphonyl may be formed from the corresponding R 3 chlorosulphonyl derivatives of the compound of formula (XIX) wherein R 3 is hydrogen, with a suitable amine or ammonia.
  • E-A moiety in compounds of the formula (XIX) is generally prepared by a cyclisation reaction.
  • E-A is of sub-formula (a) or (c) and E 1 is 0, the chroman/dihydrobenzofuran nucleus may be prepared according to the following scheme:
  • Compounds of the formula (XIX) having E-A of sub-formula (e) may be prepared by a conventional Skraup quinoline synthesis.
  • Compounds of formula (XIX) having an E-A of sub-formula (a) wherein E 1 is NH may accordingly be prepared by reduction of the corresponding quinoline.
  • a C 1-4 acylamino substituent is convertible to an amino substituent by deacylation;
  • an amino substituent is convertible to a C 1-4 acylamino substituent by acylation;
  • a hydrogen substituent is convertible to a halogen substituent by halogenation
  • a C 1-6 alkylthio or C 1-6 alkylsulphinyl substituent is convertible to a C 1-6 alkylsulphinyl or a C 1-6 alkylsulphonyl substituent respecitvely by oxidation;
  • an amino substituent is convertible to a C 1-6 alkyl SO 2 NR 14 or NR 12 R 13 SO 2 NR 14 substituent by reaction with C 1-6 alkyl SO 2 NQ 2 or NR 12 R 13 SO 2 Q 2 where Q 2 is leaving group.
  • a fluoro or chloro substituent is convertible to an optionally substituted amino substituent by reaction with a suitable amine or ammonia.
  • the reduction is carried out with a reagent suitable for reducing nitroanisole to ami noanisole.
  • deacylation is carried out by treatment with a base, such as an alkali metal hydroxide.
  • the acylation is carried out with an 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-aqueous 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-aqueous 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.
  • Q 2 is often halide, for example chloride or bromide, or hydroxy.
  • halide is the leaving group
  • the reaction is generally carried out in the presence of a base.
  • hydroxy is the leaving group
  • the reaction is generally carried out in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide, in an inert sovent at non-extreme temperature, such as ambient temperature.
  • the amination is carried out under conventional conditions using an inert solvent such as CH 2 CI 2 or an excess of amine also functioning as the solvent.
  • mono- or di-acylation may occur. If diacylation takes place, subsequent selective monodeacylation of the resultant compound is necessary to form the desired alkyl- or aminosulphonylamino group.
  • R 5 when optionally substituted benzyl as hereinbefore defined, may be replaced by another group R 5 .
  • R 5 benzyl groups may be removed for example when R 1 , R 2 or R 3 is not halogen by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (XXI):
  • R 1 4 is R 4 wherein the R 5 substituent is replaced by hydrogen and the remaining variable groups are as defined in formula (I).
  • This invention also provides an optional process step in the preparation of a compound of the formula (I) which comprises the reaction of a corresponding compound of the formula (XXI) as hereinbefore defined with a compound Q 3 R 5 wherein R 5 is as defined i n formula (I) and Q 3 is a leaving group, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I).
  • Suitable values for Q 3 include groups readily displaced by nucleophiles such as Cl, Br, I, OSO 2 CH 3 or OSO 2 C 6 H 4P CH 3 .
  • Favoured values for Q 3 include Cl, Br and I.
  • the compound Q 3 R 5 is a benzyl halide, such as the bromide or chloride.
  • 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.
  • an acid acceptor such as potassium carbonate.
  • the reaction is carried out at non-extreme temperature such as at ambient or at a slightly elevated temperature.
  • an esterified carboxy C 1-4 alkyl substituent is convertible to a carboxy C 1-4 alkyl substituent by deesterification;
  • 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;
  • 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 is convertible to C 1-4 alkyl by O-alkylation or in vivo hydrolysable C 2-4 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.
  • the reduction is carried out with a selective metal complex hydride, for example lithium aluminium hydride, under conventional conditions.
  • 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. Examples of leaving groups include halide, such as chloride, bromide or iodide, or labile acyloxy groups, such as mesyl or 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 dicylohexylcarbodiimide
  • O-alkylation and O-acylation may also produce N-alkylated and N-acylated products respectively unless the nitrogen atom(s) is (are) 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).
  • a strong acid such as trifluoroacetic acid
  • the -X-Y-linkage may have an ⁇ or ⁇ orientation with respect to the ring of the bicyclic moiety to which it is attached.
  • a mixture of ⁇ and ⁇ isomers of the compound of the formula (I) may be systhesised non-stereospecifically and the desired isomer separated conventionally therefrom eg by chromatography; or alternatively the ⁇ and ⁇ isomer may if desired by synthesised from the corresponding ⁇ or ⁇ form of the compound of the formula (XX) .
  • the ⁇ or ⁇ form of the compound of the formula (XX) may if desired be prepared by known stereospecific processes, such as those leading to the ⁇ or ⁇ isomers of the compound of the formula (XX) depicted in the Scheme and described in the Descriptions hereinafter.
  • Compounds of the formula (XX) are known from or are preparable by the methods disclosed in published European Patent Applications and U.S. Patents hereinbefore referred to.
  • salts, hydrates and N-oxides of the compounds of this invention may be formed conventionally.
  • the salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid.
  • 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 at ambient or elevated temperature with or without pressure.
  • the compounds of the present invention are dopamine antagonists and may generally be used in the treatment of emesis. 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-i ntestinal 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. Certain of the compounds of formula have blood pressure lowering activity and may also be useful in the treatment of hypertension.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an solvate or N-oxide thereof, and a pharmaceutically acceptable carrier.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconsti tutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administerable compositions are preferred.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, tabletting agents, lubricants, disintegrants, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • 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 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.
  • 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 sterilizing 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.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilized 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 disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) , or a pharmaceutically acceptable salt thereof, or an hydrate or N-oxide thereof, or a pharmaceutical composition, as hereinbefore defined to the sufferer.
  • an amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.
  • a unit dose will normally contain 0.1 to 20 mg 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 0.01 to 10mg/ kg per day.
  • the compounds of the present invention have the ability to potentiate the effect of conventional analgesics in migraine treatment when administered concurrently with the analgesic.
  • the present invention also provides a pharmaceutical compositions comprising a compound of the formula (I) and an analgesic.
  • the compound of the formula (I) and the analgesic, such as aspirin or paracetamol, are present in the composition in amounts generally similar to their usual effective dose.
  • 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 formula (I) and an analgesic.
  • the invention also provides a compound of formula (1), for use in the treatment of emesis, disorders relating to impaired gastro-intestinal motility and of disorders of the central nervous system.
  • a compound of formula (1) for use in the treatment of emesis, disorders relating to impaired gastro-intestinal motility and of disorders of the central nervous system.
  • the following examples illustrate the preparation of compounds of the invention and the following descriptions illustrate the preparation of intermediates.
  • the temperature of the mixture was maintained at 50oC for 6 hours, after the dropwise addition of allyl bromide (5.4 mls, 60m. mole).
  • 6-Chlorosulphonylchroman-8-carboxylic acid (1.3g) was added in small portions to a cooled solution of 33% dimethylamine (25mls) and the resulting solution was allowed to stand overnight.
  • Chroman-8-carboxylic acid (1.5g) was suspended in dry dichloromethane (50mls) with oxalyl chloride (0.76ml), and dry dimethylfo ⁇ namide (0.5ml) was added. The mixture was stirred at room temperature until it became homogeneous.
  • 6-Dimethylaminosulphonylchroman-8-carboxylic acid 0.8g was dissolved in dry dimethylformamide (15mls), and triethylamine (0.5ml) was added before cooling to 0oC.
  • Ethylchloroformate (0.22ml) was added dropwise to the reaction mixture whilst keeping the temperature at 0oC and the mixture was stirred at this temperature for 15 minutes.
  • 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.
  • Compounds 1, 3, 6 and 7 significantly increased index of activity post administration at a dose of 1.0 mg/kg s.c.
  • Compound 2 significantly increased index of activity post administration at a dose of 0.5 mg/kg s.c.
  • Compounds were administered subcutaneously 30 minutes prior to administration of a standard dose of apomorphine HCl (0.1 mg/kg subcutaneously) and the vomiting response compared to that obtained when the same animals were dosed with apomorphine HCl and vehicle only.
  • Compound 2 was active at a dose of 0.1 mg/kg s.c.
  • Compound 3 had an ED 50 value of 0.01 mg/kg s.c.
  • Compound 4 had an ED 50 value of 0.5 mg/kg.
  • 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 - four 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 55% of maximum taken into account. Compounds 1, 3, 4 and 7 had ED 50 values of 1.7, 0.2, 3.8 and 7 mg/kg s.c. respectively.
  • Systolic blood pressures were recorded by a modification of the tail cuff method described by J.M. Claxton, M.G. Palfreyman, R.H. Poyser and R.L. Whiting, European Journal of Pharmacology, 37, 179, (1976).
  • An oscilloscope of W+W BP recorder, model 8002 was used to display pulses. Prior to all measurements rats were placed in a heated environment (33.5 ⁇ 0.5 ⁇ C) before transfer to a restraining cage. Each determination of blood pressure was the mean of at least 6 readings. Spontaneously hypertensive rats (aged 12-18 weeks) with systolic blood pressures 170 mmHg were considered hypertensive.
  • Compound 2 gave a 41% reduction in blood pressure at 4 hours post dose at a dose of 10 mg/kg p.o.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de formule (I) ou un sel pharmaceutiquement acceptable et/ou un N-oxyde et/ou un produit de solvatation de ceux-ci dans laquelle soit X soit Y représente CO et l'autre NH; E représente O, S ou NR où R représente l'hydrogène, C1-6 alkyle ou un groupe de protection et A représente un C2-4 alkylène ou un C2-4 alkénylène ou E et A forment ensemble avec le phényle auquel ils sont rattachés un noyau de quinoline; R4 est un groupe (II), (III), (IV) dans lesquels p et q valent indépendamment entre 0 et 2; Z représente O ou S; n vaut 0 ou 1; ces composés ont une activité antagoniste de la dopamine; leur procédé de préparation et leur utilisation en tant que produit pharmaceutique.
EP84900862A 1983-02-19 1984-02-17 Derives anylides et benzamides d'azabicycloalkyle Withdrawn EP0135545A1 (fr)

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GB838304648A GB8304648D0 (en) 1983-02-19 1983-02-19 Compounds
GB8304648 1983-02-19
GB8328550 1983-10-26
GB838328550A GB8328550D0 (en) 1983-10-26 1983-10-26 Compounds

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