AZABICYCLOALKYL BENZAMIDE AND ANILIDE DERIVATIVES

Abstract: Compounds of formula (I), or a pharmaceutically acceptable salt and/or N-oxide and/or a solvate, wherein: one of X and Y is CO and the other is NH; E is O, S or NR wherein R is hydrogen, C1-6 alkyl or a protecting group and A is C2-4 alkylene or C2-4 alkenylene or E and A together with the phenyl to which they are attached form a quinoline nucleus; R4 is groups, (II), (III), (IV), wherein; p and q each independently are 0 to 2; Z is O or S; n is 0 or 1; having dopamine antagonist activity, a process for their preparation and their use as pharmaceuticals.

Description: AZABICYCLOALKYL BENZAMIDE AND ANILIDE DERIVATIVES This invention relates to novel compounds, to a process for their preparation and their use. U.S. Patent No. 4273778 and published European Application No. 80304467.6 (corresponding to allowed U.S. Application No. 213237) disclose benzamides and anilides respectively having a bicyclic side chain. These compounds are described as having dopamine antagonist activity. A novel class of benzamides and anilides have been discovered which compounds also have dopamine antagonist activity. Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt and/or N-oxide and/or a solvate thereof: OMPI /sy, wi p o wherei n : one of X and Y is CO and the other is NH; E is O, S or NR wherein R is hydrogen, C _6 alkyl or a protecting group and A is C2-4 alkylene or C2-4 alkenylene or E and A together with the phenyl to which they are attached form a quinoline nucleus; R4 is a group: or wherein: p and q each independently are O to 2; Z is O or S; n is O or 1; one of R6 and R7 when n=0 is Cτ._4 alkoxy. OMPI Cχ_4 alkoxycarbonyl, hydroxy or Cι_4 alkyl optionally substituted by hydroxy, Cι_4 alkoxy or C1-4 acyloxy, and the other is hydrogen or Cχ_4 alkyl or one of Re, R7 and R8 when n=l is Cχ-4 alkyl and the other two are the same or different and are hydrogen or Cχ_4 alkyl; R 5 is Cι_7 alkyl, - (CH2) s l0' s being O to 2 and Rχθ being C3-8 cycloalkyl, -(CH2)tRll/t being 1 or 2 and R11 being thienyl or phenyl optionally substituted by one or two substituents selected from Cχ_ alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy and Cχ_4 alkyl optionally substituted by hydroxy, Cχ_4 alkoxy, carboxy, esterified carboxy or in vi o hydrolysable acyloxy; R^ is hydrogen or Cχ_g alkyl; and R2 and R3 are the same or different and are hydrogen, halogen, trifluoromethyl, Cχ_g alkoxy, C*L_ Q alkylthio, carboxylic C _7 acyl, carboxylic Cχ_7 acylamino, Cχ_6 alkylsulphonyl, Cχ_s alkylsulphinyl, nitro or NRJ.2RI3- NR12R13CO, R12 R13SO2, or Cι_g alkyl-S02NRχ4, NR12R13SO2 R14 wherein Rχ2 and R13 are the same or different and are hydrogen Cχ__6 alkyl, phenyl or phenyl Cι_4 alkyl groups any of which phenyl moieties may be substituted by one or more halogen, trifluoromethyl, Cι_6 alkoxy or nitro groups, or Rχ2 and R 3 together form C4-5 polymethylene, and R14 is hydrogen or Ci-g alkyl. Preferably, X is CO and Y is NH. Suitable values for E-A include the following: _ _- wherein El is O, S or NR' wherein R'is hydrogen, methyl or acetyl; Preferred values for E-A include a) wherein E*- is O or NH, and c) wherein E-*- is 0 or NH. A preferred value of R4 is of formula (II). When R4 is a group of formula (II) as defined, p is suitably 0 or 1, and q is suitably 0 or 1. Often 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. When R4 is a group of formula (III) as defined Z is O or S, preferably O. When R 4 is a group of formula (IV) as defined, preferably each of Rg and R7 when n=0 and each of Rβ, R7 and Rβ when n=l are in the exo-position. Suitable examples for one of Re and R7 when n=0 include ethoxy, ethoxy, rv-propoxy, methyl, ethyl. n-propyl, methoxycarbonyl and ethoxycarbonyl, hydroxy, hydroxymethyl or hydroxethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, acetylmethyl and acetylethyl. Methyl is preferred. Suitable examples for one of Re, 7 and Rs when n=l include methyl, ethyl and ri-propyl. Suitable examples for the other of Q and R7 when n=0 and for the other two of R6, Rl and Rs when n=l include hydrogen, methyl, ethyl and n- and iso-propyl. Examples of R5 when C1-7 alkyl include methyl, ethyl and ri-and iso-propyl. Within C1-7 alkyl, C4-7 alkyl are of interest, especially those of the formula (CH 2 ) u Rχ6 wherein u is 1 or 2 and R-^g is a secondary or tertiary C3--6 alkyl group. Examples of 04. alkyl include n-,sec- and -tert-butyl, ri-pentyl, n_-heptyl, and especially iso-butyl, 3-methylbutyl, 2,2-dimethylpropyl and 3,3-dimethylbutyl. Preferred examples of R5, when -(CH2)s Rχo are those wherein s is 1 or 2, in particular those wherein R θ is c 5-8 cycloalkyl, such as cyclohexyl, and cyclopropyl. Preferred examples of R5 , when -(CH2)t R H / are those wherein t is 1. Rχι may be 2- or 3-thienyl or preferably is phenyl optionally substituted by one of Cχ-4 alkoxy, trifluoromethyl, halogen, carboxy, esterified carboxy or Cχ_4 alkyl optionally substituted by hydroxy, C _4 alkoxy, carboxy, esterified carboxy and ^n vivo hydrolysable acyloxy. When phenyl is substituted by optionally substituted C1-4 alkyl, examples of C1-4 alkyl include methyl, ethyl, rv- and iso-propyl, and rv-, iso-, sec- and tert- butyl; methyl however is preferred. Examples of substituents of such alkyl groups include hydroxy, methoxy, ethoxy, rv- and iso- propoxy, carboxy, esterified carboxy and iji vi o hydrolysable acyloxy. The substitution preferably occurs on the terminal carbon atom of the alkyl group. Examples of esterified carboxy groups include Cχ_4 alkoxycarbonyl, such as methoxy-, ethoxy-, n- and iso- propoxyca bonyl, phenoxycarbonyl or benzyloxycarbonyl, either being optionally substituted in the phenyl ring by one or two substituents selected from C _4 alkyl, Cχ-4 alkoxy, trifluoromethyl, halogen or nitro. Examples of in ^ vivo hydrolysable acyloxy groups include Cχ_6 alkanoyloxy, for example acetoxy, propionoxy, ri- 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 Cχ-4 alkyl, Cχ-4 trifluoromethyl, halogen or nitro, or other sulphonyloxy groups, for example Cχ_g alkanesulphonyloxy group, such as methanesulphonyloxy. The most preferred examples of R5, when -(CH2)tRll- are those wherein t is 1 and R is unsubstituted phenyl or monosubstituted phenyl in particular mono-p-substituted phenyl. Examples ' of 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 R5. 4 * ϊEAt OMPI Suitable examples of R include hydrogen, methyl, ethyl, n_- and iso-propyl. Preferably Rx is hydrogen or methyl. is preferably attached at the 2-position, i.e. at the carbon atom adjacent to E. Suitable examples of R2 and R3 include the following groups: hydrogen, chloro, bromo,CF3, methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and iso- propylthio, nitro, amino, Cχ_4 alkanoylamino such as formylamino, acetylamino, propionylamino, n- and iso-butyrylamino, aminosulphonyl; and amino, aminosulphonyl and aminosulphonylamino N-substituted by one or two methyl, ethyl, n- or iso-propyl iv-, sec-, or tert-butyl; cyclopropyl, cyclopentyl, cyclohexyl, phenyl or benzyl groups or N-disubstituted by C4 or C5 polymethylene; or aminosulphonylamino or methyl-, ethyl-, rv- or iso- propylsulphonylamino. Preferably R2 and R3 are independently hydrogen, chloro, amino or optionally substituted aminosulphonyl, as defined. When R2 and R3 are other than Cχ-g alkoxy or Cχ-g alkylthio, R2 is preferably in the 4-position with respect to X as the 1-position; R3 is then preferably in the 5-position similarly defined. It will of course be realised that 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. Compounds of formula (I) include those containing the moiety of formula (V) : wherein m is 1 or 2, RI3 is aminosulphonyl optionally substituted as defined and Rx and E--- are as hereinbefore defined. A group of compounds within those of formula (I) is therefore of formula (VI): wherein the variable groups are as hereinbefore defined. Suitable values for RI3 N-substituents are as described under formula (I). Preferably R---3 is aminosulphonyl optionally substituted by one or two methyl groups. Suitable and preferred values for Ri and El are as so described under formula (I). More suitably p is 0 or 1, it is believed preferably 0. Preferably q is 1 and the CONH moiety is then attached at the 3-position (conventional numbering) and in the β orientation. A sub-group of compounds within those formula (VI) those of formula (VII): wherein: RI5 is C 4 _7 alkyl or -(CH2) s χo where s is 0 to 2 and Rχθ is C5_8 cycloalkyl; and the remaining variables are as defined in formula (V). Suitable and preferred Rx and El are as so described under formula (I). Suitable and preferred RI3 are as so described under formula (I) for corresponding R3. A group of compounds within those of. formula (VII) is that wherein is (CH2) U R16 as defined or (CH2)uRlO where u and Rχo are as defined. Examples of RI5 in these compounds include iso-butyl, 3-methylbutyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl and cyclopropylethyl. It is preferred that the CONH moiety is in the β-orientation to the nortropane ring. A sub-group of compounds wi thi n those of formula (VI ) is of the formula (VIII ) : wherei n : R 2 5 is thienylmethyl or -(CH2)t R ll' fc being 1 or 2, and Rxx being phenyl optionally subsituted by one or two substituents selected from Cχ_4 alkoxy, trifluoromethyl, halogen, carboxy, esterified carboxy, and Cχ_ alkyl optionally substituted by hydroxy, Cχ_4 alkoxy, carboxy esterified carboxy or x_ι vi o hydrolysable acyloxy. Particularly preferred compounds are those wherein R^5 is benzyl optionally substituted in the phenyl ring by one or two substituents selected from Cχ_4 alkoxy, trifluoromethyl, halogen and Cχ_4 alkyl. It is especially preferred that the phenyl ring is unsubstituted. Suitable and preferred Rx and El are as so described under formula (I). Suitable and preferred R 3 are as so described under formula (V). OMPI It is preferred that the CONH moiety is in the β-orientation to the nortropane moiety. A third sub-group of compounds within those of formula (VI) is of formula (IX): wherein R 5 is as defined in formula (VII). Suitable and preferred variables are as so described under formula (VII). Another sub-group of compounds within those of the formula (VI) of interest are those of the formula (X): wherein 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 3 are as so described under formula (VIII). A second group of compounds within those of formula (I) is of formula (XI): wherein the variables are as defined in formulae (I) and (III). Suitable and preferred variables are as so described under formula (VI). Preferably Z is O, and the CONH moiety is in the β-orientation. There are further compounds within formula (I) containing the moiety of formula (XII): wherein R and R 2 3 are the same or different and are hydrogen, halogen, hydroxy, Cχ-6 alkoxy, Cχ-6 alkylthio, trifluoromethyl, amino or Cχ_7 acylamino; and RX and E are as hereinbefore defined. Another group of compounds within formula (I) is therefore of formula (XIII): wherein the variable groups are as hereinbefore defined. Suitable and preferred values for Rl and R 2 3 are as so described for the relevant R2 and R3 under formula (I). Suitable values for Rx and E are as so described 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. Suitable and preferred Ri and El are as so described under formula (I). Suitable and preferred RI2 and R 2 3 are as so described under formula (I) for corresponding R2 and R3. Often, RI2 and R 2 3 are both hydrogen. A group of compounds within those of formula (XIV) is that wherein R 5 is (CH2) u Rχn where u and R o are as defined. Examples of R 5 in these compounds include iso-butyl, 3-methylbutyl, 2,2-dimethylpropyl and cyclopropylethyl. It is preferred that the CONH moiety is in the β-orientation to the nortropane ring. A sub-group of compounds within those of formula (XIII) is of formula (XV): wherein the 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 Cχ-4 alkoxy, trifluoromethyl, halogen and Cχ_4 alkyl. Suitable and preferred R and El are as so described under formula (I). Suitable and preferred R 2 and R 2 3 are as so described under formula (XII). It is preferred that the CONH moiety is in the β-orientation to the nortrσpane moiety. A third sub-group of compounds within those of formula (XIII) is of formula (XVI): wherein the variable groups are as hereinbefore defined under formula (XIV). Another sub-group of compounds within those of the formula (XIII) of interest are those of formula (XVII): OMPI wherein R 2 5 is as defined in formula (VIII). Preferred compounds are those wherein R 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 RI2 and R 2 3 are as so described under formula (XII). Within formulae (XIV) to (XVII) there are sub-groups wherein the benzamide moiety is of formula (XVIII): CO-NH- (XVIII) NHR wherein: 21 Rlχ is halogen or Cχ_g alkyl; R-^3 is halogen; and R21 is hydrogen or C1-4 alkanoyl " SHE OMPI 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 with a compound of formula (XX): L-R 4 (XX) wherein: One of J and L is COQ, where Q is a leaving group, and the other is -NH2; and the remaining variable groups are as defined in formula (I), with the proviso that when J is -NH2, R2 or R3 is other than amino, and thereafter optionally converting R, Rχ f R2 or R3 to another R, Rx, R2 or R3 respectively; as necessary converting R5 to other R5; 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 Cχ_4 alkanoyloxy, Cχ_4alkoxycarbonyloxy and activiated hydrocarbyloxy such as pentachlorophenoxy. Another example of an acyloxy group Q is when Q is joined to El to form -O-CO-N'-. If the leaving group is hydroxy, then 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. The reaction may be carried out at a non-extreme temperature such as -10 to lOOoc, for example 0 to 80oc. If the leaving group is a halide, then 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. Alternatively, the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate. If the leaving group is acyloxy, then the reaction is preferably carried in substantially the same manner as if the leaving group were hydroxy. Suitable examples of acyloxy leaving groups include Cχ_4 alkanoyloxy, mesyloxy, tosyloxy and triflate; and when E 1 is NH, and X-Y is CO-N'. If the leaving group is Cχ_4 alkoxycarbonyloxy, then 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. If the leaving group is activated hydrocarbyloxy then 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. Preferably 0 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 R3 is aminosulphonyl may be formed from the corresponding R3 chlorosulphonyl derivatives of the compound of formula (XIX) wherein R3 is hydrogen, with a suitable amine or ammonia. The E-A moiety in compounds of the formula (XIX) is generally prepared by a cyclisation reaction. For example, when E-A is of sub-formula (a) or (c) and E 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 (d) wherein E is NH may be prepared by a conventional Fischer indole synthesis. Compounds of formula (XIX) having E-A of sub-formula (c) wherein E! is NH may accordingly be prepared by reduction of the corresponding indole. 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-* is NH may accordingly be prepared by reduction of the corresponding quinoline. The -skilled man will appreciate that the choice or necessity of conversion of groups R, Rχ f R 2 and/or R3 to other groups R, Rχ r R 2 and/or R3 will be dicatated by the nature and/or position of substituents R, Rχ f R2 and R3. It will be apparent that compounds of the formula (I) containing an 2, R3 or R5 group which is convertible to another R2 and R3 group or to an R5 group are useful novel intermediates. A number of such conversions is possible not only for the end compounds of fomula (I), but also for their ntermediates as follows: (a) an hydrogen substituent is convertible to a nitro substituent by nitration; (b) a nitro substituent is convertible to an amino substituent by reduction; (c) a Cχ_4 acylamino substituent is convertible to an amino substituent by deacylation; (d) an amino substituent is convertible to a Cχ_4 acylamino substituent by acylation; (e) a hydrogen substituent is convertible to a halogen substituent by halogenation; (f) a Cχ_6 alkylthio or Cχ-g alkylsulphinyl substituent is convertible to a Cχ-g alkylsulphinyl or a Cχ_g alkylsulphonyl substituent respecitvely by oxidation; and (g) an amino substituent is convertible to a Cχ-g alkyl S0 2 NRχ4 or NRχ Rχ 3 SO2 RX4 substituent by reaction with Cχ_g alkyl Sθ2NQ 2 or NRχ2Rχ3 02Q2 where Q is leaving group. (h) a fluoro or chloro substituent is convertible to an optionally substituted amino substituent by reaction with a suitable amine or ammonia. Conversions (a) to (h) are only exemplary and are not exhaustive of the possibilities. In regard to (a), nitration is carried out in accordance with known procedures. In regard to (b) , the reduction is carried out with a reagent suitable for reducing nitroanisole to aminoanisole. In regard to (c), deacylation is carried out by treatment with a base, such as an alkali metal hydroxide. In regard to (d), 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. In regard to (e), halogenation is carried out with conventional halogenating agents. In regard to (f), 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. In regard to (g), Q is often halide, for example chloride or bromide, or hydroxy. When halide is the leaving group, the reaction is generally carried out in the presence of a base. When 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. In regard to (h), the amination is carried out under conventional conditions using an inert solvent such as CH2CI2 or an excess of amine also functioning as the solvent. Depending on steric and/or electronic factors and/or reaction conditions 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. Treatment with a base such as methanolic sodium hydroxide at ambient or slightly elevated temperatures is apt. It is sometimes most convenient to effect the coupling of compounds (XIX) and (XX) using a compound of formula (XIX) wherein one of R2 and R3 is amino and to convert to alkyl- or aminosulphonylamino. It will be appreciated that, R5 when optionally substituted benzyl as hereinbefore defined, may be replaced by another group R5. Such R5 benzyl groups may be removed for example when Rχ f R2 or R3 is not halogen by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (XXI): wherein R 4 is R4 wherein the R5 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 O3R5 wherein R5 is as defined in formula (I) and Q3 is a leaving group, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I). Suitable values for Q3 include groups readily displaced by nucleophiles such as Cl, Br, I, OSO2CH3 or OSO2C6H4ECH3. Favoured values for Q3 include Cl, Br and I. Particularly suitably the compound Q3R5 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 dime hylformamide 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 at a slightly elevated temperature. Converting R5 to another R5 in the compound of the formula (XX) before coupling with the compound of the formula (XIX) or its derivative is preferred. Such interconversions are effected conveniently under the above conditions. It is desirable to protect the amine function with a group readily removable by hydrolysis such as a C2-7 alkanoyl group before R5 interconversion. The substituents in the phenyl ring in an R5 benzyl group in a compound of formula (I), in particular the substituted Cχ_4 alkyl substituents, are interconvertible. A number of such interconversions are possible not only for the end compounds of formula (I), but also for their intermediates as follows: (i) a carboxy Cχ-_4 alkyl substituent is convertible to an esterified carboxy Cχ-4 alkyl substituent by esterification: (ii) an esterified carboxy Cχ_4 alkyl substituent is convertible to a carboxy Cχ_4 alkyl substituent by deesterification; OMPI (iii) Cχ_4 alkoxy Cχ-4 alkyl substituent or an in vivo hydrolysable C2-4 acyloxy Cχ-4 alkyl substituent is convertible to an hydroxy Cχ_4 alkyl substituent; (iv) an optionally esterified carboxy or carboxy Cχ_3 alkyl substituent is convertible to an hydroxymethyl or hydroxy C2-4 alkyl substituent by reduction; and (v) a hydroxy Cχ_4 alkyl is convertible to C1-4 alkyl by O-alkylation or m ^ vivo hydrolysable C2-4 acyloxy Cχ_4 alkyl by O-acylation. Conversions (i) to (iv) are only exemplary and are not exhaustive of the possibilities. In regard to (i) and (ii), the esterification and de-esterification reactions are carried out in conventional manner. In regard to (iii), a Cχ_4 alkoxy Cχ-4 alkyl substituent is convertible to an hydroxy Cχ_4 alkyl substituent by conventional methods, such as warming with aqueous hydrobromic acid or by treatment with pyridine hydrochloride, boron tri romide, boron triodide or iodotrimethylsilane. As iji vivo hydrolysable C2-4 acyloxy Cχ-4 alkyl substituent is convertible to an hydroxy Cχ-4 alkyl substituent by acid or base hydrolysis. In regard to (iv), the reduction is carried out with a selective metal complex hydride, for example lithium aluminium hydride, under conventional conditions. iJREA OMPI In regard to (v), 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 Cχ-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 i_n vivo hydrolysable acyloxy group and a leaving group, such as halide, for example chloride and bromide, and hydrogen. When halide is the leaving group, the reaction is generally carried out in the presence of a base. When hydroxy is the leaving group, the reaction is generally carried out in the presence of a dehydrating agent, such as dicylohexylcarbodiimide, in an inert solvent at non-extreme temperature, such as ambient temperature or slightly above, or reflux temperature. Before carrying out any of these conversions, the effect, if any, on other substituents should be considered, and such reagents as are appropriate should be selected together with the adoption of such precautionary measures as are necessary. For example, 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). Compounds of the formula (XXI) are novel intermediates and thus form an aspect of the present invention. It will be realised that in the compound of the formula (I) the -X-Y-linkage may have anλ ' or β orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of and β 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 tf and β isomer may if desired by synthesised from the corresponding (Ji or β form of the compound of the formula (XX) . Synthesis from the corresponding ( or β isomer of the compound of the formula (XX) is in general preferred. It will be appreciated that, when X is NH, Y is CO in the compounds of the formulae (I) or (XX), epimerisation of the CO-ring linkage to the energetically more favourable orientation often takes place readily in the presence of acid or base. In such cases if the less favoured isomer is desired, it is preferred to stereospecifically synthesise the isomer of the compound of the formula (XX) and to convert it to the required comound of the formula (I) under such conditions to avoid epimersation. The ^ or β form of the compound of the formula (XX) may if desired be prepared by known stereospecific processes, such as those leading to the or β 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. Pharmaceutically acceptable 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. 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, di ethylformamide 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-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. Certain of the compounds of formula have blood pressure lowering activity and may also be useful in the treatment of hypertension. .Those compounds of the present invention which are of interest for their beneficial effect on gastric motility are the compounds of formula (I) and (VI) the quaternary ammonium salts of the compounds of formula (I). The invention also provides 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. Such 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, reconstitutable 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. For parenteral administration, 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. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vechicle. 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. Advantageously, 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. However, 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 lOmg/ 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. Accordingly, 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. 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 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. The following examples illustrate the preparation of compounds of the invention and the following descriptions illustrate the preparation of intermediates. Description 1 Ethyl 2-(propen-3—oxy. benzoate (Di) 80% sodium hydride (l.8g 6θm. mole) was added in portions to ethyl salicylate (lOg, 6θm. mole) in dimethyIformam ide (l5θ mis). The temperature of the mixture was maintained at $0 C for 6 hours, after the dropwise addition of allyl " bromide {S- mis, βOm. mole). Water was then added to the solution and the resulting mixture was extracted with ether. Concentration of the dried organic extract gave an oil which was distilled to give the title compound (DI) (I2g), 95% yield, ( .pt 95-100 O C/_L____n.Hg) Description 2 Ethyl 2-hydro_gy-3-propenylbenzoate (P2) Ethyl 2-(propen-3-oxy)benzoate (ll.Og) was heated at 230°C for 1 hour. Distillation of the reaction mixture gave the title compound (D2) (lOg), cxj/o yield, (b.pt. 100°C/-h__mHg) Doscription 3 Ethyl 2-a.cetoχy-3-propenyl benzoate (P3) A mixture of ethyl 2-hydroxy-3-propenylbenzoate (8.0g), acetic anhydride (35mls) and pyridine (35>mls) was stirred at room temperature overnight. After pouring into water, the mixture was extracted with methylene chloride. The organic extract was dried and evaporated to give the title compound (D3) (9.1 g), 98% yield. Description U Ethyl 2-acetoxy-3-bromopropylbenzoate (Dip A solution of ethyl 2-acetoxy-3~propenylbenzoate (8.5>g) and 2,2 -azobis-(2-methylpropionitrile) (θ.2g) in carbon tetrachloride (30mls) was cooled to -$ C and saturated with hydrogen bromide. The reaction mixture was then left at 0 C in a pressure vessel overnight. The product was poured into water and the organic layer was washed with dilute sodium hydrogen carbonate solution. Evapora¬ tion of the solvent in vacuo gave the title compound (Dlj.) which was used immediately. Pescri-ption _> Chrorr.an-δ-car ' boxylic acid (P5) A solution of ethyl 2-acetoxy-3-bromopropylbenzoate (llg) in ethanol (85mls) and 10 sodium hydroxide solution (li+Omls) was heated under reflux for Is, hours. The ethanol was then removed in vacuo and the residue was acidified with $N hydrochloric acid to give chroman-8-carboxylic acid (P£) ( .6g), lh% yield m.pt. 8 -86°C (Lit. m.pt. 1 85-88°C). Ref- 1 Chem. Abs. ^ lβ$3So Description 6 6-Chlorosulphonylchroman-8-carbo- ylic acid (P6) Chroman-8-carboxylic acid (l.Og) was added portionwise to chlorosulphonic acid (l mls) while keeping the temperature of the mixture below C. The reaction mixture was then warmed to 55 0 and maintained at this temperature for 2 hours before being cooled and poured into ice-water. The precipitated white solid was filtered and dried in vacuo to give the title compound (D6) (l.3g), 8lι,% yield which was used immediately. - - Description 7 6-Dimethylaminosulphonylchro_Dan-8-carboxylic acid (P7) 6-Chlo_-θsulphonylchroman-8-carboxylic acid (l.3g) was added in small portions to a cooled solution of 33% dimethylamine (25mls) and the resulting solution was allowed to stand overnight. Acidification with $8 hydrochloric acid gave a precipitate which was iltered, washed with water and dried over potassium hydroxide in vacuo to give the title compound (D7) (l.3*-»g)» 33% yield. Description 8 2- * Methvl-2.3-dihvdrobenzofuran-7-carboxylic acid (P8) A solution of ethyl 2-hydroxy-3-(propenyl)benzoate (lg) in acetic acid (5mls) was heated under reflux with a hβ% solution of hydrobromic acid (2.5mls) for 30 minutes. The solvent was then removed in vacuo and the residue was heated with 10% sodium hydrox ¬ ide solution (lO ls) for a further 30 minutes. Cooling of the solution followed by acidification, extraction with ether and evaporation of the solvent gave the title compound . fS- -D8 ' Example 1 N-[3.(8-benzyl-8-azabicyclo ( 3.2«l) octyl | chroman-8-carboxamide hydrochloride (l) Chroman-8-carboxylic acid (l.5g) was suspended in dry dichlorome hane (5θmls) with oxalyl chloride (θ.76ml), and dry dimeth l oπnamide (θ.5ml) was added. The mixture was stirred at room temperature until it became homogeneous. The solution was cooled to 0 C and kept below this temperature durin the dropwise addition of triethylamine " (3.-46ml) in dry dichloromethane (lOmls), followed by the dropwise addition of 3 -amino-8-benzyl-8-azabicyclo ( 3 j ,l) octane (l.8g) in dry dichloromethane (lOmls). The reaction mixture was allowed to warm to room temperature before being shaken with 10% sodium hydroxide solution (lOml). The organic layer was dried over anhydrous sodium sulphate, filtered and the solvent was removed in vacuo to give an oil (J4. g) which was purified by column chromatography (silica, chloroform as eluant) to give the title compound as the free base (3«25g» 11%) . This was converted into its hydrochloride salt (l) nmr (D„θ) 2._-2.85(6H,m,-NCH h and ortho H), 3-02 (_LH,d,para H), 3.32 (IB, t, <_. meta H), 5-55-6.1 (5H, m,-NCH 2 Eh, 3 H and Ar-O-CHg-), 6.25 (2H» m, "gj OMPI bridgehead As) , 7125-8.6 (12H, m, methylene A) . C 2iι H 29 N 2°2 C1 ^l 11 - 118 - 3 G » 70.12; H, 7.05; N, β .63%. Found C, 69.8; Ξ, 7.0; N f 6.7996. Mass spec. Observed mass = 376.2139 * C_.H_oNpO_ requires 376.211x0. Example 2 6-Pimethylaminosulphonyl-N-|3|S(8-benzyl-8-azabicyclo ( 3 T 2-.l) octyl) J -chroπ_an-8-carboxamide hydrochloride (2) β-Pimethylaminosulphonylchroman-S-carbox lic acid (0.8g) was dissolved in dry dimethylformamide (l5mls), and triethylamine (θ.5ml) was added before cooling to 0 C. Ethylchloroformate (θ.22ml) was added dropwise to the reaction mixture whilst keeping the temperature at 0 C and the mixture was stirred at this tempera¬ ture for 15 minutes. 3 -__mino-8-benzyl-8-azabicyclo 3.2.1 octane (θ.6g) in dry dimethylformamide (2mls) was added in one portion to the reaction mixture at 0 C before stirring at room temperature for 15 hours. The solvent was removed in vacuo to leave a residue which was treated with ammonia solution and extracted with dichloromethane. The organic extract was dried and evaporated to give an oil which on purification by column chromatography (silica, chloroform to 5% ethanol in chloroform as eluant) gave the title compound as its free base (l.3g » & ) * This was used to prepare the hydrochloride salt (2) m.pt. 253-255°C n.m.r. (P p θ) 2.25 ( S, d, aromatic H), 2,i|5 (IS, d, aromatic H), 2.52 (5H, m, -MCH 3Q. 5-25- .8 (5H, m, 3 H, -l.CH 2 Ph and Ar-0-CH_-) , 6.0 (2H, m, bridgehead A) , 7.2 (2H, t, Ar-CH 2 -CH 2 -) f 7.1+2 (6H, S, -S0 2 ((3H 3 ) 2 ) , 7.55-8.1+ (lOH, m, methylene H s). C 26 H 3i ι N 3 SG10 l i re l uires c > 59-1+; H, 6.7; H, 7.9396. Found C, 59.37; H, 6.1+7; H, 719%. Mass spec. Observed mass = 1+83.2156. C 26 H _JT_S0, requires 1+83.2192. The above mentioned method was used to prepare 2 -me th 1-2, 3~ d-_hydrobenzofuryl-7(N _ t8-benzyl-8-azabicyclo ( 3<.2 1 , l) octyl) carboxamide hydrochloride (3) m.pt.21+0-21+1 C n.m.r. (P 0) 2.1+-2.5 (7H, m, -NC__ Ph, ortho H and para H) , 3.2 (iH, t, meta H), * 1 ( H, , Ar-0-CHCH--) . 5.55-6.02 (3H, m, 3 1 and - HCH-Fh), 6.15 (2H, m, bridgehead H s), 6.6-8.5 (lOE, m, methylene H s), 8.7 (3H, d, Ar-0- CHCΞ^-) . C 2l+ Ξ 29 N 2°2 C1 re< ϊ uires c » 6 9 « 8 ? Ξ > 7.03, N, 6.79%. Found C, 69.6; H, 7.19; N, 6.76%. Mass spec. Observed mass = 376.211+7 C 2l+ H 2 gl-r 2 0 2 requires 376.2U+9 Γ E OMP EXAMPLE 3 N- [ 3B- (8-BENZYL-8-AZABICYCLO ( 3 , 2 , l ) OCTYL) ] -8-ri , ,3 ,4-TETRAHYDROQUINOLINYL]CARBOXAMIDE (4) 6,7-Dihydro-lH,3H-5H-pyrido[3,2,l,i,j] [3,1]benzoxazine-l ,3 dione (as prepared by G.M. Coppola, J. Med. Chem. , 15, 645, 1978) (2.25g) was dissolved in anhydrous dimethylform (50ml) and treated with 3-β-amino-8-benzylnortropane (2.4g). The solution was warmed to 50° for one hour then left to cool to room temperature overnight: (17 hrs). The mixture was evaporated in vacuo, and the residue was chromatographed on Kieselgel 7734 via chloroform with 1-3% methanol. The isolated product was recrystallised from methylene chloride/ether to yield the ' title compound (2.19g) as colourless microcrystals mp. 142°. C 24 H 29 N 3°2*^ H 2° re< 3 uires c * 75.00; H, 7.81; N, 10.93% Found C , 74.89, 75.14; H, 7.67, 7.69; N, 10.88, 10.82% The above method was used to prepare 6-dimeth laminosulpho N-[3β-8-benzyl-8-azabicyclo{3.2.l}octyl) _-8-f1 , 2 ,3,4-tetra hydroquinolinyl]carboxamide 65% m.pt. 193-194"C. (Compound C 26 H 34 N 4 0 3 S required C, 64.73; H, 7.05; N, 11.62% found C, 64.56; H, 7.13; N, 11.55% Mass Spec. Observed mass = 482.2351 C 26 H 34 N 4°3 S rec 3 uires 482.2352 OMPI IPO 2-Methyl-5-dimethylaminosulphonyl-2 - 3-dihvdrobenzofuryl-7 (N (8-benzyl-8-azabicyclo{3,2 , l}octyl) ]) carboxamide (Compound n : (CDC1-) τ 1.65 (IH, d, aromatic H) , 2.3 (IH, d, aromat H) , 2.45-2.95 (6H, m, -NCH Ph and -CONH-), 4.5-5.05 (IH, m C-2 H) , 5.35-5.95 (IH, m, 3αH) , 6.45 (2H, s, -NCH Ph) , 6.7 (2H, m, bridgehead H's) , 7.3 (6H, s, -N(CH ) 2 ), 8.45 (3H, d, C-2 CH 3 ) . C 26 H 33 N 3 S °4 rec I uires C ' 64.59; H, 6.83; N, 8.69 % found C, 64.45; H, 6.87; N, 8.67% Mass spec. Observed mass = 483.2182 C 26 H 33 N 3 S °4 rec ϊ uires 483.2192 6-Cyclopentylaminosulphonyl-N[3β (8-benzyl-8-azabicyclo {3.2.1} octyl ) ] -8-chromancarboxamide (Cojπ- ound 7) nmr (CDC1 3 ) 1.45 (IH, d, aromatic E) , 2.05-2.95 (7H, d and m, aromatic H, -CONH- and -NCH 2 Ph) , 4.75 (IH, d, -NHS0 2 -) , 5.6 (3H, m, Ar -0-CH 2 ~ and (CH-NH-) , 6.4 (2H, s, -NCH 2 Ph) , 6.75 (2H, m, bridgehead H's) C ' 29 H 37 N 3 SO requires C, 66.5; H, 7.07; N, 8.03' C, 66.42; H, 7.12; N, 8.01% Mass spec. Observed mass = 523.2509 C 2g H 37 N 3 SO 4 requires 523.2505 OMPI Pharmacological Data Increase in intragastric pressure 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. In each animal a pre-dose period of 40 minutes was allowed to obtain a measure of spontaneous activity. 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 V 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. Anti-emetic activity in the dog Compounds were administered subcutaneously 30 minutes prior to administration of a standard dose of OMPI apomorphine HC1 (0.1 mg/kg subcutaneously) and the vomiting response compared to that obtained when the same animals were dosed with apomorphine HC1 and vehicle only. Compound 2 was active at a dose of 0.1 mg/kg s.c. Compound 3 had an ED50 value of 0,01 mg/kg s.c. and Compound 4 had an ED50 value of 0.5 mg/kg. Dopamine Receptor Blocking Activity in the Central nervous System Compounds were tested for inhibition of apomorhine induced climbing in the mouse. The test is based on that described by Protais, P., Constantin, J. and Schwartz J.C. (1976), Psychopharmacology, 50, 1.6. 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 lmg/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. s . i p o Compounds 1, 3, 4 and 7 had ED50 values of 1.7, 0.2, 3.8 and 7 mg/kg s.c. respectively. Anti-hypertensive Activity 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. Toxicity No toxic effects were observed in the above tests. OMPI

Claims: 1. A compound of formula (I), or a pharmaceutically acceptable salt and/or N-oxide and/or a solvate thereof: wherein: one of X and Y is CO and the other is NH; E is O, S or NR wherein R is hydrogen, C _g alkyl or a protecting group and A is C2-4 alkylene or C2-4 alkenylene or- E and A together with the phenyl to which they are attached form a quinoline nucleus; 4 is a group: or wherein: p and q each independently are 0 to 2; Z is 0 or S; n is O or 1; one of Rζ and R7 when n=0 is C1.-4 alkoxy, C1-4 alkoxycarbonyl, hydroxy or C1-4 alkyl optionally substituted by hydroxy, Cχ_ 4 alkoxy or C1-4 acyloxy, and the other is hydrogen or Cι_4 alkyl or one of Rg, OMPI R7 and Re when n=l is Cι_4 alkyl and the other two are the same or different and are hydrogen or C1-4 alkyl; R5 is C1-7 alkyl, - (CH2)s R 10' s being O to 2 and RlO being C3_8 cycloalkyl, -(CH 2 )t ll,t be i«g 1 or 2 and R * being thienyl or phenyl optionally substituted by one or two substituents selected from Cι_4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy and C1-4 alkyl optionally substituted by hydroxy, Cχ_4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy; Rl is hydrogen or Cι_ alkyl; and R2 and R3 are the same or different and are hydrogen, halogen, trifluoromethyl, C _g alkoxy, C^___g alkylthio, carboxylic C\-.η acyl, carboxylic C _7 acylamino, C _g alkylsulphonyl, C^_g alkylsulphinyl, nitro or R^R]^, NR 12 R 13 c °r NR 12 R 13 so 2' or c l-6 alkyl-S02NRi4, NR--_2Ri3Sθ2NR--_ wherein R12 a** 3 R 13 are the same or different and are hydrogen C*L_g alkyl, phenyl or phenyl C1-4 alkyl groups any of which phenyl moieties may be substituted by one or more halogen, trifluoromethyl, C _g alkoxy or nitro groups, or R12 and Rχ3 together form C4-.5 polymethylene, and R14 is hydrogen or Cχ_g alkyl. 2. A compound accordi ng to claim 1 of formula ( VI ) : wherein El is 0, S or NR* wherein R' is hydrogen, methyl or acetyl, m is 1 or 2, R---3 is aminosulphonyl optionally substituted as defined for R3 in claim 1 and the remaining variables are as defined in claim 1. 3. A compound according to claim .2 of formula (VIII): wherein 5 is thienyl ethyl or -(CH2)t R ll being 1 or 2, and R * ^ being phenyl optionally substituted by one or two substituents selected from C1-4 alkoxy. trifluoromethyl, halogen, carboxy, esterified carboxy, and C1-4 alkyl optionally substituted by hydroxy, Cι_4 alkoxy, carboxy esterified carboxy or in vivo hydrolysable acyloxy, and the remaining variables are as defined in claim 2. 4. A compound according to claim 1 of formula (XIII): wherein R-^2 an< -* R ^3 are the same or different and are hydrogen, halogen, hydroxy, Cι_g alkoxy, C^_ alkylthio, trifluoromethyl, amino or Cχ_7 acylamino; and the remaining variables are as defined in claim 2, 5. A compound accordi ng to claim 4 of formula ( XV) : wherein the variable groups are as defined in claims 3 and 4. 6. A compound according to any one of claims 2 to 5 wherein E-^ is oxygen. 7. A compound according to any one of claims 2 to 6 wherein m is 1 and R-^ is 2-methyl. 8. A compound according to any one of claims 2 to 6 wherein m is 2 and Ri is hydrogen. 9. A compound according to anyone of claims 1 to 8 wherein R5 (or R 5) is benzyl. 10. N-[3β(8-benzyl-8-azabicyclo (3,2,l)octyl)]- chroman-8-carboxamide, 6-Dimethylaminosulphonyl-N-[3β(8-benzyl-8-azabicyclo- 8-(3, 2,1)octy1)]chroman-8-carboxamide, 2-meth l-2,3-dihydrobenzofuryl-7(N-3β(8-benzyl- 8-azabicyclo(3,2,l)-octyl) ]carboxamide, N-(3β-(8-benzyl-8-azabicyclo(3,2,l)octyl)]-8-[l,2,3,4- tetrahydroquinoliny1]car oxamide, 6-dimethylaminosulphonyl-N-[3β-8-benzyl-8-azabicyclo- [3.2.1)]-8-[1,2,3,4-tetrahydroquinolinyl]carboxamide, 2-Methyl-5-dimethylaminosulphonyl-2,3-dihydrobenzo- furyl-7(N[3β(8-benzyl-8-azabicyclo[3,2,l]octyl)] ) carboxamide, 6-Cyclopentylaminosulphonyl-N [3β(8-benzyl-8-azabicyclo- [3.2.1]octyl)]~8-chromancarboxamide, or a pharmaceutically acceptable salt thereof. 11 * A process for the preparation of a compound according to any one of claims 1 to 10, which process comprises reacting a compound of the formula (XIX): OMPI with a compound of formula (XX): L-R 4 (XX) wherein: One of J and L is COQ, where Q is a leaving group, and the other is - H2* and the remaining variable groups are as defined in claim I, with the proviso that when J is -NH2 R2 or R 3 is other than amino, and thereafter optionally converting R, R R2 or R3 to another R, Rχ f R2 or R3 respectively; as necessary converting R5 to other R5; and optionally forming a pharmaceutically acceptable salt of the resultant compound of the formula (I). 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 13. A method of treatment of disorders related to impaired gastric motility, emesis and/or disorders of the central nervous system in mammals, which comprises the administration to the sufferer of an effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. OMPI

Inventors: SUMMERS CHRISTINE, SUMMERS, CHRISTINE
Applicants: BEECHAM GROUP PLC, BEECHAM GROUP P.L.C.
Application year: 1984
Main classification: C07D451
IPC codes: C07D307, C07D311, C07D451