AMINO-AZABICYCLOALKYL DERIVATIVES AS DOPAMINE ANTAGONISTS

Abstract: Compounds of formula (I) and pharmaceutically acceptable salts and N-oxides and solvent aducts of any of the foregoing formula (I), wherein: G is -N= or -NR; X, Y and Z are each independently -CR1==, -N== or -NR2 or one of X, Y and Z is C:B where B is O or S and the other two are each independently -CR1, -N= or -NR2; A is a group of formulas: (II), (III) or (IV), wherein: p and q each independently are 0 to 2; z<2> is O or S; n is 0 or 1; having dopamine antagonist activity, a process for their preparation and their use as pharmaceuticals.

Description: Amino-azabicycloalkyl derivatives as dopa ine anta¬ gonists. 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. A novel class of heteroarylamines and heteroaryl- enei ines having a bicyclic heteroalkyl N-substituent have been discovered. Such compounds have dopamine antagonist activity. Accordingly, 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: wherein: G is -N ■= or -NR where R is hydrogen or C, ^ alkyl; X, Y and Z are each independently -CR,==, -N= or -NR- where R, is hydrogen, C, . alkyl, or C, , alkylthio, and R 2 is hydrogen or C, . alkyl, or one of X, Y and Z is C:B where B is 0 or S and the other two are each independently -CR., -N= or -NR- wiiere R, and R 2 are as defined; OMPI A is a grou : or wherei : p and q each independently are 0 to 2 ; 2 Z is 0 or S ; n is 0 or 1 ; and one of R g and R_ when n = 0 is C, . alkoxy, C- 4 alkoxycar onyl, hydroxy or C, 4 alkyl optionally substituted by hydroxy, C, . alkoxy or C, 4 acyloxy, and the other is hydrogen or C- 4 alkyl or one of g , R 7 and R g when n = 1 is C. . alkyl and the other two are the same or different and are hydrogen or C,_ 4 alkyl; R, and R. together are C, - alkylenedioxy, or are each independently selected from hydrogen, halogen, CF,, C 1 _ 6 alkyl, C, g alkoxy, C, , alkylthio, C_ _ acyl, C, carboxylic acylamino, N-(C 1 _ 6 alkylsulphonyDC alkylamino, c ι__g alkyl- sulphonyl, C, g alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(ainosulphonyl) - C, , alkylamino optionally N-substituted by one or two groups selected from C, g alkyl, C, ~ cycloalkyl, C,_ g cycloalkyi C, . alkyl, phenyl or phenyl C, 4 alkyl groups or optionally N-disubstituted by C . _- poly e hylene; and Rr is C , _ 7 alkyl, - (CH 2* 1 s R ιn' s ■ Dein 9 0 to 2 and R» 0 being C, g cycloalkyl, -CH 2 ) t R,,, t being 1 or 2 and R.. being thienyl or phenyl optionally substituted by one or two substituents selected from C, Δ alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy and C, . alkyl optionally substituted by hydroxy, C, 4 alkoxy, carboxy, esterified carboxy or _in vivo hydrolysable acyloxy. A group of compounds within formula (I) is those wherein X, Y and Z are each independently -CR,= or -N= as defined or Y is C:B where B is 0 or S and X and Z are each independently -CR., -N= or -NR 2 . Suitable examples of R_ and R, include hydrogen, ' chloro, bromo, CF,, formyl, acetyl, propionyl, 11- and iso-butyryl; formylamino, acetylamino, propionylamino, ri- and iso-butyrylamino; methyl≤ulphonylamino, ethyl≤ulphonylamino, n- and iso-propylsulphonylamino, methyl, ethyl and ri- and iso-propylsulphone, -sulphinyl or -thia; nitro; methoxy, ethoxy and rx- and iso-propoxy; hydroxy; amino, aminocarbonyl aminosulphonyl and amino- sulphonamido and amino, aminocarbonyl, aminosulphonyl and aminosulphonamido substituted by one or two methyl, ethyl, ii- or iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, or benzyl groups. When R 3 and R. taken together are methylenedioxy or -ethylenedioxy, they are most suitably ethylenedioxy. 3 and R. are generally independent groups. Particularly suitable " R- and R, groups include hydrogen, halogen amino, and methoxy, and acylamino and nitro, which can conveniently be converted to the corresponding amino groups. It is generally preferred that R, is in the 4-posi io as numbered in formula (I) . For the same reason, it is generally preferred that R, is in the 5-position. Particularly preferred R^ groups include 4-amino and 4-carboxylic acylamino as defined. Most preferably R_ is 4-amino. Particularly, preferred R. groups include 5-halo such 5-chloro. •t In other useful compounds R, is hydrogen, or 4 -halo (eg chloro) , or -amino ; and R 4 is 5-C_, _- alkyl S (0) (suc as 5-methylsulphonyl , -sulphinyl or -thio) or 5-σptionally substituted aminosulphonyl. Often the group G and the heterobicycle nitrogen ato 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) . When A is a group of formula (II) as defined, p is suitably 0 or 1 , preferably 1 , and g is suitably 0 or 1. When A is a group of formula (III) as defined Z is 0 or S, preferably 0. When A is a group of formula (IV) as defined, preferably each of R g and R_ when n ~ 0 and each of R g , R 7 and Rg when n. = 1 are in the exo-posi ion. Preferred examples for one of R g and R_ when n = 0 are methoxy, ethoxy, n-propoxy, methyl, ethyl, n-propyl, methoxycarbonyl and ethoxycarbon 1, hydroxy, hydroxymethyl or hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl ethoxyethyl, acetylmethyl and acetylethyl. The most preferred is methyl. Preferred examples or one of R g , R ? and R g when n = are methyl, ethyl and n-propyl. Preferred examples for the other of R g and R 7 when n = 0. and for the other two of R g , R 7 and R g when n = 1 , are hydrogen, methyl, ethyl and n- and iso-propyl. Examples of R 5 c ι_ 7 a*l-_yl include methyl, ethyl and n-and isopropyl. Within C. 7 alkyl, C, 7 alkyl are of interest, especially those of the form ( CH 2- 1 u R 16 wtιerei u is 1 or 2 and R_. g is a secondary or tertiary - g alkyl ' group or a C, « cycloalkyl group. Suitable examples of R- include cyc opropy iiiot yl , cyc obutylir-othyl, cyclopentylπiethyl,- cyc ohexy meihy , cyclopropylethyl, cyc3obutylethyl , cyc opentyloihyl r cyclohrxylethyl, fort--butylmc.thyl, i_κo-propyln*el-.y_l , i_sc>_-propylethyl and tert-buty ethyl. Favourably, R,- is cyclopropylmethyl, cyclohexylme.hyl , iso-propylπ.ethyl, tert-butylmethyl or iso-propylethyl, preferably ter -butyImethyl. Preferred examples of R_ , when -(CH_) R , are those ..herein t is 1. R-- may be 2- or 3-thaenyl or preferably is phenyl optionally substituted by one of C_._. alkoxy, trif uoromethyl, halogen, carboxy, esterified carboxy or C j _. alkyl optionally substituted by hydroxy, C, . alkoxy, carboxy, esterified carboxy and i vivo hydrolysable acyloxy. V'hen phenyl is substituted by optionally substituted . _ Δ alkyl, examples of C- . alkyl include methyl, ethyl, _- and so-propyl, and n_-, iso-, sec- and tert- butyl; methyl however is preferred. Examples of subεtituents 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. Examples of esterified carboxy groups include C_,_. alkoxycar onyl, such as methoxy-, ethoxy-, n- and iso- propoxy-carbonyl, phenoxycarbonyl or benzyloxycarbonyl , either being optionally substituted in the phenyl ring by one or two ευbstituentε selected from C._. alkyl, C._ 4 alkoxy, trifluoromethyl, halogen or nitro. ? ? ? - CET I OMH Examples of i_n vivo hydrolysable acyloxy groups iiiclnde C, 6 al noyloxy, for example aceioxy, propionoxy, n- and i_s -bu'tyroxy, and 2,3 di ethylpropanylox , benzyloxy or benzcne ulphonyloxy either being optionally substituted in the phenyl ring by one or two εubstitυents selected from C^_ 4 alkyl, C. _ . alkoxy, tri luoromethyl, halogen or nitro, or other εulphonylo.xy groups, for example C, alkanesulphonyloxy 1 —D group, such as ethaneεulphonyloxy. The most preferred examples of R- , when -(CH 2 ) t R 11 , are those wherein t is 1 and R _. is unεubstituted phenyl or monosubεtituted phenyl in particular mono-p-substitutedpn-__τ>- r l Examples of preferred p-subεtituents include methyl, trifluoromethyl, fluoro, chloro and bro o, especially fluoro. Unsubstituted benzyl, £-fluorobenzyl, p_-chlorobenzyl and £-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, aleic, citric, εuccinic, benzoic, ascorbic, ethanesulphonic, α-keto glurar ' ic, α-glycerophosphoric, and glucose-1-phosphoric; and quarternary ammonium salts. Preferably the acid addition salt is a hemiεuccinate, hydrochloride, α-ketoglutarate, cx-glycerophosphate or glucose-1-phosphate, in particular the hydrochloride salt. Examples of quarternary ammonium salts include such compounds quarternised by compounds such as R. - E wherein q is C_._ 6 alkyl, phenyl-C_,_ 6 alkyl or C- _- cycloalkyl, and E is a radical corresponding to an .anion of an acid. Suitable examples of R g include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable E include halide such as chloride, bromide and iodide. ^ jll The coir.poundε of formula (I) may also form pharma¬ ceutically acceptable N-oxides. The compounds of the formula (I) and their pharmaceutically acceptable salts and N-oxides may also form solvent adduc ε. The pharmaceut cally acceptable εalts 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. It will of course be realised that the compounds of the formula (I) have chiral or prochiral centres and, when -G-C= is =K-C=, a non-symmetric centre, and thus are capable of existing in a number of εtereoiεomeric formε. The invention extends to each of theεe εtereoiεomeric formε, and to mixtureε thereof (including race ateε) . The differs.- ; εtereoisomeric forms may be εeparated one from the other by the uεual methodε, 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 O y fr^ WI *>. RN in particular of formula (V) : NH- A group of compounds within those of formula (I) , are those of formula (VI) : wherein: . is hydrogen, halogen or optionally substituted aminosulphonyl as defined in formula (I) , R, 1 is hydrogen, chloro or amino; and the remaining variables are as defined in formula (I) . R 4 is preferably hydrogen, chloro or amino¬ sulphonyl optionally substituted by one or two methyl groups. More suitably p is 0 or 1. Preferably q is 1, and the bicyclic side-chain is then attached at its 3-position (standard numbering) . - 11 - Suitab l e and preferred examples of R 5 in formu l a (V I ) i nc l u d e those l isted under formula (I ) for R 5 . Parti ¬ cu l ar l y preferred examples of R 5 include benzy l optiona ll y su b st i tute d in the p h eny l ring as defined under formu l a ( I ) ϋnsubstituted b enzy l , -meth l, 4-fluoro-and 4-ch l oro b enzy l are inc l uded in preferred R 5 . A sub-group of compounds within those of formu l a (V I ) are those of the formula (VIII ) : wherei (CH 2 ) u R lg as defined under formula ( I ) , and R are as defined in formula ( VI ) . Suitab l e examp l es of R5 are as so describe d under formu l a ( I ) for ( H 2 ) U R 16 . Suitable and preferre d ι and R 1*** _ are as so d -escri..bed. und_.er JfΓormu,lιa - . ( V.7TI1 ) . ^ 4 It is preferre d that the aminoσuinazoline moiety is in g-orientation to the nortropane ring, that is as follows: Another sub-group of compounds within those of formula (VI) are those of the formula (VIII) : wherein R 2 5 is a group -(CH-) t R-1- wherein t is 1 or 2 and R n is optionally substituted phenyl as defined in formula (I) ; or 2-thienylmeth l; and R 4 1 and R 3 1 axe as hereinbefore defined. Suitable and' preferred R 5 are as so described for the corresponding R- groups under formula (I) . Benzyl, 4-methylbenzyl, 4-chlorobenzyl and 4-fluorobenzyl are preferred values. Suitable and preferred R. and R. are as so described under formula (VT) . It is preferred that the aminoquinazolinemoiety is in the £5-orientation to the nortropane ring. OMPI Sty WO A third sub-group within formula (VIII) is of the formula (IX) : wherein the variables are as defined in formula (VIII) . Suitable and preferred variables are as described under formula (VII) . It is preferred that the aminoquinazolineis in the B-orientation to the granatane ring, the β-orientation being the same as in the nortropane hereinbefore depicted. A fourth sub-group of compoundε within thoεe of formula (VI) is of formula (X) : wherein the variables are as defined in formula (VIII) 2 1 1 Suitable and preferred examples of R 5 , 4 and R 3 are as described under formula (VIII). It is preferred that the aminoquinazoline moiety is in 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) : with a compound of formula (XII) : EQ-. and thereafter as necessary reducing the resulting compound and optionally converting a group R, or R. in the thus formed compound to another group R_ or R 4 respectively. wherein: Qy is a monovalent leaving group, dihalo, oxo or thiooxo, or, when one of X, Y and Z is -N= and the others are -CR_ j = or -N= as defined, hydrogen; and _ 2 is NH_ and E is A as defined; or Q- is a monovalent leaving group , o ' ε or thiooxo ; and E is of one of formulae (XIII) , (XIV) or (XV) : or wherein the variables are as defined in formulae (I) to (I When the leaving group Q, is a group that is readily displaceable by a nucleophile, examples of such groups are C, ^ alkoxy, C, . alkylthio, halogen such as chloro and brom and acyloxy such as C._. alkanoyloxy. When the leaving group Q is a -group that is readily displaceable by a nucleophile, examples of ευch groups are halogen such as chloro or bromo, and l__bile sυ! honyloxy such as raeεylate or tosylate. If a leaving group is C, . alkoxy, C- . alkylthio or acyloxy, then the reaction is preferably carried out in an inert non-hydroxyl c εolvent, 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. If a leaving group iε a halide, or labile εulphonyloxy, or Q., iε dihalo, 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 aε triethylamine, tri ethylamine, pyridine or picoline, which base can also function aε the solvent. Alternatives, the acid acceptor can be inorganic, such aε calcium carbonate, sodium carbonate or potaεεium carbonate. . Preferably Q- is halogen such as chloro and Q 2 is NH^. ■ Whe Q_. or Q_ is an oxo or thiooxo group the condensation of the compounds of the formulae (XI) and (XII) iε conveniently effected at non-extreme temperatureε at about ambient, in a dry inert solvent, such as benzene, tolueney^xylene or DMF. Since the condensation eliminates water it is preferable to carry out the reaction in the presence of a dehydrating agent, for example molecular sieves. " T _ OM The use of a non-aqueous acid catalyst can be advantageous, for example hydrogen chloride or p-toluencr-l- phoni'c acid. Alterna ively 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 iε conveniently effected in situ, i.-nd moεt conveniently εimultaneouεly with the condensation. The reduction of the product compound is conveniently simultaneously effected with a mild reducing agent, such aε a mild inorganic complex hydride, for example εodiu cyanoborohydride. If a mild inorganic complex hydride reductant iε used, the reaction is generally carried out in a dry, inert polar solvent, such as dry ethanol, maintained at neutral or. aci pH, for example pH 5-7, with for example hydrogen chloride when less than 7. Non-extreme temperatures at about ambient are generally suitable. Alternatively, the reduction may be effected sequentially, optionally with isolation of the condensation product compound by reduction with tin/hydrochloric acid .* • _. ._ non-extreme temperature. When Qy is hydrogen, reaction is carried out under Chichibabin conditions. 11 v.'i 11 be apparent -that compounds of the fo. jπnl (!) con. ii.ij.g an R.., R. or R r α_ oup which 5ε convert b e 1o 5 " another R , R. a.) R j . y_ oup are r.c-fυ novel i nt r r.„. -di a . <τ . 7. Jjumbcr of r-uch convey si onε is possible not only for .he _ * - t-τιd c-o;r,] ) θυiιns of fo Rila . 1) . ^-ut al._o for their intermed ates as foi O-.'S: (a) a hydrogen subst tuent iε convert ble to a nitio substituent by nitration; (b) a nitro substituent as convertible to an amino subεtituent by reduction; (c) a C_.__- carboxylic acylamino subεtituent is convertible to an amino substituent by deacy tjon; (d) an amino substituent is convertible to a carboxylic C j , acylamino substituent by acylation; with a carboxylic acid derivative; (e) a hydrogen substituent is convertible to a halogen substituent by halogenation; (f) a C_._g alkylthio or C. , al ylεulphinyl subεtituent is convertible to a C,l— _b- alky sulphinyl or a C n _ £ al ylsulphonyl substituent respective.y by oxidation; (g) an " amino, ami ocarbonyl, aminosulphonyl, aminosulphonylamino or N-(ami osulphonyl)- C, . • alkylamino substituent is convertible to a corresponding substituent substituted by one or • - two groups selected from C_, g alkyl , C,_g cycloalkyl, C,_g cycloalkyl, C.. . alkyl or phenyl C, , alkyl groups any of which phenyl groups may be substituted by one or more yroups selected from halogen, t rJf- -OiO-nethyl, C. g alkyl, C_._ g alkoxy and niti , or substituted by C. ,. polymethylene, by N- lkyh.tion J ~~ r ^ (h) an amino substituent is convertible to a C, g al ylsulphonylamino group or an aminosulphony-lamino group optionally N-substitut as defined by acylation with a C- , alkylsulpho acid or optionally N-substituted carbamic acid derivative; i) ' a C. . alkylamino substituent group is convertib to a N-(C, 6 alkylsulphonyl) C_,_ 4 alkylamino gro or an N-(amino sulphonyl)- C- , alkylamino group optionally N-substituted as defined by acylation with a C,_ g alkylsulphonic acid or optionally N-substituted carbamic acid derivative. SUBSTITUTE SHEET OMPI " Conversions (a) to (i) are only exemp ary and are not exhaustive of the poεεibil tieε. - - 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) , (h) and (i) the acylation is carried out with an acylating agent, such aε the corresponding acid or acid chloride. Formylation iε carried out with the free acid. In regard to (e) , halogenation is carried out with conventional halogenating agents. In regard to (f)., oxidation iε carried out at below ambient temperatures in a non-agueous εolvent, such as a chlorinated hydrocarbon, in the presence of an organic peracid, such as 3-chloroperbenzoic acid, or in water in he presence of a soluble strong inorganic oxidant, such as an alkali metal permanganate or in aqueous hydrogen peroxide. It will be realiεed that thiε proceεs may alεo N-oxidiεe the N-R 5 moiety and suitable precautions will routinely be taken by the skilled man. In regard to (g) , alkylation iε 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- . Such R- benzyl grou may for example be removed, when R 3 or R. is not halogen b conventional transition metal catalysed hydrogenolysis to give compounds of the formula (XVI) : wherein A. is of the formula (XVIII ) or and the variable groups are as defined in formula (I) . This invention also provides third process for the preparation of a compound of the formula (I) which compris the reaction of a corresponding compound of the formula (X as hereinbefore defined with a compound Q j -R, wherein R ς is as defined in formula (I) and Q ς 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 displac by nucleophiles such as Cl , Br, I, OSO-CH, or OSO-C-H.pCH_ Favoured values .for Q ς 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- in the compound of the formula ( before coupling with the compound of the formula (XII) is preferred. Such interconversions are effected convenien under the above conditions. It is desirable to protect amine function with a group readily removable by acidolys such as a C__- alkanoyl group, before R- interconversion. The substituents in the phenyl ring when R- is benzy in a compound of formula (I) , in particular the εubstitut C ] _ 4 alkyl substituents, are interconvertible. A number of such interconversions axe possible not only for the en compounds of formula (I) , but also for their intermediate as follows: Γ ] OM - WWIIPP (i) a carboxy C, . alkyl substituent iε convertible to an esterified carboxy C, . alkyl substituent by esterification: (ii) an esterified carboxy C.. , alkyl substituent is convertible to a carboxy C«_. alkyl substituent by deesterification; (iii) an C . alkoxy C- , alkyl εubεtituent or an in vivo hydrolyεable C 2 _ acyloxy C, , alkyl substituent is convertible to an hydroxy C. _ . alkyl substituent by deetherif cation; (iv) an optionally esterified carboxy or carboxy C. , alkyl substituent is convertible to an hydroxymethyl or hydroxy C 2 _. alkyl εubstituent by reduction; and (v) a hydroxy C_. , alkyl subεtituent is convertible to C_,_ 4 alkoxy C_.-_. alkyl by O-alkylation or to _in vivo hydrolyεable C, . acyloxy-C_,_. alkyl by O-acylation. Co verεionε (i) to (iv) are only exemplary and are not exhauεtive of the poεεibilitieε. In regard to (i) and (ii) , the eεterification and de-esterif cation reactions are carried out in conventional manner. In regard to (iii), a C, . alkoxy C«, . alkyl substituent iε convertible to an hydroxy C- , alkyl εubεtituent by conventional methodε, εuch as.warming with aqueous hydrobromic acid or by treatment with pyridine hydrochloride, boron tribromide, boron triodide or iodotri ethyls lane. An iii vivo hydrolyεable C_ , acyloxy C- . alkyl substituent iε convertible to an hydroxy C, . alkyl substituent by acid or base hydrolysiε. Jn regard to (iv) , the reduction iε carried out with a εelective metal complex hydride, for example lithium aluminium hydride, under conventional conditionε. In regard to (v) , O-alkylation iε carried out under conventional conditions in an .inert solvent at a non-extrc-.rie temperature such aε ambient temperature or slightly above or at reflux temperature. The C, . alkylating agent has a leaving group that iε readily displaceable by a nucleophile. Examples of leaving groups include halide, such as chloride, bromide or iodide, or labile acyloxy groups, εuch aε meεyl and toεyl. O-acylation is carried out under conventional conditions with an acylating agent which has an acyl group capable of forming an __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 iε generally carried out in the presence of a base. YThen hydroxy iε the leaving group, the reaction iε generally carried out in the presence of a dehydrating agent, εuch r dicyclohexylcarbodiimide, in an inert solvent at non-extii ...e temperature, εuch 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 aχ-e appropriate should be selected together with the adoption of εuch precautionary measures as are necessary. For example, O-alkylation and O-acylation may also produce N-alk lated and N-acylated products CΛI rcr-poctive y unless the nitronen a om(ε) n (arc) previou ly ] ) . ot c-ct f-d. This may be conven ently achieved by cα.ryi.iu out tJ-o alkyl at ion or acyla on .f c ion in a strong acid, r.nch c , tri fluoroacct ic acid, winc prot onator., and t)n_(by protects, 1 lie nit.c.gen atom(ε). ' Compounds of the formula (XXI1) are novel intermediates and thus form an aspect of the present invention. The compounds of formula (XVIII) are known or are preparable analogously to or routinely from known compounds. For example the compound, wherein 0 1 iε bromo can be prepared by reacting a compound of formula (XX) : wherein R^, R, , X, ' Y and Z are aε hereinbefore defined; with a brominating agent, εuch as PBr^. Compounds of formula (XI) are either known compounds or are preparable analogously to or routinely derivable from known compounds. For example, when X, Y and Z are each CR. , aε defined and Q is -NH_, the compound may be prepared by the reduction of the corresponding Q = -NO- or -NO compounds. When X, Y and Z are each CR- or N as defined and Q 1 is -NH-_, the compound may be prepared by the Hofmann degradation of the corresponding compound where Q 1 is -CONH_ or by the Schmidt reaction of the correεponding compound where Q_, iε -C0 2 H. When one of X, Y and Z iε -N= and the other two are each C 1 or N aε defined, and Q 1 is -NH 2 , the compound may be prepared by Chichibabin amination. It will be realised that in the compound of the fomu.la (1) the -G-C-lin age may have an α or 3 orient tion with r.'-,ρc-ct to the ' ring of the bicyclic moiety to which it iε attached. A tuie of α and ir.oπic. ε of the compound of the fo.mula (I) may be synthes zed non-εtei o_.ρecifi ally and jLhe desired isoiaer separated conventionally therefrom e.g. by chromatography; or alternatively the α and 3 iεomer may if desired by synthesised from the correεponding α or form of the compound of the formula (XII). Syntheεiε from the corresponding α or 3 isomer of the compound of the formula (XII) is in general preferred. It will be appreciated that in the compounds of the formulae (I) or (XI), epimer sation of the X-Y-Z ring linkage to the energetically more favourable orientation often takes place readily in the presence of acid or base. In εuch cases if the lesε favoured isomer iε deεired, it iε preferred to εtereoεpecifically εynthesise the iεomer of the compound of the formula (XI) and to convert it to the required compound of the formula (I) under εuch conditionε to avoid epimerεation._ . . The α or 3 form of the compound of the formula (XIX) may if desired be prepared by known εtereoεpecific processes. such as those leading to the α or 3 isomerε of the compound of the formula (XI) depicted in the Scheme and deεcribed in the Deεcriptioπs hereinafter. Compounds of the formula (XII) are known from or are preparable by'the methods disclosed in published European • Patent Applications and U.S Patents. Rest o system omitte for clar ty) equatorial rhαrmacci.tically acceptable i.alt.r-, and I.-co:inc.*. c•_ t lit- compounds of thir. invention may be formed convent ioiι.;l ly. The r-altε may be formed for example by reaction of the - ■ ... ■ •_. • compound of formula (1) with a pharmaceutically accep ble o. ganic or ino. ganic acid. j 1.-oxides of the nitrogen atom of the bicyclic ring system are produced by reaction of a compound of formula (1) with an organic peracid, εuch aε m-chloroperbenzoic acid in, for example, a chlorinated hydrocarbon εolvent 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 εolvent, εuch aε acetone, ethanol, 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 ernesis. Depending on their balance between peripheral and central action on the nervous syεtem, they may also be uεed in the treatment of disorders relating to impaired gastro-inteεtinal motility, εuch aε retarded gaεtric emptying dyspepsia, flatulence, oesophagal reflux and peptic ulcer and/or in the treatment of disorders of the central nervous syεtem, such as psychosis. The invention also provides a pharmaceutical compo¬ sition 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. - 3 D - Such compositions are prepared by admixture and are suitably adapted for oral or parental administration, and aε sυ(5h may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powderε, injectable and infuεable εolutionε or suspensions or suppositor eε. Orally adminiεterable 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 excipientε εuch aε binding agents, fillers, diluents, tabletting agents, lubricants, diεintegrants, colorants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art. Suitable fillers for use include cellulose, anitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium εterate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suεpenεionε, εolutionε, emulεionε, εyrupε, or elixirε, or may be preεented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suεpending agentε, for example εorbitol, εyrup, methyl celluloεe, gelatin, hydroxyethylcelluloεe, carboxymethyl celluloεe, aluminium * stea ' rate gel or hydrogenated edible fats, emulsifying agentε, for example lecithin, εorbitan monooleate, or -acaciaj non-aqueous vehicles (which may include edible, oils) , for example almond oil, fractionated, coconut oil, oily esters εuch aε eεters of glycerine, propylene glycol, or ethyl alcohol; preεervatives, for example methyl or propyl * . P £-hydroxybenzoate or εorbic acid, and if desired conventional flavouring or colouring agentε. Oral liquid preparations are usually in the form of aqueous or oily εuεpenεionε, εolutionε, emulεions, εyrupε, or elixirs or are presented as a dry product for reconεtitution with water or other εuitable vehicle before use. Such liquid preparations may contain conventional additives εuch as suspending agents, emulsifying agentε, non-aqueous vehicles (which may include edible oilε) , 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. 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 disεolving the compound in the vehicle and .filter εteriliεing before filling into a εuitable vial, or ampoule and εealing. Advantageously, adjuvants εuch aε a local- anaesthetic, 'preservativeε and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. * Parenteral εuεpenεionε are prepared in εubεtantially the same manner except that the compound is suspended in the vehicle inεtead of being diεsolved and εteriliεed by expoεure to ethylene oxide before suspending in the sterile vehicle. OMFI • _- - 32 - Advantageously, a surfactant or wetting agt-nt iε included in the composition to facilitate uniform distribution of the co.npo_.r-d of the invention. The invention further provides a method of t eatment of emesiε, disoj erε relating to impaired cast o- test nal motality and of diεorderε of the central nervous system in majunals, such aε humans, which compriεeε the administration of an effective amount of a compound of the present invention, or a _.harmaceut cally acceptable salt thereof, or K-oxide thereof, or a solvent adduct of any of the foregoing as hereinbefore defined,to the sufferer. An amount effective to treat the diεorders hereinbefore described depends On the relative efficacies of the compounds of the invention, the nature and severity of the disorderbeing treated and the weight of the mammal. However, a unit dose will normally contain 0-1 to- 20mσ 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 εuch . tbat the total daily doεe iε normally in the range 0.03 to lOmq/kg per ' day. The compounds of the present invention have the' ability .to potentiate the effect of conventional analgesics in migraine treatment when adminiεteredconcomitantly with the analgeεic. 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 w τ ay on a number of factors such as the nature and- severity of the. alady to be treated, the weight of. the sufferer, and the actual compound used. However, the compound of the present invention and the analgesic, εuch as aspirin or pa acetamol.,.,are present in unit doεeε of the. compoεition in amounts generally similar to their usual effective dose. • O 7 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. Most suitably 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 OMPI 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. However, in order to obtain consistency of administration it is preferred that 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. In addition such compositions may contain further active agents such as other anti-hypertensive agents, diuretics and β-blocking agents. The following Examples illustrate the preparation of compounds of the invention. O " Exajiipl e 3 .- (3 . -[ 8~-Benzyl-8 "" -azabicyc3o{ 3_, 2_, Jocty_lJ mi no )_ A solution of 3β-amino-8-benzyl-8-azabicyclo{3, 2,1 } octane (1.5g), .-chloroquinazoline (1.2g) a d triethyl- a ine (1ml) in dry DHF (lO lε) waε heated on a εteam bath for 2 hours. On pouring into ice/water, the precipitate waε collected and recryεtalliεed (ethanol/water) to afford the pure 4-.3 ~ ._-.8 -benzyl-8 -azabicyclo{3,2, 1 }octyl ]amino) quinazoline (1) (2.1g, 90%) m.p. 214-5 e . n. .r. (δ, CDC1 ) 8.64 (S, 1H, aryl 2H) 7.1-7.9 ( , 9H, aryl H) 5.3-5.6 (brd, 1H, NH) 4.4-5.0 (m, 1H, 3 α-H) 3.57 (s, 2H,- NCH 2 Ph) 3.1-3.4 (m, 2H, l' and 5'H) 1.4-2.4 (m, 8H, remaining protonε) - E Following the procedures outlined in Example 1 , the following compounds were prepared: Example 2 7-Nitro-4- (3~S- [ 8~-benzyl-8~-azabicyclo{ 3, 2 , 1 }octyl) amino) -quinazoline (2) (75%) m.p. 215-7° nmr (δ, CDC1. d 6 DMSO) 8.64 (s, IK, aryl 2H) 8.6-8.3 (m, 2H, aryl 8H and 5H) 8.15 (d,d, 1H, aryl 6H) 7.95-7.7 (brd, 1H, NH) 7.5-7.1 (m, 5H, aryl -H}. 5.0-4.5 (m, 1H, 3~α-H) 3.63 (ε, 2H, NCH 2 ) 3.5-3.1 (m, 2H, l " and 5 ~ H) 2.3-1.6 (m, 8H, remaining protons Example 3 7-Chloro-4- (3~. -[ 8~-benzyl-8~-azabicyclo{3 , 2 , 1 Joctyl] amino.)-quinazoline (3) (55%) m.p. 217-8° nmr (ό, CDC1,) δ.6l (s, 1H, aryl 2H) 7.79 (d, 1H, aryl 8H, J =1.9Kz) 65-7.15 (m, 7H, aryl H) 5.6-5.3 (brd, 1H, NH) 4.9-4.3 (m, 1H, 3~α-K) 3.57 (s, 2H, NCH Ph) 3.4-3.1 (m, 2H, 1~ and 5~ H) 2 . 4- 1 . 4 (m, 8H, remaining protons) Example 4 6-Chloro-4- ( 3~S- [ 8~ * -benzy l-8 " -azabicyclo{ 3 ,2,1 }octyl] amino) -quinazoline (4) (53%) m.p. 204-5° nmr (δ, CDC1-.) 8.62 (s, 1H, aryl 2H) 7.9-7.2 (m, 8H, aryl H) 5.6-5.3 (brd, 1H, K) 5.0-4.4 (m, 1H, 3~α-H) 3.58 (s, 2H, NCH 2 Ph) 3.4-3.1 (m, 2H, 1~ and 5~-H) 2.3-1.4 (m, 8H, remaining protons) O - 39 - Example 5 6-Dimethylsulpha_noyl-4- (3 β-[8 -benzyl-8 -azabicyclo (3,2,1 ) octyll -amino) quinazoline (5) (20%) m.p. 258-9 nmr (δ, CDC1 3 ) 8.70 (s, 1H, aryl 2H) 8.23 (brs, 1H, aryl H) 8.0-7.8 *(m, 2H, aryl H) 7.55-7.1 (m, 5H, aryl H) 6.1-5.8 (brd, 1H, NH) 5.0-4.4 (m, 1H, 3~α-Ji) 3.63 (s, 2H, NCH 2 Ph) i. 5-3.15 (m, 2H, 1 and 5 H) 2.75 (s, 6H, NCH 3 ) 3' 2.35-1.5 (m, 8H, remaining protons) OM Sty ip Example 6 7-Amino-.-(3 8- f 8 *~ -benzyl_-_8_ ___5_z_ab_i cyclop, 2,1 ) octy 1 ]_ -_π * i.no)-quinazoline (6) _■_ solution of 7-ni tro-4- (3 ~ B- [ 8 ~ -benzyl-8 azabicyclo {3,2, 1 }octyl]-amino)quinazoline (Example 2) (7.3g) in ethanol (200ml) was shaken with platinum oxide (0-4g) over hydrogen at atmospheri c presεure and ambient temperatures. The theoretical quantity of hydrogen was absorbed in 1. hours. The solution was filtered, concentrated in vacυo and recrystalliεed from ethyl acetate/petrol to afforded the 7-amino-4- (3 ~ B- [8 ~ -benzyl-8~-azabicyclo{3, 2,1 }octyl] amino) quinazoline (6) (6.6g, 98%) m.p. 223-6". nmr (d 6 DMSO) 8.7-8.5 (m, 1H, NH-CH ) . 8.32 (ε, 1H, aryl 2H) 8.01 (d, 1H, aryl 5H : J = δ.9Hz) 7.5-7.1 (m, 5H, aryl H) 7.06 (d, 1H, aryl 811, J = 2Kz) 6.91 (d,d, 1H, aryl 6H, J = 8.9, 2Kz) 5.0-4.3 (m, 1H, 3 ~ α-H) 4.3-3.0 (in, 2H, aryl NH ) • 3.61 (ε, 2H, NCH 2 > 3.35-3.1 ( , 2H, 1 ~ and 5 ~ j_) 2.3-1.5 {m, 8H, remaining protons) CM? .Pharmacolog cal Data Increase in intragastric pressure Intragaεtric pressure changes were recorded from previously starved conεciouε 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 presεure tranεducer and presεure changeε recorded on a hot wire pen recorder. In each animal a pre-doεe period of 40 minutes waε allowed to obtain a me.aεure of spontaneous activity. An index of activity waε obtained by measuring the average height of pressure waves during 10 minute periods. Values for 4 such periods were obtained during assessment of εpontaneous activity and for 40 minute period after administration of compound. Student's"t n teεt waε applied to the difference in average valueε obtained for εpontaneous and post compound activity. Compound 5 -significantly increased the index of activity post administration at a dose level of 0.2mg/kg ε.c . ' Anti-emetic activity in the dog Compounds were administered subcutaneouεly 30 minutes prior to administration of a standard dose of apomorphine HCl (0.1 mg/kg subcutaneouεly) and the vomiting reεponεe compared to that obtained when the εa e animalε were doεed with apomorphine HCl and vehicle-only. The ED n values for inhibition of the vomiting response determined for compound 1 was 1.0mg/kg. Dopamine Receptor Blocking Activity in the Central Nervous System Compounds were tested for inhibition of apomorphine induced climbing in the mouse. The test is based on that escribed by Protais, P., Constantin, J. and Schwartz _J]Cj (1976), Pεychopharmacology, ^0, 1.6. Apomorphine 1 mg/kg ε.c. induceε mice to climb the wall of a wire cage (inverted food hopper - 11 x 7.5 x 18 cm high). Kice' acclimatiεed in their home cageε in groups of 5 are placed -under the hoppers immediately after the injection of apomorphine 1mg/kg ε.c. At 10, 20 and 30 minuteε after injection climbing behaviour iε scored. The mice are observed for 30 seconds and scored according to the position they spend the majority of time in, score 0 - four paw τ s on floor of cage; score 1 - Xore 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. The resultε were as follows: Compound No. ED 50 mg/kg s.c. • 5 " 10 Dopamine Receptor Activity in vitro * Dopamine receptorε were labelled using methodε εi ilar to those previously reported [εee S. Lazareno and S.R. Nahorski, Communication presented to Brit. Pharm. Soc, Bradford, 74, (1981) , and P. Greengrasε and R. Bremner, Eύr. J. Pharmacol 55, 323 (1979)]. The compounds showed displacement of 3H-Spiperone, indicating interaction with dopamine receptors. The inhibition constants (Ki) for compound (4) are shown below. Compound Inhibition Constant Ki* (M) (4) ' 5 x 1θ "8 Anti-Inflammatory Activity Cotton Pellet test In a conventional cotton pellet induced granuloma test, the results were as follows: Compound Active Doεe (mg/kg) (1) . 20 (3) 19 Antihypertenslve activity _• 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, 5. European Journal of Pharmacology, 31_, 179 (1976). W+w BP recorder, model.8005, 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 restrainin cage. Each determination of blood presεure was the mean 0 of at least 6 readings. . Spontaneously hypertensive rats (ages 12-18 weeks) with systolic blood pressures > 170 xπmH were considered hypertensive. Compound (1) was active at lOO g/kg p.o. . - Compound (5) was active at 10 mg/kg p.o. - Toxicity 5 . No toxic effects were observed in the above tests.

Claims: CLAIMS : 1. A compound of formula (I), or a pharmaceutically acceptable salt, or N-oxide thereof, or a solvent adduct of any of the foregoing: wherein: G is -N= or -NR where R is hydrogen or C, . alkyl; X, Y and Z are each independently -CR,==, -N = or - R 2 where R. is hydrogen, C, . alkyl, or C, 4 alkylthio, and R_ is hydrogen or C, . alkyl, or one of X, Y and Z is C:B where B is 0 or S and the other two are each independently -CR,, -N= or - R 2 where R, and R 2 are as defined; A is a group: OM Sty WIP or wherein : p and q each independently are 0 to 2 ; Z 2 is 0 or S ; n is 0 or 1 ; and. one of R- and R- when n = 0 -is C, 4 alkoxy, C.. . alkoxycarbonyl, hydroxy or C._ 4 alkyl optionally substituted by hydroxy, C, . alkoxy or C, . acyloxy, and the other is hydrogen or C._ 4 alkyl or one of R g , R 7 and R g when n = 1 is C._. alkyl and the other two are the same or different and are hydrogen or C 1-4 alkyl ? R_ and R. together are C.__ alkylenedioxy, or are each independently selected from hydrogen, halogen, CF 3' C l-6 alk - /1 ' c i-6 al'κox - / - c ι_*- 2-lkylthio, C , _- acyl, C- ^ _ 7 carboxylic acylamino, C, 6 alkylsulphonylamino, N-( , g alkylsulphonyl) - ^ _ alkylamino, ( - 1 _g alkyl- sulphonyl, C 1,—D,alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)- C, 4 alkylamino optionally N-substituted by one or two groups selected from C, g alkyl, 3 _g cycloalkyl, _ g cycloalkyl C._ 4 alkyl, phenyl or phenyl C, 4 alkyl groups or optionally N-disubstituted by C . _- polymethylene; and R 5 is C χ _ 7 a l ky l , - (CΞ 2 ) S R 10' s bein ? ° to 2 and R 10 being C, „ cycloalkyl, -CH .R.., t being 1 or 2 and R... being thienyl or phenyl optionally substituted by one or two substituents selected from C, 4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy and C, 4 alkyl optionally substituted by hydroxy, c ι_. 4 a-lkoxy, carboxy, esterified carboxy or _in vivo hydrolysable acyloxy. /^TJRE OMPI 2. A compound according to claim 1 of formula (VI) wherein: R^ is hydrogen, halogen or optionally substituted aminosulphonyl as defined in claim 1, R^ is hydrogen, chloro or amino; and the remaining variables are as defined in claim 1. 3. A compound according to claim 2 of formula (VII): wherein the variables are as defined in claim 2, OMP A compound according to claim 2 of formula (VIII) : wherein R 2- is a group -- H , R,1, wherein t is 1 or 2 and R__- is optionally substituted phenyl as defined in claim 1; or 2-thienylmethyl; and R 4 - and R. are as defined in claim 2. 5. A compound according to any one of claims 2, 3 or 4, wherein R 4 is hydrogen, chloro or aminosulphonyl optionally substituted by one or two methyl groups. 6. A compound according to any one of claims 2, 4 or 5, wherein R 5 or R 5 is benzyl optionally substituted in the phenyl ring as defined in claim 1. 7_ 4-(3~6-[8 ~~ -Benzyl-8 ~ ~-azabicyclo{3,2,l}octyl] amino) quinazoline (1), 7-nitro-4-(3~£-t 8 -azabicyclo (3,2,l}octyl3 amino)-quinazoline (2), 7-chloro-4- (3 ~ s-[8 " ~-benzyl-8~~-azabicyclo{3,2,1}octyl] amino) - quinazoline (3), 6-chloro-4-(3~[3-[8 -benzyl-8 — - azabicyclo{3,2,l}octyl] amino) -quinazoline (4) , OMP Sty , WIP 6-dimethylsulphamoyl-4-(3 _ β-[8~-benzyl-8 -azabicyclo {3, 2,l}octyl]-amino) quinazoline (5) ,or 7-amino-4- (3~β-[8~-benzyl-8~ * -azabicyclo{3 ,2, l>octyl] amino) -quinazoline (6) . 8. A process for the preparation of a compound according to any one of claims 1 to 7 which process comprises reacting a compound of formula (XI) : with a compound of formula (XII) : ΞQ-; and thereafter as necessary reducing the resulting compound and optionally converting a group R, or R 4 in the thus formed compound t another group R, or R 4 respectively, wherein• ' Qy is a monovalent leaving group, dihalo, oxo or thiooxo, or, when one of X, Y and Z is -N= and the others are -CR_.= or -N= as defined, hydrogen; and Q_ is NH 2 and E is A as defined; or Q. is ~NH_; and Q 2 is a monovalent leaving group, c o or thiooxo; and E is of one of formulae (XIII) , (XIV) or (XV) : - _ u - or wherein the variables are as defined in claim 1. . A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, or a solvent adduct of any of the foregoing and a pharmaceutically acceptable carrier. O 10. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, or a solvent adduct of any of the foregoing for 'use in treatment of emesis, disox-ders relating to impaired gastro-intestinal motility and/or disorders of the central nervous system.

Inventors: KING FRANCIS DAVID, KING, FRANCIS, DAVID
Applicants: BEECHAM GROUP PLC, BEECHAM GROUP P.L.C.
Application year: 1983
Main classification: C07D451
IPC codes: C07D451, C07D498, C07D513