EP0126087A1 - Amino-azabicycloalkyl derivatives as dopamine antagonists - Google Patents

Abstract

Compounds of formula (I) and N-oxides, addition solvents and pharmaceutically acceptable salts of any of these compounds, where G represents -N = or -NR; X, Y and Z each independently represent -CR1 ==, -N == or -NR2, or one of X, Y and Z is equal to C: B, where B represents O or S and the other two each represent independently -CR1, -N = or -NR2; A is a group represented by the formulas (II), (III) or (IV), where p and q are independently of one another from 0 to 2; Z2 represents O or S; n is 0 or 1. These compounds exhibit dopamine antagonist activity. Their preparation process and their use as pharmaceuticals are also described.

Description

Amino-azabicycloalkyl derivatives as dopamine antagonists.

This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.

EP.13 138 and EP.41 817 disclose benzamides having a bicyclic side chain and possessing dopamine antagonist activity.

A novel class of heteroarylamines and heteroaryl- eneimines 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_1-4 alkyl; X, Y and Z are each independently -CR₁=, -N= or -NR₂ where R₁ is hydrogen, C_1-4 alkyl, or C_1-4 alkylthio, and R₂ is hydrogen or C_1-4 alkyl, 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 wiiere R₁ and R₂ are as defined; A is a group :

or

wherein : p and q each independently are 0 to 2 ;

Z² is O or S ; n is 0 or 1 ; and one of R₆ and R₁ when n = 0 is C_1-4 alkoxy, C_1-4 alkoxycarbonyl, hydroxy or C_1-4 alkyl optionally substituted by hydroxy, C_1-4 alkoxy or C_1-4 acyloxy, and the other is hydrogen or C_1-4 alkyl or one of R₆ , R₇ and R₈ when n = 1 is C_1-4 alkyl and the other two are the same or different and are hydrogen or C_1-4 alkyl; R₃ and R₄ together are C_1-2 alkylenedioxy, or are each independently selected from hydrogen, halogen, CF₃, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylthio, C_1-7 acyl, C_1-7 carboxylic acylamino, C_1-6alkylsulphonylamino,

N-(C_1-6 alkylsulphonyl)C_1-4 alkylamino, C_1-6 alkyl sulphonyl, C_1-6alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl) - C_1-4 alkylamino optionally N-substituted by one or two groups selected from C_1-6 alkyl, C_3-8 cycloalkyl, C_3-8 cycloalkyl C_1-4 alkyl, phenyl or phenyl C_1-4 alkyl groups or optionally N-disubstituted by C_4-5 polymethylene; and

R₅ is C_1-7 alkyl, - (CH₂)_sR₁₀, s being 0 to 2 and R₁₀ being C_3-8 cycloalkyl, -CH₂)_tR₁₁, t being 1 or 2 and R₁₁ being thienyl or phenyl optionally substituted by one or two substituents selected from C_1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy and C_1-4 alkyl optionally substituted by hydroxy, C_1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy.

A group of compounds within formula (I) is those wherein X, Y and Z are each independently -CR₁= or -N= as defined or Y is C:B where B is 0 or S and X and Z are each independently -CR₁, -N= or -NR₂.

Suitable examples of R₃ and R₄ include hydrogen, chloro, bromo, CF₃ , formyl, acetyl, propionyl, n- and iso-butyryl; formylamino, acetylamino, propionylamino, n- and iso-butyrylamino; methylsulphonylamino, ethylsulphonylamino, n- and iso-propylsulphonylamino, methyl, ethyl and n- and iso-propylsulphone, -sulphinyl or -thia; nitro ; methoxy, ethoxy and n- and iso-propoxy; hydroxy; amino, aminocarbonyl aminosulphonyl and aminosulphonamido and amino, aminocarbonyl, aminosulphonyl and aminosulphonamido substituted by one or two methyl, ethyl, n- or iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, or benzyl groups.

When R₃ and R₅ taken together are methylenedioxy or ethylenedioxy, they are most suitably ethylenedioxy.

R₃ and R₄ are generally independent groups.

Particularly suitable R₃ and R₄ 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 R₃ is in the 4-position as numbered in formula (I) . For the same reason, it is generally preferred that R₄ is in the 5-position.

Particularly preferred R₃ groups include 4-amino and

4-carboxylic acylamino as defined. Most preferably R₃ is 4-amino. Particularly, preferred R₄ groups include 5-halo, such 5-chloro.

In other useful compounds R₃ is hydrogen, or 4-halo (eg chloro) , or -amino ; and R₄ is 5-C_1-6 alkyl S (O) _n (such as 5-methylsulphonyl , -sulphinyl or -thio) or 5-optionally substituted aminosulphonyl. Often the group G and the heterobicycle nitrogen atom are separated by 2 or 3 carbon atoms, preferably 3.

The C-G. moiety is preferably in an equatorial orientation to the heterobicycle ring.

A preferred value of A is of formula (II).

When A is a group of formula (II) as defined, p is suitably 0 or 1 , preferably 1 , and q 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 R₆ and R₇ when n = 0 and each of R₆ , R₇ and R₈ when n = 1 are in the exo-position.

Preferred examples for one of R₆ and R₇ when n = 0 are methoxy, ethoxy, n-propoxy, methyl, ethyl, n-propyl, methoxycarbonyl and ethoxycarbony1, hydroxy, hydroxymethyl or hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, acetylmethyl and acetylethyl. The most preferred is methyl.

Preferred examples for one of R₆ , R₇ and R₈ when n = 1 are methyl, ethyl and n-propyl.

Preferred examples for the other of R₆ and R₇ when n = 0. and for the other two of R₆ , R₇ and R₈ when n = 1 , are hydrogen, methyl, ethyl and n- and iso-propyl.

Examples of R₅ C_1-4 alkyl include methyl, ethyl and n-and isopropyl. Within C_1-7 alkyl, C_4-7 alkyl are of interest, especially those of the form (CH₂)_uR₁₆ wherein u is 1 or 2 and R₁₆ is a secondary or tertiary C_3-6 alkyl group or a C_3-8 cycloalkyl group. Suitable examples of R₅ include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, tert--butylmethyl, iso-propylmethyl, iso-propylethyl and tert-butylethyl.

Favourably, R₅ is cyclopropylmethyl, cyclohexylmethyl, iso-propylπ.ethyl, tert-butylmethyl or iso-propylethyl, preferably tert-butyImethyl.

Preferred examples of R₅ , when -(CH₂)_tR₁₁, are thosewherein t is 1. R₁₁ may be 2- or 3-thaenyl or preferably is phenyl optionally substituted by one of C_1-4 alkoxy, trifluoromethyl, halogen, carboxy, esterified carboxy or C_1-4 alkyl optionally substituted by hydroxy, C_1-4 alkoxy, carboxy, esterified carboxy and in vivo hydrolysable acyloxy.

When phenyl is substituted by optionally substituted C_1-4 alkyl, examples of C_1-4 alkyl include methyl, ethyl, n- and iso-propyl, and n-, iso-, sec- and tert- butyl; methyl however is preferred. Examples of substituents of such alkyl groups include hydroxy, methoxy, ethoxy, n- and iso- propoxy, carboxy, esterified carboxy, and in vivo hydrolysable acyloxy. The substitution preferably occurs on a terminal carbon atom of the alkyl group.

Examples of esterified carboxy groups include C₁_₄ alkoxycarbonyl, such as methoxy-, ethoxy-, n- and iso- propoxy-carbonyl, phenoxycarbonyl or benzyloxycarbonyl, either being optionally substituted in the phenyl ring by one or two sυbstituents selected from C_1-4 alkyl, C_1-4 alkoxy, trifluoromethyl, halogen or nitro. Examples of in vivo hydrolysable acyloxy groups inclnde C_1-6 alkanoyloxy, for example aceioxy, propionoxy, n- and iss-butyroxy, and 2,3 dimethylpropanyloxy, benzyl oxy or benzcnesulphonyloxy either being optionally substituted in the phenyl ring by one or two substitυents selected from C_1-4 alkyl, C_1-4 alkoxy, trifluoromethyl, halogen or nitro, or other sulphonyloxy groups, for example C_1-6 alkanesulphonyloxy group, such as methanesulphonyloxy.

The most preferred examples of R₅, when -(CH₂)_tR₁₁, are those wherein t is 1 and R₁₁ is unsubstituted phenyl or monosubstituted phenyl in particular mono-p-substitutedphenyl Examples of preferred p-substituents include methyl, trifluoromethyl, fluoro, chloro and bromo, especially fluoro. Unsubstituted benzyl, p-fluorobenzyl , p-chlorobenzyl and p-methylbenzyl are especially preferred examples of R₅.

The pharmaceutically acceptable salts of the compound of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric phosphoric, sulphuric and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto gluraric, α-glycerophosphoric, and glucose-1-phosphoric; and quarternary ammonium salts. Preferably the acid addition salt is a hemisuccinate, hydrochloride, α-ketoglutarate, α-glycerophosphate or glucose-1-phosphate, in particular the hydrochloride salt.

Examples of quarternary ammonium salts include such compounds quarternised by compounds such as R₉ - E wherein R₉ is C_1-6 alkyl, phenyl-C_1-6 alkyl or C_5-7 cycloalkyl, and E is a radical corresponding to an anion of an acid. Suitable examples of R₉ include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable E include halide such as chloride, bromide and iodide. The compounds of formula (I) may also form pharmaceutically acceptable N-oxides.

The compounds of the formula (I) and their pharmaceutically acceptable salts and N-oxides may also form solvent adducts.

The pharmaceutically acceptable salts of the compounds of the formula as hereinafter defined consist mainly of acid addition salts with conventional acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.

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 stereoisomeric forms. The invention extends to each of these stereoisomeric forms, and to mixtures thereof (including racemates). The differsnt stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. From the aforesaid it will be seen that suitably the moiety of formula may be of formulae :

in particular of formula (V) :

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), is hydrogen, chloro or amino; and the remaining variables are as defined in formula (I). is preferably hydrogen, chloro or aminosulphonyl 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). Suitable and preferred examples of R₅ in formula (VI) include those listed under formula (I) for R₅. Particularly preferred examples of R₅ include benzyl optionally substituted in the phenyl ring as defined under formula (I) ϋnsubstituted benzyl, 4-methyl, 4-fluoro-and 4-chlorobenzyl are included in preferred R₅.

A sub-group of compounds within those of formula (VI) are those of the formula (VIII):

wherein is (CH₂)_uR₁₆ as defined under formula (I) , and are as defined in formula (VI) .

Suitable examples of are as so described under formula (I) for (CH₂)_UR₁₆. Suitable and preferred are as so described under formula (VI).

It is preferred that the aminoquinazoline moiety is in β-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 is a group -(CH₂) wherein t is 1 or 2 and is optionally substituted phenyl as defined in formula (I); or 2-thienylmethyl; and and axe as hereinbefore defined.

Suitable and preferred are as so described for the corresponding R₅ groups under formula (I).

Benzyl, 4-methylbenzyl, 4-chlorobenzyl and 4-fluorobenzyl are preferred values.

Suitable and preferred and are as so described under formula (VI).

It is preferred that the aminoquinazoline moiety is in the β-orientation to the nortropane ring.

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 compounds within those of formula (VI) is of formula (X):

wherein the variables are as defined in formula (VIII)

Suitable and preferred examples of and are as described under formula (VIII). It is preferred that the aminoquinazoline moiety isin the B-orientation to the granatane ring.

The present invention also provides a process for the preparation of a compound of formula (I), which process comprises reacting a compound of formula (XI):

with a compound of formula (XII): EQ₂; and thereafter as necessary reducing the resulting compound and optionally converting a group R₃ or R₄ in the thus formed compound to another group R₃ or R₄ respectively.

wherein :

Q₁ is a monovalent leaving group, dihalo, oxo or thiooxo, or, when one of X, Y and Z is -N= and the others are

-CR₁= or -N= as defined, hydrogen; and

Q₂ is NH₂ and E is A as defined; or

Q₁ is -NH₂; and

Q₂ is a monovalent leaving group , o xo or thiooxo ; and E is of one of formulae (XIII) , (XIV) or (XV) :

or

wherein the variables are as defined in formulae (I) to (IV)

When the leaving group Q₁ is a group that is readily displaceable by a nucleophile, examples of such groups are C_1-4 alkoxy, C_1-4 alkylthio, halogen such as chloro and bromo and acyloxy such as C_1-4 alkanoyloxy. When the leaving group Q ₂ is a group that is readily displaceable by a nucleophile, examples of sυch groups are halogen such as chloro or bromo, and labile sυlphonyloxy such as raesylate or tosylate.

If a leaving group is C_1-4 alkoxy, C_1-4 alkylthio or acyloxy, then the reaction is preferably carried out in an inert non-hydroxylic solvent, such as benzene, toluene or diethyl ether. The reaction may be carried out at a non-extreme temperature such as -10 to 100°C, for example 0 to 80°C.

If a leaving group is a halide, or labile sulphonyloxy, or Q₁ is 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 as triethylamine, trimethylamine, pyridine or picoline, which base can also function as the solvent. Alternatives, the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate.

Preferably Q₁ is halogen such as chloro and Q₂ is NH₂.

When Q₁ or Q₂ is an oxo or thiooxo group the condensation of the compounds of the formulae (XI) and (XII) is conveniently effected at non-extreme temperatures 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. The use of a non-aqueous acid catalyst can be advantageous, for example hydrogen chloride or p-toluencsol- phonic acid. Alternatively an acid addition salt of the compound of formula (XI) or (XII) may be used.

The product compound must be reduced to give a compound of formula (I). This is conveniently effected in situ, and most conveniently simultaneously with the condensation.

The reduction of the product compound is conveniently simultaneously effected with a mild reducing agent, such as a mild inorganic complex hydride, for example sodium cyanoborohydride.

If a mild inorganic complex hydride reductant is used, the reaction is generally carried out in a dry, inert polar solvent, such as dry ethanol, maintained at neutral or acid pH, for example pH 5-7, with for example hydrogen chloride when less than 7.

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 at a non-extreme temperature.

When Q₁ is hydrogen, reaction is carried out under Chichibabin conditions. i t will be apparent that compounds of the fo mula (1) containing an R₃, R₄ or R₅ group which is convertible to anot her R ₃ , R₄ and R₅ g roup are u sef υl novel i nt ermediates .A number of such conver s i ons i s poss i bl e not on l y for theend compounds of formula (1), but also for their intermediates as follows:

(a) a hydrogen substituent iε convertible to a nitio substituent by nitration;

(b) a nitro substituent as convertible to an amino substituent by reduction;

(c) a C_1-7 carboxylic acylamino substituent is convertible to an amino substituent by deacylation;

(d) an amino substituent is convertible to a carboxylic C_1-4 acylamino substituent by acylation; with a carboxylic acid derivative;

(e) a hydrogen substituent is convertibl e to a halogen substituent by halogenation;

(f) a C_1-6 alkylthio or C_1-6 alkylsulphinyl substituent is convertible to a C_1-6 alkyl sulphinyl or a C_1-6 alkylsulphonyl substituent respectively by oxidation;

(g) an amino, aminocarbonyl, aminosulphonyl, aminosulphonyl amino or N-(aminosulphonyl)- C_1-4 alkylamino substituent is convertible to a corresponding substituent substituted by one or two groups selected from C_1-6 alkyl, C_3-8cycloalkyl, C_3-8 cycloalkyl, C_1-4 alkyl or phenyl C_1-6 alkyl groups any of which phenyl groups may be substituted by one or more groups selected from halogen, trifluoromethyl, C_1-6 alkyl, C_1-6 alkoxy and nitio, or substituted by C_4-5 polymet hylene, by N-alkylation (h) an amino substituent is convertible to a C_1-6 alkylsulphonylamino group or an aminosulphonylamino group optionally N-substituted as defined by acylation with a C_1-4 alkylsulphonic acid or optionally N-substituted carbamic acid derivative;

(i) a C_1-4 alkylamino substituent group is convertible to a N-(C_1-6 alkylsulphonyl) C_1-4 alkylamino group or an N-(amino sulphonyl)- C_1-4 alkylamino group optionally N-substituted as defined by acylation with a C_1-6 alkylsulphonic acid or optionally N-substituted carbamic acid derivative.

Conversions (a) to (i) are only exemplary and are not exhaustive of the possibili ties.

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 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-agueous solvent, such as a chlorinated hydrocarbon, in the presence of an organic peracid, such as 3-chloroperbenzoic acid, or in water in the presence of a soluble strong inorganic oxidant, such as an alkali metal permanganate or in aqueous hydrogen peroxide. It will be realised that this process may also N-oxidise the N-R₅ moiety and suitable precautions will routinely be taken by the skilled man.

In regard to (g), alkylation is carried out with a corresponding alkylating agent such as the chloride or bromide under conventional conditions. R₅ optionally substituted benzyl as hereinbefore defined may be replaced by other R₅. Such R₅ benzyl groups may for example be removed, when R₃ or R₄ is not halogen by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (XVI) :

wherein A₁ is of the formula :

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 comprises the reaction of a corresponding compound of the formula (XVI) as hereinbefore defined with a compound Q₅R₅ wherein R₅ is as defined in formula (I) and Q₅ 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 Q₅ include groups readily displaced by nucleophiles such as Cl , Br, I, OSO₂CH₃ or OSO₂C₆H₄pCH₃.

Favoured values for Q₅ 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 R₅ in the compound of the formula (XI) before coupling with the compound of the formula (XII) is preferred. Such interconversions are effected conveniently under the above conditions. It is desirable to protect any amine function with a group readily removable by acidolysis, such as a C_2-7 alkanoyl group, before R₅ interconversion.

The substituents in the phenyl ring when R₅ is benzyl in a compound of formula (I), in particular the substituted C_1-4 alkyl substituents, are interconvertible. A number of such interconversions axe possible not only for the end compounds of formula (I), but also for their intermediates as follows: (i) a carboxy C_1-4 alkyl substituent is convertible to an esterified carboxy C_1-4 alkyl substituent by esterification:

(ii) an esterified carboxy C_1-4 alkyl substituent is convertible to a carboxy C_1-4 alkyl substituent by deesterification;

(iii) an C_1-4 alkoxy C_1-4 alkyl substituent or an in vivo hydrolysable C_2-4 acyloxy C_1-4 alkyl substituent is convertible to an hydroxy C_1-4 alkyl substituent by deetherification;

(iv) an optionally esterified carboxy or carboxy C_1-3 alkyl substituent is convertible to an hydroxymethyl or hydroxy C_2-4 alkyl substituent by reduction; and

(v) a hydroxy C_1-4 alkyl substituent is convertible to C_1-4 alkoxy C_1-4 alkyl by O-alkylation or to in vivo hydrolysable C_1-4 acyloxy C_1-4 alkyl by O-acylation.

Coηversions (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 C_1-4 alkoxy C_1-4 alkyl substituent is convertible to an hydroxy C_1-4 alkyl substituent by conventional methods, such as. warming with aqueous hydrobromic acid or by treatment with pyridine hydrochloride, boron tribromide, boron triodide or iodotrimethylsilane. An in vivo hydrolysable C_2-4 acyloxy C_1-4 alkyl substituent is convertible to an hydroxy C_1-4 alkyl substituent by acid or base hydrolysis.

Jn regard to (iv), the reduction is carried out with a selective metal complex hydride, for example lithium aluminium hydride, under conventional conditions.

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 C_1-4 alkylating agent has a leaving group that is readily displaceable by a nucleophile. Examples of leaving groups include halide, such as chloride, bromide or iodide, or labile acyloxy groups, such as mesyl and tosyl.

O-acylation is carried out under conventional conditions with an acylating agent which has an acyl group capable of forming an in vivo hydrolysable acyloxy group and a leaving group, such as halide,. for example chloride and bromide, and hydrogen. 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 a s dicyclohexylcarbodiimide, 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 rescpect i vely unless the nitronen atom(s) in (arc) previously protected. This may be conveniently achieved by carrying out the alkylation or acylation reaction in a strong acid, such as trifluoroacetic acid, which protonates, and thereby protects, the nitrogen atom(s).

Compounds of the formula (XXII) 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 Q₁ is bromo can be prepared by reacting a compound of formula (XX) :

wherein R₃, R₄ , X, Y and Z are as hereinbefore defined; with a brominating agent, such as PBr₅.

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 CR₁ , as defined and Q₁ is -NH₂, the compound may be prepared by the reduction of the corresponding Q = -NO₂ or -NO compounds.

When X, Y and Z are each CR₁ or N as defined and Q₁ is -NH₂, the compound may be prepared by the Hofmann degradation of the corresponding compound where Q₁ is -CONH₂ or by the Schmidt reaction of the corresponding compound where Q₁ is -CO₂H.

When one of X, Y and Z is -N= and the other two are each CR₁ or N as defined, and Q₁ is -NH₂, the compound may be prepared by Chichibabin amination. It will be realised that in the compound of the fomula (1) the -G-C-linkage may have an α or β orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixtuie of α and β isomers of the compound of the formula (I) may be synthesized non-steieospeci f i c a l l y and the desired isoiaer separated conventionally therefrom e.g. by chromatography; or alternatively the α and β isomer may if desired by synthesised from the corresponding α or β form of the compound of the formula (XII).

Synthesis from the corresponding α or β 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), epimeri 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 such cases if the less favoured isomer is desired, it is preferred to stereospecifically synthesise the isomer of the compound of the formula (XI) and to convert it to the required compound of the formula (I) under such conditions to avoid epimersation.

The α or β form of the compound of the formula (XIX) may if desired be prepared by known stereospecific processes. such as those leading to the α or β isomers of the compound of the formula (XI) depicted in the Scheme and described in the Descriptions 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. pharmaceutically acceptable salts, and N-oxides of the compounds of this invention may be formed conventionally. The salts may be formed for example by reaction of the 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, 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 system, they may also be used in the treatment of disorders relating to impaired gastro-intestinal motility, such as retarded gastric emptying dyspepsia, flatulence, oesophagal reflux and peptic ulcer and/or in the treatment of disorders of the central nervous system, such as psychosis.

The invention also provides a pharmaceutical composition comprising a compound of formula (I) , or a pharmaceutically acceptable salt thereof, or N-oxide thereof, or a solvent adduct of any of the foregoing and a pharmaceutically acceptable carrier. Such compositions are prepared by admixture and are suitably adapted for oral or parental administration, and as sυch may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administerable compositions are preferred, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.

Suitable fillers for use include cellulose, manitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium sterate.

Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.

The oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.

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 sterilising 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 vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. 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 emesis, disojders relating to impaired castro-intestinal motality and of disorders of the central nervous system in majunals, such as humans, which comprises the administration of an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or N-oxide thereof, or a solvent adduct of any of the foregoing as hereinbefore defined, to the sufferer.

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 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 such that the total daily dose is normally in the range 0.03 to 10mq/kg per day.

The compounds of the present invention have the ability to potentiate the effect of conventional analgesics in migraine treatment when administeredconcomitantly with the analgesic. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the present invention and an analgesic. The effective amount of each component of the composition will depend in the usual way on a number of factors such as the nature and severity of the malady to be treated, the weight of the sufferer, and the actual compound used. However, the compound of the present invention and the analgesic, such as aspirin or paracetamol, are present in unit doses of the composition in amounts generally similar to their usual effective dose. The composition can be a combination product, for example a tablet or capsule containing both a compound of the invention and an analgesic for oral administration, or a twin pack comprising the two active ingredients made up for separate administration.

The invention accordingly provides a method of treatment of migraine comprising the administration of an effective amount of a compound of the invention and an analgesic.

The invention also provides a compound of formula (I), for use in the treatment of emesis, disorders relating to impaired gastro-intestinal motility and/or of disorders of the central nervous system.

This present invention also provides a method of treating inflammatory conditions in mammals which comprises administering per day from 50 to 4000 mg of a compound of formula (VI) or a pharmaceutically acceptable salt thereof and more usually from 100 to 3000 mg for example from 200 to 1500 of a compound of formula (VI).

Mammals which may be thus treated include humans and domestic animals such as dogs, cats or horses.

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 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.

Example 1

4-(3-β-18--Benzyl-8--azabicyclo{3,2, 1 }octyl]amino) qυi nazoline(1)

A solution of 3β-amino-8-benzyl-8-azabicyclo{3,2,1} octane (1.5g), 4-chloroquinazoline (1.2g) and triethylamine (1ml) in dry DHF (10mls) was heated on a steam bath for 2 hours. On pouring into ice/water, the precipitate was collected and recrystallised (ethanol/water) to afford the pure 4-[3-β-[8--benzyl-8--azabicyclo{3,2,1}octyl]amino) quinazoline (1) (2.1g, 90%) m.p. 214-5º. n.m.r. (δ, CDCl₃) 8.64 (S, 1H, aryl 2H)

7.1-7.9 (m, 9H, aryl H)

5.3-5.6 (brd, 1H, NH)

4.4-5.0 (m, 1H, 3^'α-H) 3.57 (s, 2H, NCH₂Ph)

3.1-3.4 (m, 2H, 1' and 5'H)

1.4-2.4 (m, 8H, remaining protons)

Following the procedures outlined in Example 1, the following compounds were prepared:

Example 2

7-Nitro-4-(3-β-[8--benzyl-8--azabicyclo{3,2,1}octyl] amino)-quinazoline (2) (75%) m.p. 215-7°

nmr (δ, CDCl₃ + d ^εDMSO) 8.64 (s, 1H, 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 (s, 2H, NCH₂)

3.5-3.1 (m, 2H, l- and 5-H)

2.3-1.6 (m, 8H, remaining protons)

Example 3

7-Chloro-4-(3-β-[8--benzyl-8--azabicyclo{3,2,1}octyl] amino)-quinazoline (3) (55%) m.p. 217-8°

nmr (ό, CDCl₃) 8.61 (s, 1H, aryl 2H)

7.79 (d, 1H, aryl 8H, J =1.9Hz)

65-7.15 (m, 7H, aryl H)

5.6-5.3 (brd, 1H, NH)

4.9-4.3 (m, 1H, 3-α-H)

3.57 (s, 2H, NCH₂Ph)

3.4-3.1 (m, 2H, 1- and 5- H)

2 . 4- 1 . 4 (m, 8H, remaining protons)

Example 4

6-Chloro-4-(3-β-[8--benzyl-8--azabicyclo{3,2,1}octyl] amino)-quinazoline (4) (53%) m.p. 204-5°

nmr (δ, CDCl₃) 8.62 (s, 1H, aryl 2H)

7.9-7.2 (m, 8H, aryl H)

5.6-5.3 (brd, 1H, NH)

5.0-4.4 (m, 1H, 3-α-H)

3.58 (s, 2H, NCH₂Ph)

3.4-3.1 (m, 2H, 1- and 5--H)

2.3-1.4 (m, 8H, remaining protons)

Example 5

6-Dimethylsulpha_noyl-4-(3-β-[8--benzyl-8--azabicyclo {3,2,1}octyl]-amino)quinazoline (5) (20%) m.p. 258-9º

nmr (δ, CDCl₃) 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-H)

3.63 (s, 2H, NCH₂Ph) i.45-3.15 (m, 2H, 1- and 5- H)

2.75 (s, 6H, NCH₃)

2.35-1.5 (m, 8H, remaining protons)

Example 6

7-Amino-4-(3-β-[8--benzyl-8--azabicyclo(3,2,1)octyl]_amino)-quinazoline (6)

solution of 7-nitro-4-(3-β-[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 atmospheric pressure and ambient temperatures. The theoretical quantity of hydrogen was absorbed in 1½ hours. The solution was filtered, concentrated in vacυo and recrystallised from ethyl acetate/petrol to afforded the 7-amino-4-(3-β-[8--benzyl-8--azabicyclo(3,2,1)octyl] amino)quinazoline (6) (6.6g, 98%) m.p. 223-6º. nmr (d⁶ DMSO) 8.7-8.5 (m, 1H, NH-CH )

8.32 (s, 1H, aryl 2H) 8.01 (d, 1H, aryl 5H : J = 8.9Hz) 7.5-7.1 (m, 5H, aryl H)

7.06 (d, 1H, aryl 8H, J = 2Hz) 6.91 (d,d, 1H, aryl 6H, J = 8.9, 2Kz) 5.0-4.3 (m, 1H, 3-α-H) 4.3-3.0 (m, 2H, aryl NH₂) 3.61 (s, 2H, NCH₂) 3.35-3.1 (m, 2H, 1- and 5-H) 2.3-1.5 (m, 8H, remaining protons) 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"t" test was applied to the difference in average values obtained for spontaneous and post compound activity.

Compound 5 significantly increased the index of activity post administration at a dose level of 0.2mg/kg s.c.

Anti-emetic activity in the dog

Compounds were administered subcutaneously 30 minutes prior to administration of a standard dose of apomorphine HCl (0.1 mg/kg subcutaneously) and the vomiting response compared to that obtained when the same animals were dosed with apomorphine HCl and vehicle only. The ED₅₀ 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 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 1mg/kg s.c. At 10, 20 and 30 minutes after injection climbing behaviour is scored. The mice are observed for 30 seconds and scored according to the position they spend the majority of time in, score 0 - four paws on floor of cage; score 1 - fore paws only on walls; score 2 - all paws on wall of cage. The scores at all 3 times and for each mouse are summed and mice drug treated orally compared to mice receiving apomorphine only. A saline only treated group is also included and any score, generally >5% of maximum taken into account.

The results were as follows:

Compound No. ED₅₀ mg/kg s.c. 5 10 Dopamine Receptor Activity in vitro

Dopamine receptors were labelled using methods similar to those previously reported [see S. Lazareno and S.R. Nahorski, Communication presented to Brit. Pharm. Soc, Bradford, 74, (1981), and P. Greengrass and R. Bremner, 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 10^-8

Anti-Inflammatory Activity Cotton Pellet test

In a conventional cotton pellet induced granuloma test, the results were as follows:

Compound Active Dose (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, European Journal of Pharmacology, 37 , 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 ± 0.5ºC) before transfer to a restraining cage. Each determination of blood pressure was the mean of at least 6 readings. Spontaneously hypertensive rats

(ages 12-18 weeks) with systolic blood pressures > 170 mmHg were considered hypertensive.

Compound (1) was active at 100mg/kg p.o.

Compound (5) was active at 10 mg/kg p.o. Toxicity

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_1-4 alkyl;

X, Y and Z are each independently -CR₁=, -N = or -NR₂ where R. is hydrogen, C_1-4 alkyl, or C_1-4 alkylthio, and R₂ is hydrogen or C_1-4 alkyl, 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 where R₁ and R₂ are as defined;

A is a group:

or

wherein : p and q each independently are 0 to 2 ; Z² is O or S ; n is 0 or 1 ; and. one of R₆ and R₇ when n = 0 is C_1-4 alkoxy, C_1-4 alkoxycarbonyl, hydroxy or C_1-4 alkyl optionally substituted by hydroxy, C_1-4 alkoxy or C_1-4 acyloxy, and the other is hydrogen or C_1-4 alkyl or one of

R₆ , R₇ and R₈ when n = 1 is C_1-4 alkyl and the other two are the same or different and are hydrogen or C_1-4 alkyl; R₃ and R₄ together are C_1-2 alkylenedioxy, or are each independently selected from hydrogen, halogen,

CF₃, C_1-6 alkyl, C_1-6 alκoxy, C_1-6 alkylthio, C_1-7acyl, C_1-7 carboxylic acylamino, C_1-6alkylsulphonylamino, N-(C_1-6 alkylsulphonyl) C_1-4 alkylamino, C_1-6 alkyl sulphonyl, C_1-6alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)- C_1-4 alkylamino optionally N-substituted by one or two groups selected from C_1-6 alkyl, C_3-8 cycloalkyl, C_3-8 cycloalkyl C_1-4 alkyl, phenyl or phenyl C_1-4 alkyl groups or optionally N-disubstituted by C_4-5 polymethylene; and

R₅ is C_1-7 alkyl, - (CH₂)_SR₁₀, s being 0 to 2 and R₁₀ being C_3-8 cycloalkyl, -CH₂)_tR₁₁, t being 1 or 2 and R₁₁ being thienyl or phenyl optionally substituted by one or two substituents selected from C_1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy and C_1-4 alkyl optionally substituted by hydroxy, C_1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy.

2. A compound according to claim 1 of formula (VI):

wherein: is hydrogen, halogen or optionally substituted amino ulphonyl as defined in claim 1, 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,

A compound according to claim 2 of formula (VIII):

wherein s a group -(CH₂)_t wherein t is

1 or 2 and is optionally substituted phenyl as defined in claim 1; or 2-thienylmethyl; and and R. are as defined in claim 2.

5. A compound according to any one of claims 2, 3 or 4, wherein 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 R₅ or is benzyl optionally substituted in the phenyl ring as defined in claim 1.

7. 4-(3-β-[8--Benzyl-8--azabicyclo{3,2,1}octyl] amino) quinazoline (1), 7-nitro-4-(3-β-[8 -azabicyclo (3,2,1}octyl] amino)-quinazoline (2), 7-chloro-4- (3-β-[8--benzyl-8--azabicyclo{3,2,1}octyl]amino)-quinazoline (3), 6-chloro-4-(3-β-[8--benzyl-8-- azabicyclo{3,2,1}octyl]amino)-quinazoline (4), 6-dimethylsulphamoyl-4-(3-β-[8--benzyl-8--azabicyclo {3,2,1}octyl]-amino)quinazoline (5),or 7-amino-4-(3-β-[8--benzyl-8--azabicyclo{3,2,1}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) : EQ₂; and thereafter as necessary reducing the resulting compound and optionally converting a group R₃ or R₄ in the thus formed compound to another group R₃ or R₄ respectively,

wherein:

Q₁ is a monovalent leaving group, dihalo, oxo or thiooxo, or, when one of X, Y and Z is -N= and the others are

-CR₁= or -N= as defined, hydrogen; and

Q₂ is NH₂ and E is A as defined; or

Q₁ is -NH₂; and Q₂ is a monovalent leaving group, cxo or thiooxo; and E is of one of formulae (XIII), (XIV) or (XV):

or

wherein the variables are as defined in claim 1.

9. 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.

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, disorders relating to impaired gastro-intestinal motility and/or disorders of the central nervous system.