GB2117379A - Benzoquinolizines - Google Patents

Abstract

The invention concerns benzoquinolizines of formula <IMAGE> and their pharmaceutically acceptable acid addition salts. In the formula R<1> and R<2> which may be the same or different each represent hydrogen, lower alkyl, lower alkoxy or halogen, R<3> represents methyl or ethyl, A represents a direct bond between the S and N atoms or a lower alkylene group having 1 to 3 carbon atoms in the chain between the S and N atoms, R<4> and R<5> each independently represent hydrogen, lower alkyl, aryl or aryl(lower)alkyl or together with the nitrogen atom to which they are attached represent a five or six membered heterocyclic ring. The compounds possess alpha 2-adrenoceptor antagonistic activity and can be incorporated into pharmaceutical compositions.

Description

SPECIFICATION Benzoquinolizines The invention relates to benzoquinolizines, to processes for preparing the benzoquinolizines, to theire use and to pharmaceutical compositions containing them.

The novel compounds of the present invention are benzoquinolizines of the general formula (I)

and their pharmaceutically acceptable acid addition salts. In formula (I), R1 and R2 which may be the same or different each represent hydrogen, lower alkyl, lower alkoxy or halogen, R3 represents methyl or ethyl, A represents a direct bond between the S and N atoms or a lower alkylene group having 1 to 3 carbon atoms in the chain between the S and N atoms, R4 and R5 each independently represent hydrogen, lower alkyl, aryl or aryl(lower)alkyl or together with the nitrogen atom to which they are attached represent a five or six membered heterocyclic ring.

The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms.

Preferably such radicals contain 1 to 4 carbon atoms. For example, a lower alkyl group may be methyl, ethyl, propyl or butyl. When R1 and/or R represent lower alkoxy the group may be, for example, methoxy, ethoxy, propoxy or butoxy. When R1 and/or R2 represents halogen the substituent may be, for example, fluorine, chlorine or bromine. Preferably both R1 and R2 are hydrogen. R3 is preferably methyl.

When A is a direct bond the compounds of the invention are sulphonamido derivatives of the formula

and the pharmaceutically acceptable acid addition salts thereof. When A is a lower alkylene group the group may be branched or straight chain provided that there are 1 to 3 carbon atoms in the chain between the S and N atoms. For example, the lower alkylene group may be methylene, ethylene, trimethylene or a branched chain group such as ethylethylene or propylene [-CH(CH3) OH2-].

When a radical, or part of a radical is referred to as "aryl" that radical or part of a radical is preferably a phenyl or substituted phenyl group. The substitued phenyl group can be a phenyl group substituted by one or more substituents chosen from, the example, halogen (e.g. chlorine, fluorine or bromine), alkoxy (e.g. lower alkoxy such as methoxy or ethoxy), lower alkyl (e.g. methyl, ethyl propyl or butyl), alkylenedioxy (e.g. methylenedioxy or ethylenedioxy), amino, lower alkylamino, diloweralkylamino or trifluoromethyl.

Examples of R4 and R5 are hydrogen, lower alkyl (e.g. methyl, ethyl, propyl or butyl), aryl (e.g.

phenyl or substitued phenyl as mentioned above) or aryl(lower)alkyl (e.g. benzyl or phenethyl in which the phenyl ring can be substituted as mentioned above). When R4 and R5 together with the N atom represent a five or six membered heterocyclic ring, the ring may be, for example, pyrrolidino, piperidino or morpholino.

The compounds of the invention may be prepared by reacting a reactive derivative of a sulphonic acid of formula (II)

(where A, R4 and R5 are as defined above) with a 2-methylamino- or 2-ethylaminobenzoquinolizine of the general formula

where R1, R2 and R3 have the meanings given above and, if required, converting a free base into a pharmaceutically acceptable acid addition salt. The reactive derivative of the sulphonic acid can be, for example, the acid halide or anhydride. Preferably it is the acid halide i.e. a compound of formula (IV)

(where R4, R5 and A are defined above and X is halogen, preferably chlorine). The reaction is generally carried out under basic conditions.If necessary a reactive substituent group in a reactant may be protected during the reaction and the protecting group may be removed at a later stage. For example, where R4 and R5 are both hydrogen the primary amino group in the reactive derivative of the sulphonic acid may be protected as an acylated amino group (e.g. as a phthalimido group) and the acyl group removed subsequently by known methods.

An alternative method of preparing the compounds of the invention involves reaction of a benzoquinolizine of formula (V)

(where R', R2, R3 and A are as defined above and X is halogen, preferably chlorine) with ammonia or an amine of formula (VI)

where R4 and R5 are as defined above. The starting materials of formula (V) in which A is lower alkylene, which are described in our co-pending application entitled 'Benzoquinolizines' filed concurrently herewith (No. 8305225) claiming priority from our UK Application No. 8207943, may be prepared by, for example, reacting a reactive derivative of a w-haioalkanesulphonic acid with the benzoquinolizine of formula (III).The aminosulphonyl halide starting materials of formula (V) in which A is a direct bond may be prepared by halogenating the corresponding aminosulphonic acid.

A further method for preparing the compounds of the invention in which A is a direct bond comprises reaction of the benzoquinolizine of formula (III) with a sulphonamide derivative of the formula

(where R4 and P5 have the meanings given above). Preferably the compound VII is sulphamide, i.e. the compound in which both R4 and R5 are hydrogen.

A preferred method for preparing certain compounds of the invention in which A is a lower alkylene group of at least two carbon atoms comprises adding ammonia or an amine of formula (VI) given to a benzoquinolizine of formula (VIII)

where R', R2 and R3 have the meanings given above and RB is a lower aikenyl group. A preferred lower alkenyl group is vinyl. The benzoquinolizines of formula (VIII) may be prepared by condensing a reactive derivative of an alkenesulphonic acid (e.g. the sulphonyl chloride) with an amine of the formula (III).

Alternatively the amine of formula (III) may be reacted with an appropriate -haloalkanesulphonyl chloride, particularly a ,B-haloethanesulphonyl chloride, under conditions basic enough to eliminate hydrogen chloride from the condensation product.

Compounds of the invention in which R4 and/or R5 are lower alkyl or aryl(lower)alkyl, in particular those compounds in which A is a lower alkylene group, may be prepared by alkylating or arylalkylating corresponding compounds in which R4 and/or R5 is hydrogen. The alkylation or arylalkylation may be carried out with, for example, a (lower)alkylhalide or aryl(lower)alkylhalide under basic conditions.

If in the processes described above the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compound.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids.

The compounds of the invention possess two asymmetric carbon atoms and hence can exist in various stereochemical forms. In addition they can exist as cis or trans isomers. It will be realised that if the starting material of formula (III) is a mixture of isomers the product of formula (I) will also be a mixture of isomers unless the mixture is separated by standard procedures. The preferred compounds of the invention are the trans isomers in which the

group is in the equatorial position, i.e. compounds of the general formula (IX)

and the pharmaceutically acceptable acid addition salts thereof. These compounds can be prepared by the methods described above from the-corresponding trans isomer starting material.

The compounds of the present invention possess pharmacological activity. In particular the compounds posses a2-adrenoceptor antagonistic activity in warm blooded animals and hence are of value in conditions where antagonism of the a2-adrenoceptor is desirable, for example, as antidepressants, in treatment of diabetes and in inhibiting blood platelet aggregation.

The compounds of the invention were tested for a2-adrenoceptor antagonistic activity on the rat field stimulated vas deferens preparation using a modification of the method of Drew, Eur. J. Pharmac, 1977, 42, 123-130. The procedure is described below.

Desheathed vasa deferentia from sexually mature rats were suspended in a 6 ml organ bath in Krebs solution at 370 and bubbled with 5% CO2 in oxygen. Platinum ring electrodes were positioned above and below the tissue for field stimulation. The stimulus parameters being 0.1 Hz 1 ms pulse width at supramaximal voltage. Twitch responses were recorded isotonically with a 0.5 g loading.

Clonidine hydrochloride was used as the a-adrenoceptor agonist and cumulative concentration response curves were constructed for the inhibition of twitch obtained with clonidine in the range 0.125 to 4 ng ml1. After washing out,clonidine, the twitch response quickly recovered and an anta gonist was then introduced into the Krebs reservoir. Clonidine concentration-response curves were repeated 90 min after introduction of the antagonist. The concentration of clonidine producing 50% inhibition of twitch before and after introduction of antagonist were obtained and the dose-ratio of clonidine was calculated. Various concentrations of the antagonists were used.

These results were plotted in the manner described by Arunlakshana s Schlid, Br. J. Pharmac.

Chemother., 1959, 14, 48-58 and the values of pA2 and slope were calculated. The compounds of the invention possess potent a2-adrenoceptor antagonistic activity. The results are shown in the following Table Table I PA2 Compound of example (a) 1 7.44 2 7.4 3 7.26 4 7.43 The compounds of the invention antagonise the a2-adrenoceptors to a much greater extent than the a1-adrenoceptors. The a1 antagonistic activity can be evaluated by a number of different methods.

One method involves assessing the activity on the isolated anococcygeus muscle of the rat The method is based on that of Gillespie, Br. J. Pharmac., 1 972, 45, 40441 6. In the procedure male rats (250-360g) are killed by a blow on the head and bled. The two anococcygeus muscles are removed from their position in the midline of the pelvic cavity, where they arise from the upper coccygeal vertebrae. The muscles are suspended in 5 ml organ baths in Krebs solution containing 10-4M ascorbic acid, to prevent drug oxidation. The tissues are gassed with a 95% oxygen, 5% CO2 mixture and maintained at 370. Longitudinal muscle contractions are recorded using isotonic transducers.

Cumulative dose response curves are then obtained to phenylephrine or in some cases methoxamine, both agents being presynaptic alpha adrenoceptor agonists. The concentration range of phenylephrine or methoxamine used is 0.02 to 0.8 CIS yg ml-l. The agonist is then washed from the bath and the test drug added to the bathing medium at a concentration of 1 O-eM. After 30 min equilibration with the test drug a further agonist dose response curve is obtained. The washing, equilibration and agonists dosing procedures are then repeated using 10-5M and 10-4M solutions of the test drug.

Estimates of the pA2 value for the test drug as an antagonist of phenylephrine or methoxamine were made from the agonist dose-ratios using the method of Arunlakshana s Schild, Br. J. Pharmac.

Chemother., 1959 14 48-58.

The pA2 for a1 antagonistic activity and the a2/a2 selectivity for compounds of the invention are given in Table II below.

Table II P2 a2/a1 Compound of example (a1) selectivity * 1 6.19 18 2 5.95 28 3 5.6 46 4 6.44 10 *antilog of (a2pA2-a1pA2) The invention further provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt for use in antagonising ce2-adrenoceptors in a mammal.

The invention also provides a pharmaceutical composition comprising a compound of general formula (II) or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a solid and a liquid.

Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatin capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, e.g. from 0.03 to 99%, preferably 1 to 80% of the active ingredient.Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

The term "composition" is intended to include the formation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredients, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators.

Suitable examples of liquid carriers of oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.

The following Examples illustrate the invention: Example 1 N-Methyl-N-(1,3,4,6,7,11 ba-hexahydro-2H-benzo[alquinol izin-2ss-yl)-N'-methylsulphamide An ice-cold stirred solution of 2P-methyla m ino-l ,3,4,6,7,1 1 bcg-hexahydro-2H-benzo[a]quino- lizine (2.16 g) and triethylamine (1.2 g) in dichloromethane (25 cm3) was treated with a solution of Nmethylsulphamoyl chloride (1.30 g) in dichloromethane (25 cm3). The clear solution was kept at room temperature for 3 days, washed with water (25 cm3), then brine (25 cm3) and dried (MgS04). Filtration and evaporation gave a yellow gum which was chromatographed on silica eluted with 10% ethanolethyl acetate to give a pale yellow gum (2.19 g).This was taken up in ethanol (5 cm3), acidified with ethanolic HCI, diluted with ethyl acetate (25 cm3) and filtered to give pale cream crystals.

Trituration with boiling ethanol gave pure title compound as the hydrochloride (2.19 g), very pale cream crystals, m.p. 205--2060 (dec).

Example 2 N.N.N'-Trimethyl-N'-[1 ,3,4,6,7,11 b-hexahydro-2H-benzo jea]quinolizin-2p-yl]sulphamide An ice-cold stirred solution of 2p-methylamino-1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinolizine (2.16 g) and triethylamine (1.15 g) in dichloromethane (25 cm3) was slowly treated with a solution of dimethylsulphamoyl chloride (1.44 g) in dichloromethane (25 cm3). The clear solution was kept at room temperature for 2 days, when tic showed that the reaction was essentially complete. The mixture was washed with water (2x25 cm3), dried, filtered and evaporated to give a red-brown syrup (3.29 g). This was dissolved in ethanol (5 cm3), acidified with ethanolic HCI, diluted with ethyl acetate (15 cm3) and allowed to crystallise overnight. The crystals were collected by filtration and triturated with boiling methanol to give the title compound as the hydrochloride (2.19 g), colourless, short rods, m.p. 240--2480 (dec, decomposition and softening occurs over a wide range above 1450).

Example 3 N-Methyl-N-( 1,3,4,6,7,11 ba-hexahydro-2H-benzo[aiquinolizin-2-yl)-2-dimethylaminoethane- sulphonamide (a) An ice-cold, stirred solution of 2P-methylamino-l ,3,4,6,7,1 1 ba-hexahydro-2H-benzo[a]quinolizine (2.16 g) and triethylamine (1.2 g) in dichloromethane (25 cm3) was slowly treated with a solution of 2-chloroethanesulphonyl chloride (1.63 g) in dichloromethane (25 cm3). The clear solution was kept at room temperature for 3 days, then washed with aq NaHC03 and brine, and dried (MgS04).

Filtration and evaporation gave a yellow gum which was chromatographed on silica eluted with 10% ethanol-ethyl acetate to give a yellow gum (1.56 g).This was dissolved in ethanol (5 cm3, acidified with ethanolic HCI, diluted with ethyl acetate (7 cm3) and cooled. The crystals were filtered off and washed with 10% ethanol-ethyl acetate to give N-methyl-N-(1 3,4,6,7,11 ba-hexahydro-2H-benzo[a] quinolizin-2ss-yl)ethenesulphonamide, hydrochloride (1.58 g) as very pale cream crystals, with no clear m.p. (decomp. occurs above 1 900 causing liquefaction, no solid remains at 2340).

b) The free base from (a) (1.18 g) was dissolved in 33% dimethylamine-ethanol solution (25 cm3) and the clear solution kept at room temperature overnight. The solvents were evaporated, the residual oil taken up in hot ethanol (5 cm3), acidified with ethanolic HCI, diluted with ethyl acetate (15 cm3) and cooled. The crystals were filtered off and washed with ice-cold 20% ethanol-ethyl acetate, then dried at 800/1 00 mm to give title compound as the dihydrochloride, hemihydrate (1.50 g), pale cream crystals, m.p. 258-261. (dec).

Example 4 N-(i-Propyl)-N'-(l ,3.4,6,7,11 ba-hexahydrn-2H-benzo[a]quinolizin-2-yl)-N'-methylsulphamide An ice-cold, stirred solution of 2P-methylamino-l ,3,4,6,7,1 1 bcr-hexahydro-2H-benzo[a]- quinolizine (2.16 g) and triethylamine (1.2 g) in dichloromethane (25 cm3) was slowly treated with a solution of N-isopropylsulphamoyl chloride (1.58 g) in dichloromethane (15 cm3). The clear solution was kept at room temperature for 1 day, washed with water (25 cm3) and brine (25 cm3) and dried (MgS04). Filtration and evaporation gave an orange syrup (3.53 g) which was chromatographed on silica and eluted with 10% ethanol-ethyl acetate to give a yellow syrup (3.19 g). This was taken up in hot ethanol (10 cm3), acidified with ethanolic HCI, diluted with ethyl acetate (25 cm3) and cooled.The crystals which separated overnight were collected by filtration and recrystallised from methanol to give pure title compound as the hydrochloride, hemimethanolate (1.55 g), colourless crystals, m.p. 1 70- 1730 (dec.).

Example 5 N-Methyl-N-sulphamido-1 ,3,4.6.7.11 b-hexahydro-2H-benzo[a]quinolizin-2ss-amine A mixture of 2P-methylamino-l ,3,4,6,7,1 1 ba-hexahydro-2H- benzo[a]quinolizine (4.64 g) and sulphamide (2.61 g) in 1,2-dimethoxyethane (50 cm3) was stirred and heated to reflux for 17 hours.

After cooling, the supernatant liquid was decanted from some red gum and evaporated in vacuo. The residue was dissolved in dichloromethane and allowed to stand. After several hours the precipitated crystals were filtered off and washed with dichloromethane and water. The crystals were triturated with boiling ethanol, cooled and refiltered to give the title compound as colourless crystals, m.p. 1 90- 1920 (dec.).

The crystals were suspended in hot ethanol (10 cm3), acidified with ethanol HCI and cooled. The gummy solid which initially formed crystallised after re-heating and cooling and was filtered to give the title compound' as the hydrochloride (2.49 g), colourless crystals, m.p. 200--2020 (dec.).

Example 6 N-Methyl-N-(l ,3,4.6,7,1 1 ba-hexahydro-2H-benzo[a]quinolizin-2ss-yl)-2- aminoethanesulphonamide (a) 2-Phthalimidoethanesulphonyl chloride (1.65 g) was added over 2 min to a stirred mixture of 2,i-methylamino-1 3,4,6,7,11 ba-hexahydro-2H-benzo[ajquinolizine (1.24 g), triethylamine (1.2 cm3), and dichloromethane (1 5 cm3). After stirring for a further 2 hours the solution was washed with sodium carbonate solution, then dried and evaporated.Chromatography on neutral Woelm alumina with dichloromethane as eluent gave 1.53 of pure crystalline base, N-( 1,3,4,6,7,11 b-hexahydro-2H benzo[a]quinolizine-2P-yl)-2-( 1 H-isoindole-l ,3-dione-2-yl)-N-methylethanesulphonamid The base was dissolved in ethanol (15 cm3) and p-toluenesulphonic acid hydrate (0.7 g) added to precipitate the salt as a gum, the mixture was warmed to redissolve the sum and then allowed to cool slowly to give the crystalline p-toluenesulphonate, hemihydrate, m.p. 137--1390.

(b) A mixture of hydrazine hydrate (0.7 ml), the phthalimidosulphonylbenzoquinolizine from part (a) (4.55 g, 0.01 ml), and ethanol (30 ml) was heated at reflux for 1 hour. The mixture was initially a suspension but on heating cleared then partly crystallised. The solvent was then removed by evaporation, the residue was dissolved in water, basified with ammonia and, extracted with chloroform. The extract was dried and evaporated to yield the title compound as an oil (3.4 g). A sample (1 g) was dissolved in ethanol (10 cm3) and acidified by addition of p-toluenesulphonic acid hydrate to precipitate the di-p-toluenesulphonic salt, m.p. 21000.

Claims (16)

Claims

1. A benzoquinolizine of the general formula (I)

or a pharmaceutically acceptable acid addition salt thereo, wherein R' and R2 which may be the same or different each represent hydrogen, lower alkyl, lower alkoxy or halogen, R3 represents methyl or ethyl, a represents a direction bond between the S and N atoms or a lower alkylene group having 1 to 3 carbon atoms in the chain between the S and N atoms, R4 and R5 each independently represent hydrogen, lower alkyl aryl or aryl(lower)alkyl or together with the nitrogen atom to which they are attached represent a five or six membered heterocyclic ring.

2. N-Methyl-N-(1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinolizin-2p-yl)-N'-methylsulphamide or a pharmaceutically acceptable acid addition salt thereof.

3. N,N,N'-Trimethyl-N'-[1 ,3,4,6,7,1 1 ba-hexahydro- 2H-benzo[a]quinolizin-2p-yl]sulphamide or a pharmaceutically acceptable acid addition salt thereof.

4. N-Methyl-N-(1,3,4,6,7,11 ba-hexahydrn-2H-benzo[a]quinolizin-2-yl)-2-dimethyIamino- ethanesulphonamide or a pharmaceutically acceptable acid addition salt thereof.

5. N-(i-Propyl)-N'-( 1 ,3,4,6,7,1 1 bct-hexahydro-2H-benzo[a]quinolizin-2p-yl)-Nt-methyl- sulphamide or a pharmaceutically acceptable acid addition salt thereof.

6. N-Methyl-N-sulphamido-1 ,3,4,6,7,1 1 ba-hexahydro-2H-benzo[a]quinolizin-2,B-amine or a pharmaceutically acceptable acid addition salt thereof.

7. N-Methyl-N-(1,3,4,5,6,7,11ba-hexahydro-2H-benzo[a]quinolizin-2aB-yl)-2-aminoethane- sulphonamide or a pharmaceutically acceptable acid addition salt thereof.

8. A process for preparing a compound claimed in Claim 1 which comprises reacting a reactive derivative of a sulphonic acid of formula (II)

(where A, R4 and R5 are as defined in Claim 1) with a 2-methylamino- or 2-ethylamino-benzoquinolizine of the qeneral formula

(where R', R2 and R3 have the meanings given in Claim 1) and, if required, converting a free base into a pharmaceutically acceptable acid addition salt.

9. A process as claimed in Claim 8 wherein the reactive derivative is an acid halide or anhydride.

10. A process for preparing a compound claimed in Claim 1 which comprises reacting a benzoquinolizine of formula (V)

(where R', R2, R3 and A are as defined in Claim 1 and Xis halogen with ammonia or an amine of formula (VI)

(where R4 and R5 are as defined in Claim 1) and, if required, converting a free base into a pharmaceutically acceptable acid addition salt.

11. A process for preparing a compound claimed in Claim 1 in which A is a direct bond which comprises reacting a benzoquinolizine of formula (III)

(where R1, R2 and R3 have the meanings given in Claim 1) with a sulphonamide derivative of formula

(where R4 and R5 have the meanings given in Claim 1), and, if required, converting a free base into a pharmaceutically acceptable acid addition salt.

12. A process for preparing a compound claimed in Claim 1 in which A is a lower alkylene group of at least two carbon atoms which comprises adding ammonia or an amine of formula (VI)

(where R4 and R5 are as defined in Claim 1) to a benzoquinolizine of formula (VIII)

(where R1, R2 and R3 have the meanings given in Claim 1 and RB is a lower alkenyl group), and, if required, converting a free base into a pharmaceutically acceptable acid addition salt.

13. A process for preparing a benzoquinolizine substantially as hereinbefore described with reference to any one of Examples 1 to 6.

14. A benzoquinolizine whenever prepared by a process claimed in any one of Claim 8 to 13.

1 5. A pharmaceutical composition comprising a compound claimed in any one of Claims 1 to 7 and 1 4 in association with a pharmaceutically acceptable carrier.

16. A compound claimed in any one of Claims 1 to 6 and 14 for use in antagonising a2- adrenoceptors in warm blooded animals.