BENZOQUINOLIZINES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS

Abstract: The invention concerns benzoquinolizines of formula and their acid addition salts. In the formula R⁷ is lower alkyl or a phenyl or naphthyl radical optionally substituted with specified substituents and R⁸ is methyl or ethyl. The compounds possess high presynaptic α-adrenoceptor anta­ gonistic activity and a good presynaptic/postsynaptic anta­ gonistic selectivity.

Description: This invention relates to benzoquinolizines, to processes for preparing the benzoquinolizines and to pharmaceutical preparations containing them. U.K. Patent Specification No. 1,513,824 discloses that benqoquinolizines of the general formula (I) EMI1.1 and the pharmaceutically acceptable acid addition salts thereof, wherein R1 and R2 which may be the same or different, each represent hydrogen, lower alkyl, lower alkoxy or halogen, R3 represents hydrogen, lower alkyl or. aryl and R 4 represents -S02R (where R is lower alkyl or aryl), -CONH2 or -CXNHR6 (where X is oxygen or sulphur and Ru is aryl or aryl.CO.-), generally exhibit hypotensive activity upon administration to warm-blooded animals. We have now found that a small group of compounds falling within general formula (I) but not specifically disclosed in the above mentioned specification, and their pharmaceutically acceptable acid addition salts possess high presynaptic a-adrenoceptor antagonistic activity in warm blooded animals. This activity is not disclosed or foreshadowed in the above mentioned specification. Accordingly the present invention provides benzoquinolizines of the general formula (II) EMI2.1 and the pharmaceutically acceptable acid addition salts thereof, wherein R7 is lower alkyl, phenyl or naphthyl optionally substituted by one or more lower alkyl, lower alkoxy or halogen substituents and R8 is methyl or ethyl. The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably the radical contains 1 to 4 carbon atoms. For example a lower alkyl may be methyl, ethyl, propyl or butyl and a lower alkoxy group may be methoxy, ethoxy, propoxy or butoxy. Examples of halogen substituents 7 include fluorine, chlorine and bromine. When R is lower alkyl it is preferably methyl or propyl. Preferably R8 is methyl. Preferred compounds of formula (II) are NmethylN(I,3,4,6,?,11ba-hexahydro-2H-benzo[a]quinolizin 28-yl)methanesulphonamide N-methyl-N-(1,3,4,6,7,1lba-hexahydro-2H-benzo[a]quinolizin- 2R-yl)propan-1-sulphonamide N-methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizin 2ss-yl)benzenesulphonamide and their pharmaceutically acceptable acid addition salts. The compounds of the invention were tested for their presynaptic a-adrenoceptor antagonistic activity on the ra field stimulated vas deferens preparation using a modification of the method of Drew, Eur.O.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 37 and bubbled with 6% C02 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 ml 1. After washing out clonidine, the twitch response quickly recovered and an antagonist 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 for clonidine was calculated. Various concentrations of the antagonists were used. These results were plotted in the manner described by Arunlakshana & Schild, Br.J.Pharmac. Chemother., 1959, 14, 48-58 and the values of pA2 and slope were calculated. The compounds of the invention possess potent presynaptic a-adrenoceptor antagonistic activity having, in general, values of pA2 of 7.5 or more and substantially greater than other compounds of general formula I as is shown in the following Table I: TABLE I PA2 Compound (presynaptic) Compounds of the invention A. N-methyl-N-(1,3,4,6,7,11ba-hexahydro 2H-benzo[a]quinolizin-2ss-yl)methane- sulphonamide 7.7 B. N-methyl-N-(1,3,4,6,7,11b -hexahydro- 2H-benzo[a]quinolizin-2B-yl)ethane- sulphonamide 7.7 C. N-methyl-N-(1,3,4,6,7,11ba-hexahydro 2H-benzo[a]quinolizin-2B-yl)propan-l- sulphonamide 8.3 D. N-methyl-N-(1,3,4,6,7,llba-hexahydro- 2H-benzo[a]quinolizin-2P-yl)benzene- sulphonamide 8.4 E. N-Ethyl-N-I,3,4,6,7,Ilba-hexahydro- 2H-benzo[alquinolizin-28-yl)methane- sulphonamide 7.8 F. N-methyl-N-(1,3,4,6,7,11b&alpha;-hexahydro- 2H-benzo[a]quinolizin-2B-yl)toluene-4- sulphonamide 8.1 G. N-methyl-N-(I,3,4,6,7,11ba-hexahydro-- 2H-benzoEa]qu nolizin-2ss-yl)-4-methOxy- benzenesulphonamide 8.1 H. N-methyl-Ng1,3,4,6,7,11ba-hexahydro- 2H-benzo[ajquinolizin-2ss-yl)-4-chloro- benzenesulphonamide 7.6 I. N-methyl-N-(1,3,4,6,7,llba-hexahydro- 2H-benzo[a]quinolizin-2-yl)-2-methyl- benzenesulphonamide 7.9 J. N-methyl-N-(I,3,4,6,7,11ba-hexahydro- 2H-benzoEa]quinolizin-2ss-yl)-3,4- dichlorobenzenesulphonamide 7.5 K. N-methyl-N-(1,3,4,6,7,11ba-hexahydro- 2H-benzo[a]quinolizin-2P-yl)-n-butane- sulphonamide 7.9 Other compounds of formula I 2-methanesulphonamido-1,3,4,6,7,11b hexahydro-2H-benzoEa]quinolizine 6.9 N-methyl-N-(9,10-dimethoxy-1,3,4, 6,7,11ba-hexahydro-2H-benzo[a] quinolizin-20-yl)-methane- sulphonamide 6.8 N-(n-Propyl)-N-(1,3,4,6,7,11bahexahydro-2H-benzo[a]quinolizin-2ss- yl)methanesulphonamide 7.0 2ss-(n-propanesulphonamido-1 3,4,6, 7,11ba-hexahydro-2H-benzo[a quinolizine 6.5 1-(1,3,4,6,7,11b-hexahydro-2H- benzo[a]quinolizin-2yl)-3-phenyl urea 5.4 1-(1,3,4,6,7,11b-hexahydro-2H-benzo[a] quinolizin-2yl)-3-phenylthiourea 5.6 2ss-phenylsulphonamido-1,3,4,6,7,11b- hexahydro-2H-benzo[a]quinolizine 6.4 2ss-ethanesulphonamido-1,3,4,6,7,11b- hexahydro-2H-benzo[a]quinolizine 5.3 The compounds of the invention have been found to antagonise the presynaptic cc-adrenoceptors to a much greater extent than the postsynaptic a-adrenoceptors. The postsynaptic 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 basedLon that of Gillespie, Br.O.Pharmac., 1972, 45, 404-416. 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 5ml 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 phenylephnn or methoxamine used is 0.02 to 0.8g.ml 1. The agonist is then washed from the bath and the test drug added to the bathing medium at a concentration of 10-619. 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 & Schild, Br.J.Pharmac.Chemother., 1959, 14, 48-58. The pA2 for postsynaptic antagonistic activity and the presynaptic selectivity (pA2 presynaptic antagonistic activity/pA2 postsynaptic antagonistic activity) for the compounds of the invention are given in Table II below. In this table the compounds are referred to by the references given in Table I. TABLE II PA2 Presynaptic Compound (postsynaptic) selectivity A 5.95 56 B 6.17 34 C 6.14 144 D 6.34 102 E 6.25 35.5 F 6.33 59 G 6.5 40 H 6.09 32 I 6.27 40 5.48 93 K 6.6 19 Compounds having good presynaptic a-adrenoceptor antagonistic activity, particularly those with a high presynaptic selectivity are potentially useful, for example, as antidepressants, in treatment of peripheral vascular disease in treatment of diabetes and in inhibiting blood platelet aggregation. In such use any substantial hypotensive activity of the compound would be an undesirable side effect. We have found unexpectantly that some of the compounds of the present invention (such as compound A above) do not possess such activity when tested by a standard pharmacological procedure employing rats rendered hypertensive by implantation of desoxycorticosterone acetate. The compounds of the present invention can be prepared by reacting a reactive derivative of a sulphonic acid derivative of general formula (III) R7SO20H (III) where R7 has the meaning given above with 20-ethylamino or methylamino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]- quinolizine 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 halide i.e. a compound of general formula R7SO2X (where R7 is as defined above and X is halogen, preferably chlorine). The reaction is preferably carried out under basic conditions, for example in the presence of a tertiary amine, e.g. triethylamine. If in the process 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 2-ethylamino or methylamino-1,3,4,6,7,11bhexahydro-2H-benzo[a]quinolizine starting materials for the above process can be prepared from the corresponding 2-ox- compound by the procedure described in U.K. Patent Specification No. 1,513,824. Alternatively the 2-methylamino starting material can be prepared from the corresponding 2-amino compound, e.g. by reacting the amino compound with an alkylhaloformate or with formic acid and reducing, e.g. with a hydride transfer reagent such as lithium aluminium hydride the resulting 2-NHC02Alkyl or 2-NHCHO intermediate. The invention further 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 aids, binders or tablet-disintegrating agents; it can also be an encapsulat-ing material. In powders the:carrier isa 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 gig%, 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 formulation 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 pressurised compositions. The active ingredient, 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 for 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 utilised by, for example, intramuscular, intaperitoneal 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 a 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 2ss-Methylamino-1,3,4,6,7,11ba-hexahydro-2H-benzoLa] quinolizine (a) 2ss-Amino-1,3,4,6,7,11b -hexahydro-2H-benzo[a]- quinolizine (17.79) was cooled to 00(ice) and cautiously treated with 100% formic acid (100 cm3). The mixture was stirred until homogenous, then slowly treated with acetic anhydride (10.09) over about 1 hour at 0 . After stirring for a further 1 hour, the mixture was heated to reflux for 2 hours, cooled and excess solvent evaporated in vacuo. The residual oil was basified with 10% aq.Na2C03 (ca.500cm3) and extracted with dichloromethane (3 x 100 cm ). The combined extracts were washed with brine (100 cm3) and dried (MgS04). Glc at this stage revealed incomplete reaction (ca. 50%), and the entire cycle was repeated with fresh formic acid and acetic anhydride. Evaporation of the organic extract gave a mixture of solid and oil (16.49). Crystallisation from ethanol- 60/80 petrol afforded pure N-[1,3,4,6,7,11ba-hexahydro-2H-benzo-(a)- quinolizin-2B-yl]formamide (7.12 g) as off-white microneedles, mp 162-40 (partial decomposition occurs above 1470). (b) A suspension of the product of part (a) (7.3 g) in dry THF (80cm3) was added slowly to a solution of lithium aluminium hydride (49) in dry THF (120 cm3). The mixture was stirred and heated to reflux for 24 hours under a blanket of dry nitrogen, then decomposed by the dropwise addition of water (4cm3), 15% aq. NaOH (4cm3) and water (12cm3). After filtration, the solution was evaporated, the residue taken up in dichloromethane, dried (19gas04), filtered and evaporated to give a red-brown oil (6.199) virtually pure by tlc, which set solid on standing. A sample (0.579) was converted to the hydrochloride in ethanol (7cm3) and ethanolic hydrogen chloride. On cooling, crystals were obtained which were filtered off, washed with 1:2 ethanol/ethyl acetate and dried in vacuo to give pure 2ss-methylamino-1,3,4,6,7,11ba-hexahydro-2H- benzo[a]quinolizine hydrochloride (0.679; 88;2) as colourless micro-needles, mp 248-2510(dec.) (fast rate of heating; decomposition begins at temperatures above 2000). EXAMPLE 2 N-Methyl-N-(1,3,4,6,7,11b -hexahydro-2H-benzo[a]quinolizin- 26-yl)methanesulphonamide 2ss-Methylamino-1,3,4,6,7,11ba-hexahydro-2H-benzo[a]- quinolizine (1.889) and triethylamine (0.909) were dissolved in ice-cold dichloromethane (10cm3) and treated with an ice-cold solution of methane sulphonyl chloride (1.009) in dichloromethane (5cm3). The clear solution was allowed to stand overnight. The resulting mixture of crystals and solution was diluted with dichloromethane (10cm3) and water (5cm3), and extracted with water (2 x 20cm3). The organic layer was separated and dried (MgS04). Filtration and evaporation gave a pink gum (2.379). The hydrochloride was prepared from ethanolic hydrogen chloride, and recrystallised from ethanol-ethyl acetate, to yield the title compound hydrochloride as off-white micro-needles (1.459), mp 198-2000(dec). EXAMPLE 3 N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizin- 2B-yl)ethanesulphonamide A solution of ethanesulphonyl chloride (1.459) in dichloromethane (20cm3) was added slowly to an ice-cold solution of 2ss-methylamino-1,3,4,6,7,11ba-hexahydro-2H- benzo[a]quinolizine and triethylamine (1.29; 0.0119M) in dichloromethane (30cm3). The clear mixture was stirred briefly, then kept at room temperature for 7 days, when tic showed that the reaction was complete. It was washed with water (2 x 25cm3) and dried (MgS04). Filtration and evaporation afforded a yellow-orange syrup (3.139) which was dissolved in hot ethanol (5cm3), acidified with ethanolic hydrogen chloride, diluted with ethyl acetate (15cm3) and cooled. The precipitated, sticky crystals were filtered off and washed with 1:3 ethanol/ethyl acetate Two recrystallisations from 1:1 ethanol/ethyl acetate afforded the title compound as the hydrochloride (0.979), colourless crystals, mp 207-2120 (dec) (decomposition causes local melting above 1800). EXAMPLE 4 N-Methyl-N-(1,3.4,6,7,11ba-hexahYdro-2H-benzoralquinûlizin 2B-yl)propan-1-sulphonamide An ice-cold, stirred solution of 2B-methylamino-1,3,4, 6,7,11ba-hexahydro-2H-benzo[a]quinolizine (2.169) and triethylamine (1.1g) in dichloromethane (25cm3) was slowly treated with a solution of n-propanesulphonyl chloride (1.439) in dichloromethane (25cm3). The clear solution was then kept at room temperature for 72h, when tic showed complete reaction had occurred. The mixture was washed with water (2 x 25 cm3), dried (MgS04), filtered and evaporated to give a viscous, pale-yellow oil (3.099). This was dissolved in hot ethanol (7cm3), acidified with ethanolic hydrogen chloride, diluted with ethyl acetate (25 cm3) and cooled, with scratching. The crystals which slowly separated were collected by filtration, washed with 20% ethanol-ethyl acetate and recrystallised from methanol to give the title compound as the hydrochloride (1.989), colourless plates, m.p. approx. 222-2400(dec. violent decomposition occurring about 2000 without melting). EXAMPLE 5 N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizin- 2ss-yl)benzenesulphonamide An ice-cold, stirred solution of 28-methylamino- 1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizine and triethylamine (0.79) in dichloromethane (25cm ) was slowly treated with a solution of benzenesulphonyl chloride (1.29) in dichloromethane (25 cm3). The clear solution was kept at room temperature for 72h when tic showed complete reaction had occurred. The mixture was washed with water (2 x 25cam3), dried (MgSO4), filtered and evaporated to give an off-whiteglass (2.449). This was dissolved in ethanol (7cm3), acidified with ethanolic HCl, diluted with ethyl acetate (10cm3) and cooled. The crystals were filtered off and washed with 1:1 ethanol/ethyl acetate to give the title compound as the hydrochloride (2.32 g), colourless needles, m.p. 225-228 (dec, partial decomposition occurring above 1930). EXAMPLE 6 N-Ethyl-N-(1,2,3,4,6,7,llba-hexahydro-2H-benzo[a] quinolizin-2ss-yl)methanesulphonamide An ice-cold solution of 2-ethylamino-1,3,4,6,7,11bhexahydro-2H-benzo[a]quinolizine (1.359) and triethylamine (0.609) in dichloromethane (50cm3) was treated, with stirring, with a solution of dimesyl anhydride (1.029 in dichloromethane (25cm3). The mixture was stirred for a further 2h, then allowed to stand at room temperature until tic indicated that reaction was virtually complete (11 days). The mixture was then washed with water (2 x 25cm3), dried (M9SO4), filtered and evaporated to give an oil (1.599). Chromatography on silica eluted with 5-10% ethanol/ethyl acetate afforded a purified product (0.889) which was acidified with ethanolic hydrogen chloride and, after evaporation of the solvent, crystallised from iso-propanol. The crystals were recrystallised from boiling ethanol (3cm3) to which ethyl acetate (5cm3) was added, to give pure title compound as the hydrochloride quaterhydrate (0.559), colourless crystals, m.p. 217-2230 (dec) (with sublimation and partial decomposition above 200 ). EXAMPLE 7 N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizin- 2F-yl)toluene-4-sulphonamide A stirred solution of 2ss-methylamino-1,3,4,6,7,11b - hexahydro-2H-benzo[a]quinolizine (2.169) and triethylamine (1.1g) in dichloromethane (25cm3) was cooled in ice and treated with a solution of tosyl chloride (1.919) in dichloromethane (25 cm3). The clear mixture was kept at room temperature for 6 days, then washed with water (2 x 25cm3) and dried (MgS04). Filtration and evaporation afforded a red-orange glass (3.699) which crystallised from hot ethanol (10cm ). After cooling, the crystals were filtered off and washed with ice-cold ethanol to give the title compound (4.439) as cream crystals, m.p. 161-164 . Trituration with boiling ethanol and acidification with ethanolic HCl (which caused dissolution followed by re-precipitation), followed by stirring to break up lumps and filtration afforded the pure hydrochloride (3.399) as light buff rods, m.p. 258-2610 (dec; decomposition occurred at all temperatures above 2200). EXAMPLE 8 N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizin- 2B-yl)-4-methoxybenzenesulphonamide An ice-cold, stirred solution of 2-methylamino- 1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizine (2.169) and triethylamine (1.1g) in dichloromethane (25cm3) was treated with a solution of p-methoxybenzenesulphonyl chloride (2.079) in dichloromethane (25cm3). After standing for 7 days, the solution was washed with water (2 x 25cm3), dried (MgS04) and evaporated to give a residue (3.619) which was crystallised from ethanol (1 5cm3) to give the title compound as cream crystals, m.p. 154-6 . The base was triturated with boiling ethanol (10cm3), acidified with ethanolic HCl (which caused partial dissolution followed by reprecipitation), cooled and stirred well to breakup lumps. Filtration gave off-white crystals which were triturated well with a boiling mixture of ethanol/methanol/water. After cooling, the crystals were filtered off and washed well with ethanol, to give the title compound as the hydrochloride (2.629) as pale buff crystals with no clear m.p. (decomp. occurs above 2200). EXAMPLE 9 N-19ethyl-N- (1,3,4,6,7,1 Iba-hexahydro-2H-benzo[a]quinolizin- 2p-yl)-4-chlorobenzenesulphonamide An ice-cold, stirred solution of 2ss-methylamino-1,3, 4,6,7,11ba-hexahydro-2H-benzoEa]quinolizine (1.089) and triethylamine (0.559) in dichloromethane (25cm3) was treated with a solution of 4-chlorobenzenesulphonyl chloride (1.069) in dichloromethane. The mixture was kept at room temperature for 7 days, then washed with water (2 x 25cm3), dried (MgS04), filtered and evaporated to give the title compound as a brown semi-crystalline gum (1.649) which crystallised from hot ethanol (5cm3) to give pale-buff crystals, m.p. 50-3 (dec). The crystals were taken up in boiling ethanol (10cm3), acidified with ethanolic HCl (causes partial dissolution followed by re-precipitation), cooled and stirred well. Filtration gave very pale pink crystals which were triturated with a hot ethanol/methanol/water mixture, cooled, filtered and washed with ethanol to give the title compound hydrochloride (1.109), colourless, short plates, with no clear m.p. (decomp. occurs above 2300). EXAMPLE 10 N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizin- 26-yl)-2-methylbenzenesulphonamide An ice-cold, stirred solution of 2B-methylamino- 1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizine (1.849) and triethylamine (0.99) in dichloromethane (25cm3) was slowly treated with a solution of o-toluenesulphonyl chloride (1.629) in dichloromethane (25cm3). The solution was kept at room temperature for 2 days, then washed with water (2 x 50cm3) and dried (MgS04). Filtration and evaporation afforded an orange syrup (3.379) which was dissolved in hot ethanol (10cm3), acidified with ethanolic HCl and cooled. The crystals were filtered off after Ihour, and washed with ethanol to give the title compound as the hydrochloride (2.889) as pale cream crystals. Recrystallisation from ethanol/water gave the pus hydrochloride, quarterhydrate (2.039) as colourless needles, m.p. 197-2030 (dec; decomp. occurred above 1750). EXAMPLE 11 N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizin- 2ss-yl)-3,4-dichloroDenzenesulphonamide An ice-cold, stirred solution of 2B-methylamino- 1,3,4,6,7,11b -hexahydro-2H-benzo[a3quinolizine (1.849) and triethylamine (0.99) in dichloromethane (25cm ) was slowly treated with a solution of 3,4-dichlorobenzenesulphonyl chloride (2.099) in dichloromethane (25cm3). The mixture was kept at room temperature for 2 days, then washed with water (2 x 50cm3) and dried (MgS04). Filtration and evaporation afforded an off-white solid (3.309) which was purified by trituration with hot ethanol, to give pure title compound, m.p. 1913O. A suspension of the sulphonamide in boiling ethanol (10cm3) was acidified with ethanolic HCl and the clear solution cooled. Filtration and washing with ethanol gave the hydrochloride (3.039) as pale cream crystals. Recrystallisation from ethanol/water afforded the title compound as the pure hydrochloride, quarterhydrate (2.719), as colourless crystals, m.p. 195-1970(dec). EXAMPLE 12 N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizin- 2ss-yl)-n-butanesulphonamide An ice-cold, stirred solution of 2B-methylamino- 1,3,4,6,7,i1ba-hexahydro-2H-benzo[a]quinolizine (2.169) and triethylamine (1.29) in dichloromethane (25cm3) was treated with a solution of n-butanesulphonyl chloride (1.579) in dichloromethane (25cm3). The clear solution was kept at room temperature for 4 days, washed with water (2 x 50cm3) and dried (MgS04). Filtration and evaporation afforded a dark gum (2.969) which was chromatographed on silica eluted with 10% ethanol-ethyl acetate to give a pale yellow syrup (2.049). This was dissolved in hot ethanol (5cm3), acidified with ethanolic HCl, diluted with ethyl acetate (20cm3) and cooled. After several hours, the precipitated crystals were filtered, washed with ethyl acetate and dried at 600/100mum to give the title compound as the hydrochloride (2.259), colourless microplates, m.p. 224-2260(dec).

Claims: CLAIMS 1. A benzoquinolizine of the general formula EMI21.1 or a pharmaceutically acceptable acid addition salt thereof, wherein R7 is lower alkyl or a phenyl or naphthyl radical optionally substituted by one or more lower alkyl, lower alkoxy or halogen substituents and R8 is methyl or ethyl. 2. A compound according to Claim 1 wherein R8 is methyl. 3. N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a]- quinolizin-2ss-yl)methanesulphonamide or a pharma ceutically acceptable acid addition salt thereof. 4. N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a] quinolizin-2e-yl)propan-1-sulphonamide or a pharmacautically acceptable acid addition salt salt thereof. 5. N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a] quinolizin-2P-yl)benzenesulphonamide or a pharmaceut ically acceptable acid addition salt thereof. 6. N-Methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a] quinolizin-2p-yl)ethanesulphonamide or a pharmaceuti cally acceptable acid addition salt thereof. 7. A compound according to Claim 1 which is N-ethyl-N (1,3,4,6,7,11ba-hexahydro-2H-benzo[a]quinolizin-2,8- yl)methanesulphonamide, N-methyl-N-(1,3,4,6,7,11ba- hexahydro-2H-benzo[a]quinolizin-2-yl)toluene-4 sulphonamide,N-methyl-N-(1,3,4,6,7,11ba-hexahydro-2H- benzo[a]quinolizin-2,ss-yl)-4-methoxybenzenesulphona- mide, N-methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo [a]quinolizin-2ffi-yl)-4-chlorobenzenesulphonamide, N-methyl-N-(1,3,4,6,7,11b&alpha;-hexahydro-2H-benzo[a] quinolizin-2(3-yl) -2-methylbenzenesulphonamide, N-methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a] quinolizin-2ss-yl)-3,4-dichlorobenzenesulphonamide or N-methyl-N-(1,3,4,6,7,11b&alpha; ;-hexahydro-2H-benzo[a] quinolizin-2ss-yl)-n-butanesulphonamide or a pharmaceutically acceptable acid addition salt thereof. 8. A process for preparing a compound claimed in any one of Claims 1 to 7 which comprises reacting a reactive derivative of a sulphonic acid of general formula (III) R7SO20H (III) where R7 is as defined in claim 1, with 2B-ethylamino or -methylamino - 1,3,4,6,7,lIba- hexahydro-2H-benzo[a]quinolizine and, if required, converting a free base into a pharmaceutically acceptable acid addition salt. 9. A pharmaceutical composition having presynaptic a-adrenoceptor antagonistic activity comprising a benzoquinolizine of the formula EMI24.1 or on a pharmaceutically acceptable acid addition salt thereof, wherein R7 is lower alkyl or a phenyl or naphthyl radical optionally substituted by one or more lower alkyl, lower alkoxy or halogen substituents 8 and R is methyl or ethyl, in association with a pharmaceutically acceptable carrier. 10. A compound as claimed in any one of claims 1 to 7 for use in antagonising presynaptic a-adrenoceptors in warm blooded animals. CLAIMS FOR AUSTRIA 1. A process for preparing a benzoquinolizine of the general formula EMI25.1 or a pharmaceutically acceptable acid addition salt thereof, wherein R7 is lower alkyl or a phenyl or naphthyl radical optionally substituted by one or more lower alkyl, lower alkoxy or halogen substituents and R8 is methyl or ethyl, which comprises reacting a reactive derivative of a sulphonic acid of general formula R7SO,OH (III) where R7 is as defined above with 2-ethylamino or methylamino-1,3,4,6,7,11bo-hexahydro-2H- benzoquinolizine and, if required, converting a free base into a pharmaceutically acceptable acid addition salt. 2. A process as claimed in Claim 1 wherein the reactive derivative of the sulphonic acid is an acid halide or anhydride. 3. A process for preparing a pharmaceutically acceptable acid addition of a benzoquinolizine of general formula (II) as defined in claim 1 which comprises reacting the base of general formula (II) with an inorganic or organic acid. 4. A process according to any one of Clays 1 to 3 wherein the product is N-methyl-N-(1,3,4,6,7,11ba-hexahydro 2H-benzo[a] quinolizin-2ss-yl)methanesulphonamide or a pharmaceutically acceptable acid addition salt thereof. 5. A process according to any one of Claims 1 to 3 wherein the product is N-methyl-N-(1,3,4,6,7,11ba- hexahydro-2H-benzo[a]quinolizin-2p-yl)propan-1- sulphonamide or a pharmaceutically acceptable acid addition salt thereof. 6. A process according to any one of Claims 1 to 3 wherein the product is N-methyl-N-(1,3,4,6,7,11ba- hexahydro-2H-benzo[a]quinolizin-2p-yl)benzenesulphona- mide or a pharmaceutically acceptable acid addition salt thereof. 7. A process according to any one of Claims 1 to 3 wherein the product is N-methyl-N-(1,3,4,6,7,11ba hexahydro-2H-benzo[agquinolizin-2ss-yl)ethane- sulphonamide or a pharmaceutically acceptable acid addition salt thereof. 8. A process according to any one of Claims 1 to 3 wherein the product is N-ethyl-N-(1,3,4,6,7,11ba- hexahydro-2H-benzo[a]quinolizin-2p-yl)methane- sulphonamide, N-methyl-N-(1,3,4,6,7,11b&alpha;-hexahydro- 2H-benzo[ a] quinolizin-2 P-yl) toluene-4-sulphonamide, N-methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a] quinolizin-2ss-yl)-4-methoxybenzenesulphonamide, N-methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a] quinolizin-2B-yl) -4-chlorobenzenesulphonamide, N-methyl-N-(1,3,4,6,7,11b&alpha;-hexahydro-2H-benzo[a] quinolizin-2ss-yl)-2-methylbenzenesulphonamide, N-methyl-N-(1,3,4,6,7,11b&alpha; ;-hexahydro-2H-benzo[a] quinolizin-2iyl)-3,4-dichlorobenzenesulphonamide or N-methyl-N-(1,3,4,6,7,11ba-hexahydro-2H-benzo[a] quinolizin-2P-ylfn-butanesulphonamide or a pharmaceutically acceptable acid addition salt thereof. 9. A process for preparing a pharmaceutical composition having presynaptic a-adrenoceptor antagonistic activity which comprises bringing into association with a pharmaceutically acceptable carrier a benzoquinolizine of the formula EMI28.1 or a pharmaceutically acceptable acid addition salt thereof, wherein R7 is lower alkyl or a phenyl or naphthyl radical optionally substituted by one or more lower alkyl, lower alkoxy or halogen substituents and R8 is methyl or ethyl. 10. A process as claimed in Claim 9 wherein the benzoquinolizine of formula (II) or the pharmaceuti cally acceptable acid addition salt thereof is prepared by a process claimed in any one of Claims 1 to 3.

Inventors: ARCHIBALD, JOHN LEHEUP, WARD, TERENCE JAMES
Applicants: JOHN WYETH & BROTHER LIMITED
Application year: 1981
Main classification: C07D455
IPC codes: C07D455