GB2134108A - Benzoquinolizines - Google Patents

Abstract

The invention concerns benzoquinolizines of general 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 hydrogen or lower alkyl and R<4> represents a heterocyclic radical attached to the SO2 group through a carbon atom of the heterocyclic ring. The compounds possess alpha 2-adrenocoptor antagonistic activity in warm blooded animals, and are useful as antidepressants, in the treatment of diabetes and in inhibiting blood platelet aggregation.

Description

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

The present invention provides benzoquinolizines of the general formula (I)

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 or lower alkyl and R4 represents a heterocyclic radical attached to the SO2 group through a carbon atom of the heterocyclic ring.

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.

Examples of R1 and R2 are hydrogen, lower alkyl such as methyl, ethyl, propyl or butyl, lower alkoxy such as methoxy, ethoxy, propoxy or butoxy or halogen such as chlorine, fluorine or bromine. R1 and R2 can be different or the same. Preferably, both R' and R2 are hydrogen.

R3 can be hydrogen or lower alkyl such as methyl, ethyl, propyl or butyl. Preferably R3 is lower alkyl, particularly methyl.

The R4 heterocyclic radical can be aromatic or non-aromatic. Preferably the heterocyclic radical is a mono or bicyclic heterocyclic group, which may be substituted or unsubstituted. The heterocyclic group may, for example, contain 1 or 2 hetero ring atoms, particularly nitrogen, oxygen or sulphur.

Preferably the ring or each ring of the mono or bicyclic heterocyclic group contains 5 or 6 ring atoms (including the hetero atoms). The heterocyclic group may be substituted by one or more substituents.

For example, the substituents may be selected from the group consisting of halogen (e.g. chlorine, fluorine or bromine), lower alkoxy (e.g. methoxy, ethoxy, propoxy or butoxy), lower alkyl (e.g. methyl, ethyl, propyl or butyl), alkylene-dioxy (e.g. methylenedioxy or ethylenedioxy), amino, loweralkylamino, diloweralkylamino, trifluoromethyl, carbamoyl, phenyl and phenyl substituted by one or more of those substituents mentioned immediateiy above in connection with heterocyclic group. Examples of heterocyclic radicals R4 include substituted and unsubstituted quinoline, furan, thiophene, imidazole, pyridine, piperidine, pyrrolidine, indolyl and 1 ,2,3,4-tetrahydroquinoline.

The compounds of the invention can be prepared by a process in which an amine of general formula (II)

or an acid addition salt thereof (where R', R2 and R3 have the meanings given above) is reacted with a reactive derivative of a sulphonic acid compound of general formula (III) R4SO2OH (Ill) (where R4 is as defined above) and, if required, converting a free base into a pharmaceutically acceptable acid addition salt. The reactive derivative of the sulphonic acid compound of general formula (Ill) can be, for example, the acid halide or anhydride. Preferably it is the halide, i.e. a compound of general formula R4SO2X (where R4 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 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 compounds.

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

The reactive derivatives of the sulphonic acid compound of general formula (Ill) are known compounds or they can be prepared by methods known in the art for preparing analogous compounds.

Processes for preparing the amines of general formula (II) are described in UK Patent Specification 1,513,824.

The compounds of the invention possess two asymmetric carbon atoms and hence they 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 (II) is a mixture of isomers the product of formula (I) will also be a mixture of isomers which can be separated, if required, by standard procedures. If the starting material is a single isomer then the product will also be a single isomer. Preferably the starting material of formula (II) is of the 2,B-NHR3-1,3,4,6,7,11 ba-hexahydrnconfigurntion.

The compounds of the invention possess pharmacological activity. For example the compounds are useful as antidepressants, in treatment of diabetes and in inhibiting blood platelet aggregation as evidenced by their a2-adrenoceptor antagonistic activity in warm blooded animals when tested by standard pharmacological test procedures.

The compounds of the invention were tested for 2-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 vas deferentia from sexually mature rats were suspended in a 6ml 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 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-'.

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 8 Schild, Br.J.Pharmac.

Chemother., 1 959, 14, 48--58 and the values of pA2 and slope were calculated. It was found, for example, that N-methyl-NA 1,3,4,6,7,11 ba-hexahydrn-2N-benzo[ajquinolizin-2-yl)quinoline-8- sulphonamide and N-methyl-NA 1,3,4,6,7,11 ba-hexahydrn-2H-benzo[a]quinolizin-2-yl-3-pyridine- sulphonamide, representative compounds of the invention, had pA2 values of 8.46 and 8.22 respectively.

The compounds of the invention, in general, antagonise the a2-adrenoceptors to a greater extent than the a1-adrenoceptors. The , antagonistic activity can be evaluated by a method based on that of Gillespie, Br. J. Pharmac., 1972,45, 4041 6. In the procedure male rats (250--3609) are killed by a blow on the head and bled. 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 suspensed 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 370C.

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 cz, alpha adrenoceptor agonists. The concentration range of phenylephrine or methoxamine used in 0.02 to 0.8 yg.ml-'. The agonist is then washed from the bath and the test drug added to the bathing medium at a concentration of 10-6M. After 30 min. equilibration with the test drug a further agonist does response curve is obtained. The washing, equilibration and agonists dosing procedures are then repeated using 10-5M and 1 0-4M 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 8 Schild, Br.J. Pharmac. Chemother., 1959, 14, 48-58. The pA2 for a1 antagonistic activity and the lye2/ selectivity ratio for N-methyl-N (1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinolizin-2,B-yl) quinoline-8-sulphonamide are respectively 6.84 and 42 and for N-methyl-N-(1,3,4,6,7,1 lba-hexahydro-2H-benzo[aj quinolizin-2P-yl)-3-pyridine- sulphonamide are respectively 6.73 and 31.

Some of the compounds of the invention, for example, N-methyl-NA 1,3,4,6,7, 11 ba-hexahydro- 2H-benzo[a] quinolizin-2,B-yl)-3-pyridinesulphonamide and N-(1,3,4,6,7,11ba-hexahydro-2H- benzo[a]quinolizin-2p-yl)pyridine-3-sulphonamide, also possess antihypertensive activity as determined by standard pharmacological test procedures in hypertensive rats.

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 includes 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 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 suspensed 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 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-dividad 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, 11ba-hexahydro-2H-benzo[a]quinolizin-2,B-yl)quinoline-8-sulphonamide An ice-cold stirred solution of 2p-methylamino-1,3,4,6,7,1 1 ba-hexahydro-2Hbenzo[a]quinolizine (2.1 6g) and triethylamine (1.29) in dichloromethane (25cm3) was treated with a suspension of 8-quinolinesulphonyl chloride (2.28 g) in dichloromethane (25cm3). The clear solution was kept at room temperature for 8 days, washed with water and brine and dried (MgSO4). Filtration and evaporation gave a yellow syrup which slowly crystailised from ethanol. The pale cream crystals were suspended in hot ethanol, acidified with ethanolic HCI and the clear solution cooled.The crystals which separated were triturated well with ethanol containing a little ethanolic HCI, collected by filtration and dried at 800/1 OOmm to give the title compound as the monohydrochloride, hydrate (3.00g), colourless crystals, m.p. 176-181 0(dec).

Example 2 N-Methyl-N-( 1,3,4,6,7,11 bce-hexahydro-2H-benzo[a]quinolizin-2}s-yl)-2-carbamoylfuran-4- sulphonamide An ice-cold stirred solution of 2p-methylamino-1,3,4,6,7,1 1 ba-hexahydro-2Hbenzo[a]quinolizine (0.57g) and triethylamine (0.4g) in dichloromethane (15cm3) was stirred as a solution of 2-carboxamidofuran-4-sulphonyl chloride (0.55g containing a little of the 5-sulphonyl chloride) in dichloromethane (15cm3) was added slowly. The dark, clear solution was kept at room temperature for 3 days, washed with water (2x50cm3) and dried (MgSO4). Filtration and evaporation gave a pink glass (0.879) which was chromatographed on silica eluted with 520% ethanol-toluene.

The main fraction was a pale yellow solid (0.49) which was dissolved in ethanol, acidified with ethanolic HCI and cooled. The crystals which separated were triturated with boiling ethanol/water to give the title compound as the hydrochloride (0.309), as pale cream crystals, m.p. 258-2620(dec), contaminated with a little of the 5-sulphonamide isomer.

Example 3 N-Methyl-N-(1,3,4,6,7,11 b-hexahydro-2H-benzo[a]quinolizin-2 -yl) thiophenv2-sulphonamide An ice-cold, stirred solution of 2-methylamino-1 ,3,4,6,7,1 1 ba-hexahydro-2H benzo[a]quinolizine (2.089) and triethylamine (1.2g) in dichloromethane (25cm3) was treated with a solution of 2-thiophenesulphonyl chloride (1.76g) in dichloromethane (25cm3). The clear solution was kept at room temperature for 4 days, washed with water and brine and dried (MgSO4).Evaporation gave an orange syrup which was chromatographed on silica eluted with 10% ethanol-ethyl acetate to give a red-brown syrup (2.189) which was taken up in hot ethanol (10cm3), acidified with ethanolic HCI, diluted with ethyl acetate (25cm3) and cooled to give crystals which were collected by filtration, washed well with ethyl acetate and dried to give the title compound as the hydrochloride (1.60g), pale buff crystals, m.p. 220--30 (dec).

Example 4 N-Methyl-N-(1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinolizin-2p-yl)-2-(3,4-dichloro- phenyl )imidazole-4-sulphonamide An ice-cold, stirred solution of 2P-methylamino-l .3,4,6,7,1 1 ba-hexahydro-2Hbenzo[a]quinolizine (2.169) and triethylamine (39) in dichloromethane (25cm3) was treated with crude 2-(3,4-dichlorophenyl)imidazole-4-sulphonyl chloride (4.49). The dark solution was kept at room temperature for 3 days, washed with water and brine and dried (MgSO4). Evaporation gave a dark syrup which was chromatographed on silica eluted with 10% ethanol-ethyl acetate to give a yellow glass (1.69g). This was dissolved in hot ethanol (10cm3), acidified with ethanolic HCI and cooled.The crystals which separated were collected by filtration, then triturated with boiling ethanol (15cm3) and water (3cm3) cooled and refiltered to give the title compound as the hydrochloride (1.199), pale cream crystals, m.p. 245--2500 (decomp) (decomp. begins above 2200).

Example 5 N-Methyl-N-(1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinoIizin-2yl)-3-pyridine sulphonamide (A) Preparation of pyridine-3-sulphonyl chloride A mixture of pyridine-3-sulphonic acid (3.09) and PCl5 (7.99) was stirred in an oil bath maintained at 1 500 for 3 hours, in a flask fitted with a reflux condenser. After cooling, the liquid formed set solid.

The solid was triturated with xylene (10cm3) and evaporated at the water pump in an oil-bath maintained at a maximum temperature of 1100, and with a splash-head to reduce frothing. The evaporation was repeated twice more, and the residue was pumped on a rotary evaporator to remove the last traces of xylene. The yellow, semi-crystalline mass (6.879) occluded unreacted OILS.

The crude product was used at once in the procedure of Example 5(B) below.

(B) Preparation of N-methyl-N-(1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinolizin-2pyl)-3- pyridinesulphonamide An ice-cold, stirred solution of 2,B-methylamino-1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinolizin (1.80g) and triethylamine (2.0g) in dichloromethane (25cm3) was treated with a suspension of crude pyridine-3-sulphonyl chloride (1.5g) in dichloromethane (15cm3). The clear solution was kept at room temperature for 6 days, washed with water (2x50cm3) and dried (MgSO4). Filtration and evaporation gave a dark red syrup (2.749) which was chromatographed on silica eluted with 10% ethanol-ethyl acetate to give a yellow syrup (1.61 g) which crystallised on standing.The solid was dissolved in hot ethanol (5cm3), acidified with ethanolic HCI, diluted with ethyl acetate (10cm3) and cooled. The sticky, pink crystals which separated were recrystallised from ethanol, filtered and dried to give the title product as the monohydrochloride, hemihydrate (1.019), pale pink, hygroscopic crystals, m.p.

1 55-1 900 (dec).

Example 6 N-( 1,3,4,6,7,11 b-hexahydro-2H-benzo[a] quinolizin-2/3-yl)pyridine-3-sulphonamide An ice-cold, stirred solution of 2p-amino-1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinolizine (3.8g) and triethylamine (2.59) in dichloromethane (50cm3) was treated with a suspension of freshlyprepared pyridine-3-sulphonyl chloride (0.0188M) in dichloromethane (25cm3). The mixture was stirred at room temperature for 2 hours, then the clear solution kept for 2 days. It was then washed with water and brine, and dried (MgSO4). Filtration and evaporation gave a dark syrup (3.479) which was chromatographed on silica eluted with 10% ethanol-ethyl acetate, to give a yellow solid (2.379).

This was triturated with boiling ethanol (10cm3), cooled in ice and filtered to give the title compound as colourless crystals.

The base was taken up in boiling ethanol, strongly acidified with ethanolic HCI, diluted with ethyl acetate and cooled. Crystals formed from the clear solution over 2-3 days; these were filtered off and washed well to give the title compound as the hydrochloride (1.32 g) colourless crystals, m.p. 225- 231O (dec).

Claims (15)

Claims

1. A benzoquinolizine of the general formula (I)

or a pharmaceutically acceptable acid-addition salt thereof, wherein R1 and R2 which may be the same or different each represent hydrogen, lower alkyl, lower alkoxy or halogen, R3 represents hydrogen or lower alkyl and R4 represents a heterocyclic radical attached to the SO2 group through a carbon atom of the heterocyclic ring.

2. A compound according to Claim 1 wherein R4 is a mono or bicyclic heterocyclic group in which the ring or each ring of the mono- or bicyclic heterocyclic group contains 5 or 6 ring atoms.

3. A compound according to Claim 1 wherein R4 is a substituted or unsubstituted quinoline, furan, thiophene, imidazole, pyridine, piperidine, pyrrolidine, indolyl or 1 ,2,3,4-tetrahydroquinoline radical.

4. N-Methyl-N-(1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinolizin-2jB-yl)quinoline-8- sulphonamide or a pharmaceutically acceptable acid addition salt thereof.

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

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

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

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

9. N-(1,3,4,6,7,1 N-(1,3,4,6,7,11 ba-hexahydro-2H-benzo[a]quinoIizin-2-yl)pyndine-3-sulphonamide or a pharmaceutically acceptable acid addition salt thereof.

10. A process for preparing a compound claimed in Claim 1 which comprises reacting an amine of general formula (II)

or an acid addition salt thereof (where R1, R2 and R3 are as defined in Claim 1) with a reactive derivative of a sulphonic acid compound of general formula (III) B4SO2OH (III) (where R4 is as defined in Claim 1) and, if required, converting a free base into a pharmaceutically acceptable acid addition salt.

11. A process as claimed in Claim 10 wherein the reactive derivative of the sulphonic acid compound is an acid halide or anhydride.

12. A process for preparing a compound claimed in Claim 1 substantially as hereinbefore described with reference to any one of Examples 1 to 6.

13. A compound whenever prepared by the process claimed in any one of Claims 10 to 12.

14. A pharmaceutical composition comprising a compound claimed in any one of Claims 1 to 9 and 13 in association with a pharmaceutically acceptable carrier.

15. A compound as claimed in any one of Claims 1 to 9 and 13 for use in an antagonising CE2- adrenoceptors in warm blooded animals.