GB2163155A - Thieno2,3-a quinolizin-9-yl sulphonamides - Google Patents

Description

1

SPECIFICATION

Thienoquinolizines GB 2 163 155 A - 1 The invention relates to thienoquinolizin.es, to processes for preparing the thienoquinolizines, to their use 5 and to pharmaceutical compositions containing them.

The novel compounds of the present invention are thienoquinolizines of the general formula (1) R "-,,so 2 R 2 (I) and their pharmaceutically acceptable acid addition salts, where R, is hydrogen or lower alkyl and R2 is lower alkyl, haloflower)alkyl, -A-NR3R4 [where 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 and R3 and R4 each independently represent hydrogen, lower alkyl, aryl or aryl(lower)alkyl or together with the nitro- 20 gen atom to which they are attached represent a five or six membered heterocyclic ring], aryl or a heterocyclic radical or R1 is -A'NR5.SO,R6 [where A' is a lower alkylene group having 1 to 3 carbon atoms in the chain between the two N atoms, R5 is hydrogen or lower alkyl and R6 is lower alkyl, halo(lower)alkyl or aryl] and R2 is lower alkyl halo(lower)alkyl or aryl.

The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Pref- 25 erably such radicals contain 1 to 4 carbon atoms. For example, a lower alkyl group may be methyl, ethyl, propyl or butyl (e.g. i-butyl).

When A represents 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. Similarly, the lower alkylene group A' has 1 to 3 carbon atoms between the two N atoms. For example, the lower alkylene group A 30 and A, may be methylene, ethylene, trimethylene or a branched chain group such as ethylethylene or propylene [-CH(CHj.CH,-j.

When a radical is referred to as "aryl" that radical is preferably a phenyl or substituted phenyl group.

The substituted phenyl group can be a phenyl group substituted by one or more substituents chosen from, for example, halogen (e.g. chlorine, fluorine or bromine), alkoxy (e.g. lower alkoxy such as meth- 35 oxy or ethoxy), lower alkyl (e.g. methyl, ethyl, propyl or butyl), alkylenedioxy (e.g. methylenedioxy or ethylenedioxy), nitro, amino a cylamino (particularly lower acylamino), lower alkylamino, diloweralkylam ino or trifluoromethyl.

A halo substituent in a halo (lower)al kyl group may be fluorine, chlorine, bromine or iodine. More than one halo atom may be present in the halo(lower)alkyl group; if more than one halo atom is present the 40 halo atoms may be on the same carbon atom of the (lower)alkyl radical or on different carbon atoms (if the radical contains more than one carbon atom). Examples of halo(lower)alkyl groups include, for exam ple, trifluoromethyl and chloromethyl.

When R2 is a heterocyclic radical the radical can be aromatic or nonaromatic. Preferably the hetero cyclic radical is a mono or bicyclic heterocyclic group, which may be substituted or unsubstituted. The 45 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 substi tuents. For example, the substituents may be selected from the group consisting of halogen (e.g. chlor ine, fluorine or bromine), lower alkoxy (e.g. methoxy, ethoxy, propoxy or butoxy), lower alkyl (e.g.

methyl, ethyl, propyl or butyl), alkylenedioxy (e.g. methylenedioxy or ethylenedioxy), amino, loweralky lamino, diloweralkylamino, trifluoromethyl, carbamoyl, phenyl and phenyl substituted by one or more of those substituents mentioned immediately above in connection with the heterocyclic group. Examples of heterocyclic radicals include substituted and unsubstituted quinoline, furan, thiophene, imiclazole, pyri dine, piperidine, pyrrolidine, indolyl and 1,2,3,4-tetrahydroquinoline.

Preferably in formula (1) R, is lower alkyl (particularly methyl or ethyl) and R2 is lower alkyl or option ally substituted phenyl. Other preferred compounds are those in which R, is -A'-NR5.So2R6 (where A' is preferably ethylene, R5 is preferably hydrogen and R6 is preferably lower alkyl) and R2 is lower alkyl.

2 GB 2 163 155 A 2 The compounds of the invention in which R' is hydrogen or lower alkyl can be prepared by a process in which an amine of general formula (11) a-- S N NHR1 10 where R' is hydrogen or lower alkyl or an acid addition salt thereof, is reacted with reactive derivative of a sulphonic acid compound of general formula (111) R2S020H (Ill) 15 (where R2 is as defined above) and, if required, converting a free base into a pharmaceutically acceptable acid addition salt. The.reactive derivative of the sulphoniG acid compound of general formula (111) can be, for example, the acid halide or anhydride. Preferably it is the halide, i. e. a compound of general formula R2S 02X (where R2 is as defined above and X is halogen, preferably chlorine). The reaction is Preferably 20 carried out under basic conditions, for example in the presence of a tertiary amine, e.g. triethylamine.

The reactive derivatives of the sulphonic acid compound of general formula (111) are known compounds or they can be prepared by methods known in the art for preparing analogous compounds.

The amine of general formula (11), in which R1 is hydrogen may be prepared from the ketone (IV) by the following procedure using known methods', reduction %SN oximation 7 CS S-N) S---- N 0 NOH NH2 (IV) - - M (VI) 35 The amine of general formula (11) in which R, is lower alkyl may be prepared from the ketone (R) by_ the following procedure using known methods:

(lower)alkyl-NH2 > N S:t N reduction 0 (IV) N(lower)alkyl e1 s- N VM) R(lower)alkyl (VII) 3 GB 2 163 155 A 3 The ketone of formula (IV) may be prepared by the following procedure:- %CN reduction (CH 2)2 NH2_ IF T\ IT 1.1 S S,.-, ethyl formate 5 ((IX) (X) (CH 2)2 NHCHO 10 e.g. PC1 cyclisation (n) (Xii) 15 methyl vinyl ketone - (iv) The above route for preparing ketone (IV) is exemplified in Example 1 (a) to (d), below.

Compounds of general formulae (11) and (R) are novel compounds which are also provided by the present invention.

Compounds of the invention in which R, is hydrogen or lower alkyl and R2 is -NIR3R4 may also be prepared by reacting the amine of general formula (11) with a sulphonamide derivative of formula R 3 R 4,--" N.SO 2 NH 2 (where R3 and R4 have the meanings given above).

Preferably both R3 and R4 are hydrogen, i.e. the compound is sulphamide.

Compounds of the invention in which R, is -Al-NRSS02R6 may be prepared by reacting a reactive deriv ative of the sulphonic acid compound of formula (111) in which R2 is the same as R6 and is lower alkyl, 35 halo(lower) alkyl or aryl, e.g. the acid halide, with a diamine of general formula 1 S _ N 40 (Mil) 1 5 NH.A. NHR (where A, and R5 are as defined above). The reaction may be carried out in a similar manner to the reaction of compound (11) with the reactive derivative of the sulphonic acid derivative (111).

The starting materials of general formula (XIII) may be prepared by reductive amination of the ketone 50 of general formula (IV). For example, the ketone (IV) may be reacted with a diamine of formula NH,-Al-NHR5 (XIV) (where A' and R5 have the meanings given above) and with a hydride transfer agent. When R5 in the diamine is a lower alkyl group it may be necessary to replace the hydrogen on the amino carrying the 55 lower alkyl substituent with a protecting group, and remove the protecting group after the reductive ami nation.

4 GB 2 163 155 A Compounds of the invention in which R' is -Al-NIR5SO2R6 may be prepared by other alternative meth- ods. For example, a thienoquinolizine of general formula (XV) 4 le N 5 S (XV) H A 1 NRSO 2 R 6 (wherein A', R and RI; have the meanings given above) may be reacted with a reactive derivative of the sulphonic acid of formula (111) above, in an analogous manner to that described above in connection with the reaction of the thienoquinolizine (XIII). The thienoquinolizine (XV) may be prepared by known methods. For example the thienoquinolizine of formula (XIII) may be selectively sulphonated with the reactive 15 derivative of the sulphonic acid (111) using the requisite amount of reactive derivative for forming the monosulphonamide (XV) rather than the disulphonamide: it may be necessary to block one of the amine groups in the diamine (XIV) with a protecting group and remove the protecting group after the sulphonation. The thienoquinolizine (XV) alternatively may be prepared by reductive amination of the ketone (IV) with an amine NHAINRSO,R6 (where A,, R and R6 have the meanings given above) and a hydride trans- 20 fer agent such as Sodium borohydride.

Another method of preparing the compounds of the invention in which R, is -A,-NR5SO,Re comprises reaction of a thienoquinolizine of general formula S: 25 (XVI) 30 AO 2 A NH 2 (where A' and R2 are as defined above) with an appropriate reactive derivati,-f; of the sulphonic acid of formula (111) in an analogous manner to that described above in connection with the reaction of the thien- 35 oquinolizine (Xlif). The thlenoquinolizine starting material of formula (XVI) may be prepared by methods known per se. For example, a thienoquinolizone of general formula - - / 1 40 CO, si N 2 YO (XVII) R SO- i 2 45 (where R2 has the meaning given above) may be reacted with a phthalimido protected haloamine of formula 0 50 Y-Al -N (XVIII) (where A1 has the meaning given above and Y is halogen, preferably bromine) in presence of a strong 55 base such as sodium hydride or lithium diisopropylamide and the phthalimido protecting group re moved.

Yet another method of preparing the compounds of the invention in which R, is -A'-U5SO,R6 com prises reaction of a thienoquinolizine of formula (XVII) above with a compound of formula X-Al-NRSO,R6 (XIX) (where X, A' and R6 are as defined above) in presence of a strong base such as sodium hydride or lith!urn diisopropylamide.

If in the processes described above the compound of the invention is obtained as an acid addition salt, 65 GB 2 163 155 A 5 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 5 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 ptoluenesulphonic 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 (e.g. of formula 11) is a mixture of isomers the product of formula (1) 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 - NC).SO,R2 group is the equatorial position, i.e. compounds of the general formula <S N H 1 2 N(R).50 2 R (M) 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. Resolution of a racemic final product or intermediate may be carried out by known procedures so as to give the product as an optically active enantiomorph.

The compounds of the present invention possess pharmacological activity. For example, the com pounds, in general, possess O2-adrenoceptor antagonistic activity in warm blooded animals and hence are of value in conditions where antagonism of the u.-adrenoceptor is desirable, for example, as antide- 30 pressants, in treatment of diabetes and in inhibiting blood platelet aggregation.

The compounds of the invention are tested for %-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 cleferentia from sexually mature rats were suspended in a 6 ml organ bath in Krebs 35 solution at 37' and bubbled with 50/0 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 supra maximal voltage. Twitch responses were recorded isotonically with a 0.5 g loading. Clonidine hydrochlo ride was used as the (x-adrenoceptor agonist and cumulative concentration- response curves were constructed for th inhibition of twitch obtained with clonicline in the range 0.125 to 4 ng ml-1. After washing out clonicline, the twitch response quickly recovered and an antagonist was then introduced into the Krebs reservoir. Cionicline concentration-response curves were repeated 90 min after introduction of the antagonist. The concentration of clonidine'producing 50% inhibition of twitch before and after intro duction of antagonist were obtained and the dose-ratio for clonicline was calculated, Various concentra tions of the antagonists were used.

These results were plotted in the manner described by Arunlakshana & Schild, Br.J.Pharmac. Chemo ther., 1959, 14, 48-58 and the value of pA, and slope were calculated. The compounds of the invention possess potent 0-2-adrenoceptor antagonistic activity. For example, N-(4, 5,8,9,10,10aa-hexahydro-7Hthieno[2,3-alquinolizin-9p-yl)-N-methyl-propanesulphonamide and N-(4,5,8, 9ot,10,10au--hexahydro-7H50thieno[2,3-alquinolizin-9-yl)-N-(2-ethanesulphonamidoethyl)ethanesulphona mide, representative com- 50 pounds of the invention, have been found to have a pA2 for %-adrenoceptor antagonistic activity of 7.5 and 7.31 respectively.

The compounds of the invention generally antagonise the %-adrenoceptors to a much greater extent than the a-l-adrenoceptors. The a-, antagonistic activity can be evaluated by a number of different meth ods. 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., 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 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% CO, mixture and maintained at 37'. Longi- 60 tudinal 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 0.81.Lg,ml-1. 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 dose response 65 6 GB 2 163 155 A 6 curve is obtained. The washing, equilibration and agonists dosing procedures are then repeated using 10-M and 10-M solutions of the test drug. Estimates of the pA, 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 pA, values for (xl antagonistic activity for N-(4,5,8,9,10,10a(y.hexahydro-7H-thieno[2,3-alquinolizin9p-yl)-N -methyl p ropan esu 1 pho nam ide and N-(4,5,8,9u-,10,10a(x-hexahydro-7H-thieno[2,3-alquinolizin-9yi)N-(2-ethane-sulphonamidoethyi)ethane sulphonamide have been found to be 5.9 and 5.18 respectively and the eL,Iot, selectivity [i.e.. antilog of (%pA2-(xpAJ1 for these compounds are respectively 40 and 132. The compounds show selectivity towards the (Y2 receptors.

The invention further provides a compound of formula (1) or a pharmaceutically acceptable acid addi- 10 tion salt for use in antagonising %-adrenoceptors in a mammal.

Compounds of the invention in which R, is hydrogen are useful as anti hypertensive agents.

The invention also provides a pharmaceutical composition comprising a compound of general formula (11) or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical ly ac ceptable carrier. Any suitable carrier known i n the art can be used to prepare the pharmaceutical compo- 15 sition. 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 gelatine cap sules), 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, compres sion aides, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders 20 the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tab lets the active ingredient is mixed with a carrier having the necessary compression properties in suitable prop-ortions.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, tale, sugars, lactose, dextrin, starch, gelatin., celiu- 25 lose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrro Ii dine, low melting waxes and ion exchange resins.

The term "composition" is intended to include the formulation of an active ingredient with encapsulat ing 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 phar maceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharma ceutically 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 40 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 adminis tered intravenously. When the compound is orally active it can be administered orally either in liquid or 45 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 ingredi ent; the unit dosage forms can be packaged compositions, for example packeted powders, vials, am poules, 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 i nvention 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

4,5,8,9, 10, 10a(x-Hexahydro-9p-methylamino-7H-thieno [2,3-al-quinolizine (a)- A solution of thiophene-3-acetonitrile (25 g) in THF (150 mL) was treated with IM, BHJHF (340 60 mL) and stirred at room temperature under argon for 3 hours. The reaction was worked up by the addi tion of water followed by 6MI-IC1 and stirred for - 112 hour. The THF was evaporated off, the residue basified and extracted into dichloromethane, dried (Na,S04) and evaporated to an oil. The oil was sub jected to acid-base extraction followed by azeotroping with toluene. Yield 10 9.

(b) The amine from step (a) (10 g) was heated under reflux in ethyl formate for 4 hours. The reaction 65 7 GB -2 163 155 A 7 mixture was evaporated to an oil and distilled b.p. 200-205' at 3mbar. Yield 9.5 g.

(c) The formamide from, step (b) (9 g) in dry, ethanol free chloroform (100 mL) was added dropwIse over a period of 90 mins to a solution of phosphorus pentachloride (12.1 g) in dry chloroform (120 mL) at room temperature under argon. After 3 hours the reaction was poured on to 2M sodium hydroxide, ex5 tracted into dichloromethane, dried (Na,SOJ and evaporated to an oil. Yield 4 g.

(d) The dihydrothienopyridine from step (c) (4 g) in dichloroethane (50 mL) was treated with gaseous HCI for 30 mins.. Methyl vinylRetone (2.6 mL) was added slowly to a stirred reaction mixture at reflux under argon. After 1 hour the addition was completed, the reaction mixture allowed to cool to room temperature, filtered, washed with acetone and dried. Yield 4,8 g.

(e) A fine suspension of the ketone from step (d) (4.7 g) in 2-propanol (50 mL) under argon was 10 treated with 33% Solution of methylamine in ethanol (6.9 mL) over 15 min. with ice.-water cooling (temp 10-15'C). After stirring for a further 2 hours, sodium hydroxide (1.55 g) was added, followed by sodium borohydride (1.2 g) portionwise over 1 hour. The reaction was stirred for 1 hour at about 100C then worked up by removal of half the isopropanol at reduced pressure, dilution with water (50 mIL) followed by extraction into dichloromethane. The extract was washed with water, dried (Na,SOJ and evaporated 15 to an oil (4.2 g). The oil was dissolved in Et,01PA and treated with ethereal HCL The resulting oil was stirred until crystalline, filtered, recrystailised from IPA then triturated with CH,Cl\1 yielding 2 g of the title compound as the dihydrochloride, m.p. 240-2:dgC. The residues were chromatographed on SiO, (10% MeOH, 1% NH, 89% CHQ,) yielding further 1 9 of title base.

Analysis: Found: C, 47.2; H, 7.1; N, 9.0% C121-11,,N2S1/21-120 requires: C, 47.4; H, 7.0; N, 9.2%.

EXAMPLE2

N-(4,5,8,9, 10, 10a(x-hexahydro-7H-thieno[2,3-aj quinolizin-9p-yl)-Nmethylpropenesulphonamide n-Propane sulp honylch lo ride (0,76 g) in dichioromethane (8 mL) was added dropwise to a stirred solu tion of 4,5,8,9, 10,10au--hexahydro-9p-methylamino-7H-thieno[2,3aj quinolizine (1.18g) in dichiorome thane (5mL). After 3 hours at room temperature the reaction mixture was washed with 2M sodium hydroxide (2 x 5 mL) dried (Na,SOJ and evaporated to an oil which crystallised after chromatography on basic alumina/diethyl ether. The product was converted to the crystalline tosylate salt, 1.4g, m.p. 176- 30 177'C.

Analysis:

Found: C, 52.0; H, 6.1; N, 5.4% C1,1-124N202S2. C7H,SO,H1/2H20 requires: C, 51.9; H, 6.3; N, 5.4%.

EXA MPL E 3 M(4,5,8j9, 10, 10aa-hexahydro-7H-thieno[2,3-al quinolizine-9p-yl)N,2- dimethylpropanesulphonamide 2-Methyl propane sulphonyl chloride (0.21 g) in dichloromethane (1 mIL) was added dropwise to a stirred solution of 4,5,8,9.10,10aa-hexahydro-9p-methylamino-7H-thieno[2, 3-alquinolizine (400 mg) in dichforomethane (5 mL). After 2 hours at room temperature the reaction mixture was washed with 2M 40 sodium hydroxide solution, dried (Na,SO:i4), evaporated to an oil and purified by chromatography on siiica/Et20. The product was converted to a tosylate salt yield 230 mg, m. p. 212-2130C.

Analysis:

Found: C. 53.6; H, 6.6; N, 5.3% C16H2,N2S202 C,H,S0,1-1 requires: G, 63.7; H, 6.6; N, 5.4% EXAMPLE 4

N-(4,5,8,9, 10, 10aahexahydro-7H-thienyl[2,3-a1 quinolizin-9p-yl)-Nmethyl sulphamide 4,5,8,9,10,10au--Hexahydro-gp-methylamino-7H-thieno [2,3-alquinolizine (530 mg) and sulphamide (600 mg) were heated under reflux for 24 hours. The solvent was removed under reduced pressure leaving a 50 crystalline solid which was washed with water, and converted to the hydrochloride and recrystallised from 2-propanol affording 810 mg, m.p. 208-209'C.

Analysis:

Found: C, 42.2; H, 6.0; N, 12.0% C121-1,,N.02S2 requires: C, 42.2; H, 5.8; N, 12.3%.

EXA MPL E 5 N-(4,5,8,9ot, 10, 10au--Hexahydro-7H-thieno[2,3-a] quinolizin-9-yl)-N- (2ethanesulphonamidoethyl)ethane sul phonamide (a) The ketone from Example ld, (0.879) in isopropanol (1OmL) was treated with ethylenediamine 60 (1.4mL) in ethanoi (2mL) at O'C. Sufficient ethereal HCi was added to bring the pH to 8. After 24 hours tic (ROAc/Si0J shows no starting material remains. Solid NaOH (0.25g) was added followed by NaBH4 (0.359) portionwise over - 1 hour. After 3 hours the solvent was removed and the product partitioned between dichloromethane and water. The organic phase was separated, dried (Na,S04) and evaporated to an oil.

8 GB 2 163 155 A 8 Yield 0.59.

(b) The diamine from Example 5a, in-CH3CN (3.5mL) containing triethylamine (0.55mL) was treated very slowly over 20 hours with ethanesulphonylchloride (0.519) in acetonitrile (10mIL). One hour after the addition was complete the solvent was evaporated off and the residue partitioned between dichforome- thane, and water. The organic phase was separated, dried (Na,SOJ and evaporated to an oil (0.79). The obtained monosuIphonamide was used crude in the next stage.

(c) The crude product from Example 5(b) (0.7g) in acetonitrile (1OmL) containing triethylamine (0.28mL), was treated with ethanesulphonylchloride (0.25g) in acetonitrile (4mL) over 5-10 mins. After standing for 10 mins at room temperature absolute ethanol (91mg) was added and the reaction allowed to stir for 5- mins. The solvent was evaporated off, the residue dissolved in chloroform and washed with a 10 saturated sodium bicarbonate solution. The organic phase was dried (NaSO,,), evaporated down and dissolved in ethyl acetate and filtered through neutral Al,Q, The eluent was stirred with charcoal, filtered and evaporated to give the title compound as an oil which was converted to the acid maleate salt in ethylacetate, yielding 0.17g, m.p. 145-7'C.

AnalysisFound, C, 45.7; H, 6.4; N, 7.8% Cl,H,,,N,O,S,,.C,H404 requires C, 453; H, 6.0; N, 7.6%.

Claims (20)

1. Athienoquinolizine of the general formula S N 25 R S02R 2 30 or a pharmaceutically acceptable acid addition salt thereof, where R, is hydrogen or lower alkyl and R2 is lower alkyl, halo(lower)alkyl, -A-NR3R4 [where 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 and R3 and R4 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], aryl or a heterocyclic radical or R, is -A,NR5.SO,R6 [where A, is a lower alkylene group having 1 to 3 carbon atoms in the chain between the two N atoms, R5 is hydrogen or lower alkyl and RG is lower alkyl, halo(lower)alkyl or aryll and R2 is lower alkyl, halo(lower)alkyl or aryl.

2. A compound according to Claim 1 wherein Ri is lower alkyl and R2 is lower alkyl or phenyl. -

3. A compound according to Claim 1 wherein R, is -A'-NR5.SO2R6 (where A, R5 and R6 are as defined in Claim 1) and R2 is lower alkyl.

4. A compound according to Claim 3 wherein A' is ethylene, REi is hydrogen and R6 is lower alkyl. -

5. N-(4r5r8r9rlO,10aa-hexahydra-7H-thieno[2,3-aI quinolizin-9p-yl)-N- methylpropanesulphonamide or a 45 pharmaceutically acceptable acid addition salt thereof.

6. N-(4,5,8,9,10,10a:ga-hexahydro-7H-thieno[2,3-aI quinolizine-9p-yl)-N,2dimethylpropanesulphonam- ide or a pharmaceutically acceptable acid addition salt thereof.

7. N-(4,5,8,9,10au--hexahydro-7H-thienyl[2,3-aI quinolizin-9:gb-yl,)-Nmethyl sulphamide or a pharma- ceutically acceptable acid addition salt thereof.

8. N-(4,5,8,9oL,10,10aoL-hexahydro-7H-thieno[2,3-a] quinolizin-9-yi)-N-(2ethanesulphonamidoethyl)ethane sulphonamide or a pharmaceutically acceptable acid addition salt thereof.

9. A process for preparing a compound claimed in Claim 1 in which R1 is hydrogen or lower alkyl which comprises reacting an amine of general formula (11) 1 1 li - S 11:

- C NHR 1 50:

(11) 9 GB 2 163 155 A 9 where R' is hydrogen or lower alkyl with a reactive derivative of a sulphonic acid compound of general formula (111) R2SOOH (where R2 is as defined in Claim 1) and, if required, converting a free base into a pharmaceutically acceptable acid addition salt.

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

11. A process for preparing a compound claimed in Claim 1 in which R1 is A,-NRrSo2R6 (where A', R5 10 and Re are as defined in Claim 1) which comprises reacting a reactive derivative of a sulphonicacid compound of general formula (111) R2S0,0H where R2 is lower alkyl, halo(lower)aikyl or aryl with a diamine of general formula (XIII) C - 11 N S S NH.A 1. NfR 5 (Xili) is (where A, and R5 are as defined in Claim 1) and, if required, converting a free base into a pharmaceuti cally acceptable acid addition salt.

12. A process as claimed in Claim 11 wherein the reactive derivative of the acid is an acid halide.

13. A process for preparing a compound claimed in Claim 1 substantially as hereinbefore described 30 with reference to any one of Examples 2,to 5.

14. A compound whenever prepared by the process claimed in any one of Claims 9 to 13.

15. A pharmaceutical composition comprising a compound claim. ed in any one of Claims 1 to 8 and 14 in association with a pharmaceutically acceptable carrier.

16, A compound as claimed in any one of Claims 1 to 8 and 14 for use in antagonising:ga2-adreno- 35 ceptors in warm blooded animals.

17. The use of a compound as claimed in any one of Claims 1 to 8 and 14 for the manufacture of a medicament for use as an antidepressant, in the treatment of diabetes or in inhibiting blood platelet ag gregation.

18. An amine of general formula (11) - sx N 1 NHR 1 where R, is hydrogen or lower alkyl or an acid addition salt thereof.

(II)

19. 4,5,8,9,10,1 Oaa-h exa hyd ro-9p-m ethyl am in o-7H-th ien o [2,3- alquinolizine or an acid addition salt thereof.

20. A ketone of general formula (IV) 1 55 CS3 N (M 60 0 Printed in the UK for HMSO, D8818935 12185, 7102. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.