BENZOTHIAZOLONE DERIVATIVES

Abstract: A compound of formula (I), including optical isomers thereof, wherein X represents -SO2NH- or -NHSO2-, p, q and r independently represent 2 or 3, Y represetns thienyl optionally substituted by alkyl or halogen, or phenylthio- or phenyl optionally substituted by alkyl or halogen, and each R independently represents H or alkyl, and pharmaceutically acceptable salts, esters and amides thereof.

Description: BENZOTfflAZOLONE DERIVATIVES Field ofthe invention This invention relates to novel benzothiazolone derivatives, in particular novel 7-(2- 5 aminoethyl)-benzothiazolone derivatives, and to processes for their preparation, pharmaceutical compositions containing them and methods of treatment involving their use. The novel compounds are dopamine DA 2 - receptor agonists and β 2 -adrenoreceptor agonists — 10 Background Benzothiazolone derivatives are known. For example, international patent applications, publication numbers WO92/08708 and WO93/23385 disclose biologically active amines, among them biologically active aminoethyl benzothiazolone derivatives which are β 2 - adrenoreceptor agonists and dopamine DA 2 -receptor agonists, and which are indicated in is the treatment of obstructive airways diseases. WO 93/24473 discloses 7-(2-aminoethyl)-benzothiazolone compounds of formula -(CH 2 ) q -Y- (CH 2 ) r -Z 20 wherein X and Y are independently -S(O) n - or -O-; n is 0, 1 or 2; p, q and r are independently 2 or 3, Z is phenyl optionally substituted by halogen, OR 1 , NO 2 or NR 2 R 3 ; or Z is a 5 or 6 membered N, O or S containing heterocycle; and R 1 , R : and R 3 are independently hydrogen or alkyl C-. 6 . The compounds are β 2 -adrenoreceptor agonists and dopamine D A 2 -receptor agonists, and are indicated in the treatment of obstructive airways :5 diseases We have now found a group of novel 7-(2-aminoethyl)-benzothiazolone derivatives which are useful as dopamine DA 2 -receptor agonists and β 2 -adrenoreceptor agonists. Outline ofthe invention Accordingly, in one aspect ofthe present invention there are provided compounds of formula I, including optical isomers thereof, wherein X represents -SO2NH- or -NHSO2-, p, q and r independently represent 2 or 3, Y represents thienyl optionally substituted by alkyl or halogen, or phenylthio- or phenyl optionally substituted by alkyl or halogen, and each R independently represents H or alkyl, and pharmaceutically acceptable salts, esters and amides thereof The compounds are pharmacologically active They show both dopamine DA 2 -receptor agonism and β 2 -adrenoreceptor agonism They exhibit little or no cti-adrenoreceptor agonism The compounds have an advantageous duration of action and DA2 B2 ratio Preferably, q in formula I above is 2 r is preferably 2 When Y is phenyl substituted by alkyl, the alkyl group is preferably a C w , for example a Ci or C 2 group, most preferably methyl. When Y is phenyl substituted by halogen, the halogen substituent is preferably a chloro- or fluoro-substituent Preferred compounds ofthe present invention are compounds of formula I wherein X is SO 2 NH, p is 3 and q and r are each 2. Other preferred compounds are compounds of formula I wherein X is NHSO 2 , and p, q and r are all 2. Suitable pharmaceutically acceptable salts ofthe compounds of formula I include acid addition salts derived from inorganic and organic acids. The compounds may also form salts with suitable bases. Examples of suitable salts include the hydrochloride, citrate, D, - lactate, hemisulphate, hemitatrate, D-gluconate, methanesulphonate, p-toluenesulphonate, hemifumarate, benzoate, xinafoate, hemisuccinate, 3-hydroxy-2-naphthoate, hemiembonate, hemimaleate, D-camphorsulphonate, 10-undecanoate, mandelate, naphthalene- 1 -sulphonate, naphthalene-2-sulphonate, 4-methoxybenzoate, 4-chlorobenzoate, 5-methylsalicylate, saccharinate, monomethyl suberate, hemisuberate and diphenyl acetate salts Suitable pharmaceutically acceptable esters ofthe compounds of formula I include phenylalkyl and alkyl esters. Suitable amides include unsubstituted or mono- or di-substituted alkyl or phenyl amides The most preferred compounds ofthe invention are 3-[2-(4-Hydroxy-2-oxo-3H-l,3-benzothiazol-7-yl)ethylamino]-N-[2-(2-phenylethoxy)ethyl] propanesulphonamide; N-[2-[2-(4-Hydroxy-2-oxo-3H-l,3-benzothiazol-7-yl)ethylamino]ethyl]-2-(2- phenylethoxy)ethanesulphonamide, 3-[2-(4-Hydroxy-2-oxo-3H-l,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(5-methyl-2- thienyl)ethoxy]ethyl]propanesulphonamide; N-[2-[2-(4-Fluorophenyl)ethoxy] ethyl] -3 -[2-(4-hydroxy-2-oxo-3 H- 1 , 3 -benzothiazol-7- yl)ethylamino] propanesulphonamide; ~ ~ N-[2-[2-(4-Chlorophenyl)ethoxy]ethyl]-3-[2-(4-hydroxy-2-oxo-3H-l,3-benzothiazol-7- yl)ethylamino]propanesulphonamide; 3-[2-(4-Hydroxy-2-oxo-3H-l,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(4- methylphenyl)ethoxy]ethyl]propanesulphonamide; (R,S)-3-[2-(4-Hydroxy-2-oxo-3H-l,3-benzothiazol-7-yl)ethylamino]-N-[2-(2-phenyl-l- propoxy)ethyl]propanesulphonamide; 3-[2-(4-Hydroxy-2-oxo-3H-l ,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(2- methylphenyl)ethoxy] ethyl] propanesulphonamide; and 3 -[2-(4-Hydroxy-2-oxo-3 H- 1 , 3 -benzothiazol-7-yl)ethylamino] -N-[2-(2- phenylthioethoxy)ethyl]propanesulphonamide; preferably in salt form and more preferably as the hydrochloride The present invention also provides a method for the production of compounds of formula I, comprising selective reductive alkylation of a compound of formula II, with a compound of formula III, R O=CH-(CH 2 ) p . X-(CH 2 ) q -O-(CH) r -Y III in which p, q, r, R, X and Y are as defined above, in the presence ofa reducing agent. The reducing agent may be, for example, hydrogen in the presence ofa catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium, on a support e.g. charcoal, using an alcohol, e.g. ethanol, or an ester, e.g. ethyl acetate, or an ether, e g. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, at normal or elevated temperature and pressure. The preferred temperature is room temperature. The preferred pressure is 1-3 atmospheres. Alternatively the reducing agent may be sodium borohydride or a metal hydride e.g. sodium cyanoborohydride. Suitable solvents for use with hydride reducing agents will depend on the particular hydride used and will be well known to the person skilled in the art. Suitable solvents will include alcohols, for example ethanol or methanol The process may give rise to intermediate imine compounds, which may be reduced under the described conditions, to give compounds of formula I The compound of formula II may be prepared by known methods, for example by the method described in J Med. Chem., 1987, 30, 1 1 16. Aldehydes of formula III may be prepared in a number of ways known per se. For example, isothiazolidine dioxides (as in Example lc, for instance) may be reduced with DEBAL in toluene; acetals (as in Example 2b, for instance) may be hydrolysed with 70% aqueous acetic acid; and esters (as in Example 3d, for instance) may be reduced with DLBAL in toluene. Specific syntheses of certain precursor compounds are described in the Examples and may be adapted to a variety of targets. The aldehydes of formula UI may alsoUe prepared from the corresponding alcohols by partial oxidation using DMSO, DCC and anhydrous phosphoric acid; or using pyridinium chlorochromate or pyridinium dichromate. The present invention also provides a further process for preparing compounds of formula I, comprising the selective reduction ofa compound of formula IV, in which p, q, r, R, X and Y are as defined above. Suitable reducing agents include electrophilic reducing agents, e.g., diborane and alane (aluminium hydride), or nucleophilic reducing agents, e.g., a complex metal hydride such as sodium bis(2-methoxyethoxy)aluminium hydride. The preferred reducing agent is diborane The solvent should be inert to the reaction conditions. Aprotic solvents are preferred, e.g. tetrahydrofuran. diethyl ether, or 1,2-dimethoxyethane. The reaction may be carried out at a temperature of from about 0°C, to about 100°C, preferably at reflux temperature Compounds of formula IV may be prepared by coupling ofthe amine of formula II and an appropriate acid, of formula V HOOC-(CH 2 ) -X-(CH 2 ) q -O-(CH) r -Y V or corresponding acid chloride by conventional means For example, the coupling may be performed in the presence of dicyclohexylcarbodiimide using the method of Sheehan and Hess, J Am Chem. Soc, 1955, 77, 1067, or l '-carbonyldiimidazole as described by Staab, Angew Chem. Int Ed. Engl , 1962, 1, 351, or bromotπpyrrolidinophosphonium hexafluorophosphate in a solvent such as DMF, following the procedure of Example le The acids required for the process may be obtained from the corresponding esters, by hydrolysis with lithium hydroxide in aqueous methanol, following the procedure of Example lb Examples la, 2d, 3d, 4f, 5d, 6d, 7d, 8d and 9d describe specific processes for forrning the esters, and these process may be adapted to give other esters, for forming further acids for coupling with formula II amines The acid chlorides may be prepared from the acids for example by reaction with oxalyl chloride or thionyl chloride in toluene at a temperature from ambient to reflux The compounds ofthe present invention may be prepared by several other methods as well Alkylation ofthe compound of formula II, or a salt, ester or amide thereof, with an alkylating agent of formula VI R L-(CH 2 ) p -X-(CH 2 ) q -O-(CH) r -Y VI in which p, q, r, R, X and Y are as defined above and L represents a good leaving group, for example a halide e g. chloride, bromide or iodide, or an alkyl- or aryl-sulphonyloxy group, for example methanesulphonyloxy, is one such method The reaction may be carried out for example in the presence ofa base, for example an inorganic base, e g., sodium or potassium carbonate, or an organic base, e g , triethylamine, N,N'-diisopropylethylamine or pyridine The reaction may be performed in a solvent, for example an ether, e g. tetrahydrofuran or dioxan, a ketone, e g butanone or methyl isobutyl ketone, a substituted amide, e g dimethylformamide, or a chlorinated hydrocarbon, e g chloroform, at a temperature of between ambient temperature and the reflux temperature ofthe solvent Preferably the reaction is carried out at ambient temperature The alkylating agent of formula VI may be prepared from the corresponding alcohol (i.e. the compound in which represents OH) by methods known to the person skilled in the art. For example, the alcohol may be reacted with a halogenating agent to yield the compound of formula VI in which L represents a halogen atom Suitable halogenating agents include, for example, tπphenylphosphine-tetrahalogenomethane adduct (conveniently formed in situ, e g by the reaction of triphenylphosphine and carbontetrabromide). The reaction may take place in the presence of a solvent such as acetonitrile, or a chlorinated hydrocarbon, e.g dichloromethane, for example at a temperature in the range of 0-30°C Another method is the selective reduction ofa compound of formula VTI, in which p, q, r, R, X and Y are as defined above. Suitable reducing agents include electrophihc reducing agents, e.g., diborane and alane (aluminium hydride), or nucleophilic, e.g., a complex metal hydride such as sodium bis(2- methoxyethoxy)aluminium hydride. The preferred reducing agent is diborane. The solvent should be inert to the reaction conditions. Aprotic solvents are preferred, e.g. tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane. The reaction may be carried out at a temperature of from about 0°C, to about 100°C, preferably at reflux temperature. Compounds of formula " VTI may be prepared by coupling of an amine and an acid or acid chloride by conventional means. For example, the coupling may be performed in the presence of dicyclohexylcarbodiimide or l. T-carbonyldiimidazole or bromotripyrrolidinophosphonium hexafluorophosphate, as described above in relation to compounds of formula IV. The amines required for the coupling reaction may be prepared by reaction of compounds of formula VI, where L represents a good leaving group for example a halide such as chloride or bromide, with phthalimide in the presence of a base. The resulting imides may then be treated with hydrazine hydrate in ethanol to give compounds of formula VI with the leaving group replaced by an amino group. In the above processes it may be necessary for any functional groups, e.g. hydroxy or amino groups, present in the starting materials to be protected. Suitable protecting groups and methods for their removal are, for example, those described in "Protective Groups in Organic Synthesis" by T W Greene and P.G. M Wuts, John Wiley and Sons Inc , 1991 Another process for preparing compounds of formula I comprises removal of a protecting group from a corresponding protected compound of formula I in which one or more ofthe functional groups is protected, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable salt, ester or amide thereof, or vice versa. Pharmaceutically acceptable salts may be prepared for example by reacting the compound of formula I with an appropriate acid in the presence of a suitable solvent Pharmaceutically acceptable esters ofthe compounds of formula I may be made by conventional techniques, e.g. esterification or transesterification. Pharmaceutically acceptable amides ofthe compounds of formula I may be made by conventional techniques, e.g. reaction of a compound of formula I with an acid or acid chloride The intermediates of formula IV are novel, thus according to a further aspect ofthe invention there are provided compounds of formula IV, in which p, q, r, R, X and Y are as defined above. The intermediates of formula VII as defined above are also novel and are thus also provided in accordance with the present invention. Further, the aldehydes of formula III as defined above are novel and are provided by the present invention. Still further the acids of formula V and corresponding acid chlorides are novel and are provided by the present invention. The compounds of formula I and salts, esters and amides thereof are dopamine DA2- receptor agonists. The binding affinities ofthe test compounds for the DA2 receptor binding 3 sites in bovine pituitary membranes may be determined from the displacement off H]-N-n -propylnorapomorphine and of [ H]-spiperone in the absence or presence of nonhydrolysable GTP analogue respectively, D.R Sibley, A. DeLean and I. Creese, Anterior Pituitary Dopamine Receptors, Demonstration of Interconvertible High and Low Affinity States ofthe D-2 Dopamine Receptor, J. Biol. Chem., 1982, 257(11), 6351-6361. The DA2-receptor activity may also be demonstrated in a functional screen, the rabbit isolated ear artery, as described by Brown and O'Connor, Br. J. Pharmacol., 1981, 73, 189P. The compounds are also β2-adrenoreceptor agonists. This activity may be demonstrated in the isolated trachea ofthe guinea pig, as described by I.G. Dougall, D. Harper, D M. Jackson, and P. Leff, Br. J. Pharmacol., 1991, 104, 1057. α Receptor activity may be analysed using the rabbit isolated ear artery screen described in Pharmacological Example herein. The compounds of formula I and salts, esters and amides thereof are thus indicated for use in the treatment ofthe range of airways diseases, including conditions such as asthma, including bronchial asthma, allergic asthma, intrinsic asthma (for example late asthma and airway hyper-responsiveness), and bronchitis and the like (see, for example, UK Patent No 2022078 and Br J Pharmacol , 1987, 24, 4983) The compounds of formula I and salts, esters and amides thereof are also indicated for use in the treatment of various other conditions, e g inflammatory and allergic skin disorders, cancer e g small cell lung cancer, congestive heart failure and glaucoma The term "treatment" as used herein includes prophylaxis as well as relief of the symptoms of disease Accordingly, in a further aspect ofthe present invention, there is provided the use ofa compound of formula I, or a pharmaceutically acceptable salt, ester or amide thereof, in therapy Further, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt, ester or amide thereof, in the manufacture ofa medicament for the treatment of obstructive airways disease, in particular for the treatment of asthma or chronic bronchitis Still further, the present invention provides a method of treatment of airways disease, which method comprises administering a therapeutically effective quantity ofa compound of formula I, or a pharmaceutically acceptable salt, ester or amide thereof, to a patient suffering from or susceptible to such a condition Typical daily unit doses may be for example lμg - lOmg for topical administration, preferably 10-500μg, for example divided two or three times, or lOμg - lOOmg for oral administration, preferably lOOμg-lOmg, for example divided two or three times The compounds of formula I and salts, esters and amides thereof may be used on their own or in the form of appropriate pharmaceutical compositions Administration may be by inhalation as well as by other routes, for example by oral or intraveneous administration. Nasal or pulmonary administration may be achieved via a suitable inhalation device. For example metered dose inhaler devices may be used to administer the compound, dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants and stabilising agents. Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane propellants, or mixtures of any such propellants. Especially preferred propellants are PI 34a and P227 each of which may be used alone or in combination with other propellants and/or surfactants and/or other excipients, for example in combination with each other. Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose device. Dry powder inhalers may be used to administer the compound, alone or in combination with a pharmaceutically acceptable carrier, in the latter case either as a finely divided powder or as an ordered mixture. The dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule. Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available. The invention is illustrated, but in no way limited, by the following Examples, in which temperatures are in degrees Celsius. Where necessary, the reactions were performed under an inert atmosphere of either nitrogen or argon. Where necessary, preparative HPLC ® ® ..® separations were generally performed using a Novapak , Bondapak or Hypersπ column packed with BDSC-18 reverse phase silica. Flash chromatography was carried out using Fisher Matrix 60 silica, 35-70 micron. Example 1 3-r2-('4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethylamino1-N-f2-( ' 2-phenylethoxy ethyll propanesulphonamide hydrochloride ~~ a) Methyl 3- 2-(2-phenylethoxy)ethylaminosulphonyl1propanoate 2-(2-Phenylethoxy)ethanamine (1.95 g) was stirred in dichloromethane at room temperature. Triethylamine (3 36 ml) followed by methyl 3-(chlorosulphonyl)- 2 propanoate were added and the mixture stirred overnight at room temperature. The mixture was diluted with a further amount of dichloromethane, washed with dilute hydrochloric acid then water, then dried (MgSO.j.). The solvent was removed in vacuo to yield a pale yellow oil which was further purified by flash chromatography (01% ethanol: dichloromethane as eluant) to give the subtitle compound as pale yellow oil (1.68 g) Mass spectrum: FAB 316 (M+H); H nmr (360 MHz, CDCI3) δ. 2.75 (2H, t), 2.85 (2H, t), 3.18-3.35 (4H, m), 3.46-3.57 (2H, m), 3.60-3.77 (5H, m), 4 44 (IH, bit), 7 12-7.35 (5H, m) m. Ber., 1964, 97, 510-519. 2 J. Am. Chem. Soc, 1950, 72, 128-132. b) 3-f2-f2-Phenylethoxy)ethylaminosulphonyl]propanoic acid The product of step a) (1 68 g) was dissolved in methanol (30 ml). Lithium hydroxide (0 45 g) in water (30 ml) was added and the mixture stirred overnight at room temperature Water was added and the mixture washed with ether. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ether. The ether extract was washed with water then brine, then dried (MgSO4). The solvent was removed in vacuo to give the subtitle compound as a white solid (0.97 g) which was used without further purification mp 80-82°, Mass spectrum: ESI 300 (M-H); ~~ H nmr (360 MHz, CDCI3 δ: 2 77-2.95 (4H, m), 3.20-3 47 (4H, m), 3.51-3.58 (2H, m), 3 69 (2H, t), 4 66 (IH, t), 7.18-7 38 (5H, m) c) 2-| " 2-(2-Phenylethoxy ' )ethyll-3-isothiazolidinone-l .1 '-dioxide The product of step b) (34 g) was dissolved in dimethylformamide (200 ml). To this stirred solution was added 1,1 '-carbonyldiimidazole (20.12 g) and the mixture stirred for 2 hours. Triethylamine (15.7 ml) was added and the mixture was stirred at room temperature for 60 hours. The mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate (x3). The combined organic extracts were washed with saturated sodium bicarbonate solution then brine, dried (MgSO,- * .) and the solvent removed in vacuo to yield a pale yellow oil which was further purified by flash chromatography (50% ethyl acetate:petrol as eluant) to give the subtitle compound as an oil (27.4 g). Mass spectrum: ESI 301 (M+NH4), HH nnmmrr ((336600 MMHHzz,, CCDDII33)) δδ.. 22..887 (2H, t), 2.99 (2H, t) 3.51 (2H, t), 3.64-3.68 (4H, m), 3 76 (2H, t), 7 18-7 43 (5H, m) d) 3-f2-r4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethylaminol-N-r2-f2- phenylethoxy)ethyl1 propanesulphonamide hydrochloride The product of step c) (0 62 g) was stirred in toluene (20 ml) then cooled to -70°. Diisobutylaluminium hydride (1 6 ml of a 1 5 M solution in toluene) was added over 15 min keeping the temperature below -58° The mixture was stirred for 10 min after which time tic showed that no starting material remained Ethyl acetate (9 ml) was cautiously added keeping the temperature below -60° The mixture was allowed to warm to room temperature and a 10% aqueous solution of sodium potassium tartrate added After stirring for 1 hour the mixture was extracted with ethyl acetate (x3). The combined orgamc extracts were dried (MgSO-i) and then about 70% ofthe solvent was removed in vacuo Methanol (20 ml) was added to the mixture and again about 70% of the solvent was removed in vacuo, this was repeated twice more This solution was diluted with methanol (20 ml) and 7-(2-amιnoethyl)-4-hydroxy-l,3-benzothιazol- 2(3H)-one hydrobromide (0 64 g) added. The pH was adjusted to pH 4 with glacial acetic acid Sodium cyanoborohydride (0 14 g) was added followed by sodium sulphate (50 mg) and the mixture stirred for 72 hours. The mixture was made basic by the addition of concentrated aqueous ammonium hydroxide solution. The volatiles were remove in vacuo and the residue purified by flash chromatography (10-25% methanol in chloroform as eluant) The material was further purified by reverse phase HPLC (25% methanol in 0 1% aqueous trifluoroacetic acid as eluant) to give, after conversion to the hydrochloπde salt, the title compound as a white solid (0 417 g) mp 205-206°, Mass spectrum FAB 480 (M+H), l H nmr (360 MHz, d 6 DMSO) δ 2 00 (2H, t), 2 73-2 92 (4H, m), 2 96-3 19 (8H, m), 3 44 (2H, t), 3 60 (2H, t), 6 75 (IH, d), 6 85 (IH, d), 7 13-7 35 (6H, m), 8 92 (2H, s), 1041 (lH, s), I I 77 (IH, s), Analysis Found C,51 48, H,6 25, N,8 41, S, 12 50% Required for C22H29N3O5S2 HCl C,51 20, H,5 86, N,8 14, S, 12 43% In an alternative method, steps a) and b) above were repeated, followed by steps e) and f) below e) N-f2-r4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethyll-3-r2-f2- phenylethoxy)ethylaminosulphonyl]propanamide A solution ofthe product from step b) (3.89 g), 7-(2-aminoethyl)-4-hydroxy-l,3- benzothiazol-2(3H)-one hydrochloride (3.22 g), bromotripyrrolidinophosphonium hexafluorophosphate, PyBroP, (6.32 g) in dimethylformamide (50 ml) was cooled to -15° C and diisopropylethylamine (9.0 ml) was added dropwise over 5 minutes. The solution was stirred at -15° C for 5 ~ rnin then allowed to warm to 13° C over 4 hours. This mixture was then added dropwise over 40 min to dilute hydrochloric acid (2N, 500 ml) and after stirring over the weekend the solid was collected by filtration. This solid was dried in vacuo to give the subtitle compound (4 5 g). Mass spectrum FAB 492 (M-H). f) 3-r2-( , 4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethylaminol-N-r2-f2- phenylethoxy)ethyl " |propanesulphonamide hydrochloride To a solution ofthe product from step e) (0.28 g) in tetrahydrofuran (2 ml) was added borane tetrahydrofuran (2.44 ml of 1 M solution) over 5 min. The mixture was heated at reflux for 3 hours and, after cooling, methanol ( 1 ml) was added cautiously. The volatiles were removed in vacuo, the residue was redissolved in methanol (5 ml) and concentrated hydrochloric acid (1 ml) was added. The volatiles were again removed in vacuo. The residue was partitioned between water and ethyl acetate, the aqueous layer collected and extracted again with ethyl acetate. The aqueous layer was then made basic with sodium hydrogen carbonate and extracted four times with chloroform. The combined chloroform extracts were dried and the volatiles removed in vacuo to provide after conversion to the hydrochloride salt, the title compound (0 070 g) Example 2 N-r2-r2-r4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethylamino]ethvπ-2-( ' 2- phenylethoxy thanesulphonamide hydrochloride a) 2-(2-Phenylethoxy)ethanesulphonylchloride A stirred suspension of 2-(2-phenylethoxy)ethanethiol (1.0 g) in water (40 ml) was saturated at 5-10° with chlorine over 20 min. The mixture was flushed under a stream of nitrogen to remove any excess chlorine. The mixture was then extracted with dichloromethane (x2), the combined organic extracts were washed with water then dried (CaCl2). The solvent was removed in vacuo to give an oil which was azeotroped with toluene to give the subtitle compound as a yellow oil (1.36 g) which was used without further purification. Mass spectrum: El 248/250 (M); HH nnmmrr ((336600 MMHHzz,, CDC1 3 ) δ: 2.90 (2H, t), 3.74 (2H, t), 3.88 (2H, t), 3.99 (2H, t), 7.13-7.36 (5H, m). b) N-(2.2-DimethoxyethylV2-(2-phenylethoxy ' )ethanesulphonamide A stirred solution ofthe product of step a) (1.0 g) in dichloromethane (20 ml) and pyridine (0.358 ml) was treated dropwise over 5 min with a solution of aminoacetaldehyde dimethylacetal (0.438 ml) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 days. The mixture was washed with water then dried (CaCl2). The volatiles were removed in vacuo to yield an orange oil which was further purified by flash chromatography (ether as eluant) to give the subtitle compound as a yellow oil (0.42 g). Mass spectrum: 335 (M+NH4); l nmr (360 MHz, CDCI3) δ: 2.90 (2H, t), 3.13 (2H, t) 3.26 (2H, t), 3.38 (6H, s), 3 73 (2H, t), 3.85 (2H, t), 4.38 (IH, t), 4.46 (IH, t), 7 14-7.35 (5H, m). c) N-r2-( ' 2-( ' 4-Hvdroxy-2-oxo-3H-1.3-benzothizol-7-vnethylamino)ethyll-2-f2- phenylethoxy)ethanesulphonamide hydrochloride A solution of the product of step b) (0.26 g) in 70% aqueous acetic acid (5 ml) was heated to 100° for 2 hours after which time tic indicated that no starting material remained. The solvent was removed in vacuo. The residue was taken up into methanol (10 ml) and to this stirred solutiomvas added 7-(2-aminoethyl)-4-hydroxy-l,3- benzothiazol-2(3H)-one hydrobromide (0.238 g), sodium cyanoborohydride (0.038 g) followed by acetic acid (1 drop). The mixture was stirred at room temperature for 24 hours. The mixture was made basic by the addition of concentrated aqueous ammonium hydroxide solution. The volatiles were removed in vacuo and the residual material purified by flash chromatography (17% ethanol in dichloromethane as eluant) to give a light yellow gum. This was further purified by reverse phase HPLC (30-45% acetonitrile in 0.1% aqueous trifluoroacetic acid as eluant) to give, after conversion to the hydrochloride salt, the title compound as a white powder (0.080 g). Mass spectrum: 466 (M+H); H nmr (360 MHz, dόDMSO) δ: 2.81-2.90 (4H, m), 3.04-3.09 (4H, brd), 3.26-3.28 (2H, m), 3.24 (2H + H 2 O), 3.63 (2H, s), 3.74 (2H,t), 6.78 (lH,d), 6.87 (lH,d), 7.19- 7.30 (5H, m), 7.43 (IH, t), 9.10 (2H,s), 10.16 (IH, s), 1 1.78 (IH, s); Analysis Found: C,49.35; H,5.69; N,8.30; S, 1 1.94% Required for C21H27N3O5S2.HCI.O.5 H 2 O: C,49.31; H,5.67; N,8.22; S, 12.52% In an alternative method, step a) was repeated, followed by steps d) to g) below: d) Methyl f2-f2-phenylethoxy)ethylsulphonylamino]acetate A suspension of glycine methylester hydrochloride (2.52 g) in dichloromethane (30 ml) was stirred at -18° C and diisopropylethyl amine (8 ml) was added over 10 min. To this was added the product from part a) (2.64 g) in dichloromethane (10 ml) dropwise over 10 minutes keeping the temperature below -5° C The cooling bath was removed and the stirred mixture allowed to warm to room temperature After a further 50 minutes the mixture was washed with 5% aqueous potassium hydrogen sulphate the dried (Na2SO4) and the volatiles removed in vacuo to give the subtitle compound as a brown oil (58 5 g) Mass spectrum FAB 302 (M+H) — H nmr (360 MHz, CDCL 3 ) 2 90 (2H, t), 3.36 (2H, t), 3.72-3 85 (7H, m), 3.96 (2H, t), 4 70 (IH, brs), 7 20-7 31 (5H, m) e) 2-rf2-Phenylethoxytethylsulphonylamino]acetic acid A solution ofthe product from part d) (3.2 g) in methanol (30 ml) was cooled in an ice bath and treated with a solution of lithium hydroxide, hydrate (1 06 g) in water (7 ml) over 5 minutes. The cooling bath was removed and the mixture stirred for 16 hours. The mixture was acidified with concentrated hydrochloric acid (3 ml) and then concentrated in vacuo to approximately 15 ml. The residue was mixed with sodium bicarbonate and extracted with ether. The aqueous phase was then reacidified with satuated aqueous potassium hydrogen sulphate solution and extracted with ether This extract was dried (MgSO4) and volatiles removed in vacuo to give a solid. The product was further purified by recrystallisation from dichloroethane-toluene mixture to give the subtitle compound as a crystalline solid (1 57 g) Mass spectrum FAB 288 (M+H), L H nmr (360 MHz, CDCL 3 ) 2 90 (2H, t), 3 32 (2H, t), 3 74-3 78 (4H, m), 3 89 (2H, t), 4 66 (IH, t), 7 20-7 33 (5H. m), 8 07 (IH, brs) f N-r2-C4-Hvdroχy-2-oxo-3H-1.3-benzothiazol-7-vnethyll-2-r2-( ' 2- phenylethoxylethylsulphonylaminolacetamide A solution ofthe product from part e) (70 g) in dimethylformamide (605 ml) was cooled to -10° C and l, l '-carbonyldiimidazole (39.5 g) was added. The mixture was stirred for 119 minutes then 7-(2-aminoethyl)-4-hydroxy-l,3-benzothiazol-2(3H)-one hydrochloride (68.87 g) was added followed by triethylamine (34 ml) drop wise over 3 minutes keeping the temperature at -10° C. After a further 10 minutes at -10° C the mixture was allowed to warm to room temperature and stirred for 24 hours. This mixture was then added dropwise to dilute hydrochloric acid (2N, 1870 ml) and aqueous mixture was extracted with ethyl acetate. The organics were then washed with dilute hydrochloric acid, aqueous sodium bicarbonate and then dried (MgSO4). The volatiles were removed in vacuo to provide the subtitle compound as a foam (92.21 g). Mass spectrum FAB 480 (M+H); H nmr (360 MHz, dόDMSO): 2.61 (2H, t), 2.81 (2H, t), 3.29-3.32 (4H, m overlapping water), 3.56 (2H, s), 3.61 (2H, t), 3.74 (2H, t), 6.70 (IH, d), 6.80 (IH, d), 7.16-7.53 (5H, m), 8.03 (IH, bit). g) N-r2-f2-r4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethylamino)ethyll-2-('2- phenylethoxytethanesulphonamide hydrochloride A solution ofthe product from part f) (38.7 g) in tetrahydrofuran (200 ml) was cooled in an acetone/ice bath and lithium borohydride (727 ml, 2.0M in tetrahydrofuran) was added over 30 minutes. After 15 minutes the cooling bath was removed and trimethylsilyl chloride (205 ml) was added and the stirring continued for 162 hours at room temperature. The mixture was cooled to -20° C and methanol carefully added. After this addition a further 50 ml of methanol saturated with hydrogen chloride was added and the mixture allowed to warm to room temperature. After 1 hour the mixture was heated at reflux for 30 minutes then cooled and the volatiles were removed in vacuo. Water (400 ml) was added and the flask thoroughly shaken and, after standing in an acetone/ice bath for 30 minutes, the water was decanted off. A further amount of water was added (100 ml) and the process repeated. The semi solid remaining was then dissolved in hot ethanol (40 ml), treated with activated charcoal (3 g) and stirred for 1 hour The mixture was filtered and the solvent removed in vacuo The residue was redissolved in hot ethanol (80 ml) and allowed to stand at room temperature for 16 hours. The crystals that had precipitated out were then loosened and broken up with a spatula, swirled and left to stand for a further 16 hours The sohd was then collected by filtration and washed with ethanol, ether then dried under vacuum to provide the title compound (23 g) ~~ Example 3 3-r2-( ' 4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethylamino1-N-| " 2-r2-(5-methyl-2- thienvDethoxy] ethyllpropanesulphonamide hydrochloride a) 2-f2- 5-Methyl-2-thienynethoxy]acetic acid Sodium hydride (0 622 g) was suspended in dry dimethylformamide (5 ml) and treated dropwise with a solution of 2-(5-methyl-2-thienyl)ethanol (1 0 g) in dry dimethylformamide (5 ml) The mixture was stirred at room temperature under nitrogen for 2 hours then a solution of chloroacetic acid (0 664 g) in dry dimethylformamide (5 ml) added. The mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue quenched with water and extracted with ethyl acetate The aqueous layer was adjusted to pH 2 using dilute hydrochloric acid and then extracted with ethyl acetate This extract was washed with water, brine then dried (MgSO4) The solvent was removed in vacuo to give a brown oil (1 51 g) which was used without further purification Mass spectrum 200 (M), *H nmr (360 MHz, CDCI3) δ 2 45 (3H, s), 3 05-3 09 (2H, t), 3 75-3 83 (2H, t), 4 17 (2H, s), 6 56 (1H, d), 6 63 (IH, d) b) 2-r2-f5-Methyl-2-thienv0ethoxy1acetamide The product of step a) (6 48 g) was dissolved in toluene (55 ml) and oxalyl chloride (2 877 ml) added dropwise at room temperature under nitrogen. A drop of dimethylformamide was added and the mixture stirred for 3 hours after which time tic showed no starting material The volatiles were removed in vacuo to provide a brown oil (6 7 g) which was added dropwise to a stirred solution of concentrated ammonium hydroxide (50 ml) at 0° The mixture was allowed to warm to room temperature and stirred for 4 hours A brown solid precipitated out This solid was collected by filtration and washed with water to give the subtitle compound (2 02 g). Mass spectrum * 200 (M+H); H nmr (360 MHz, CDCI3) δ 2.45 (3H, s), 3.04 (2H, t), 3 73 (2H, t), 3 97 (2H, s), 5 61 (2H, brs), 6 57 (IH, d), 6.63 (IH, d). c) 2-f2-f5-Methyl-2-tMenvPethoxy]ethanarnine Borane-tetrahydrofuran solution (1 0 M in THF, 21.7 ml) was added dropwise to a stirred solution ofthe product from step b) (1 25 g) in dry tetrahydrofuran (100 ml) The reaction was heated at reflux under an inert atmosphere for 5 hours. The reaction was cooled and methanol (10 ml) added cautiously The solvents were removed in vacuo and the residue dissolved in methanol (100 ml) to which was added concentrated hydrochloric acid (sg 1 18, 0 45 ml) This solution was heated at reflux for 15 min then the solvent removed in vacuo The residue was purified by flash chromatography (dichloromethane 5% methanol as eluant) to give the subtitle compound as a white solid (0 916 g) Mass spectrum 186 (M+H), H nmr (360 MHz, CDC1 3 ) δ 2 45 (3H), s), 3 04 (2H, t), 3 73 (2H, t), 3 97 (2H, s), 5 61 (2H, brs), 6 57 (IH, d), 6 63 (IH, d) d) Methyl 3-f2- r 2-f5-methyl-2-thienv0ethoxy]ethylanτιnosulphonyl]propanoate The product of step c) as the hydrochloride salt (1 50 g) was stirred under nitrogen in dichloromethane (25 ml) Triethylamine (2 21 ml) was added followed by methyl 3- (chlorosulphonyl)propanoate (1 18"g). The mixture was stirred at room temperature overnight The solution was diluted with a further amount of dichloromethane and the organics washed with dilute hydrochloric acid then water, then dried (MgSO 4 ) The mixture was filtered and the volatiles removed in vacuo to give the subtitle compound as an oil (1 4 g) Mass spectrum 336 (M+H), HH nnmmrr ((336600 MMHHzz,, CCDDCCLL33)) 1 δ. 2 38 (3H, s), 2 80 (2H, t), 3 00 (2H, t), 3 26-3 36 (4H, m), 3 56 (2H, t), 3 64 (2H, t), 3 72 (3H, s), 4 71 (IH, t), 6 57 (IH, d), 6 60 (IH, d) e) 3-r2-(4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethylaminol-N-r2-r2-('5-methyl-2- thienvOethoxy]ethyl]propanesulphonamide hydrochlonde The product of step d) (0 60 g) was dissolved in toluene (30 ml) under nitrogen and cooled to -78° Diisobutylaluminiumhydride (1 5 M in toluene, 1 78 ml) was added dropwise and the mixture kept at -78° for 10 min The reaction was quenched with ethyl acetate followed by a 10% aqueous sodium potassium tartrate solution The mixture was warmed to room temperature and after stirring for 1 hour extracted with toluene (x3) The combined organic extracts were washed with water, dried (MgSO 4 ) then about 70% ofthe solvent removed in vacuo Methanol (20 ml) was added to the mixture and again about 70% ofthe solvent removed in vacuo, this was repeated twice more This solution was diluted with methanol (20 ml) and 7-(2-ammoethyl)-4- hydroxy- 1 ,3-benzothιazol-2(3H)-one hydrochloride (0 516 g) added The pH was adjusted to pH 4 with glacial acetic acid. Sodium cyanoborohydride (0.114 g) was added and the mixture stirred under nitrogen for 2 hours. The mixture was made basic by the addition of concentrated aqueous ammonium hydroxide solution. The volatiles were removed in vacuo and the residue purified by flash chromatography (5-20% methanol: dichloromethane as eluant). The material was further purified by reverse phase HPLC (25-85% methanol in 0.1 % aqueous trifluoroacetic acid as eluant) to give, after conversion to the hydrochloride salt, the title compound (0.12 g) as a white solid. mp 210-212°; Mass spectrum: FAB 500 (M+H), H nmr (360 MHz, d 6 DMSO) δ: 2.00 (2H, q, 2.37 (3H, s), 2.85 (2H, t), 2.93 (2H, t), 3.01-3.17 (8H, m), 3.46 (2H, t), 3.58 (2H, t), 6.60 (IH, d), 6.65 (IH, d), 6.75-6.88 (2H, m), 7.31 (IH, t), 8.93 (2H, s), 10.15 (IH, s), 11.7 (IH, brs). Example 4 N-f2-r2-f4-Fluorophenyl')ethoxy1ethvπ-3-r2-f4-hvdroxy-2-oxo-3H-1.3-benzothiazol-7- yl)ethylamino]propanesulphonamide hydrochloride a) t-Butyl 3-r2-(4-fluorophenvπethoxylpropanoate 2-(4-Fluorophenyl)ethanol (20.5 g) and Triton-B (2.4 ml, 40% in methanol) were mixed together and the methanol removed in vacuo. t-Butyl acrylate (21.38 ml) was added and the solution heated at 50° for 2 hours then stirred at room temperature overnight. The mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO 4 ) and filtered. The volatiles were removed in vacuo to give the subtitle compound (37.91 g) which was used without further purification. l H nmr (360 MHz, CDC1 3 ) δ 1 46 (9H, s), 2 47 (2H, t), 2 84 (2H, t), 3.55-3 69 (4H, m), 6 93-6 98 (2H, m), 7 15-7 18 (2H, m) b) 3- r 2-(4-FluorophenvPethoxy1propanoic acid The product of step a) (37 91 g) was dissolved in dichloromethane (50 ml) and trifluoroacetic acid (50 ml) added. The solution was stirred at room temperature for 1 hour then diluted with water and extracted with ethyl acetate (x4). The combined organic extracts were washed with water (x4) then brine, dried (MgSO4) and filtered. The volatiles were removed in vacuo to give an oil, this oil was taken into diethyl ether and extracted with aqueous sodium bicarbonate solution (x3) The combined aqueous layers were acidified with concentrated hydrochloric acid then extracted with diethyl ether (x4) The combined organic extracts were washed with brine, dried (MgSO4) and filtered. The volatiles were removed in vacuo to give the subtitle compound (19 95 g) which was used without further purification. Mass spectrum 212 (M); l H nmr (360 MHz, CDCI3) δ 2 62 (2H, t), 2.85 (2H, t) 3 66 (2H, t), 3 73 (2H, t), 6 94-6 99 (2H, m), 7 14-7 18 (2H, m), 7 37 (IH, brs) c) 2-r2-(4-Fluorophenvπethoxy1ethylisocvanate The product of step b) (15 49 g), triethylamine (1 1 2 ml) and diphenylphosphoryl azide (15 7 ml) were heated in toluene (150 ml) at 80° for 5 hours under nitrogen. The mixture was allowed to cool, then left at room temperature overnight The mixture was diluted with water and extracted with ethyl acetate (x3) The combined organic extracts were washed with aqueous sodium bicarbonate, dilute hydrochloric acid, brine then dned (MgSO 4 ) and filtered The volatiles were removed in vacuo and the residue further purified by flash chromatography (50% diethyl ether iso-hexane as eluant) to give the subtitle compound (5 54 g) Mass spectrum. 209 (M), ! H nmr (360 MHz, CDC1 3 ) δ 2 89 (2H, t), 3 38 (2H, t), 3.56 (2H, t), 3.68 (2H, t), 6 95-7 01 (2H, m), 7.17-7.21 (2H, m). d) Methyl N-[2- 2- 4-fluorophenyl')ethoxy)ethyl carbamate The product of step c) (9 0 g) was-dissolved in methanol (300 ml) and to this stirred solution was added sodium methoxide (4.65 g). The mixture was stirred at room temperature for 3 hours The volatiles were removed in vacuo and the residue was extracted with ethyl acetate The ethyl acetate was washed with brine, dried (MgSO4) and filtered The volatiles were removed in vacuo and a portion ofthe residue was further purified by flash chromatography (60% diethyl ether: iso-hexane as eluant) to give the subtitle compound (0.375 g). Mass spectrum; FAB 242 (M+H), l K nmr (360 MHz, CDCI3) δ 2.84 (2H, t), 3.34 (2H, t), 3 49 (2H, t), 3 63 (2H, t), 3 67 (3H, s), 6 95-7 00 (2H, m), 7 14-7.18 (2H, m), Analysis Found C,59 1, H,6 83, N,5.83% Required for C12H16FNO3 C,59 74, H,6.68, N,5.81% e) 2-f2-f4-Fluoropheπyl thoxy]ethanamine The product of step d) (8.0 g) was dissolved in ethylene glycol and to this was added potassium hydroxide (48 g) and hydrazine hydrate (8 3 ml). The stirred mixture was heated to 140° for 4 hours then allowed to cool to room temperature overnight. The mixture was then diluted with water and extracted with diethyl ether (x3) The combined organic extracts were washed with brine, dried (MgOS4) and filtered The volatiles were removed in vacuo to give the subtitle compound (5 36 g) Mass spectrum: 184 (M+H); l H nmr (360 MHz, CDCI3) δ: 2.82-2.88 (4H, m), 3.47 (2H, t), 3.64 (2H, t), 6.95-6.99 (2H, m), 7.16-7.20 (2H, m). f) Methyl 3-[2-f2-f4-fluorophenvDethoxylethylaminosulphonyl]propanoate The subtitle compound (8.32 g) was prepared according to the method of Example 3d) using 2-[2-(4-fluorophenyl)ethoxy]ethanamine (5.36 g), triethylamine (4.6 ml) and methyl 3-(chlorosulphonyl)propanoate (5.6 g) in diethyl ether (150 ml). mp 49°; Mass spectrum: 334 (M+H); H nmr (360 MHz, CDCI3) δ: 2.78-2.87 (4H, m), 3.24-3.28 (2H, m), 3.34 (2H, t), 3.51-3.56 (2H, m), 3.65 (2H, t), 3.73 (3H, s), 6.97-7.01 (2H, m), 7.15-7.19 (2H, m); Analysis Found: C,50.52, H,6.24; N,4.16; S,9.40% Required for C14H20FNO5S: C,50.44; H,6.05; N,4.20; S,9.62%. g) N-r2-r2-( , 4-Fluorophenvnethoxylethyll-3-r2-r4-hvdroxy-2-oxo-3H-1.3-benzothiazol-7- vπethylamino] propanesulphonamide hydrochloride The title compound (0.092 g) was prepared according to the method of Example 3e) using methyl 3-[2-[2-(4-fluorophenyl)ethoxy]ethylaminosulphonyl]propanoate (1.0 g), diisobutylaluminiumhydride (1.5 M in toluene, 4 ml), 7-(2-aminoethyl)-4-hydroxy-l,3- benzothiazol-2-(3H)-one hydrochloride (0.875 g) and sodium cyanoborohydride (0.354 g). mp 195-7°; Mass spectrum: FAB 498 (M+H); *H nmr (360 MHz, d 6 DMSO) δ: 1.99 (2H, q), 2.78-2.87 (4H, m) 3.04-3.16 (8H,m), 3 45 (2H, t), 3.59 (2H, t), 6.86 (IH, d), 6.85 (IH, d), 7 01 (2H, t), 7.26-7.31 (3H, m), 8.90 (2H, s), 10.15 (IH, s), 11.77 (IH, brs); Analysis Found: C,49.01; H,5.74; N,7.96; S, 11.50% Required for C22H29FN3O5S2.HCI.O.5 H 2 O: C,49.48; H,5.47; N,7.87; S, 12.01%. Example 5 N-f2-f2-('4-Chlorophenvnethoxylethvn-3-| ' 2-(4-hvdroxy-2-oxo-3H-1.3-benzothiazol-7- vπethylamino]propanesulphonamide hydrochloride. a) 2-r2-(4-Chlorophenv0ethoxy]acetic acid 2-(4-Chlorophenyl)ethanol (10 g) was stirred in 50 % aqueous sodium hydroxide (70 ml), tetrabutylammoniumbromide (1.4 g) was added and the mixture stirred for 1 hour. t-Butylbromoacetate (28.6 ml) in toluene (140 ml) was added and stirring continued for 18 hours. Water (50 ml) was added and after 2 hours the mixture was cooled in ice and acidified to pH 1 with concentrated hydrochloric acid. The organic layer was separated and the aqueous extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSU4). The solvent was removed in vacuo to give a pale yellow oil This was dissolved in dichoromethane (100 ml) and trifluoroacetic acid (100 ml) added, the mixture was heated at reflux for 1 hour. The volatiles were removed in vacuo and the residue taken up in sodium hydroxide and washed with ethyl acetate. The aqueous layer was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate, this ethyl acetate was washed with water, dried (MgSO 4 ) and the volatiles removed in vacuo to provide the subtitle compound as a buff solid (16.4 g) which was used without further purification Mass spectrum El 214/6 (M) b) 2-f2-f4-ChlorophenvD ' )ethoxy " [acetamide The product from part a) (16 4 g) was dissolved in toluene (300 ml) and oxalyl chloride (13 ml) was added dropwise at room temperature and under nitrogen. The mixture was stirred for 1 hour and then dimethylformamide (0 3 ml) was added After a further 2 hours the volatiles were removed in " vacuo to provide a brown oil which was added dropwise to a stirred solution of concentrated ammonium hydroxide (60 ml) The solid which precipitated out was collected by filtration and washed with water and isohexane to yield the subtitle compound (6 6 g) Mp 106-9° C, Mass spectrum FAB 214/6 (m+H), ll HH nnmmrr ((336600 MMHHzz,, CCDDCC1I 3 3)),, 22 8899 ((27H, t), 3 73 (2H, t), 3 93 (2H,s), 5 87 (IH, brs), 6 22 (IH, brs), 7 16 (2H, d), 7 28 (2H,d) c) 2-f2-(4-ChlorophenvD ethoxylethanamine The product from step b (6 g) was added portion wise to a stirred solution of boranetetrahydrofuran (1 0 M in THF, 85 ml) The reaction was then heated at reflux under an inert atmosphere for 3 hours The reaction was cooled and methanol (10 mis) was cautiously added The solvents were removed in vacuo and the residue redissolved in methanol (100 ml) to which was added concentrated hydrochloπc acid (sg 1 18, 4 ml) This solution was heated at reflux for 30 minutes and then the solvent removed in vacuo The residue was taken up into water and washed with ether Sodium bicarbonate was added and the aqueous extracted with ethyl acetate The ethyl acetate was washed with water, brine and dried (MgSO 4 ) The volatiles were removed in vacuo to provide the subtitle compound as a oil (5 5 g) which was used without further puπfication Mass spectrum El 200/2 (M+H), d) Methyl 3-[2-f2-(4-Chlorophenylkthoxy]ethylaminosulphonyllpropanoate The product from part c (1.1 g) was stirred under nitrogen in dichloromethane (30 ml), triethylamine (1.52 ml) was added followed by methyl 3-(chlorosulphonyl)propanoate (2.04 g). The mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue purified by flash chromatography over silica (60% ether/petrol) to provide the subtitle compound as an oil (1.1 g). M M Maaassssss ssspppeeeccctttrrruuummm FFFAAABBB 333555000///222 (((mmm+++HHH))); H nmr (360 MHz, CDC1 3 ) ; 2.80 (2H, t), 2.82 (2H, t), 3.26 (2H, q), 3.33 (2H, t), 3.54 (2H, t), 3 67 (2H, t), 3.72 (3H, s), 4.63 (IH, t), 7.14 (2H, d), 7.27 (2H, d). e) N-r2-r2-f4-Chlorophenvnethoxy1ethvn-3-r2-r4-hvdroxy-2-oxo-3H-1.3-benzothiazol-7- vOethylan * uno]propanesulphonamide hydrochloride The product from part d (1.1 g) was dissolved in toluene (50 ml) under nitrogen and cooled to -78°C. Diisobutylaluminiumhydride (1.5 M in toluene, 2.6 ml) was added dropwise and the mixture kept at -78°C for 10 minutes. The reaction was quenched with 10% hydrochloric acid in methanol and the mixture allowed to warm to room temperature. The mixture was poured into 10% hydrochloric acid and extracted with ether The combined organic extracts were washed with water then dried over magnesium sulphate and then about 70% ofthe solvent was removed in vacuo. Methanol (20 ml) was added to the mixture and again the about 70% ofthe solvent was removed in vacuo, this was repeated twice more The solution was then diluted with methanol (20 ml) and 7-(2-aminoethyl)-4-hydroxy-l,3-benzothiazol-2(3H)-one hydrochloride (0 92 g) added. The pH was adjusted to pH 4 with glacial acetic acid Sodiumcyanoborohydride (0 247 g) was added and the mixture stirred under nitrogen for 2 hours The mixture was made basic by the addition of concentrated aqueous ammonium hydroxide solution The volatiles were removed in vacuo and the residue purified by flash chromatography (2 5-10% methanol/dichloromethane) The material was further purified by reverse phase HPLC using 50% to 100% methanol in 0 1% aqueous trifluoroacetic acid as eluant to yield, after conversion to the hydrochloride salt, the title compound (0 089 g) as a white solid Mp. 190-3°C, ~ Mass spectrum. FAB 514/6 (M+H), H nmr (360 MHz., d 6 DMSO) 1 99 (2H, m), 2 82 (4H, m), 3 12 (8H, m), 3 45 (2H, t), 3 60 (2H, t), 6 76 (IH, d), 6 87 (IH, d), 730 (5H, m), 8 87 (2H, brs), 10 14 (IH, s), 11 77 (lH, brs), Analysis Found: C, 46.68, H, 5 55, N, 747; S, 10 86%. Required for C22H28N3O5S2 HCl H 2 O, C,46 47, H, 5 50; N, 7.39, S, 11.28% Example 6 3-r2-f4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-yl')ethylamino1-N-f2-r2-<'4- methylphenyl)ethoxy ethyl]propanesulphonamide hydrochloride a) 2-| " 2-f4-Methylpheny0ethoxyacetic acid 2-(4-Methylphenyl)ethanol (8 16 g) was stirred in 50% aqueous sodium hydroxide (25 ml) t-Butylbromoacetate (9 05 ml) in toluene (30 ml) was added together with tetrabutylammoniumbromide (2 2 g) and the mixture stirred for 18 hours Iced water (100 ml) was added followed by ether, the organic layer was separated and then the aqueous layer acidified with hydrochloric acid The acidified aqueous was extracted with ether and this extract was washed with brine, dried (MgSO 4 ) The solvent was removed in vacuo to give the subtitle compound as a white solid (1 1 g) which was used without further purification l H nmr (360 MHz, CDCI3), 2 32 (3H, s), 2 91 (2H, t), 3 77 (2H, t), 4 10 (2H, S), 7 11 (4H, m) b) 2-T2 -(4-MethylphenvOethoxy acetamide The subtitle compound (0 77 g) was prepared according to the procedure in example 1 part b usmg 2-[2-(4-methylphenyl)ethoxy]acetιc acid (1 1 g) oxalyl chloride (1 44 g), concentrated ammonium hydroxide (20 ml), and toluene (40 ml) mp 106-7°C, Mass spectrum FAB 194 (M+H, 100). c) 2-f2-( ' 4-Methylphenyl1ethoxy]ethanamine hydrochloride The subtitle compound (6 25 g) was prepared according to the procedure in example 5 part c usmg 2-[2-(4-methylphenyl)ethoxy]acetamide (5 79 g), borane-tetrahydrofuran solution (1 0 M in THF, 75 ml), and tetrahydrofuran (40 ml) Mass spectrum FAB 180 (M+H, 100), *H nmr (360 MHz, CDCI3), 2.30 (3H, s), 2 87 (2H, t), 3 17 (2H, d), 3 65-3 73 (4H, m), 7 11 (4H, m), 8 30 (2H, brs) d) Methyl 3- r 2-f2-f4-methylphenvDethoxy]ethylammosulphonyl]propanoate The subtitle compound (2 49 g) was prepared according to the procedure in example 5 part d using 2-[2-(4-methylphenyl)ethoxy]ethanamιne hydrochloride (3 5 g) triethylamine 4 74 ml) methyl 3-(chlorosulphonyl)propanoate (3.08 g), and dichloromethane (80 ml) Mass spectrum FAB 330 (M+H, 119 (100) e) 3-r2-(4-hvdroxy-2-oxo-3H-1.3-benzothiazol-7-v0ethylaminol-N-f2-f2- 4- methylphenyl thoxy]ethyl]propanesulphonamide hydrochloride The title compound (0 2 g) was prepared according to the procedure in example 5 part e using methyl 3-[2-[2-(4-methylphenyl)ethoxy]ethylamιnosulphonyl]propanoate (2 49 g), diisobutylalummiumhydride (1 5 M in toluene, 7 5 ml), 7-(2-aminoethyl)-4-hydroxy- l,3-benzothιazol-2(3H)-one hydrochloride (2.2 g) and sodium cyanoborohydride (048 g) m p 213-5°C, Mass spectrum FAB 494 (M+H); ! H nmr (360 MHz , dόDMSO) 1 99 (2H, m), 2.25 (3H, s), 2.74-2 84 (4H, m), 3 06- 3 15 (8H, m), 3 45 (2H, t), 3 57 (2H, t), 6 75 (IH, d), 6 87 (IH, d), 7 10 (4H, m), 7 30 (lH, t), 8 61 (2H, s), 10.11 (IH, s), 11 77 (IH, brs) Example 7 3 - r2-(4-Hvdroxy-2-oxo-3H- 1.3 -berιzothiazol-7-vnethylaminol -N-r2-(2-phenyl- 1 - propoxy)ethyllpropanesulphonamide hydrochloride a) 2-f2-Phenyl-l-propoxy)acetιc acid The subtitle compound (14 95 g) was prepared according to the procedure in example 6 part a using 2-phenyl-l-propanol (13 6 g), t-butylbromoacetate ( 19 5 g), tetrabutylammoniumbromide (3.2 g), toluene (70 ml), 50% aqueous sodium hydroxide (25 ml). H nmr (360 MHz, CDC1 3 ); 1.32 (3H, d), 3.08 (IH, m), 3.67 (2H, t), 4.07 (2H, S), 7.23-7.34 (5H, m). b) 2-(2-Phenyl- 1 -propoxy ' tecetamide The subtitle compound (4.39 g) was prepared according to the procedure in example 5 part b using 2-(2-phenyl-l-propoxy)acetic acid (5.0 g), oxalyl chloride 4.5 ml), concentrated ammonium hydroxide (20 ml), and toluene (30 ml). Mass spectrum GC 134 (M-59); l H nmr (360 MHz, CDCI3); 1.31 (3H, d), 3.05 (IH, m), 3.61 (2H, m), 3.90 (2H, q), 7.22 (3H, m), 7.33 (2H, m). c) 2-f2-Phenyl- l-propoxy)ethanamine hydrochloride The subtitle compound (3.58 g) was prepared according to the procedure in example 5 part c using 2-(2-phenyl-l-propoxy)acetamide (3.86 g), borane-tetrahydrofuran solution (1.0 M in THF, 50 ml), and tetrahydrofuran (40 ml). Mass spectrum GC 180 (M+H). d) Methyl 3-| " 2-f2-phenyl-l -propoxy ' )ethylaminosulphonyl]propanoate The subtitle compound (2.0 g) was prepared according to the procedure in example 5 part d using 2-(2-phenyl-l-propoxy)ethanamine hydrochloride (3.58 g), triethylamine (5 65 ml) methyl (3-chlorosulphonyl)propanoate (3 73 g), and dichloromethane (70 ml) Mass spectrum GC 224 (M-105), H nmr (360 MHz, CDC1 3 ), 1.27 (3H, d), 2 75 (2H, t), 3 02 (IH, m), 3.20-3 29 (4H, m), 3 45-3 56 (4H, m), 3 72 (3H,s), 4.42 (lH,t), 7 21-7.34 (5H, m) e) 3-r2-r4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethylaminol-N-r2-(2-phenyl-l- propoxy)ethyl]propanesulphonamide hydrochloride The title compound (0 164 g) was prepared according to the procedure in example 5 part e using methyl 3-[2-(2-phenyl-l-propoxy)ethylaminosulphonyl]propanoate (1.01 g), diisobutylaluminiumhydride (1 5 M in toluene, 3 ml), 7-(2-aminoethyl)-4-hydroxy- l,3-benzothiazol-2(3H)-one hydrochloride (0 89 g) and sodium cyanoborohydride (0 19 g). m.p 183-4°C, Mass spectrum FAB 494 (M+H); Analysis Found C, 52 42, H, 6 31, N, 8.28, S, 1 1 74%. Required for C23H31N3O5S2 HCl, C, 52 11, H, 6 08; N, 7.93, S, 12 10% Example 8 3-r2-C4-Hvdroxy-2-oxo-3H-1.3-benzothiazol-7-vnethylamino1-N-r2-r2-r2- methylphenv0ethoxy1ethyl]propanesulphonamide hydrochloride a) 2-r2-(2-MethylphenvDethoxy1acetic acid The subtitle compound (8.91 g) was prepared according to the procedure in example 5 part a using 2-(2-methylphenyl)ethanol (5.0 g), t-butylbromoacetate (5.47 ml), tetrabutylammoniumbromide (0.78 g), toluene (80 ml), 50% aqueous sodium hydroxide (40 ml), trifluoroacetic acid (20 ml) and dichloromethane (20 ml). *H nmr (360 MHz, CDC 3 ); 2.34 (3H, s), 2.97 (2H, t), 3.75 (2H, t), 4.13 (2H, S), 7.12- 7 17 (4H, m) 8.14 (lH, brs). b) 2-r2-(2-MethylphenvDethoxy acetamide The subtitle compound (5.02 g) was prepared according to the procedure in example 5 part b using 2-[2-(2-methylphenyl)ethoxy]acetic acid (6.726 g), oxalyl chloride (6.22 ml), concentrated ammonium hydroxide (60 ml), and toluene (60 ml). Mass spectrum FAB 194 (M+H); ! H nmr (360 MHz, CDC1 3 ); 2.22 (3H, S), 2.86 (2H, t), 3.60 (2H, t), 3.80 (2H, S), 7.06-7.19 (4H, m), 7.25 (2H, brs). c) 2-r2-f2-Methylphenv0ethoxykthanamine hydrochloride. The subtitle compound (5.4 g) was prepared according to the procedure in example 5 part c using 2-[2-(2-methylphenyl)ethoxy]acetamide (5.13 g), borane-tetrahydrofuran solution (1.0 M in THF, 53.5 ml), and tetrahydrofuran (100 ml). Mass spectrum FAB 180 (M + +H). d) Methyl 3-f2-[2-(2-methylphenvπethoxy]ethylaminosulphonyl ' |propanoate The subtitle compound (5 4 g) was prepared according to the procedure in example 5 part c using 2-[2-(2-methylphenyl)ethoxy]ethanamιne hydrochlonde (5 4 g) tπethylamine (8 73 ml) methyl 3-(chlorosulphonyl)propanoate (4 66 g), and dichloromethane (100 ml) Mass spectrum FAB 330 (M+H), H nmr (360 MHz, CDC1 3 ), 2 32 f?H, s), 2 71 (2H, t), 2 91 (2H, t), 3 24 (2H, t), 3 34 (2H, t), 3 53 (2H, m), 3 62 (2H, t), 3 70 (3H, s), 4 64 (IH, t), 7 14 (4H, m) 3-r2-r4-Hvdroxy-2-oxo-3H-1.3-benzothιazol-7-vnethylamιnol-N-r2-f2-r2- methylpheny0ethoxy1ethyl]propanesulphonamιde hydrochlonde The product from part d (2 0 g) was dissolved m toluene (100 ml) under nitrogen and cooled to -78°C Diisobutylalumimumhydride (1 5 M in toluene, 6 22 ml) was added dropwise and the mixture kept at -78°C for 10 minutes The reaction was quenched with ethyl acetate followed by a 10% aqueous sodium potassium tartrate solution The mixture was warmed to room temperature and after stirπng for one hour the mixture was extracted with toluene The combined organic extracts were washed with water then dπed over magnesium sulphate and then about 70% ofthe solvent was removed in vacuo Methanol (50 ml) was added to the mixture and agam about 70% of the solvent was removed in vacuo, this was repeated twice more This solution was then diluted with methanol (50 ml) and 7-(2-amιnoethyl)-4-hydroxy-l,3-benzothιazol-2(3H)-one hydrochloπde ( 1 8 g) added The pH was adjusted to pH 4 with glacial acetic acid Sodium cyanoborohydπde (0 398 g) was added and the mixture was stirred under nitrogen for 18 hours The mixture was made basic by the addition of concentrated aqueous ammonium hydroxide solution and the volatiles were then removed in vacuo The residue was puπfied by flash chromatography over silica ( 1 % methanol/dichloromethane) The material was further puπfied by reverse phase HPLC using 35%-85% methanol in 0 1% aqueous tπfluoroacetic acid as eluant to yield, after conversion to the hydrochlonde salt, the title compound (0 38 g) as a white solid m.p. 184-7°C, Mass spectrum FAB 494 (M+H); *H nmr (360 MHz., dόDMSO) 1.74-1.77 (2H, m), 1.99 (2H, t), 2.27 (3H, s), 2.79-2.85 (4H, m), 3.07-3.16 (6H, m), 3.45-3.48 (2H, m), 3.55-3.61 (2H, m) , 6.74 (IH, d), 6.88 (IH, d), 7.08-7.17 (4H, m), 7.32 (IH, t), 8.81 (IH, s), 10.17 (IH, s), 11.77 (IH, brs). Example 9 3-r2-(4-Hvdroxy-2-oxo-3H- 1.3-benzotMazol-7-yl Vethylamino1-N-r2-f2- phenylthioethoxy)ethyl]propanesulphonamide hydrochloride. a) t-Butyl 2-( ' 2-phenylthioethoxy)acetate 2-Phenylthioethanol (6.1 g), t-butylbromoacetate (7.9 ml), tetrabutylammoniumbromide (1.3 g), toluene (80 ml), and 75% aqueous sodium hydroxide (40 ml) were stirred together for 72 hours. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organics were washed with brine, dried (MgSO4) and the solvent was removed in vacuo to provide the subtitle compound (12.07 g). Mass spectrum FAB 269 (M+H). b) 2-(2-Phenylthioethoxy)acetamide The product from part a (12.07 g) was dissolved in dichoromethane (50 ml) and trifluoroacetic acid (50 ml) was added, the mixture was stined for 2 hours. The volatiles were removed in vacuo and the residue taken up in aqueous sodium bicarbonate and washed with ether. The aqueous layer was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgSO4) and the volatiles removed in vacuo. The residue was dissolved in toluene (50 ml) and oxalyl chloride (50 ml) was added dropwise at room temperature and under nitrogen. Dimethylformamide (0.3 ml) was added dropwise and the mixture was stirred for 45 minutes. Volatiles were removed and the crude acid chloride was added dropwise to a stirred solution of concentrated ammonium hydroxide (50 ml) at -TO°C. The solid which precipitated out was collected by filtration and washed with water and ether to yield the subtitle compound (3.53 g). Mass spectrum FAB 212 (M+Fϊ); H nmr (360 MHz, CDC1 ); 3.13 (2H, t), 3.72 (2H, t), 3.95 (2H, s), 5.58 (IH, brs), 6.56 (IH, brs), 7.20-7.39 (5H, m). c) 2-f2-Phenylthioethoxy)ethanamine hydrochloride. The subtitle compound as its hydrochloride salt (6.0 g) was prepared according to the procedure in example 5 part c using 2-(2-phenylthioethoxy)acetamide (5.5 g), boranetetrahydrofuran solution (1.0 M in THF, 60 ml), and tetrahydrofuran (60 ml). d) Methyl 3-[2-(2-phenylthioethoxy)ethylaminosulphonyl]propanoate The subtitle compound (2.85 g) was prepared according to the procedure in example 5 part d using 2-(2-phenylthioethoxy)ethanamine hydrochloride (6 g), triethylamine (4 ml) methyl 3-(chlorosulphonyl)propanoate (5.8 g), and dichloromethane (50 ml). Mass spectrum FAB 348 (M+105). e) 3 - f 2-(4-Hvdroxy-2-oxo-3 H- 1.3 -benzothiazol-7-yl thylaminol-N-r2-f 2- phenylthioethoxy)ethyπpropanesulphonamide hydrochloride. The title compound (0.106 g) was prepared according to the procedure in example 8 s part e using methyl 3-[2-(2-phenylthioethoxy)ethylaminosulphonyl]propanoate (1.4 g), diisobutylaluminiumhydride (1.5 M in toluene, 3 ml), 7-(2-aminoethyl)-4-hydroxy-l,3- benzothiazol-2(3H)-one hydrochloride (1.2 g) and sodium cyanoborohydride (0.3 g). m.p. 193-4°C; o Mass spectrum FAB 512 (M+H); H nmr 360 MHz., dόDMSO) 2.06 (2H, m), 2.85 (2H, m), 3.08 (6H, m), 3.15 (4H, m), 3.46 (2H, t), 3.59 (2H, t), 6.76 (IH, d), 7.19 (IH, m), 7.31-7.36 (4H, m), 9.06 (2H, s), 10.17 (1H. S), 11.78 (lH. br). 5 Pharmacological Example The binding affinities of compounds ofthe above Examples for the DA2 receptor binding sites in bovine pituitary membranes were determined from the displacement of fH]-N-n -propylnorapomorphine and of [ H -spiperone in the absence or presence of nonhydrolysable GTP analogue respectively, D.R.Sibley, A. DeLean and I. Creese, Anterior Pituitary Dopamine Receptors, Demonstration of Interconvertible High and Low Affinity States ofthe D-2 Dopamine Receptor, J. Biol. Chem., 1982, 257(1 1), 6351-6361. The DA2-receptor activity was also demonstrated in a functional screen, the rabbit isolated ear artery, as described by Brown and O'Connor, Br. J. Pharmacol., 1981, 73, 189P. β2-adrenoreceptor activity was demonstrated in the isolated trachea ofthe guinea pig, as described by I.G. Dougall, D. Harper, D M. Jackson, and P. Leff, Br. J. Pharmacol., 1991, 104, 1057. cti-Receptor activity was determined in the rabbit isolated ear artery using the following method: Rabbit isolated ear artery Male NZW rabbits (2.5-3.0 kg) were killed by intravenous injection of pentobarbitone sodium (60 mg/kg). The ears were removed and the proximal portion ofthe middle ear artery exposed and cannulated using a polypropylene cannula (0 75mm external diameter). After removal, the artery was cleared of adherent connective tissue and 6 rings, 5 mm wide, were prepared preserving the plane ofthe circular smooth muscle. Tissues were mounted on fine tungsten wire hooks (0.25mm diameter) in 20 ml organ baths containing Krebs solution ofthe following composition (mM) : NaCI 117.56; NaHCO 3 25.00; KCI 5.36; NaH 2 PO 4 0.89; MgSO 4 1.18; glucose 11.10 and CaCl 2 2.55. Cocaine (30μM) and propanolol (lμM) were included in the Krebs solution to block neuronal uptake and β- receptors respectively. Ascorbate (lOOμM) was also added to prevent catecholamine oxidation. This solution was maintained at 37°C and continuously gassed with 95% O 2 : 5% CO 2 The upper wire hook was attached to an Ormed force displacement transducer, the lower hook being attached to a stationary support in the bath. Changes in isometric force were recorded on Advance Bryans AB500 flat-bed recorders. Experimental General At the beginning of each experiment, a force of 1 0g was applied to each tissue This force was reinstated two or three times during a stabilisation period of approximately 60 min. until it remained constant. At the same time as the force was reinstated the baths were washed out. Agonist concentration-effect, E/[A], curves were constructed by cumulative additions of agonist at 0.5 logio increments. Responses (contractions) were recorded as a percentage ofthe maximum response ofthe standard agonist. Quantification of agonism Phenylephrine has been adopted as the standard agonist. An E/[A] curve to phenylephrine was constructed first. The phenylephrine was then washed out and an E/[A] curve to the test compound was constructed. Responses of compounds that produced agonism were expressed as a percentage ofthe maximum response to phenylephrine. The value ofthe asymptote ofthe test compound curve relative to phenylephrine indicated the intrinsic activity ofthe compounds. (Phenylephrine was assumed to have an intrinsic activity of 1). The p[A 5 o] value is a measure of agonist potency. It is the negative logarithm ofthe agonist concentration which produces a response that is half the maximum response. For compounds with intrinsic activities significantly less than 1, i.e. =<0.8, it is possible to calculate efficacy (τ) values and affinity (pK A ) values using the comparative method of analysis. This analysis assumes that phenylephrine is acting as a full agonist in this system and thus uses it to define the operational model parameters E™ and n (ref. Leff, et al., "Estimation of agonist affinity and efficacy by direct and operational model fitting.," J. Pharmacol. Methods., 1989, 23, 225-237). These parameters can then be utilised to perform a comparative analysis on the test compound to be made. Affinity is expressed as a pK A (the negative logarithm of the agonist concentration that occupies half of the receptors). Quantification of antagonism Compounds that did not demonstrate agonism were investigated as antagonists by incubating tissues with as high a concentration ofthe compound as possible and subsequently constructing phenylephrine curves E/[A] curves. The degree of rightward shift of these phenylephrine curves compared to the control phenylephrine curve allowed an estimation ofthe affinity of a test compound to be made. Such affinity estimates are shown as pA 2 values (negative logarithm ofthe concentration of antagonist that produces a 2-fold rightward displacement ofthe control E/[A] curve) Confirmation of α mediated agonism Prazosin has been adopted as the standard α- antagonist. If a test compound showed agonism then, upon reaching the asymptote ofthe test compound E/[A] curve, prazosin (lμM) was added to see if the response was reversed. If an α- antagonist reverses the response ofthe test compound this suggests that the agonism is α* mediated.

Claims: Claims 1 A compound of formula I, including optical isomers thereof, wherein X represents -SO2NH- or -NHSO2-, p, q and r independently represent 2 or 3, Y represents thienyl optionally substituted by alkyl or halogen, or phenylthio- or phenyl optionally substituted by alkyl or halogen, and each R independently represents H or alkyl, and pharmaceutically acceptable salts, esters and amides thereof. 2. A compound as claimed in claim 1, wherein q is 2. 3. A compound as claimed in claim 1, wherein r is 2. 4. A compound as claimed in claim 1, wherein Y is phenyl substituted by methyl. 5 A compound as claimed in claim 1 , wherein Y is phenyl substituted by a halogen substituent selected from a chloro- or fluoro-substituent. 6 A compound as claimed in claim 1, wherein X is SO 2 NH, p is 3 and q and r are each 2 7 A compound as claimed in claim 1, wherein X is NHSO 2 , and p, q and r are all 2. 8 A compound as claimed in any preceding claim, in the form ofa pharmaceutically acceptable salt selected from the hydrochloride, citrate, D,L-lactate, hemisulphate, hemitatrate, D-gluconate, methanesulphonate, p-toluenesulphonate, hemifumarate, benzoate, xinafoate, hemisuccinate, 3-hydroxy-2-naphthoate, hemiembonate, hemimaleate, D-camphorsulphonate, 10-undecanoate7 mandelate, naphthalene- 1 -sulphonate, naphthalene- 2-sulphonate, 4-methoxybenzoate, 4-chlorobenzoate, 5-methylsalicylate, saccharinate, monomethyl suberate, hemisuberate and diphenyl acetate salts. 9 A compound as claimed in claim 1 , selected from 3-[2-(4-Hydroxy-2-oxo-3H-l,3-benzothiazol-7-yl)ethylamino]-N-[2-(2-phenylethoxy)ethyl] propanesulphonamide; N-[2-[2-(4-Hydroxy-2-oxo-3H-l,3-benzothiazol-7-yl)ethylamino]ethyl]-2-(2- phenylethoxy)ethanesulphonamide, 3-[2-(4-Hydroxy-2-oxo-3H-l,3-berιzothiazol-7-yl)ethylamino]-N-[2-[2-(5-methyl-2- thienyl)ethoxy]ethyl]propanesulphonamide; N-[2-[2-(4-Fluorophenyl)ethoxy]ethyl]-3-[2-(4-hydroxy-2-oxo-3H-l,3-benzothiazol-7- yl)ethylamino] propanesulphonamide, N-[2-[2-(4-Chlorophenyl)ethoxy]ethyl]-3-[2-(4-hydroxy-2-oxo-3H-l,3-benzothiazol-7- yl)ethylamino]propanesulphonamide; 3-[2-(4-Hydroxy-2-oxo-3H-l , 3-benzothiazol-7-yi)ethylamino]-N-[2-[2-(4- methylphenyl)ethoxy]ethyl]propanesulphonamide; (R,S)-3-[2-(4-Hydroxy-2-oxo-3H- 1 ,3-benzothiazol-7-yl)ethylamino]-N-[2-(2-phenyl- 1 - propoxy)ethyl]propanesulphonamide; 3-[2-(4-Hydroxy-2-oxo-3H- 1 ,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(2- methylphenyl)ethoxy] ethyl] propanesulphonamide; and 3-[2-(4-Hydroxy-2-oxo-3H- 1 ,3-benzotBazol-7-yl)ethylamino]-N-[2-(2- phenylthioethoxy)ethyl]propanesulphonamide. 10. A compound as claimed in claim 9, in the form ofthe hydrochloride salt. 11. A method for the production ofa compound as claimed in any of claims 1-10, comprising selective reductive alkylation ofa compound of formula JJ, with a compound of formula IH, R I 0=CH-(CH 2 ) -X-(CH 2 ) q -O-(CH) r -Y in which p, q, r, R, X and Y are as defined in claim 1, in the presence of a reducing agent. 12. A process for preparing a compound as claimed in any of claims 1-10, comprising the selective reduction ofa compound of formula IV, in which p, q, r, R, X and Y are as defined in claim 1 above. 13. A process for preparing a compound as claimed in any of claims 1-10, comprising alkylation ofthe compound of formula II, or a salt, ester or amide thereof, with an alkylating agent of formula VI R I L-(CH 2 ) p -X-(CH 2 ) q -O-(CH) r -Y VI in which p, q, r, R, X and Y are as defined in claim 1 and L represents a good leaving group selected from chloride, bromide, iodide and methanesulphonyloxy. 14. A process for preparing a compound as claimed in any of claims 1-10, comprising selective reduction of a compound of formula VII, in which p, q, r, R, X and Y are as defined in claim 1. 15. Compounds of formula IV, in which p, q, r, R, X and Y are as defined in claim 1. 16. Compounds in which p, q, r, R, X and Y are as defined in claim 1. 17. Compounds of formula HI R I O=CH-(CH 2 ) p . 1 -X-(CH 2 ) q -O-(CH) r -Y III in which p, q, r, R, X and Y are as defined in claim 1. 18 Compounds of formula V R HOOC-(CH 2 ) -X-(CH 2 ) q -O-(CH) r -Y V in which p, q, r, R, X and Y are as defined in claim 1. 19. Use ofa compound of formula L or a pharmaceutically acceptable salt, ester or amide thereof, in therapy. 20. Use ofa compound of formula I, or a pharmaceutically acceptable salt, ester or amide thereof, in the manufacture ofa medicament for the treatment of obstructive airways disease, in particular for the treatment of asthma or chronic bronchitis. 21. A method of treatment of airways disease, which method comprises administering a therapeutically effective quantity ofa compound of formula I, or a pharmaceutically acceptable salt, ester or amide thereof, to a patient suffering from or susceptible to such a condition. 22. A pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, ester or amide thereof, dispersed in a propellant optionally including excipients, lubricants or stabilising agents. 23. A pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, ester or amide thereof, in the form ofa nebulised aqueous suspension or solution optionally with a pH and/or tonicity adjustment. 24. A pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, ester or amide thereof, in the form ofa dry powder for inhalation, optionally including a pharmaceutically acceptable carrier.

Inventors: BONNERT ROGER VICTOR, BROWN ROGER CHARLES, CAGE PETER ALAN, INCE FRANCIS, PAIRAUDEAU GARRY, BONNERT, ROGER, VICTOR, BROWN, ROGER, CHARLES, CAGE, PETER, ALAN, INCE, FRANCIS, PAIRAUDEAU, GARRY
Applicants: ASTRA PHARMA PROD, BONNERT ROGER VICTOR, BROWN ROGER CHARLES, CAGE PETER ALAN, INCE FRANCIS, PAIRAUDEAU GARRY, ASTRA PHARMACEUTICALS LIMITED, BONNERT, ROGER, VICTOR, BROWN, ROGER, CHARLES, CAGE, PETER, ALAN, INCE, FRANCIS, PAIRAUDEAU, GARRY
Application year: 1996
Main classification: C07D277
IPC codes: A61K31, A61P11, A61P29, C07C311, C07C323, C07D277, C07D333, C07D417