GB2124622A

GB2124622A - Thiadiazole derivatives

Info

Publication number: GB2124622A
Application number: GB08318525A
Authority: GB
Inventors: Barry John Price; Roger Hayes; David Edmund Bays; John Wilson Macfarla Mackinnon
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1982-07-08
Filing date: 1983-07-08
Publication date: 1984-02-22
Also published as: SE8303913L; FR2532937A1; NL8302450A; ZA835009B; AU1666583A; DE3324771A1; IT8348653A0; SE8303913D0; JPS5927880A; GB8318525D0; DK317283A; DK317283D0; BE897247A

Abstract

The invention relates to compounds of the general formula (I> <IMAGE> and physiologically acceptable salts, solvates and hydrates thereof, in which R1 represents hydrogen, C1-14 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl, heteroaralkyl or alkyl substituted by cycloalkyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino; and R2 represents hydrogen or a C1-4 alkyl group; or R1 and R2 together with the nitrogen atom to which they are attached form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C1-3 alkyl groups or a hydroxy group and/or may contain another heteroatom selected from oxygen or sulphur; Alk represents a straight or branched alkylene chain or 1 to 3 carbon atoms; Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1- and 3- or 1- and 4-positions; R5 represents hydrogen or acyl; n and m, which may be the same or different, are each 1 or 2; R3 represents hydrogen or alkyl; R4 represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, pyridyl, aralkyl, heteroaralkyl or alkyl substituted by hydroxy, C1-3 alkoxy, amino C1-3 alkylamino or C1-3 dialkylamino, or R3 and R4 together with the nitrogen atom to which they are attached form a 5-7 membered ring which may contain another heteroatom; and r represents an integer which is 1 or 2. The compounds of formula (I) show biological activity as selective histamine H2-antagonists.

Description

SPECIFICATION Heterocyclic derivatives This invention relates to novel heterocyclic derivatives having action on histamine receptors, to processes for the preparation thereof, to pharmaceutical compositions containing them and to their use in therapeutics.

Certain novel heterocyclic derivatives have now been found which have potent activity as H2antagonists. These compounds, which are more particularly described below, for example show inhibition of the secretion of gastric acid when this is stimulated via histamine receptors (Ash and Schild, Brit. J. Pharmacol. Chemother, 1966, 27, 427). Their ability to do so can be demonstrated in the perfused rat stomach using the method described in British Patent Specification Number 1565966, modified by the use of sodium pentobarbitone (50 mg/kg) as anaesthetic instead of urethane, and in conscious dogs equipped with Heidenhain pouches using the method described by Black eft at Nature 1972 236, 385. Furthermore the compounds antagonise the effect of histamine on the contraction frequency of isolated guinea pig right atrium.

Compounds with histamine H2-blockin g activity may be used in the treatment of conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration, as a prophylactic measure in surgical procedures, and in the treatment of allergic and inflammatory conditions where histamine is a known mediator. Thus they may be used for example, either alone or in combination with other active ingredients in the treatment of allergic and inflammatory conditions of the skin.

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

and physiologically acceptable salts, solvates and hydrates thereof, in which R1 represents hydrogen, C1~,4 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl, heteroalkyl or alkyl substituted by cycloalkyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino; and R2 represents hydrogen or a C14 alkyl group; or R1 and R2 together with the nitrogen atom to which they are attached form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C13 alkyl groups, e.g. methyl, or a hydroxy group and/or may contain another heteroatom selected from oxygen or sulphur; Alk represents a straight or branched alkylene chain of 1 to 3 carbon atoms; Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1 - and 3- or 1- and 4- positions; R5 represents hydrogen or acyl; n and m, which may be the same or different, are each 1 or 2; R3 represents hydrogen or alkyl;; R4 represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, pyridyl, alkyl, heteroaralkyl or alkyl substituted by hydroxy, C,,"alkoxy, amino, C 1-3 alkylamino or C 1-3 dialkylamino, or R3 and R4 together with the nitrogen atom to which they are attached form a 5-7 membered ring which may contain another heteroatom e.g. oxygen; and r represents an integer which is 1 or 2.

The term "alkyl" as a group or part of a group means that the group is straight or branched, and unless otherwise stated, has 1 to 6 carbon atoms and in particular 1 to 4 carbon atoms, e.g. methyl or ethyl, and the terms "alkenyl" and "alkynyl" mean that the groups contain 3 to 6 carbon atoms. The term "cycloalkyl" means that the group has 3 to 8 carbon atoms. The term "aryl" as a part of a group when applied to the group R1 preferably means phenyl or substituted phenyl, for example phenyl substituted with one or more C13 alkyl or alkoxy groups or halogen atoms, e.g. fluorine. The term "aryl" as part of a group when applied to the group R4 preferably means phenyl. The term "acyl" means an aroyl, e.g. benzoyl, aralkanoyl e.g. phenylacetyl, or C16 alkanoyl group, e.g. acetyl.The term "heteroaryl" as part of a group when applied to the group R, means a 5 or 6 membered monocyclic ring containing from 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, e.g. thienyl, pyrrolyl, pyridyl, furyl or thiazolyl which may optionally be substituted by C13 alkyl, C13 alkoxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. The term "heteroaryl" as part of a group when applied to the group R4 preferably means pyridyl, furyl or imidazolyl. The alkyl portion of a heteroaralkyl group is a straight or branched C 1-4 alkyl chain, and the heteroaryl ring is linked to the alkyl portion through a carbon atom.

Preferred compounds of formula (I) are those in which R1 represents C18 alkyl (e.g. methyl, propyl, butyl or heptyl), C14 alkyl substituted by a trifluoromethyl group (e.g. 2,2,2-trifluoroethyl), C24 alkyl substituted by hydroxy or a di C 1-3 alkyl amino group (e.g. 3-hydroxypropyl or dimethylaminoethyl), C57 cycloalkyl (e.g.

cyclohexyl), C35 alkenyl (e.g. allyl), phenyl C13 alkyl (e.g. benzyl), or a heteroaryl C13 alkyl group where the heteroaryl ring contains one heteroatom (e.g. 2-furylmethyl); R2 represents hydrogen or methyl; or R1R2N represents a 5 to 7 membered ring optionally containing a double bond, an oxygen atom or an alkyl (e.g. methyl) substituent (e.g. piperidino, morpholino, 4-methylpiperidino, pyrrolidino, hexamethylenimino or tetrahydropyridino); Alk represents methylene; Q represents a benzene ring incorporated into the rest of the molecule through bonds at the 1 and 3- positions; R3 represents hydrogen;; R4 represents hydrogen, C1-6 alkyl, alkenyl, alkynyl, phenyl, phen C14 alkyl, pyridyl C13 alkyl, furyl C13 alkyl or imidazolyl C13 alkyl, or C,, alkyl substituted by hydroxy or C 1-3 alkoxy; R5 represents hydrogen or alkanoyl; and the sum of n and m is 2 or 3.

More preferably R,R2N represents di-C1-4 alkylamino (e.g. dimethylamino), furylmethylamino or a 5 to 7 membered ring such as piperidino or hexamethylenimino; R3 represents hydrogen; R4 represents hydrogen, C 1-4 alkyl (e.g. methyl or n-propyl), C36 alkynyl (e.g. 2-propynyl), phenyl, pyridyl C13 alkyl (e.g. 3-pyridylmethyl), furyl C13 alkyl (e.g. 2-furylmethyl), or C24 alkyl substituted by hydroxy or C13 alkoxy (e.g. 2-hydroxyethyl or 2-methoxyethyl) and R5 represents hydrogen or alkanoyl (e.g. acetyl).

A particularly preferred group of compounds are those of the formula (IA)

and physiologically acceptable salts, solvates and hydrates thereof, in which R,R2N is dimethylamino, or a 5, 6 or 7 membered ring (e.g. piperidino or hexamethylenimino); the sum of n and m is 2 or 3; r represents 1 or 2; R5 represents hydrogen or acetyl; and R4 represents hydrogen, C14 alkyl (e.g. methyl or n-propyl), propynyl, pyridylmethyl (e.g. 3-pyridylmethyl), hydroxy C24 alkyl (e.g. hydroxyethyl) or C13 alkoxy C24 alkyl (e.g. methoxyethyl).

Particularly preferred compounds are: 1 -[(4-amino-i ,2,5-thiadiazol-3-yl)amino]-3-[3-( 1 -piperidinylmethyl)phenoxy]-2-propanol S,S- dioxide; 1 -[(4-a mino- ,2,5-thiadiazol-3-yl)amino]-3-[3-(1 -piperidinylmethyl)phenoxy]-2-propanol Soxide; 1 1-[[4-(methylamino)-1 ,2,5-thiadiazol-3-yl]amino]-3-[3-( 1 -piperidinylmethyl)phenoxyl;2- propanol S-oxide; 1 1-[[4-(methylamino)- ,2,5-thiadiazol-3-yl]amino]-3-[3-( 1 -piperidinylmethyl)phenoxy]-2- propanol S,S-dioxide; 1 -[3-( 1 -piperidinylmethyl)phenoxy]-3-[[4-(propylamino) 1 ,2,5-thiadiazol-3-yl]amino-2-propanol S,S-dioxide; 1 -[(4-amino-i ,2,5-thiadiazol-3-yl)amino]-4-[3-( 1 -piperidinylmethyl)phenoxy]-2-butanol S,S- dioxide;; 1 -[3-( 1 -piperidinylmethyl)phenoxy]-3-[[4-[(3-pyridinylmethyl)amino]- 1 ,2,5-thiadiazol-3-ylj- amino-2-propanol S,S-dioxide; 1 -[[4-[(2-methoxyethyl)amino]-1 ,2,5-thiadiazol-3-yl]amino]-3-[3-( 1 -piperidinylmethyl)phenoxy]-2-propanol S,S-dioxide; 1 -[(4-amino-1,2,5-thiadiazol-3-yl)amino]-3-[3-(1 -dimethylaminomethyl)phenoxyj-2-propanol S,S-dioxide; 1 -[(4-a mino- ,2,5-thiadiazol-3-yl)aminoi-3-[3-( 1 -piperidinylmethyl)phenoxy]-2-prnpanol S,Sdioxide, acetate (ester); and 1 -[(4-amino- 1 ,2,5-thiadiazol-3-yl)amino]-3-[3-[(hexahydro- 1 K-azepin-1 -yl)methyl] phenoxy]-2- propanol S,S-dioxide; and physiologicaliy acceptable salts thereof.

The invention includes the compounds of formula (I) in the form of physiologically acceptable salts with inorganic and organic acids. Particularly useful salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, acetates, maleates, succinates, citrates, tartrates, fumarates and benzoates. The compounds of formula (I) and their salts may also form hydrates and solvates which contain organic solvents such as ethanol, which hydrates and solvates are also to be considered as part of the invention. The compounds of formula (I) can exhibit tautomerism and the formula is intended to cover all tautomers. Where optical isomers may exist the formula is intended to cover all diastereoisomers and optical enantiomers and mixtures thereof. The invention also includes bioprecursors of the compounds of formula (I).Bioprecursors are compounds having a formula different from formula (I) but which on administration to the human or animal body are converted into a compound of formula (I).

The compounds according to the invention, preferably in the form of a salt may be formulated for administration in any convenient way and the invention includes within its scope pharmaceutical compositions containing at least one compound according to the invention adapted for use in human or veterinary medicine. Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Such compositions may also contain if required other active ingredients e.g. H,-antagonists.

Thus the compounds according to the invention may be formulated for oral, buccal, topical parenteral or rectal administration. Oral administration is preferred.

For oral administration, the pharmaceutical compositions may take the form of for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative. The compositions may take such forms as supensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water before use.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.

For topical application, the compounds of the invention may be formulated as ointments, creams, gels, lotions, powders or sprays in a conventional manner.

For internal administration a convenient daily dosage regime of the compounds according to the invention would be 1 to 4 doses to the total of some 5 mg to 1.5 g per day, preferably 5 to 500 mg per day dependent upon the condition of the patient.

It will be appreciated that in the methods for the preparation of compounds of formula (I) given below, for certain reaction steps it may be necessary to protect various reactive substituents in the starting materials for a particular reaction and subsequently to remove the protecting group. Such protection and subsequent deprotection may be particularly pertinent where R, and/or R2 in intermediates used to prepare compounds of formula (I) are hydrogen atoms. Standard protection and deprotection procedures can be employed. For example an amino group may be protected by formation of a phthalimide which may subsequently be cleaved by treatment with a hydrazine, e.g. hydrazine hydrate or a primary amine, for example methylamine.

In describing the processes which may be used for preparing the compounds of formula (I) or intermediates useful in the preparation thereof, any of R1 to R5, Alk, O, n, m and r are as defined in formula (I) unless otherwise stated.

Compounds of formula (I) in which R5 represents hydrogen may be prepared by reacting a diamine of formula (II)

with a compound of formula (Ill)

in which R6 is the group -NR3R4 or a group convertible thereto, and P is a leaving group such as alkoxy, e.g. methoxy or ethoxy, or alkylthio, e.g. methylthio.

In one embodiment of this process the diamine (II) may be reacted with a compound of formula (Ill) in which R6 is the group -NR3R4. The reaction may be carried out in the absence or presence of a suitable solvent such as an alkanol, e.g. methanol, at a temperature from 0--1000, preferably at room temperature.

Alternatively, the diamine (II) may be reacted with a compound of formula (III) in which R6 is a group convertible into the group -NR3R4 e.g. a leaving group such as alkoxy (e.g. methoxy or ethoxy), phenoxy or alkylthio (e.g. methylthio), more particularly methoxy, in the presence of a solvent e.g.

methanol or tetrahydrofuran at a temperature in the range of --800 to +500 preferably 5 to +300, followed by subsequent conversion of the leaving group R6 into the group -NR3R4. This may be achieved by reaction with the appropriate amine R3R4NH in the absence or presence of a suitable solvent such as an alkanol e.g. methanol, at a temperature from 0--1000, preferably at room temperature.

Compounds of formula (I) in which R5 is acyl may be prepared by treating a compound of formula (IV)

in which R6 is the group -NR3R4 our a group convertible thereto, with an acid corresponding to the acyl group R5 or an activated derivative thereof (e.g. an acid anhydride or acid chloride), and where R6 is a group convertible into the group -NR3R4, converting the group R6 into the group -NR3R4. The reaction with an acid may be carried out at a temperature of 500 to the reflux temperature of the acid.

The reaction with the activated derivative of an acid may be carried out at a temperature of --100 to + 1000, optionally in the presence of a solvent (e.g. pyridine, tetrahydrofuran, acetone or dimethylformamide), and optionally in the presence of a base (e.g. pyridine, triethylamine or an alkali metal carbonate such as potassium carbonate). When one or both of R3 and R4 is hydrogen or R4 contains a hydroxy or NH group, it may be appropriate to carry out the above acylation reaction on a compound of formula (IV) in which R6 is a group convertible into the group NR3R4 e.g. methoxy, followed by subsequent convertion of the group R6 into NR3R4 as described above.

Compounds of formula (I) in which Alk is CH2 and R6 is hydrogen may be prepared by treating an aldehyde of formula (V)

with an amine R 1R2NH in a solvent such as tetrahydrofuran or an alkanol, e.g. ethanol, followed by reduction using for example a hydride reducing agent such as an alkali or alkaline earth metal borohydride, e.g. sodium borohydride or lithium aluminium hydride, or hydrogen and a metal catalyst such as palladium or platinum. The reactions may be carried out at a temperature of 0 to 30"C. In this process the group NR3R4 may in certain instances (particularly when R3 and R4 both represent hydrogen) be converted into another meaning within the definition of NR3R4.

The intermediates of formula (V) may be prepared from compounds of formula (VI)

in which W represents a protected aldehyde group, e.g. a cyclic acetal such as an ethylene acetal, by methods analogous to those described herein for preparing compounds of formula (I) from the amine of formula (II).

Diamines of formula (II) and intermediates of formula (VI) may be prepared by the methods described in European Patent Application Publication No. 0071434, or methods analogous thereto.

Intermediates of formula (it1) are either known compounds or may be prepared by methods analogous to those described in European Patent Application Publication No. 0040696.

Where the product of any of the above processes is a free base and an acid addition salt, particularly a physiologically acceptable salt is required, the salt may be formed in conventional manner. Thus, for example, a generally convenient method of forming the salts is to mix appropriate quantities of the free base and the acid in an appropriate solvent(s) e.g. an alcohol such as ethanol or an ester such as ethyl acetate. The invention also includes conversion of one salt of the compound of formula I into another.

The invention is illustrated but not limited by the following Preparations and Examples.

In the following Examples and Preparations temperatures are in C and the following abbreviations are used: Compound A: 3,4-Dimethoxy-1 2,5-thiadiazole 1,1-dioxide Compound B: 3,4-Dimethoxy-1 2,5-thiadiazole 1-oxide Compound C: 1 -Amino-3-[3-( 1 -piperidinylmethyl)-phenoxy]-2-propanol Compound D: 1 -Amino-3-[3-( 1 ,3-dioxolan-2-yl)phenoxy]-2-propanol In n.m.r. spectra values are used.

Unless otherwise stated column chromatography was carried out on Merck Kieseigel 60 (7734) silica using one of the following solvent systems: System A; methanol : 0.88 ammonia (200:1) System B; dichloromethane : ethanol :0.88 ammonia (10:8:1) System C: dichloromethane : ethanol :0.88 ammonia (25 : 8 1) System D; dichloromethane : ethanol : 0.88 ammonia (50 : 8 1) System E; dichloromethane : ethanol : 0.88 ammonia (100 : 8 1) Preparative High Performance Liquid Chromatography (HPLC) was carried out using a DuPont Zorbax-Sil 21.2 mmx25 cm column.

Preparation 1 2-[3-[3-(1,3-Dioxolan-2-yl)phenoxy]-2-hydroxypropyl]-1 H-isoindole-1 ,3(2H)-dione A mixture of 2-(oxiranylmethyl)-1H-isoindole-1,3(2H)-dione (60.9 g) and 3-(1,3-dioxolan-2- yl)phenol (49.0 g) in xylene (300 ml) was heated at 1400 under nitrogen for 24 h. Sodium hydride (0.5 g) was added and the mixture was heated for a further 2 h at 1400. The mixture was cooled and evaporated and the residue was dissolved in chloroform, washed with 2N sodium hydroxide, dried and evaporated to give the title compound (61 g) as a white solid mp. 114--116 .

Preparation 2 1 -Amino-3-[3-( 1 ,3-dioxolan-2-yl)phenoxyi-2-propanol 2-[3-[3-( 1 ,3-dioxolan-2-yl)phenoxyj-2-hydroxypropyl]- 1 H-isoindole- 1 ,3(2H)-dione (45 g) was dissolved in tetrahydrofuran (500 ml) and stirred with hydrazine hydrate (25 ml) at room temperature for 72 h. The precipitate was removed by filtration and washed with diethyl ether. The filtrates and washings were combined and evaporated to give a white solid (22 g) which was continuously extracted with hot diethyl ether. On cooling the ether solution white crystals formqd which were filtered off and dried to give the title compound (14 g) as a white solid, m.p. 58--63 .

Preparation 3 3-Amino-4-methoxy-1 2,5-thiadiazole 1,1-dioxide Hexamethyldisilazane (0.41 g) was added dropwise to a stirred solution of compound A (0.51 g) in dry dichloromethane (2.5 ml) at room temperature. The reaction mixture was stirred for 24 h and chromatographed, using 4% methanol/dichloromethane, to give the title compound (0.19 g) as a white solid, m.p. 1671710.

Preparation 4 4-Methoxy-N,N-dimethyl-1 ,2,5-thiadiazol-3-amine 1,1-dioxide A solution of dimethylamine (0.70 g) in dry methanol (25 ml) was added dropwise to a stirred suspension of compound A (2.79 g) in dry methanol (25 ml), at room temperature, to produce a colourless solution. The reaction mixture was stirred for 2 h and filtered to give the title compound (2.10 g) as a white solid, m.p. 1331360.

Example 1 1-[(4-Amino-1,2,5-thiadiazol-3-yl)aminoj-3-[3-(1-piperidinyl methyl)phenoxyj-2-propanol s,s- dioxide hydrate A solution of compound C (1.06 g) in methanol (25 mi) was added dropwise to a stirred suspension of compound A (0.71 g) in methanol (20 ml) and the mixture stirred at 05 0 for 2 h.

Anhydrous ammonia was bubbled into the solution for 10 min and the mixture stirred at ambient temperature for 17 h. The solution was evaporated to give a white foam which was chromatographed using system A to give a gum. This material was chromatographed using system B to give the title compound (0.38 g) as a paie yellow foam, m.p. ca 1000 (softens).

N.m.r. (CDCl3+d4MeOH) 2.73-3.33, m, (4H); 5.80, m, (1 H): 5.95, m, (2H); c6.30, m, (4H); c7.30, m, (4H); c8.40, m, (6H).

Example 2 a) 1 -[[4-(Methylamino)- 1 ,2,5-thiadiazol-3-yl]amino]-3-[3-( 1 -piperidin ylmethyl)phenoxy]-2-propanol S,S-dioxide A solution of compound C (1.2 g) in methanol (25 ml) was added dropwise to a stirred suspension of compound A (0.80 gi in methanol (20 ml) and the mixture stirred at room temperature for 30 min. Anhydrous methylamine was bubbled into the solution for 1 5 min and the mixture was stirred at ambient temperature for 1 h. The solution was evaporated to give a yellow foam which was chromatographed using system C to give the title compound (1.27 g) as a white foam, m.p. 8595 (softens), 146--1480 (flows).

N.m.r. (C5D5N) 2.71, t, ( 1 H); 2.88-3.14, m, (3H); 5.46, m, (1 H); 5.84, d, (2H); 5.94-6.20, ABX, (2H): 6.48, s, (2H); 7.08, s, (3H); 7.64, m (4H); 8.50, m, (4H); 8.65, m, (2H).

b) Similarly prepared by this procedure from compound C (1.2 g) compound A (0.8 g) and n propylamine (0.36 g), except that the crude produce was chromatographed using system D, was {1-piperidinylmethyl)phenoxy]-3-[[4-(propylamino)-1,2,5-thiadiazol-3-yl]amino]-2-propanol S,S dioxide (1.50 g) as a cream solid, m.p. 206209 .

Found: C, 54.6; H, 7.1; N, 15.6; S, 7.2.

C30H31N504S requires C, 54.9; H, 7.1; N, 16.0; S, 7.3%.

c) Similarly prepared by this procedure from 4-amino-1-[3-(1-piperidinylmethyl)phenoxy]-2-butanol (0.62 g), compound A (0.4 g) and ammonia, except that the crude product was chromatographed twice using system C, was 4-[14-amino- 1,2,5-thiadiazol-3-yl)amino]- 1 -[3-(1 -piperidinylmethyl)phenoxy]-2- butanol S,S-dioxide (0.30 g) as a white foam, m.p. 8894 .

N.m.r. (d6-DMS0) 2.70--3.20, m, (4H); 6.00-6.15, m, (3H); 6.40--6.65, m, (4H); 7.60-7.75, m, (4H); 8.00-8.30, m, (2H); 8.40--8.70, m, (6H).

d) Similarly prepared by this procedure from 1 -amino-4-[3-( 1 -piperidinylmethyl)phenoxyj-2-butanol (1.25 g) compound A (0.8 g) and ammonia, except that the crude product was chromatographed using system C and further purified by HPLC using ethanol+0.5% 0.880 ammonia, was 1-[(4-amino-1,2,5- thiadiazol-3-yl)amino]-4-[3-( 1 -piperidinylmethyl)phenoxy]-2-hutanol S,S-dioxide (0.46 g) as a white solid, m.p. ca. 1630 (softens).

N.m.r. (C5D5N) 2.70, t, (1 H); 2.84-3.14, m, (3H); 5.55, m, (1 H); c5.75, m, (2H); 6.08-6.33, ABX, (2H); 6.55, s, (2H); 7.63, m, (4H); c7.98, m, (2H); 8.48, m, (4H); 8.64, m, (2H).

e) Similarly prepared by this procedure from compound C (1.2 g), compound A (0.8 g) and 3 aminomethylpyridine (0.54 g), except that the crude product was chromatographed using system C and was recrystallised from isopropanol, was 1 -[3-(1-piperidinylmethyl)phenoxy]-3-[[4-[(3-pyridinyl- methyl)amino]- 1,2,5-thiadiazol-3-yl]amino]-2-propanol S,S-dioxide (1.24 g) as a white solid m.p.

164.5--167.50.

Found: C, 56.5; H, 6.3; N, 17.1; S, 6.6.

C23H30N604S requires C, 56.8; H, 6.2; N, 17.3; S, 6.6%.

f) Similarly prepared by this procedure from compound C (1.2 g), compound A (0.8 g) and 2 methoxyethylamine (0.38 g), except that the crude product was chromatographed using system C and was crystalíised from ethanol, was 1 [[4-[(2-methoxyethyl)amino]- 1,2,5-thiadiazol-3-yl]amino]-3-[3- (1-piperidinylmethyl)phenoxy]-2-propanol S,S-dioxide (1.24 g) as a white solid m.p. 1461500.

Found: C, 52.9; H, 6.9; N, 15.2; S. 6.8.

C20H3,N505S requires C, 53.0; H, 6.9; N, 15.4; S, 7.1%.

g) Similarly prepared by this procedure from compound C (1.2 g), compound A (0.8 g) and ethanolamine (0.30 g), except that the crude product was chromatographed using system D and was recrysta I lised from isopropanol, was 1 -[[4-[(2-hydroxyethyl)amino]- 1 ,2,5-thiadiazol-3-yl]amino]-3-J3- (1-piperidinylmethyl)phenoxy]-2-propanolS,S-dioxide (1.04 g) as a white solid, m.p. 177180 .

Found: C, 51.6; H, 6.7; N, 15.7; S, 7.2.

C1gN29N505S requires C, 51.9; H, 6.7; N, 15.9; S, 7.3%.

h) Similarly prepared by this procedure from compound C (1.2 g), compound A (0.8 g) and 2-propyn 1 -amine (0.37 g), except that the crude product was chromatographed using system C and further purified by HPLC using chloroform ethanol (3:2), was 1-[3-{1-piperidinylmethyl)phenoxy]-3-[[4-r2- propynylamino)- 1,2,5-thiadiazol-3-ylJaminoJ-2-propanol S,S-dioxide (0.68 g) as a white solid, m.p. ca.

900 (softens), 100--1050 (melts).

N.m.r. (C5D5N) 2.74,t, (1H); 2.90-3.18, m, (3H); 5.48, m, (1H); 5.65, d, (2H); 5.86, d, (2H); 5.96-6.23, ABX, (2H); 6.59, s, (2H); 6.80, t, (1 H); c7.65, m, (4H); c8.50, m, (4H); c8.70, m, (2H).

i) Similarly prepared by this procedure from compound C (1.2 g), compound A (0.8 g) and aniline (0.63 g), except that the mixture was stirred for 2 days after addition of the aniline, and was chromatographed using system D and further purified by HPLC using ethanol:chloroform (2:1)+0.5% 0.880 ammonia, was I -[[4-(phenylamino) 1,2,5-thiadiazol-3-yllamino]-3-[3-( 1 -piperidinylmethyl)- phenoxy]-2-propanol S,S-dioxide (0.59 g) as a white solid, m.p. 207--2090.

Found: C, 58.3; H, 6.3; N, 14.7; S, 6.4.

C23H29N504S requires C, 58.6; H, 6.2; N, 14.8; S, 6.8%.

Example 3 1 -[(4-Amino-I ,2,5-thiadiazol-3-yl)amino]-3-[3-( 1 -piperidinylmethyl)phenoxy]-2-propanol Soxide A solution of compound C (1.2 g) in methanol (25 ml) was added dropwise to a stirred suspension of compound B (0.8 g) in methanol (20 ml), and the solution stirred at 80C for 1.5 h.

Anhydrous ammonia was bubbled into the solution for 10 min and the mixture was stirred at ambient temperature for 18 h. The solution was evaporated to give a white foam which was chromatographed using system C. The resultant foam was precipitated from chloroform to give the title compound (0.60 g) as a pale cream powder, m.p. ca. 1000 (softens).

N.m.r. (C5D5N) 2.71, t, (1H); 2.85, br.s (1H); 2.94, dm, (1 H); 3.05dm, (1H); 5.28, m, (1H); 5.74, d, (2H); 5.85-6.07, ABX, (2H); 6.50, m, (2H); 7.60, m, (4H); 8.48-8.65, m, (6H).

Example 4 1 -[[4-( Methyla mino)-1,2,5-thiadiazol-3-yl]amino]-3-[3-(1 -piperidinyl methyl)phenoxy]-2- propanol S-oxide A solution of compound C (1.2 g) in methanol (25 ml) was added dropwise to a stirred suspension of compound B (0.72 g) in methanol (20 ml) and the solution stirred at room temperature for 30 min. Anhydrous methylamine was bubbled into the solution for 1 5 min and the mixture was stirred at ambient temperature for 1.5 h. The solution was evaporated to give a white foam which was chromatographed using system C to give the title compound (0.96 g) as a white solid, m.p. 140- 1430 (1240 softens).

Found: C, 54.6; H, 7.0; N, 17.7; S. 8.3.

C18H27NsO3S requires C, 54.9: H, 6.9; N, 17.8; S,8.2%.

Example 5 1 -[(4Amino-1 ,2,5-thiadiazol-3-yI)amino]-3-[3-( 1 -dimethylaminomethyl )phenoxy]-2-propanol S,S-dioxide A solution of 1-amino-3-[3-(1-dimethylaminomethyl)phenoxy]-2-propanol (0.38 g) in dry methanol (20 ml) was added dropwise to a stirred suspension of 3-amino-4methoxy-1 ,2,5-thiadiazole 1,1-dioxide (0.28 g) in dry methanol (20 ml) and reaction mixture stirred at room temperature for 1 h.

The solution was evaporated to give a yellow foam which was purified by HPLC using ethanol:hexane (3:1)+0.5% 0.880 ammonia to give the title compound (0.32 g) as a white solid, m.p. 1101130, N.m.r. (C > D5N) 2.70-3.15, m, (4H); 5.40, m, (1H); 5.82, d, (2H); 5.90-6.10, ABX, (2H); 6.64, s, (2H); 7.83, s, (6H).

Example 6 1 -[[4-(Dimethylamino)-1 ,2,5-thiadiazol-3-yl]amino]-3-[3-(1 -piperidinylmethyl)phenoxy]-2propanol S,S-dioxide A solution of compound C (1.2 g) in methanol (25 ml) was added dropwise to a stirred suspension of 4-methoxy-N,N-dimethyl-1 ,2,5-thiadiazol-3-amine 1 ,1 -dioxide (0.86 g) in methanol (20 ml) at room temperature. After 15 min a white solid crystallised from the solution. The reaction mixture was stirred for a further 1 h and then filtered to remove the title compound (1.27 g) as a white solid, m.p. 144--147 0.

N.m.r. (CsD5N)2.653.10, m, (4H); 5.18, m, (1H);5.74,d, (2H); 5.94,d, (1H);6.14,d, (1H); 6.56, s, (2H); 6.83, s, (6H); 7.66, m, (4H); 8.40--8.70, m, (6H).

Example 7 1 -[(4Amino-1 ,2, 5-thiadiazol-3-yl )a mino]-3-[3-(1 -piperidinyl methyl)phenoxyj-2-propanol S,S- dioxide, acetate (ester) 1-[(4-Amino-1,2,5-thiadiazol-3-yl)amino]-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol S,Sdioxide (1.5 g) in glacial acetic acid (35 ml) was heated, at the reflux, for 72 h. The solvent was removed in vacuo and the resultant dark oil chromatographed twice using system D to give the title compound (0.17 g) as a yellow foam, m.p. ca. 900 (softens).

N.m.r. (C5D5N) 2.74, t, (1 H); 2.90-3.20, m, (3H); 4.30, m, (1 H); 5.73, m, (2H); 5.93,ABX, (2H); 6.60, s, (2H); 7.69, m, (4H); 8.00 s, (3H); 8.40--8.80, m, (6H).

Example 8 a) 1 -[(4-Amino- 1,2, 5-thiadiazol-3-yl)amino]-3-[3-[(hexahydro- l H-azepin- 1 -ylJmethyl]phenoxy]-2- propanol S,S-dioxide.

A solution of compound D (1.0 g) in methanol (25 ml) was added dropwise to a stirred suspension of compound A (0.74 g) in methanol (20 ml) and the mixture stirred at room temperature for 30 min. Anhydrous ammonia was bubbled into the solution for 10 min and the mixture stirred at ambient temperature for 1 h. The solution was evaporated to give a yellow foam which was dissolved in ethanol (20 ml) and was treated with 2N hydrochloric acid (4 ml). After 30 min, hexamethyleneimine (1.98 g) was added to the reaction mixture and stirring continued for 2 h. Sodium borohydride (0.5 g) was added, portionwise, to the reaction which was then stirred at room temperature overnight and quenched by the addition of water.The crude product was extracted into ethyl acetate and concentrated to give a dark foam which was purified by chromatography using system C and by HPLC using ethanol:chloroform (2:1)+0.5% 0.880 ammonia, to give the title compound (60 mg) as a white foam, m.p. 900 (softens).

N.m.r. (C5D5N) 5.40, m, (1 H); 5.82, d, (2H); 5.92-6.20, ABX, (2H); 6.42, s, (2H); 7.45, m, (4H); 8.48, m, (8H).

b) Similarly prepared by this procedure from compound D (1.0 g), compound A (0.74 g), ammonia and furfurylamine (2.20 g), except that the crude product was chromatographed using system E, was 1 -[3-[[(2-furanylmethylvamino]methyl]phenoxy]-3-[[4-[(2-furanylmethylwaminoj- 1,2,5-thiadiazol-3-yl]- amino]-2-propanolS,S-dioxide (0.65 g) as a white solid, m.p. 150--1530.

N.m.r. (C5D5N) 2.42, d, (1 H); 2.66, d, (1 H); 2.75, t, (1 H); 2.93, m, (2H); 3.16, dd, (1 H); 3.56- 3.80, 2xd+2xdd. (4H); 5.38, s, (2H); 5.52, m, (1 H); 5.91, d, (2H); 6.00-6.25, ABX, (2H); c6.1 6, 2xs, (4H).

Examples of pharmaceutical compositions Tablets mg/tablet Active ingredient 20.0 Microcrystalline Cellulose USP 178.5 Magnesium Stearate BP 1.5 Compression weight 200.0 The active ingredient is sieved through a suitable sieve, blended with the excipients and compressed using 7 mm diameter punches.

Tablets of other strengths may be prepared by altering the compression weight and using punches to suit.

The tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques. Alternatively the tablets may be sugar coated.

Injection for intravenous administration % wlv Active ingredient 0.2 Sodium Chloride BP as required Water for Injection BP to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient.

Alternatively suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable cycles.

Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen or another suitable gas.

Claims

1. Compounds of the general formula (I)

and physiologically acceptable salts, solvates and hydrates thereof, in which R1 represents hydrogen, C1-,14 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl, heteroaralkyl or alkyl substituted by cycloalkyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino; and R2 represents hydrogen or a C14 alkyl group; or R, and R2 together with the nitrogen atom to which they are attached form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C13 alkyl groups or a hydroxy group and/or may contain another heteroatom selected from oxygen or sulphur; Alk represents a straight or branched alkylene chain or 1 to 3 carbon atoms; 0 represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1-and 3-or 1-and 4- positions; R5 represents hydrogen or acyl; n and m, which may be the same or different, are each 1 or 2; R3 represents hydrogen or alkyl;; R4 represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, pyridyl, aralkyl, heteroaralkyl or alkyl substituted by hydroxy, C13 alkoxy, amino, C13 alkylamino or C13 dialkylamino, or R3 and R4 together with the nitrogen atom to which they are attached form a 5--7 membered ring which may contain another heteroatom; and r represents an integer which is 1 or 2.

2. Compounds as claimed in claim 1 in which R, represents C18 alkyl, C14 alkyl substituted by a trifluoromethyl group, C24 alkyl substituted by hydroxy or a di C13 alkylamino group, C57 cycloalkyl, C35 alkenyl, phenyl C13 alkyl, or a heteroaryl C13 alkyl group where the heteroaryl ring contains one heteroatom; R2 represents hydrogen or methyl; or R,R2N represents a 5 to 7 membered ring optionally containing a double bond, an oxygen atom or an alkyl substituent; Alk represents methylene; Q represents a benzene ring incorporated into the rest of the molecule through bonds at the 1 and 3- positions; R3 represents hydrogen; R4 represents hydrogen, C16 alkyl, alkenyl, alkynyl, phenyl, phen C14 alkyl, pyridyl C13 alkyl, furyl C13 alkyl or imidazolyl C13 alkyl, or C2-4 alkyl substituted by hydroxy or C13 alkoxy; R5 represents hydrogen or alkanoyl; and the sum of n and m is 2 or 3.

3. Compounds as claimed in claim 1 in which R,R2N represents di C,, alkylamino, furylmethylamino or a 5 to 7 membered ring; R3 represents hydrogen; R4 represents hydrogen, C,, alkyl, C36 alkynyl, phenyl, pyridyl C1-3 alkyl, furyl C1-3 alkyl, or C24 alkyl substituted by hydroxy or C1-3 alkoxy; and R5 represents hydrogen or alkanoyl.

4. Compounds of the general formula (IA)

and physiologically acceptable salts, solvates and hydrates thereof, in which R,R2N is dimethylamino, or a 5, 6 or 7 membered ring; the sum of n and m is 2 or 3; r represents 1 or 2; R5 represents hydrogen or acetyl; and R4 represents hydrogen, C14 alkyl, propynyl, pyridylmethyl, hydroxy C2-4 alkyl or C1-3 alkoxy C24 alkyl.

5. Compounds as claimed in claim 1 which are: 1 -[(4-amino-1 ,2,5-thiadiazol-3-yl)amino]-3-[3-( 1 -piperidinylmethyl)phenoxy]-2-propanol S,Sdioxide; 1-[(4-amino-1,2,5-thiadiazol-3-yl)amino]-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol Soxide; 1 1-[[4-(methylamino)- 1 1,2,5-thiadiazol-3-yl]amino]-3-[3-( 1 -piperidinyl methyl)phenoxy]-2propanol S-oxide; and 1 -[[4-(methylamino)-1 ,2,5-thiadiazol-3-yl]amino]-3-[3-( 1 -piperidinylmethyl)phenoxy]-2propanol S,S-dioxide; and physioiogically acceptable salts thereof.

6. Compounds as claimed in claim 1 which are: 1 -[3-( 1 -piperidinylmethyl)phenoxy]-3-[[4-(propylamino)- 1 ,2,5-thiadiazol-3-yl]amino-2-propanol S,S-dioxide; 1 -[(4-amino-1 1,2,5-thiadiazol-3-yl)amino]-4-[3-(1 -piperidinylmethyl)phenoxy]-2-butanol S.S- dioxide; 1 -[3-( 1 -piperidinylmethyl)phenoxyj-3-[[4-[(3-pyridinylmethyl)amino]- 1 ,2,5-thiadiazol-3-yl]- amino-2-propanol S,S-dioxide; 1 -[[4-[(2-methoxyethyl)aminoj- 1 ,2,5-thiadiazol-3-yl]amino]-3-[3-( 1 -piperidinylmethyl)phenoxy]-2-propanol S,S-dioxide; 1 -[(4-amino- 1 ,2,5-thiadiazol-3-yl)amino]-3-[3-( 1 -dimethylaminomethyl)phenoxy]-2-propanol S,S-dioxide; and 1 -[(4-amino-1 ,2,5-thiadiazol-3-yl)amino]-3-[3-( 1 -piperidinylmethyl)phenoxy]-2-propanol S,Sdioxide,acetate(ester); and physiologically acceptable salts thereof.

7. 1 -[(4-Amino-1 ,2,5hiadiazoI-3-yI)amino]-3-[3-[(hexahydrn-1 H-azepin- 1 -yl) methyl]phenoxy]- 2-propanol S,S-dioxide and physiologically acceptable salts thereof.

8. A process for the preparation of compounds of formula (I) as claimed in claim 1 which comprises: a) for the preparation of compounds in which R5 represents hydrogen, reacting a diamine of formula (II)

with a compound of formula (III)

in which R6 is the group -NP3P4 or a group convertible thereto, and P is a leaving group;; b) for the preparation of compounds in which R5 is acyl, reacting a compound of formula (IV)

in which R6 is the group -NP3P4 or a group convertible thereto, with an acid corresponding to the acyi group R5 or an activated derivative thereof, and where R6 is a group convertible into the group -NP3P4, converting the group R6 into the group -NP3P4; or c) for the preparation of compounds in which Alk is CH2 and R5 is hydrogen, treating analdehyde of formula (V)

with an amine R1R2NH in a solvent, followed by reduction; and optionally converting the compound of formula (I) produced into a physiologically acceptable salt.

9. A pharmaceutical composition comprising at least one compound of formula (I) as claimed in any of claims 1 to 7 together with at least one pharmaceutically acceptable carrier or excipient and optionally containing one or more other ingredients.