GB2227744A - Nitro-methyl-sulphonyl substituted compounds - Google Patents

Abstract

The invention concerns novel pharmaceutically useful aliphatic nitromethane derivatives of the formula: Q.SO2.CH2.NO2 in which Q is an optionally substituted alkyl (or cycloalkyl) moiety; and the non-toxic salts thereof. The nitromethane derivatives (I) are inhibitors of the enzyme aldose reductase. The invention also concerns processes for the manufacture of, and pharmaceutical compositions containing, a nitromethane derivative (I). Also claimed are the corresponding thio and sulphoxide derivatives.

Description

ALIPHATIC COMPOUNDS This invention concerns novel aliphatic compounds and, more particularly novel aliphatic nitromethane derivatives which are inhibitors of the enzyme aldose reductase and are of value, for example, in the treatment of certain peripheral effects of diabetes or galactosemia. The invention also concerns pharmaceutical compositions containing a novel aliphatic nitromethane derivative. In addition, the invention concerns processes for the manufacture of the said novel derivatives and for the preparation of medicaments containing them, as well as a method of medical treatment of peripheral effects of diabetes or galactosemia using such a derivative.

The enzyme aldose reductase is responsible for the catalytic conversion of aldoses, such as glucose and galactose, to the corresponding alditols, such as sorbitol and galactitol respectively, in warm blooded animals such as man. Alditols penetrate cell membranes poorly and, once formed, tend to be removed only by further metabolism. Consequently, alditols tend to accumulate within cells where they are formed, causing a rise in internal osmotic pressure which may in turn be sufficient to destroy or impair the function of the cells themselves. In addition, raised alditol levels may result in abnormal levels of their metabolites which may themselves impair or damage cellular function. The enzyme aldose reductase has a relatively low affinity and is generally only effective in the presence of relatively large concentrations of aldose.Such large concentrations are present in the clinical conditions of diabetes (excessive glucose) and galactosemia (excessive galactose). Consequently, aldose reductase inhibitors are useful in the reduction or prevention of the development of those peripheral effects of diabetes or galactosemia which may be due in part to the accumulation of sorbitol or galactitol, respectively, in tissues such as the eye, nerve and kidney. Such peripheral effects include, for example, macular oedema, cataract, retinopathy, neuropathy and impaired neural conduction.

Although a number of aldose reductase inhibitors have been discovered and clinically evaluated, there is a continuing need for alternative inhibitors. The present invention is based in part on this need and on our discovery of the unexpected inhibition of the enzyme aldose reductase by certain nitromethane derivatives.

According to the invention there is provided a novel nitromethane derivative of the formula O.[C(Rd)ReJ n .502 C112. NO2 (I) wherein Q is a monovalent group of the formula Ra.C(Rb)Rc- in which Ra and Rb are independently hydrogen, (1-4C)alkyl or phenyl; or Ra and Rb together with the adjacent carbon atom form cyclopropyl, cyclobutyl or a (5-lOC)cycloalkyl moiety optionally bearing up to four (l-4C)alkyl substituents, in which (5-lOC)cycloalkyl moiety: (a), a carbon atom, other than that bearing the group [C(Rd)Reln.SO2.CH2.NO2, may optionally be replaced by oxy, thio, sulphinyl, sulphonyl, imino or (1-4C)alkylimino, and (b) one or two adjacent pairs of carbon atoms may option^.lly be fused to one or two benzene moieties, respectively; and Rc is (l-6C)alkyl optionally bearing a (.-4C)alkoxy, (2-8C)dialkylamino, pyrrolidino, morpholino piperidino or N-[(l-4C)alkyljpiperazino substituent, or Rc is hydrogen when Ra or Rb is other than hydrogen; Rd and Re are independently hydrogen or (l-4C)alkyl; n is zero or the integer 1 or 2; and any of which phenyl or benzene moieties may optionally bear up to three substituents, independently selected from halogeno, cyano, (l-4C)alkyl, (1-6C)alkoxy and trifluoromethyl; or a non-toxic salt thereof.

In this specification the term "alkyl" includes both straight and branched alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain ("normal") version only, any branched chain isomer such as "isopropyl" being referred to specifically. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds of formula I defined above may exist in optically active or racemic forms by virtue of the presence of an asymmetrically substituted carbon or sulphur atom, the invention includes any such optically active or racemic form which possesses the property of inhibiting the enzyme aldose reductase. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the inhibitory properties against aldose reductase may be evaluated using the standard laboratory tests referred to hereinafter.

A particular value for Ra or Rb, when it is alkyl is, for example, methyl, ethyl, propyl or isopropyl; for Rc when it is alkyl is, for example, methyl, ethyl, propyl, butyl or pentyl; and for Rd or Re when it is alkyl is, for example, methyl.

A particular value for an optional alkoxy or dialkylamino substituent on Rc is, for example, methoxy, ethoxy, propoxy, dimethylamino or diethylamino, and for an N-[(1-4C)alkyljpiperazino substituent is, for example N-methylpiperazino or N-ethylpiperazino.

A particular value for Ra and Rb when together with the adjacent carbon atom they form (5-lOC)cycloalkyl is, for example, norbornyl, adamantyl, cyclopentyl, cyclohexyl or cycloheptyl, in the latter three of which one or two adjacent pairs of carbon atoms may optionally be fused to one or two benzene moieties, themselves optionally substituted as defined above.

A particular value for Ra and Rb when together with the adjacent carbon atom they form cycloalkyl one carbon atom of which may optionally be replaced by oxy, thio, sulphinyl, sulphonyl, imino or (l-4C)alkylimino is, for example, tetrahydropyranyl, N-methylpyrrolidinyl, N-ethylpyrrolidinyl, N-methylpiperidinyi.

N-ethylpiperidinyl, tetrahydrothiopyranyl or the corresponding oxide and dioxide thereof.

A particular value for an optional alkyl substituent which may be present when Ra and Rb together with the adjacent carbon atom is cycloalkyl is, for example, methyl or ethyl.

Specific values for optional substituents which may be present on a phenyl or benzene moiety which is part of Q include the following by way of example:for halogeno: fluoro, chloro, bromo and iodo; for (l-4C)alkyl: methyl, ethyl, propyl and isopropyl; and for (1-4C)alkoxy, methoxy, ethoxy, propoxy and isopropoxy.

A preferred value for n is zero or the integer 1.

Specific values for Q include, for example, ethyl, propyl, butyl, isobutyl, t-butyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl, 2-N,N-dimethylaminoethyl, 3-N,N-diethylaminopropyl, benzyl, benzhydryl, N-methyl-4-piperidinyl, N-ethyl-3-pyrrolidinyl, cyclopropylmethyl, cyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, cyclohexylmethyl, cycloheptyl, N-methyl-1,2,3,4-tetrahydro-4-quinolyl, 2-norb- ornyl, 2-adamantyl, tetrahydro-4-pyranyl, tetrahydro-4-thiopyranyl (and the corresponding oxide and dioxide), chroman-4-yl, thiochroman- 4-yl, 1,2,3,4-tetrahydro-l-naphthyl, 4-xanthenyl, 2-indanyl, 1-indanyl, 9-fluorenyl, and 2,3,6,7-dibenzocycloheptyl.

One group of novel compounds of the invention of particular interest comprises compounds of the formula II (set out hereinafter) wherein Rf, Rg, Rh and Ri are independently hydrogen or (l-4C)alkyl; or Rf and Rg together, and/or Rh and Ri together, in either case with their adjacent carbon atoms of the carbocyclic ring, form benzene moieties fused thereto and which may optionally bear up to three substituents independently selected from halogeno, cyano, (l-4C)alkyl and trifluoromethyl; n is zero or the integer 1;X is a direct bond, methylene, [di(l-4C)alkyl]methylene, oxy, thio, imino or (l-4C)alkylimino, and the dotted bonds indicate that the appended carbon atoms are joined by an aromatic double bond when a benzene moiety is present and otherwise bear a hydrogen substituent and are joined by a single bond; provided that only two of Rf, Rg, Rh and Ri may be alkyl when X is [di(l-4C)alkyljmethylene; together with the non-toxic salts thereof.

A particular value for Rf, Rg, Rh or Ri when it is alkyl is, for example, methyl.

A particular value for an optional halogeno or alkyl substituent when a pair of Rf, Rg, Rh and Ri, together with the adjacent carbon atoms on the carbocyclic ring, form a substituted benzene moiety is, for example, fluoro, chloro, bromo, methyl or ethyl.

A particular value for X when it is [di(l-4C)alkyl]- methylene is, for example, isopropylidene and when it is alkylimino is, for example, methylimino.

The invention also includes a method of treating or preventing one or more of the peripheral effects of diabetes or galactosemia by administration of an effective amount of a compound of the formula I or of a non-toxic salt thereof. A further feature of the invention is the use of a compound of the formula I or of a non-toxic salt thereof in the manufacture of a novel medicament for use in the treatment or prevention of one or more of the peripheral side-effects of diabetes or galactosemia.

The compounds of formula I will generally be administered in the form of pharmaceutical compositions comprising a compound of formula I or a non-toxic salt thereof together with a pharmaceutically acceptable diluent or carrier. Such compositions are provided as a further feature of the invention and may be in various conventional forms. Thus, they may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intravascular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as gelatin or starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.

Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as arachis oil, liquid paraffin or olive oil.

Aqueous suspensions will generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharin or aspartame).

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.

The compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, or esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.

The compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedures well known in the art. Topical formulations for administration to the eye will generally be in the form of an ointment, gel or sterile solution buffered at an ophthalmically acceptable pH, for example in the range pH 7.0-7.6.

The amount of compound of formula I that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain for example from 5mg to Ig of active agent compounded with appropriate and convenient amounts of excipients which may vary from about 5 to about 98 X by weight of the total composition. Dosage unit forms will generally contain about 5 mg to about 600 mg of an active ingredient.

Suitable non-toxic salts of the formula I compounds include, for example, pharmaceutically acceptable salts such as alkali metal (such as potassium or sodium), alkaline earth metal (such as calcium or magnesium) and ammonium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine.

In addition, for those active ingredients which are sufficiently basic (for example those which contain an imino, ~ kylimino, alkylamino or dialkylamino group), suitable non-toxic salts include, for example, pharmaceutically and physiologically acceptable acid-addition salts such as salts with hydrogen halides, sulphuric acid, phosphoric acid, citric acid and maleic acid.

Novel compounds of the invention are described in the accompanying Examples and are provided, together with their non-toxic salts, as a further feature of the invention.

The novel compounds of the invention may be obtained by standard procedures of organic chemistry already known for the production of structurally analogous compounds, for example using one or more of the procedures reviewed in the paper by Zeilstra et alia in Rec.Trav.Chim.Pays Bas 1974, 93, 11-14. Such procedures are provided as a further feature of the invention and are illustrated by the following in which Q, the various substituents thereon, Rd, Re and n have any of the meanings defined hereinbefore.

(a) Oxidising a thioether of the formula Q.[C(Rd)Reln.S.CH2.N02 (III).

Suitable oxidising agents include those which are well known in the art for the conversion of thio to sulphonyl groups and which are compatible with the presence of other sensitive functional groups which may be present as substituents on Q. Thus, for example, hydrogen peroxide, an organic peracid (such as perbenzoic acid) or lead tetraacetate may be used. Alternatively, an alkali metal periodate (such as sodium metaperiodate), persulphate (such as potassium monopersulphate) or permanganate (such as potassium permanganate), or gaseous oxygen in the presence of a suitable catalyst such as platinum, may be employed. The oxidation is preferably carried out in a suitable conventional solvent or diluent for such oxidations, for example in acetic or propionic acid, and at a temperature in the general range, for example 0 to 80 OC.

In certain cases, the corresponding sulphoxide derivative of the thioether of formula III may be formed as an isolable intermediate. The process of the invention also includes the oxidation of such a sulphoxide intermediate to a sulphone of formula I, for example, by reaction with an alkali metal permanganate (such as potassium permanganate) in a suitable solvent such as acetic acid and at a temperature in the range, for example, 20 to 80 OC.

The starting thioethers of formula III may be obtained by conventional procedures of organic chemistry, for example, from a potassium or sodium salt of the corresponding thiol (IV) of the formula Q.[C(Rd)Re]n.SH by conversion to the corresponding thioacetic acid (V) of the formula Q.[C(Rd)ReJn S. CH2. CO2H (or a (1-4C)alkyl ester thereof, such as a methyl or ethyl ester) by reaction with chloro- or bromo-acetic acid (or a (l-4C)alkyl ester thereof) in the presence of a suitable base.The acid V (or a (l-4C)alkyl ester thereof) is then reacted with an alkali metal (1-6C)alkane and a (1-5C)alkyl nitrate, for example butyllithium and isoamyl nitrate, and under similar conditions to those used for process (b) below, to give the alkali metal salt of the corresponding 2-nitroacetic acid (VI) of the formula Q.[C(Rd)Rein.S.CB(N02).CO2H (or of the (l-4C)alkyl ester thereof). The acids of formula VI are unstable and readily decarboxylate so that acidification of the alkali metal salt of an acid of formula VI allows the isolation of a thioether-of formula III.

An ester of an acid of formula VI may be hydrolysed, for example, using aqueous base, to the salt of the corresponding acid which is then acidified to produce a thioether of formula III.

b) Reacting an alkali metal sulphinate of the formula Q.[C(Rd)ReJ n 502 H+ (VII) wherein M+ is an alkali metal cation, such as sodium or potassium, with nitromethane and iodine in the presence of an alkali metal (1-6C)alkoxide such as potassium t-butoxide or sodium methoxide.

The reaction is preferably carried out in the presence of a suitable polar solvent, for example, dimethylformamide (which is preferred) or N-methyl-2-pyrrolidone, and at a temperature in the range, for example, -30 to 20 OC and, conveniently, at about 0 OC. The nitromethane is generally present in an excess.

The alkali metal sulphinates may be obtained from the corresponding sulphinic acids of the formula Q.lC(Rd)Re]n.S02H (VIII) by reaction with the appropriate alkali metal hydroxide or (1-6C)alkoxide such as sodium or potassium methoxide or ethoxide. The sulphinic acids may themselves be obtained from the corresponding sulphonyl chlorides of the formula ().[C(Rd)Reln.SO2Cl (IX) by a conventional reduction using sodium sulphite or zinc dust and water.

The sulphonyl chlorides may be obtained by conventional procedures of organic chemistry, for example from the corresponding thiol.

(c) Reacting a sulphone of the formula Q.[C(Rd)Re]n.S02.CH3 (X) with a (1-5C)alkyl nitrate, such as ethyl, propyl, isopropyl or amyl nitrate in the presence of a strong base.

A particularly suitable strong base is, for example, an alkali metal (1-6C)alkane such as butyllithium.

The reaction is preferably carried out in the presence of a suitable solvent or diluent, for example an ether such as tetrahydrofuran or t-butyl methyl ether, and at a temperature in the range, for example, -80 to 10 OC.

The necessary sulphones of the formula X may be made by standard procedures well known in the art, for example by oxidation of the corresponding methylthio compound of the formula Q.lC(Rd)Reln.S.CH3 (XI) using analogous conditions to those described for process (a) above.

Whereafter, when a non-toxic salt is required, a compound of formula I may be reacted with an appropriate base having a non-toxic cation, and, when Q contains a suitably basic group (such as alkylamino or dialkylamino), a non-toxic, acid-addition salt may be prepared by reaction with an appropriate acid having a non-toxic anion.

As stated previously, the compounds of formula I inhibit the enzyme aldose reductase. The compounds are thus of value, for example, in treating those diseases or conditions which are caused by excessive quantities of the products such as sorbitol formed in the body by processes catalysed by the enzyme aldose reductase.

The property of inhibiting the enzyme aldose reductase in vivo may be demonstrated in the following standard laboratory test.

Thus, rats are made diabetic (as evidenced by severe glucosuria being present) by dosing with streptozotocin. The animals are then dosed daily with the test compound for one, two or five days. The animals are then killed 2-6 hours after the final dose and the eye lenses and/or sciatic nerves are removed. After a standard work-up procedure, the residual sorbitol levels in each tissue are determined by gas liquid chromatography after conversion to the poly-trimethylsilyl derivatives. Inhibition of aldose reductase in vivo is then assessed by comparing the residual sorbitol levels in tissues from the dosed diabetic group of rats with those of an undosed group of diabetic rats and an undosed, normal group of rats.

The property of inhibiting the enzyme aldose reductase may also be demonstrated in vitro. Thus, partially purified aldose reductase is isolated in known manner from bovine lenses. The percentage inhibition of this enzyme's ability in vitro to catalyse the reduction of aldoses to polyhydric alcohols, and particularly to reduce glucose to sorbitol, caused by a test compound is then determined using standard spectrophotometric methods.

By way of illustration of the aldose reductase inhibitory properties of compounds of formula I, the compound of Example 2 had an IC50 of 4.2 x 10 8M in the above in vitro test. Although the activity of individual compounds of formula necessarily varies to some extent with chemical structure, in general, compounds of the formula I show significant inhibition in the above mentioned in vivo test at a dose (generally p.o.) of 100 mg/kg or much less with no evidence of overt toxicity, and have an IC50 in the above mentioned in vitro test of 10 M or much less.

The compounds of formula I will primarily be administered systemically (generally by mouth) to a warm-blooded animal to produce a therapeutic or prophylactic effect mediated by inhibition of the enzyme aldose reductase, for example at a daily dose in the range of 1 to 40 mg/kg. In man, it is envisaged that a total daily dose in the range 15 to 800 mg per man will be administered, given if necessary, in divided doses.

However, the precise amount of compound administered will naturally vary somewhat, for example, with the age and sex of the patient and the severity and extent of the condition being treated.

The compounds of formula I may also be administered topically, for example by topical administration direct to the tissue or organ in which inhibition of the enzyme is required, for example by topical administration to the eye. The precise amount of compound administered will necessarily depend on the formulation used. Thus, for example, when a solution is administered, a concentration of the compound containing up to 0.01% by weight will generally be used.

Similarly, when an ointment is administered, a concentration of the compound of up to 2% by weight will generally be used. Topical formulations of compounds of formula I may be administered to the eye of an animal, for example, man or dog, requiring treatment and/or prevention of diabetic cataracts or retinopathy, in a conventional manner, for example, using a drop or eyewash topical formulation.

The compositions may also contain one or more other agents which are known to have a useful effect in the treatment of diabetes or galactosemia, for example a hypoglycaemic agent such as tolbutamide, chlorpropamide or glybenclamide.

The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated: (i) all evaporations were carried out by rotary evaporation in vacuo.

(ii) all operations were carried out at room temperature, that is in the range 18-26 OC; (iii) the purity of chemical products was assessed by nuclear magnetic resonance spectroscopy, thin layer chromatographic analysis and/or microanalysis; (iv) mmol stands for millimolecular equivalents; (v) petroleum ether (b.p. 60-80 OC) is referred to as "petrol 60- 80; (vi) yields are for illustration only and are not necessarily the maximum attainable by diligent process development; and (vii) medium pressure liquid chromatography (MPLC) was carried out on silica (Merck Art. 9385, available from E Merck and Co., Darmstadt, West Germany).

Example 1 A solution of potassium monopersulphate ('Oxone' brand, 20.76 g) in water (47.5 ml) was added to a vigorously stirred solution of (benzylthio)nitromethane (1.87 g) in methanol (47.5 ml) cooled to 0-50C with an ice-water bath. When the addition was complete, the mixture was allowed to warm up to ambient temperature and was then stirred for 14 hours. An excess of water was added (about 300 ml) and the mixture was extracted with ethyl acetate. The combined extracts were washed with water and then with brine, dried (MgS04) and the solvent removed by evaporation. The residual solid was purified by medium pressure liquid chromatography (MPLC) on silica using ethyl acetate and hexane (1:10 v/v, gradually increasing to 1.5:10 v/v) as eluant.There was thus obtained (benzylsulphonyl)nitromethane as a colourless solid (1.0 g), m.p. 123-125 C, microanalysis; found: C, 44.6; H, 4.2; N, 6.4%; C8HgN04S requires: Ç 44.65; H, 4.2; N, 6.5%.

['Oxone' is a trade mark of the DuPont Corperation of Wilmington, Delaware, USA].

The starting material was obtained as follows: A l.lM solution of butyllithium (50 ml) was added dropwise to a stirred solution of (benzylthio)acetic acid (5.08 g) in dry tetrahydrofuran (THF) (150 ml) cooled to -400C and maintained under an atmosphere of argon. When the addition was complete, the temperature of the mixture was allowed to rise to -50C and a solution of propyl nitrate (6.3 ml) in dry THF (15 ml) added dropwise with stirring, the temperature being controlled at -5 to OOC by external cooling. After the addition was complete, the resultant yellow solution was stirred for 14 hours at ambient temperature. The reaction mixture was added to an excess of water (about 500 ml). The aqueous mixture was acidified (2M hydrochloric acid) and extracted with ethyl acetate (2 x 150 ml). The. combined extracts were dried (MgS04) and the solvent removed by evaporation. The residual liquid was purified by MPLC on silica, eluting with ethyl acetate and hexane (1:200 v/v). There was thus obtained (benzylthio)nitromethane as an evil smelling, pale orange-yellow liquid (2.15 g). This liquid was used without further purification in view of its odour.

Example 2 Using a similar procedure to that described in Example 1 but using a solution of potassium peroxymonosulphate ('Oxone' brand, 15.81 g) in water (50 ml) to oxidise (cyclohexylthio)nitromethane (1.5 g) dissolved in methanol (25 ml) for 2 hours, there was obtained (after recrystallisation of the ethyl acetate extracts from ethyl acetate/hexane), (cyclohexylsulphonyl)nitromethane as a white solid (1.32 g), m.p. 110-1130C; microanalysis, found: C,40.9; H,6.3; N,6.6%; C7H13NO4S: requires: C,40.6; H,6.3; N,6.8%.

The starting (cyclohexylthio)nitromethane was obtained as follows:- (i) Sodium chloroacetate (9.6 g) was added in portions to a stirred solution of cyclohexylthiol (10.55 ml) in 1M aqueous sodium hydroxide (129.3 ml). When the addition was complete, stirring was continued for 14 hours, during which time a thick white precipitate formed. The reaction mixture was added to water (200 ml). The aqueous mixture was acidified to pH 2 with 2M hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with 10% (w/v) aqueous potassium carbonate. The combined aqueous washings were acidified to pH 2 with 2M hydrochloric acid and again extracted with ethyl acetate.These combined extracts were dried (MgS04) and the solvent removed by evaporation to give 2-(cyclohexylthio)acetic acid as a colourless oil (13.5 g); NMR (200 MHz, d6DMSQ): 1.21.9(m,lOH), 2.8(m,lH), 3.21(s,2H).

(ii) A 1.6M solution of butyllithium in hexane (71.9 ml) was added dropwise to a stirred solution of 2-(cyclohexylthio)acetic acid (10.0 g) in dry THF (150 ml) maintained at -400C under an atmosphere of argon. When the addition was complete, the mixture was stirred for 1 hour at -50C. Isoamyl nitrate (23 ml) was added dropwise to the stirred mixture at -50C, which was then stirred for a further two hours, maintaining the temperature below OOC throughout.

The mixture was then acidified to pH 2 with 2M hydrochloric acid and then left at ambient temperature for 30 minutes, after which time evolution of carbon dioxide had ceased. Water (300 ml) was then added and the mixture was extracted with ethyl acetate. The combined extracts were washed successively with aqueous sodium hydrogen carbonate, water and brine and then dried (MgS04) and the solvent removed by evaporation. The residual oil was purified by MPLC on silica, eluting with ethyl acetate/hexane (1:10 v/v) to give (cyclohexylthio)nitromethane as an orange oil (2.35 g); NMR (200 MHz, d6 DMSO): 1.1-l.9(m,lOH), 3.5(m,lH), 6.4(s,2H).

Example 3 Using a similar procedure to that described in Example 1 except that the oxidation was carried out at 500C for 2 hours, there was obtained [(2,4,6-trimethylbenzyl)sulphonyllnitromethane as a colourless solid, m.p. 1540C [after purification by MPLC chromatography, eluting with ethyl acetate/hexane (1:10 v/v)J in 53% yield; microanalysis, found: C,51.7; H,5.9; N,5.3%; C11H15NO4 S requires; C,51.4; H,5.8; N,5.4%.The starting material [(2,4,6-trimethylbenzyl)thio]nitrometllane, was itself obtained as an oil, having a satisfactory NMR spectrum (200 MHz, CDC13): 2.25(s,3H), 2.36(s,6H), 4.10(s,2H), 5.21(s,1H), 6.86(s,lH) [after purification by MPLC using ethyl acetate/hexane (1:10 v/v)], starting from 2-(2,4,6-trimethylbenzylthio)acetic acid, using an analogous procedure to that described for the starting material in Example 1.

Example 4 A solution of potassium permanganate (10.6 g; 67.1 mM) in water (200 ml) was added in one portion to a solution of (cyclopentylthio)nitromethane (8.79 g; 54.6 mM) into acetic acid (100 ml). The mixture was stirred for 2 hours and then poured into water (200 ml). The mixture was extracted with ethyl acetate (2 x 200 ml).

The combined extracts were washed with brine, dried (MgSO4) and the solvent evaporated. The residual yellow oil, crystallised to give (cyclopentylsulphonyl)nitromethane as a solid (3.13 g), m.p. 54-560C; microanalysis, found: C,37.8; H,5.7; N,6.9%; C6H11NO4 S requires; C,37.4; H,5.7; N,7.25%; NMR (200 MHz, CDC13): 1.6-1.9(m,4H), 2.0-2.2(m,4H), 3.7-4.0(pentuplet, 1H), 5.4(s,2H).

The required thioether was itself obtained as an oil, NMR (200 MHz, CDC13): 1.47-1.87(m,8H), 3.40(pentuplet, 1H), 5.26(s,2H) [after purification by column chromatography using ethyl acetate/hexane (1:10 v/v)J, starting from (cyclopentylthio)acetic acid, itself obtained as an oil starting from cyclopentanethiol, by a procedure analogous to that described for Example 2.

Example 5-7 Using an analogous procedure to that described in Example 4, the following compounds were obtained: (Example 5): [(2-Phenylethyl)sulphonyl]nitromethane; obtained as a colourless oil in 33% yield, starting from [(2-phenylethyl)thio]nitromethane [itself obtained as an oil, having a satisfactory NMR (200 MHz, CDC13): 2.8-3.2(m,4H), 5.1(s,2H), 7.1-7.4(m,5H) after purification by flash chromatography using ethyl acetate/hexane (1:20 v/v)J; (Example 6): (Hexylsulphonyl)nitromethane; obtained as a white solid, m.p. 62-640C (after trituration with ether/hexane) in 30% yield; NMR (200 MHz; CDC13): O.91(m,3H), 1.33(m, 4H), 1.51(m,2H), l.91(m, 2H), 3.37(m,2H), 5.47(m,2H); starting from (hexylthio)nitromethane [itself obtained as an oil having a satisfactory NMR (200 MHz, CDC13): O.9(m,3H), 1.3(m,6H), 1.6(m,2H), 2.8(t,2H), 5.2(s,2H), after purification by flash chromatography using hexane as eluant]: and (Example 7): (t-Butylsulphonyl)nitromethane; obtained as a white solid, m.p. 73-750C (after trituration with hexane) in 47% yield; NMR (200 MHz; CDC13): 1.54(s,9H), 5.57(s,2H); microanalysis, found: C,33,5; H, 6.0; N, 7.2%; C5H1lNO4S requires: C, 33.1; H, 6.1; N, 7.7%; starting from (t-butylthio)nitromethane [itself obtained as an oil having a satisfactory NMR (200 MHz, CDC13): 1.4(s,9H), 5.3(s,2H), after purification by flash chromatography using hexane as eluant].

Note: the above-mentioned alkylthionitromethanes were obtained using an analogous procedure to that described for Example 2 but starting from 2-phenylethane thiol, hexanethiol and 1, l-dimethylethanethiol, respectively.

Example 8 Using a similar procedure to that described in Example 1, but starting from 4-(nitromethylthio)chroman and carrying out the reaction at 600C, there was obtained 4-(nitromethylsulphonyl)chroman as a white solid, m.p. 101-1030C [after purification by flash chromatography using toluene/ethyl acetate (9:1 v/v) as eluant and crystallisation from cyclohexane/toluene], in 7% yield; NMR (200 MHz, CDC13): 2.22 and 2.48(1H,m), 4.1 and 4.34 and 4.68(1H,m,), 5.2 and 5.56(1H,d), 6.7-7.3(4H,m); microanalysis, found: C,46.5; H,4.2; N,5.2; C1oHllNO5S requires: C,46.7; H,4.3; N,5.4%.

The starting material was obtained as follows: (i) 2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4- disulphide (9.0 g 22.3 mM) was added to a stirred solution of chroman-4-ol (6.0g, 40 mM) in toluene (120 ml). The reaction mixture was stirred at 700C for 45 minutes, then cooled and evaporated. The residue was purified by flash chromatography using hexane/toluene (4:1 v/v) as eluant to give chroman-4-thiol as a mobile oil in 47% yield; NMR (200 MHz, CDCl3): 2.0(1H,m), 2.4(2H,m), 4.3(2H,m), 4.45(1H, d of t), 6.7-7.3(4H,m).

(ii) Using a similar procedure to that described in part (i) of Example 2, but starting from chroman-4-thiol, 2-(chroman-4-ylthio)acetic acid was obtained as a solid, m.p. 87-890C (after recrystallisation from cyclohexane) in 67% yield; NMR (200 MHz, CDCl3): 2.1(1H,m), 2.35(1H,m), 3.3(2H,q), 4.3(2H,m), 4.45(1H, d of t), 6.35-7.35(4H,m).

(iii) Using a similar procedure to that described in part (ii) of Example 2, but starting from 2-(chroman-4-ylthio)acetic acid and carrying out the reaction at -20 C and nitrating with isobutyl nitrate, there was obtained 4-(nitromethylthio)chroman as an oil, in 39% yield, after flash vacuum chromatography using toluene/hexane (2:1 v/v) as eluant; NMR (200 MHz, CDCl3): 2.1(1H,m), 2.4(1H,m), 4.2-4.5(3H,m), 5.25(2H,q), 6.8-7.3(4H,m).

Example 9 Using a similar procedure to that decribed in Example 1, but starting from 2,2-dimethyl-6-fluoro-4-(nitromethylthio)chroman and carrying out the reaction at 600C, there was obtained 2,2-dimethyl6-fluoro-4-(nitromethylsulphonyl)chroman as a solid, m.p. 112-1130C (after recrystallisation from cyclohexane/toluene) in 40% yield; NMR (200 MHz, CDCl3): 1.22(3H,s), 1.54(3H,s), 2.40(2H,d), 4.78(1H,t), 5.43(2H,q), 6.87(1H,dd), 7.01(1H,dq), 7.52(1H,dd); microanalysis, found: C, 47.5; H, 4.5; N, 4.5%; C12H14FN05S requires: C, 47.5; H, 4.6; N, 4.6%.

The starting material was obtained as follows: (i) A mixture of 2-acetyl-4-fluorophenol (10.0 g, 65 mM), acetone (7.2 ml, 98 mM) and pyrrolidine (8.2 ml, 98 mM) was prepared in methanol (250 ml). After 18 hours at ambient temperature, the solvent was removed by evaporation. The residue was purified by flash chromatography eluting with toluene, to give 2,2-dimethyl-6fluorochroman-4-one (11.15 g) as a pale yellow mobile oil; NMR (90 MHz, CDC13): 1.5(6H,s), 2.7(2H,s), 6.8-7.6(3H,m).

(ii) Sodium borohydride (1.7 g, 45mM) was added to a solution of 2,2-dimethyl-6-fluorochroman-4-one (17.3 g, 89 mM) in ethanol (125 ml) and the mixture was stirred for 1 hour. The reaction mixture was diluted with water (300 ml) and 2M sodium hydroxide solution (100 ml) and then extracted with ethyl acetate. The extracts were washed with brine, concentrated in vacuo and the residue purified by flash chromatography using toluene as eluant. There was thus obtained 2,2-dimethyl-6-fluorochroman-4-ol as a white solid (7.6 g, 43%); NMR (200 MHz, CDCl3): 1.3(3H,s), 1.42(3H,s), 1.82 and 2.16(1H,q), 1.88(1H,bs), 4.79(1H,t), 6.65-7.2(3H,m).

(iii) Using a similar procedure to that described in part (i) of Example 8, but starting from 2,2-dimethyl-6-fluorochroman-4-ol, there was obtained 2,2-dimethyl-6-fluorochroman-4-thiol as an evil smelling oil, in 45% yield; NMR (200 MHz, CDCl3): 1.23(3H,s), 1.42(3H,s), 1.88(1H,s) 1.95 and 2.3(1H,m), 4.1(1H,m), 6.63-7.35(3H,m).

(iv) Using a similar procedure to that described in part (i) of Example 2, but starting from 2,2-dimethyl-6-fluorochroman-4-thiol, there was obtained (2,2-dimethyl-6-fluorochroman-4-thio)acetic acid as a white solid, m.p. 94-960C (after recrystallisation from cyclohexane) in 72% yield; NMR (200 MHz, CDC13): 1.24(3H,s), 1.44(3H,s), 1.98-2.3(2H,m), 3.26(2H,dd), 4.18(1H,dd), 6.68-7.36(3H,m).

(v) Using a similar procedure to that described in part (ii) of Example 2, but starting from the foregoing thioacetic acid carrying out the reaction at -200C and starting with isobutyl nitrate, there was obtained 2,2-dimethyl-6-fluoro-4-(nitromethylthio)chroman as a red oil [after flash chromatography using hexane/ethyl acetate (9:1 v/v) as eluant] in 24% yield; NMR (200 MHz, CDC13): 1.26(3H,s), 1.44(3H,s), 2.0-2.35(2H,m), 4.34(1H,dd), 6.71-7.26(3H,m).

Example 10 The following illustrate representative pharmaceutical dosage forms containing a compound of formula I (such as any of those described in the preceding Examples), or a non-toxic salt thereof (hereafter referred to as "DRUG"), for therapeutic or prophylactic use in humans: (a) Tablet I mg/tablet DRUG 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 (b) Tablet II mg/tablet DRUG 50 Lactose Ph.Eur. 223.75 Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c) Tablet III mg/tablet DRUG 1.0 Lactose Ph.Eur. 93.25 Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0 (d) Capsule mg/capsule DRUG 10 Lactose Ph.Eur. 488.5 Magnesium stearate 1.5 (e) Injection I (50 mg/ml) DRUG 5.0% w/v 1M Sodium hydroxide solution 15.0% v/v O.lM Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5X w/v Water for injection to 100% (f) Injection II (10 mg/ml) DRUG 1.0% w/v Sodium phosphate EP 3.6% w/v 0.1M Sodium hydroxide solution 15.0% v Water for injection to 100% (g) Injection III (lmg/ml, buffered to pH6) DRUG 0.1X v/v Sodium phosphate BP 2.26% w/v Citric acid 0.38% v/v Polyethylene glycol 400 3.5% w/v Water for injection to 100% Note: The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

CHEMICAL FORMULAE Q. [C(Rd)Re]n.SO2.CH2.NO2 I

Q.[C(Rd)Re]n.S.CH2.NO2 III Q.[C(Rd)Re]n.SE IV Q.[C(Rd)Re]n.S.CH2.CO2H V Q.[C(Rd)Re]n.S.CH(NO2).CO2H VI Q.[C(Rd)Re]n.SO2- M+ VII Q.[C(Rd)Re]n.SO2H VIII Q.[C(Rd)Re]n.SO2Cl IX Q.[C(Rd)Re]n.SO2.CH3 X Q.[C(Rd)Re]n.SCH3 XI

Claims (16)

1. CLAIHS What is claimed is:1. A nitromethane derivative of the formula Q. [C(Rd)ReJ.SO2.CH2.NO2 CH2 wherein Q is a monovalent group of the formula Ra.C(Rb)Rc- in which Ra and Rb are independently hydrogen, (1-4C)alkyl or phenyl; or Ra and Rb together with the adjacent carbon atom form cyclopropyl, cyclobutyl or a (5-lOC)cycloalkyl moiety optionally bearing up to four (1-4C)alkyl substituents, in which (5-lOC)cycloalkyl moiety: (a), a carbon atom, other than that bearing the group [C(Rd)Re]n.SO2.CH2.NO2, may optionally be replaced by oxy, thio, sulphinyl, sulphonyl, imino or (1-4C)alkylimino, and (b) one or two adjacent pairs of carbon atoms may optionally be fused to one or two benzene moieties, respectively; and Rc is (1-6C)alkyl optionally bearing a (1-4C)alkoxy, (2-8C)dialkylamino, pyrrolidino, morpholino, piperidino or N-[(1-4C)alkyl]piperazino substituent, or Rc is hydrogen when Ra or Rb is other than hydrogen; Rd and Re are independently hydrogen or (1-4C)alkyl; n is zero or the integer 1 or 2; and any of which phenyl or benzene moieties may optionally bear up to three substituents, independently selected from halogeno, cyano, (1-4C)alkyl, (l-6C)alkoxy and trifluoromethyl; or a non-toxic salt thereof.
2. 2. A compound as claimed in claim 1 wherein Ra and Rb are independently hydrogen, methyl, ethyl, propyl, isopropyl or phenyl; or Ra and Rb together with the adjacent carbon atom form a cyclopropyl, cyclobutyl, norbornyl, adamantyl, cyclopentyl, cyclohexyl or cycloheptyl moiety; which last five cycloalkyl moieties may: (a) optionally bear up to four methyl or ethyl substituents; and (b) optionally have one carbon atom, other than that bearing the group [C(Rd)Re] n SO2.CR2.N02, replaced by oxy, thio, sulphinyl, sulphonyl, imino, methylimino or ethylimino, and any of which last three cycloalkyl moieties may optionally have one or two adjacent pairs of carbon atoms fused to one or two benzene moieties; and Rc is methyl, ethyl, propyl, butyl or pentyl, any of which may optionally bear a methoxy, ethoxy, propoxy, dimethylamino, diethylamino, pyrrolidino, morpholino, piperidino, N-methylpiperazino or N-ethylpiperazino substituent, or Rc is hydrogen when Ra or Rb is other than hydrogen;Rd and Re are independently hydrogen or methyl; and any phenyl or benzene moieties may optionally bear up to 3 substituents, independently selected from fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy and trifluorormethyl.
3. 3. A compound as claimed in claim 1 or 2 wherein Q is selected from ethyl, propyl, butyl, isobutyl, t-butyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl, 2-N,N-dimethylaminoethyl, 3-N,N-diethylaminopropyl, benzyl, benzhydryl, N-methyl-4-piperidinyl, N-ethyl-3-pyrrolidinyl, cyclopropylmethyl, cyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, cyclohexylmethyl, cycloheptyl, N-methyl-1,2,3,4-tetrahydro-4-quinolyl, 2-norbornyl, 2-adamantyl, tetrahydro-4-pyranyl, tetrahydro-4-thiopyranyl (and the corresponding oxide and dioxide), chroman-4-yl, thiochroman-4-yl, 1,2,3,4-tetrahydro-l-naphthyl, 4-xanthenyl, 2-indanyl, 1-indanyl, 9-fluorenyl, and 2,3,6,7-dibenzocycloheptyl, a benzene moiety of any of which may be optionally substituted as defined in claim 1 or 2.
4. 4. A compound as claimed in any of claims 1-3 in which n is zero or the integer 1.
5. 5. A compound of the formula II:

   wherein Rf, Rg, Rh and Ri are independently hydrogen or (1-4C)alkyl; or Rf and Rg together, and/or Rh and Ri together, in either case, with their adjacent carbon atoms of the carbocyclic ring, form benzene moieties fused thereto and which may optionally bear up to three substituents independently selected from halogeno, cyano, (1-4C)alkyl and trifluoromethyl; n is zero or the integer 1;X is a direct bond, methylene, [di(1-4C)alkyllmethylene, oxy, thio, imino or (1-4C)alkylimino; and the dotted bonds indicate that the appended carbon atoms are joined by an aromatic double bond when a benzene moiety is present and otherwise bear a hydrogen substituent and are joined by a single bond; provided that only two of Rf, Rg, Rh and Ri may be alkyl when X is [di(1-4C)alkyl]methylene; or a non-toxic salt thereof.
6. 6. A compound as claimed in claim 5 wherein Rf, Rg, Rh and Ri are independently hydrogen or methyl; or Rf and Rg together, and/or Rh and Ri together, in either case, with their adjacent carbon atoms of the carbocyclic ring, form benzene moieties fused thereto and which may optionally bear up to three substituents independently selected from fluoro, chloro, bromo, cyano, methyl, ethyl and trifluoromethyl; and X is a direct bond, methylene, isopropylidene, oxy, thio, imino or methylimino.
7. 7. A compound selected from: (benzylsulphonyl)nitromethane, (cyclohexylsulphonyl)nitromethane, (2,4,6-trimethylbenzylsulphonyl)nitromethane, (cyclopentylsuiphonyl)- nitromethane, [(2-phenylethyl)sulphonyljnitromethane, (hexylsulphonyl)nitromethane, (t-butylsulphonyl)nitromethane, 4-(nitromethylsulphonyl)chroman and 2,2-dimethyl-6-fluoro-4 (nitromethylsulphonyl)chroman, or a non-toxic salt thereof.
8. 8. A salt as claimed in any one preceding claim which is selected from alkali metal, alkaline earth metal, and ammonium salts, and salts with organic bases affording physiologically acceptable cations.
9. 9. A salt of a compound of formula I which contains an imino, alkylimino, alkylamino or dialkylamino group, as claimed in any one of claims 1-6, which salt is selected from salts with hydrogen halides, sulphuric acid, phosphoric acid, citric acid and maleic acid.
10. 10. A process for the manufacture of a compound of the formula I or a non-toxic salt thereof, as claimed in claim 1 or 5, which comprises: a) oxidising a thiother of the formula Q.[C(Rd)Re]n.S.CH2.N02 (III), or the corresponding sulphoxide; b) reacting an alkali metal sulphinate of the formula Q.[C(Rd)Re]n.SO2- M+ (VII), wherein M+ is an alkali metal cation, with nitromethane and iodine in the presence of an alkali metal (1-6C)alkoxide; or c) reacting a sulphone of the formula Q.[C(Rd)Re]n.S02.CH3 (X), with a (1-5C)alkyl nitrate in the presence of strong base; whereafter, when a non-toxic salt is required, the compound of the formula I is reacted with the appropriate or base or, for those compounds of formula I which contain an in io, alkylimino, alkylamino or dialkylamino group, with appropriate acid, affording a physiologically acceptable ion; and wherein Q, Rd, Re and n have any of the meanings defined in claims 1-4.
11. 11. A thiother of the formula Q.[C(Rd)Reln.S.CH2.N02 (III), or the corresponding sulphoxide.
12. 12. A pharmaceutical composition comprising a compound of formula I or a non-toxic salt thereof, as defined in any of claims 1-9 together with a pharmaceutically acceptable diluent or carrier.
13. 13. A composition as claimed in claim 12 which is in a form suitable for oral administration.
14. 14. A compound of the formula I, or a non-toxic salt thereof, in which Q, Rd, Re and n have any of the values set out in any of claims 1-7, substantially as described herein with reference to any one of Examples 1-9.
15. 15. A process for the manufacture of a compound of the formula I, or a non-toxic salt thereof, in which Q has any of the values set out in any of claims 1-7, substantially as described herein with reference to any one of Examples 1-9.
16. 16. A pharmaceutical composition comprising as active ingredient a compound of the formula I, or a non-toxic salt thereof, in which Q, Rd, Re and n have any of the values set out in any of claims 1-7, substantially as described in any part of Example 10 hereof.