Amidobenzene derivatives, compositions and use
This is a continuation of application Ser. No. 07/738,438, filed on Jul. 31, 1991, which was abandoned. 
    
    
     This invention concerns novel phenoxy- and phenylthioacetamidobenzene derivatives which are inhibitors of the enzyme aldose reductase and which are of value, for example, in the treatment of certain peripheral effects of diabetes or galactosemia. A method of treating one or more of such peripheral effects using an acetamide derivative and pharmaceutical compositions containing such a derivative are also provided. In addition, the invention concerns novel processes for the manufacture of the novel derivatives and for the preparation of medicaments containing any of the said derivatives. 
     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 substrate 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. In our European patent application, publication number 304,190, there is described a series of (phenylsulfonyl)nitromethane derivatives as inhibitors of the enzyme aldose reductase. We have now discovered that a specific group of novel phenoxy- and phenylthio-acetamido benzene derivatives set out below are potent inhibitors of aldose reductase and this is a basis for the present invention. 
     According to the invention there is provided a novel acyl derivative of the compound (4-amino-2,6-dimethylphenylsulfonyl)nitromethane having the formula I (set out hereinafter together with the other chemical formulae assigned Roman numerals) wherein R 0  and R 1  are independently hydrogen or (1-4C)alkyl; and on benzene ring A, one, two or three of R 2 , R 3 , R 4 , R 5  and R 6  are independently selected from hydrogen, halogeno, trifluoromethyl, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkanoyl, and the remainder of R 2  -R 6  is hydrogen; or an adjacent pair of R 2 , R 3 , R 4 , R 5  and R 6  completes (together with the adjoining carbon atoms) a further benzene ring which may itself optionally bear a halogeno, (1-4C)alkyl or (1-4C)alkoxy substituent, another of R 2  -R 6  is hydrogen, halogeno, trifluoromethyl, nitro, cyano, (1-4C)alkyl or (1-4C)alkoxy and the remainder of R 2  -R 6  is hydrogen; and X is oxygen or sulfur; or a pharmaceutically acceptable salt thereof. 
     It will be appreciated that, depending on the nature of the substituents, (for example, the nature of R 0  and R 1 ), the compounds of formula I may contain one or more chiral centres and may exist and be isolated in one or more racemic and enantiomeric forms. It is to be understood that the present invention includes any one of such forms which possesses useful effects as an inhibitor of the enzyme aldose reductase, it being well known in the art how to prepare individual enantiomers (for example, by synthesis from chiral intermediates or by separation of racemic forms) and how to assess their efficacy as aldose reductase inhibitors (for example, by the test procedures described hereinafter. 
     In this specification it is to be understood that generic terms such as &#34;alkyl&#34; include all isomeric possibilities i.e. both straight and branched chain forms. However, individual radical names such as &#34;propyl&#34; are specific to the form indicated i.e. the straight chain form, any chain branching being specifically indicated as needed. 
     A particular value for R 0  or R 1  when it is (1-4C)alkyl is, for example, methyl or ethyl, of which methyl is of particular interest. 
     Particular values for generic substituents as defined above on benzene ring A include, for example: for halogeno: fluoro, chloro and bromo; for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl and isobutyl; for (1-4C)alkoxy: methoxy and ethoxy; and for (1-4C)alkanoyl: acetyl and propionyl. 
     A particular value for an optional substituent which may be present on a second benzene ring when a pair of R 2  -R 6  as defined above complete such a ring is, for example, fluoro, chloro, methyl or methoxy. 
     A preferred value for X is oxygen. 
     A preferred group of compounds of the invention comprises compounds of the formula II set out hereinafter wherein Ra and Rb are independently hydrogen or methyl; and benzene ring B optionally bears one or two substituents independently selected from halogeno (especially fluoro or chloro), (1-4C)alkyl (especially methyl) and (1-4C)alkoxy (especially methoxy); and the pharmaceutically acceptable salts thereof. 
     A further group of compounds of particular interest comprises compounds of the formula IIa set out hereinafter wherein Acyl is selected from: 2-phenoxyacetyl, 2-(3-methylphenoxy)acetyl, 2-(3-chlorophenoxy)acetyl, 2-(2-naphthyloxy)acetyl, 2-(4-methylphenoxy)acetyl, 2-(phenylthio)acetyl, 2-(4-acetylphenoxy)acetyl, 2-(2,6-dimethylphenoxy)acetyl, (R,S)-2-phenoxypropionyl, 2-(2,6-dichlorophenoxy)acetyl, 2-(4-nitrophenoxy)acetyl, 2-(4-fluorophenoxy)acetyl, 2-(3-methoxyphenoxy)acetyl, 2-methyl-2-phenoxypropionyl, 2-(2-methylphenoxy)acetyl, 2-(4-methoxyphenoxy)acetyl, 2-(2-methoxyphenoxy)acetyl and 2-(4-chlorophenoxy)acetyl; or a pharmaceutically acceptable salt thereof. 
     Specific compounds of the invention are set out in the accompanying Examples and are provided together with their pharmaceutically acceptable salts as a further feature of the invention. Of these exemplified compounds, those which are of particular interest include the compounds described in Examples 1, 8, 9 and 10. 
     Suitable pharmaceutically acceptable salts include, for example, alkali metal (such as potassium or sodium), alkaline earth metal (such as calcium or magnesium), ammonium and aluminium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine. 
     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 as described in our aforementioned European patent application. Such procedures are provided as a further feature of the invention and are illustrated by the following procedures in which R 0 , R 1 , R 2 , R 3 , R 4 , R 5  and R 6  have any of the meanings defined hereinbefore. 
     a) (4-Amino-2,6-dimethylphenylsulfonyl)nitromethane is acylated by reaction with an acetic acid derivative of the formula III, or with a reactive acylating agent derived therefrom, such as an acid halide, azide, anhydride or mixed anhydride thereof. 
     When a free acid of formula III is used, the process is preferably carried out in the presence of a suitable condensing agent, for example, a carbodiimide such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide optionally together with an N-hydroxytriazole such as 1-hydroxybenzotriazole and in a suitable solvent or diluent, for example, methylene chloride or dimethylformamide, and at a temperature in the range, for example, -20° to 35° C. and, preferably, at or near ambient temperature. When 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is used as condensing agent, it is conveniently used in the form of a hydrohalide (such as the hydrochloride) salt and, preferably, in the presence of a suitable organic base, for example, triethylamine. 
     The acid of formula III may also conveniently be utilised in the form of its alkali metal salt, for example, its lithium, sodium or potassium salt. In these cases a suitable condensing agent such as a carbodiimide optionally together with an N-hydroxytriazole is used as described above. However, in this case, when a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrohalide is used as the condensing agent, no added organic base is required. 
     A particularly suitable reactive derivative of an acid of formula III is, for example, the acid halide of the said acid, for example the acid chloride or bromide (obtainable, for example, by reaction of the corresponding acid with an agent such as thionyl chloride or bromide), a mixed anhydride of the said acid with a (1-4C)alkanoic acid (such as formic acid) or a hemi(1-4C)alkyl carbonate [obtainable, for example, by reaction of said acid with respectively, an appropriate alkanoyl halide or a (1-4C)alkyl chloroformate (such as isobutyl chloroformate)], or an azide of the said acid, (obtainable, for example, by reaction of said acid with diphenylphosphoryl azide and triethylamine or from the corresponding hydrazide of the said acid by reaction with an alkyl nitrite such as t-butyl or amyl nitrite in the presence of strong acid.) When a reactive derivative of an acid of the formula III is used in process (a), a suitable base such as a metal carbonate, for example, potassium, sodium, lithium, calcium, barium or magnesium carbonate (of which calcium carbonate is particularly preferred) or an organic base such as triethylamine, N-methylmorpholine, N-methylpiperidine or 4-(dimethylamino)pyridine is conveniently also present and the reaction is carried out in a suitable solvent or diluent such as dioxan, N,N-dimethylformamide or methylene chloride and a temperature in the range, for example, 0° to 40° C. and, conveniently, at or near ambient temperature. 
     The starting amino compound, (4-amino-2,6-dimethylphenylsulfonyl)nitromethane, may be made by any of the general methods described in our aforesaid European patent application or as illustrated in the accompanying Examples. The starting acetic acid derivatives of formula III are in general well known, or may be obtained by procedures already known in the art for the production of structurally analogous compounds. 
     (b) A thioether of the formula (IV) is oxidised. 
     This process is particularly suitable for the production of those compounds in which X is oxygen. 
     Suitable oxidising agents for this reaction include any of those which are well known in the art for the conversion of thio to sulfonyl groups and which are compatible with the presence of the acylamino and methyl groups which are also present as substituents on the benzene moiety. 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), persulfate (such as potassium monopersulfate) 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° C. 
     In certain cases, the corresponding sulfoxide derivative of the thioether of formula IV may be formed as an isolable intermediate. The process of the invention also includes the oxidation of such a sulfoxide intermediate to a sulfone 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° C. 
     The starting thioethers of formula IV may be obtained by conventional procedures of organic chemistry, for example, from a potassium or sodium salt of the corresponding thiophenol of the formula V by conversion to the corresponding thioacetic acid of the formula VI (or a (1-4C)alkyl ester thereof, such as a methyl or ethyl ester) by reaction with chloro- or bromo-acetic acid (or a (1-4C)alkyl ester thereof) in the presence of a suitable base. The acid VI (or a (1-4C)alkyl ester thereof) is then reacted with a (1-5C)alkyl nitrate and an alkali metal (1-6C)alkane, for example propyl nitrate and butyllithium, to give the alkali metal salt of the corresponding 2-nitroacetic acid of the formula VII (or of the (1-4C)alkyl ester thereof). The acids of formula VII are unstable and readily decarboxylate and acidification of the alkali metal salt of an acid of formula VII allows the isolation of a thioether of formula IV. An ester of an acid of formula VII may be hydrolysed, for example, using aqueous base, to the acid of formula VII and then acidified to produce a thioether of formula IV. 
     The thiophenols of formula V may conveniently be obtained by N-acylation of 4-amino-2,6-dimethylbenzenethiol using a procedure analogous to that in (a) above. 4-amino-2,6-dimethylbenzenethiol may be obtained, for example by reaction of 3,5-dimethylaniline with thiocyanogen (generated in situ from lead(II) thiocyanate and bromine in methyl acetate) or with copper(II) thiocyanate to give 4-amino-2,6-dimethylphenyl isothiocyanate, which latter is then reduced, for example, with sodium borohydride in ethanol to give the required thiol. 
     (c) Reacting an alkali metal salt of a 4-N-acylamino-2,6-dimethylbenzenesulfinic acid of the formula VIII 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, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) or N,N-dimethylformamide (which are preferred), or N-methyl-2-pyrrolidone, and at a temperature in the range, for example, -30° to 20° C. and, conveniently, at about 0° C. The nitromethane is generally present in an excess. 
     The starting alkali metal salt may be obtained, for example, from the corresponding sulfinic acid of formula VIII by reaction with the appropriate alkali metal hydroxide or (1-6C)alkoxide, such as sodium or potassium methoxide or ethoxide. The sulfinic acid may itself be obtained by reacting 3,5-dimethylaniline with the appropriate acetic acid of formula III (or a reactive derivative thereof such as the chloride, bromide or anhydride) under analogous conditions to those used in the acylation process (a) above, to give the corresponding N-acyl-3,5-dimethylaniline. The acylation is generally performed with an excess of the acylating agent in the presence of a base such as triethylamine in a suitable solvent or diluent such as t-butyl methyl ether or tetrahydrofuran and at a temperature of, for example, 10° to 40° C. and conveniently at or near ambient temperature. The N-acyl-3,5-dimethylaniline is then chlorosulfonated by reaction with chlorosulfonic acid to give the 4-N-acylamino-2,6-dimethylbenzenesulfonyl chloride, which latter is reduced, for example, with a suitable sulfite (such as sodium sulfite) in the presence of a suitable buffer (such as sodium hydrogen carbonate) at a temperature of, for example, 60° to 90° C., to give the 4-N-acylamino-2,6-dimethylbenzenesulfinic acid. 
     Alternatively, the sulfonyl chloride may also be obtained, for example, from the appropriate 4-N-acylamino-2,6-dimethylphenyl isothiocyanate by reaction with chlorine in water, using conditions analogous to those described by Johnson et alia in J. Amer. Chem. Soc., 1939, 61, 2548. The isothiocyanate may itself be obtained, for example, by reaction of the appropriate 3,5-dimethyl-N-acylaniline with thiocyanogen (generated in situ from lead(II) thiocyanate and chlorine in acetic acid) or copper(II) thiocyanate in methyl or ethyl acetate. 
     Whereafter, when a pharmaceutically acceptable salt is required, a compound of formula I may be reacted with an appropriate base having a physiologically acceptable cation. 
     According to another aspect of the invention there is provided a pharmaceutical composition comprising a compound, of the formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. 
     The compositions of the invention 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 and 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. Compositions for oral use may also be in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil such as arachis oil, liquid paraffin or olive oil. 
     Suitable pharmaceutically acceptable excipients for use in tablet formulations 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. 
     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, polyvinylpyrrolidone, 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 sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions will also typically 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 pharmaceutical compositions of the invention 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 pharmaceutical 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 parenterally-acceptable 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 active ingredient 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 0.5 mg to 1 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. 
     As stated previously, the compounds of the invention inhibit the enzyme aldose reductase and 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: 
     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 sacrificed 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 polytrimethylsilyl derivatives. Inhibition of aldose reductase in vivo can then be 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 group of normal rats. 
     In a variation of the above test diabetic rats are dosed at a fixed daily oral dose for five days and then sacrificed 6 hours after the final dose and the reduction of sciatic nerve sorbitol assessed relative to that in control animals. 
     The property of inhibiting the enzyme aldose reductase may also be demonstrated in vitro. Thus, in a standard procedure partially purified aldose reductase is isolated in known manner from bovine lenses. The percentage inhibition of this enzyme&#39;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 can then be determined using standard spectrophotometric methods. 
     In general, the majority of compounds of the invention show significant reduction of sciatic nerve sorbitol levels at a dose of 5 mg/kg or less in one of the above in vivo tests, together with an IC 50  in the above in vitro test in the order of 10 -8  M to 10 -7  M. As an illustration, the compound of Example 1 produced an 78% reduction in sciatic nerve sorbitol levels after 5 daily oral doses of 3 mg/kg and had an IC 50  of 4.4×10 -8  M. 
     A compound of the formula I (or a pharmaceutically acceptable salt thereof) 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, for example, 15 to 800 mg. per man will be administered, given if necessary, in divided doses. However, the precise amount of the 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. 
     A compound of the formula I (or a pharmaceutically acceptable salt thereof) may also be administered topically, for example by direct topical administration to the tissue or organ in which inhibition of the enzyme is required, for example, to the eye. The precise amount of the 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 a compound of the formula I (or a pharmaceutically acceptable salt thereof) 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. 
     A compound of the invention may be conveniently administered at or about the same time as 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. Any one or more such agents may also be conveniently present as an additional active ingredient in a composition according to the present invention. 
     Although the compounds of the invention are expected to be of use in the treatment or prophylaxis of human and animal diseases and conditions caused at least in part by elevated tissue sorbitol levels, they may be also be used whenever it is necessary to inhibit the enzyme known as aldose reductase either in vitro (for example during a research programme to discover other therapeutic agents) or in vivo (for example in plants, when it is desired to modify their development by affecting the metabolism/utilisation of aldoses). 
    
    
     The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated: 
     (i) solvents were removed by rotary evaporation in vacuo with a bath temperature of 40°-50° C.; 
     (ii) all operations were carried out at room temperature, that is in the range 18°-26° C.; 
     (iii) column and flash chromatography was carried out on silica (Merck Art. 7736) and medium pressure liquid chromatography (MPLC) on silica (Merck Art. 9385), both materials available from E Merck and Co., Darmstadt, West Germany; 
     (iv) all end-products were characterised by microanalysis and NMR spectoscopy; 
     (v) yields are given for illustration only and are not necessarily the maximum attainable by diligent process development. 
     EXAMPLE 1 
     Phenoxyacetyl chloride (427 mg, 2.5 mM) was added to a stirred suspension of calcium carbonate (300 mg, 3 mM) and (4-amino-2,6-dimethylphenylsulfonyl)nitromethane (488 mg, 2 mM) in dry tetrahydrofuran (THF; 2.5 mL). The mixture was stirred for 30 minutes during which time carbon dioxide was released. Water (10 mL) and ethyl acetate (30 mL) were then added and the mixture acidified with 2M hydrochloric acid to pH 3. The organic phase was separated and washed with saturated sodium chloride solution (2×10 mL) and then dried (MgSO 4 ). The solvent was evaporated and the residue recrystallised from ethyl acetate. The solid obtained was washed with ether and air dried to give (2,6-dimethyl-4-[2-phenoxyacetamido]phenylsulfonyl)nitromethane as white crystals, having m.p. 166°-167° C. and in 67% yield after recrystallisation from ethyl acetate/hexane; microanalysis, found: C, 54.1; H, 5.1; N, 7.3%; C 17  H 18  N 2  O 6  S requires: C,  54.0: H, 4.8; N, 7.4%. 
     The starting amino derivative may be obtained as follows: 
     (1) N-Acetyl-3,5-dimethylaniline (obtained as a solid, 138° C., by acetylation of 3,5-dimethylaniline) is reacted with an excess of chlorosulfonic acid at 60° C., using an analogous procedure to that described in Organic Syntheses, Coll. Vol.I, at page 85, to give 4-acetamido-2,6-dimethylbenzenesulfonyl chloride as a solid [thin layer chromatographic analysis (TLC): Rf ca. 0.27 (SiO 2  : ethyl acetate/hexane 1:1 v/v)] in about 90% yield, which is used without drying or characterisation. 
     (2) The above sulfonyl chloride (10.95 g, 50 mmol) is added in portions to a vigorously stirred solution of sodium bicarbonate (8.4 g, 100 mmol) and anhydrous sodium sulfite (12 g, 95 mmol) in water (50 ml) at 70°-80° C. The temperature is kept at 70°-80° C. by intermittent heating. When the addition is complete, the mixture is heated and stirred at 70°-80° C. for a further hour. The mixture is then allowed to cool to room temperature during 4 hours and acidified with 2M hydrochloric acid. The precipitated solid is collected by filtration, washed with water, air dried and to give 4-acetamido-2,6-dimethylbenzenesulfinic acid, as a solid in about 80% yield; TLC: Rf ca. 0.02 (silica: ethyl acetate). This acid is converted to its sodium salt by addition to a solution of sodium methoxide (1 equivalent) in methanol and evaporation of the resultant solution. The sodium salt is used without purification or characterisation. 
     (3) Nitromethane (6.72 ml, 124 mM) is added to a stirred solution of sodium methoxide (3.01 g, 55.8 mM) in N,N-dimethylformamide (DMF; 250 ml), cooled to 0° C. in an ice-bath. When the addition is complete, stirring is continued for an additional 30 minutes at 0° C. 4-Acetamido-2,6-dimethylbenzenesulfinic acid sodium salt (11.59 g, 56 mmol) is then added, followed immediately by iodine (7.2 g, 28.3 mmol). The mixture is stirred for 16 hours and allowed to attain room temperature. A concentrated solution of aqueous sodium sulfite is then added to partially decolourise the reaction mixture, which latter was is then poured into water (about 1 liter) and acidified with 2M hydrochloric acid. The aqueous mixture is extracted with ethyl acetate. The combined extracts are washed with water, then with brine, and dried (MgSO 4 ). The solvent is removed by evaporation and the residue is purified by medium pressure liquid chromatography (MPLC) on silica, eluting with ethyl acetate-hexane (1:10  v/v, gradually increasing to 1:5 v/v) to give (4-acetamido-2,6-dimethylphenylsulfonyl)nitromethane as a solid, m.p. 179°-180° C. [purified by trituration with methanol] in 21% yield; NMR (d 6  -DMSO, 200 MHz): 2.08(3H, s), 2.54(6H, s), 6.42(2H, s), 7.51(2H, s), 10.26(1H, s); microanalysis, found: C,46.2; H,5.0; N,9.7%; C 11  H 14  N 2  O 5  S requires: C,46.15; H,4.9; N,9.8%. 
     (4) (4-Acetamido-2,6-dimethylphenylsulfonyl)nitromethane (11.5 g, 40 mM) is added in one portion to a boiling mixture of concentrated hydrochloric acid (22 ml), water (110 ml) and ethanol (45 ml). The mixture is stirred at reflux until a clear solution formed (about 20 minutes) and then for a further 10 mins. The hot reaction mixture is then poured into an excess of ice-cold saturated sodium bicarbonate solution. The aqueous mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO 4 ) and the solvent removed by evaporation to give (4-amino-2,6-dimethylphenylsulfonyl)nitromethane, as a solid, m.p. 132°-133° C. [after recrystallisation from ethanol] in 73% yield; NMR(d 6  -DMSO, 200 MHz): 2.39(6H, s), 6.19(4H, s), 6.35(2H, s); microanalysis, found: C,44.5; H,4.9; N,11.6%; C 9  H 12  N 2  O 4  S requires: C,44.3; H,4.9; N,11.5%. 
     EXAMPLES 2-18 
     Using a similar procedure to that described in Example 1, but using the appropriate acyl chloride, the following (4-N-acylamino-2,6-dimethylphenylsulfonyl)nitromethanes of the invention and of the formula IIa may be obtained: 
     
         __________________________________________________________________________
                     m.p.  recryst.                                       
                                   yield                                  
Example                                                                   
       .sub.-- N-acyl- group                                              
                     (°C.)                                         
                           solvent(s)                                     
                                   (%)                                    
__________________________________________________________________________
2     2-(3-methylphenoxy)acetyl                                           
                     159-160                                              
                           Et.sub.2 O                                     
                                   89                                     
3     2-(3-chlorophenoxy)acetyl                                           
                     198-199                                              
                           Et.sub.2 O                                     
                                   95                                     
4     2-(2-naphthyloxy)acetyl                                             
                     229-230                                              
                           EtOAc   86                                     
5     2-(4-methylphenoxy)acetyl                                           
                     172-173                                              
                           Et.sub.2 O                                     
                                   89                                     
6     2-(phenylthio)acetyl                                                
                     189-190                                              
                           EtOAc   65                                     
7     2-(4-acetylphenoxy)acetyl                                           
                     201-202                                              
                           EtOAc   64                                     
8     2-(2,6-dimethylphenoxy)acetyl                                       
                     148-149                                              
                           Et.sub.2 O                                     
                                   86                                     
9     ( .sub.-- R, -S)-2-phenoxypropionyl                                 
                     159-160                                              
                           Et.sub.2 O/Hexane                              
                                   83                                     
10    2-(2,6-dichlorophenoxy)acetyl                                       
                     120-121                                              
                           EtOAc/Hexane                                   
                                   84                                     
11    2-(4-nitrophenoxy)acetyl                                            
                     221-222                                              
                           EtOAc   95                                     
12    2-(4-fluorophenoxy)acetyl                                           
                     164-165                                              
                           EtOAc/Hexane                                   
                                   73                                     
13    2-(3-methoxyphenoxy)acetyl                                          
                     150-152                                              
                           Et.sub.2 O                                     
                                   92                                     
14    2-methyl-2-phenoxypropionyl                                         
                     122-123                                              
                           Et.sub.2 O/Hexane                              
                                   68                                     
15    2-(2-methylphenoxy)acetyl                                           
                     171-172                                              
                           Et.sub.2 O                                     
                                   94                                     
16    2-(4-methoxyphenoxy)acetyl                                          
                     164-165                                              
                           EtOAc   94                                     
17    2-(2-methoxyphenoxy)acetyl                                          
                     169-170                                              
                           Et.sub.2 O                                     
                                   87                                     
18    2-(4-chlorophenoxy)acetyl                                           
                     150-151                                              
                           Et.sub.2 O                                     
                                   93                                     
__________________________________________________________________________
 Notes:                                                                   
 1. Et.sub.2 O = ether; EtOAc = ethyl acetate.                            
 2. In the majority of cases the solvent(s) were used to solidify the     
 initially isolated reaction product rather than to effect                
 recrystallisation.                                                       
 
    
     The starting acyl chlorides may be obtained using a conventional procedure from the corresponding acids, which latter are well known in the chemical art and in the majority of cases are commercially available. 
     The production of the acyl chlorides is illustrated by the following preparation of (2-methylphenoxy)acetyl chloride: 
     Oxalyl chloride (2.2 mL, 25 mM) was added to a stirred solution of (2-methylphenoxy)acetic acid (3.32 g, 20 mM) in dichloromethane (10 mL). Dry N,N-dimethylformamide (1 drop) was added to catalyse the reaction and the mixture was stirred for 16 hours. The solvent was removed by evaporation to leave (2-methylphenoxy)acetyl chloride as a pale yellow oil, which was used without further purification. 
     EXAMPLE 19 
     The following illustrate representative pharmaceutical dosage forms containing a compound of the formula I, such as is described in one of the previous examples, or a pharmaceutically acceptable salt thereof, for therapeutic or prophylactic use in humans: 
     
         ______________________________________                                    
(a)   Tablet I              mg/tablet                                     
______________________________________                                    
      Compound              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                                     
______________________________________                                    
      Compound              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                                     
______________________________________                                    
      Compound              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                                    
______________________________________                                    
      Compound              10                                            
      Lactose Ph.Eur        488.5                                         
      Magnesium stearate    1.5                                           
______________________________________                                    
 
    
     The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may conveniently be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. ##STR1##