AP261A - Phenylacetamides derivatives. - Google Patents

Abstract

The invention concerns novel

Description

ACETAMIDE DERIVATIVES

This invention concerns novel phenylacetamide derivatives which are inhibitors of the enzyme aldose reductase and which are of value, for example, in the treatment of certain peripheral effects of _t 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

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- 2 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)nicromethane derivatives as inhibitors of the enzyme aldose reductase. Ve have nov discovered that a specific group of novel phenylacetamide derivatives set out belov are potent inhibitors of aldose reductase and this is a basis for the present invention.

According to the invention there is provided a novel phenylacetyl derivative of the compound (4-amino-2,6-dimethylphenylsulfonyl)nitromethane having the formula I (set out hereinafter together vith the other chemical formulae assigned Roman numerals) wherein and R^ are independently hydrogen, (l-4C)alkyl, (l-4C)alkoxy, cyano or trifluoromethyl, or together constitute 1 2 (2-6)alkylene, or R together vith R of the adjacent benzene ring A constitutes methylene, ethylene, oxyethylene, ethyleneoxy, methyleneoxymethylene. vinylene, trimethylene or tetramethylene; and

3 4 5 on benzene ring A, one. two or three of the available R , R , R , R and R^ are independently selected from hydrogen, halogeno, trifluoromethyl, nitro, cyano, (l-4C)alkyl and (l-4C)alkoxy, and the remainder of R^-R is hydrogen; or an adjacent pair of the available 9345 β

R·⁶, R , R , R^J and R° completes (together vith the adjoining carbon atoms) a further benzene ring vhich may itself optionally bear a

6 halogeno, (l-4C)alkyl or (l-4C)alkoxy substituent, another of R -R^P is hydrogen, halogeno. trifluoromethyl, nitro, cyano, (l-4C)alkyl or (l-4C)alkoxy, and the remainder of R -R° is hydrogen; or a pharmaceutically acceptable salt thereof.

It will be appreciated that, depending on the nature of the substituents, (for example, the nature of R^ and R^), 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 vhich possesses useful effects as an inhibitor of the enzyme aldose reductase, it being veil known in the art hov to prepare individual enantiomers (for example, by synthesis from chiral intermediates or by

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- 3 resolution of racemic forms, for example by chromatography on a chiral support) and hov to assess their efficacy as aldose reductase inhibitors (for example, by a test procedure described hereinafter).

In this specification it is to be understood that generic terms such as alkyl include all isomeric possibilities i.e. both straight and branched chain forms. However, individual radical names 2 such as propyl 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^ or R^ when it is (l-4C)alkoxy is, for example, methoxy, ethoxy or isopropoxy, of which methoxy is of particular interest.

Particular combinations of R^ and R^ which are of interest include, for example:

(a) Ηθ = r! = hydrogen; (b) R^ = hydrogen and R^ * methyl; (c) Ηθ » hydrogen and R¹ * ethyl: (d) x = hydrogen or methyl, and R¹ * cyano;

(e) Ηθ = hydrogen or tri fluoromethyl and R^ * methoxy or ethoxy; and (f) rQ and r! together = ethylene.

A particular value for R^ and R^ when together they constitute (2-6C)alkylene is, for example, ethylene,

1,1-dimethylethylene, trimethylene, tetramethylene or pentamethylene.

Particular values for generic substituents as defined above on benzene ring A include, for example: for halogeno: fluoro, chloro and bromo;

for (l-«*C)alkyi: methyl, etnyl. propyl, isopropyl and isobutyl: and for (l-iC)aikcxy: methoxy and ethoxy.

A particular value for an optional substituent which may be present on a second benzene ring when a pair of R -R as defined above complete such a ring is. tor example, fluoro, chloro, methyl or methoxy.

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- 4 A specific group of compounds within the invention comprises bi- or tri-cyclic amides of the formula Ia set out hereinafter wherein Q is methylene, ethylene, oxyethylene, ethyleneoxy, vinylene or trimethylene and the substituents R^-R^ on benzene ring A have any of the meanings defined above, and the pharmaceutically acceptable salts thereof.

A preferred group of compounds of the invention comprises compounds of the formula II set out hereinafter wherein Ra and Rb are independently hydrogen, methyl, ethyl or cyano, or one of Ra and Rb is hydrogen or trifluorornethyl and the other is methoxy, ethoxy or isopropoxy; and benzene ring B is selected from phenyl,

2-halogenophenyl (especially 2-fluoro or 2-chlorophenyl),

2-(l-4C)alkylphenyl (especially 2-methylphenyl), 2-(l-4C)alkoxyphenyl (especially 2-methoxyphenyl), 4-(l-4C)alkoxyphenyl (especially 4-methoxy or 4-ethoxyphenyl) and 2,4,6-tri ((l-4C)alkyl]phenyl (especially 2,4,6-trimethylphenyl); and the pharmaceutically acceptable salts thereof.

A further group of compounds of particular interest comprises compounds of the formula Ila set out hereinafter wherein Acyl is selected from:

phenylacetyl, (2,4,6-trimethylphenyl)acetyl, (2-methylphenyl)acetyl, (2-fluorophenyl)acetyl, (2-chlorophenyl)acetyl, (2-methoxyphenyl)acetyl, l-(4-chlorophenyl)-l-cyclopropanecarbonyl, l-(phenyl)1- eyelopropanecarbony1, (4-ethoxyphenyl)acetyl, (R,S)-2-(phenyl)propionyl, (4-methoxyphenyl)acetyl, (R,S)-benzocyclobutanecarbonyl, (2-bromophenyl)acetyl, (2-ni trophenyl)ace tyl, 2-(4-chlorophenyl)2- methylpropionyl, (4-methoxy-3-methylphenyl)acetyl, ( 3-fluorophenyl)acetyl. (R,S)-2-methoxy-2-(2-fluorophenyl)acetyl, (2-trifluoromethylphenyl)acetyl, (3,4-difluorophenyl)acetyl, (2,6-dichlorophenyl)acetyl, (4-tri fluoromethylphenyl)acetyl, (4-chlorophenyl)acetyl, (3-methylphenyl)acety1, (3-methoxyphenyl)acetyl, 1-phenylcyclopentanecarbonyl, l-(4-methoxyphenyl)cyclopropanecarbony1, (2-naphthyl)acetyl, (R,S)-l-(4-chlorophenyl)cyclobutanecarbonyl, (1-naphthyl)acetyl, (2-methyl-6-nitrophenyl)BAD ORIGINAL ft

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- 5 acetyl, (4-fluorophenyl)acetyl, (3,4-dichlorophenyl)acetyl, (2, 4-dichlorophenyl)acetyl, (R,S)-2-(4-isobutylphenyl)propionyl, (R) -3,3,3-trifluoro-2-methoxy-2-phenylpropionyl, (S)-3,3,3-trifluoro2-methoxy-2-phenylpropionyl, (R,S)-2-methoxy-2-(2-methylphenyl)acetyl, (S) -2-methoxy-2-phenylacetyl, (R,5)-1,2,3,4-tetrahydro-l-naphthoyl, (R)-2-methoxy-2-phenylacetyl, (R,S)-2-methoxy-2-phenylacetyl, (R,S)-2-(2-chlorophenyl)-2-methoxyacetyl, (R,5)-2-(2-chlorophenyl)2-isopropoxyacetyl, 3-indenylcarbonyl, (R,S)-l-indanylcarbonyl, (R,S)-2-(3-fluoro-2-methyIphenyl)-2-methoxyacetyl, (R,S)-2(2,6-difluorophenyl)-2-methoxyacetyl, (2,6-difluorophenyl)acetyl, (1-isochromanyl)carbonyl, (R,S)-2-cyano-2-(phenyl)propionyl, (R,S)-2-methoxy-2-(2-methoxyphenyl)acetyl, (R,S)-2-(2,3-di fluorophenyl )-2-methoxyacetyl, (S)-2-phenylpropionyl, (R)-2-phenylpropionyl, (R,S)-2-(2-methyIpheny1)propionyl, (R,S)-2-phenylbutyryl, (R,S)-2-ethoxy-2-(phenyl)acetyl and (R,S)-2-ethoxy-2-(2-methylphenyl)acetyl; and the pharmaceutically acceptable salts thereof.

A still further group of compounds of the invention comprises compounds of the formula Ila vherein Acyl is selected from: (R)-2-methoxy-2-(2-methyIphenyl)acetyl, (R,S)-2-ethoxy-2-(2-fluorophenyl )acetyl , 2-(2,3-d ime thy Ipheny l)acetyl, 2-(2, b-dimethylpheny^acetyl, (R,S)-2-(2,6-difluorophenylpropionyl, (S)-2-methoxy-2(2-methylphenyl)acetyl, 2-(4-methylphenyl)acetyl, 2-(2-fluorophenyl)propionyl, 2-(2,4-dimethylphenyl)acetyl, (R)-l,2,3,4-tetrahydro-l-naphthoyl, (5)-1,2,3,4-tetrahydro-1-naphthoyl, (R)-2-methoxy-2-(2-methoxyphenyl)acetyl and (S)-2-methoxy-2(2-methoxyphenyl)acetyl; and the pharmaceutically acceptable salts thereof.

Specific compounds of the invention are set out in the accompanying Examples and are provided together vith their pharmaceutically acceptable salts as a further feature of the invention. A group of exemplified compounds which is of particular interest comprises the compounds described in Examples 1-12, 19,

37-44, 47-48, 50-52, 60-68 and 71-74; or a pharmaceutically acceptable salt thereof. Of these, the compounds described in Examples 2, 3,

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37-40. 52, 58, 60, 62, 71 and 73, or a pharmaceutically acceptable salt thereof, are particularly preferred.

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 vith organic bases affording physiologically acceptable cations, such as salts vith methylamine, dimethylamine, trimethylamine, piperidine and morpholine.

The novel compounds of the invention may be obtained by standard procedures of organic chemistry already knovn 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 folloving procedures in vhich R^, Κθ, benzene ring A and the optional substituents thereon have any of the meanings defined hereinbefore.

(a) (4-Amino-2,6-dimethylphenylsulfonyl)nitromethane is acylated by reaction vith a carboxylic acid of the formula III, or vith 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-diisopropylcarbodi imide or 1-ethy1-3-(3-dimethylaminopropyl)carbcdiimide optionally together vith an N-hydroxytriazole such as 1-hydroxybenzotriazole and in a suitable solvent or diluent, for example, methylene chloride or dimethyl formamide, and at a temperature in the range, for example, -20 to 35’C and, preferably, at or near ambient temperature. When l-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,

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AP Ο Ο Ο 2 6 1 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 vith an N-hydroxytriazole is used as described above. Hovever, in this case, when a l-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 vith an agent such as thionyl chloride or bromide), a mixed anhydride of the said acid vith a (l-4C)alkanoic acid (such as formic acid) or a hemi(l-4C)alkyl carbonate [obtainable, for example, by reaction of the said acid vith, respectively, an appropriate alkanoyl halide or a (l-AC)alkyl chloroformate (such as isobutyl chloroformate), or an azide of the said acid, (obtainable, for example, by reaction of the said acid vith diphenylphosphoryl azide and triethylamine or from the corresponding hydrazide of the said acid by reaction vith 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, lichium, calcium, barium or magnesium carbonate (of which calcium carbonate is particularly preferred) or an organic base such as triethylamine, N-methylmorpholine, N-methylpiperidine or <*-(dimethylamino)pyridine is conveniently also present and the reaction is carried out in a suitable solvent or diluent such as dioxan, N, N-d i me thy 1 fo mam ide or methylene chloride and a temperature in the range, tor example. 0 to +C ³C and. conveniently, at or near ambient temperature. When a compound of formula I in optically form is required, the acid of formula III or the reactive derivative thereof may conveniently be used as a single enantiomeric form.

The starting amino compound, (-»-amino-2,6-dimethylphenylsulfonyl)nitromethane, may be made by any of the general methods described in our aforesaid European patent application or as

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illustrated in the accompanying Examples. The starting carboxylic acids of formula III are in general veil known and, in many cases, are commercially available. Alternatively, they may be obtained by procedures already established for structurally analogous carboxylic acids, for example, as is indicated in the accompanying Examples.

(b) A thioether of the formula (IV) is oxidised.

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 (l-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 VI (or a

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- 9 (l-4C)alkyl ester thereof) is then reacted with a (l-5C)alkyl nitrate and an alkali metal (l-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 (l-4C)alkyl ester thereof). The acids of formula VII are unstable and readily c 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-dimethylbenzene thiol using a procedure analogous to that in (a) above. 4-Amino-2,6-dimethylbenzene thiol may itself 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-acylaaino2,6-dimethylbenzenesulfinic acid of the formula VIII with nitromethane and iodine in the presence of an alkali metal (l-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- x2( lH)-pyrimidinone (DMPU) or Ν,Ν-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 Q’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 (l-6C)alkoxide, such as sodium or potassium methoxide or ethoxide. The sulfinic acid may itself be obtained by reacting 3,5-dimethylaniline with the

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- 10 appropriate phenylacetic 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 vith 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^eC and conveniently at or near ambient temperature. The N-acyl-3,5-dimethylaniline is then chlorosulfonated by reaction vith chlorosulfonic acid to give the (4-N-acylamino-2,6-dimethylphenyl)sulfonyl chloride, vhich latter is reduced, for example, vith 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-dimethylphenyl)sulfinic acid.

Alternatively, the sulfonyl chloride may also be obtained, for example, from the appropriate 4-N-acyla.mino-2,6-dimethylphenyl isothiocyanate by reaction vith chlorine in vater, 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 vith thiocyanogen (generated in situ from lead(II) thiocyanate and bromine in methyl acetate) 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 vith 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 vith 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

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- 11 (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible povders 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, veil knovn in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sveetening, flavouring and/or preservative agents and may be in the form of hard gelatin capsules in vhich the active ingredient is mixed vith 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 vhich the active ingredient is mixed vith vater or an oil such as arac.nis 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 vithi.n the gastrointestinal tract, or to improve their stability anc or appearance, in either case, using conventional coating agents and procedures veil k.novn in tne art.

Aqueous suspensions vill generally contain the active ingredient in finely powdered form together vith one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, bad original

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- 12 polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or vetting agents such as lecithin or condensation products of an alkylene oxide vith fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide vith long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide vith partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide vith partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions vill also typically contain one or more preservatives (such as ethyl or propyl £-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sveetening 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 beesvax, hard paraffin or cetyl alcohol. Sveetening 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 povders and granules suitable for preparation of an aqueous suspension by the addition of vater generally contain the active ingredient together vith a dispersing or vetting agent, suspending agent and one or more preservatives. Suitable dispersing or vetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sveetening, flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-vater 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.

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- 13 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 vith '> ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sveetening, flavouring and preservative agents.

Syrups and elixirs may be formulated vith sveetening 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, vhich may be formulated according to knovn procedures using one or more of the appropriate dispersing or vetting agents and suspending agents, vhich 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 vith a suitable non-irritating excipient vhich is “ solid at ordinary temperatures but liquid at the rectal temperature and vill 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 vith a conventional, topically acceptable, vehicle or diluent using conventional procedures veil knovn in the art. Topical formulations for administration to the eye vill generally be in the form of an ointment, gel or sterile solution

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- 14 buffered at an ophthalmically acceptable pH, for example in the range pH 7.0-7.6.

The amount of active ingredient that is combined vith one or more excipients co 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 lg of active agent compounded vith 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

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- 15 assessed relative to that in control animals.

The property of inhibiting the enzyme aldose reductase may also be demonstrated i_n vitro. Thus, in a standard procedure 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 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

5mg/kg or less in one of the above in vivo tests, together with an -8 -7

IC_5Q in the above in vitro test in the order of 10 M to 10 M. As an illustration, the compound of Example 1 produced an 83X reduction in sciatic nerve sorbitol levels after 5 daily oral doses of 3 mg/kg and had an Ιϋ^θ of 11.3 x 10’θΜ.

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 300 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 τ

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- 16 administered, a concentration of the compound containing up to 0.01Z 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 ijn 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 13-26°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, Vest Germany;

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AP Ο Ο Ο 2 6 1

- 17 (iv) all end-products vere characterised by microanalysis and NMR spectoscopy;

(v) yields are given for illustration only and are not necessarily the maximum attainable by diligent process development.

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- 18 Example 1

Phenylacetyl chloride (1.16g, 7.5mM) vas added to a stirred suspension of calcium carbonate (l.Og, lO.OmM) and (4-amino-2,6-dimethylphenylsulfonyl)nitromethane (1.22g, 5.0mM) in dry tetrahydrofuran (THF; 20 mL). The mixture vas stirred for 16 hours during vhich time carbon dioxide vas slovly released. Ethanol (1.0 mL) vas then added and the mixture stirred for a further hour in order to decompose excess phenylacetyl chloride. Ethyl acetate (100 mL) vas then added and the insoluble material removed by filtration. The filtrate vas vashed first vith vater (50 mL) containing 2M hydrochloric acid (2.0 mL) and then vith saturated sodium chloride solution (2 x 40 mL) and then dried (MgSO^). The solvent vas evaporated and the residue recrystallised from ethyl acetate. The solid obtained vas vashed vith ether and air dried to give (2,6-dimethyl-4-Iphenylacetamido]phenylsulfonyl)nitromethane as vhite crystals, having m.p. 158-159 °C and in 54 % yield after recrystallisation from ethanol; microanalysis, found: C, 56.7;

H, 5.0; N, 8.OX; CpH.gN^S requires: C, 56.4: H, 5.0; ii, 7.7%.

The starting amino derivative may be obtained as follovs:(1) N-Acetyl-3,5-dimethylaniline (obtained as a solid, 138^eC, by acetylation of 3,5-diT.ethylaniline) is reacted vith an excess of chlorosulfonic acid at 60°C, using an analogous procedure to that described in Organic Syntheses, Coll VolI, at page 85, to give 4-acetamido-2,6-dimethyIbenzenesulfonyl chloride as a solid (thin layer chromatographic analysis (TLC): Rf ca. 0.27 (SiO2t ethyl acetate/hexane 1:1 v/v)] in about 90X yield, vhich is used vithout 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 vater (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 alloved to cool to room temperature during 4 hours and acidified vith 2M hydrochloric acid. The precipitated solid is collected by filtration,

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AP Ο Ο Ο 2 6 1

- 19 vashed with water, air dried and to give 4-acetamido-2,6-dimethylbenzenesulfinic acid, as a solid in about 802 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 O’C in an ice-bath. When the addition is complete, stirring is continued for an additional 30 minutes at O’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 litre) 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^). 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 212 yield; NMR (d^-DMSO, 200MHz): 2.08(3H. s), 2.54(6H, s), 6.42(2H, s), 7.51(2H, s), 10.26(lH, s); microanalysis, found: C,46.2; H,5.0; N,9.72; requires:

C.46.15; H.4.9; N,9.82.

(4) (4-Acetamido-2,6-dime thyIphenylsuifonyl)ni tromethane (11.5g, 40mM) 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 is 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 (MgSOp and the solvent removed by evaporation to give

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- 20 (4-amino-2,6-dimethylphenylsulfonyl)nitromethane, as a solid, m.p. 132-133°C (after recrystallisation from ethanol) in 73X yield; NMR(dg-DMSO, 200MHz): 2.39(6H, s), 6.19(4H, s), 6.35(2H,s)j microanalysis, found: 0,44.5; H.4.9; N,11.62; requires:

C,44.3; H,4.9; N,11.52.

Examples 2-59

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 may be obtained: -

|Example | i 1	N-acyl group	m.p. (°C)	recryst. | solvent(s)|	yield| (X) |
1 2 ι	(2,4,6-1rime thyIphenyl)acetyl	203-204	EtOH |	72 |
1 3 |	(2-methyIpheny1)acetyl	188-190	Et2O |	89 |
1 * ί	(2-fluorophenyl)ace tyl	183-184	Et20 (	84 |
i 5 |	(2-chloropheny1) ace tyl	188-190	Et20 |	80 |
1 6 I	(2-methoxypheny1)acetyl	140-142	EtOH |	28 |
1 1 1 1 !	1-(4-chlorophenyl)-1- cyclopropanecarbonyl	150-151	EtOH | 1	68 | 1
1 8 |	1-( phenyl)-1-cyclopropanecarbonyl	127-128	Et20/Hexane|	69 |
1 9 |	(4-ethoxyphenyl)acetyl	124-126	Et20/Hexane|	78 |
1 10 1	(R,S)-2-( phenyl) propionyl	175-176	EtOH |	71 I
1 11 1	(4-methoxyphenyl)acetyl	182-183	Et2O |	99 |
1 12 i	(R,S)-benzocyciobutanecarbonyl	193-194	EtOH |	80 |
1 13 !	(2-bromopheny1)ace tyl	188-190	EtOH |	79 |
i 14	(2-ni trophenyl)acetyl	218-220	Et2O |	46 |
! 15 1	2-(4-chloropheny1)-2-methyl- propionyl	197-198	Et2O | i	75 | 1
ί 16	(4-methoxy-3-methyIpheny1)acetyl	143-144	EtOH/'Hexane J	69 |
1 Π	(3-fluorophenyl) acetyl	139-141	Et2O |	73 |
ί 18	(R,S)-2-methoxy-2- (2-fluorophenyl)acetyl	154-155	toluene | 1	35 | 1
1 19 1	(2-tri fluoromethylphenyl)acetyl	194-196	Et2o_L	29 i

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ΑΡ Ο Ο η 2 6 1

|Example! 1 1	N-acyl group	1 «·ρ· 1 ! (°C) !	recryst. | solvent(s)|	yield! (Ό |
1 20 1	(3,4-difluorophenyl)acetyl	I 180-182!	Et2O |	82 !
1 21 1	(2,6-dichlorophenyl)acetyl	1210-212!	Et20 |	75 |
1 22 1	(4-trifluoromethylphenyl)acetyl	1182-183!	Et20 I	38 |
1 23 !	(4-chlorophenyl)acetyl	1190-1911	Et20 |	96 |
1 24 1	(3-methylpheny1)acetyl	|168-170|	Et2O |	63 |
1 25 1	(3-methoxyphenyl)acetyl	|140-142|	EtOH |	28 |
1 26 1	1-phenylcyclopentanecarbonyl	1119-1201	EtOH |	35 |
1 27 1 1 1	l-(4-methoxyphenyl)- cyclopropanecarbonyl	|178-179| 1 1	EtOH | 1	52 | 1
1 28 1	(2-naphthy1)acetyl	|174-1751	Et20/Hexane j	53 |
1 29 1 1 1	(R,S)-1-(4-chlorophenyl)- cyclobutanecarbonyl	|147-1481 1 1	EtOH | 1	36 | 1
1 30 1	(1-naphthyl)acetyl	|213-214|	EtOH/Et2O ]	56 |
1 31 1	(2-methyl-6-ni trophenyl)acetyl	|205-207|	Et2O |	75 |
1 32 1	(4-fluorophenyl)acetyl	1161-162!	Et20/Hexane|	90 |
1 33 1	(3,4-dichlorophenyl)acetyl	1199-200!	EtOH |	60 |
1 34 1	(2,4-dichlorophenyl)acetyl	|190-1921	EtOAc/Hexane	69 1
1 35 1 1 1	(R,S)-2-(4-isobutylpheny1)- propionyl	|116-1181 1 1	EtjO/Hexane| 1	23* | 1
1 36 1 1 1	(R)-3,3,3-tri fluoro-2-methoxy- 2-phenylpropionyl	1106-1081 I 1	Me0H/H20 | 1	60 | 1
I 37 1 1 1	(5)-3,3,3-tri fluoro-2-methoxy2-phenylpropionyl	i110-112! i |	MeOH/H2O | !	66 j
1 38 1	(R,S)-2-methoxy- 2-(2-me thylpheny1)acetyl	! 176-1771 I 1	EtOAc I 1	87 ! 1
1 39 I	(S)-2-methoxy-2-phenylacetyl	!138-140!	EtOAc |	75 |
! 40 ! I 1	(R,5)-1,2,3,4-tetrahydro- 1-naphthoyl	!120-122ί i i	EtOAc j 1	62 ! 1
1 41 I	(R)-2-methoxy-2-phenylacetyl	| 140-141)	itOAc/EtjO |	64 j
1 42 |	(R,S)-2-methoxy-2-phenylacetyl	i169-1701	EtOAc/Hexane	73 (
1 43 | ! I	(R,S)-2-(2-chlorophenyl)- 2-methoxyacetyl	; 171-172! ; 1	Toluene | 1	76 ! L

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|Example| 1 !	N-acyl group	1 m.p. | ! (°C) !	recryst. | solvent(s)|	yield| (X) I
1 U 1	(R,S)-2-(2-chlorophenyl)-	ί180-181f	MeOH I	10 1
1 1	2-isopropoxyacetyl	i 1	1	1
I 45 1	3-indenylcarbonyl	| 222-2241	MeOH !	4 I
ί 46 |	(R.S)-l-indanylcarbonyl	1181-1831	EtOAc |	9 1
! 47 I	(R,S)-2-(3-fluoro-2-methyl-	|174-176|	Et2O |	61 1
1 ί	phenyl)-2-methoxyacetyl	1 1	1	1
1 43 1	(R,S)-2-(2,6-d ifluorophenyl)-	|165-167|	Et2O |	27 |
1 1	2-methoxyacetyl	1 1	1	1
1 49 1	(2,6-di fluorophenyl)acetyl	1195-1971	Et2O |	67 |
1 50 1	(1-isochromanyl)carbonyl	|162-163|EtOAc/Hexane	31 1
ί 51 1	(R,S)-2-cyano-2-(phenyl)propionyl	ί120-121|	Toluene |	25 |
1 52 1	(R,S)-2-methoxy-2-(2-methoxy-	1177-1781	Et2O I	87 |
1 1	phenyl)acetyl	I 1	1	1
ί 53 I	(R,S)-2-(2,3-di fluorophenyl)-	1132-1331	Et20/Hexane|	60 |
; 1	2-methoxyacetyl	! 1	1	I
; 54 )	(S)-2-pnenylpropionyl	j133-134|Et20/Hexane|	62 I
1 55 1	(R)-2-phenylpropionyl	|137-138|EtjO/Hexane|	53 i
! 56 1	(R,S)-2-(2-methylphenyl)-	|142-143|EtjO/Hexane|	76 |
ί 1	propionyl	1 1	!	1
! 57 1	(R,S)-2-phenylbutyryl	I 140-141i	Et2O/Hexane|	49 |
! 58 1	(R,S)-2-ethoxy-2-phenylacetyl	| 135-1361	Et2O |	50 |
59 1	(R,S)-2-ethoxy-2-(2-methyl-	ί172-173!	Et2O |	69 !
1 1	phenyl)acetyl	! 1	I 1	] _L

Notes:

1. The following abbreviations are used for solvents: EtjO = ether; EtOH = ethanol; EtOAc = ethyl acetate; MeOH = methanol; H₂0 = water.

2. Where ether or ether/hexane is indicated as the solvent(s), this was used to solidify the initially isolated reaction product rather than recrystallisation.

3. * The reaction product was first purified by flash chromatography on silica using dichloromethane as eluant.

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AP Ο Ο Ο 2 6 1

- 23 The starting acyl chlorides may be obtained using a conventional procedure from the corresponding acids, vhich are veil knovn and in the majority of cases are commercially available.

Hovever, the acids for use in Examples 38, 43, 44, 47, 48, 52, 53, 58 and 59 vere obtained by the general procedure described by Reeve et al. in Synthesis, 1971 at page 133, vhich involves reacting the appropriate benzaldehyde vith bromoform, potassium hydroxide and an excess of methanol (except for Ex. 44, vhere 2-propanol is used and for Exs. 58 and 59, vhere ethanol is used) at about 0 to 5°C. The acid for use in Example 40 vas obtained by the procedure described by Dauben et al. in J. Amer. Chem. Soc., 1951, 1399. The acid for use in Example 46 vas obtained by the procedure described in Synthesis, 1987, 845. The acid, for use in Example 50 vas obtained by the procedure described in Arch. Pharm., 1966, 299, 931 and that for use in Example 51, by the procedure described in Arch. Pharm., 1972, 305, 54.

The production of the acyl chlorides is illustrated by the folloving preparation of (R,S)-2-methoxy-2-(phenyl)acetyl chloride:Oxalyl chloride (2.2 mL, 25 mM) vas added to a stirred solution of (R,S)-2-methoxy-2-(phenyl)acetic acid (3.32g, 20 mM) in dichioromethane (10 mL). Dry N,N-dimethylformamide (1 drop) vas added to catalyse the reaction and the mixture vas stirred for 16 hours.

The solvent vas removed by evaporation to leave (R,S)-2-methoxy-2(phenyl)acetyl chloride as a pale yellov oil, vhich vas used vithout further purification.

Example 60

3-Chloroper'oenzoic acid (55-602; 1.0 g, 2.9 mM) vas added in portions to a solution of (2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]phenylthio)nitromethane (A) (0.5 g, 1.45 mmol) in chloroform (25 mL) at ambient temperature. The mixture was heated under reflux for 2 hours then allowed to cool. The precipitate of 3-chlorobenzoic acid vas removed by filtration. The filtrate vas vashed vith an aqueous solution of sodium metabisulfite (2 x 50 mL). The organic phase vas dried (MgSO^) and the solvent removed by evaporation. The

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- 24 cream solid obtained vas purified by chromatography on silica eluting with ethyl acetate/hexane (Q-»2OX v/v) to give (2,6-diaethyl-4(2-{2-methylphenyl)acetamido]phenylsulfonyl)nitromethane, as a cream coloured solid, m.p. 138-190 °C (m.p. 196-199 °C after recrystallisation from ether) in 552 yield; NMR (200MHz, d^-DMSO): 2.29(s, 3H), 2.55(s, 6H), 3.31(s, 2H), 6.44(s, 2H), 7.1-7.5(m, 4H), 7.52(s, 2H), 10.5(s, IH).

The starting phenylthio derivative (A) may be obtained as follows: (i) Sodium borohydride (2.5 g, 66 mM) vas added in portions to an ice-water cooled suspension of 2,6-dimethyl-4-[2-(2-methylphenyl)acetamidojphenyl thiocyanate (B) (5.0 g, 16 mM) in ethanol (100 mL) and dimethoxyechane (100 mL). After 2 hours, water (200 mL) vas added to the clear yellow solution. The mixture was acidified to pH4 vith 2M HCI and extracted with ethyl acetate. The combined extracts were washed vith water, then with saturated sodium chloride solution, and dried (MgSO^). The solvent was removed by evaporation to yield 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]benzenethiol as a cream coloured solid (4.89 g) which vas used without characterisation.

(ii) The above thiol (4.89 g, 17.16 mM) vas added to a stirred solution of sodium hydroxide (1.4 g), 35 mM) in water (50 mL) under oxygen. After 10 minutes, nitromethane (0.93 mL, 17.2 mmol) vas added dropwise. The mixture was cooled using an ice-bath and after 10 minutes a solution of potassium ferricyanide (5.7 g, 17.3 mM) in water (30 mL) was added in portions. The mixture vas stirred at ambient temperature for 1 hour. A further portion of nitromethane (0.31 mL, 5.7 mM) was added, followed after 10 minutes by a solution of potassium ferricyanide (1.9 g, 5.7 mM) in water (20 mL). After 30 minutes, the aqueous mixture was extracted vith ethyl acetate. The combined extracts were washed with water (2 x 50 mL), dried (MgSO^) and the solvent vas evaporated. The solid obtained was triturated vith ethyl acetate and the solid was discarded. The filtrate vas evaporated to yield (2,6-dimetnyl-4-[2-(2-methylphenyl)acetamido]phenylthio)nitromethane (A) as a pale brown solid in 622 yield: NMR (CDC1₃, 200MHz): 2.28(s, 3H), 2.4(s, 6H), 3.65(s, 2H), 5.6(s, 2H),

I

AP Ο Ο Ο 2 6 1

- 25 7.1-7.22(m, 4Η), 7.42(s, 2Η), 10.14(s, ΙΗ).

The starting thiocyanate (B) may be obtained as follovs:(iii) Cupric thiocyanate (28 g, 155.6 mM) vas added to a stirred solution of 3,5-dimethylaniline (7.6 mL, 62.2 mM) in ethyl acetate (150 mL). The mixture vas then heated at 60°C for 2.5 hours, cooled to ambient temperature and solid material removed by filtration through a bed of diatomaceous earth. The residue vas washed veil vith ethyl acetate. The purple filtrate vas then washed vith 52 v/v (?) aqueous sodium bicarbonate. The pale yellov organic layer vas separated, washed successively vith vater and saturated sodium chloride solution and dried (MgSO^). The solvent vas removed by evaporation and the solid obtained vas triturated vith ether to give 4-amino-2,6-dimethylphenyl thiocyanate, as a cream coloured solid in 652 yield: NMR: 2.37(s, 6H), 6.43(s, 2H).

(iv) 2-(2-Methylphenyl)acetyl chloride (9.9 g, 58.8 mM) vas added to a stirred suspension of calcium carbonate (7.87 g, 78.7 mM) and 4-amino-2,6-dimethylphenyl thiocyanate (7 g, 39.3 mM) in dry THF (150 mL). The mixture vas stirred for 1 hour. Vater (1000 mL) vas added. The mixture vas acidified to pH4 vith 2M HCl and extracted vith ethyl acetate. The combined extracts vere washed vith vater, then vith saturated sodium chloride solution and dried (MgSO^). The solvent vas removed by evaporation. The pale green solid obtained vas triturated vith ether to give 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]phenyl thiocyanate (B), as a cream coloured solid in 832 yield; NMR (CDCl^, 200MHz): 2.47(s, 3H), 2.49(s, 6H), 3.69(s, 2H), 7.14-7.17(m, 4H), 7.55(s, 2H), 10.27(s, IH).

Alternatively steps (i) and (ii) may be telescoped for the production of the phenylthio derivative (A) as follovs:Sodium borohydride (0.24 g, 6.3 mM) vas added in portions to a stirred suspension of 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]phenyl thiocyanate (0.5 g, 1.6 mM), in ethanol (20 mL). After 30 minutes, acetone (0.47 mL, 6.4 mM) vas added to remove excess sodium borohydride and the mixture stirred for 10 minutes to give a clear 'BAD ORIGINAL

- 26 yellov solution containing 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]benzenethiol. Nitromethane (0.09 mL, 1.6 mM) vas then added followed, after 10 minutes, by a solution of potassium ferricyanide (0.53 g, 1.6 mM) in vater (10 mL). Progress of the reaction vas folloved by standard thin layer chromatographic (tic) analysis. After 1 hour, unreacted thiol remained and so further nitromethane (0.45 mL, 0.8 mM) and a solution of potassium ferricyanide (0.27 g, 0.8 mM) in vater (5 mL) vas added. After about a further 1 hour, thiol vas no longer detectable by tic analysis. Vater (500 mL) vas then added.

The reaction mixture vas acidified to pH4 vith 2M HCl and extracted vith ethyl acetate. The extracts vere dried (MgSOp and the solvent evaporated. The sticky, orange solid vas triturated vith ether. The orange filtrate vas separated and the solid residue discarded. The filtrate vas evaporated to give (2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]phenylthio)nitromethane as an orange/brovn solid, m.p. 152 °C (decomposition) in 202 yield and vhich vas used vithout purification.

Example 61

Nitromethane (5.4 mL, 98 mM) vas added to a stirred solution of sodium methoxide (2.7 g, 49 mM) in Ν,Ν-dimethylformamide (DMF; 250 mL), cooled to about 0°C. Vhen the addition vas complete, stirring vas continued for an additional 30 minutes at about 0°C.

4-(4-(2-Tri fluoromethyl phenyl]ace tamido)-2,6-dimethylbenzenesulfinic acid sodium salt (16.9 g, 43 mM) (estimated by NMR analysis to be no more than 502 strength) vas then added, folloved immediately by iodine (6.35 g, 49 mM). The mixture vas stirred for 16 hours and alloved to attain room temperature. A concentrated solution of aqueous sodium sulfite vas then added to partially decolourise the reaction mixture, vhich latter vas then poured into vater (about IL). The aqueous mixture vas acidified vith 2M hydrochloric acid and extracted vith ethyl acetate. The combined extracts vere washed vith vater, then vith saturated sodium chloride solution, and dried (MgSOp. The solvent vas removed by evaporation and the residue vas purified by vacuum flash chromatography on 60H silica, eluting vith ethyl acetate-hexane (1:10 v/v, gradually increasing to 1:5 v/v) to give

BAD ORIGINAL

APο 00 2 6 1

- 27 (4-(2-(2-trifluoromethylphenyl)acetamidol-2,6-diaethylphenylsulfonyl)nitronethane as a solid, m.p. 2O3-2O4°C (after crystallisation from ethyl acetate/hexane) in 102 yield; NMR (d^-DMSO,

(i)

The starting sulfinic acid may be obtained as follovs:4-(2-(2-TrifluoromethyIphenylJacetyl)-3,5-dimethylaniline (obtained as a solid, m.p. 168^eC, by reacting 2-(2-trifluoromethylphenyl)acetyl chloride vith 3,5-dimethylaniline in THF solution in the presence of calcium carbonate) vas reacted vith an excess of chlorosulfonic acid at 60°C, using an analogous procedure to that described in Organic Synthesis, Coll Vol. I, at page 85, to give 4-(2-(2-1ri fluoromethylphenyl]acetamido )-2,6-dimethylbenzenesulfonyl chloride, as a solid in about 472 yield, vhich vas used vithout purification.

(ii) The above sulfonyl choloride (17.4 g, 43 mM) vas added in portions to a vigorously stirred solution of sodium bicarbonate (7.9 g, 46 mM) and anhydrous sodium sulfite (11.5 g, 92 mM) in vater (92 mL) at 70-80°C. The temperature vas kept at 7O-8O°C by intermittent heating. Vhen the addition vas complete, the mixture vas heated and stirred at 70-80°C for a further hour. The mixture vas then allowed to cool to room temperature during 4 hours and acidified vith 2M hydrochloric acid. The precipitated solid vas collected by filtration, vashed vith vater, air dried to give crude

4-(2-(2-trifluoromethyiphenyl]acetamido)-2,6-dime thylbenzenesulfinic acid, as a lov melting point solid contaminated vith sodium sulfate and the corresponding sulfonic acid. This acid vas converted to its sodium salt by addition of a soiution of sodium methoxide in methanol to pH9 and evaporation of the resultant solution. The sodium salt vas used vithout purification or characterisation.

Examples 62-74

Using a similar procedure to that described in Example 1 but starting from the appropriate acyl chloride in place of phenylacecyl

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- 28 chloride the folloving (4-N-acylamino-2,6-dimethylphenylsulfonyl)nitromethanes of the invention may be obtained:-

|Example; 1 i	N-acyl group	I «·ρ· 1 I (°C) |	recryst. solvent(s)	|yield, 1 (X) 1
1 62 ι 1 ί	(-)-2-methoxy- 2-(2-me thylphenyl)acetyl	(152-1531 i 1	EtOAc note (a)	1 34 1 1 1
1 63 ί 1 ί	(R,S)-2-ethoxy- 2-(2-fluorophenyl)acetyl	)132-1331 1 1	Et2O	1 61 1 1 1
1 64 ι	2-(2,3-dimethylphenyl)acetyl	1210-2111	Et2O	1 27 1
1 65 ι	2-(2,6-dime thy1phenylacetyl	|213-215|	Et2O	1 45 1
1 66 i	(R,S)-2-(2,6-difluorophenyl)-	| 82-84 |	EtOAc/	1 20 1
1 :	propionyl	1 1	Hexane	1 1
1 67 I ι ι	(-)-2-methoxy- 2-(2-methylphenyl)acetyl	|163-164| 1 i	EtOAc Note (b)	1 79 1 1 1
1 68	2-(4-me thylpheny1)ace tyl	ί163-164[	Et2O	1 35 |
ί 69 ί ί '	2-(2-iluorophenyl)propionyl	1111-113( 1 1	EtOAc/ Hexane	1 15 I 1 1
1 70 ί ! i	2-(2,4-dime thy1 phenyl)acetyl	1173-174 i i 1	EtOAc/ Hexane	1 78 | 1 1
1 71 ί ΐ !	(-)-1,2,3,4-tetrahydro- 1-naphthoyl	|180-181| 1 1	EtOAc (note (c)	1 60 1 1 1
; 72	(-)-1,2,3.4-tetrahydro- 1-napnthoyl	| 178-180, 1 I i !	EtOAc Note (d)	ί 50 1 I (
1 73 ί ;	(-)-2-metboxy-2-(2-methoxy- phenyl)acetyl	( 138-139( i i	Et2O Note (e)	i 87 i 1 1
74	(~)-2-methoxy-2-(2-methoxy- phenyDacetyl	I 139-1411	Et2O Note (f)	1 36 |

No tes:

(1) The following optical rotations were obtained for individual enantiomers obtained above at the sodium D line at approximately 20°C (c = 1, in ethanol or ethyl acetate as solvent):BAD ORIGINAL &

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- 29 Note Ι^α!ρ_Solvent

(a)	>71’	EtOAc
(b)	-69’	EtOAc
(c)	-42’	EtOAc
(d)	+40’	EtOAc
(e)	-80’	EtOH
(f)	+ 77°	EtOH

(2) The starting acyl chlorides may be obtained from the corresponding carboxylic acids by conventional procedures such as that described above for (R,S)-2-methoxy-2-(phenyl)acetyl chloride. The starting carboxylic acids are in general already known or may be obtained by conventional procedures well knovn in the art.

For example, 2-ethoxy-2-(2-fluorophenyl)acetic acid may be obtained as follows :A solution of potassium hydroxide (22.4 g, 42.8 mM) in ethanol (88 mL) was added during 3 hours to a stirred mixture of 2-fluorobenzaldehyde (10.0 g, 80.5 mM) and bromoform (24.3 g, 6.0 mM) in ethanol (40 mL) at 0’C. The mixture was then allowed to warm to ambient temperature and stirred overnight. Vater (100 mL) and 50Z v/v (?) saturated sodium chloride solution (30 mL) were then added. The mixture was extracted with ether and the extracts discarded. The aqueous phase was warmed to remove traces of ether, acidified to pH3 vith 2M hydrochloric acid, and then extracted vith ethyl acetate (2 x 100 mL). The extracts were combined, washed vith saturated sodium chloride solution, dried (MgSO^) and the solvent evaporated to leave 2-ethoxy-2-(2-fluorophenyl)acetic acid as a pale brown oil which was used without further purification in the production of the corresponding acid chloride.

(3) The separate enantiomers of (R,S)-2-methoxy-2-(2methoxyphenyl)acetic acid may be obtained by the following resolution procedure:BAD ORIGINAL ά

- 30 (R, S)-2-methoxy-2-(2-methoxyphenyl)acetic acid (20.75 g, 105.9 mM) vas dissolved in hot ethanol (53 mL) and added quickly to a vigorously stirred, hot solution of (IS,2R)-(*)-ephedrine (17.5 g, 105.9 mM) in ethanol (50 mL). The mixture was allowed to cool to ambient temperature. The white solid obtained was collected by filtration and recrystallised from ethanol to give a crystalline ephedrine salt (15.65 g). This salt vas dissolved in water (150 mL). The solution vas acidified by adding 1 equivalent of M hydrochloric acid (43 mL) and then extracted with ethyl acetate (2 x 100 mL). The extracts were washed with water, then with saturated sodium chloride solution, dried (MgSO^) and the solvent evaporated to give (+)-2-methoxy-2-(2-methoxyphenyl)acetic acid as an oil, which slowly crystallised to give solid (8.0 g), ^[ α]θ = +151.8° (c = 1, EtOH); optical purity 97.6% e.e. [by NMR analysis using the NMR shift reagent (R)-(-)-TFAEj.

Using an analogous procedure but adding (lR,2S)-(-)ephedrine to (R,S)-2-methoxy-2-(2-methoxyphenyl)acetic acid there was obtained (-)-2-methoxy-2-(2-methoxyphenyl)acetic acid as a white crystalline solid (overall yield 36.52), ^^[α[θ = -158.9° (c =* 1, EtOH); optical purity 99.52 e.e.[by NMR analysis using (R)-(-)-TFAEJ.

(4) The separate (R) and (S) enantiomers of (R,S)-l,2,3,4tetrahydro-l-naphthoic acid may be obtained using essentially the same procedure to that described by Vestman in Arkiv fur Kemi, 1958,

12(17), 161.

(5) The separate (R) and (S) enantiomers of (R,S)-2-methoxy-2(2-methylphenyl)acetic acid may be obtained by analogous resolution procedures to that described in note (3) hereinabove and had the following properties:

(-)-form: m.p. 69-70 °C; “[ aJ_D -145’ (c = 1, ethyl acetate); optical purity 99.52 e.e. [by NMR analysis using (R)-(-)-TFAEJ;

(-)-form: m.p. 66-63 °C; ²[a|_D -139° (c = 1, ethyl acetate); optical purity 98.32 e.e. [by NMR analysis using (R)-(-)-TFAE].

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- 31 Exaaple 75

A solution of (2,6-dimethyl-4-[2-methoxy-2-(2-methoxyphenyl)acetamido]phenylsulfonyl)nitromethane (2 mM) in methanol (50 mL) vas treated vith a solution of sodium methoxide (2.05 mM) in methanol (30 mL) cooled to about 5^eC. The mixture vas stirred for 10 minutes and then the solvent removed by evaporation to give (2,6-dimethy1-4-12-me thoxy-2-(2-me thoxyphenyl)ace taaidoJ phenylsulfonyl)nitromethane sodium salt as a deliquescent solid residue, in essentially quantitative yield.

Example 76

The folloving illustrate representative pharmaceutical dosage forms containing a compound of the formula I, such as is described in any 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 (52 v/v paste)............ 2.25

Magnesium stearate........................... 3.0 (b) Tablet II mg/tablet

Compound ...................................

Lactose Ph.Eur...............................

Croscarmellose sodium........................

Maize starch.................................

Polyvinylpyrrolidone (52 v/v paste)..........

Magnesium stearate...........................

223.75

6.0

15.0

2.25

3.0

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- 32 (c) Tablet III mg/tablet

Compound ................................... 1.0

Lactose Ph.Eur............................... 93.25

Croscarmellose sodium........................ 4.0

Maize starch paste (5Z v/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 veil knovn in the pharmaceutical art. If required, the tablets (a)-(c) may conveniently be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

SS35862 SCS 06JUL91

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- 34 CHEMICAL FORMULAE (continued)

VI

VII

vm bad original $

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Claims (10)

1. What is claimed is:1. A phenylacetyl derivative of the compound (4-amino-2,6dimethylphenylsulphonyl)nitromethane having the formula I:

   wherein R-θ and R^ are independently hydrogen, (l-4C)alkyl, (l-4C)alkoxy, cyano or tri fluoromethyl, or together constitute 1 2 (2-6)alkylene, or R together vith R of the adjacent benzene ring A constitutes methylene, ethylene, oxyethylene, ethyleneoxy, methyleneoxymethylene, vinylene, trimethylene or tetramethylene; and
2. 2 3 4 5 on benzene ring A, one, tvo or three of the available R , R , R , R and R^ are independently selected from hydrogen, halogeno, trifluoromethyl, nitro, cyano, (l-4C)alkyl and (l-4C)alkoxy, and the remainder of R -R° is hydrogen; or an adjacent pair of the available r2, r\ r\ r^{2 * * 5} and R^ completes (together vith the adjoining carbon atoms) a further benzene ring vhich may itself optionally bear a

   2 6 halogeno, (l-4C)alkyl or (l-4C)alkoxy substituent, another of R -R is hydrogen, halogeno, trifluoromethyl, nitro, cyano, (l-4C)alkyl or 2 6 (l-4C)alkoxy, and the remainder of R -R is hydrogen; or a pharmaceutically acceptable salt thereof.

   2. A compound as claimed in claim 1 wherein R^ and are selected from hydrogen, methoxy, ethoxy, isopropoxy, cyano or

   0 1 tri fluoromethyl, or R and R^x together constitute ethylene,

   1,1-dimethylethylene, trimethylene, tetramethylene or pentamethylene, 1 2 or R together vith R of the adjacent benzene ring A constitutes methylene, ethylene, oxyethylene, ethyleneoxy, methyleneoxymethylene, vinylene, trimethylene or tetramethylene; and on benzene ring A, one, tvo or three of the available R^, r\ r\ R^ and are independently

   BAD ORIGINAL

   - 36 selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl, ethyl, propyl, isopropyl, isobutyl, methoxy and ethoxy, 2 6 and the remainder of R -R is hydrogen; or an adjacent pair of the 2 3 4 5 6 available R , R , R , R and R completes (together vith the adjoining carbon atoms) a further benzene ring which may itself optionally bear 2 6 a fluoro, chloro, methyl or methoxy substituent, another of R -R is hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl, ethyl, propyl, isopropyl, isobutyl, methoxy and ethoxy, and 2 6 the remainder of R -R is hydrogen.
3. 3. A compound as claimed in claim 1 or 2 vherein R® and R^ have one of the folloving combinations (a)-(f):

   (a) Ηθ and R¹ are both hydrogen; (b) R^ is hydrogen and R^ is methyl; (c) rQ is hydrogen and R^ is ethyl; (d) R^ is hydrogen or methyl, and r1 is cyano; (e) R is hydrogen or trifluoromethyl, and R^ is methoxy or ethoxy; or (f) R^ and R^ together constitute ethylene.
4. 4.

   amide of the formula la:

   A bi- or tri-cyclic la vherein Q is methylene, ethylene, oxyethylene, ethyleneoxy, vinylene or trimethylene and the substituents R³-R^ on benzene ring A have any of the meanings defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof.

   bad ORIGINAL

   AP Ο Ο η ? 4 ι

   - 37 wherein Ra and Rb are independently selected from hydrogen, methyl, ethyl and cyano, or one of Ra and Rb is hydrogen or trifluoromethyl and the other is methoxy, ethoxy or isopropoxy; and benzene ring B is selected from phenyl, 2-halogenophenyl, 2-(l-4C)alkylphenyl,

   2-(l-4C)alkoxyphenyl, 4-(l-4C)alkoxyphenyl and 2,4,6-tri[(l-4C)alkyl]phenyl; or a pharmaceutically acceptable salt thereof.
5. 6. A compound of the formula Ila:

   Ila wherein Acyl is selected from:

   phenylacetyl, (2,4,6-trimethylphenyl)acetyl, (2-methylphenyl)acetyl, (2-fluorophenyl)acetyl, (2-chlorophe.nyl)acetyl, (2-methoxyphenyl)acetyl, l-(4-chlorophenyl)-l-cyclopropanecarbonyl, 1-(phenyl)-l-cyclopropanecarbony1, (4-ethoxyphenyl)acetyl, (R,S)-2-(phenyl)propionyl, (4-methoxyphenyl)acetyl, (R,S)-benzocyclobutanecarbonyl, (2-bromophenyl)acetyl, (2-nitrophenyl)acetyl, 2-(4-chloropheny1)-2-methylpropionyl, (4-methoxy-3-methylphenyl)acetyl, (3-fluorophenyl)acetyl, (R,S)-2-methoxy-2-(2-fluorophenyl)acetyl, (2-trifluoromethylphenyl)acetyl, (3,4-difluorophenyl)acetyl, (2.6-di chlorophenyl)acetyl, (4-1 ri fluoromethyl phenyl)acetyl, (4-chloropheny1)acetyl, (3-methylphenyl)acetyl, (3-methoxyphenyl)acetyi, 1-phenylcyclopentanecarbonyl,

   1-(4-me thoxyphenyl)-eyelopropanecarbony1, (2-naphthyl)ace tyl, (R,S)-1-(4-chloropheny1)-cyclobutanecarbonyl, (1-naphthyl)acetyl, (2-me thy1-6-ni tropheny1)acetyl, (4-fluorophenyl)acetyl, (3,4-dichlorophenyl)acetyl, (2,4-dichlorophenyl)acetyl, (R,S)-2-(4-isobutylphenyl) propionyl, (R) -3,3,3-tri fluoro-2-me thoxy-2-phenylpropionyl, (S) -3,3,3-tri fluoro-2-me thoxy-2-phenylpropionyl,

   BAD ORIGINAL

   i 4».

   - 38 (R,S)-2-methoxy-2-(2-me thyIphenyl)acetyl, (S)-2-methoxy-2-phenylacetyl, (R,S)-1,2,3,4-tetrahydro-l-naphthoyl, (R)-2-methoxy-2-phenylacetyl, (R,S)-2-methoxy-2-phenylacetyl, (R,S)-2-(2-chlorophenyl )-2-methoxyacetyl, (R,S)-2-(2-chloropheny1)-2-isopropoxyacetyl, 3-indenylcarbonyl, (R,S)-l-indanylcarbonyl, (R,S)-2-(3-fluoro-2-methylpheny1)-2-methoxyacetyl, (R,S)-2-(2,6-difluorophenyl )-2-methoxyacetyl, (2,6-difluorophenyl)acetyl, (l-isochromanyl)carbonyl, (R,S)-2-cyano-2-(phenyl)propionyl, (R,S)-2-methoxy-2-(2-methoxyphenyl)acetyl, (R,S)-2-(2,3-di fluorophenyl)-2-methoxyacetyl, (S)-2-phenylpropionyl, (R)-2-phenylpropionyl, (R,S)-2-(2-methyIphenyl)propionyl, (R,S)-2-phenylbutyryl, (R,S)-2-ethoxy-2-(phenyl)acetyl and (R,S)-2-ethoxy-2-(2-methylphenyl)acetyl; or a pharmaceutically acceptable salt thereof.
6. 7. A compound of the formula Ila wherein Acyl is selected from:

   (R) -2-methoxy-2-(2-me thyIphenyl)acetyl, (R,S)-2-ethoxy-2-(2-fluorophenyl)acetyl, 2-(2,3-dimethylphenyl)acetyl, 2-(2,6-dimethylphenylacetyl, (R,S)-2-(2,6-difluorophenylpropionyi, (S) -2-methoxy-2-(2-methyIphenyl)acetyl, 2-(4-methylphenyl)acetyl,

   2-(2-fluorophenyl)propionyl, 2-(2,4-dimethylpheny1)acetyl, (R) -1,2,3,4-tetrahydro-1-naphthoyl, (S) -1,2,3,4-tetrahydro-1-naphthoyl, (R) -2-methoxy-2-(2-methoxyphenyl)acetyl and (S) -2-methoxy-2-(2-methoxyphenyl)acetyl; or a pharmaceutically acceptable salt thereof.
7. 8. A compound of the formula I selected from:

   (2,6-dime thyl--* - [ 2-(2, *. 6- trime thy iphenyl) acetamido] phenylsulphonyl)ni tromethane, (2,6-dime thy 1-4-[2-(2-me thyiphenyl)acetamido]phenylsulphonyl)ni tromethane.

   (S)-(2,6-dime thy1-4-(3,3,3-trifluoro-2-methoxy-2-phenyIpropionamido]phenylsulphonyl)ni tromethane, bad ORIGINAL

   AP Ο Ο Ο 2 6 1

   - 39 (R, S) - (2 ,6-dimethyl-4-(2-methoxy-2-(2-methylphenyl)acetamido]phenylsulphonyl)ni tromethane, (5)-(2,6-dimethy1-4-[2-methoxy-2-phenylace tain ido]phenylsulphonyl)ni tromethane, (R,S)-(2,6-dimethy1-4-(1,2,3,4-tetrahydro-l-napthoylaminolphenylsulphonyl )nitromethane, (R,S)-(2,6-dimethy1-4-[2-methoxy-2-(2-methoxyphenyl)acetamido]phenylsulphonyl )ni t rome thane, (R,S)-(2,6-dimethy1-4-[2-ethoxy-2-phenylacetamido]phenylsulphonyl )ni t rome thane , (+)-(2,6-dimethy1-4-(2-methoxy-2-(2-methylphenyl)acetamido]pheny1ni tromethane, (-)-(2,6-dimethy1-4-(1,2,3,4-tetrahydro-l-napthoylamino]pheny1sulphonyl)nitromethane and (-)-(2,6-dimethy1-4-(2-methoxy-2-(2-methoxyphenyl)acetamido Jpheny1sulphonyl)nitromethane; or a pharmaceutically acceptable salt thereof.
8. 9. A pharmaceutically acceptable salt as claimed in any one preceding claim which is an alkali metal, alkaline earth metal, ammonium or aluminium salt, or a salt vith an organic base affording a physiologically acceptable cation.
9. 10. A pharmaceutical composition vhich comprises a compound of formula I, la, II or Ila, or a pharmaceutically acceptable salt thereof as defined in any one preceding claim, together vith a pharmaceutically acceptable diluent or carrier.
10. 11. A process for the manufacture of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, vhich is characterised in that:

    (a) (4-amino-2,6-dimethylphenylsulphonyl)nitromethane is acylated by reaction vith a carboxylic acid of the formula III:

    III

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    - 40 or with a reactive acylating agent derived therefrom;

    is oxidised; or (c) an alkali metal salt of a 4-N-acylamino-2,6-dimethylbenzenesulphinic acid of the formula VIII:

    is reacted with nitromethane and iodine in the presence of an alkali metal (l-6C)alkoxide;

    and wherein R¹^, R^ and benzene ring A and the substituents thereon have any of the meanings defined in claims 1, 2 or 3; whereafter, when a pharmaceutically acceptable salt is required, the compound of formula I is reacted with an appropriate base having a physiologically acceptable cation; and when the compound of formula I contains a chiral centre, process (a), (b) or (c) is carried out with a suitable optically active starting material of formula III, IV or VII, or the formula I in racemic form is resolved.