IL42640A - Substituted 2'-phenoxyalkane-sulfonanilides - Google Patents

Abstract

1435755 2 - Phenoxyalkylsulphonanilides RIKER LABORATORIES Inc 2 July 1973 [3 July 1972] 31454/73 Heading C2C Novel compounds of the Formula I wherein R x is C 1-2 alkyl or monohaloalkyl; R is hydrogen, cyano, alkyl, alkylsulphonyl, haloalkylsulphonyl, a cation or -COAR<SP>1</SP> where R<SP>1</SP> is alkyl and A is oxygen or a bond between the carbonyl carbon and the alkyl group; X is alkoxyl, alkyl, halogen, acetamido, nitro, hydrogen, amino, alkoxycarbamoyl or dialkylamino; Y is nitro, amino, alkoxycarbamoyl, dialkylamino or hydrogen, provided that one of X and Y is nitro, amino, alkoxycarbamoyl, or dialkylamino; Z is halogen, nitro or hydrogen; Z<SP>1</SP> is halogen, alkyl, alkoxy, nitro, amino, alkanamido, haloalkyl, hydroxy dialkylamino, alkoxycarbamoyl, alkylthio, alkyl sulphonyl, alkanoyl or alkylsulphinyl and n is 0, 1 or 2 in which aliphatic moieties in R, X, Y and Z<SP>1</SP> contain one to four carbon atoms may be prepared (1) where X and Y are not NH 2 , Z<SP>1</SP> is not hydroxy or amino and R is hydrogen, by reacting a compound R x SO 2 Q where Q is fluorine or chlorine with a compound of the Formula II (ii) where R is hydrogen, reacting compounds III and IV wherein D is chlorine, bromine or iodine, providing that when D is chlorine X is an activating group and M is an alkali metal or copper provided that if Z or Z<SP>1</SP> is halogen, Z or Z<SP>1</SP> is a lower atomic weight halogen than D; (iii) reacting a compound I wherein R is hydrogen with a base to introduce a cation; (iv) reacting a product of III where R 1 is a metal cation with an alkyl bromide or iodide dialkylsulphate; (v) reacting a product of (i), (ii) or (iii) with cyanogen halide, alkylsulphonyl or haloalkylsulphonyl halide, alkanoyl halide, or alkyl chloroformic acid to introduce the appropriate group at R; (vi) nitrating a compound I in which Y is hydrogen to introduce an NO 2 group at Y; (vii) modifying the substituents X, Y, Z and Z<SP>1</SP> by known methods. Pharmaceutical compositions of the compounds I show anti-inflammatory activity when administered orally, topically, parenterally or rectally with the usual excipients. Selected compounds also show analgesic, antipyretic, antimicrobial and herbicidal activity. [GB1435755A]

Description

42640/2 o»nonva 0'·τ» »aR3ls¾1oa ,?«»o 1«3a-·2, Substituted 2*-p enoxyalkanesuIfionanilides RIEEE LABORATORIES, C. 40722 ■This invention relates to diphenyl ethers sub stituted by an alkyl- or (raonohalo ) alkanesulfonamido group and a nitro or amino group (as defined herein) wherein the orientation of the groups is critical. In particular the invention relates to such compounds wherein the alkyl- or (monohalo) alkanesulfonamido group is oriented in the 2 position (ortho) with respect to the ether linkage and the nitro or amino group is oriented in the 4 or position with respect to the alkyl- or (monohalo )alkanesulfonamido group, and to salts thereof. The rings and the sulfonamido nitrogen are optionally substituted. The compounds are anti-inflammatory agents. Methods for the preparation and use of the compounds are also described.

Alkanesulfonamido and haloalkanesulfonamido substituted diphenyl ethers have been alluded to heretofore. Thus, see British patents 738,758, 85 , 956 and 8 6, 52, French patent 1, 188, 591 and U.S. patent 3, 223, 582. However, none of these patents disclose or suggest the compounds of the present invention wherein a nitro or amino group fes defined herein) must be present, nor do they sugge the critical nature of the orientation of the substituent groups to obtain high activity. Furthermore, the Pharmacol gical activity of the compounds of the invention is not is suggested by th^ prior art.

Many non-steroidal anti-inflammatory agent.s have been discovered in recent years, and some are currently marketed for the treatment of various condi- S tions treated by anti-inflammatory, analgesic and antipyretic agents. However, these agents have significant side -effects which prevent their use in many patients.

The search for anti-inflammatory agents with reduced side effects and improved therapeutic ratio is continuing. The compounds of the present invention are effective anti- inflammatory agents with excellent therapeutic ratios.

According to the present invention there is provided a class of compounds of. the formula wherein Rx is an alkyl or monohaloalkyl radical containing one or two carbon atoms, R is hydrogen, . alkyl, alkylsulfonyl, haloalkylsulfonyl, a cation or C-A-R1 , where R' is alkyl and A is oxygen or a carbon-carbon bond, X is alkoxy , alkyl, halogen, nitro, hydrogen or amino, Y is nitro, amino, dialkylamino or hydrogen, provided that one of X and Y is nitro or amino or is dialkylamino, Z is halogen, nitro or hydrogen, Z1 if; halogen, alkyl, alkoxy, nitro, hydroxy or alkanoyl, and n.is 0, 1 or 2 (zero, one or two), provided that the individual aliphatic groups appearing in the R, X, Y and Z' moieties, including those characterized as lower alkyl, contain from one to four carbon atoms each, the compound 4 ' , 6 ' -dinitro-2 ' -phenoxyethanesulfonanilide being excluded. 42640/2 •V in which R is alk l, alkylsulfonyl or are preferred to those in which R is haloalkylsulfonyl . When R is alkyl, alk lsulfonyl or haloalkylsulfonyl it preferably contains one carbon atom. The preferred halogens in the haloalkylsulfonyl R moieties are fluorine and chlorine. When R is -ΰ-Α-R'j R' preferably contains one or two .carbon atoms.

Rx preferably contains one carbon atom. Rx is preferably methyl, chloromethyl or fluoromethyl, and most preferred is methyl.

It is preferred that n is zero or one. Most preferred is n equal to zero. When n is one, Z' is preferably oriented para or drtho, and most preferably Z' is halogen oriented para. Orientation is relative to the diphenyl ether oxygen.

It is presently preferred that Z is hydrogen. When Z is halogen it is preferably chlorine.

Most preferably X is hydrogen and Y is nitro. Other preferred combinations are those in which X is amino and Y is hydrogen.

The compounds of the invention are acidic in nature when R is hydrogen. Consequently, they form salts, i.e. compounds of Formula I wherein R is a pharmaceutically acceptable cation, or any cation which forms salts stable to ambient conditions, which salts are useful intermediates. These are generally metal, ammonium and organic amine salts and can be prepared by treating the acid form (compounds of Formula I in which R is hydrogen) with a stoichiometrica lly equivalent amount of an appropriate base under mild conditions. Among the metal saltj^-- of the invention are alkali metal (e.g. lithium, sodium, and potassium), alkaline earth metal (e.g. barium, calcium and magnesium) and heavy metal (e.g. zinc and iron) salts as well as other metal salts such as aluminum. Appropriate bases for use in preparing the metal salts include metal oxides, hydroxides, carbonates, bicarbonates and alkoxldes. Some salts are also prepared by cation exchange reactions (by reacting a salt of the invention with an organic or inorganic salt in a cation exchange reaction) „ The organic amine salts include the salts of aliphatic (e.g. alkyl), aromatic and heterocyclic amines, as well as those having a mixture of these types of structures. The amines useful in preparing the salts of the invention can be primary, secondary or tertiary and preferably contain not more than 20 carbon atoms. Such amines include, for example, morpholine, methyl cyclohexylamine, glucosamine, etc. These and the ammonium salts can be prepared by reacting the acid form with the appropriate organic base or ammonium hydroxide. The pharmaceutically acceptable salts are generally the alkali metal, alkaline earth, ammonium and amine salts.

The salts of the invention are frequently formed by reacting the precursors in aqueous solution. This solution can be evaporated to obtain the salt of the compound, usually as a dry powder. In some cases, it may be more convenient to use a non-aqueous solvent such as • alcohols, acetone, etc. The resulting solution is then treated to remove the solvent, for example, by evaporation under reduced pressure. Since many of the salts are water soluble, they are often used in the form of aqueous solutions. Also, they can be used in making pharmaceutical preparations in the form of capsules for oral adminis tration.

The compounds of this invention wherein R is hydrogen (the acid form) are prepared by two different general methods from precursors (i.e. compounds not falling within the scope of Formula I) and, in addition, certain of the compounds of Formula I are prepared from other compounds of Formula I, as shown below. In addition, compounds of the invention wherein Y is nitro and R is H are preferably prepared by a novel nitration process Method A This method can be generally useful when the necessary intermediates of Formula II are synthetically readily available : ■ - where Q is fluorine or preferably chlorine, and Ry., X, Y, Z, Z' and n are as previously defined with the exceptions that Z1 is not hydroxy, and X and/or Y are not amino. ; The reaction is usually run in the presence of a suitable acid acceptor, which may, be an organic or inorganic base.

A solution of the appropriate primary arylamine of Formula II and at least an equimolar quantity of a suitable acid acceptor (such as dimeth laniline or tri-ethylamine) in an inert organic solvent is prepared.

Among the suitable solvents are glyme, benzene, dichlo.ro-methane and chloroform. An equimolar quantity of the appropriate sulfonic halide is added to the solution. The addition is advantageously carried out at -15° to 150° C, but this may be raised or lowered if desired. In cases where the amine is of lower reactivity, it is advantageous to allow the reaction mixture to remain at reflux temperature for a few hours following addition.

After completion of the reaction, the product is isolated by conventional methods. For example, the reaction mixture can be extracted with excess aqueous sodium hydroxide. The aqueous extract is then washed with organic solvents and treated with charcoal to remove impurities. Subsequent acidification of the aqueous extract with mineral acid then affords the product as an oil or solid which is distilled, sublimed, chromatographed or recrys-tallized as required to give pure product. When water-soluble solvents are used, the reaction mixture can be poured directly into aqueous mineral acids. The product is then isolated by conventional extraction techniques and purified as above.

The reaction may also be run in a closed reactor. When this is done, solvent is not usually necessary, Q is usually fluorine, and an acid acceptor, generally triethylamine, is necessary. The temperatures utilized depend on the reactivity of the reactants, but may be between 0 and 200° C, and are generally 50 to 150° C.

Method B Some of the compounds of the invention can also be prepared by the nucleophilic displacement reaction of a metal salt of an aromatic compound with a halogen deriv ative as follows: wherein D is halogen (chlorine, bromine or iodine), M is alkali metal or copper and R , X, Y, Z, Z' and n are as defined hereinabove provided that if , Z or Z' is halogen, x, Z or Z' is a lower atomic weight halogen than D. The substituted alkyl- and (monohalo)alkylsulfonamidobenzene derivatives are known in the chemical literature. Solvents used in the reaction are pyridine, quinoline, dimethyl-formamide and the like. Preferably D is bromine or iodine. When D is chlorine X must be an activating group such as nitro. Cuprous chloride is a suitable cuprous catalyst for the reaction. The alkali metal salts may be preformed or formed in situ. Temperatures of 0 to 200° C. may be used, depending upon the reactivity of the substrates. Extended reaction periods are sometimes necessary.

Method C This includes the various ways in which Z, Z1, X and Y are changed in the compounds of Formula I. For example, compounds wherein X or Y is amino, Z and Z1 are other than nitro and R is H, are prepared by reduction of nitro compounds; compounds of Formula I wherein R is hydrogen can be nitrated or halogenated on the phenyl rings .

Compounds wherein Ζ' is hydroxy, R is hydrogen and X is other than alkoxy are preferably prepared by simple hydrogej£ iodide cleavage of the corresponding compound wherein Z* is alkoxy. When Y is amino but X is other than amino, Y can be converted to dialkylamino by known methods. Preferably in carrying out such processes to prepare compounds in which Z1 is hydroxy, the hydroxy is protected using conventional methods such as formation of the comparable benzyloxy compound, followed by regeneration of the hydroxy group.

The preparation of compounds wherein R is hydrogen, Z is halogen or hydrogen, Z' is halogen, alkyl, alkoxy, nitro or alkanoyl and Y is nitro is particularly facile starting with intermediate compounds of Formula I wherein both X and Y are hydrogen, or where X is as previously defined and Y is hydrogen. The nitration can be carried out with 70 percent nitric acid in acetic acid. Generally this provides excellent yields of compounds of Formula I wherein Y is nitro. Other nitration techniques which also provide satisfactory results include nitric acid and acetic anhydride, concentrated nitric acid without solvent, dinitro-gen tetraoxide in an inert solvent, either nitrosyl chloride and ferric chloride in an inert solvent or nitrite salts such as sodium nitrite in an acidic solvent (which require the presence of an oxygen donor such as air or the solvent), nitrate salts such as sodium nitrate in an acidic solvent, nitric acid in an acidic solvent, and the like.

In general about one equivalent of nitrating agent per mole of a 2 ' -phenoxyalkanesulfonanilide is sufficient to give reaction, and the minimum amount of nitrating agent necessary to give reaction of virtually all of the starting material is used. In order to determine the V' amount of nitrating agent necessary to obtain complete reaction may be monitored by thin layer liquid solid chroma-tography or vapor phase chromatography. This allows one to maximize the yield while minimizing the reaction time.

The reaction temperature may vary from about -300 C. to 110° C, but this may be raised or lowered somewhat to adjust the rate of reaction, and varies with the nitrating agent. Novel intermediates can be prepared by known methods from known starting materials. This nitration exclusively para to the sulfonamido group is unexpected because substantial ortho nitration would be predicted according to principles of e lectrophilic aromatic substitution.

Method D This includes the various ways in which R is changed in the compounds of Formula I. Preferably in carrying out such processes to prepare compounds in which / Z is hydroxy, the hydroxy is protected using conventional methods such as formation of the comparable benzyloxy compound, followed by regeneration of the hydroxy group.

The preparation of the salts (wherein R is a cation) from the acid form compounds has already been discussed. To prepare the compounds of the invention wherein R is lower alkyl, compounds of Formula I wherein R is a metal ion, for example sodium or potassium, are reacted with a stoichiometric amount of alkyl bromide or iodide or a di-alkyl sulfate in a non-reactive solvent such as acetone. 42640/2 Compoun'ds of the invention wherein R is alkyl- sulfonyl or haloalkylsulfonyl are prepared by reacting the corresponding compounds of the invention wherein R is a cation such as sodium or potassium with an alkyl- sulfonyl or haloalkylsulfonyl halide or anhydride. · Compounds of the invention wherein R is a -c'-A-R radical are prepared "by reacting the corresponding compounds wherein R is a cation with an acylating agent of the formula 0 R'-A-C-Q III wherein A and R' are as defined hereinabove and Q is halogen, preferably fluorine, chlorine or bromine, or the residue of an anhydride, i.e. an acyloxy group.

Suitable alkane- and (monohalo)alkanesulfonyl halides (for example chlorides and fluorides) for use in preparing compounds of Formula I are known to the art.

The primary arylamines of Formula II are also either known to the art, or may be made by methods well-known to the art, generally by the reduction of the corresponding nitro compound. Conventional reduction techniques, both chemical and catalytic, are used, such as iron in acetic acid, sodium sulfide, and most commonly Raney nickel and hydrogen gas. The nitro compound precursors of the compounds of Formula II are also known to the art, or may be prepared by well-known methods. - 10 - As noted previously, the compounds of the inven-tion are active anti -inflammatory agents . Further, some ~ are analgesic and anti-pyretic agents and some have "been found to possess anti -microbial activity . The compounds are also generally active as herbicides.

The anti-inflammatory activity can be conveniently demonstrated using assays designed to test the ability of these compounds to antagonize the local edema characteristic of the inflammatory response (rat foot edema test) and to inhibit the onset of the erythematous manifestation of inflammation (guinea pig erythema test). Leading references to the rat foot edema test ares 1. Adamkiewicz et al, Canad. J. Biochem. Physio, 32:332, 19555 2. Selye, Brit. Med. J. 2; 1129, 1 ^9 and 3. Winter, Proc. Soc. Exper. Biol. Med. Ills 554. 1962.

Leading references to the guinea pig erythema test are : 1. Wilhelmi, Schweiz. Med. Wschr. T3%551 » 19^9 and 2. Winder et al, Arch. Int. Pharmacodyn Il6s26l, 19 8.

Analgesic activity has been observed in standard test methods such as the phenylquinone writhing and Randall-Selitto tests. Anti-inflammatory activity may also be detected by assays known to the art such as the cotton pellet granuloma and adjuvant arthritis tests.

The compounds are preferably administered orally as anti-inflammatory agents but other known methods of administration are contemplated as well, e.g. dermatomu-cosally (for example dermally, rectally, and the like) and parenterally, for example by subcutaneous injection, intramuscular injection, intravenous injection and the like. Ocular administration is also included. Dosages ordinarily fall within the range of about 1 to 500 mg./kg. of body weight of the mammal to be treated although oral dosages are not usually above 100 mg./kg. and injection dosages are not usually above 0 mg./kg. Suitable forms for oral administration include liquids (such as four percent acacia suspensions), tablets (which may contain anhydrous, lactose, microcrystalline cellulose, modified starch, calcium stearate and talc, as well as other conventional compounding agents together with the active anti-inflammatory agent) and capsules. Suitable carriers for topical application include creams, gels, tapes and the like. Liquid formulations, such as solutions or suspensions of the active ingredient in inert carriers, are contemplated for dosage by injection.

The presently preferred compounds of the invention with respect to anti-inflammatory activity inc lude : *-Nitro-^-phenoxychloromethanesulfonanilide , '-Nitro-2'-phenoxymethane sulfonanilide , 2-(4-Chlorophenoxy)- -nitrofluoromethanesulfonanilide, '-Nitro-2'-phenoxyfluoromethanesulfonanilide, N-Metriyl-^'-nitro^-phenoxymethanesulfonanilide , N-Ethyl-4'-nitro-2-phenoxymethanesulfonanilide , '-Nitro-2-phenoxyethanesulfonanilide , 2-(4-Chlorophenoxy ) - -nitrochlorome thanesulfon- anilide, N-Methyl-2'-( ~chlorophenoxy) -4-nitrof luoromethane - sulfonanilide, N-Me thy1- -nitro -2 -phe noxye thanes uIfonani lide , N-Ace tyl-4'-nitro-2-phenoxymethane sulfonanilide , and the pharmaceutically acceptable salts of these compounds.

The compounds of the invention designated as preferred have been tested in animals in one or more assays to determine anti-inflammatory activity. All of the preferred compounds were tested in the carrageenin rat foot edema test, and were found in one or more repetitions to be active at 25 mg./kg. or less. Most of these compounds have a therapeutic ratio = T.R.) of five or more. For some compounds t s been precisely measured, while, for other compounds it is estimated.

The following examples are given for the purpose of further illustrating the procedures of the present invention, but are not intended, in any way, to be limiting on the scope thereof.

All melting points in the examples are uncorrected. The boiling points and melting points are given in degrees Centigrade and the pressures in millimeters of mercury.

Example 1 relates to the preparation of a compound of Formula I by Method A.

Example 1 5-Nitro~2-phenoxyaniline (10*5 g«j 0.046 mole) ^ is dissolved in pyridine (100 ml.), me hanesulfonyl chloride (5*22 g., 0.θ4β mole) is added and the mixture is stirred for about 16 hours. The mixture is poured into concentrated hydrochloric acid with cooling and the solid product is collected by filtration. After recr.ys- tallization twice from ethanol and treatment with de- I f colorizing charcoal, the product, 5~nitro-2-phenoxy- methanesulfonanilide , is recovered as a light tan solid, m.p. IO7. -IO8. ° C.

Analysis: C oU Calculated for C13H12 205S: 50.6 3-9 9-1 Found: 50=6 4.1 9.0 Example 2 relates to the preparation of a compound of Formula I by Method B.

Example 2 . A solution of potassium hydroxide (4 to 1 molar ratio) , ,2-bromo-4-nitromethanesulfonanilide, phenol (equi-molar to anilide), pyridine (5 ml/mmole) and benzene (10 ml/mmole) is stirred and heated, removing water by means of a Dean-Stark trap. After all of the benzene has di tilled off, more pyridine is added and the mixture is heated in a bath at 150° C. A small amount of cuprous chloride is added and heating is continued for several hours. The mixture is poured into water, treated with decolorizing charcoal, then acidified. The organic layer is separated, and the product isolated b evaporation of the solvent. Recrystallization provides 4-nitro-2-phenoxymethanesulfonanilide, m.p. l43-l44° C.

Example 3 relates to the preparation of a compound of Formula I by nitration of optionally substituted.. 2-phenoxyalkane- or (monohalo)alkanesulfonanilides .

Exam le, 3. 2-Phenoxymethane sulfonanilide (17-3 > 0.675 mole) is dissolved in glacial acetic acid (175 ml.) by warming. The mixture is stirred and 70 percent nitric acid (5.92 g., 0.0β7 mole) is added dropwise over 15 minutes. The mixture is heated on a steam bath for four hours, poured into water and the precipitate is separated by filtration. The product, 4-nitro-2-phenoxymethane -sulfonanilide, is a light tan solid, m.p. l43-l44.5° C. after recrystallization from ethanol.

Analysis: < Ά < Calculated for C-^H^NgO^ : 50.6 3.9 9-1 Found: 50.6 3.8 9.1 The following compounds are also prepared using the method of Example 3. 2-(4-Chlorophenoxy) -4-nitrof luoromethane sulfon-anilide, m.p. I37-I38.50 C. . 4'-Nitro~2'-phenoxyfluoromethane sulfonanilide , m.p. 104-105° C. 2- ( -Chlorophenoxy) - -nitrochloromethane sulfonanilide, m.p. 148-149.5° C. 5-Chloro-2'-(2,4-dichlorophenoxy)-4-nitro-methane sulfonanilide, m.p .. I63-I650 C. 5-Chloro-4-nitro-2-p"henox me hanesuIfonanilide , m.p. 137-139° C. 41,6-Dinitro-2-phenoxymethanesulfonanilide , m.p. 149-151° C.

Example 4 relates to the preparation of a compound of Formula I wherein X or Y is amino by reduc- v- tion of the corresponding nitro compound.

Example 4, 2-(4-Chlorophenoxy) -4-nitromethanesulf onanilide in ethanol is reduced over palladium on charcoal at about 5 psi. After hydrogen uptake is complete the mixture is filtered-, then the filtrate is evaporated in vacuo to • a solid which is sublimed to give white solid 4-amino-2- (4-chlorophenoxy)me thane sulf onanilide, m.p. ΐβθ-ΐβ4° C.

The following compounds are prepared using the method of Example 4, or alternatively Raney nickel may be used as the reduction catalyst, and is generally preferred. 4-amino -^-phenoxychlorome thane sulf onanilide isolated as the hydrochloride, m.p. > 95° C. (d) ^-amino-^-phenoxymethanesulf onanilide , m.p. 161-162.5° c., 4-amino -2*- ( -me thy lphenoxy) me thane sulf onanilide , isolated as the trie th lammonium salt, m.p. 123~138° C., 4'-amino-2-(4-chlorophenoxy)f luorome thane sulf onanilide, m.p. ΐ4θ.5-142° C. 4-amino-2l-(4-chlorophenoxy)chloromethane sulf onanilide, m.p. II8-II9. ° C. 4- amino -2-phenoxyf luorome thane su If onani lide , m.p. 126-127. ° C. 5- amino -2-phe noxyme thane s u If onani lide , iso la te d as the hydrochloride salt, m.p. I8 -20 0 C. 4l-amino-5-chloro-2-(2,4-dichlorophenoxy)methane-' sulf onanilide, m.p. 165.5-I 7.50 C. 42640/2 -amino-5-chloro-2-phenoxyme thanesulfonanilide , isolated as the hydrochloride salt, m.p. l6.0° . C . (d.) N-me thyl-4-amino-2-phenoxyme thanesulfonanilide., isolated as the hydrochloride salt, m.p. 90° C. (d.) Example 5. / 4 '-Amino-2-phenoxymethanesulfonanilide is reacted with formaldehyde and formic acid according to the well-known Eschweiler-Clarke reaction and 4'-(N,N-dime thylamino) -2-phenoxyme thane sulfonani 13 de is obtained, m.p. 119-120°C. (Structure proved by NMR spectral analysis) Example 6 I t Crude 5~amino-2-phenoxymethanesulfonanilide is dissolved in isopropyl ether and excess triethylamine is added. The mixture is stirred for six hours at room temperature, the solution is filtered and the salt is isolated by removing the volatiles in vacuo . The product is triethylammonium 5-amino-2-phenoxyme thanesulfonanilide .

Example 7 · -Nitro-2-phenoxymethanesulfonanilide is stirred with sodium carbonate in acetone for six hours, then methyl iodide is added and the mixture is stirred for about 16 hours. The mixture is filtered, evaporated in vacuo and the residue is stirred with diehloromethane and water. The dichloromethane fraction is separated, then dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystallized twice 42640/2 from a benzene -hexane mixture with concomitant treatment with decolorizing charcoal. The product, -methyl -4- / nitro~2-phenoxymethanesulfonanilide, is a solid, m.p. 92-94° C. - The following compounds are prepared using the method of Example 8 : / / N-methyl~4,6-dinitro-2-phenoxymethanesulfon- · anilide, m.p. 135-137° C.

N-methyl- —nitro— 2— phenoxyethanesulfon-anilide, m.p. 77.5~79 · 5° C. rr-ethy 1-4-nitro -2- henoxymethanesulfonanilide , m.p. 9 .5-96.5° C.

N- (n-butyl) - -nitro-2-phenoxymethane sulfon-anilide, m.p. 82-84° C.

Exam le 8 Sodium 4-nitro-2-phenoxymethane sulfonanilide is reacted with an equimolar amount of methanesulfonyl chloride in Ν,Ν-dimethylformamide by stirring overnight, the mixture is filtered, then evaporated in vacuo. The residue is washed thoroughly with water to provide limethylsulfonyl-4-nitro -2-phenoxymethane sulfonanilide , - 18 - Example 9 Sodium ^-nitro-^-phenoxymethane sulfonanilide is reacted with ethyl chlo'roformate in acetone by stirring overnight. The mixture is filtered, the filtrate is evaporated in vacuo and the residue is extracted with di-chlorome thane . The extracts are dried over magnesium sulfate, filtered and evaporated in vacuo to provide the desired product, N-ethoxycarbonyl- -nitro-2-phenoxy-methane suIfonanilide .

Exam le 10 Sodium 4-nitro~2-phenoxymethane sulfonanilide is reacted with acetyl chloride in dichloromethane by re-fluxing overnight. The mixture is filtered, the filtrate is evaporated in vacuo and the residue is washed thoroughly with water to provide N-acetyl-4-nitro-2-phenoxy-methane sulfonanilide, m.p. 139-l o.5° C. after recrystal-lization from a benzene -petroleum ether m xture.

Exam le 11 Sodium 4-nitro-2-phenoxymethane sulfonanilide is reacted with a slight excess of fluoromethanesulfonyl chloride in dimethyIformamide by stirring overnight, the mixture is filtered, then .evaporated in vacuo. The residue is washed thoroughly with water to provide N-fluoromethanesuIfonyl-4'-nitro-2-phenoxymethanesuIfonanilide.

Using the procedure of Example 3 the following compounds are prepared: 41 -nitro-2 ' -phenoxyethanesulfonanilide , m.p. 113-115° C. 42640/3 5Lmethox - -nitro -2-phenoxyme thane sulfonani lideV m.p. I50-I52.5° C. 2L ( -methox;yphenoxy)-4^nitrome thanesuIfonanilide, m.p. 125-127° C. 2L(4-acetylphenoxy)-4'-nitromethane sulfonanilide , m.p. 169-173°C. 2 ' - (2-nitrophenoxy) -41 -nitromethanesulfonanilide itrophenoxy) -4-nitromethane sulfonanHide The product shown in the following table is prepared from another compound of the invention as described.

Starting Material Synthetic Method Product 2'-(4-methoxy- Hydrogen iodide 2-(4-hydroxyphen-phenox ) -^nitrocleavage oxy) -4-nitromethmethanesuIfon- anesuIfonanilide , anilide m.p. 159-160.5°C. - 20 - 42640/2 Example 12 To an ice-cooled solution of 5*0 g. (19 mmole) of 2-phenoxyme thane sulfonanilide in o ml. of trifluoro-acetic acid is added dropwise a solution of 1.3 g. (19 mmole) of sodium nitrite in 10 ml. of water. After stirring one hour the mixture is poured into water and extracted with dichloromethane . The extracts are dried over magnesium sulfate and ■ evaporated under vacuum. The resulting solid residue is recrystallized three times from a dichloroethane/hexane mixture to provide 3· 5 g-(6θ$) of 4-nitro-2-phenoxymethanesulfonanilide . m.p. 144-147° C.

Example 13.

To a solution of 1.685 kg (8.9 mole) of 2-phenoxyaniline in I.65 liters of pyridine at a temperature of 85" C. is gradually added 1.02 kg (8.9 mole) of methanesulfonyl chloride over three hours. The mixture is stirred and heated for one additional hour, then „ - 21 - poured into a mixture of six liters of ice and three liters of concentrated hydrochloric acid. The solid product is collected by filtration, washed with 10% hydro chloric acid and then washed with water. The crude / product 2-phenoxyrnethanesulfonanilide (2.33 kg, 85$, m.p. 110-117° C.) is recrystallized from an ethanol- water mixture to give a product of greater purity, m.p. 118.5-120°. C.

Example 14 To an ice cold solution of 1.0 g. (0.011 mole) of dinitrogen tetraoxide in chloroform (50 ml.) is added 2-phenoxymethanesulfonanilide (1.0 g., Ο.ΟΟ38). After 15 minutes of stirring the mixture is evaporated under vacuum to dryness. The solid residue is recrystallized from 'aqueous ethanol to provide 0.77 g« of 4-nitro-2-phenoxymethane suIfonanilide , m.p. 146-1.48° C, yield 66%.

Example 15 To an ice-cooled 20 ml. portion of concentrated nitric acid is added 2.0 g. (7·6 mmole) of 2-phenoxymethanesulfonanilide and the mixture is stirred for 20 minutes. The mixture is added to 100 ml. of water and the product is separated by filtration and washed with water. Recrystallization from ethanol provides 1.7 g. {13%) o 4-nitro-2-phenoxymethanesul onanilide, m.p. l43" 146° C.

Example 16 2-Phenoxymethanesulfonanilide (I3.I6 g., O.050 mole) and 250 ml. of acetic anhydride are heated to 100° C. and nitric acid (4.5 &·, 0.05 mole) is added dropwise over 0.5 hour. The mixture is maintained at about 90° C. overnight, then cooled and poured into water. The solid product, is separated by filtration and dried to provide 1.3.5 g. (87$) of 2-phenpxy- -nitrome thane sulfon-. anilide.

Example 17 To an ice-cooled solution of 2.0 g. (7»6 mmole)' of 2-phenoxymethanesuIfonanilide in 30 ml. of trifluoro- acetic acid is added dropwise a solution of 0.66 g. (7·7 mmole) of sodium nitrate in 3 ml* of water. The mixture is allowed to warm to about 25° C.3 then poured into water. The product is isolated by filtration and recrys- tallized from ethanol to provide 2.0 g. (86$) of -nitro- 2-phenoxyrnethanesulfonanilide 3 m.p. l -l 7° C.

Example 18 Into a solution of 2.0 g. (7.6 mmole) of 2-phenoxyme thane suIfonanilide in 20 ml. of dichloroethylene containing 0.5 g. of ferric chloride is bubbled nitrosyl chloride for twenty minutes. The mixture is poured into water and extracted with dichloroethane . The extracts are evaporated under vacuum -leaving a dark oily solid.

Two recrystallizations provide a 2 $ yield of 4-nitro-2-phenoxymethane suIf.onanilide, m.p. l l-l45° C.

Example 19 ANTI-INFLAMMATORY TEST DATA The procedure is a conventional one designed to demonstrate anti-inflammatory activity by means of the ability of the compound under test to antagonize the local edema, which is a characteristic of the anti-inflammatory response (rat foot edema, test). Leading references to the rat foot edema test are: 1. Winter, Proc. Soc. Exper. Biol. Med. 111:5^, 1962. 2. Swingle KF, "Evaluation for Antiinflammatory Activity" — pgs . 33-122 qf Anti-inflammatory Agents — Vol. II, Edited by R. A. Scherrer and M. W. White- house, Academic Press, New York, 197^ · The edema test is performed on adult male or female rats. One group of 5 to 10 rats serves as non-medicated controls while another group of 5 to 10 rats receives the test compound at various times prior to the induction of the edema, usually 15 minutes. The test compound is administered as a suspension in Ί percent aqueous solution of acacia. Edema is induced by the plantar injection of 0.5 percent carrageenan (0.1 ml/foot) into one hind foot. The other hind foot receives a like volume of 0.9 percent saline solution. Three hours later, the volume of each hind foot is determined plethysmographically . The edema is expressed as the increase in the volume of the edemogen injected foot (volume of the "edemogen" foot less the volume of the "saline" foot). The percent inhibition is calculated according to the expression A-j-—B x 100 where A is the amount of edema in the non-medicated group of rats and B is the amount of edema in the medicated group of rats. The dose of drug required to give 35 percent inhibition is defined as the ED^ . This level of inhibition (35 percent) is indicative of an active anti-inflammatory.

The ALDJ-Q (the approximate dose required to kill 50 >, percent of the test animals) values are determined using the conventional procedure .

The data, keyed to the structure is as follows: Anti-inflam. Therapeutic Compound Structure Compound Activity Ratio Designs. B X, Y, Z, Z» ALD (ALD50/ED35) ED35 5P_ 42640/3 (1) Three determinations were made for the ED^. Tne results », were 0.5, 0.6 and 0.95· The average is 0.†· (2) The EDgg for this compound has been measured as 100 (mg/kg) The estimated EDocr is 5- 3o (3) The ED2j^ for this compound has been measured at 10. In another test it was found to be inactive at 10 mg/kg. (4) The ED^ ?or this compound has been measured at 20. The estimated ED^ is 6· (5) The estimated ED^ is 250. (6) The ED^ for this compound has been measured at 19. - 7")—This—e^mp^uft^-^as-^ ei5!—f-o¾«<3—^ tirO—be^^ G ±v ^1?- QQ-^ /-icg- (8) This compound has been found to be inactive at 20 mg/kg.

Its estimated ED c is 38. (9) The D^ for this compound has been measured at 20. In another test the was measured as 20 and the estimated ED-,, was 56.

DO (10) The estimated ED^ is 27. (11) The ED|j2 for this compound has been measured at 20. Its estimated ED^ is 32. (12) The estimated ED^ is 76.

Claims (4)

1. 42640/4 CLAIMS ; 1.. A sulfonamidoaryl compound characterized by the formula: wherein Rx is an alkyl or monohaloalkyl radical containing one or. two carbon atoms , R is hydrogen, alkyl, II alkylsulfonyl, ha loalkylsulfonyl, a cation or -C-A-R', where R' is alkyl and A is oxygen or a carbon-carbon bond, X is alkoxy, alkyl, halogen, nitro, hydrogen or amino, Y is nitro, amino, dialkylamino or hydrogen, provided that one of X and Y is nitro or amino or Y is dialkyl amino, Z is halogen^, nitro or hydrogen, Z' is halogen,' alkyl>■ alkoxy, nitro," hydroxy or alkanoyl , and n is 0, 1 or 2, provided that the individual aliphatic groups appearing in the R, X, Y and Z' moieties contain from one ■ Θ/ to four carbon atoms each, the com und 4 ' , 6 ' -dinitro-2 ' -phenoxyethanesulfonanilide being excluded.

2. A compound according to claim 1 wherein R is hydrogen.

3. A compound according. to claim 1 wherein R is a cation.

4. A compound according to claim 1 wherein R is alkyl. j - 27 - 42640/2 5· A compound according to claim 1 wherein R is alkyl. 6. A compound according to claim 1 wherein Rx is monohaloalkyi. 7· A compound according to claim 5 wherein Rx is methyl. 8. A compound according to claim 6 wherein Rx is fluoromethyl. 9· A compound according to claim 6 wherein Rx is chloromethyl. ~ 10. A compound according to claim 1 wherein Y is nitro. 11. A compound according to claim 1 wherein X is amino. 12. A compound of the formula wherein is methyl,, fluoromethyl, chloromethyl or ethyl, R is hydrogen, an alkyl radical containing from one to four carbon atoms or a cation, X is hydrogen, methyl, amino or nitro, 'dimothy1amino Y is nitro or hydrogen, provided that if Y is hydrogen, X is amino, Z is chlorine or hydrogen, Z' is oriented ortho and/or para to the diphenyl ether oxygen and is chloro, fluoro or methyl and n is 0, 1 or 2. - 2-5- - 42640/2 13 · A compound according to claim 12 wherein X is hydrogen and Y is nitro. 14. A compound according to claim 13 wherein Έ.ν is methyl. 15. A compound according to claim 12 wherein Rx is methyl. / 16. The compound 4-nitro-2-phenoxymethane -sulfonanilide according to claim 12 . 17. A compound according to claim 12 wherein R is methyl or ethyl. 18. The compound 4-nitro-2~phenoxy luoromethanesulfonanilide according to claim 12. 19. The compound 2- (4-chlorophenoxy) -4-nitro-fluoromethanesulfonanilide according to claim 12. , / / 20. The compound N-methyl-4-nitro-2-phenoxy- methanesulfonanilide according to claim 12. 21. The compound N-ethyl-4 I-1nitro-21-phenoxy-methanesulfonanilide according to claim 12. 22. Compounds according to Claim 1 substantially as herein described and exemplified. 23. Compounds according to Claim 12, substantially as herein described and exemplified. 42640/ 4 24. A process of preparing a sulfonamidoaryl compound characterized by A. Reacting a compound, of the formula RxS02Q wherein Rv is an alkyl or monohaloalk l radical containing one or two carbon atoms and Q is fluorine or chlorine with an aryl amine of the formula i wherein X^ is alkoxy, alkyl, halogen, nitro or hydrogen, is nitro, dialkylamino or hydrogen, provided that one of X^ and is nitro or is dialkylamino, Z is halogen, nitro or hydrogen, Z" is halogen, alkyl, alkoxy, nitro or alkanoyl, and n is 0, 1 or 2 , provided that the individual aliphatic groups appearing in the , and Z" moieties contain from one to four carbon atoms each, and recovering a compound of the formula wherein Ι1χ, X1 , Υχ , Z, Z" and n have the same meaning as above and R is hydrogen, the compound 41 , 61 -dinitro-21 -phenoxyethanesulfonanilide being excluded; or 42640/2 B. Reacting a compound of the formula wherein Rx, Y-^ and Z have the same meaning as above and D is chlorine, bromine or iodine, provided that when D is chlorine must be an activating group, with a compound of the formula wherein M is alkali metal or copper and Z " has the same meaning as above, provided that if Xj, Z or Z" is halogen, ^, Z or Z" is a lower atomic weight halogen than D, and recovering a compound of Formula I wherein R is hydrogen and, if desired, C. Further reacting a product of A. or B. with a suitable base to form a compound according, to Formula wherein R is a cation, and, if desired, Do Further reacting a product of C. wherein R is a suitable cation, such as sodium or potassium, with a suitable lower alkyl halide or dialkyl sulfate, to form a compound according to Formula I wherein R is lower alkyl. 42640/3 25. A process for the preparation of a compound of the formula wherein R is alkyl or monohaloalkyl of one or two carbon atoms, Zj^is halogen or hydrogen, Z" is halogen, alkyl, alkoxy, nitro or alkanoyl, provided that the alkyl groups within the Z" moieties contain no more than four carbon atoms each, and n is zero, one or two which comprises treating a compound of the formula with at least one equivalent of a nitrating agent. 26. A process according to Claim 24 or 25, substantially as herein described and exemplified. - 32 - 42640/2 .27. Anti-inflammatory compositions containing as an active agent a compound of the formula wherein Rv is an alkyl or monohaloalk l radical con--taining one or two carbon atoms, R is hydrogen, alkyl, alkylsulfonyl, haloalkylsulfonyl, a cation or 0 -d-A-R1, where R 1 is alkyl and A is oxygen or a carbon-carbon bond, X is alkoxy, alkyl, halogen, nitro, hydrogen or amino, Y is nitro, amino, dialkylamino or hydrogen, provided that one of X and Y is nitro or amino or is dialkylamino, Z is halogen, nitro or hydrogen, Z' is halogen, alkyl, alkoxy, nitro, hydroxy or alkanoyl, and n is 0, 1 or 2 , provided that the individual aliphatic groups appearing in the R, X, Y and Z' moieties contain from one to four carbon atoms each; the compound 4 ' , 6 '-dinitro-21 -phenoxyethane-sulfonanilide being excluded, 28. A composition according to Claim 27, wherein R is hydrogen. 29. A composition according to Claim 27, wherein R is a cation. 30. A composition according to Claim 27, wherein R is alkyl. - 33 - 42640/2 31. A composition according to claim 27 wherein R¾ is alkyl. 32. A composition according to claim 27 wherein Rx is monohaloalkyl. 33. A composition according to claim 27 wherein Rx is methyl. , 34. A composition according to claim 27 wherein Rx is fluoromethyl. 35. A composition according to claim 27 wherein Rx is chloromethyl . 36. A composition according to claim 27 wherein Y ia nitro. 37. A composition according to claim 27 wherein X is amino. 38. Anti-inflammatory compositions containing as active agent a compound of the formula Y wherein Rx is methyl, fluorometh l, chloromethyl or ethyl, R is hydrogen, an alkyl radical, containing ■ from one -to. four carbon atoms or a cation, X is hydrogen, methyl, amino or nitro, Y is nitro or hydrogen, provided that if Y is hydrogen, X is amino, Z is chlorine or hydrogen Z1 is oriented ortho and/or para to the diphenyl ether oxygen and is chloro, fluoro or methyl and n is 0. 1 or 42640/2 39. A composition according to Claim 38 wherein X is hydrogen and Y is nitro. * 40. A composition according to Claim 39 wherein is methyl, 41. A composition according to Claim 38 wherein R is methyl. 42. A composition according to Claim 38 wherein the compound is 4~nitro-2-phenoxyniethanBulfonanilide. 43. A composition according to Claim 38 wherein R is methyl or ethyl. 44. A composition according to Claim 38 wherein the compound is 4-nitro~2-phenoxyfluoromethanesulfonanilide. 45. A composition according to Claim 38 wherei the compound is 2- (4-chlorophenoxy)-4-nitro-fluoromethanesulfonanilide. 46. A composition according to Claim 38 wherei the compound is N-methyl-4-nitro-2-phenoxymethane-sulfonanilide. 47. A composition according to Claim 38 wherein the compound is N-ethyl-4-nitro-2-phenoxymethanesulfon-anilide. 48. Anti-inflammatory composition according to any one of Claims 27. to 47, substantially as herein described and exemplified. For the DR. mil )LD COHN AND PARTNERS Bys