US3682968A - Anti-inflammatory salicylic acid derivatives - Google Patents

Abstract

Salicylic acid derivatives and their non-toxic pharmaceutically acceptable salts, esters and amides are claimed. Also encompassed is the treatment of inflammation with said derivatives.

Description

United States Patent Shen et a1. [45] Aug. 8, 1972 [54] ANTI-INFLAMMATORY SALICYLIC 260/332.2 R, 260/612 R, 260/619 R, ACID DERIVATIVES 260/332.3 R, 260/621 R, 260/622 R, [72] Inventors: Tsung-Ying Shen; Bruce E. Witzel; 260/347'2 260/623 260/623 Gordon L walford a" of westfield 260/347.3, 424/274, 424/275, 260/347.4, N J 424/285, 424/248, 260/347.5, 424/267, 424/308, 260/463, 424/309, 424/316, [73] Assignee: Merck 8: Co., Inc., Rahway, NJ. 260/465 D, 424/317, 424/324, 260/465 E, [22] Filed June 25 1969 260/465 F, 260/468 R, 260/470, 260/471 R, 260/472 [21] Appl. No.: 836,622 [51] Int. Cl.....A6lk 27/00, C07d 63/14, C07d 63/16 [58] Field of Search ..260/332.2 A [52] US. Cl. .....260/332.2 A, 260/247.l, 260/473 R,

260/474, 260/247.2 A, 260/473 G, 260/475 [56] References CM SC, 260/247.2 B, 260/479 R, 260/50l.l, NITED ST E p TE 260/242.2 R, 260/50l.l6, 260/50l.l7, U AT S A NTS 2 293 7 2 0 501 9 2 050121 3,558,641 1/1971 Sarett et al. ..260/295 260/293.68, 260/515 R, 260/515 A, 260/293.7l, 260/515 M, 260/515 P, 260/293.73, 260/514 R, 260/516, 260/293.75, 260/518 A, 260/518 R, 260/293.78, 260/519, 260/545 R, 260/293.8l, 260/551 R, 260/556 R, 260/293.82, 260/557 R, 260/558 A, 260/326.3, 260/558 S, 260/558 D, 260/326.5 L, 260/558 R, 260/559 T, 260/326.5 M, 260/559 R, 260/559 S, 260/326.5 S, 260/559 A, 260/561 R, 260/326.55 M, 260/562 A, 260/571, 260/326.55 F, 260/590, 260/607 A, 260/326.5 J, 260/609 F, 260/612 D,

Primary Examiner-Henry R. Jiles Assistant Examiner-Cecilia M. Shurko Attorney-1. Louis Wolk, Harry E. Westlake, Jr. and Michael C. Sudol, Jr.

[ ABSTRACT Salicylic acid derivatives and their non-toxic pharmaceutically acceptable salts, esters and amides are claimed. Also encompassed is the treatment of inflammation with said derivatives.

4 Claims, No Drawings ANTI-INFLAMMATORY SALICYLIC ACID DERIVATIVES (Formnla I) and the esters, amides, anhydrides and'non-toxic pharmaceutically acceptable salts thereof in which,

A is S, So, S 0,

l Nacetyl.

NH, NR Yis CH III, III, S or O;

wherein R is lower alkyl R is H; acyl (preferably lower acyl such as formyl, acetyl, propionyl, butyryl etc.); alkyl (preferably lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.); alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexoxycarbonyl, etc.). R may be hydrogen, halogen (such as chloro, bromo, fluoro, or iodo, preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl such as trifluoromethyl,etc.), alkyl (preferably loweralvkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (for example, cyclobutyl, cyclopentyl, cyclopropyl, cyclohexyl .and cycloheptyl), or alkoxy (preferably loweralkoxy such as methoxy, ethoxy, isopropoxy :or butoxy etc.);

i X may be. hydrogen, alkyl, (preferably loweralkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), hydroxy, alkoxy (preferably loweralkoxy such as methoxy, ethoxy, isopropoxy or butoxy etc. acyloxy (such as benzoyloxy, acetoxy or propionoXy), halogen (such as chloro, bromo, fluoro or iodo, preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl such as trifluoromethyl, etc.), nitro, amino, alkylamino (preferably loweralkylamino such as methylamino, propylamino, pentylamino, etc.), diloweralkylamino (dimethylamino, dibutylamino, propylpentylamino, etc.), acylamino (preferably loweracylamino such as formylamino, acetylamino, propionylamino, butrylamino, etc.), mercapto, alkylmercapto (preferably loweralkylmercapto such as methylmercapto, ethylmercapto, etc.), alkylsulfinyl (preferably loweralkylsulfinyl such as methylsulfinyl, ethylsulfinyl, butylsulfinyl, etc.), alkylsulfonyl (preferably loweralkylsulfonyl such as methylsulfonyl; ethylsulfonyl, butylsulfonyl, etc.),

1 sulfonamido, sulfonylamido, amiiioalkyl, alkylaminoalkyl (preferably loweralkylaminoloweralkyl such as methylaminom ethyl,

ethylaminomethyl, etc., (such as dimethylaminomethyl, methylethylaminomethyl); hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxymethyl', hydroxyethyl, hydroxypropyl, acylaminomethyl, alkoxyalkyl (preferably loweralkoxyloweralky] such as methoxymethyl, methoxyethyl, ethoxyethyl, ethoxypropyl, etc.), mercaptoalkyl (preferably mercaptoloweralkyl such as mercaptomethyl, mercaptoethyl, etc.), alkylmercaptoalkyl (preferably loweralkylmercap toloweralkyl such as methylmercaptomethyl, ethylmercaptoethyl, ethylmercaptopropyl, etc.), cyano, carboxy, carboalkoxy (carbomethoxy, carboethoxy etc.), carbamoyl, aryl (such as phenyl, halophenyl, tolyl, salicyl), aralkyl such as benzyl, aryloxy, and, aralkoxy and acyl (preferably lower acyl such as forrnyl, acetyl and butyryl etc. The preferred class of acids of the salicylic configuration where the OR is ortho to the COOH; the

. bridging member A is attached to the 4 or 5 position of the benzene ring and to the 2 or 3 position of the five membered ring above.

The acid derivatives of the above description possess a high degree of anti-inflammatory activity. They are of value in the treatment of arthritic and dermatological disorders or like conditions responsive to anti-inflammatory drugs. Included within this category are diseases such as rheumatoid arthritis, osteo arthritis, gout, infectious arthritis and rheumatic fever. The acid derivatives also possess a useful degree of analgesic and anti-pyretic activity.

For these purposes the compounds of the invention may be administered orally, topically, parenterally or rectally in formulations containing conventional nontoxic pharrnaceutically acceptable carriers, adjuvants and vehicles. In addition to the treatment of warmblooded animals such as mice, rats, etc., the com pounds of the invention are efi'ective in the treatment of humans.

The non-toxic pharmaceutical carriers indicated above include either solids or liquids. Exemplary of solid carriers are lactose, corn starch, gelatin, talc,

sterotix, stearic acid, magnesium stearate, terra alba,

sucrose, agar, pectin, cab-o-sil, and acacia. Exemplary of liquid carriers are peanut oil, olive oil, sesame oil and water. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositions can be used. For example, if a solid carrier is used, the compositions may take the form of tablets, capsules, powders, troches or lozenges,

' prepared by standard pharmaceutical techniques. If a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a syrup or a liquid suspension. Suppositories may be prepared in a conventional manner.

The compounds of Formula I are present in an amount sufficient to treat inflammation. Advantageously, the composition will contain the active ingredient, in an amount of from about 1 to mg. per kg. body weight per day (50 mg. to 7 g. per patient per day), preferably from about 2 to 50 mg./kg. body weight per day 100 mg. to 3 g. per patient per day).

The preferred method of treatment comprises internal administration to a patient (animal or human), a compound of Formula I, admixed with a non-toxic pharmaceutical carrier such as exemplified above. The compounds of Formula I will be administered in an amount of from 1 to 100 rngJkg. body weight per day, preferably fromabout 2 to about 50 mg. per kilogram body weight per day and especially from 4 to 20 mg./kg. body weight per day. The most rapid and effective anti-inflammatory effect is obtained from oral administration of a daily dosage of from about 4 to 20 mg./kg. per day. It should be understood, however, that although preferred dosage ranges are given, the dose level for any particular patient depends upon the activity of the specific compound employed. Also many other factors that modify the action of drugs will be taken into account by those skilled in the art in the therapeutic use of the medicinal agents of Formula I, for example, age, body weight, sex, diet, time of administration, route of administration, rate of excretion, drug combination, reaction sensitivities, and severity of the particular disease.

The compounds of the invention may be produced utilizing the following starting materials:

Members of this class such as and are known and convenient techniques for their preparation are available to the skilled artisan.

lnaddition to the above, a number of processes for the preparation of the phenolicstarting materials from available reactants may be presented as follows:

x-- um on X =hydrogen, alkyl, halogen, haloalkyl, N0 alkylsulfonyl, alkylsulfinyl, aryloxy, aralkyl, carboalkoxy and acylaminomethyl;

Y and R are as defined above.

An oxidizing agent such as potassium permanganate is added to the sulfide; S0 added; the mixture filtered; concentrated in vacuo to a residue.

CH: 2) l Hal e g- 0. X, Y, R, as defined in (a) above. 7 l. A mixture of potassium carbonate, cuprous iodide and the benzyl phenylether is added to thefive memcordance with process illustrated at section (c).

It will be appreciated that hydrolysis of the acetanilide type compound shall result in compounds wherein Carboxylation of the starting materials of the formu- OH H (1-3) prepared in accordance with section (a), (b), (c) and (d) proceeds as follows:

COOH

X is hydrogen, alkyl, halogen, haloalkyl, N

acylamino, alkylmercapto, alkylsulfonyl, alkylsulfinyl, acyl, aryloxy, aryl, aralkyl, carboalkoxy and acylaminomethyl.

Y, A, R and R are as defined above.

An economical method for the carboxylation of the starting material with a carbonate such as potassium carbonate in a high pressure CO atmosphere; heat is applied; the mixture cooled; added to water; filtered; the filtrate is acidified to yield the carboxylated product.

In addition carboxylation may be effected by the use of the Grignard reagent with carbon dioxide in dry ether, followed by hydrolysis. Furthermore, the technique known as the Wanklyn reaction may be employed in this regard.

EXAMPLE 1 Preparation of -fluoro-2-thienyl-4hydroxyphenylsulfide To 2-fluorothiophene (0.1 m.) in ether at 20 C. is added n-butyl lithium (0.1 m.), the mixture stirred 1 hour, (p-hydroxyphenyl)-disulfide (0.1 m.) added carefully, allowed to stir 1 hour, refluxed gently for another hour, cooled, water added cautiously and the layers separated. Chromatography (silica gel using an ether-petroleum ether systen (v/v 0-70 percent ether as jeluant) yields 5-fluoro-2-thienyl 4'-hydroxyphenyl sulfide, I

When 2-chlorothiophene, 2-bromothiopheme, thiophene, 2-methylthiophene, 2-benzylthiophene, 2- phenylthiophene, Z-methylmercaptothiophene, 3- fluorothiophene, 2 (and 3) methylsulfonylthiophene, 2,5-dimethylthiophene, 2,3,5-trimethylthiophene, furan, 2 (and 3) fluorofuran, 2 (and 3) chlorofuran, 2- bromofuran, 2,3,5-trimethylfuran, 2-phenoxyfuran, 2- nitrofuran, 2-trifluoromethylfuran, or 2,5- dichlorothiophene are used in place of 2- fluorothiophene in the above reaction, the corresponding hydroxyphenyl sulfides are obtained.

It may be further noted that the cyclopentadienyl moiety may beemployed in the above reaction in place of the thiophenes and furans exemplified above.

5 Representative members of this class include: 2-fluorocyclopenta( 2,4 )-dienyl; 3-methylcyclopenta( 2,4 )-dienyl; and, ethoxycyclopenta(2,4)-dienyl.

EXAMPLE 2 Preparation of 5-fluoro-2-thienyl-4'-hydroxyphenyl Sulfone To a solution of S-fluoro-Z-thienyl 4'-hydroxy-phenyl sulfide (0.1 m) in 1:1 acetic and acid-acetone is added a 3 percent aqueous solution of potassium permanganate (20 percent excess over theoretical) dropwise and the mixture allowed to stir several hours. Sulfur dioxide is added in a slow stream until all excess permanganate is destroyed and the mixture filtered, concentrated in vacuo, to a residue. The residue is taken up, in chloroform, filtered, and concentrated to 5- fluoro-2-thienyl 4-hydroxyphenyl sulfone and then purified via column chromatography.

It shall be readily, apparent to one skilled in the art that utilizing the various substituted thiophenes contemplated by the invention such as those set forth in Example 1, in place of the fluorothiophene illustrated above shall result in the preparation of the corresponding substituted thienyl-4-hydroxyphenyl sulfones. For example when 2-chlorothiophene, thiophene; (2- methylthiophene); (2-acetylthiophene); (2- benzylthiophene); and 2-methylmercaptothiophene hydroxyphenylsulfide are oxidized in accordance with the reaction illustrated above, the following phenolic materials are obtained, respectively: 5-chloro-2-thienyl 4'-hydroxyphenyl sulfone; 2-thienyl 4'-hydroxyphenyl sulfone; 5-methyl-2-thienyl-4'-hydroxyphenyl sulfone; 5-chloro-2thie nyl 4'-hydroxyphenyl sulfone; S-benzyl- 2-thienyl 4'-hydroxyphenyl sulfone; S-methylsulfonyl- 2-thienyl-4'-hydroxyphenyl sulfone.

With the methylmercapto-substituted thienyl 4- hydroxyphenyl sulfide, 120 percent excess is used to account for oxidation of both sulfur atoms.

EXAMPLE 3 Preparation of p-benzyloxy-N-(2-thienyl)-acetanilide A mixture of 2-acetaminothiophene g.), finely powdered potassium carbonate (5g.), benzyl piodophenyl ether g), cuprous iodide (0.5 g.), and nitrobenzene (50 ml.) is refluxed gently under a nitrogen atmosphere for 20 hours, the mixture steam distilled, the residue taken up in chloroform washed with water, dried, concentrated in vacuo, and the residue chromatographed on a silica gel column (10 l00 percent ether-petroleum ether) to yield pbenzyloxy-N-(2-thienyl)-acetanilide.

lt should be noted that 5substituted 2- 60 acetaminothiophenes and furans may also be employed in the above process including the substituents indicated at Example I.

It should be noted that benzyl m-iodophenyl ether is employed in place of the p-isomer when a 4- substituted salicylic acid is ultimately desired.

EXAMPLE 4 Preparation of p-benzyloxyphenyl 2-thienyl Ether A mixture of 2-bromothiophenev (0.15 m.); pbenzyloxyphenol (0.18 m.), powdered anhydrous potassium carbonate (6.9 g.) and copper bronze (0.2

g.) is heated at 210 C. for 2 hours, cooled, excess al-,

EXAMPLE Preparation of p-hydroxy-N-( 2-thieny1)acetanilide A mixture of p-benzyloxy-N-(Z-thienyD-acetanilide (0.01 m.), Spercent Pd/C (2 g.) and ethanol (50 ml.) is shaken in a 40 p.s.i. hydrogen atmosphere at room temperature until the theoretical amount (0.01 m.) of hydrogen has been absorbed. The mixture is filtered and the solvent removed in vacuo to yield p-hydroxy- N-( 2-thienyl)acetani1ide.

When the benzyl ethers of Examples 3 and 4 are treated accordingly, the corresponding phenols are obtained.

EXAMPLE 6 Preparation of p-hydroxyphenyl 2-thienyl ether To a cold (-60) mixture of p-benzyloxyphenyl 2-thienyl ether (0.03 m.) and methylene chloride (50 ml.), which is stirred and protected from moisture, is added boron tribromide (0.01 m.) and the resultant mixture allowed to warm slowly to room temperature. After stirring several hours, a minimum of percent aqueous sodium hydroxide is added to hydrolyze the complex. The mixture is then acidified with 2 percent hydrochloric acid and the layers separated. The methylene chloride mixture is dried, filtered, concentrated in vacuo, and the residue chromatographed on silica gel using an ether-petroleum ether system as eluant to yield p-hydroxyphenyl Z-thienyl ether.

When the ethers of Examples 3 and 4 are reacted with boron tribromide, the corresponding phenols are obtained.

EXAMPLE 7 Preparation of 5(5'fiuoro-2-thienylsu1fonyl)salicyclic Acid An intimately ground mixture of 2-fluoro-5-(phydroxyphenylsulfonyl)thiophene (5 g) and anhydrous potassium carbonate g.) is heated at 100 in a 1,200-1 ,400 p.s.i. carbon dioxide atmosphere for 8 hours. The mixture is cooled, added to water (300 ml. allowed to stir, filtered, and the filtrate acidified with dilute hydrochloric acid to yield 5(5'-fluoro-2-thienylsulfonyl )salicylic acid.

Purification may be effected via recrystallization or via chromatography of the methyl ester.

When the phenols of Example 1, 2, 5, and 6 are used in the above procedure, the corresponding salicylic acid is obtained.

A representative list of salicylic acids are as follows:

5-( 2-phenyl-5 -cyclopenta( 2,4)dienylthio-salicylic acid 5-( 2-mercapto-4-cyclopenta( 2,4)dienyl salicylic acid 4( 3 -methyl-5 -thienylsulfinyl )salicylic acid 5(2'-methoxy-5-thienylsulfonyl)salicylic acid N-(5mercapto-2-thieny1)-3-carboxy-4-hydroxyacetanilide N-(4-methyl-2-furyl)-3-carboxy 4-hydroxyacetanilide 5-( 5 -fluoro-2 -thienylsu1fonyl )-salicylic acid 5-( 5 -methyl-2'-furylsulfonyl )-salicylic acid 5-( 5'-chloro-2-thienylthio)-salicylic acid 5-( 1 2' ,4' cyclopentadienyl)-thio-salicy1ic acid 3-carboxy-4-hydroxy-N-( 2'-( 1 -methy1pyrryl)- acetanilide 4-( 5 '-fluoro-2-thienyloxy)-salicylic acid 5-( 5'-trifluoromethyl-2'-thienylthio)-salicylic acid 4-carboxy-3-hydroxy-N-( 3-thienyl )-acetanilide 5-( 5 '-methylsulfonyl-2-thienylsulfonyl )-salicylic acid 3-carboxy-4-hydroxy-N-( 2-thienyl )-acetanilide EXAMPLE 8 Preparation of Methyl 5-(5-cyano-2-thienylthio)salicylate A mixture of methyl 5-(5bromo-2-thienylthio) salicylate (0.02 m.), cuprous cyanide (0.03 m.), and N- methyl-pyrrolidone is de-aerated, covered with a nitrogen atmosphere and heated slowly to C., the mixture is kept at this temperature for 3 hours, allowed to cool, partitioned between benzene-7% hydrochloric acid containing ferric chloride (0.03 m.), the benzene layer then separated, dried, concentrated and the residue chromatographed on a silica gel column using an ether-petroleum ether system as eluant (v/v 5-80 percent ether) to yield methyl 5-(5-cyano-2'-thienylthio) salicylate.

EXAMPLE 9 Preparation of 5-(5-fluoro-2'-thienylsulfinyl-salicylic acid A stirred mixture of 5-(5-fluoro-2-thienyl-mercapto)-salicylic acid (0.01- m.) in acetone-methanol (1:1) is cooled to 5, and sodium metaperiodate (0.01 m.) in a minimum of water is added. When precipitation of sodium iodate is complete, the mixture is allowed to warm to room temperature, filtered, and the filtrate concentrated in vacuo. The residue is taken up in chloroform, the chloroform mixture filtered, and the filtrate concentrated in vacuo to 5-(5'-fluoro-2'- thienylsulfinyl)salicylic acid.

It should be noted that this procedure may be carried out on the phenol and the resulting sulfinylphenol carbonated as in Example 7 to yield the same product.

When the 5-(5'-methylthiothienyloxy)-, 5-(5'- methylthiothienylthio),- 5-( 5 -methylthiothienylthio 5 5 '-methylthiofuryloxy 4-( 5 '-methylthiofury1thio salicylic acids, etc., are oxidized as above, the corresponding ,methylsuflinyl analogs are obtained. With those containing two oxidizable groups, e.g. 5-(5- methylthio-thienylthio)- salicylic acid, 2 equivalents of sodium metoperiodate are needed.

EXAMPLE 10 EXAMPLE 1 1 Preparation of Methyl 5-(5-hydroxymethyl 2- thienyloxy salicylate A mixture of methyl 2-acetoxy-5-(5-bromomethyl- 2'-thienyloxy)benzoate (0.01 m.), silver acetate (0.01 m.) and acetic acid (30 ml.) is heated gently for 3 hours, cooled, filtered, and the filtrate concentrated in vacuo to a residue of crude methyl 2-acetoxy-5-(5- acetoxymethylthienyloxy)-benzoate. Anhydrous methanol (50 ml.) and p-toluene sulfuric acid (0.1 g.) is added and the mixture heated for 3 hours, concentrated, distributed between watenchloroform, the chloroform layer dried, concentrated, and the contents chromatographed on a silica gel column using an etherpetroleum ether system (v/v -100 percent ether) as eluant, yielding methyl 5-(5-hydroxymethyl-2'- thienyloxy) salicylate.

When potassium thiolacetate is used in place of silver acetate in the above reaction; methyl 5-(5-mercaptomethyl-2 '-thienyloxy )salicylate is obtained.

EXAMPLE 12 Preparation of Methyl 5-(5-dimethylaminomethyl-2'- thienyloxy)salicylate Methyl 2-acetoxy-5(5'-bromomethyl-2-thienyloxy)- benzoate (0.02 m.) is heated in methanolic dimethylamine. The solvents removed in vacuo and the residue taken up in 1.0 N hydrochloric acid, filtered, basified, and the resultant methyl 5-(5- dimethylaminomethyl-Z'-thienyloxy)-salicylate collected.

When methanolic ammonia is used in place of the dimethylamine in the above reaction, the corresponding 5 -aminomethyl salicylate is obtained.

EXAMPLE 13 Preparation of Methyl 5(5-methoxymethyl-2-thienylsulfonyl)-salicylate Methyl 2-acetoxy-5-( 5 '-bromomethyl-2-thienyl-sulfonyl benzoate (0.01 m.) is added to a stirred solution of sodium methoxide (0.02 m.) in anhydrous methanol. The mixture is refluxed gently for 1 hour, cooled, dilute hydrochloric acid added to neutralize the mixture, and the solvents removed in vacuo. The residue is chromatographed on a silica gel column using an etherpetroleum ether system (v/v 0-80 percent ether) as eluant to yield methyl 5-(5'-methoxymethyl-2'-thienylsulfonyl)-salicylate.

' 10 When potassium methylmercaptide is used in place of sodium methoxide, methyl 5-(5'-methylthiomethyl- 2-thienylsulfonyl)salicylate is obtained.

EXAMPLE 14 Preparation of Methyl 5-(5-carbamyl 2'-thienylsulfonyl) Salicylate A mixture of methyl 5 5-cyano-2-thienylsulfonyl)- salicylate (0.02 m.) and polyphosphoric acid (50 ml.) is heated on a steam cone for 1 hour. The mixture is cooled, added to water and the aqueous mixture extracted with chloroform. The chloroform layer is dried, filtered, and then concentrated in vacuo to yield methyl 5-(5-carbamyl 2'-thienylsulfonyl)salicylate which may be purified via column chromatography or recrystallization of the corresponding salicylic acid.

EXAMPLE 15 Preparation of N(5'-carboxy-2-thienyl)-3-carboxy-4- hydroxy-acetanilide To a mixture of N(5'-carbomethoxy-2'-thienyl) 3- carboxy-4-hydroxy acetanilide (0.01 m.) and methanol ml.) is added with stirring sodium hydroxide (0.06 m.) and water (15 ml.). The resultant mixture is stirred overnight at room temperature, diluted with water (200 ml.), filtered and the filtrate acidified with 2.5 N hydrochloric acid and the N(5-carboxy-2'-thienyl)-3- carboxy-4-hydroxyacetanilide collected.

EXAMPLE 16 tered solution yields 2-acetoxy-5-(5-chloro-2-thienylsulfonyl)-benzoic acid.

When propionic or butyric anhydride is used in place of acetic anhydride in the above example, the corresponding propionoxy or butyroxy compounds are obtained.

EXAMPLE 17 Preparation of Methyl 2-carboxy-4-(5'-fluorothienylthio)-phenyl Carbonate To a mixture of 5-(5'-fluorothienylthio)salicylic acid (0.01 m.), dimethylaniline (0.02 m.) and benzene (30 ml.) is added methylchloroforrnate (0.011 m.) over 1 hour with constant shaking and cooling. When the odor of the chlorocarbonate is essentially absent, hydrochloric acid (1 N, 100 ml.) is added and the mixture filtered. The benzene layer is then separated, dried, filtered, and the solvent removed in vacuo to yield methyl 2-carboxy-4-(CN5 '-fluorothienylthio)-phenyl carbonate.

EXAMPLE 18 Preparation of 2(3'carboxy-4-methoxy phenoxy)-5- fluorothiophene To a mixture of 2(3-carboxy-4'-hydroxy phenoxy)- 5-fluorothiophene (0.01 m.) in 2N sodium hydroxide solution at 70 is added dimethyl sulfate (0.10 m.) in small portions over hours, the mixture being kept basic throughout the addition. Water is added, the mixture filtered, the filtrate acidified and 2(3'carboxy-4- methoxyphenoxy)5-fluorothiophene collected.

The esters of the invention may be obtained by utilizing a diazomethane reagent. Alternatively, esterification may be effected with an appropriate alcohol in an inert solvent in the presence of an acid catalyst such as an aryl sulfonic acid. Further exemplification of esterification procedures is indicated in the following three examples:

EXAMPLE 19 Preparation of Methyl Z-acetoxy 5(5-fluoro-2-thienyl-sulfonyl)-benzoate Diazomethane in methylene chloride is added to an ice cooled mixture of 2-acetoxy-5-(5'-fluoro-2'- thienylsulfonyl)-benzoic acid in methylene chloride until nitrogen evolution ceases and the color of diazomethane persists. The solvent is then removed in vacuo to yield methyl 2-acetoxy-5-(5'-fluoro-2'- thienylsulfonyl)-benzoate.

When other diazo compounds are used in place of diazomethane in the above example, for example diazoethane, phenyldiazomethane, etc., the corresponding esters are obtained.

When the acids of Examples 7, 9, 15, l6, l7 and 18 are treated thusly, the corresponding esters are obtained.

EXAMPLE 20 Preparation of Methyl 5(5'-fluoro-5-thienylsulfonyl)- salicylate I 5(2-fluoro-5-thienylsulfonyl)salicylic acid 0.01 m.) is added to a solution of anhydrous methanol (25 ml.) containing ca. 100 mg. of anhydrous sulfuric acid. The resultant mixture is heated under gentle reflux, the solvent removed in vacuo and the residue partioned between chloroform-dilute sodium bicarbonate solution and the layers separated. The chloroform layer is dried over anhydrous sodium sulfate, filtered and evaporated to leave methyl 5(5'-fluoro-2'-thienylsulfonyl)salicylate.

When ethanol, propanol, isopropanol, or butanol, is used in place of methanol in the above reaction, the corresponding ester is produced.

When the salicylic acids of Example 7 are used in place of 5(2-fluoro-5-thienylsulfonyl)salicylic acid in the above example, the corresponding esters are obtained.

EXAMPLE 21 Preparation of phenyl-5 5 -fluoro-2 -furylsulfonyl )salicylate To a mixture of polyphosphate esters (P.P.E.) chloroform is added one equivalent each of 5-(5'- fluoro-2 furylsulfonyl)salicylic acid and phenol, and the resultant mixture is heated gently for 30 minutes. The chloroform mixture is cooled, washed with dilute bicarbonate solution. The chloroform layer is then When the salicylic acids of Example 7 are used in the above reaction, the corresponding phenyl esters are obtained.

EXAMPLE 22 Preparation of 5(5-fluoro-2-thienylsulfonyl)salicylanilide A mixture of phenyl 5-(5-fluoro-2'-thienyl-sulfonyl) salicylate (0.1 m.); (aniline (0.1 m.) and l-methylnaphthalene (50 ml.) are heated slowly to 230 C., kept at this temperature until phenol has stopped distilling. Charcoal (2 g.) is then added and then 20 ml. additional methylnaphthalene added. The mixture is heated for 10 minutes, filtered hot, and cooled. The collected anilide is then recrystallized yielding pure 5(5-fluoro- 2'-thienylsulfonyl)salicylanilide.

EXAMPLE 23 Preparation of 5(5-chloro 2-furylsulfinyl)salicylamide A mixture of methyl 5-(5-chloro 2-furylsulfinyl) salicylate and concentrated ammonium hydroxide five-fold excess) is heated at 100 C. in a sealed tube for 6 hours. After cooling, water is added and the 5(5- chloro 2-furylsulfinyl)salicylamide collected.

When monomethylamine, dimethylamine, ethylamine, diethylamine, morpholine, piperidine, etc. are used in place of ammonium hydroxide, the corresponding amides are obtained.

EXAMPLE 24 Preparation of Methyl 5-(5-methoxyfurylsulfonyl)salicylate A mixture of 10 g. of methyl 5(5-bromo-2'-furylsulfonyl)salicylate and 125 ml. of 2.5 M sodium methoxide in absolute methanol is heated for 30 minutes at ca. 90 in a stoppered bottle, the excess methanol removed in vacuo, dilute hydrochloric acid added and the mixture extracted with chloroform. Concentration of the chloroform solution yields methyl 5-(5'-methoxyfurylsulfonyl) salicylate.

When an equivalent amount of sodium benzylate in methanol is used in place of sodium methoxide, the 5- benzyloxy analog is obtained.

When the salicylates of the invention are reacted with silver acetate in acetic acid, the corresponding acetoxy analog are obtained.

When reacted with excess methanolic dimethylamine, the S-dimethylamino analog is obtained. EXAMPLE 25 Preparation of Sodium 3-carboxy-4-hydroxy-N-(2'-( 1 methylpyrryl)acetanilide Solutions of 3-carboxy-4-hydroxy-N-(2'-( 1 '-methylpyrryl)acetanilide in methanol and sodium hydroxide (1 equivalent) in water are mixed, heated for solution,

dried, filtered and evaporated in vacuo to yield phenyl 5 5 2-furylsulfonyl )salicylate.

filtered, and the filtrate concentrated in vacuo to obtain sodium 3-carboxy-4-hydroxy-N-(2'-( l -methylpyrryl)-acetanilide.

When potassium hydroxide is used in place of sodium hydroxide in the above example, the corresponding potassium salt is obtained.

When 2 equivalents of the above bases are used, the corresponding disodioand dipotassio-salts are obtained.

Preparation of Diethylaminoethanol Salt of l-24- cyclopentadienyl)-thio )-salicylic Acid N,N-diethylethanolamine (0.001 m.) in ether (5 ml.) is added to a stirred solution of S-(l-(24-cyclopentadienyl)-thio)-salicylic acid (0.001 m.) in chloroformmethanol, the resultant mixture allowed to stir for 1 hours, the salt collected or the solvent removed in vacuo to yield the diethylaminoethanol salt of 5-(l'- (2 '4A Y-cyclopentadienyl )-thio)-salicylic acid.

When piperidine, morpholine, triethylamine; N- methylpiperidine, N-methylmorpholine, tributyl amine or other organic amines are used in place of diethylethanolamine in the above example, the corresponding salt is obtained.

What is claimed is:

l. A compound of the formula:

0 lRr CR2 L or a pharmaceutically acceptable salt, wherein A is S, SO, SO or 0; R is H, lower alkanoyl, lower alkyl or lower alkoxycarbonyl; R is H, lower alkyl, lower alkoxy, haloloweralkyl or halo; X is H, lower alkyl, hydroxy, lower alkoxy,. benzoyloxy, lower alkanoyloxy, halo, haloloweralkyl, nitro, amino, loweralkylamino, diloweralkylamino, loweralkylsulfinyl, loweralkylsulfonyl, sulfonamido, loweralkanoylamino, mercapto, loweralkylthio, sulfinylamido, aminoloweralkyl, loweralkylaminoloweralkyl, diloweralkylaminoloweralkyl, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoylaminomethyl, mercaptoloweralkyl, loweralkylthioloweralkyl, cyano, carboxy, carboloweralkyl, carbarnyl, phenyl, halophenyl, tolyl, salicyl, benzyl, loweralkanoyl; and R is hydroxy, loweralkoxy or phenoxy.

2. 5(5'-Fluoro-4'-thienylsulfinyl)salicyclic acid.

3. 5-(5-Fluoro 2'-thienylsulfonyl)salicylic acid.

4. 5-(5'-Fluoro-2'-thienyloxy)-salicylic acid.

Claims (3)

1. 2. 5(5''-Fluoro-4''-thienylsulfinyl)salicyclic acid.
2. 3. 5-(5''-Fluoro 2''-thienylsulfonyl)salicylic acid.
3. 4. 5-(5''-Fluoro-2''-thienyloxy)-salicylic acid.