US3657432A

US3657432A - Anti-inflammatory salicylic acid derivatives

Info

Publication number: US3657432A
Application number: US30323A
Authority: US
Inventors: Tsung-Ying Shen; Gordon L Walford; Bruce E Witzel
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1969-06-25
Filing date: 1970-04-20
Publication date: 1972-04-18
Anticipated expiration: 1989-04-18
Also published as: GB1265924A; FR2053009A1; NL7008637A; FR2053009B1; CH542809A

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 Ofice 3,657,432 Patented Apr. 18, 1972 3,657,432 ANTI-INFLAMMATORY SALICYLIC ACID DERIVATIVES Tsung-Ying Shen, Gordon L. Walford, and Bruce E. Witzel, Westfield, N.J., assignors to Merck & Co., Inc.,

Rahway, NJ.

No Drawing. Continuation-impart of application Ser. No. 836,622, June 25, 1969. This application Apr. 20, 1970, Ser. No. 30,323

Int. Cl. A61u 27/00 U.S. Cl. 424-232 4 Claims ABSTRACT OF THE DISCLOSURE 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.

CROSS REFERENCES TO RELATE APPLICATIONS This application is a continuation-in-part of our copending US. application Ser. No. 836,622, filed June 25, 1969.

This invention relates to novel anti-inflammatory com.- pounds. More particularly, it relates to acids of the formula:

and the esters, amides, anhydrides and non-toxic pharmaceutically acceptable salts thereof in which,

A is S, So, S 0,

I N-acety1 NH, NR Y is CH N, 1 1 i H S or 0; 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 trifiuoromethyl, etc.), alkyl (preferably loweralkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (for example, cyclobtuyl, cyclopentyl, cyclopropyl, cyclohexyl and cycloheptyl), or alkoxy (preferably loweralkoxy such as methoxy, ethoxy, isopropoxy or butoxy etc.);

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, =butyrylamino, etc.), mercapto, alkylmercapto (preferably loweralkylm-ercapto such as methylmercapto, ethylmercapto, etc.), alkylsulfinyl (preferably loweralkylsulfinyl such as methylsulfinyl, ethylsulfinyl, butylsulfinyl, etc.), alkylsulfonyl (preferably loweralkylsulfonyl such as methylsulfony, ethylsulfonyl, butylsulfonyl, etc.), sulfonamido, sulfonylamido, aminoalkyl, alkylaminoalkyl (preferably loweralkylaminoloweralkyl such as methylaminomethyl, ethylaminomethyl, etc., (such as dimethylaminomethyl, methylethylaminomethyl); hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxymethyl, hydroxyethyl, hydroxypropyl, acyl-aminomethyl, alkoxyalkyl (preferably lowerallcoxyloweralkyl such as methoxymethyl, methoxyethyl, ethoxyethyl, ethoxypropyl, etc.), mercaptoalkyl (preferably mercaptoloweralkyl such as mercaptomethyl, mercaptoethyl, etc.), alkylmercaptoalkyl (preferably loweralkylmercaptoloweralkyl such as methylmercaptomethyl, ethylmercaptoethyl, ethylmercaptopropyl, etc.), cyano, carboxy, car- :boalkoxy (carbomethyl, canboethoxy etc.), carbamoyl, aryl (such as phenyl, halophenyl, tolyl, salicyl), aralkyl such as benzyl, aryloxy, and, aralkoxy and acyl (preferably lower acyl such as formyl, acetyl and butyryl etc.).

The preferred class of acids of the salicylic configuration where the 0R is ortho to the COOH; the bridging member A is attached to the 4 or 5 position of the henzene 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, anti-pyretic, diuretic, anti-fibrinolytic and hypo-glycemic activity and when used for these utilities the same dosage ranges and conditions described subsequently for the treatment of inflammation will apply.

For these purposes the compounds of the invention may be administered orally, topically, parenterally or rectally in formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. In addition to the treatment of warm-blooded animals such as mice, rats, etc., the compounds of the invention are effective 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 sufiicient to treat inflammation. Advantageously, the composition will contain the active ingredient, in an amount of from about 1 mg. to 100 mg. per kg. body weight per day (50 mg. to 7 g. per patient per day), preferably from about 2 mg. 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 mg. to 100 mg./kg. body weight per day preferably from about 2 mg. to about 50 mg. per kilogram body weight per day and especially from 4 mg. 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 actions 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:

x (1-3) Members of this class such as and 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.

Hal=chloro or fiuoro; X, Y and R are as defined in (a) above.

atmosphere of hydrogen.

OCH2

and further treatment with an alkylating agent results in the production of those compounds wherein Carboxylation of the starting materials of the formula:

X (l-IDH prepared in accordance with section (a), (b), (c) and (d) proceeds as follows:

COOH OOOH 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 C0 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 5-fluoro-2-thienyl-4'-hydroxyphenylsu1fide To 2fluorothiophene (0.1 m.) in ether at 20 C. is added n-butyl lithium (0.1 m.), the mixture stirred one hour, (p-hydroxyphenyl)-disulfide (0.1 m.) added carefully, allowed to stir one hour, refluxed gently for another hour, cooled, water added cautiously and the layers separated. Chromatography (silica gel using an ether-petroleum ether system (v./v. 0-70% ether as eluant) yields S-fiuoro-Z-thienyl 4'-hydroxyphenyl sulfide.

When 2 chlorothiophene, 2 bromothiophene, thio phene, 2-methylthiophene, 2-benzylthiophene, z-phenylthiophene, Z-methylmercaptothiophene, 3-fluorothiophene, 2 (and 3) methylsulfonylthiophene, 2,5 dimethylthiophene, 2,3,S-trimethylthiophene, furan, 2 (and 3) fluorofuran, 2 (and 3) chlorofuran, 2-bromofuran, 2,3,5-trimethylfuran, 2-phenoxyfuran, Z-nitrofuran, Z-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 be employed in the above reaction in place of the thiophenes and furans exemplified above. Representative members of this class include:

2-fiuorocyclopenta(2,4)-dienyl; 3-methylcyclopenta(2,4)-

dienyl; and, ethoxycyclopenta(2,4)-dienyl.

6 EXAMPLE 2 Preparation of 5-fluoro-2-thienyl-4'-hydroxyphenyl sulfone To a solution of 5-fluoro-2-thienyl 4'-hydroxyphenyl sulfide (0.1 m.) in 1:1 acetic and acid-acetone is added a 3% aqueous solution of potassium permanganate (20% 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-fiuoro-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; (Z-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: S-chloro-Z- thienyl 4-hydroxyphenyl sulfone; 2-thienyl 4-hydroxyphenyl sulfone; 5-methyl-2-thienyl-4'-hydroxyphenyl sulfone; 5-chloro-2-thienyl 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, excess is used to account for oxidation of both sulfur atoms.

EXAMPLE 3 Preparation of p-benzoyloxy-N-(Z-thienyl)-acetanilide A mixture of 2-acetamin0thiophene (10 g.), finely powdered potassium carbonate (5 g.), benzyl p-iodophenyl ether (20 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 (10-100% ether-petroleum ether) to yield pbenzyloxy-N-(2-thienyl)-acetanilide.

It should be noted that S-substituted Z-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-bromothiophene (0.15 m.); p-benzyloxyphenol (0.18 m.), powered anhydrous potassium carbonate (6.9 g.) and copper bronze (0.2 g.) is heated at 210 C. for two hours, cooled, excess alkali added, the mixture extracted well with ether and benzene, the combined extracts dried well over anhydrous magnesium sulfate, filtered and concentrated. Distillation under reduced pressure-or chromatography (silica gel using an etherpetroleum ether system) yields p-benzyloxyphenyl 2-thienyl ether.

The above reaction is not only applicable to the substituted thiophenes of this invention containing a 2-bromo group, but may be employed utilizing halo furans and pyrroles. It should be noted that m-benzyloxyphenol is used in place of p-benzyloxyphenol when ultimately a 4- substituted salicylic acid is desired.

7 EXAMPLE Preparation of p-hydroxy-N-(2-thienyl)acetanilide A mixture of p-benzyloxy-N-(2-thienyl)-acetani1ide (0.01 m.), 5% 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-(Z-thienyl) acetanilide.

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 aqueous sodium hydroxide is added to hydrolyze the complex. The mixture is then acidified with 2% 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 2-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'-fluoro-2-thienylsulfonyl) salicyclic acid An intimately ground mixture of 2- fiuoro-5(p-hydroxyphenyl)thiophene (5 g.) and anhydrous potassium carbonate g.) is heated at 100 in a 1200-1400 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 Examples 1, 2, 5, and 6 are used in the above procedure, the corresponding salicylic acid is obtained.

A representative list of salicyclic acids are as follows:

5-(2-pheny1-5'-cyclopenta(2,4) dienyl-thio-salicylic acid 5-(5'-fluoro 2'-cyclopenta(2,4)dienylsulfinyl)salicylic acid 5-(2'-mercapto-4-cyclopenta(2,4) dienyl sulfinyl)-salicylic acid 5 (5'-fluoro-4'-thienylsulfinyl)-salicylic acid 4( 3-methyl-5'-thienylsulfinyl) salicylic acid 4(2-methoxy-5'-thienylsulfonyl)salicylic acid N-(5'-mercapto-2-thienyl)-3-carboxy-4-hydroxyacetanilide N-(4'-methyl-2-furyl)-3-carboxy 4-hydroxyacetanilide 5-(5-fiuoro-2'-thienylsulfonyl) -salicylic acid 5-(5'-methyl-2'-furylsulfonyl)-salicylic acid 5-(5-chloro-2'-thienylthio)-salicylic acid 5-(1'-(2',4-cyclopentadienyl)-thio)-sa1icylic acid 3-carboxy-4-hydroxy-N-(2'-( 1-methylpyrryl)-acetanilide 4-(5'-fluoro-2'-thienyloxy)-salicylic acid 5-(5-trifluoromethy1-2-thienylthio)-salicylic acid 4-carboxyl-3-hydroxy-N-(3-thienyl)-acetanilide 5-(5'-methylsulfonyl-2-thienylsulfonyl)-salicylic acid 5-(5-fluoro-2-thienyloxy)-salicylic acid 3-carboxy-4-hydroxy-N-(Z-thienyl)-acetanilide 8 EXAMPLE 8 Preparation of methyl 5-(5'-cyano-2-thienylthio) salicylate A mixture of methyl 5-(5'-bromo-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 hrs., 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 systems as eluant (v./v. 580% ether) to yield methyl(5-5'-cyano-2'-thienylthio)salicylate.

EXAMPLE 9 Preparation of 5-(5-fluoro-2'-thienylsulfinyl)- salicyclic acid A stirred mixture of 5-(5'-fluoro-2'-thienylmercapto)- 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'-fiuoro-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 S-(5'-methylthiothienyloxy)-, 5-(5'-methylthiothienylthio)-, 5 (5-methylthiothienylthio-, 5 (5- methylthiofuryloxy)-, 4-(5'-methylthiofurylthio) -salicylic acids, etc., are oxidized as above, the corresponding methylsulfinyl analogs are obtained. With those containing two oxidizable groups, e.g. 5-(5'-methylthiothienylthio)-salicylic acid, two equivalents of sodium metaperiodate are needed.

EXAMPLE 10 Preparation of methyl 2-acetoxy-5(5'-ibromomethyl- 2'-thienyloxy)-benzoate A mixture of methyl 2-acetoxy-5(5'-methyl-2'-thienyloxy)benzoate (0.05 m.), N-bromosuccinimide (0.05 m.), carbon tetrachloride (500 ml.) and dibenzoyl peroxide (0.002 m.) is refluxed gently for 3 hrs. and cooled. The succinimide is removed by filtration, and the solvent removed in vacuo to yield methyl 2-acetoxy-5(5'-bromomethyl-2-thienyloxy) benzoate.

It will be appreciated by the skilled artisans that substituted furans may be employed in the practice of the above process in place of the thiophene moiety.

EXAMPLE 11 Preparation of methyl 5-(5-hydroxymethyl 2'-thienyloxy)salicylate A mixture of methyl 2-acet'oxy-5-(5'-bromomethyl-2- thienyloxy)benzoate (0.01 m.), silver acetate (0.01 m.) and acetic acid (30 ml.) is heated gently for three hours, cooled, filtered, and the filtrate concentrated in vacuo to a residue of crude methyl 2-acetoxy-5-(S-acetoxymethylthienyloxy)-benzoate. Anhydrous methanol (50 ml.) and p-toluene sulfuric acid (0.1 g.) is added and the mixture heated for three hours, concentrated, distributed between water-chloroform, the chloroform layer dried, concentrated, and the contents chromatographed on a silica gel column using an ether-petroleum ether system (v./v. 0100% 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.

9 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-2'-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 Z-acetoxy-S(5'-bromomethyl 2 thienylsulfonyl 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 one 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 ether-petroleum ether system (v./ v. 80% ether) as eluant to yield methyl 5-methoxymethyl-2'-thienylsulfonyl) -salicyl ate.

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

EXlAMPLE 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'-thienylsulfony1)-silicylate 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-l1ydroxy-acetanilide To a mixture of N-(5'-carbomethoxy-2'-thienyl)-3- carboxy-4-hydroxy-acetanilide (0.01 m.) and methanol (100 ml.) is added with stirring sodium hydroxide (0.06 m.) and water (15 ml.). The resulting 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- 4hydroxy-acetanilide collected.

EXAMPLE 16 Preparation of Z-acetoxy-S-(5'-chloro-2'-thienylsulfonyl)benzoic acid To a mixture of 5-(5'-chloro-2-thienylsulfonyl)salicylic acid (0.04 m.) in anhydrous pyridine (15 ml.) is added acetic anhydride (28 ml.) and the resultant mixture heated on the steam cone for 1.5 hrs. The mixture is kept free from moisture during this time. On cooling, the mixture is added to a stirred 500 ml. portion of water. The aqueous system is then extracted well with chloroform, the chloroform extracts washed with 1 N hydrochloric acid, water, and then dried over anhydrous magnesium sulfate. Concentration of the filtered solution yieIdsZ-acetOxy-S- (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.

10 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 methyl chloroformate (0.011 In.) over one hour with constant shaking and cooling. When the odor of the chlorocarbonate is essentially absent, hydrochloric acid (1 N, 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- (5'-fiuorothienylthio)-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- fiuorothiophene (0.01 m.) in 2 N sodium hydroxide solution at 70 is added dimethyl sulfate (0.10 m.) in small portions over ten hours, the mixture being kept basic throughout the addition. Water is added, the mixture filtered, the filtrate acidified and 2(3'-carbox y-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'-thienylsulfonyl)-benzoate Diazomethane in methylene chloride is added to an ice cooled mixture of Z-acetoxy-S-(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-actoxy- 5- 5'-fiuoro-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, 16, 17 and 18 are treated thusly, the corresponding esters are obtained.

EXAMPLE 20 Preparation of methyl 5(5'-fluoro-5-thienylsulfonyl)- salicylate 5-(2-fiuoro-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 partitioned 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'-fiuoro-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-S-(5'-fluoro-2'-furylsulfonyl)- salicylate To a mixture of polyphosphate esters (PLP.E.) chloroform is added one equivalent each of 5-(5-fluoro-2'- fury1sulfonyl)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 dried, filtered and evaporated in vacuo to yield phenyl (5fiuoro-2-furylsulfon-yl salicylate.

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'-fiuoro-2'-thienylsulfonyl) salicylate (0.1 m.); aniline (0.1 m.) and l-methylnaph' thalene (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 min., filtered hot, and cooled. The collected anilide is then recrystallized yielding pure 5(5'-fiuoro-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 six 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-furylsulfo- 11yl)salicylate and 125 ml. of 2.5 M sodium methoxide in absolute methanol is heated for 30 min. 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 equiv.) in water are mixed, heated for solution, filtered, and the filtrate concentrated in vacuo to obtain sodium 3-carboxy-4-hydroxy-N-(2-(1-methylpyrryl)acetanilide.

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

When two equivalents of the above bases are used, the corresponding disodioand dipotaSsio-salts are obtained.

EXAMPLE 26 Preparation of diethylaminoethanol salt of 5-(l'-2'4-cyclopentadienyl)-thio)-salicylic acid N,N-diethylethanolamine (0.001 m.) in ether (5 ml.) is added to a stirred solution of 5-(l'-(24'-cyclopentadien- 4 3 X {B g- A 3. wherein A is S, S0 or S0 Y is S, R2 is H, R is H,

X is H or halogen, and R is hydroxy,

with the proviso that the OR; group and the 0 II 1-C-R group are always ortho to one another.

2. The method of claim 1 wherein the compound is 5- 5 -fiuoro-4-thienylsulfinyl salicylic acid.

3. A pharmaceutical preparation in dosage unit form adapted for administration to obtain an antiinflammatory effect, comprising a pharmaceutical diluent and, per dosage unit, an antiinflammatory effective non-toxic amount within the range from about 50 to about 7,000 milligrams of a compound of structural formula:

wherein A is S, S0 or S0 Y is S,

R2 is H,

R3 iS H,

X is H or halogen, and

R is hydroxy,

with the proviso that the -OR group and the 0 ll -c-R1" group are always ortho to one another.

4. A pharmaceutical preparation in accordance with claim 3 in a form adapted for oral administration.

No references cited STANLEY J. FRIEDMAN, Primary Examiner U.S. Cl. X.R.

424230, 248, 274, 275, 285, 300, 304, 308, 317, 325; 260-247.1, 247.2 B, 247.5 R, 247.7 H, 332.2 A, 347.3, 347.4, 465, 469, 470, 471, 473, 476, 478, 515, 516, 518, 520, 559 S, 559 H UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIQN Patent No. 3,657,432 Dated April 18, 1972 Inventofls) 'Ifsung-Ying Shen et a1.

It is certified that error appears in the above-identified patent and that said Letters Patent} are hereby corrected as shown below:

In column 2, line 10, the word "methylsulfony" should be --methylsulfonyl--; v V v In column 2, line 25, the word "ca'rbomethyl" should be -carbomethoxy---;

In column 3, line 60, the right hand ring of the structure should read Q 0H In column 5, line 30, from left he w COOHII In column 7, line 60,the number "4" should be --5---;

hiensulf'onyl) should nd formula, delete and In column 9, line 30, the word "t be -thienylsulfonyl) Signed and sealed this 26th day of September 1972.

(SEAL) Attest ROBERT GOTTSCHALK Commissioner of Patents EDWARD M.FLE'I'CHER,JR. Attesting Officer