US3674844A

US3674844A - Salicylic acid derivatives

Info

Publication number: US3674844A
Application number: US30322A
Authority: US
Inventors: Tsung-Ying Shen; Howard Jones; Bruce E Witzel; Gordon L Walford
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1970-04-20
Filing date: 1970-04-20
Publication date: 1972-07-04
Anticipated expiration: 1989-07-04

Abstract

New substituted salicylic acids and non-toxic pharmaceutically acceptable salts, esters, and amides derived therefrom. The substituted salicylic acids described herein are useful as antiinflammatory compounds. Also included herein are methods of preparing said salicylic acid compounds, pharmaceutical compositions having said salicylic acid compounds as an active ingredient and methods of treating inflammation by administering these particular compositions to patients.

Description

United States Patent Shen et al. 451 J l 4, 1972 SALICYLIC ACID DERIVATIVES [5 References Cited [72] Inventors: Tsung-Ying Shen, Westfield; Howard OTHER PUBLICATIONS Jones, Matawan; Bruce E. Witzel; Gordon Final. L or gamc Chemistry, Vol. I, (1963), Pub. by bah fwestfiel Richard clay Co., London (QD251F6), pp. 191, 571, 567 & [73] Assignee'. Merck & Co., Inc., Rahway, NJ. 65 Cited- [22] Flled: Apnl 1970 Primary ExaminerLorraine A. Weinberger Assistant ExaminerL. Arnold Thaxton [2!] Appl. No.: 30,322 AttorneyMichel C. Sudol, Jr., Harry E. Westlake, Jr. and l.

Louis Wolk Related [1.8. Application Data [63] Continuation-impart of Ser. No. 836,623, June 25, ABSTRACT 1969 New substituted salicylic acids and non-toxic pharmaceuti- [52] USCL I I 4 r 260/519 260/247 5 R 260/293 73 cally acceptable salts, esters. and amides derived therefrom. 260/32655 6 9 ,4 The substituted salicylic acids described herein are useful as 2 0 4 5 D, 2 0 470 2 0 71 26Q/472J60/479' anti-inflammatory compounds. Also included herein are n 260/55 5, 260/559 T,424/248, methods of preparing said salicylic acid compounds, phar- 424/267, 424/274, 424/304, 424/310, 424/319 maceutical compositions having said salicylic acid compounds [51] Int.- Cl ..C07c 103/30 as an active ingredient and methods of treating inflammation [58] Field of Search --260/5 47l R, 479 R by administering these particular compositions to patients.

8 Claims, No Drawings SALICYLIC ACID mznrwmvss CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of our co-pending U. S. application Ser. No. 836,623 filed June 25, 1969.

BACKGROUND OF THE INVENTION The development of anti-inflammatory compounds in the past two decades has seen the growth of a great many new drugs. Most of these have been steroids of ll-oxygenated pregnane series. These, while highly effective, have the drawback of causing many side effects. There is a need in the market for equally effective compounds of much simpler structure and having less side effects.

SUMMARY OF THE INVENTION Generally, this invention relates to new substituted salicylic acid compounds and processes for producing the same. This invention also relates to pharmaceutical compositions containing said salicylic acid compounds as an active ingredient and to methods of treating inflammation by administering these particular compositions to patients. In addition, some of them have a useful degree of anti-pyretic, analgesic, diuretic, anti-fibrinolytic and hypo-glycemic activity.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to new substituted salicylic acids and processes for producing the same. More specifically, this invention relates to substituted salicylic acids, esters, amides, anhydrides and non-toxic pharmaceutically acceptable salts thereof. Still more specifically, this invention relates to compounds having the following general formula:

(X) (b) a boloweralkoxyphenoxy), phenylamino, hydrazino, morpholino, N-piperidino, pyrrolidino, or hydroxyloweralkylamino;

R may be hydrogen, acyl (preferably loweracyl such as formyl, acetyl, propionyl, butyryl, etc.), alkyl (preferably loweralkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), or alkoxy carbonyl (preferably loweralkoxy carbonyl such as methoxy carbonyl, ethoxy carbonyl, hexoxy carbonyl, 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 loweralkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl), or alkoxy (preferably loweralkoxy such as methoxy, ethoxy, isopropoxy or butoxy);

X may be hydrogen, alkyl, (preferably loweralkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), hydroxy, alkoxy (preferably loweralkoxy such as methoxy, acetoxy, isopropoxy or butoxy), acyloxy (such as benzoyloxyacetoxy 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 loweralkylmercapto such as methylmercapto, ethylmercapto, etc.), alkylsulfinyl (preferably loweralkylsulfinyl such as methylsulfinyl, ethylsulfinyl, butylsulfinyl, etc.), alkylsulfonyl, (preferably loweralkylsulfonyl such as methyl sulfonyl, ethylsulfonyl, butylsulfonyl, etc. sulfonamido, sulfonylamido, alkylaminoalkyl (preferably loweralkylaminoloweralkyl such as methylaminomethyl, ethylaminomethyl, etc.), dialkylaminoalkyl (preferably diloweralkylaminoloweralkyl such as dirnethylaminomethyl, diethylaminoethyl, etc.), hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.), alkoxyalkyl (preferably loweralkoxyloweralkyl such as methox ymethyl, methoxyethyl, ethoxyethyl, ethoxypropyl, etc.), mercaptoalkyl (preferably mercaptoloweralkyl such as mercaptomethyl, mercaptoethyl, etc.), alkylmercaptoalkyl (preferably loweralkylmercaptoloweralkyl such as methylmercaptomethyl, ethylmercaptoethyl, ethylmercaptopropyl, etc.), cyano, carboxy, carboalkoxy (carbomethoxy, carboethoxy, etc.), carbamoyl, aryl (such as phenyl, halophenyl, tolyl, salicyl), aralkyl such as benzyl, phenethyl, etc., aryloxy or arylalkoxy;

Y may be methyleneimino (CH NH-), iminomethylene (NHCH methylidenenitrilo (CH N--), nitrilomethylidene, (N Cl-l), carbonylimino O P H,

or iminocarbonyl I (NH-JP-N provided that the OR group is always ortho to the group.

Representative compounds of this invention are as follows: 4-(p, 0, or m-fluorobenzylideneamino)-salicylic acid;

5-(p, 0, or m-fluorobenzylideneamino)-salicylic acid;

4-(p, 0, or m-fluorobenzylamino)-sa1icylic acid;

5-(p, 0, or m-fluorobenzylamino)-salicylic acid;

4-( p, 0, or m-fluorobenzamido )-salicylic acid;

5(p, 0, or m-fluorobenzamido )-salicylic acid;

4-(p, 0, or m-fluoroanilinomethyl)-salicylic acid;

S-(p, 0, or m-fluoroanilinomethyD-salicylic acid;

4-(p, 0, or m-fluorophenyliminomethyl)-salicylic acid;

5-( p, 0, or m-fluorophenyliminomethyl)-sa]icylic acid; and the corresponding salts, esters, anhydrides and amides.

This invention also relates to a method of treating inflammation in patients using a compound of Formula I, particu- 7 larly an especially preferred compound as the active constituent.

The compounds of the instant invention can be used to treat inflammation by reducing inflammation and relieving pain in such diseases as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever. Furthermore, the compounds of the instant invention have better potency at the same dosage levels than similar type compounds known in the prior art and exhibit a lower incidence of side effects.

The compounds of Formula I also have anti-pyretic, analgesic, diuretic, anti-fibrinolytic and hypo-glycemic activity and would be administered and used in the same manner and in the same dosage ranges as if they were being used to treat inflammation as discussed further on.

The treatment of inflammation in accordance with the method of the present invention is accomplished by orally, rectally or parenterally administering to patients a composition of a compound of Formula I, particularly the especially preferred compounds in a non-toxic pharmaceutically acceptable carrier.

The non-toxic pharmaceutical carrier may be, for example, either a solid or a liquid. 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 for rectal administration and gels, lotions, etc. for topical application may be prepared in a conventional manner.

The active compounds of Formula I and of the compositions of this invention are administered in an amount sufficient to treat inflammation, that is to reduce inflammation. Advantageously, the composition will contain the active ingredient, namely, the compounds of Formula I 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 50mg./kg. body weight per day (100 mg. to 3 g. per patient per day).

The method of treatment of this invention comprises administering to a patient (animal or human), a compound of Formula I, particularly an especially preferred compound admixed with a non-toxic pharmaceutical carrier such as exemplified above. The compounds of Formula I and particularly the especially preferred compounds 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 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./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 medicinal agents, particularly those 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 benzalaminosalicylic acids of this invention may be prepared by reacting an aminosalicylic acid with a substituted benzaldehyde.

The benzalaminosalicylic acid compounds may then be reduced to form the substituted benzylaminosalicylic acid compounds of this invention. The benzylaminosalicylic acid compounds may also be prepared via direct benzylation of sodium (or potassium) salicylate in ethanol containing anhydrous potassium carbonate.

The anilinomethylsalicylic acid compounds of this invention may be prepared by reacting a halo-methylsalicylic acid with a substituted aniline. They may also be produced by reacting a methyl halogen substituted methylsalicylate with a substituted aniline and hydrolyzing the resultant methyl anilinomethylsalicylate.

The benzarnidosalicylic acid compounds of this invention may be prepared by reducing a 4 (or 5) nitro methylanisole to form an amino methyl anisole, reacting the amino methylanisole with a substituted benzoylhalide to form a benzarnidoanisole, demethylating said benzamidoanisole to form a benzamidophenol and carboxylating said benzamidophenol, or via direct benzoylation of an aminosalicylic acid.

The phenylirninomethylsalicylic acid compounds of this invention may be produced by reacting 4 (or 5 )-formyl salicylic acid with a substituted aniline.

The compounds of this invention, where R is a group such that an ester is the final compounds, (i.e. R=alkoxy), are prepared by any esterification procedure using an esterifying agent containing the appropriate R group. For example, the acid compounds of this invention may be reacted with the appropriate loweralkanol (preferably methanol) at elevated temperatures in the presence of a strong acid, such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and the like, to form the desired ester.

The compounds of this invention, wherein R is a group such that an amide is the final compound (i.e., R is amino), may be prepared by any suitable amidation reaction. For example, the acid compound (preferably the methyl or ethyl ester) may be reacted with ammonia, ammonium hydroxide, or an amide compound, at any suitable temperature (room temperature to reflux). When the amino group is desired, it is preferred to carry out the reaction with ammonia in a bomb at temperatures about C. to form the desired R (amino) compound. Preferably, when an amide is desired which is derived from an amino acid, the following reaction sequence is followed: The benzoic acid final compound is reacted with isobutyl chlorocarbonate to form the mixed anhydride. This compound is in turn reacted with the desired amino acid ester and subsequently hydrolyzed to form the desired amide.

The final compound, wherein R is loweralkyl (preferably methyl), may be prepared by any appropriate alkylation reaction. For example, the corresponding hydroxy benzoic acid, ester, or amide (preferably the ester), may be reacted with a di(loweralkyl)sulfate (preferably dimethyl sulfate) in the presence of a base (such as alkali carbonate) at any suitable temperature (room temperature to reflux but preferably at or near reflux) with subsequent acidification of the reaction mixture, such as with hydrochloric acid, sulfuric acid, and the like, to form the desired R compound.

The salts of the final acid compounds of this invention may be prepared by any of the well-known metathesis procedures. For example, the acid compound may be reacted with an inorganic base, such as sodium hydroxide, and the like. The anhydrides of this invention may be prepared by any of the wellknown procedures in the art.

The following examples are presented to further illustrate the invention:

EXAMPLE 1 5-(p-fluorobenzoylamino)-salicylic acid To methyl S-aminosalicylate (0.01 m.) in pyridine at 10 C. is added p-fluorobenzoyl chloride (0.01 m.), stirrings, over 10 minutes. The resulting mixture is allowed to warm to room temperature, stir overnight, added to excess dilute hydrochloric acid, stirring, and the methyl 5-(p-fluorobenzoylamid-salicylate collected and hydrolyzed under standard conditions to yield 5-(p-fluorobenzoylamino)-salcylic acid, m.p. 280-28 1 When other substituted benzoyl chlorides, e.g. with ofluoro, m-fluoro, 0-, m-, and p-chloro, o, m-, and p-methoxy, o-, m-, and p-trifluoromethyl, o-, m-, and p-nitro, o, mand pdimethylamino (or hydrochlorides), o-, m, and p-acetamido, o-, m-, and p-methylmercapto, o-, mand p-carbomethoxy, o-,

mand p-phenyl, o-, m-, and p-benzyl, mand p-phenoxy, o-, mand p-benzyloxy or o-, mand p-acetyl benzoyl chloride are used, the corresponding substituted S-benzamidosalicylate is obtained.

When the 3-c'hloro, 3-methoxy, 3-methyl, and 4-iluoro analogs of -aminosalicylate are used in the above example in place of methyl 5-aminosalicylate, the corresponding substituted salicylates are obtained. When methyl 4-amino analogs are used in the above procedure the corresponding substituted salicylates are obtained.

The above benzoylations may be carried out by other means known to those in the art, such as addition of the benzoyl halide to an aqueous, nitrogen covered solution of a metal salt, such as sodium or potassium, of the salicylic acid with concomittant addition of base to maintain the pH of the reaction mixture at 8. Only those benzoyl halides with groups compatible with aqueous hydroxide are used in this procedure.

EXAMPLE 2 5-( p-fluorobenzylideneamino)-salicylic acid A mixture of S-aminosalicylic acid (0.005 m.) and pfluorobenzaldehyde (0.005 m.) in ethanol 150 ml.) is heated, protected from moisture, for 5 hours, concentrated and cooled, and the 5-(p-fiuorobenzylideneamino)-salicylic acid collected.

A trace of p-toluene sulfonic acid may be employed as a catalyst in the above reaction.

When o-, and m-fluorobenzaldehyde, o-, mand pchlorobenzaldehyde, o-, m-, and p-methylbenzaldehyde, pdimethylaminobenzaldehyde, o, m and p-trifluoromethylbenzaldehyde, p-acetamidobenzaldehyde, o-, m-, and pmethylthiobenzaldehyde, p-cyanobenzaldehyde, mand pbenzyloxybenzaldehyde, biphenylcarboxaldehyde, benzylbenzaldehyde, p-phenoxybenzaldehyde, p-acetylbenzaldehyde, p-methylsulfonylbenzaldehyde, dichlorobenzaldehyde, trichlorobenzaldehyde, 2,3,4,5-tetramethylbenzaldehyde, or p-carbomethoxybenzaldehyde are used in place of p-fluorobenzaldehyde in the above procedure, the corresponding substituted benzalaminosalicylic acids are obtained.

When the 3-chloro, 3-methoxy, 3-methyl, or 4-fluoro analogs of S-aminosalicylic acid are used in place of 5- aminosalicylic acid in the above example, the corresponding substituted salicylic acids are obtained.

When 4-aminosalicylic acid and its analogs are used in place of S-aminosalicylic acid in the above procedure, the corresponding substituted salicylic acids are obtained.

EXAMPLE 3 5-(p-fluorobenzylamino)-salicylic acid A mixture of 5-(p-fluorobenzylideneamino)-salicylic acid (0.01 m.), ethanol (50 ml.) and 5% palladium on charcoal (0.5 g.) is reacted in a 40 p.s.i. hydrogen atmosphere at room temperature until 0.01 m. hydrogen has been absorbed, the mixture filtered, the cake washed well with ethanol, the filtrates combined and concentrated in vacuo to 5-(pfluorobenzylamino)-salicylic acid.

The above reduction may be achieved using metal hydrides as the reducing agent.

The above product may also be obtained via direct pfluorobenzylation of sodium (or potassium) S-amino-salicylate in ethanol containing anhydrous potassium carbonate.

When the substituted benzylideneamino compounds of Example 2 which are compatible with the reduction conditions are treated with hydrogen as above, the corresponding substituted S-benzylaminosalicylic acids are obtained.

EXAMPLE 4 5-(p-fluoroanilinomethyl)-salicylic acid A mixture of methyl 5-chloromethylsalicylate (0.01 m.), and p-fluoroaniline (0.01 m.) in methanol (25 ml.) containing anhydrous potassium carbonate is heated for 8 hours, cooled,

filtered, the cake washed well with fresh methanol, the combined filtrates concentrated in vacuo, the residue taken up in chloroform, dried, filtered, the chloroform removed in vacuo, and the residue chromatographed on a silica gel column using an ether-petroleum ether system (v/v l0-l00% ether) as eluant yielding methyl S-(p-fluoroanilinomethyl)-salicylate. Hydrolysis of the ester yields 5-)p-fluoroanilinomethyl)-salicylic acid.

When o-, and m-fluoroaniline, the toluidines, the anisidines, o-, mand p-chloroaniline, the trifluoromethylanilines, o-, m and p-nitroaniline, o-, mand p-methylthioaniline, methyl paminobenzoate, the biphenylamines, p-benzylaniline, 4- aminophenyl ether, and 4-benzyloxyaniline are used in place of p-fluoroaniline in the above reaction, the corresponding 5- (anilinomethyl)-salicylate is obtained.

EXAMPLE 5A 3-trifluoromethyl-4-nitroanisole A stainless steel lined shaker is charged with 6-nitro-manisic acid (0.1 in.) under a nitrogen atmosphere, the system cooled in dry ice, sulfur tetrafluoride (0.5 m.) condensed into the tube, and the mixture then heated at C. for 8 hours. After cooling, the tube is vented, the material taken up in chloroform, the chloroform mixture washed with dilute bicarbonate solution, the chloroform dried, filtered, concentrated in vacuo, and the residue chromatographed on a silica gel column using an ether-petroleum ether system (v/v 080% ether) as eluant to yield 3-trifluoromethyl-4-nitroanisole.

EXAMPLE 5B 4-(p-fluorobenzamido)-3-trifluoromethylanisole A mixture of 4-nitro-3-trifluoromethylanisole (0.1 m.), and 5% palladium on charcoal catalyst (2 g.) in ethanol (500 ml.) is reacted with hydrogen (40 p.s.i.) at room temperature. When hydrogen uptake has stopped, the mixture is filtered, the ethanol removed in vacuo, anhydrous pyridine (300 ml.) added, and the resulting mixture treated with p-fluorobenzoyl chloride as per Example 1, 4-(p-fluorobenzamido )-3- trifluoromethylanisole is obtained.

When the substituted benzoylhalides of Example 1 are used in place of p-tluorobenzoyl chloride in Example 6, above, the correspondingly substituted benzamidoanisole is obtained.

When the free amino compound obtained above is benzylated with substituted benzylhalides as in Example 3, or using pyridine as the solvent base, the correspondingly substituted benzylamino anisole is obtained.

EXAMPLE 5C p-(4-fluorobenzamido)-m-trifiuoromethylphenol A mixture of p-(4-fluorobenzamido)-mtrifluoromethylanisole (5g.) and pyridine hydrochloride (25 g.) under a dry nitrogen atmosphere is placed in an oil bath set at 230, kept 10 minutes, cooled, and the mixture extracted with chloroform. The chloroform extracts are washed with water, dried, concentrated in vacuo, and the residue chromatographed on a silica gel column using a methanolmethylene chloride (v/v 0-50% methanol) system as eluant to yield p-( 4-fiuorobenzamido)-m-trifluoromethylphenol.

When the other substituted benzamido and substituted benzylaminoanisoles of Example 513, and 4-amino-3- trifluoromethylanisole from Example 5B are reacted with pyridine hydrochloride as above, the corresponding phenols are obtained. Other standard procedures for demethylation may also be employed.

EXAMPLE 5D S-(p-fluorobenzamido )-4-trifluoromethylsalicylic acid An intimately ground mixture of p-(4-fluorobenzamido )-3- trifluoromethylphenol (5 g.) and anhydrous potassium carbonate 15 g.) is heated at 200 C. in a l,200-l,400 p.s.i. carbon dioxide atmosphere for 8 hours. The mixture is cooled,

added to water (300 ml.), stirred, filtered, and the filtrate neutralized with dilute hydrochloric acid to yield -(pfluorobenzamido)-4-trifluoromethylsalicylic acid.

When the phenols of Example 5C are reacted with carbon dioxide as above, the correspondingly substituted salicylic acids are obtained.

EXAMPLE 6 S-(p-fiuorobenzylidenearnino )-4-trifluoromethyl salicylic acid When 5-amino-4-trifluoromethylsalicylic acid is reacted with p-fluorobenzaldehyde as per Example 2, 5-(pfluorobenzylideneamino)-4-trifluoromethyl salicylic acid is obtained.

When the benzaldehydes of Example 2 are used in place of p-fluorobenzaldehyde in the above case, the correspondingly substituted 5-benzylideneaminosalicylic acid is obtained.

EXAMPLE 7 Methyl 5(p-hydroxybenzylamino )-salicylate When methyl 5-(p-methoxybenzylamino)-salicylate is reacted with pyridine hydrochloride as per Example 5C, methyl 5(p-hydroxybenzylamino)-salicy1ate is obtained.

EXAMPLE 8 Methyl S-(p-mercaptobenzamido)-salicylate When methyl 5-(p-methylthiobenzamido)-salicylate is reacted with pyridine hydrochloride as per Example 5C, methyl S-(p-mercaptobenzamido )-salicylate is obtained.

EXAMPLE 9 Methyl-5-(p-aminobenzamidosalicylate) When methyl 5-(p-nitrobenzamido)-salicylate in methanol is reacted with hydrogen as per the reduction conditions of Example 58 methyl 5-(p-aminobenzamidosalicyalte is obtained.

When the nitro compounds of Examples 1 and 3 are used in the above process, the corresponding amino substituted compounds are obtained.

EXAMPLE 10 5-(p-methylthiobenzamido)-salicy1ic acid To 5-(p-methylthiobenzamido)salicylic acid (0.01 M.) in 1:1 methanol-acetone, ice-cooling and stirring, is added sodium metaperiodate (0.01 m.) in a minimum of water, and the reaction mixture stirred until precipitation of sodium iodate is completed. The mixture is filtered, the filtrate concentrated in vacuo, the residue taken up in chloroform, filtered and concentrated in vacuo to crude 5-(p-methylsulfinylbenzamido)- salicylic acid.

When two equivalents of metaperiodate are used and the reaction carried out at ca. 50 C., S-(p-methylsulfonylbenzamido)-salicylic acid is obtained.

When the methylmercapto compounds of Examples 2 and 3 are oxidized as above, the corresponding methylsulfinyl and methylsulfonyl analogs are obtained.

EXAMPLE 1 l 5-(p-carboxybenzylaminosalicylic acid To a solution of potassium hydroxide (0.05 m.) in water (100 ml.) is added 5-(p-carbomethoxybenzylamino)-salicylic acid (0.01 m.), stirring, and the resultant mixture heated gently for solution, allowed to stir at room temperature for 5 hours, filtered, the pH of the filtrate adjusted with dilute hydrochloric acid, and the S-(p-carboxybenzylamino) salicylic acid collected.

EXAMPLE 12 5-(p-carbamylbenzylamino)-salicylate To a mixture of methyl 5-(p-cyanobenzylamino)-salicylate (2 g.) in methylene chloride (25 ml.), stirring, is added manganese dioxide (12 g.) and the mixture stirred for hours at room temperature. The mixture is filtered, the cake washed well with warm methylene chloride, the filtrates concentrated in vacuo to a residue, the residue chromatographed on a silica gel column using a methanol-methylene chloride system (v/v 0-80% methanol) as eluant to yield methyl S-(p-carbamylbenzylamino)-salicylate.

The nitn'le may also be converted to the amide using concentrated sulfuric acid in the cold.

EXAMPLE 13 Methyl 5 -(p-fluorobenzamido )-o-anisate When methyl S-amino-o-anisate is reacted with pfluorobenzoyl chloride as per the procedure of Example 1, methyl 5-(p-fluorobenzarnido)-o-anisate is obtained.

When the other benzoylhalides of Example 1 are used in place of p-fluorobenzoyl chloride in the above reaction, the correspondingly substituted analog is obtained.

When methyl S-amino-o-anisate is reacted with the aldehydes of Example 2 using the procedure of Example 2, the corresponding benzylideneaminoanisic acid derivatives are obtained.

When the benzylideneaminoanisic acid derivatives are reduced following the procedure of Example 3, the corresponding benzylaminoanisic acid derivatives are prepared.

EXAMPLE l4 2-Acetoxy-5-(N-acetyl-p-acetoxybenzylamino)-benzoic acid To a solution of 5-(p-hydroxybenzylamino)-sa1icy1ic acid (2 g.) in pyridine (15 ml.) is added acetic anhydride (28 ml.) and the resultant mixture heated on the steam cone for 5 hours, protected from moisture. On cooling, the mixture is added to water (300 ml.) with stirring, the aqueous system extracted well with chloroform, the chloroform layer washed with dilute hydrochloric acid, water, dried over magnesium sulfate, filtered and concentrated in vacuo to 2-acetoxy-5-(N-acetyl-pacetoxybenzylamino)-benzoic acid.

EXAMPLE 15A m-Methoxymethylbenzoic acid m-Carbomethoxybenzylbromide (0.02 m.) is added to sodium methoxide (0.04 m.) in methanol and the mixture heated gently for several hours. Water is added, the mixture heated to boil away methanol, filtered and acidified with dilute hydrochloric acid to yield m-methoxymethylbenzoic acid.

When potassium methylmercaptide is used in place of sodium methoxide in the above reaction, m-methylthiomethylbenzoic acid is obtained.

When m-carbomethoxybenzyl bromide is reacted with sodium benzylate or potassium benzylmercaptide, and the product hydrolyzed as above, m-benzyloxymethyland mbenzylthiomethylbenzoic acids are obtained.

EXAMPLE 15B 5-(m-Methoxymethylbenzamido)-salicylic acid m-Methoxymethylbenzoic acid (2 g.) is added gradually to stirred thionyl chloride (20 ml.), heated gently until reaction ceases, and the excess thionyl chloride removed in vacuo. Anhydrous benzene (30 ml.) is added, and then removed in vacuo to get rid of traces of thionyl chloride. The residual mmethoxymethylbenzoyl chloride is used as is in the reaction with 5-aminosalicylic acid, via the procedure of Example 1, to yield 5-(m-methoxymethylbenzamido)-salicylic acid.

When m-methylthiomethylbenzoic acid, m-benzyloxymethylbenzoic acid, and m-benzylthiomethylbenzoic acid of Example 18 are used in place of m-methoxymethylbenzoic acid, above, 5-(m-methylthiomethylbenzamido) salicylic acid, 5-(m-benzyloxymethylbenzamido)-salicy1ic acid, and 5-(mbenzylthiomethylbenzarnido)-salicylic acid are obtained, respectively.

Phosphorous pentachloride in phosphorous oxychloride may be used in place of thionyl chloride in the above reaction.

EXAMPLE 16 EXAMPLE l7 Methyl 5-(p-aminomethylbenzylamino)-salicylate dihydrochloride Methyl 5-(p-cyanobenzylamino)-salicylate (0.01 m.) in acetic acid (100 ml.) is reduced at room temperature under a 40 psi. hydrogen atmosphere, using 0.5 g. platinum oxide as a catalyst. When the theoretical amount of hydrogen is consumed, the mixture is filtered, the solvent removed in vacuo, the residue taken up in chloroform-ether, filtered, anhydrous ethereal-hydrogen chloride added and the methyl S-(paminomethylbenzylarnino)-salicylate dihydrochloride collected.

EXAMPLE l8 Methyl 5-( p-dirnethylaminomethylbenzylamino)-salicylate A mixture of methyl 5-(p-aminomethylbenzylamino)-salicylate (0.008 m.), 37% formaldehyde (6 ml.), dried 1,2- dimethoxyethane (120 ml.), glacial acetic acid (50 ml.) and Raney nickel (2 tsp.) is treated with hydrogen (40 psi.) at room temperature. When uptake is completed, the mixture is filtered, the cake washed well with fresh dimethoxy ethane, the combined filtrates distributed between chloroform-dilute sodium bicarbonate solution, the chloroform layer dried, concentrated, and the residue chromatographed on a silica gel column using a methanol-methylene chloride system (v/v -90% methanol) as eluant to yield methyl -(pdimethylaminomethylbenzylamino)-salicylate.

EXAMPLE 19 Methyl 2-carboxy-4-(p-fluorobenzamido)-phenyl carbonate To a mixture of 5-(p-fluorobenzamido)-salicylic acid (0.01 m.), dimethylaniline (0.02 m.) and benzene (30 ml.) is added methyl chloroformate (0.01 m.) over one hour with constant shaking and cooling. When the odor of the chlorocarbonate is absent, hydrochloric acid (IN, 100 ml.) is added and the mixture filtered. The benzene layer is separated, dried, filtered, and the benzene removed in vacuo to yield methyl 2-carboxy- 4-(p-fluorobenzamido)-phenyl carbonate.

EXAMPLE 20 N-( 3-carboxy-4-hydroxybenzal)-p-fluoroaniline When 5-formylsalicylic acid (0.005 m.) and p-fluoroaniline are reacted as per Example 2, N-(3-carboxy-4-hydroxybenzal)-p-fluoroaniline is obtained.

When other substituted aniline compounds are used in place of p-fluoroaniline in the above procedure, the corresponding substituted phenyliminomethylsalicylic acids are obtained.

EXAMPLE 21A Methyl 5'(p-fluorobenzylamino)-salicylate To a mixture of 5-(p-fiuorobenzylaminoJ-salicylic acid (0.0l5 m.) and absolute methanol (50 ml.), is added slowly, with stirring, concentrated sulfuric acid (2.0 ml.). The mixture is then heated gently for 18 hours. Excess methanol is removed by evaporation in vacuo, the residue partitioned between chloroform-water, the chloroform layer washed with dilute sodium bicarbonate sulution, water, dried, filtered and concentrated to yield methyl S-(p-fluorobenzylamino)-salicylate.

When the 5-(p-fluorobenzylamino)-salicylic acid of the above procedure is replaced by any of the other salicylic acid compounds of this invention, the corresponding methyl ester is prepared.

When methanol in the above procedure is replaced by other appropriate alcohols such as ethanol, propanol, isopropanol, butanol, isobutanol, 2-methoxyethanol or 2-ethoxyethanol, etc., the corresponding ester is prepared.

Diazo compounds, such as diazomethane, may also be used to prepare the corresponding ester, and in some cases is preferred.

EXAMPLE 2 l B 4-(p-fluorobenzylamino)-salicylamide A mixture of methyl 4-(p-fluorobenzylamino)-salicylate and concentrated ammonium hydroxide five-fold excess) is heated at C. in a sealed tube for 6 hours. After cooling, water is added and the 4-(p-fluorobenzyl-amino)-salicylamide collected.

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

EXAMPLE 22 Sodium 5-(p-fluorobenzamido )-salicylate To a solution of sodium hydroxide (0.001 m.) in water (15 ml.) is added S-(p-fiuorobenzamido )-salicylic acid (0.001 m.) in ethanol, the mixture stirred and gently heated for 2 hours, and the solvents removed in vacuo on a rotary evaporator to yield sodium S-(p-fluorobenzamido )-salicylate.

When one equivalent of potassium hydroxide or sodium carbonate are used in place of sodium hydroxide, the corresponding salt is prepared.

When two equivalents of the above bases are used in the above examples, the corresponding di-salt is obtained.

When 5-(p-fluorobenzamido)-salicy1ic acid is replaced by the other salicylic acid compounds of this invention, the corresponding salt is obtained.

We claim:

]. A compound of the formula:

wherein:

R is hydroxy, loweralkoxy, loweralkoxyloweralkoxy,;

R is hydrogen, or loweralkyl;

K, is hydrogen, chloro, fluoro, trifluoromethyl, loweralkyl,

or lower alkoxy;

X is loweralkyl, hydroxy, loweralkoxy, lower alkanoyloxy,

fluoro, chloro, trifluoromethyl, nitro, amino,, diloweralkylamino, lower alkanoylamino, loweralkylsulfinyl, loweralkylsulfonyl, aminoloweralkyl, diloweralkylaminoloweralkyl, hydroxyloweralkyl, alkoxyloweralkyl, carboxy, carboalkoxy, carbamoyl;

Y is selected from the group of methyleneirnino CH NH), iminomethylene (NHCH methylidenenitrilo (CH N), nitrilomethylidene (-N CH-), and carbonylimino ENIL) provided that the 0R group is always ortho to the group.

2. A compound of the formula:

R is hydrogen or loweralkyl; R is hydrogen, loweralkyl, or fluoro;

X is loweralkoxy, fluoro, trifluoromethyl or diloweral- 20 kylamino; and

Y is selected from the group of methyleneimino CH NH), iminomethylene (NHCH lidenenitrilo (CH N-), nitrilomethylidene (-N CH- and carbonylimino methy- 5 provided that the 0R group is always ortho to the group.

3. 4-(p-fluorobenzylideneamino)-salicylic acid. 4. 5-(p-fluorobenzylamino)-salicylic acid.

5. 5-(p-fluorobenzamido)-salicylic acid.

6. 4-(pdluoroanilinomethyl)-sa1icylic acid.

7. 5-(p-fluorophenyliminomethyl)-salicylic acid. 8. A compound of the formula:

wherein X is fluoro or chloro, provided that the hydroxy group is always ortho to the carboxy group.

i i IF UNITED STATES PATENT oEETcE CERTIFICATE OF CURRECTION Patent No. 316741344 Dated July 4, 1972 Inventor-(s) T-Y. Shen, G.L. Walford, B.E. Witzel, and H. Jones It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In Claim 8, that portion of the formula reading Signed and sealed this 9th day of January 1973.

(SEAL) Attest:

- EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents

Claims

2. A compound of the formula: wherein R is hydroxy; R2 is hydrogen or loweralkyl; R3 is hydrogen, loweralkyl, or fluoro; X is loweralkoxy, fluoro, trifluoromethyl or diloweralkylamino; and Y is selected from the group of methyleneimino (-CH2NH-), iminomethylene (-NHCH2-), methylidenenitrilo (-CH=N-), nitrilomethylidene (-N=CH-), and carbonylimino ; provided that the OR2 group is always ortho to the group.
3. 4-(p-fluorobenzylideneamino)-salicylic acid.
4. 5-(p-fluorobenzylamino)-salicylic acid.
5. 5-(p-fluorobenzamido)-salicylic acid.
6. 4-(p-fluoroanilinomethyl)-salicylic acid.
7. 5-(p-fluorophenyliminomethyl)-salicylic acid.
8. A compound of the formula: wherein X is fluoro or chloro, provided that the hydroxy group is always ortho to the carboxy group.