US3686291A

US3686291A - Thio derivatives of 2-hydroxy-3-naphthioc acid

Info

Publication number: US3686291A
Application number: US69426A
Authority: US
Inventors: Brjan Gadsby; Peter Rodway Leeming; Michael Barrie Thomas
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1970-09-03
Filing date: 1970-09-03
Publication date: 1972-08-22
Anticipated expiration: 1989-08-22

Abstract

Fibrinolytic agents related to 1-thio- and 1-thiomethyl-2hydroxy-3-naphthoic acid.

Description

Unlted States Patent 1151 3,686,29 1 Gadsby et al. 14 Aug. 22, 1972 [54] THIO DERIVATIVES OF Z-HYDROXY- S-NAPHTHIOC ACID [56] References Cited [72] Inventors: lirian (Fadsby; Peter Rodway Leem- FOREIGN PATENTS OR APPLICATIONS mg; Mlchael Bame Thomas, all of Pfi Inc 235 E, 42 s New 706,659 4/1941 Germany ..280/5 l6 A ZZ F' L Z k N Y OTHER PUBLICATIONS [73] sslgnee' w or Whitmore et al., Chem. Abst. 61, 7151 (1964) [22] Filed: Sept. 3, 1970 [21] AppL 69,426 Primary Examinerl /orraine A. Weinberger Assistant Examiner-John F. Terapane Attorney-Connolly and Hutz [52] US. Cl ..260/5l6, 260/247.1, 260/251 A,

260/294.8 B, 260/302 R, 260/326.3, TRQ

260/470, 260/473 S, 260/50l.2l, 260/5'43 H, [57] ABS CT 260/609 1) 424/243, 424/251 424/263, Fibrinolytic agents related to l-thioand l-thiomethyl- 424/270, 424/274, 424/308, 424/309, 2-hy yp acid- 51 Int. Cl ..c07 149/40 17 Drawmgs [58] Field of Search ..260/470, 516, 302, 294.8

TI'IIO DERIVATIVES OF 2-HYDROXY-3- NAPI-ITHIOC ACID BACKGROUND OF THE INVENTION lower alkyl esters thereof, useful as fibrinolytic agents.

British Pat. No. 1,007,021, published Oct. 13, 1965,

discloses 4,4-thiobis(3-hydroxy-2-naphthoic acid), rem ported useful as salts of l-aryl-1,2-dihydro-4,6- diamino-s-triazines, and 2-hydroxy-6-methylthio-3- naphthoic acid is reported, German Pat. No. 548,823, to be useful as a dyestuff intermediate. Barber, U.S. Pat. No. 2,641,610, and Elslager, et a1., U.S. Pat. No.

report l,l-methylenebis(2-hydroxy-3- naphthoic acid) useful as a derivatizing salt in pharmaceutical preparation.

SUMMARY OF THE INVENTION The fibrinolytic agents of the present invention are represented by the formula:

and the basic salts and lower alkyl esters thereof, wherein:

R is selected from the group consisting of alkyl and cycloalkyl each containing from three to 10 carbon atoms; phenyl, benzyl and monoand disubstituted phenyl and benzyl said substituent being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, alkyl and alkoxy each containing from one to four carbon atoms, trifluoromethyl, nitro and amino and substituted amino said substituent being selected from the group consisting of alkyl and acyl each containing from one to four carbon atoms, dialkyl each containing from one to four carbon atoms and phenylsulfonyl; naphthyl; pyridyl and thiazolyl; and

n is an integer of 0 or 1.

As has been previously noted, a characteristic feature of the acidic compounds of the instant invention is their ability to form basic metal salts. Acid congeners of the present invention are converted to basic salts by the interaction of said acid with an appropriate base in an aqueous or non-aqueous medium. Such basic reagents suitably employed in the preparation of said salts can vary in nature, and are meant to contemplate such bases as organic amines, ammonia, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkali earth metal hydroxides, hydrides, alkoxides and carbonates. Representative of such bases are ammonia, primary amines such as npropylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethylamine, octylamine, tertiary amines such as diethylaniline, N-methyl-pyrrolidine, N-methylmorpholine and 1,5-diazabicyclo- [4,3,01-5-nonene; sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, magnesium hydroxide, calcium hydride and barium hydroxide.

In a similar manner, treatment of the basic salts with an aqueous acid solution, e.g., mono-, dior tribasic acid results in the regeneration of the free acid form. Such conversions are best carried out as rapidly as possible and under temperature conditions and method dictated by the stability of said acid products. The acids thus generated can be reconverted to the same or a different basic salt.

In the utilization of the chemotherapeutic activity of those compounds of the present invention which form basic salts, it is preferred, of course, to use pharmaceutically acceptable salts. Although water-insolubility, high toxicity, or lack of crystalline nature may make some salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the water insoluble or toxic salts can be converted to the corresponding acids by decomposition of the salts as described above, or alternately they can be converted to any desired pharmaceutically acceptable basic salt. The said pharmaceutically acceptable salts preferred are those wherein the cation is ammonium, sodium or potassium.

The term lower alkyl encompasses those alkyl groups containing one to four carbon atoms.

Of particular interest, because of their fibrinolytic activity, are compounds where R is monoand disubstituted phenyl or branched alkyl containing three to 10 carbon atoms and n is an integer of 0 or DESCRIP- TION 1.

DETAILED DESCRO OF THE INVENTION In accordance with the process employed for preparing the l-thioand 1-thiomethyl-2-hydroxy-3-naphthoic acids of the present invention of the formula:

,CO2I-I (|CII2),.SR

wherein R is as previously indicated, n is l and R is alkyl containing from one to four carbon atoms, the following scheme is illustrative:

A lower alkyl ester of 1-chloromethyl-2-hydroxy-3- naphthoic acid in a reaction-inert solvent such as ethanol or methanol is contacted with at least an equirnolar amount of a mercaptan of the formula RSI-I, in the presence of a base, e.g., sodium and potassium (lower) alkoxides or carbonates. It is preferred that at least two equivalents of said base be employed.

The aforedescribed reaction is carried out at a reaction temperature of 40 C. to the reflux temperature of the selected solvent for a reaction time of 12 to 24 hours; reflux temperatures are preferred.

A convenient method of isolation employs cooling, filtration of the alkali metal chloride and evaporation of the reaction mixture filtrate to dryness, followed by dissolution of the residue in water and subsequent acidification of the aqueous solution. The precipitated acid is filtered and further purified by recrystallization from a suitable solvent.

Also within the purview of this invention are the esters of final products. These intermediate products are isolated by reducing the amount of base in the aforedescribed reaction such that only one equivalent is employed. Said esters are isolated, after filtration of the alkali metal chloride, by evaporation of the filtrate to dryness and recrystallization of the residue from a suitable solvent.

Alternately, the esters can be formed from the acids by the conventional Fischer esterification methods well known to those skilled in the art.

The requisite mercaptans, RSI-I, are either available commercially or can easily be prepared by one skilled in the art by the methods of Newman, et al., J. Org. Chem., 31, 3980 (1966), Kipnis, et al., J. A. C. S., 71, 2270 (1949) and those outlined by Wagner, et al., Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York, 1953, Chapter 31, page 778.

The lower alkyl esters of l-chloromethyl-2-hydroxy- 3-naphthoic acid are prepared via chloromethylation of the corresponding 2-hydroxy-3-naphthoate esters by the procedures as taught by Tarbell, et al., J. Am. Chem. Soc., 76, 5766 (1954).

Compounds of the present invention wherein R is as previously described, n is an integer of O and R is alkyl containing from one to four carbon atoms, are synthesized by the reactions outlined as follows:

The reaction leading to compounds of formula II employs contacting a lower alkyl ester of 2-hydroxy-3- naphthoic acid with a sulfenyl chloride, R-S-Cl, in a reaction-inert solvent such as chloroform, carbon tetrachloride, benzene or toluene.

In practice, a solution of the naphthoate ester is treated with at least an equimolar amount of the requisite sulfenyl chloride plus as much as a 50 percent excess. Reaction times are not critical and vary with reaction temperature, concentration and reactivity of the respective reactants. In general, reaction times of 24-48 hours are operative, with corresponding reaction temperatures of 15 C. up to the reflux temperature of the solvent employed.

Evaporation of the reaction solvent followed by recrystallization of the residual solid leads to the isolation of the purified esters of formula II, which are also considered within the scope of this invention.

Subsequent hydrolysis of the esters of formula II to yield the products of the instant invention is carried out in a manner familiar to those skilled in the art and comprises treating II in an inert solvent such as ethanol or water with at least an equimolar amount of base such as sodium hydroxide, potassium hydroxide or sodium carbonate, at temperatures of 60l00 C. for 12 to 20 hours.

When ethanol is the employed solvent, the aforedescribed reaction is cooled, filtered and the ethanol removed in vacuo. The residual solid is dissolved in a minimum amount of water and the product precipitated by the addition of 2N hydrochloric acid. Filtration and recrystallization leads to the pure products of the present invention.

The requisite sulfenyl chlorides employed in the aforedescribed reaction are either commercially available or can be prepared from the corresponding mercaptan by one skilled in the art according to literature procedure, such as those taught by Reid, Organic Chemistry of Bivalent Sulphur, Chemical Publishing Co., Inc., New York, 8, Volume 1, Chapter 3, page 262.

Compounds of the instant invention wherein R is derived from a nitrophenyl or nitrobenzyl moiety can be further transformed through reduction to the corresponding arnino congeners. Said reduction is most conveniently carried out using stannous chloride and hydrochloric acid at temperatures of 4075 C. for reaction periods of 2 to 4 hours. After the reaction is complete it is made strongly basic with ammonium hydroxide, the stannic hydroxide filtered and the product isolated from the basic filtrate by adjusting the pH to the isoelectric point with an acid such as acetic acid.

Amines resulting from the aforedescribed reduction of the corresponding nitro compounds can subsequently be reacted with a wide variety of reagents including alkanoyl halides, anhydrides, sulfonyl halides and alkyl halides.

Reaction of said amino compounds with alkanoyl halides leads to the preparation of the corresponding acylamino analogs. In practice, the alkanoyl halide, preferably the chloride, is added slowly to the requisite amino compound in a solvent such as pyridine. Reaction temperatures of from 6085 C. are employed with reaction times of 3 to 6 hours. The solvent is removed under reduced pressure and the residual pyridium salt of the product converted to the free acid by treating an aqueous solution thereof with sufficient acid to precipitate the product.

Analogously, sulfonyl halides are reacted under similar conditions and give rise to the corresponding sulfonarnides.

Formation of acylamino analogs employing simple or mixed anhydrides in place of the alkanoyl halides can be carried out with equal ease. Experimentally, the amino compound is contacted with at least an equimolar amount of the requisite anhydride plus as much as a 20-50 percent excess. A solvent such as benzene, chloroform or tetrahydrofuran can be employed or the reaction can be run neat, i.e., without solvent. Said reaction is carried out at 4080 C. for 2-8 hours. The desired product is isolated by removal of the excess anhydride and solvent in vacuo.

Alkylation of the amine moiety is carried out using an appropriate alkyl halide, preferably iodide. The extent of alkylation is controlled by the relative amount of alkyl halide to the amino compound employed. For mono alkylation equimolar quantities of the two reactants are used plus a small, percent, excess of the alkyl halide, dialkylation requires at least 2 moles of halide per mole of amino substrate for optimum yields. In practice, a suspension or solution of the amino compound and at least 2 moles of an alkali metal carbonate is treated with the appropriate alkyl halide in the amounts previously described. The solvents for this alkylation can vary in nature and are selected from the group including (lower)alkanols, N,N-di(lower)alkyl(lower)alkylcarboxamides, cyclic ethers and water. Elevated temperatures of from 50l 10 C. are employed, with reaction times of 1-8 hours. The product is isolated by dilution with water followed by adjustment of the pH with acid to the isoelectric point, generally just acid to Congo red paper. Cooling and seeding facilitates crystallization.

As previously indicated, the l-thioand lthiomethyl-2-hydroxy-3-naphthoic acids and lower alkyl esters thereof of the present invention are all readily adapted to therapeutic use as fibrinolytic agents. Typical member compounds of interest in this series include 1-(o-isopropylphenylthiomethyl)-2- hydroxy-3-naphthoic acid, l-(o-bromophenylthiomethyl)-2-hydroxy-3-naphthoic acid, l-(l,l,3,3- tetramethyl-n-butylthiomethyl)-2-hydroxy-3-naphthoic acid, l-(o-chlorophenylthiomethyl)-2-hydroxy-3- naphthoic acid, l-(p-chlorophenylthiomethyl)-2- hydroxy-3-naphthoic acid, l-(p-chlorophenylthio)-2- hydroxy-3-naphthoic acid, 1-( o-tolylthiomethyl )-2- hydroxy-3-naphthoic acid, 1-( m-tolylthiomethyl )-2- hydroxy-3-naphthoic acid, l-( p-tolylthiomethyl)-2- hydroxy-3-naphthoic acid, l-(o-bromophenylthiomethyl)-2-hydroxy-3-naphthoic acid, l-(mbromophenylthiomethyl)-2-hydroxy-3-naphthoic acid and l-(2,3-dichlorophenylthiomethyl)-2-hydroxy-3- naphthoic acid.

As previously mentioned, the corresponding esters of the compounds of the instant invention are also valuable fibrinolytic agents and are hydrolyzed in vivo to the corresponding acids. Further, said esters are valuable intermediates leading to the synthesis of the subject compounds.

Also considered within the scope of the present invention are compounds of the formula:

where R n and R are as previously described and R is alkanoyl containing one to four carbon atoms. Said acylated products are conveniently prepared by acylation of the phenolic hydroxyl group. In practice, the phenolic compound is contacted with at least an equimolar amount of an anhydride or acid halide,

preferably chloride, in a reaction-inert solvent such as chloroform, benzene or tetrahydrofuran. Reaction temperatures of 50 C. are employed with reaction periods of l-4 hours. When an acid halide is used as the acylating agent it is desirable to use in addition at least an equivalent of a tertiary amine such as pyridine or triethylamine. The products are isolated by evaporation of the reaction mixture to dryness followed by trituration with water, filtration and drying.

The terminal complication of thrombus formation in ischaemic heart disease, cerebral vascular disease, legvein thrombosis, pulmonary embolism and peripheral vascular disease is well documented in the medical literature, and has recently been reviewed by Poole, et al., J. Atheroscler. Res, 1, 251-282 (1961).

One approach to the problem of thrombi formation is to enhance the rate of dissolution of the fibrin, a major constituent of both clots and thrombi. It is through this mechanism that the compounds of the present invention mediate their remarkable fibrinolytic activity.

The activity of compounds of the invention as fibrinolytic agents is assessed in vitro as their ability to facilitate:

l. the visible lysis of clots formed on addition of thrombin and calcium chloride to human blood plasma:

2. the release of fluorescein from clots fonned on the addition of thrombin to human blood plasma containing fluorescein-labelled fibrinogen; or

3. the release of erythrocytes, by potentiation of urokinase-induced lysis, from clots formed on addition of thrombin and urokinase to freshly withdrawn human or animal blood samples.

In test (1), the test compound, dissolved in neutral buffer, is mixed with human plasma to provide concentrations of 2.5, 1.0 and 0.25 mM; clotting is initiated by addition of CaCl and thrombin. The clots are then removed and immersed in solutions of the test compound in buffer, at the same concentrations as in the plasma mixtures. The clots are inspected for lysis after incubation for 24 and 48 hours at 37 C.

In test (2), human plasma (2 vols) is mixed with 0.5 percent fluorescein labelled fibrinogen (1 vol). Clots are prepared by adding thrombin (0.1 ml., 0.1 mg/ml.) to 0.2 ml. of the mixture. The clots are washed with neutral buffer, and are then incubated in a mixture containing 0.3 ml. of human serum, 0.1 ml. of 0.5 M Na CI, 0.8 ml. of the test compound (1, 2, 3, 4 and 5 mM) in tris(hydroxymethyl)methylamine/HCl buffer, pH 7.4. The fluorescence of the supernatant fluid is measured at 0 and 16 hours.

In test (3), into ice-cold test-tubes are pipetted various concentrations of the test compound, urokinase (10 units per clot for human blood and 200-250 units per clot for rat blood), and thrombin (2 units) all in a final volume of 0.2 ml. Freshly drawn blood is quickly chilled and a 0.3 ml. aliquot is pipetted into each tube. The clots are incubated for 1 hour at 37 C., and then filtered through cotton wool and washed with saline. Filtrate and washings are combined, made to a standard volume, and the erythrocytes lysed with Triton X 100. Determination of the hemoglobin at 540 my. provides a measure of fibrinolysis.

Activity in vivo is also assessed by method (3), by administering the compounds, orally or parenterally, e.g.,

intravenously, to experimental animals before withdrawing the blood samples, instead of including them in the test medium.

The l-thioand l-thiomethyl-2-hydroxy-3-naphthoic acids and the pharrnaceutically acceptable salts and lower alkyl esters thereof, which are useful as fibrinolytic agents, may be administered either as individual therapeutic agents or as mixtures of therapeutic agents. They may be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar or certain types of clay, etc. They may be administered orally in the form of elixirs or oral suspensions with the active ingredients combined with emulsifying and/or suspending agents. They may be injected parenterally, and for this use they, or appropriate derivatives, may be prepared in the form of sterile aqueous solutions. Such aqueous solutions should be suitably buffered, if necessary, and should contain other solutes such as saline or glucose to render them isotonic.

The dosage required to prevent thrombus formation in subjects prone to said disorder would be determined by the severity of the symptoms and is within the skill of the art. Generally, small doses will be administered initially, with a gradual increase in the dosage until the optimum level is determined. It will generally be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a small quantity administered parenterally. In general, from about 10 to about 200 mg. of active ingredient per kilogram of body weight are administered in single or multiple dose units, to effectively facilitate thrombus dissolution.

The following examples are provided solely for the purpose of illustration and are not to be corlstrued as limitations of this invention, many variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE I l -(o-Isopropylphenylthiomethyl )-2-hydroxy-3- naphthoic Acid and Ethyl Ester A. A mixture of 7.5 g. of methyl l-chloromethyl-Z- hydroxy-3-naphthoate, 4.6 g. of o-isopropylbenzenethiol and 4.2 g. of potassium carbonate in 160 ml. of ethanol is heated to reflux for 18 hours. The reaction mixture is cooled, filtered and evaporated to dryness. The residual solid is dissolved in water, the crude product precipitated by the addition of 2N hydrochloric acid and solids filtered and recrystallized from ethanol, 6.3 g., m.p. 192-l93 C.

Anal. Calcd. for C, H, O,S: C, Found: C,

B. The above acid is suspended in 50 ml. of dry ethanol and heated to reflux while hydrogen chloride gas is slowly bubbled into solution. After 30 minutes the addition of gas is terminated and the solution allowed to reflux for an additional hour. The excess gas and solvent are removed in vacuo and the residue recrystallized from chloroform.

EXAMPLE II Starting with methyl l-chloromethyl-2-hydroxy-3- naphthoate and the appropriate mercaptan, and following the procedure of Example I, the following congeners are prepared:

l-( o-Tolylthiomethyl )-2-hydroxy-3-naphthoic acid,

m.p. 202204 C.; l-( m-Tolylthiomethyl )-2-hydroxy-3-naphthoic acid,

m.p. l93l95 C.; l-(p-Tolylthiomethyl)-2-hydroxy-3-naphthoic acid,

m.p. 205-207 C.;

l -Phenylthiomethyl-2-hydroxy-3-naphthoic acid,

m.p. 2l62l9 C.; l -Benzylthiomethyl-2-hydroxy-3-naphthoic acid,

l 2-Naphthylthiomethyl )-2-hydroxy-3-naphthoic acid, mp 21 2-2 14 C.;

l p-chlorophenylthiomethyl )-2-hyd roxy-3- naphthoic acid, m.p. 229230 C.;

l o-chlorphenylthiomethyl )-2-hydroxy-3-naphthoic acid, m.p. 228-229 C.;

l 2,3-Dichlorophenylthiomethyl )-2-hydroxy-3- naphthoic acid, mp. 25 525 7 C.;

l-( o-Bromophenylthiomethyl )-2-hydroxy-3- naphthoic acid, m.p. 237-240 C.;

l p-Bromophenylthiomethyl)-2-hydroxy-3- naphthoic acid, m.p. 221224 C.;

l m-Bromophenylthiomethyl )-2-hydroxy-3- naphthoic acid, m.p. 220222 C.;

l-( p-Fluorophenylthiomethyl )-2-hydroxy-3- naphthoic acid, m.p. l99-20l C.;

1 m-Trifluoromethylphenylthiomethyl )-2-hydroxy- B-naphthoic acid, m.p. 22823 1 C.;

l o-Methoxyphenylthiomethyl)-2-hydroxy-3- naphthoic acid, m.p. 2082 1 0 C.;

l m-Methoxyphenylthiomethyl )-2-hydroxy-3- naphthoic acid, m.p. 182-l 84 C.;

l p-Methoxyphenylthiomethyl )-2-hydroxy-3- naphthoic acid, mp. 21 12 1 3 C.;

l p-Hydroxyphenylthiomethyl )-2-hydroxy-3- naphthoic acid, m.p. 226-228 C.;

l pNitrophenylthiomethyl )-2-hydroxy-3-naphthoic acid, m.p. 256257 C.;

l p-Acetarnidophenylthiomethyl )-2-hydroxy-3- naphthoic acid, m.p. 240-242 C.;

l -(p-t-Butylphenylthiomethyl )-2-hydroxy-3- naphthoic acid, m.p. l95-l 97 C.;

l 3 ,S-Dimethylphenylthiornethyl )-2-hydroxy-3- naphthoic acid, m.p. 222-224 C.;

l Z-Pyridylthiomethyl )-2-hydroxy-3-naphthoic acid, m.p. 248250 C.',

1 -I'sobutylthiomethyl-2-hydroxy-S-naphthoic m.p. l52-153 C.; a

l t-Butylthiomethyl)-2-hydroxy-3-naphthoic acid,

m.p. 247-250 C.;

l-( l ,l ,3 ,3-Tetramethylbutylthiomethyl)-2-hydroxy- 3-naphthoic acid, mp. 1 62 C l n-Decylthiomethyl)-2-hydroxy-3-naphthoic acid,

m.p. l25-127 C.;

l -Cyclohexylthiomethyl-2-hydroxy-3-naphthoic acid, m.p. -177 C.

along with their methyl esters.

acid,

d-nitro Z-i-propyl 2-nitro 6-bromo 4-nitro 2-bromo 2-nitro 4-fluoro 4-nitro Z-n-butyl Z-nitro 4-t-butyl EXAMPLE VII EXAMPLE VIII Starting with an appropriately substituted benzyl mercaptan and methyl l-chloromethyl-2-hydroxy-3* naphthoate and following, again, the procedure of Example I, the following congeners are prepared:

along with their ethyl esters.

EXAMPLE IX l-(o-Tolylthio)-2-hydroxy-3-naphthoic acid To a solution of l 1.1 g. of o-toluenesulfenyl chloride in 300 ml. of carbon tetrachloride is gradually added 14.1 g. of methyl 3-hydroxy-2-naphthoate and the resulting reaction mixture stirred at room temperature for 48 hours. The solvent is removed in vacuo and the residue, methyl 1-(o-tolylthio)-2-hydroxy-3- naphthoate, recrystallized from ethanol-chloroform, 9.0 g., m.p. 159l60 C.

Four grams of the above ester in 50 ml. of ethanol containing 3 g. of potassium carbonate is heated to reflux for 18 hours, followed by filtration and evaporation to dryness. The residue is dissolved in water and acidified with 2N hydrochloric acid. The resulting precipitate is filtered and recrystallized from benzene to provide the pure product, 2.2 g., m.p. 200 C.

EXAMPLE X acid, m.p.

acid,

EXAMPLE XI The procedure of Example IX is repeated, starting with the requisite alkyl or cycloalkyl sulfenyl chloride,

to provide the following analogs:

0 CO2H I SR n-propyl cyclopropyl i-propyl cyclobutyl n-butyl cyclopentyl t-butyl cyclohexyl s-butyl cycloheptyl n-pentyl 4-methylcyclohexyl Z-meIhyI-n-butyl cyclooctyl S-methyl-n-butyl 4,4-dimethylcyclohexyl n-hexyl 4-ethylcyclohexyl' Z-methyl-n-pentyl cyclononyl 4-methyl-n-pentyl 4,5-dimethylcycloheptyl 4,4-dimethyl-n-butyl cyclooctyl n-hcptyl cyclodecyl EXAMPLE XVII l -(p-Acetamidophenylthiomethyl )-2-hydroxy-3- naphthoic acid of l-(p-nitrophen- A. Anhydride Method To a solution of 3.25 g. of l-(p-aminophenylthiomethyl)-2-hydroxy-3-naphthoic acid in 35 ml. of chloroform is added dropwise 1.12 g. of acetic anhydride and the resulting solution heated to reflux for 2 hours. The excess reagent and solvent is removed under reduced pressure and the residual product recrystallized from ethanol. The product proves to be identical to that prepared in Example H.

B. Acid Chloride Method To a solution of 4.87 g. of l-(p-aminophenylthiomethyl)-2-hydroxy-3-naphthoic acid in 40 ml. of pyridine and cooled to 10 C. is added slowly 1.33 g. of acetyl chloride and the resulting solution heated in a water bath to 75 C. for 4 hours. The excess reagent and solvent is removed in vacuo, the residue dissolved in a minimum amount of water and sufficient 3N hydrochloride acid added to precipitate the product. The solid which is filtered, dried and recrystallized from isopropanol is identical to that prepared by the Anhydride Method above and Example II.

EXAMPLE XVIII Starting with the suitable amino compound and requisite acylating reagent, and following the appropriate procedure method in Example XVII, the folsuspension of 3.55 ylthiomethyl)-2-hydroxy-3-naphthoic acid in 48 ml. of

EXAMPLE XVI The reduction procedure of Example XV is followed, using the corresponding nitro substituted phenylthio-, phenylthiomethyl-, benzylthioand benzylthiomethylcom (CH2)n S-(CH2)m 12N hydrochloric acid is treated with 1.0 g. of stannous chloride and the mixture heated for 3 hours at C. and then allowed to stir at room temperature until a 5 complete solution is effected. The resulting solutionis made basic with ammonium hydroxide and the tin hydroxide filtered. The filtrate is gradually made acidic with glacial acetic acid until a precipitate no longer forms. The desired product is filtered, dried and further 10 purified by recrystallization from methanol-water.

substituted naphthoic acid, to provide the following compounds:

mooooooooooooooooooooooooo ooo nllllllllll llllllllllllllllllllllooo 1 9 1 ..m s m. mm. ..w....... H 1..H .ii HHHHHHHHH HHHoHHH eff Lfiem? mcmmmmwmw YHHH43423654423222HHH445544444545LL2HHHHHHMWLIT $LL "mmmmmmmmmmmmmmmmmmmmamm mmm mmmm m u ..H a ..Fl HHH BF N N N N N N N.N.N N N N.N NN.wwmwmzzacccuauuod mN NNNmmm qwzcwww 2342223333334 444234 239 .1 W30 LLJLLLJLZ} ..bm. 2 2

nllllllllllllllllllllllllllllllllllll.l

EXAMPLE XXIII Following the procedure of Example XXII, substituting water for methanol and employing the appropriate alkali earth metal hydroxide, the corresponding beryllium, calcium, magnesium, barium and strontium salts are prepared.

EXAMPLE XXIV Ammonium l-benzylthio-2-hydroxy-3-naphthoate To a solution of 6.2 g. of l-benzylthio-2-hydroxy-3- naphthoic acid in methanol is added sufficient ammonia to render the solution strongly alkaline. The ex cess ammonia and solvent are removed under reduced pressure and the residual ammonium salt triturated with isopropanol and filtered.

In a similar manner other organic amines are substituted for ammonia to provide the corresponding amine salts.

EXAMPLE XXV Tablets A tablet base is prepared by blending the following ingredients in the proportion by weight indicated:

Sucrose, U.S.P. 80.3 Tapioca starch 13.2 Magnesium stearate 6.5

Into this tablet base there is blended sufficient l-(o- Isopropylphenylthiomethyl)-2-hydroxy-3-naphthoic acid to provide tablets containing 20, 100 and 250 mg. of active ingredient per tablet. The compositions are each compressed into tablets, each weighing 360 mg., by conventional means.

EXAMPLE XXVI Capsules A blend is prepared containing the following ingredients:

Calcium carbonate, U.S.P. 17.6 Dicalcium phosphate 18.8 Magnesium trisilicate, U.S.P. 5.2 Lactose, U.S.P. 5.2 Potato starch 5.2 Magnesium stearate A 0.8 Magnesium stearate B 0.35

-To this blend is added sufficient sodium l-(o- Isopropylphenylthiomethyl)-2-hydroxy3-naphthoate to provide capsules containing 20, 100 and 250 mg. of active ingredient per capsule. The compositions are filled into conventional hard gelatin capsules in the amount of 350 mg. per capsule.

EXAMPLE XXVIl EXAMPLE XXVIII Suspension A suspension of 1-(o-bromophenylthiomethyl)-2- hydroxy-3-naphthoic acid is prepared with the follow ing composition:

Effective ingredient 25.00 g.

% aqueous sorbitol 741.29 g.

Glycerine, U.S.P. 185.35 g.

Gum acacia (10% solution) 100.00 ml.

Polyvinylpyrrolidone 0.50 g.

Distilled water Sufficient to make 1 liter To this suspension, various sweeteners and flavorants are added to improve the palatability of the suspension. The suspension contains approximately 25 mg. of effective agent per milliliter.

EXAMPLE XXIX Solution A solution of sodium l-(l,l,3,3-tetramethyl-n-butylthiomethyl)-2-hydroxy-3-naphthoate is prepared with the following composition:

Effective ingredient 30.22 grams Magnesium chloride hexahydrate 12.36 grams Monoethanolamine 8.85 ml. Propylene glycol 376.00 grams Water, distilled 94.00 ml.

The resultant solution has a concentration of effective ingredient of 50 mg./ml. and is suitable for parenteral and especially for intramuscular administration.

PREPARATION A Alkyland Cycloalkylmercaptans The procedure of Urquhart, et al., Org. Syn., Col. Vol. 3, 363, which comprises alkylation of thiourea with an equimolar amount of an alkyl or cycloalkyl halide, formed by hydrolysis of the resulting isothiouronium salt, is employed in the preparation of the following mercaptans not previously reported in the chemical literature:

R-SI-I R R 2-methyl-n-pentyl cyclopropyl 4-methyl-n-pentyl cyclobutyl 4,4-dimethyl-n-butyl 4,4-dimethyl-n-penty1 4,4-dimethylcyclohexyl 4-ethylcyclohexyl 2,2,3 -trimethyl-n-butyl cyclooctyl 3 ,4,4-trimethyl-n-pentyl cyclononyl 2,2,3 ,3 -tetramethyl-n-pentyl 4,5-dimethylcycloheptyl cyclodecyl PREPARATION B Benzenethiols The following thiophenols not previously reported in the literature are synthesized by the method of Newman, et al., J. Org. Chem, 31, 3980 (1966), which employs acylation of a substituted phenol with dimethylthiocarbamyl chloride, thermal rearrangement to the s-aryl dimethylthiocarbamate and subsequent hydrolysis to the benzenethiol:

PREPARATION F 1. A naphthoic acid selected from those of the formula:

and the sodium, potassium and ammonium salts and alkyl esters containing from one to four carbon atoms thereof, wherein:

R is selected from the group consisting of cycloalkyl containing from three to 10 carbon atoms; phenyl, benzyl and monoand disubstituted phenyl and benzyl said substituents being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, alkyl and alkoxy each containing from one to four carbon atoms, trifluoromethyl, amino and substituted amino said substituent being selected from the group consisting of alkyl and alkanoyl each containing from one to four carbon atoms, dialkyl each containing from one to four carbon atoms and phenylsulfonyl; naphthyl; pyridyl and thiazolyl; and

n is an integer of 0 or 1.

2. The compound of claim 1 wherein R is monosubstituted phenyl and n is l.

3. l-(o-Tolylthiomethyl)2-hydroxy-3-naphthoic acid.

4. l -(m-Tolylthiomethyl )-2-hydroxy-3-naphthoic acid.

5. l p-Tolylthiomethyl )-2-hydroxy-3-naphthoic acid.

6. l-( o-Chlorophenylthiomethyl)-2-hydroxy-3- naphthoic acid.

7. l-(p'Chlorophenylthiomethyl)-2-hydroxy-3- naphthoic acid.

8. l-( o-Bromophenylthiomethyl )-2-hydroxy-3- naphthoic acid.

9. l-(m-Bromophenylthiomethyl)-2-hydroxy-3- naphthoic acid.

10. l-( 2,3-Dichlorophenylthiomethyl )-2-hydroxy-3- n is an integer of or 1. naphthoic acid. 15. l-Phenylthiomethyl-2-hydroxy-3-naphthoic acid. 11. P PY P y y Y- 16. A compound of claim 1 wherein R is substituted naphthoic acidphenyl and n is 0.

(112. Tlie compound of claim 1 wherein R is naphthyl 5 l ((ychlorophenyhhio) 2 hydroxy 3 naphthoic an n is acid.

13. l-(2-Naphthyl)-2-hydroxy-3 -naphthoic acid. 14. A compound of claim 1 wherein R is phenyl and

Claims

2. The compound of claim 1 wherein R is monosubstituted phenyl and n is 1.
3. 1-(o-Tolylthiomethyl)-2-hydroxy-3-naphthoic acid.
4. 1-(m-Tolylthiomethyl)-2-hydroxy-3-naphthoic acid.
5. 1-(p-Tolylthiomethyl)-2-hydroxy-3-naphthoic acid.
6. 1-(o-Chlorophenylthiomethyl)-2-hydroxy-3-naphthoic acid.
7. 1-(p-Chlorophenylthiomethyl)-2-hydroxy-3-naphthoic acid.
8. 1-(o-Bromophenylthiomethyl)-2-hydroxy-3-naphthoic acid.
9. 1-(m-Bromophenylthiomethyl)-2-hydroxy-3-naphthoic acid.
10. 1-(2,3-Dichlorophenylthiomethyl)-2-hydroxy-3-naphthoic acid.
11. 1-(2-Isopropylphenylthiomethyl)-2-hydroxy-3-naphthoic acid.
12. The compound of claim 1 wherein R is naphthyl and n is 1.
13. 1-(2-Naphthyl)-2-hydroxy-3-naphthoic acid.
14. A compound of claim 1 wherein R is phenyl and n is an integer of 0 or 1.
15. 1-Phenylthiomethyl-2-hydroxy-3-naphthoic acid.
16. A compound of claim 1 wherein R is substituted phenyl and n is 0.
17. 1-(o-Chlorophenylthio)-2-hydroxy-3-naphthoic acid.