US3725417A - Carboxamidobenzoic acids as hypolipemic agents - Google Patents

Abstract

2-Substituted-5-carboxamidobenzoic acids and the pharmaceutically acceptable salts thereof as hypolipemic agents.

Description

Unite Holland CARBOXAMIDOBENZOIC ACIDS AS HYPOLIPEMIC AGENTS I Gerald F. Holland, Old Lyme, Conn.

Assignee: Pfizer Inc., New York, NY.

Filed: Nov. 2, 1971 Appl. No.: 194,922

Inventor:

US. Cl ..260/293.77, 260/516, 2601518 A, 260/519, 260/239 B, 260/247.1, 260/247.2

A, 260/243 B, 260/268 C, 260/293.73, 260/326.3, 260/470, 260/473 R, 260/476 R, 260/471 R, 260/475 F, 260/475 R,

Int. Cl. ..C07d 29/22 Field of Search....260/5l8 A, 516, 519, 293.77, 260/239 B, 247.2 R, 243 B, 268 C, 326.3

[451 Apr. 3, 1973 [56] References Cited UNITED STATES PATENTS 3,268,526 8/1966 Newallis et al. ..260/293.77

OTHER PUBLICATIONS J. Indian Chem. Soc. 34 371-374 (1957) Patel et al.

Primary Examiner-Henry R. Jiles Assistant Examiner-S. D. Winters Attorney-Arthur G. Connolly et al.

57 ABSTRACT 2-Substituted-5-carboxamidobenzoic acids and the pharmaceutically acceptable salts thereof as hypolipemic agents.

8 Claims, N0 Drawings 7 CARBOXAMIDOBENZOIC ACIDS AS HYPOLIPEMIC AGENTS BACKGROUND OF THE INVENTION Atherosclerosis, a form of arteriosclerosis, is characterized by deposition of lipids in the aorta and in the coronary, cerebral and peripheral arteries of the lower extremities. As these masses increase in size, the risk of thrombosis and the ensuing occlusion arises.

Although the etiology of this disease is not fully understood, it has been found that those afflicted with atherosclerosis exhibit elevated lipoprotein, of which cholesterol and triglycerides are the major constituents. In addition to the recommendation that dietary habits leading to lower fl-lipoprotein levels be observed, various therapeutic agents such as estrogens, thyroxine analogs, sitosterol preparations and, more recently, Atromid-S (ethyl p-chlorophenoxyisobutyrate) have been used to lower cholesterol levels in individuals prone to the condition.

It has now been discovered that carboxamidobenzoic acids, and more particularly a series of 2-substituted-5- carboxamidobenzoic acids are effective agents in reducing plasma lipid levelsand can be expected to be useful in the treatment of atherosclerosis and related cardiovascular diseases associated with elevated lipid levels.

Benzoic acid derivatives of a wide variety have been known in the chemical literature for some time and have been reported to possess varied utilities, the most common of which is as intermediates leading to more complicated and diverse chemical structures. For example, 3-chloro-2-carboxamidobenzoic acid has been employed in the preparation of tricyclic acridines by Patel, et al., J. Indian Chem. Soc., 34, 371 (1957); C.A., 53, 3818 (1958), while 4-(N-hydroxymethyl)carboxamidobenzoic acid has been used in the synthesis of arylbenzo[e]-l,3-thiazine derivatives by Vinkler, et al., Acta. Pharm. Hung, 31 75 (1961); C.A., 55, 16554 (1961 Erlenmeyer, British Pat. No. 802,841; C.A., 53, l 1315 (1959), reports the preparation of 4-hydroxy-3- (N-methyl)carboxamidobenzoic acid, claimed to have utility as ananalgesic agent.

Interest in 4-hydroxyisophthalic acid derivatives as potential analgesics, diuretics, fungicides, local anesthetics and neuromuscular blocking agents led Gladych, et al., J. Chem. Soc., 4834 (1957) and 2720 (1960), to prepare a wide variety of related analogs including the corresponding 4-alkoxymon0- and diamides thereof.

SUMMARY OF THE INVENTION It has now been unexpectedly found that 2 -substituted-5-carboxamidobenzoic acids represented by the formula:

and the pharmaceutically acceptable salts thereof, wh-rein R and R when considered-separately are each selected from the group comprising hydrogen, alkyl containing from 1 to 4 carbon atoms, phenylalkyl and levels of plasma substituted phenylalkyl wherein said alkyl contains from 1 to 2 carbon atoms and said substituent is selected from the group comprising fluorine, chlorine, bromine, methyl and methoxy, R and R when taken together with the nitrogen to which they are attached fonn a heterocyclic ring of the formula:

wherein Z is selected from the group comprising 0, S, NH and (CH wherein said m is an integer from 0 to 3, and methyl, benzyl and dimethyl substituted derivatives of said heterocyclic rings; and X is selected from the group comprising fluorine, chlorine, bromine, methoxy, methylthio and benzylthio and substituted benzylthio wherein said substituent is selected from the group comprising fluorine, chlorine, bromine, trifluoromethyl, methyl and methoxy, are hypolipemic agents in mammals.

The preferred compounds of the instant invention are those congeners wherein X is chlorine and R is alkyl containing from 1 to 4 carbon atoms and R is alkyl containing from 1 'to 4 carbon atoms or substituted phenylalkyl where said alkyl contains from 1 to 2 carbon atoms and said substituent is fluorine, chlorine, bromine, methyl or methoxy. Also of interest are those compounds where-X is chlorine and R, and R taken together with the nitrogen to which they are attached form a piperidine ring which is substituted by dimethyl or benzyl.

In like manner, compounds of the present invention wherein X is amino and monoand disubstituted amino as well as those wherein R, and R -taken together represent a piperidine ring substituted by chlorine, hydroxy, methoxy, benzyloxy, hydroxymethyl and chloromethyl are also considered within the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION In practice, the starting acid halide, preferably the chloride, dissolved in a reaction-inert solvent such as benzene, methylene chloride, ether or dim'ethylforma mide is added to an excess of the requisite amine,

R R Nl-l, dissolved in the same type of aforementioned solvent. At least two to three moles of amine are employed per mole of acid halide. Said reaction is conducted at room temperature with a corresponding reaction time of 1-2 hours.

At the conclusion of the reaction, the solvent is removed and the resulting crude product, I, is subsequently dissolved in ethanol and hydrolyzed with 1N aqueous sodium hydroxide. The desired product, II, is isolated by removal of the ethanol and acidification of the residual aqueous solution. The hydrolysis of I is effected at room temperature and requires approximately 1-3 hours for completion. The newly formed product can be filtered from the acidified solution or extracted with a water immiscible solvent such as ethyl acetate.

The starting reagent leading to the synthesis of the above-mentioned acid halides is methyl 2-amino-5-carboxybenzoate, synthesized according to the procedure of Wegscheider, Monatsh. Chem., 37, 219 (1916); C.A., 10, 3009 (1916).

Introduction of the substituent, X, ortho to the carbomethoxy moiety is achieved by replacement of the amino group with the appropriate substituent employing methods commonly known to those skilled in the art. Diazotization of the amino moiety followed by treatment of the resulting diazonium salt with cuprous chloride or cuprous bromide results in the preparation of the starting acids wherein X is chlorine and bromine, respectively. The experimental conditions employed are those of the Sandmeyer Reaction which are well known in the art, Buck, et al., Org. Syn., Coll. VoL, 2, 132 (1943).

Treatment of the diazonium salt with fluoboric acid leads to the starting acid wherein X is fluorine. The experimental procedures of the Schiemann Reaction are employed as exemplified in the synthesis of pfluorobenzoic acid, Schiemann, et al., Org. Syn, Coll. Vol., 2, 299 (1943).

Hydrolysis of the requisite diazonium salt with aqueous sulfuric acid, copper sulfate or sodium sulfate leads v to the preparation of the appropriate starting acid wherein X is hydroxy. This conversion is well known in' the art and has been reviewed by Wagner and look, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York, 1956, page 168. Methylation employing one equivalent of methyl iodide and the appropriate base provides for the preparation of the starting acid wherein X is methoxy.

Preparation of congeners of formula [I wherein X is methylthio or benzylor substituted benzylthio is conveniently carried out by treatment of the corresponding compound where X is chloro or bromo with at least an equimolar amount of the sodium salt of methyl mercaptan or the appropriate benzyl mercaptan in an aprotic solvent such as dimethylformamide.

The requisite amines R R Nl-l employed as starting reagents are either commercially available or can be synthesized according to one of the procedures reported by Wagner and Zook, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York, 1956, page 653.

The appropriate benzyl mercaptans used in the above-described displacement on 4-halo-3-carbomethoxybenzoic acids are synthesized from the corresponding, commercially available benzyl halides according to the method as taught by Frank, et al., J. Am. Chem. Soc., 68, 2103 (1946).

As has been previously noted, a characteristic feature of the acidic compounds of the instant invention is their ability to form basic 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. Said 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 n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethylamine, octylamine, tertiary amines such as diethylaniline, N-methylpyrrolidine, N-methylmorpholine and 1,5-diazabicyclo-[4,3,0]-nonene; sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, magnesium "hydroxide, calcium hydride and barium hydroxide.

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.

As previously indicated, the benzoic acids of the present invention are all readily adapted to therapeutic use as hypolipemic agents in mammals. Outstanding for their effectiveness in this regard include the following agents:

2-chloro-5-diethylcarbamylbenzoic acid, 2-chloro-5- (N-ethyl-N-[2-p-chlorophenethyl]carbamyl)benzoic acid, 2-chloro-5-(4-benzylpiperidinocarbonyl)benzoic acid and 2-chloro-5-(3,5-dimethylpiperidinocarbonyl)benzoic acid. i

The products of the invention are tested in vivo for hypolipemic activity in rats. Groups, each comprising 4 animals, of normal Sprague-Dawley (Charles River) male rats weighing from to 220 grams are fed rat chow containing the compound under test for two overnight feeding periods. On the morning of the third day the animals are anesthetized and bled from the ab dominal aorta. The total plasma cholesterol is then determined by the method of J. J. Carr and I. J. Drekter, reported in Clin. Chem., 2, 353 (1956). Most of the tests are conducted at a feed concentration of 0.15 to 0.25 weight per cent of the compound under test, but lower levels, 0.01 to 0.10 weight per cent, are employed in some instances where particularly high potency is anticipated. The plasma cholesterol level of the treated animals is found to be significantly reduced when compared to animals not receiving the test compound.

This pharmacological test for measuring hypocholesteremic activity is a reliable indication that similar activity in humans can be expected because those compounds effective in the rat which have been tested in humans have demonstrated similar activity. p- Chlorophenoxyisobutyric acid, ethyl ester, marketed as Atromid-S, a well-known and clinically effective hypocholesteremic agent, causes a 30-35 percent cholesterol fall in the rat test when administered at a level of 0.25 percent in the feed.

Although the use of the present invention is directed toward the treatment of mammals in general, the preferred subject is humans. In determining an efficacious dose for human therapy, results of animal testing are frequently extrapolated and a correlation is assumed between animal test behavior and proposed human dosage. When a commercially employed standard is available, the dose level of the clinical candidate in humans is frequently determined by comparison of its performance with the'standard in an animal test. For example, Atromid-S is employed as a standard hypolipemic agent and is administered to humans at the rate of 2.0 g. daily in individual doses. It is assumed, then, that if compounds of the present invention have activity comparable to Atromid-S in the test assay, that similar doses will provide comparable responses in humans.

Obviously, the physician will ultimately determine the dosage which will be most suitable for a particular individual, and it will vary with the age, weight and response of the particular patient as well as with the nature and extent of the symptoms and the pharmacodynamic characteristics of the particular agent to be administered; Generally, small doses will be administered initially, with a gradual increase in the dosage until the optimum level is determined. It will often 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 small quantity administered parenterally.

Having full regard for the foregoing factors it is considered that an effective daily dosage of the compounds of the present invention in humans will generally range from 0.3 to 5 g. per day in single or divided doses. These values are illustrative, and there may, of course, be individual cases where higher or lower dose ranges are merited.

The benzoic acids of this invention can be administered either alone, or, preferably, in combination with a pharmaceutically acceptable carrier. They may be combined with various pharmaceutically acceptable, inert carriers in the form of tablets, capsules, lozenges, troches, powders, aqueous suspensions or solutions, elixirs, syrups and the like. Suitable carriers include solid diluents or aqueous media and non-toxic organic .solvents. The oral pharmaceutical compositions of this invention may be suitable sweetened and flavored by means of various agents commonly em ployed for such'a purpose.

For parenteral administration, solutions or suspensions of the herein described benzoic acids in sesame or peanut oil or in aqueous propylene glycol solutions can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such solutions are suitable for intramuscular and subcutaneous administration. Sterile aqueous solutions are additionally useful for intravenous injection, provided that their pH is suitably adjusted and buffered, if necessary, and the limitations of this invention, many variations of which 7 are possible without departing from the spirit or scope thereof.

EXAMPLE 1 2-Chloro-5-diethylcarbamylbenzoic Acid To a solution containing 3 ml. of diethylamine in 25 ml. of methylene chloride is added in small portions 1.5

g. (7 m moles) of 3-carbomethoxy-4-chlorobenzoyl chloride in 10 ml. of the same solvent. The reaction mixture is allowed to stir at room temperature for 1 hour and is then concentrated to dryness in vacuo.

The residual solid is dissolved in 25 ml. of ethanol, treated with 20 ml. of an aqueous 1N sodium hydroxide solution and allowed'to stand at room temperature for 1 hour. The ethanol is removed from the reaction mixture under reduced pressure and the residual aqueous solution acidified with 12N hydrochloric acid. The product is extracted with ethyl acetate, and the organic phase separated, dried over sodium sulfate and concentrated to dryness in vacuo, 1.1 g., m.p. l20-l22 C. Recrystallization from acetone-hexane provides the pure product, m.p. l2l-l23 C.

Anal. Calcd for C H O NCl: C, 56.4; H, 5.5; N, 5.5.Found:C,56.3;H,5.7;N,5.5.

EXAMPLE 2 Starting with l g. (4.3 m moles) of 3-carbomethoxy- 4-chlorobenzoyl chloride in 20 ml. of acetone and 25 ml. of concentrated ammonium hydroxide, and repeat- 1 ing the procedure of Example 1 provides, after recrystallization from methanol/acetone/hexane, 400 mg. of 2- chloro-5-carbamylbenzoic acid, m.p. 231-23 3 C.

Anal. Calcd for C H O NCI; C, 48.1; H, 3.0; N, 7.0. Found: C, 48.9; H, 3.6; N, 7.1.

EXAMPLE 3 EXAMPLE 4 Starting with the appropriate 4-substituted-3-car- I bomethoxybenzoyl' chloride and requisite amine, and following the general procedure of Example 1, the following congeners are synthesized:

2-Chloro-5-(N-ethyl-N-[2-pchlorophenethyl]carbamyl)benzoic Acid A solution of 3.7 g. (20 m moles) of N-ethyl-N-Z-(pchlorophenethyl) amine in 30 ml. of acetone is treated with 2.33 g. m moles) of 3-carbomethoxy-4- chlorobenzoyl chloride in 20 ml. of the same solvent, and the resulting mixture allowed to stir for 2 hours at room temperature.

The solvent is removed in vacuo and the residue is treated with 30 ml. of ethanol and 18 ml. ofa 1N aqueous sodium hydroxide solution. After one hour at room temperature the ethanol is removed under reduced pressure, and the remaining aqueous solution is acidified with 6N hydrochloric acid. The precipitated product is extracted into chloroform, and the organic layer separated, dried over sodium sulfate and concentrated to dryness to provide the desired product.

EXAMPLE 6 Employing the requisite acid chloride and amine, and following the procedure of Example 5, the following compounds are prepared:

2-bromo-5-(N-m-fluorobenzylcarbamyl)benzoic acid; 2-fluoro-5-(N-methyl-N-[ l-p-methoxyphenethyl]carbamyl)benzoic acid; 2-chloro-5-(N-omethylbenzylcarbamyl)benzoic acid; 2-bromo-5-(N-nbutyl-N-[2-p-bromophenethyl]-carbamyl)benzoic acid; 2-methoxy-5-N-p-chlorobenzylcarbamyl)benzoic acid; 2-methylthio-5-dibenzylcarbamylbenzoic acid; 2- benzylthio-S-(N-m-fluorobenzylcarbamyl)benzoic acid; 2-m-methoxybenzylthio-5-(N-i-propyl-N-[l-pmethoxyphenethyl]carbamyl)benzoic acid; 2-omethylbenzy1thio-5-bis( 1-m-bromophenethyl)-carbamylbenzoic acid.

EXAMPLE 7 2-Chloro-5-hexamethyleneiminocarbonylbenzoic Acid A mixture of 2.3 g. (20 m moles) of hex amethyleneimine and 1.5 g. (7 m moles) of 3-carbomethoxy-4-chlorobenzoyl chloride in 25 ml. of 6 The residual product is dissolved in 30 ml. of methanol, treated with 20 ml. of a 1N aqueous sodium hydroxide solution and allowed to stir for one hour. The methanol is removed in vacuo, and the residual aqueous solution rendered acid with 6N hydrochloric acid. The resulting precipitate in filtered, dried and recrystallized from acetone, 1.0 g., m.p. 188l90 C.

Anal. Calcd for c,,H,,,o,Nc1: C, 60.9; H, 6.1; N, 4.7. Found: C, 61.1; H, 5.9; N, 4.6.

EXAMPLE 8 The procedure of Example 7 is repeated, using the requisite heterocyclic amine and the appropriately substituted benzoyl chloride, to provide the following 2-Chloro-5-(4-Morpholinocarbonyl)benzoic acid In a manner similar to the procedure of Example 8, 1.75 g. (20 m moles) of morpholine and 1.5 g. (7m mols) of 3-carbomethoxy-4-chlorobenzoyl chloride gives, after recrystallization from acetone, 700 mg. of the desired product, m.p. l73l75 C.

Anal. Calcd for C,,H ,O NCl: C, 53.4; H, 4.5; N, 5.2. Found: C, 53.7; H, 4.6; N, 5.3.

EXAMPLE l0 Employing the procedure of Example 7, and starting with the appropriate starting reagents, the following benzoic acids are synthesized:

2-br0mo-5-(4-morpholinocarbonyl)benzoic acid; 2- fluoro--(4-morpholinocarbonyl)benzoic acid; 2- chloro-5-(4-thiomorpholinocarbonyl)benzoic acid; 2-' bromo-5-( 1-piperizinocarbonyl)benzoic acid; 2- methoxy-S-(4-morpholinocarbonyl)benzoic acid; 2- methoxy-5-(l-piperizinocarbonyl)benzoic acid; 2- methylthio-S-(4-thiomorpholinocarbonyl)benzoic acid; 2-benzylthio-5-(4-morpholinocarbonyl)benzoic acid; 2-m-methoxybenzylthio-5-( l-piperizinocarbonyl)-benzoic acid and 2-o-methylbenzylthio-5-(4- morpholinocarbonyl)benzoic acid.

EXAMPLE 1 1 2-Chloro-5-(4-benzylpiperidinocarbonyl)benzoic Acid Starting with 3.5 g. (20 m moles) of 4-benzylpiperidine and 1.5 g. (7 m moles) of 3-carbomethoxy- 4-chlor0benzoyl chloride in 25 ml. of methylene chloride, and following the general procedure of Example 1, there is obtained 1.5 g. of an amorphous product, m.p. 80-85 C.

Anal. Calcd for C l-l O Nclz C, 67.0; H, 5.9; N, 3.9. Found: C, 67.1; H, 5.6; N, 3.9.

EXAMPLE l2 2-Chloro-5-( 3 ,5 -dimethylpiperidinocarbonyl )benzoic Acid The procedure ofxExample -11 is followed,-employing 3,5-dimethylpiperidine in place of 4-benzylpiperidine, to provide 700 mg. of the desired product, m.p. 152154C.

Anal. Calcd for C,,,H O NCl: C, 60.9; H, 6.1; N,- 4.7. Found: C, 60.8; H, 6.1; N, 4.6.

EXAMPLE l3 Theprocedure of Example 1 is again repeated, starting with the appropriately substituted benzoyl chloride and requisite heterocyclic amine to provide, in moderate yields, the following products:

Z-methylplperldlnc 2,4-dlmethylplperidino 2,4-dlmethylplporldlne 3,3-dimethylplperidlno 4-methylhexamcthyleneimine p-bromobenzylthio m-mothylbenzylthio o-methoxybenzylthio m-trifluoromethylbenzylthio chlorine 4-mcthylhexamethyleneimine 5-methylheptamethyleneimine 5-methylheptamethyleneimine p-fluorobenzylthio p-chlorobenzylthio 'methoxy EXAMPLE 14 Groups, each comprising 4 animals, of normal (Sprague-Dawley Charles River) rats weighing from 160-220 grams are fed rat show containing the test compounds for 2 overnight feeding periods. On the morning of the 3rd day the animals are anesthetized and bled from the abdominal aorta. The total plasma cholesterol is then determined by the method of J. J.

Carr and vI. J. Drekter reported in Clin. Chem., 2, 353

(1956). Most of the tests are conducted at a concentration in the feed of 0.15 to 0.25 weight percent of the compound under test, but lowerlevels are employed in some instances. The total quantity of test compound consumed is computed from feed consumption over the 2-day period and is tabulated, in milligrams per kilogram body weight per day, along with the associated percent cholesterol fall measured:

% Choles- Daily terol Dose Compound Fall mg./kg. 2-chloro-5-(3,5-

dimethylpiperidinocarbonyl)benzoic acid 15 153 vfZ-chloro-S-( t-morpholinocarbonyl)benzoic acid 12 233 2-chloro-5- hexamethyleneiminocarbonylbenzoic acid 12 215 2-chloro-5-diethylcarbamylbenzoic acid 25 210 2-chloro-5-(4- benzylpiperidinocarbonyl)benzoic acid 23 209 2-chloro-5-carbamylbenzoic acid 15 227 2-chloro-5-di-n-buty1carbamylbenzoic acid 8 146 EXAMPLE 15 A dry solid pharmaceutical composition is prepared by combining the following materials in the indicated weight proportions:

2-chlore-5-diethylcarbamylbenzoic acid 50 calcium carbonate 20 polyethylene glycol, average molecular weight The dry mixture is thoroughly agitated to obtain a completely uniform blend. Soft elastic and hard gelatin capsules containing this composition are then prepared, employing sufficient material to provide each capsule with 190 mg. of active ingredient.

EXAMPLE 16 A dry solid pharmaceutical composition is prepared by blending the following materials together in the specified weight proportions:

2-chloro-5-(4- benzylpiperidinocarbonyl)benzoic acid 50 sodium citrate 25 alginic acid 10 polyvinylpyn'olidone l0 magnesium stearate 5 After the dried composition is thoroughly blended,

tablets are punched from the mixture, each tablet being of. such size as to contain mg. of the active ingredient. Tablets are also prepared containing, respectively, 5, 10, 25 and 50 mg. of the active ingredient, by

employing the appropriate proportions of 2-chloro-5- (4-benzylpiperidinocarbonyl)benzoic acid and the excipient blend in each case.

EXAMPLE 17 2-Chloro-5-(3 ,5-dimethylpiperidinocarbonyl)benzoic acid Sodium Salt To a solution of 400 mg. (0.01 mole) of sodium hydroxide in 30 ml. of water is added, in portions and with stirring, 2.95 g. (0.01 mole) of 2-chloro-5-(3,5- dimethylpiperidinocarbonyl)benzoic acid. The slightly hazy solution is filtered and the filtrate concentrated at room temperature and under reduced pressure to dryness. The residual sodium salt is triturated with acetone and filtered.

In a similar manner the products of the present invention are converted to their pharmaceutically acceptable basic salts.

PREPARATION A 3-Carbomethoxy-4-substitutedbenzoic Acids a. 3-carbomethoxy-4-chlorobenzoic acid To a stirred mixture of 1.1 g. (5.7 m moles) of 3-carbomethoxy-4-aminobenzoic acid in 25 ml. of l2N hydrochloric acid containing 25 ml. of ice is added over a 2-minute period 430 mg. (6.3 m moles) of sodium nitrite dissolved in 3 ml. of water, maintaining the temperature at -5 C. After allowing the mixture to stir for 20 minutes, it is filtered and the filtrate added in small portions to 630 mg. (6.3 m moles) of cuprous chloride in 15 ml. of l2N hydrochloric acid. Stirring is continued at room temperature for 45 minutes, followed by the addition of 25 ml. of water. The resulting product is filtered and dried, 1.0 g., m.p. 195-198 C. The analytical sample is sublimed at 160 C./0.05 mm pressure, m.p. 198200 C.

Anal. Calcd for C,,1-I O,Cl: C, 50.4; H, 3.3. Found: C, 50.4;1-1, 3.3. b. 3-carbomethoxy-4-bromobenzoic acid The diazotization of 1.95 g. (10 m moles) of 3carbomethoxy-4-aminobenzoic acid is repeated as in Preparation A-a followed by the addition of 1.4 g. (11 m moles) of cuprous bromide and ml. of 48% hydrobromic acid. The resulting reaction mixture is worked up in the usual manner, and the resulting product is filtered, dried and recrystallized from etherhexane. c. 3-carbomethoxy-4-fluorobenzoic acid The diazonium salt from 1.95 g. m moles) of 3- carbomethoxy-4-aminobenzoic acid, prepared according to the conditions of Preparation A-a, is treated with fluoboric acid prepared from 680 mg. (l l m moles) of boric acid and 1.33 g. (40 m moles) of 60 percent hydrofluoric acid. The resulting diazonium fluoborate is filtered, dried and slowly decomposed with heating until the evolution of boron trifluoride ceases. The crude product is washed from the flask and recrystallized from ether. d. 3-carbomethoxy-4-methoxybenzoic acid 1 In a manner similar to that employed in Preparation A-a, 2.9 g. (15 m moles) of 3-carbomethoxy-4- aminobenzoie acid is diazotized with 4.5 ml. of water containing 8 g. of ice, 3.3 ml. of concentrated sulfuric acid and 1.05 g. (15.2 m moles) of sodium nitrile. The precipitated solid diazonium salt is separated from the supernatant by decantation and added in small portions to a hot solution of 10 ml. of water and 10 ml. of concentrated sulfuric acid. When nitrogen evolution ceases, the solution is cooled and the product, 3 carbomethoxy-4-hydroxybenzoic acid, is filtered and dried.

To 980 mg. (5 m moles) of the hydroxybenzoic acid in 2 ml. of dry dimethylformamide is added 480 mg. (10 m moles) of a 50 percent sodium hydride suspension in oil. When the evolution of hydrogen ceases, 710 mg. 5 m moles) of methyl iodide is added and the mixture warmed for 15 minutesQThe reaction is cooled, added to 10 ml. of ice water, filtered and the filtrate acidified with 6N hydrochloric acid. The precipitated product is filtered and dried.

e. 3-carbomethoxy-4-methylthiobenzoic acid To a mixture of 6 g. (0.03 mole) of 3-carbomethoxy- 4-chlorobenzoic acid and 3.6 g. (0.066 mole) of sodium methoxide in 45 ml. of dimethylformamide is added, through a gas dispersion tube, 4.5 g. (0.1 mole) of methyl mercaptan over a period of 5 minutes. The reaction mixture is heated at C. for 15 hours, and is then cooled and the pH adjusted to 5 with l2N hydrochloric acid. The mixture is poured into ml. of water, the product extracted with ether and the ether layer dried over sodium sulfate and concentrated to dryness under reduced pressure. The residual crude product is purified by recrystallization from benzenehexane.

Substituting the appropriate benzyl mercaptan for methyl mercaptan and repeating the displacement procedure the following benzoic acids are prepared:

3-carbomethoxy-4-benzylthiobenzoic acid; 3-carbomethoxy-4-p-chlorobenzylthiobenzoic acid; 3-carbornethoxy-4-m-trifluoromethylbenzylthiobenzoic acid; 3-carbomethoxy-4-m-methoxybenzylthiobenzoic acid; 3-carbomethoxy-4o-methylbenzylthiobenzoic acid; 3-carbomethoxy-4-p-bromobenzylthiobenzoic acid; 3-carbomethoxy-4-m-methylbenzylthiobenzoic acid, 3 -carbomethoxy-4-o-.methoxybenzylthiobenzoic acid and 3-carbomethoxy-4-p-fiuorobenzylthiobenzoic acid.

PREPARATION B 3-Carbomethoxy-4-substitutedbenzoyl chlorides a. 3-carbomethoxy-4-chlorobenzoyl chloride To 100 ml. of thionyl chloride is added 6 g. of 3-carbomethoxy-4-chlorobenzoic acid and the resulting solution heated to reflux for 20 minutes. The reaction mixture is cooled and the excess thionyl chloride removed under reduced pressure. The residual oily product is employed in subsequent reactions without further purification. b. Starting with the appropriate benzoic acid and thionyl chloride, the following benzoyl chlorides, not previously reported in the chemical literature, are synthesized:

O Cl C 02011;

PREPARATION C Aralkyl Amines a. N,a-dimethyl-p-methoxybenzylamine A mixture of g. of p-methoxyacetophenone and an excess of methylamine are hydrogenated in 900 ml. of methanol at 809 0 C. over a Raney nickel catalyst. On completion of the reaction the catalyst is filtered and the filtrate concentrated to an oily product, which on fractional distillation provides the purified intermediate.

The above procedure, which is essentially that which is employed for the preparation of N,a-dimethyl-mmethoxybenzylamine, Netherlands Pat. No. 6,504,208 is also utilized in the synthesis of a-methyl-N-isopropylp-methoxybenzylamine by replacing methylamine with isopropylamine.

b. N-ethyl-2-p-chlorophenethylamine To 15.5 g. (0.1 mole) of 2-p-chlorophenethylamine in 100 ml. of ethanol is added 4.8 g. (0.11 mole) of acetaldehyde and the resulting solution allowed to stir for minutes. Sodium borohydride (3.8 g.; 0.1 mole) is added in small portions with stirring and cooling. When the addition is complete, the mixture is allowed to stir 2 hours at room temperature and is then added to water. The aqueous solution is made strongly basic and the crude product is extracted into ether. The ether layer is separated, dried over sodium sulfate and removed in vacuo. The residual product ispurified by fractional distillation.

Starting with Z-p-bromophenethylamine and n-butyraldehyde and repeating the above procedure provides N-n-butyl-2-p-bromophenethylamine, while starting with m-bromoacetophenone and a-methyl-mbromobenzylamine provides bis(a-methyl-mbromobenzyl)amine.

PREPARATION D Benzyl Mercaptans a. 4-fluorobenzyl mercaptan v A mixture of 20 g. (0.14 mole) of 4-fluorobenzyl chloride and 11 g. (0.14 mole) of thiourea in 100 ml. of anhydrous ethanol is heated at steam bath temperatures for 3 hours. A solution of 8.6 g. of sodium hydroxide in 80 ml. of water is then added and heating is continued under nitrogen for an additional 2 hours. The solution is cooled, extracted with ether, and the ether layer separated and dried over sodium sulfate. Removal of the ether, followed by distillation of the residual product provided 11.9 g. of the desired intermediate, b.p. 37 C./0.l mm.

Anal. Calcd for C,H SF: C, 59.1; H, 5.0. Found: C, 58.8; H, 5.0. I

In a similar manner, starting with the appropriate l4 benzyl halide, are prepared the following benzyl mercaptans:

What is claimed is: l l. A compound selected from those of the formula:

and the pharmaceutically acceptable basic salts thereof, wherein:

R, and R when considered separately are each selected from the group consisting of hydrogen, alkyl containing from 1 to 4 carbon atoms, phenylalkyl and substituted phenylalkyl wherein said alkyl contains from I to 2 carbon atoms and said substituent is selected from the group consisting of fluorine, chlorine, bromine, methyl and methoxy; R, and R, when taken together with the nitrogen to which they are attached form a heterocyclic ring of the formula:

wherein Z is selected from the group consisting of O, S,

NH and (CH wherein said m is an integer from 0 to 3, and methyl, benzyl and dimethyl substituted derivatives of said heterocyclic rings; and

X is selected from the group consisting of fluorine,

chlorine, bromine, methoxy, methylthio and benzylthio and substituted benzylthio wherein said substituent is selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, methyl and methoxy.

2. A compound of claim 1' wherein R, is alkyl containing from 1 to 4 carbon atoms and X is chlorine.

3. The compound of claim 2 wherein R, and R are each ethyl.

4. Thecompound of claim 2 wherein R, is ethyl and R, is 2-(4-chlorophenyl)ethyl.

5. A compound of claim 1 wherein R, and R when taken together with the nitrogen atom to which they are attached form a benzyl substituted piperidine ring.

6. The compound of claim 5 wherein R, and R are 4- benzylpiperidine and X is chlorine.

7. A compound of claim 1 wherein R, and R when I taken together with the nitrogen atom to which they areattached form a dimethylpiperidine ring.

8. The compound of claim 7 wherein R, and R are 3,5-dimethylpiperidine and X is chlorine.

Claims (7)

1. 2. A compound of claim 1 wherein R1 is alkyl containing from 1 to 4 carbon atoms and X is chlorine.
2. 3. The compound of claim 2 wherein R1 and R2 are each ethyl.
3. 4. The compound of claim 2 wherein R1 is ethyl and R2 is 2-(4-chlorophenyl)ethyl.
4. 5. A compound of claim 1 wherein R1 and R2 when taken together with the nitrogen atom to which they are attached form a benzyl substituted piperidine ring.
5. 6. The compound of claim 5 wherein R1 and R2 are 4-benzylpiperidine and X is chlorine.
6. 7. A compound of claim 1 wherein R1 and R2 when taken together with the nitrogen atom to which they are attached form a dimethylpiperidine ring.
7. 8. The compound of claim 7 wherein R1 and R2 are 3,5-dimethylpiperidine and X is chlorine.