GB1560281A - Hypolipidemic 4-(p-fluorobenzylamino)-benzoic acid and salts and esters thereof - Google Patents

Description

(54) HYPOLIPIDEMIC 4-(p-FLUORO BENZYLAMINO)BENZOIC ACIDS, AND SALTS AND ESTERS THEREOF (71) We, THE DOW CHEMICAL COMPANY, a corporation organised and existing under the laws of the State of Delaware, United States of America, of Midland, County of Midland, State of Michigan, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention concerns the novel compounds 4 - (p - fluorobenzylamino)benzoic acid and the pharmaceutically acceptable salts and esters thereof (hereinafter referred to as the compounds of the present invention).

It is recognized that cholesterol and triglycerides play a major role in the formation of artherosclerotic plaques by accelerating the deposition of blood lipids in the arterial wall.

Very few hypolipidemic benzoic acids have been reported until recently. The most important hypolipidemic derivatives of benzoic acid disclosed to date is tibric acid.

U.S. Patent 3,843,662 and U.S. Patent 3,855,255; see also Ryan et al. Clinc.

Pharmacol. Therap., 15. 218 (1974). There have been two reports of hypolipidemic activity in p-aminobenzoic acid analogs: German Offen. 2,316,914 and Belgian Patent 815,703. Alkylamino benzoic acid derivatives have also been described as hypolipidemic agents; U.S. Patent 3,868,416.

Pharmaceutically-acceptable salts refer to the acid addition salts of those bases which will form a salt with a carboxylic acid and which will not cause an adverse physiological effect when administered to an aminal at dosages consistent with good pharmacological activity. Suitable bases thus include, for example, the alkali metal and alkaline earth metal hydroxides, carbonates, and bicarbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate.

sodium bicarbonate, magnesium carbonate, ammonia, and primary, secondary, and tertiary amines. Also, aluminum salts may be obtained by treating the corresponding sodium salt with an appropriate aluminum complex such as aluminum chloride hexahydrate. Esters refers to C15 alkyl esters.

The compounds of the present invention are crystalline solids which are soluble in many common organic solvents such as, for example. acetone, benzene. alcohols, and liquid alkanes.

The compounds of the present invention have shown hypolipidemic activity in animals and in particular in mammals.

Hvpolipidemic activity as used herein refers to the effect of lowering the blood lipid content and in particular the cholesterol and triglyceride content of the serum.

although not all member compounds will displav both hypocholesterolemic and hypotriglyceridemic acitivity. The compounds of the present invention are therefore suitable for use in treating serum hyperlipidemia in mammals and in particular are useful for the treatment of hypercholesterolemia and hypotriglyceridemia, that is, abnormally high levels of lipids, cholesterol, or triglycerides, respectively, in the serum. The compounds can be administered orally or parenterally by subcutaneous. intravenous, or intraperitoneal injection or by implantation, oral administration being preferred.

According to a further aspect of the present invention, therefore, there is provided a pharmaceutical preparation comprising a compound of the present invention prepared for pharmaceutical use.

Also included in the invention is a pharmaceutical composition comprising a compound of the present invention together with a pharmaceutically-acceptable carrier.

The hypolipidemic amount of the compounds of the present invention to be administered to an aminal, that is, the amount which is effective to significantly lower the serum lipid level, can vary depending upon such factors as the aminal treated. the particular compound employed, the desired lipid level to be obtained, whether or not the animal is hyperipidemic, the period of administration, and the method of administration. In general, an effective daily dosage range is from about I to 400 milligrams per kilogram of body weight: with a daily dosage range of from 5 to 30 mg/kg of body weight being preferred.

For oral administration, pharmaceutical preparations may be made by following the conventional techniques of the pharmaceutical chemist. These techniques involve granulating and compressing when necessary or variously mixing and dissolving or suspending the ingredients as appropriate to the desired end product. Numerous pharmaceutical forms to carry the compounds can be used. For example, the pure compound can be used or it can be mixed with a solid carrier. Generally, inorganic pharmaceutical carriers are preferable and particularly solid inorganic carriers. One reason for this is the large number of inorganic materials which are known to be parmaceutically safe and acceptable, as well as very convenient in preparing formulations.The compositions may take the form of tablets, linguets, powders, capsules, slurries, troches or lozenges and such compositions may be prepared by standard pharmaceutical techniques. Tablet compositions may be coated or uncoated and they may be effervescent or non-effervescent.

Conventional excipients for tablet formations may be used. For example, inert diluents, such as magnesium carbonate or lactose, disintegrating agents such as maize starch or alginic acid, and lubricating agents such as magnesium stearate may be used.

If a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a syrup. a liquid solution or suspension.

The hydrocarbon solubility of most of the compounds of this invention is high enough to allow the use of pharmaceuticallyacceptable oils as carriers. For Example vegatable or animal oils such as sunflower oil. safflower oil, maize oil or cod liver oil can be used. Glycerine can also be used.

With this latter solvent. from 2 to 30 percent water may be added. When water alone is the carrier, or when the solubility of the compound in the oil is low. the preparations can be administered in the form of a slurry.

Emulsion compositions may be formulated using emulsifying agents such as sorbitan trioleate, polyoxyethylene sorbitan monooleate, lecithin, gum acacia or gum tragacanth. Aqueous based suspensions may be prepared with the aid of wetting agents such as polyethylene oxide condensation products of alkylphenols, fatty alcohols or fatty acids with the suspending agents, for example a hydrophilic colloid such as polyvinylpyrrolidone. The emulsions and suspensions may contain conventional excipients such as sweetening agents, flowing agents, coloring materials, or preservatives.

The compounds can also be incorporated in a nutritive foodstuff such as, for example, butter, margarine, edible oils, casein, or carbohydrates. Such nutritive compositions are adapted to be administered as a partial or total diet or as a supplement to the diet.

Such compositions preferably contain from 0.02 to 2.0 weight percent of the active ingredient when administered as the total diet. The compositions can contain higher concentrations of the active ingredient when administered as a supplement.

For parenteral use, the compounds of this invention can be formulated with sterile ingredients. compounded and packaged asceptically. They may be administered intravenously or intramuscularly. Useful solvents for formulation in such use are the polyhydric aliphatic alcohols and mixtures thereof. Especially satisfactory are the pharmaceutically-acceptable glycols, such as propylene glycol, and mixtures thereof Glycerine is another example of a polyol which is particularly useful. Up to 25-30 percent by volume of water may be incorporated in the vehicle if desired. An 80 percent aqueous propylene glycol solution is a particularly convenient solvent system.

A pH of about 7.4, and isotonicity compatible with body isotonicfty. is desirable. Basicity may be controlled by addition of a base as required, and a particularly convenient base is monoethanolamine. It may often be desirable to incorportate a local anesthetic and such are well known to those skilled in the art.

The percentage of the compound to be used with the pharmaceutical carrier may be varied. It is necessary that the compound constitutes a proportion such that a suitable dosage will be obtained and it is preferred to use pharmaceutical compositions containing at least 10 weight percent of the compound. Activity increases with concentration of the agent in the carrier, but those compositions containing a significant amount of carrier, e.g. at least 1 weight percent and preferably at least 5 weight percent, are preferred as they allow for the easier administration of the compound.

The 4-(p-fluorobenzylamino)benzoic acid can be prepared by any known procedure for preparing p-benzylamino benzoic acids.

For example, it can be made by reacting paminobenzoic acid with pfluorobenzaldehyde to form a Schiff base and reducing the Schiff base. The Schiff base may be reduced according to known procedures. A convenient method of carrying out this latter procedure involves mixing the Schiff base with an excess of ethanol and water. Dilute aqueous sodium hydroxide, for example about 1 molar equivalent of the Schiff base, optionally can be added to the mixture. A reducing agent such as sodium borohydride or dimethylaminoborane is added at room temperature and stirred until it dissolves.

The mixture is then heated to reflux for 1 to 2 hours. The mixture is poured onto ice and acidified. The product may be filtered off as a precipitate and further purified by known procedures as required.

The esters of the 4-(pfluorobenzylamino)benzoic acid are conveniently prepared from a selected paminobenzoic acid ester as for example paminobenzoic acid ethyl ester. In such a procedure the p-aminobenzoic acid ester is reacted with the p-fluorobenzaldehyde in the same manner as described for the paminobenzoic acid.

In the following examples, only Examples 2 and 3 illustrate the present invention, and they are not to be construed as a limitation thereof.

Example 1 Synthesis of 4 - (p - Chlorobenzylamino)benzoic Acid A mixture of p-chlorobenzaldehyde (17.5 g, 1.25 mole) and p-aminobenzoic acid (17.1 g, 1.25 mole) in 1.5 liters of benzene was refluxed until the theoretical amount of water had been collected. The reaction mass was cooled and filtered. The off-white crystals were dried under reduced pressure.

The Schiff base after drying weighed 29.8 g (1.15 mol, 91 "). The Schiff base was dissolved in 1 liter of ethanol by addition of 46 g (1.15 mole) NaOH in 150 ml water.

Then 1.3 moles ofNaBH4 in 200 ml H2O was added and the resultant mixture was heated to reflux for 2 hours. The reaction mass was cooled and stirred overnight. The slurr- was acidified with conc. HC1 and diluted with 1 liter of H2O. This mixture was filtered.

washed and dried. The crude 4-(4chlorobenzylamino)benzoic acid weighed 31.6 g. The product was recrystallized from isopropanol to give 31.3 g (710,,) of the compound.

The compound was found to have a melting point of 210--213"C. Elemental analysis showed carbon 64.2 ". hydrogen 4.824,, and nitrogen 5.63",,. Theoretical analysis of the compound is carbon 64.95 ", hydrogen 4.62In, and nitrogen 5.35 ".

Example 2 Synthesis of 4 - (p - Fluorobenzylamino)benzoic Acid Following a modification of the general procedure set forth in Example 1. 4-(pfluorobenzylamino)benzoic acid was prepared using p-fluorobenzaldehyde and paminobenzoic acid as the starting materials.

The product was recrystallized from toluene and had a melting point of 20O202.50C.

Elemental analysis showed carbon 68.65In, hydrogen 4.890O, and nitrogen 5.80",,.

Theoretical analysis of the compound is carbon 67.56%, hydrogen 4.93% and nitrogen 5.7lav0.

Example 3 The hypolipidemic effect of 4-(pfluorobenzylamino)benzoic acid was illustratively demonstrated in rats. The compound of the present invention was dissolved in acetone, taken up on a silica gel and mixed with normal ground feed to yield concentrations of 0.125 weight percent of the compound in the aminal feed. The treated feed was administered to male rats weighing 150-160 grams over a 14-day period. Following the feeding period, the rats were sacrificed, and blood samples were collected. The liver was removed, weighed, and frozen for future analysis. The relative levels of serum cholesterol in the blood samples were determined by the Henly method; A. A. Henly, Analyst, 82, 286 (1957). Liver cholesterol was measured by the Sperry-Webb method; Journal of Biological Chemistry 187, 97 (1950).The relative levels of triglycerides in the blood and liver samples were determined by the Van Handel and Zilversmit method: J. Lab.

Clin. Med. 50, 152 (1957) and Clin. Chem. 7.

249 (1961). Taking the average levels of control rats which were similarly treated except only silica gel was added to the ground feed as standard, the mean results obtained in the treated groups were thereby ascertained. The results are as follows: Serum Cholesterol* -41 Serum Triglycerides* -75 Liver Cholesterol* +11 Liver Triglycerides* +1 Liver Weight +7 *All data represents relative percent change in values for the treated aminals when compared to the control group.

WHAT WE CLAIM IS: 1. 4-(p-fluorobenzylamino)benzoic acid.

2. A pharmaceutically-acceptable salt or ester of the compound claimed in Claim 1.

3. A process for the preparation of the compound as claimed in Claim 1, which process comprises reacting p-aminobenzoic acid with p-fluorobenzaldeltyde to form a Schiff base and reducing the said Schiff base.

4. A process as claimed in Claim 3 substantially as hereinbefore described.

5. A process as claimed in Claim 3 substantially as hereinbefore described in Example 2.

6. A compound as claimed in Claim 1 which has been prepared by a process as claimed in any one of Claims 3 to 5.

7. A process for the preparation of a compound as claimed in Claim 2 substantially as hereinbefore described.

8. A compound as claimed in Claim 2 which has been prepared by a process as claimed in Claim 7.

9. A pharmaceutical preparation comprising a compound as claimed in any one of Claims 1, 2, 6 and 8 prepared for pharmaceutical use.

10. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1, 2, 6 and 8 together with a pharmaceutically-acceptable carrier.

11. A composition as claimed in Claim 10 which contains at least 10 weight percent of the compound.

12. A nutritive foodstuff comprising a compound as claimed in any one of Claims 1, 2, 6 and 8.

13. A nutritive foodstuff as claimed in Claim 12 which comprises from 0.02 to 2 weight percent of the compound.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (13)

**WARNING** start of CLMS field may overlap end of DESC **. Serum Cholesterol* -41 Serum Triglycerides* -75 Liver Cholesterol* +11 Liver Triglycerides* +1 Liver Weight +7 *All data represents relative percent change in values for the treated aminals when compared to the control group. WHAT WE CLAIM IS:

1. 4-(p-fluorobenzylamino)benzoic acid.

2. A pharmaceutically-acceptable salt or ester of the compound claimed in Claim 1.

3. A process for the preparation of the compound as claimed in Claim 1, which process comprises reacting p-aminobenzoic acid with p-fluorobenzaldeltyde to form a Schiff base and reducing the said Schiff base.

4. A process as claimed in Claim 3 substantially as hereinbefore described.

5. A process as claimed in Claim 3 substantially as hereinbefore described in Example 2.

6. A compound as claimed in Claim 1 which has been prepared by a process as claimed in any one of Claims 3 to 5.

7. A process for the preparation of a compound as claimed in Claim 2 substantially as hereinbefore described.

8. A compound as claimed in Claim 2 which has been prepared by a process as claimed in Claim 7.

9. A pharmaceutical preparation comprising a compound as claimed in any one of Claims 1, 2, 6 and 8 prepared for pharmaceutical use.

10. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1, 2, 6 and 8 together with a pharmaceutically-acceptable carrier.

11. A composition as claimed in Claim 10 which contains at least 10 weight percent of the compound.

12. A nutritive foodstuff comprising a compound as claimed in any one of Claims 1, 2, 6 and 8.

13. A nutritive foodstuff as claimed in Claim 12 which comprises from 0.02 to 2 weight percent of the compound.