IE44858B1

IE44858B1 - Hypolipidemic p-aminobenzoic acids

Info

Publication number: IE44858B1
Application number: IE104/77A
Authority: IE
Original assignee: Dow Chemical Co
Priority date: 1976-01-19
Filing date: 1977-01-19
Publication date: 1982-04-21
Also published as: GB1521459A; DE2702058A1; IE44858L; SE435175B; JPS5289660A; BE850516A; ATA31277A; DK153471C; GB1521458A; JPS6233230B2; CH628340A5; NO145839C; DK153471B; AT347923B; AU2114077A; NO770151L; DK8177A; FR2338040A1; DE2702058C2; CA1072969A

Abstract

Schiff's bases of the formula I in which R is hydrogen or lower alkyl are obtained by reacting piperonal with p-aminobenzoic acid or with a p-aminobenzoic ester. 4-(1,3-Benzodioxol-5-ylmethylamino)benzoic acid and 4-(1,3-benzodioxol-5-ylmethylamino)benzoic esters of the formula II in which R is hydrogen or lower alkyl are obtained by reducing Schiff's bases of the formula I. The compound 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid which can be prepared according to the invention can be used, for example, for the reduction of the lipid level in the plasma of animals.

Description

The present invention relates to certain novel p-sminobenzoic acid derivatives which have been found to be useful as hypolipidemic agents, to a process for their preparation, and pharmaceutical compositions containing them.

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

Although 4-(1,3-benzodioxol-5-ylmethylamino) benzoic acid ethyl ester and 4- ((2-napht.hyenylmethyl)aminS)’benzoic acid are known TO compounds (see German Patent 716,567 and Chemical Abstracts 58, 521f), their usefulness in lowering serum lipid levels in animals, has not been reported.

We have now found that both these known.compounds as well as other known- and novel jj-aminobenzoic acid derivatives can lower the T5 serum lipid level in an animal.

According to one aspect of the present invention, there is provided a hypolipidemic composition comprising, as the active ingredient, a compound of formula: (I) in which R is 9-anthracenyl, l,J-benzodioxol-b-yi, 1-naphthalenyl, or 2-naphthalenyl, and is an alkyl group containing from 1 to 5 carbon atoms or a hydrogen atom, or a pharmaceutically acceptable salt of a compound of formula (I) in which R is as defined above and R is a hydrogen atom, and a pharmaceutically acceptable diluent or carrier therefor.

We have found that those compounds of formula (I) in which R is 1,3-benzodioxol-5-yl and pJ is an alkyl group containing 1 to 5 carbon atoms, 4-(9-anthracenylmethylamino) benzoic acid, 4-(1,3-benzodioxol-5-yl-methylamino) benzoic acid, 4-(l-naphtha1enylmethylamino)benzoic acid, and 4-(2-naphthenylmethylamino)benzoic acid are particularly useful as hypolipidemic agents.

Of the above named compounds, 4-(9-anthracenylmethylamino) benzoic acid and 4(1,3-benzodiczol-5-ylmethylamit;o) benzoic acid are novel and form another aspect of the present invention. The preparation of these and other useful compounds will be described later.

As used herein, pharmaceutically acceptable salt refers to an acid addition salt of any 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 animal at dosages consistent with good pharmacolog· ical activity. Suitable bases include the alkali metal and alkaline earth metal hydroxides, carbonates, and bi carbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate, or magnesium carbonate; ammonia; and primary, ¢48% <. secondary, and tertiary amines. Aluminium salts, obtained by treating the corresponding sodium salt with an appropriate aluminium complex such as aluminium chloride hexahydrate, are also considered to be pharmaceutically acceptable.

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

The compounds described above have shown hypolipidemic activity in animals, particularly mammals. Hypolipidemic 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 of these compound? display both hypocholesterolemic and hypertriglyceridemic activity. The compounds described above are therefore suitable for treating serum hyperlipidemia, and particularly serum hypercholesterolemia and/or hypertriglyceridemia, that is, abnormally high level cholesterol, and/or triglycerides, in animals.

According to a further aspect of the present invention, there is provided a method for lowering the serum lipid level in a non-human animal which comprises administering internally to the animal a compound of formula (I) as defined above, a pharmaceutically acceptable salt of a compound of formula (I) as defined above, or a composition according to the invention.

The active ingredient can be administered orally or parenterally by subcutaneous, intravenous, or intraperitoneal injection or by implantation, oral administration being preferred.

The hypolipidemic amount of the p-aminobenzoic acid compounds to be administered to an animal, that is the amount which is effective to 4 8 5 8 ίϊΜΙΙ I f firttH ly hwi' (lip '.piiiiii lipid level, un van depending upnn ϊΐη.Ιι factors as the animal treated, the particular p-aminobenzoic acid compound employed, the desired lipid level to be obtained whether or not the animal is hyperlipidemic, the period of administration and the method of administration. In general, an effective daily dosage range is from 1 to 400 mg/kg of body weight, with a daily dosage range of from about 5 to 30 mg/kg of body weight being preferred.

For oral administration, pharmaceutical preparations of the g-aminobenzoic acid derivatives can be made by conventional techniques. 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 alone or it can be mixed with a 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 pharmaceutically 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 can be prepared by standard 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. 5S 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 described above is high enough to allow the use of pharmaceutically-acceptable oils as carriers. For example, vegetable 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, colouring materials, or preservatives.

The jj-aminobenzoic acids 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 die! or as a supplement to the diet. Such compositions preferably contain from 0,02 to 2.0 percent by weight 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 ran he formulated wflit sterile ingredients, compounded and packaged aseepticaIly. 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 particularly useful. From 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 the body isotonicity, 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 incorporate a local anesthetic such as known to those skilled in the art. .

The percentage of the compound to be used in 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 compound in the composition, but those compositions containing a significant amount of carrier, e.g. at least 1 percent and preferably at least 5 percent, are preferred as they allow for the easier administration of the compound.

The compounds of formula (1} in which R1 is a hydrogen atom, i.e. the free acids, may be prepared by reacting p-aminobenzoic acid or an alkyl ester thereof, preferably in an inert solvent therefor, with a compound of formula R-GHO in which R is as hereinbefore defined, to form a Schriff base, and treating the Schiff base vzith a reducing agent, and, when a £-aminobenzoic acid alkyl ester is used, hydrolysing the resulting benzoic acid alley! ester derivative.

The compound of formula (I) in which R^ is an alkyl group containing from 1 to 5 carbon atoms may be prepared by reacting a Cj_g alkyl ester of £-aminobenzoic acid, preferably in an inert solvent therefor, with a compound of formula R-CHO, in which R is as hereinbefore defined, to form a Schiff base, and treating the Schiff base with a reducing agent.

The compounds of formula (II) of the present invention may be prepared by reacting £-aminobenzoic acid or an alkyl ester thereof, preferably in an inert solvent therefor, with a compound of formula R-CHO in which R is 9-anthracenyl or 1,3-benzodioxol-5-yl, to form a Schiff base, and treating the Schiff base with a reducing agent, and, when a £-aminobenzoic acid alkyl ester is used, hydrolysing the resulting benzoic acid alkyl ester derivative.

In all of the above processes the reducing of the Schiff base involves mixing it 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. Sodium borohydride, NaBH^, (1 molar equivalent) 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.

The following examples illustrate the preparation of specific compounds.

EXAMPLE 1 4-(1,3-Benzodioxol-5-ylmethylamino)benzoic acid ethyl ester.

A mixture of 22.5 grams (0.15 mol) piperonal and 24.8 grams (0.15 mol) ethyl £-aminobenzoate in 500 ml of benzene was refluxed until 0.15 mol. of water had been collected in a trap. The reaction was cooled and yellow crystals formed. The mixture was filtered and the crystalline product was washed with benzene and vacuum dried.

This Schiff base weighed 31.97 grams (0.107 mol.).

The Schiff base was dissolved in 500 ml of anhydrous ethanol and warmed to 40°C. Sodium borohydride (4.5 grams) was added, and the resulting slurry was refluxed for 45 minutes. The reaction mass was cooled, poured over 800 ml. of ice water, and the crude 4-(l,3-benzodioxol - 5 - ylmethylamino)benzoic acid ethyl ester precipitated out. The precipitate was collected and washed with water. After vacuum drying, 30.4 grams of the white crystalline ester was obtained The ester had a melting point of 120-122°C. Elemental analysis: C Η N Calculated 68.21 5.72 4.68 Found 68.1 5.82 4.74 20 EXAMPLE 2 4 - (1,3 - Benzodioxol - 5 - ylmethyl amino)benzoic acid was prepared from the above ester as follows. 15 Grams of the ester was mixed with 150 ml. of 20% sodium hydroxide and 150 ml of ethyl alcohol. The resulting slurry was refluxed for 4 hours and then cooled. The clear solution that resulted was poured onto 800 grams of ice. The reaction mass was acidified with concentrated HCl. 4485-8 Crystalline 4 - (1,3 - benzodioxol - 5 - ylmethylamino)benzoic acid formed and was filtered off, washed with water, and dried. The product was recrystallized from acetonitrile. The compound had a melting point of 193-196°C.

Elemental analysis: C Calculated 66.42 Found 66.7 Η N 4.83 5.16 4.90 5.50 Alternatively, tha free benzoic acid derivative can be prepared directly through the reaction of piperonal with p-aminobenzoic acid.

The resulting Schiff base can be reduced with sodium borohydride as described above.

EXAMPLE 3 Following the general procedues set forth in Example 1, 4-(9- anthracenylmethylamino)benzoic acid was prepared. The compound had a melting point of 255-259°C. Elemental analysis: Calculated: Found: C 80.71 80.43 H .24 .35 N 4.28 4.68 Following the general procedures set forth above a number of p-aminobenzoic acid derivatives and their esters were prepared having the general formula: (I) Table I summarizes the results of these studies TABLE I Analysis Melting Point °C Recrystallization Solvent Calculated Found Example Number ' R R‘ C H N C H In 3 9-anthracenyl- H 80.71 5.24 4.28 80.43 5.36 4.68 255- 259 CHgCN 4 1-naphthalenylC2H5 78.66 6.27 4.59 78.6 5.17 4.78 105- 107 hexane 5 1-naphthalenyl H 77.96 5.45 5.05 78.1 5.47 5.23 210- 212 ch3cn/ acetone 6 2-naphthalenyl H 77.96 5.45 5.05 77.64 5.68 5.21 203- 206 CHgCN The hypolipidemic effect of the representative active compounds employed in the practice of the invention is illustratively demonstrated in rats. In this procedure, a compound is dissolved in acetone, taken up on a silica gel, and mixed with ground feed to yield concentrations of 0.125 weight percent of the compound in the animal feed. The treated feed was administered to male rats weighing 150-150 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 SperryWebb method; Journal of Biological Chemistry 187, 97 (1950). The relative levels of triglycerides in the blood and liver samples were determined by the Val Handel and Zilversmit method; £. £®£· £11)1· Msd. 50, 152 (1957) and Clin. Chem. 2’ 249 (1961)- Taking the average levels of the control rats as standard, the mean results obtained in the treated groups is thereby ascertained.

The data presented in Table II summarize the results of the above studies.

TABLE II Compound Serum Serum Liver Liver Liver Txample Number Cholesterol* Triglycerides* Cholesterol* Triglycerides* Weight* 1 -36 -61 -2 0 +6 2 -32 -77 +15 -21 +5 -13 -35 - - -5 5 -9 -50 - - +10 *6 -10 -30 -2 -3 +5 * all data represent relative change in values for the treated animals when compared to the control group.

H's

Claims

I. A hypolipidemic composition comprising, as the active ingredient, a compound of formula: R— CHg— NH· COOR 1 (I) 5 in which R is 9-anthracenyl, 1,3-benzodioxol-5-yl,1-naphtha!enyl, or
2. Naphthalenyl, and R is an alkyl group containing from 1 to 5 carbon atoms or a hydrogen atom, or a pharmaceutically acceptable salt of a compound of i formula (I) in which R is as defined above and R is a hydrogen atom, and a pharmaceutically acceptable diluent or carrier therefor. 10 2. A composition as claimed in claim 1, in which R is 1,3-benzodioxol-5-yl and R 1 is an alkyl group containing 1 to 5 carbon atoms.
3. A compound as claimed in claim 1, in which the compound is 4-(9-anthracenylmethyl aminoJbenzoic acid. 15 4. A composition as claimed in claim 1, in which the compound is
4. -(1,3-benzodioxol-5-ylmethylamino)benzoic acid.
5. A composition as claimed in claim 1, in which the compound is 4- (1-naphthdenylmethyl ami no jbenzoic aci d.
6. A composition as claimed in claim 1, in which the compound is 20 4-(2-naphthalenylmethylamino)benzoic acid.
7. A composition as claimed in any one of the preceding claims, which is in a form suitable for oral or parenteral administration.
8. A composition as claimed in any one of the preceding claims, in which the active ingredient is present in an amount of at least 10 weight percent:
9. A composition as claimed in claim 1 substantially as hereinbefore described.
10. A method for lowering the serum lipid level in a non-human animal which comprises administering internally to the animal a compound of formula (I) as defined in claim 1, a pharmaceutically acceptable salt of a compound of formula (I) as defined in claim 1, or a 10 composition as claimed in any of the preceding claims.
11. A method as claimed in claim 10, in which the compound is “ 4-(9-anthracenylmethylamino)benzoic acid.
12. A method as claimed in claim 10, in which the compound is 4-(1,3-benzodioxol-5-yImethylamino)benzoic acid. 15
13. A method as claimed in claim 10, in which the compound is 4-(l-naphthalenylmethylamino) benzoic acid.
14. A method as claimed in claim 10, in which the compound is 4-(2-naphthalenylmethylamino)benzoic acid.
15. A compound of formula: COOH (Π) in which R is 9-anthracenyl or l,3-benzodioxol-5-yl.
16. A pharmaceutically acceptable salt of a compound as claimed in claim 15.
17. A process for the preparation of a compound as claimed in claim 15 which comprises reacting framinobenzoic acid or an alkyl ester thereof 5 with a compound of formula R“-CHO in which R is as defined in claim 15 to form a Schiff base, and treating the Schiff base with a reducing agent, and, when a £-aminobenzoic acid alkyl ester is used, hydrolysing the resulting benzoic acid alkyl ester derivative.
18. A process as claimed in dim 17 in which the Schiff base, 10 before its treatment with the reducing agent, is mixed with an excess of ethanol and water.
19. A process as claimed in claim 18 in which dilute aqueous sodium hydroxide is added to the mixture of Schiff base, ethanol and water. 15 20. A process as claimed in any one of claims 17 to 19 in which the reducing agent is sodium borohydride. 21. A process as claimed in claim 17 substantially as hereinbefore described in any of Examples 1 to 3. 22. A compound of formula (II) as defined in claim 15 which has
20. Been prepared by the process claimed in any one of claims 17 to
21. Dated this 19th day of January 1977, ^0MFSNS & CO., Applicants' Agents,