US3716644A - Hypolipidemic agents - Google Patents

Abstract

A METHOD FOR THE LOWERING OF SERUM LIPIDS IN MAMMALS BY THE ADMINISTRATION OF META AND PARA ALKOXYBENZOIC ACIDS, ESTERS AND PHARMACEUTICALLY ACCEPTABLE SALT OF SAID BENZOIC ACIDS AND DIMETHYLAMINOETHYL ESTERS, WHEREIN THE ALKOXY GROUP COMPRISES FROM 12 TO 20 CARBON ATOMS; AND PHARMACEUTICAL COMPOSITION THEREOF.

Description

United States Patent M 3,716,644 HYPOLHIDEMIC AGENTS Henry John Albers and Stephen Joseph Riggi, Sulfern, N .Y., Frederick Louis Bach, Montvale, N.J., and Elliott Cohen, Pearl River, N.Y., assignors to American Cyanamid Company, Stamford, Conn. No Drawing. Filed July 15, 1971, Ser. No. 163,083 Int. Cl. A61k 27/00 US. Cl. 424-308 5 Claims ABSTRACT OF THE DISCLOSURE A method for the lowering of serum lipids in mammals by the administration of meta and para alkoxybenzoic acids, esters and pharmaceutically acceptable salts of said benzoic acids and dimethylaminoethyl esters, wherein the alkoxy group comprises from 12 to 20 carbon atoms; and pharmaceutical compositions thereof.

SUMMARY OF THE INVENTION This invention relates to a method for lowering serum lipids in mammals by the administration of compounds of the following formula:

COOR

BACKGROUND OF THE INVENTION Considerable effort has been directed in recent years to obtain substances which are useful in the treatment of hyperlipidemia, a condition associated with elevated cholesterol, phospholipid and/ or triglyceride 'blood levels. This condition is associated with a number of diseases, one of the most serious being atherosclerosis. Medicaments used to lower blood cholesterol, phospholipid and triglyceride blood levels are termed hypolipidemic drugs. Presently four major lipid lowering agents are available; clofibrate, D-thyroxine, nicotinic acid, and cholestyramine; [R. I. Levy and D. S. Fredrickson, Postgraduate Medicine, vol. 47, pps. 130-136 (1979)]. It has now been found that another class of compounds also exhibits marked hypolipidemic activity. The class of compounds encompassed by the present invention may be termed alkoxybenzoic acids and esters thereof.

SPECIFIC DISCLOSURE The compounds of this invention are generally prepared by the following reaction sequence:

3,716,644 Patented Feb. 13, 1973 base 0 00R 0 00B.

solvent l nHZn-H O CnH2n+1 ?CnH2n+1 (1) NaOH (2) HCl 0 0 OH 0 00B.

R is a lower alkyl having 1 to 5 carbon atoms, phenyl, benzyl or 3-pyridyl; n is 12-20 and the alkoxy group may be meta or para to the car'boxyl or carboxylate group. While it is preferred that the alkoxy group be composed of a straight chain alkyl group, some branching is permissible, such as the presence of one or two methyl groups or an ethyl group as part of the chain.

Of the active compounds, the preferred group comprises those compounds which are alkoxy benzoic acids wherein the alkyl group consists of 12 to 20 carbon atoms. These compounds may be utilized either as the free acids or in the form of a pharmaceutically acceptable salt. The salts may be either of an inorganic nature, such as the ammonium salt, sodium salt, potassium salt, etc., or of an organic type, such as an organic amine salt.

The Z-dimethylaminoethyl alkoxybenzoic acid esters may also be utilized either in the form of the free base or as a pharmaceutically acceptable acid addition salt, there of. These salts may be prepared by reacting the free 'base with an inorganic acid, such as hydrochloric, sulfuric, phosphoric, etc. or an organic acid, such as acetic, citric, tartaric, etc.

While the invention encompasses groupings comprising 12 to 20 carbon atoms as the alkyl portion of the ether function, the preferred groupings are straight chain alkyls with a length of about 1-6 carbon atoms. Of the two possible positions that the alkoxy group may be in relation to the carboxyl or carboxylate group, the preferred one is when the groups are para to each other.

The mechanism of action of the compounds of this invention is not known and the inventors do not wish to be limited to any particular mechanism. However, it is believed that the hypolipidemic activity results from the free acid, or ester of the above general formula which are readily converted in mammals to the acid or its metabolites (e.g. glycerol or cholesterol esters of the parent acid).

In preparing compounds of this invention, the appropriate ester of a hydroxybenzoic acid is employed. The esters are converted to the corresponding phenolate salts which may be used directly without isolation or isolated and purified prior to formation of the ether linkage. Numerous strong bases may be employed, such as sodium hydride, sodamide, sodium methoxide, sodium ethoxide, etc., and solvents which are compatible with the base being employed, such as sodium hydride or sodamide in dimethylformamide, dimethylacetamide, toluene and dimethylsulfoxide or sodium methoxide in methanol. Where the phenolate salt is to be isolated, an aqueous or alcoholic sodium hydroxide solution may be used provided calculated quantities are used so as not to cleave the ester portion of the intermediate to be prepared. Other TABLE I salts could be utihzed with an equal degree of success such as potassium or magnesium. The phenolate salt is 2 3? f gg g converted to the hypolipidenn'c ether by reaction with a lgwering Zvering compound having the general formula C H X, where Compound P r g i 0051223 3 1 X represents a group which is chemically termed an efiicient leaving group, such as bromo, iodo and benzene- P Tridecyloxybeuzoic acid 3g sulfonyloxy. The esters are converted to the correspond- 0.1 5 57 Methyl p-tndecyloxybeuzoate 0 03 0 3 mg acids by hydrolysis with a base, such as sodium hy- 3 Methyl p-tetradeeyloxybenzoate- 0. 1 29 29 droxide, potassium hydroxide, etc. and acidlfication. Ethyl p-tetradeoyloxybenzoate- 0.1 16 59 Occasionally special procedures are employed in the g i tg 14 35 h th 1 metra ecyloxybenzoic ac 1 0.1 27 42 preparation of a particular ester. T e ime y am1n p-Pentadegyloxybenzo c acld 30 2g ethyl esters are prepared by converting the alkoxybenzoic ggg gfigzg gg g ggggggg g} g 2% acid to the corresponding acid chloride and interacting Ben zylpAgetradecyloxybenzgatjI:: 47 said acid chloride with Z-dimethylammoethanol. The ethyl 15 Sdmm vq 1 18 58 Methyl p-(l-methylundecyloay) and phenyl esters are conveniently prepared by estcnfybenzoate 0.1 14 5a 2-dimethylarninoethyl p mg the correspond ng alkoxybenzolc acids with ethanol adecyloxybenzoate M 14 54 and phenol, respectively. In the case of ethanol, sulfuric acid is utilized to facilitate esterification, while the pheno- TABLE II Percent Percent Percent Percent serum sterol triglyceride phospholipid n lowering lowering lowering Compounds diet from control from control from control p-Dodeeyloxybenzoie acid 0. 1 37 62 43 p-Hexadeeyloxybenzoic acid 0. 1 33 53 32 p-Pentadecyloxybenzoie acid- 0. 1 38 45 33 p-Tetradecyloxybenzoie acid 0. 1 33 40 40 p-Tridecyloxybenzoie acid. 0. 1 34 60 43 -Heptadecyloxybenzoie act 0. 1 1 66 7 p-Oetadeeyloxybenzoie acid... 0.1 1 4 59 13 p-Nonadecyloxybenzoie acid 0. 1 l 51 1 3 p-Elcosyloxybenzoic acid 3.; 1 14 24 10 10 1 16 (infiltrate 2 i 3 22 13 1 48 25 S83 mos 1o 35 1s 1 These values are increases from control.

2 Tested for two weeks.

late esters are formed with the aid of carbonyldiimidazole. In addition, numerous other standard esterification techniques are available to prepare the compounds of this invention.

The compounds of the present invention were shown to possess hypolipidemic activity as determined by animal experiments as follows: the compounds studied were administered orally admixed with the diet to groups of 4-6 male rats, CFE strain from Carworth Farms. A control group of 6-8 rats was maintained on the diet alone; test groups were maintained on the diet plus the indicated percentage of compound by weight. After 6 days or 2-4 weeks treatment, serum sterol concentrations were determined either (1) according to the saponification and extraction method of P. Trinder, Analyst 77, 321 (1952) and the colorimetric determination of Zlatkis, et al., J. Lab. Clin. Med. 44, 486 (1953) or (2) by the extraction method of H. H. Lefiier, Amer. J. Clin. Path. 31, 310 (1959), and the colorimetric determination of Zlatkis (vide supra), the overall method appropriately modified for use with an automatic mechanical analyzer. Serum triglycerides were estimated by the automated procedure of Kessler and Lederer [Automation in Analytical Chemistry, Skeggs, L. T. (Ed), Mediad Inc., New York, 1965, p. 341]. The phospholipids were determined by standard methods [6. R. Bartlett, J. Biol. Chem. 234, 466 (1959)]. Concentrations of serum lipids are expressed as milligrams per 100 milliliters.

In these tests, a compound is considered to have hypolipidemic activity if it depresses serum sterol levels 15% or more below that of the controls, and/or depresses triglyceride levels by 25% or more below controls. Table I shows several of the compounds of the present invention and the degree to which they depress serum sterols and triglyceride levels after a 6 day dosing period.

Table II gives the results of a 4 week dosing period using several compounds from this invention and clofibrate. Clofibrate and Sal-I 42-348 [1-methyl-4-piperidylbis-(p chlorophenoxy)acetate] which were administered to animals for two weeks are included for comparison.

The effect of one of the compounds in this series on serum sterol levels was also determined in mice (Table III). 03H mice from the Roscoe B. Jackson Memorial Labs., Bar Harbor, Maine were used. The methods used for lipid analysis were the same as those disclosed above. The results obtained in two tests using ptetradecyloxybenzoic acid are presented.

TABLE III Experiment 1 Experiment 2 Treatment Control Drug Control Drug Dose, percentof diet 0 0.1 0 0. 1 Food Intake, g.lday 3.2 3. 0 2. 9 2. 4 Body weight change, grams. 0. 8 0. 8 0. 3 1. 7 erum sterol, percent lowering 21 16 The compounds of this invention, that is the alkoxybenzoic acids, esters or pharmaceutically acceptable salts, have potencies similar to l-methyl-4-piperidyl bis-(pchlorophenoxy)acetate and clofibrate; and thus have been found to be highly useful as hypolipidemic compounds in mammals when administered in amounts ranging from about .5 mg. per kg. to about 40 mg. per kg. of body weight per day. A preferred dosage regimen for optimum results would be from about 2 mg. per kg. to about 29 mg. per kg. Thus the daily dosage employed for a subject of about 70 kg. of body weight is about 35 mg. to about 2.8 g., and preferably about mg. to about 2.0 g.

The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they-may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 75% or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about and 500 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non toxic in the amounts employed.

In addition, the active ingredients may be incorporated into sustained release preparations. Preparations of this type would contain greater quantities of the active ingredients.

EXAMPLE 1 Methyl p-tridecyloxybenzoate A 4.8 gram (0.1 mole) (50% in oil) portion of sodium hydride was added to 15.2 grams (0.1 mole) of methyl p-hydroxybenzoate in 150 ml. of dimethylformamide, followed by 26.3 grams (0.1 mole) of l-bromotridecane. The reaction was heated at 90-100 (steam bath) for 4 hours, and then it was poured into about 1000 ml. of water. The resulting mixture was extracted with four 250 ml. portions of chloroform. The combined extracts were dried over magnesium sulfate, then taken to an oil using the rotary evaporator. Upon crystallization, the compound was crystallized from ethanol to give 23.49 g. (70%) of methyl p-tridecyloxybenzoate. An analytical sample was obtained by recrystallization from methanol; M.P. 6063.

Analysis-Called. for C H O (percent): C, 75.40; H, 10.25. Found (percent): C, 75.65; H, 10.03.

EXAMPLE 2 p-Tridecyloxybenzoic acid Methyl p-tridecyloxybenzoate 13.49 grams (0.403 mole) was refluxed in 100 ml. of 1 N sodium hydroxide and 100 ml. of ethanol for 3 hours. The hot solution was acidified with 10 ml. of 12 N hydrochloric acid. On cooling the precipitate was filtered and recrystallized from ethanol to give 10.72 g. (80%) of p-tridecyloxybenzoic acid; M.P. 132-4".

Analysis.-Calcd. for C H O (percent): C, 74.96; H, 10.06. Found (percent): C, 74.87; H, 9.79.

EXAMPLE 3 Methyl p-tetradecyloxybenzoate Method I.1-bromotetradecane 27.7 grams (0.1 mole) dissolved in 50 ml. of methanol was added to 15.2 grams (0.1 mole) of methyl p-hydroxybenzoate and 5.4 g. (0.1

mole) of sodium methoxide in 50 ml. of methanol. After refluxing for 17 hours, 0.5 gram of sodium hydroxide was added, and the solvent was removed in vacuo, and the solid was extracted with ether. The ethereal extracts were taken in vacuo to a solid, which was recrystallized from hexane to give 14 g. (40.3%) of methyl p-tetradecyloxybenzoate; M.P. 52-57.

Method II.To 15.2 grams (0.1 mole) of methyl phydroxybenzoate in 50 ml. of dimethylformamide was added 4.8 grams (0.1 mole) (50% in oil) of sodium hydride, followed by 27.7 g. (0.1 mole) of l-bromotetradecane. The reaction was heated at '100 (steam bath) for 4 hours, and then poured into about 600 m1. of water. The resulting crystals were filtered and recrystallized from hexane to give 21.1 g. (60.7%) of methyl p-tetradecyloxybenzoate, M.P. 5054.

Method III.--In a manner analogous to Example 1, 45.6 grams (0.3 mole) of methyl p-hydroxybenzoate, 14.4 grams (0.3 mole) (50% in oil) of sodium hydride, and 83.1 grams (0.3 mole) of l-bromotetradecane gave 74.87 g. (70%) of methyl p-tetradecyloxybenzoate.

Analysis.-Calcd. for C H O (percent): C, 75.81; H, 10.41. Found (percent): C, 75.42; H, 10.21.

EXAMPLE 4 p-Tetradecyloxybenzoic acid In a manner analogous to Example 2, 39.61 g. (0.112 mole) of methyl p-tetradecyloxybenzoate, gave, after refluxing for 3 hours, 34.62 g. (90%) of p-tetradecyloxybenzoic acid, M.P. 129132.

Analysis.Calcd. for C H O (percent): C, 75.40; H, 10.25. Found (percent): C, 75.27; H, 10.15.

EXAMPLE 5 Methyl p-pentadecyloxybenzoate In a manner analogous to Example 1, 30.66 g. (84.8%) of methyl p-pentadecyloxybenzoate was prepared from 15.2 grams (0.1 mole) of methyl p-hydroxybenzoate, 4.8 grams (0.1 mole) (50% in oil) of sodium hydride, and 29.1 grams (0.1 mole) of l-bromopentadecane. The analytical sample melted at 63-66".

Analysis.Calcd. for C H O (percent): C, 76.19; H, 10.57. Found (percent): C, 76.57; H, 10.50.

'EXAMPLE 6 p-Pentadecyloxybenzoic acid In a manner analogous to Example 2, 24.66 grams (0.068 mole) of methyl p-pentadecyloxybenzoate gave 22.11 grams (90%) of p-pentadecyloxybenzoic acid; M.P. 124-130. (softens at Analysis.-Calcd. for C H O (percent): C, 75.81; H, 10.41. Found (percent): C, 75.81; H, 10.29.

EXAMPLE 7 Methyl hexadecyloxybenzoate In a manner analogous to Example 1, 175.92 grams (93.5%) of methyl hexadecyloxybenzoate was prepared from 76 grams (0.5 mole) of methyl p-hydroxybenzoate, 21.1 grams (0.5 mole) (57% in oil) of sodium hydride, and 157.5 grams (0.5 mole) of l-bromohexadecane. The product melted at 6265.

Analysis.Calcd. for C I-E 0 (percent): C, 76.55; H, 10.71. Found (percent): C, 76.34; H, 10.59.

EXAMPLE 8 p-Hexadecyloxybenzoic acid In a manner analogous to Example 2, 170.92 grams (0.455 mole) of methyl p-hexadecyloxybenzoate gave, after refluxing for 16 hours, 118.09 grams (70%) of phexadecyloxybenzoic acid; M.P. 128-131. (softens 97).

Analysis.Ca1cd. for C H O (percent): C, 76.19; H, 10.57. Found (percent): C, 75.89; H, 10.28.

7 EXAMPLE 9 Methyl p-heptadecyloxybenzoate In a manner analogous to Example 1, 24.13 g. (61.8%) of methyl p-heptadecyloxybenzoate was prepared from 15.2 grams (0.1 mole) of methyl p-hydroxybenzoate, 4.8 grams (0.1 mole) (50% in oil) of sodium hydride, and 31.9 g. (0.1 mole) of l-bromoheptadecane. The product melted at 68-71.

Analysis.Calcd. for C H O (percent): C, 76.87; H, 10.84. Found (percent): C, 77.05; H, 10.77.

EXAMPLE 10 p-Heptadecyloxybenzoic acid In a manner analogous to Example 2, 7.48 g. (42.8%) of p-heptadecyloxybenzoic acid was obtained from 18.13 g. (0.0464 mole) of methyl p-heptadecyloxybenzoate; M.P. 130-131 (softens 103).

Analysis.Calcd. for C H O (percent): C, 76.55; H, 10.71. Found (percent): C, 76.70; H, 10.56.

EXAMPLE 11 Methyl octadecyloxybenzoate In a manner analogous to Example 1, 32.58 g. (80.0%) of methyl octadecyloxybenzoate was prepared from 15.2 grams (0.1 mole) of methyl p-hydroxyhenzoate, 4.8 grams (0.1 mole) (50% in oil) of sodium hydride, and 33.3 g. (0.1 mole) of l-bromooctadecane. The product melted at 6972.

EXAMPLE 12 p-Octadecyloxybenzoic acid In a manner analogous to Example 2, 26.58 grams (0.0654 mole) of methyl p-octadecyloxybenzoate gave, after refluxing for 16 hours, 16.40 grams (61.9%) of p-octadecyloxybenzoic acid; M.P. 124127 (softens 97).

Analysis.Calcd. for C H O (percent): C, 76.87; H, 10.84. Found (percent): C, 76.50; H, 10.60.

EXAMPLE 13 Methyl p-nonadecyloxybenzoate In a manner analogous to Example 1, 15.35 grams (73.5%) of methyl p-nonadecyloxybenzoate was prepared from 7.6 grams (0.05 mole) of methyl p-hydroxybenzoate, 2.4 grams (0.05 mole) (50% in oil) of sodium hydride, and 17.37 grams (0.05 mole) of l-bromononadecane. The product melted at 73-75".

Analysis.-Calcd. for C H O (percent): C, 77.46; H, 11.08. Found (percent): C, 77.57; H, 10.92.

EXAMPLE 14 p-Nonadecyloxybenzoic acid In a manner analogous to Example 2, 9.35 grams (0.0222 mole) of methyl p-nonadecyloxybenzoate, after refluxing for 16 hours, gave 6.66 grams (74.2%) of p-nonadecyloxybenzoic acid; M.P. 123-126 (softens 105).

Analysis.Calcd. for C H O (percent): C, 77.17; H, 10.96. Found (percent): C, 77.43; H, 10.85.

EXAMPLE l Methyl p-eicosyloxybenzoate 8 ArzwZysis.-Calcd. for C H O (percent): C, 77.66; H, 11.17. Found (percent): C, 77.26; H, 11.05.

EXAMPLE 16 p-Eicosyloxybenzoic acid Forty three grams (0.1 mole) of the methyl ester of p-eicosyloxybenzoic acid was dissolved in 750 ml. of hot EtOH. When solution was complete 15 ml. of 10 N NaOH was added all at once. The sodium salt of the desired product formed in quantitative yield after 20 minutes. Filtration afforded the solid salt which was triturated with two -ml. portions of ether and two 100 ml. portions of acetone. After this treatment the salt of the p-eicosyloxybenzoic acid was suspended in water (300 ml.) and warmed with 50 ml. of cone. BC]. The desired product p-eicosyloxybenzoic acid was collected by filtration, airdried, and recrystallized from benzene; transition point temperature 126-127.

Analysis.--Calcd. for C27H4603 (percent): C, 77.46; H, 11.08; 0, 11.47. Found (percent): C, 76.41; H, 10.76; 0, 12.83 (dith).

EXAMPLE 17 Phenyl p-tetradecyloxybenzoate p-Tetradecyloxybenzoic acid 6.7 grams (0.02 mole) and 3.3 grams (0.02 mole) of 1,1'-carbonyldiimidazole were dissolved in 50 ml. of tetrahydrofuran for two hours. Then, 2 grams (0.021 mole) of phenol, and a trace of sodium hydride were added, and the reaction was refluxed for 3 hours. The reaction mixture was filtered, and the filtrate was taken to an oil in vacuo. The compound solidified and was recrystallized from isopropanol to give 6.59 grams (80%) of phenyl p-tetradecyloxybenzoate, M.P. at 78-81".

Analysis.--Calcd. for C H O (percent): C, 78.98; H, 9.33. Found (percent): C, 78.70; H, 9.20.

EXAMPLE 18 Ethyl p-tetradecyloxybenzoate Ten grams (0.03 mole) of p-tetradecyloxybenzoic acid was dissolved in ca. ml. of absolute EtOH and 3 drops of concentrated H 80 The clear solution was refluxed for 8 hours and then concentrated to a crude solid which was recrystallized from hot EtOH to afford 8.5 grams (70%) of the desired ethyl p-tetradecyloxybenzoate; M.P. 80-82".

Analysis.Calcd. for C H O (percent): C, 76.19; H, 10.57. Found (percent): C, 75.80; H, 10.42.

EXAMPLE 19 Methyl m-tetradecyloxybenzoate A solution consisting of 3.2 grams (0.02 mole) of the methyl ester of m-hydroxybenzoic acid and 5.7 g. (0.02 mole) of l-bromotetradecane in 50 ml. of DMF was treated with 1.0 gram (0.02 mole) of NaH (51.2% active) suspended in mineral oil. When addition of NaH was complete the reaction mixture was heated at steam cone temperature for ca. 3 hours. At the end of this period the reaction mixture was poured into approximately 2 liters of H 0 and the crude product was separated by filtration. Two recrystallizations from hot ethanol afforded the desired methyl ester of m-tetradecyloxybenzoic acid; M.P. 40-42.5.

Analysis.Calcd. for C H O (percent): C, 75.82; H, 10.41. Found (percent): C, 75.54; H, 10.24.

EXAMPLE 20 m-Tetradecyloxybenzoic acid Three grams (0.009 mole) of the methyl ester of mtetradecyloxybenzoic acid were dissolved in 50 ml. of 3A ethanol by heating the solution to reflux tempera ture. To the refluxing solution was added 3 ml. of 10 N sodium hydroxide solution which caused a precipitation of the sodium salt of the desired product. Th suspension 9 was allowed to cool to room temperature and then acidified with an excess of concentrated hydrochloric acid. Following this procedure 2.8 grams of m-tetradecyloxybenzoic acid was isolated; M.P. 95-97.

Analysis.Calcd. for C H O (percent): C, 75.40; H, 10.25. Found (percent): C, 75.33; H, 10.14.

EXAMPLE 21 Benzyl p-tetradecyloxybenzoate In a manner analogous to Example 1, 11.4 grams (0.05 mole) of benzyl p-hydroxybenzoate, 2.4 grams (0.05 mole) (50% in oil) of sodium hydride, and 13.85 grams (0.05 mole) of l-bromotetradecane gave 12.39 grams (0.0293 mole) (60%) of benzyl p-tetradecyloxybenzoate; M.P. 49-52".

Analysis.Calcd. for C H O (percent): C, 79.20; H, 9.50. Found (percent): C, 79.53; H, 9.44.

EXAMPLE 22 Sodium p-tetradecyloxybenzoate 3-pyridyl p-tetradecyloxybenzoate In a manner analogous to Example 17, 5.8 g. (0.0173 mole) of p-tetradecyloxybenzoic acid and 0.82 g. (0.0173 mole) of l,l-carbonyldiimidazole followed by 1.65 g. (0.0173 mole) of 3-hydroxypyridine and a trace of sodium hydride gave 5.44 g. (80%) of 3-pyridyl p-tetradecyloxybenzoate; M.P. 61-64".

Analysis.-Calcd. for C H NO (percent): C, 75.87; H, 9.06; N, 3.40. Found (percent): C, 75.56; H, 9.14; N, 3.39.

EXAMPLE 24 Methyl pl-methylundecyloxy benzo ate In a manner analogous to Example 1, methyl p-(2- dodecyloxy)benzoate was prepared from 25.0 g. (0.1 mole) of 2-bromododecane, 15.2 g. (0.1 mole) of methyl p-hydroxybenzoate and 4.8 g. (0.1 mole) of sodium hydride (50% active; dispersed in mineral oil). The product melted at 6870.

Analysis.Calcd. for C H O (percent): C, 74.95; H, 10.07. Found (percent): C, 74.24; H, 9.73.

EXAMPLE 25 Z-dimethylaminoethyl p-(p-hexadecyloxy)benzoate hydrochloride A solution of 4.1 g. (0.012 mole) of 4-(n-hexadecyloxy)benzoic acid and 6.0 ml. (0.083 mole) of thionyl chloride in 50 ml. of benzene is stirred under reflux for one hour and then concentrated under reduced pressure.

Crystallization of the residue from petroleum ether (B.P. 30-60) affords 4- (n-hexadecyloxy)benzoyl chloride as a white solid. A solution of this material and 1.0 ml. (0.010 mole) of Z-dimethylaminoethanol in 50 ml. of benzene is stirred under reflux for 90 minutes, allowed to cool, and filtered. Recrystallization of the solid from acetone affords 2-dimethylaminoethyl p-(n-hexadecyloxybenzoate hydrochloride, M.P. 130133.

EXAMPLE 26 Methyl p-dodecyloxybenzoate In a manner analogous to Example 1, 30.4 grams of methyl p-hydroxybenzoate, 9.6 g. (50% in oil) of so- 10 dium hydride, and 49.8 g. of l-bromododecane gave about 65 grams of crude methyl p-dodecyloxy benzoate. Careful purification of 10 g. of this gave 4.39 grams of pure material; M.P. 52-54".

Analysis.-Calcd. for C 'H O (percent): C, 74.96; H, 10.06. Found (percent): C, 74.96; H, 9.99.

EXAMPLE 27 p-Dodecyloxy benzoic acid In a manner analogous to Example 2, about 55 grams of crude methyl p-dodecyloxy benzoate gave after careful purification, 6.42 grams of p-dodecyloxy benzoic acid; M.P. -133.

Analysis.-Calcd. for C H O (percent): C, 74.47; H, 9.87. Found (percent): C, 74.54; H, 9.71.

EXAMPLE 28 The present compounds can be dispersed in dosage unit form such as hard shell capsules or soft shell capsules. A formulation found useful in the preparation of such capsules is as follows:

p-Hexadecyloxybenzoic: Per 100 capsules, grams Acid 50.0 Lactose, USP 300.0 Magnesium stearate (0.5%) 3.1

Total 353.1

The above formulation is thoroughly mixed and placed in equal quantities in 100 capsules.

EXAMPLE 29 The following example represents a formulation useful in preparing tablets. Larger tablets can be scored and divided in halves to be given once or twice a day. Obviously smaller tablets can be used in multiple doses to obtain the daily amount of active material. The following formulation has been found useful.

Per tablet, mg.

p-Hexadecyloxybenzoic acid 500 Corn starch 210 Methylcellulose 400 350 Magnesium stearate 1% 182 Total 1242 The active ingredient, corn starch and methylcellulose are blended together. The mixture, after drying, is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.

EXAMPLE 30 The following example represents a formulation useful in preparing an oral syrup.

Ingredient: Amount 2-dimethylaminoethyl p-hexadecyloxybenzoate hydrochloride mg 5000 Sorbitol solution (70% NF.) ml 40 Sodium benzoate mg Saccharin mg 10 Red dye (F.D. & C. No. 2) mg 10 Cherry flavor m 50 Distilled water, q.s. ad 100 ml.

The sorbitol solution is added to 40 ml. of distilled water and the active ingredient is suspended therein. The saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 ml. with distilled water. Each ml. of syrup contains 50 mg. of drug.

We claim:

1. A method of lowering elevated serum lipid levels in mammals which comprises orally administering to said 11 mammals an efiiective lipid-lowering amount of a compound of the formula:

wherein the position of the COOR group is meta or para to the OC H group, n is an integer from 12 to 20 inclusive, and R is selected from the group consisting of hydrogen, lower alkyl having 1 to 5 carbon atoms, phenyl, benzyl, 3-pyridyl, Z-dimethylaminoethyl and where R is hydrogen or Z-dimethylaminoethyl the pharmaceutically acceptable salts thereof.

2. The method of claim 1 wherein said compound is administered to provide a daily dosage of from about .5 mg. to about 40 mg. per kg. of body weight of said mammal.

3. The method of claim 2 wherein said daily dosage is about 2 mg. to about 29 mg. per kg. of body weight of said mammal.

4. The method of claim 1 wherein the compound is P( 16 33 s 4 2 5. The method of claim 1 wherein the compound is p-(nC H O)C H CO CH CH N(CH and pharmaceutically acceptable salts thereof.

References Cited J. Pharm. and Pharmacol, vol. 6, 119-26 (1954). Chemical Abstracts, vol. 48, 6218.

ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, Assistant Examiner U.S. C1. X.R. 424263, 317

a'm' ha Em @FFEGE Patent No. 5 716 644 hated February 15 1975 HENRY JOHN All BEES STEPEEN JOSH H IRIGrGrI Inventvfls) FRKHERTOK LOUIE 134M351a OTT 60% It is certified that error: appeate in the above-identified patent and that said Letters Patent are hereby eorrected as shown below:

Column 1 line 58 "1979" should read 1970 Column 4 line 11 "methy" should read methyl Column 7., line 60 "C should read C Column 9 line 26 "when" should read Water 0 Signed and sealed this 10th day of July 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. Rene Tegtmeyer Attesting Officer Acting Commissioner of Patents ORM PO-IOSO (10-69) UECOMM-DC 603764 69