Abstract:
Novel amides of norfenfluramine having the formula ##STR1## wherein R is selected from the group consisting of alkyl and alkenyl radicals having 12 to 22 carbon atoms and compositions and methods for combating atherosclerosis and hypercholesteremia, with beneficial side effects useful for combating obesity in atherosclerotic subjects are disclosed. The compounds lower lipid values and simultaneously inhibit appetite and reduce weight gain from ingested food with minimal side effects.

Description:
BACKGROUND OF THE INVENTION 
     This application is a continuation-in-part of application Ser. No. 655,195 filed Feb. 4, 1976 now abandoned. 
    
    
     The present invention relates to novel fatty acid amides or norfenfluramine which are cholesterol-lowering agents having beneficial side effects. More particularly, the invention is concerned with the long chain fatty acid amides of norfenfluramine which have dual action in reducing elevated cholesterol levels in mammalian subjects on a high cholesterol diet by interfering with cholesterol absorption and cholesterol synthesis in the liver and complementary activity in reducing weight gain, said reduction in weight gain due in part to reduced appetite and in part to lowered feed efficiency of ingested food. The cholesterol-lowering agents of this invention are ideally suited for combating diseases of atherosclerosis and hypercholesteremia in mammalian subjects without objectionable side effects and combating obesity in subjects afflicted with said diseases. 
     Atherosclerosis, a form of arteriosclerosis characterized by clogging of blood vessels, is due in part from deposition of excess lipids from the blood stream, primarily cholesterol and triglycerides which circulate through the body conjugated with proteins as lipoproteins, cholesterol appearing to be the larger threat. Decreasing the concentration of lipids in the blood appears to be a desirable means of combating atherosclerosis and heart disease associated therewith. Lipid values in the blood may be reduced by each or a combination of several methods depending upon the primary type of hyperlipemia-limiting lipid intake by selection of foods, by voluntary dietary restriction of food generally, by administration of anorectic drugs which limit food intake generally, or by use of drugs known as antihyperlipidemic agents. In the use of an antihyperlipidemic agent, it may be generalized that no one drug is completely effective in lowering all classes of serum lipids, and no one drug is equally effective in lowering cholesterol and triglycerides. Consequently, there is need for more effective drugs in combating atherosclerosis. 
     Anti-hyperlipidemic agents are believed to function in one or more ways to lower serum cholesterol as follows: 
     (1) Inhibition of synthesis of cholesterol in the liver and/or in the ileum; 
     (2) Inhibition of absorption of dietary cholesterol; 
     (3) Promotion of excretion by increased catabolism of cholesterol from the circulating lipids and from extra hepatic tissue. 
     The association of atherosclerosis with high serum cholesterol levels has directed the treatment of this disease to agents which lower serum cholesterol. Cholestyramine, which is polystyrene trimethylbenzylammonium chloride, and clofibrate, which is ethyl p-chlorophenoxyisobutyrate, act selectively to reduce cholesterol primarily by interfering with its alimentary absorption and synthesis respectively. 
     Other prior art compounds which are long chain fatty acid amides of certain α-methylbenzylamines and anilines having cholesterol-lowering activity ascribed thereto are disclosed in U.S. Pat. Nos. 3,621,043 and 3,728,459, α-methylbenzyl linoleamide being of particular interest. 
     Obesity is often closely associated with atherosclerosis and may be caused by the same root anomaly in the chemistry of individual mammalian subjects. 
     The present invention is based on the unexpected findings that certain fatty acid amides of norfenfluramine act to reduce cholesterol not only by lowering its absorption but its synthesis as well and that feed efficiency as well as appetite are both lowered to effect reduction in weight gain. 
     Thus the compounds of the present invention have multiple functions in controlling lipid values in mammalian blood serum as follows: 
     (1) Appetite inhibition which lowers cholesterol intake; 
     (2) Lowering of cholesterol absorption; and 
     (3) Lowering of cholesterol synthesis in the liver. 
     One of these functions, (3) the lowering of cholesterol synthesis in the liver, is not characteristic of the prior art, α-methylbenzylamides, and function (2) the lowering of liver and serum cholesterol, is more pronounced in the compounds of the present invention in the hypercholesteremic diet. In addition, the compounds differ from prior art amide compounds in that the amides of the present invention reduce weight gain dually in two ways, i.e., by (1) reducing appetite, and (2) reducing feed efficiency. While it has been stated in U.S. Pat. No. 3,621,043 that the prior art compounds do not affect the appetite, it was reported in the Journal of Atherosclerosis Research, Vol. 9, pages 65-71 (1969) that one prior art compound, α-methylbenzyl linoleamide, did suppress gain in body weight of rats which seemed to be caused by reduced feed intake. As set forth hereinbelow, it will be seen that in addition to suppressing appetite the compounds of the present invention reduce feed efficiency, a function not seen with prior art compounds studied. 
     A further distinction over the said prior art amides is greater reduction in low-density lipid carriers in blood serum. A reduction with decrement in high density lipid carriers with increasing concentration using compounds of the present invention was observed. 
     The compounds of the present invention are, therefore, more suitable for controlling lipid values in blood serum and have beneficial side effects in controlling obesity not attributable to said prior art amide compounds. 
     SUMMARY OF THE INVENTION 
     The present invention provides novel amides of norfenfluramine and compositions and methods for lowering elevated serum cholesterol levels in mammalian subjects fed an hypercholesteremic diet. The compounds act in multiplicity of ways of lower serum liver cholesterol and are ideally suited for combating atherosclerosis in subjects suffering therefrom. In addition, the compounds retain some of the anorectic activity of the parent amine, norfenfluramine, without any of the undesirable side effects attendant to the administration of norfenfluramine. Equally important, the amides of norfenfluramine affect the utilization of ingested food so as to decrease expectable weight gain. Thus, in addition to lowering cholesterol, the effects of anorexia and decreased food utilization combine to bring about reduction of weight gain without any apparent effect on the well-being of the subject and without more than mildly affecting the appetite and are, therefore, effective in controlling obesity in hypercholesteremia affected subjects. Metabolic studies show that the blood level of the norfenfluramine moiety of the fatty acid amides is small considering the amount of drug given. 
     The compounds of the present invention have the formula ##STR2## wherein R is selected from the group consisting of alkyl and alkenyl radicals having 12 to 22 carbon atoms. 
     In the preparation of the amides of norfenfluramine of this invention, any of the known processes for preparation of acid amides may be used, such as 
     (1) Reaction of norfenfluramine in dry pyridine with phosphorus trihalide to form the phosphazo compound followed by reaction with the fatty acid or a mixture of fatty acids, which is the preferred method. 
     (2) Reaction of norfenfluramine with fatty acid halide or mixture of fatty acid halides; 
     (3) Reaction of fatty acid or mixture of fatty acids, norfenfluramine and suitable di-substituted carbodiimide; 
     (4) Reaction of fatty acid or mixture of fatty acids or mixture of fatty acids with norfenfluramine at 100°-300° C.; 
     (5) by catalytic dehydration of fatty acid or mixtures of fatty acids and norfenfluramine over a dehydrating agent such as sulfuric acid, p-phenolsulfonic acid and the like, or a cation exchange resin. 
     The acids used in the preparation of the amides of this invention may be of any origin, but usually the acids will originate from any of various natural fats and oils, specifically vegetable oils such as the tall oils, linseed oil, hempseed oil, safflower oil, soybean oil, sunflower oil, rice bran oil, corn oil, cottonseed oil, olive oil, peanut oil, palm oil, coconut oil, and animal oils which are found in most animal fats and fish oils. 
     It is therefore an object of the present invention to provide effective agents for reducing blood serum lipids and liver lipid levels in mammalian subjects, in particular cholesterol. Another object of the invention is to provide compositions and methods for lowering blood serum cholesterol in mammalian subjects for the purpose of combating hypercholesteremia and atherosclerosis. A still further object is to provide a method of combating obesity associated with atherosclerosis patients. Still other objects will become apparent to one skilled in the art from the description which follows and the appended claims. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention encompasses the novel fatty acid amides of norfenfluramine of Formula I as composition of matter and utilization of these amides primarily as cholesterol-lowering agents in combating atherosclerosis in mammalian subjects and secondarily in combating obesity. 
     The following chemical examples illustrate the preparation and establish physical constants of the preferred amides of Formula I. 
     EXAMPLE 1 
     (Linoleamide of Norfenfluramine) 
     N-[1-methyl-2-(3-trifluoromethylphenyl)ethyl]octadeca-9,12-dienamide(cis-cis) 
     A mixture of 61.56 g. (0.18 mole) of norfenfluramine hydrochloride in chloroform was extracted with a 10% aqueous solution of sodium hydroxide. The chloroform layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in one liter of dry pyridine and 15.0 g. (0.11 mole) of phosphrous trichloride was added dropwise with ice bath cooling and stirring. After stirring at room temperature for one hour, 50.0 g. of pure linoleic acid (0.18 mole) was added. This solution was refluxed for 2 hours. Upon cooling, the solution was concentrated in vacuo. The residue was partitioned between chloroform and a 10% solution of sodium hydroxide. The chloroform layer was dried with sodium sulfate, filtered and concentrated in vacuo and distilled. B.P. 225°-230°/0.1 mm. Hg; Yield was 44.0 g. (0.09 mole); 50% of theory. 
     Analysis: Calculated for C 28  H 42  F 3  NO: C, 72.23; H, 9.09; N, 3.01. Found: C, 72.37; H, 9.08; N, 2.97. 
     EXAMPLE 2 
     (Oleamide of Norfenfluramine) 
     N-[1-methyl-2-(3-trifluoromethylphenyl)ethyl]octadec-9-enamide cis isomer 
     A mixture of 61.56 g. (0.18 mole) of norfenfluramine hydrochloride in chloroform was extracted with a 10% solution of sodium hydroxide. The chloroform layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 1 liter of dry pyridine, and 15.0 g. (0.11 mole) of phosphorus trichloride was added dropwise while stirring, with ice bath cooling. After stirring at room temperature for 1 hour, 50.0 g. of pure oleic acid (0.18 mole) was added and the solution was refluxed for 15 hours. Upon cooling, the solution was concentrated in vacuo and the residue was partitioned between chloroform and a 10% solution of sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was distilled. B.P. 230°-235°/0.1 mm. Hg. Yield was 42.0 g. (0.09 mole); 50% of theory. 
     Analysis: Calculated for C 28  H 44  F 3  NO: C, 71.91; H, 9.48; N, 3.03. Found: C, 71.90; H, 9.43; N, 2.98. 
     EXAMPLE 3 
     (Elaidicamide of Norfenfluramine) 
     N-[1-methyl-2-(3-trifluoromethylphenyl)ethyl]octadec-9-enamide trans isomer 
     Following the procedure of Example 2 but substituting 50.0 g. (0.18 mole) elaidic acid for the oleic acid, the titled compound was obtained in 15% yield. B.P. 230°-235°/0.1 mm Hg; 
     Analysis: Calculated for C 28  H 44  F 3  NO: C, 71.91; H, 9.48; N, 3.00. Found: C, 71.83; H, 9.40; N, 2.99. 
     EXAMPLE 4 
     (Stearamide of Norfenfluramine) 
     N-[1-methyl-2-(3-trifluoromethylphenyl)ethyl]octadecanamide 
     Following the procedure of Example 2 but substituting 50.0 g. (0.18 mole) of stearic acid for oleic acid and recrystallizing the final concentrated residue from ethyl acetate rather than distilling it, the titled compound was obtained in 29% yield; m.p. 74°-76° C. 
     Analysis: Calculated for C 28  H 46  F 3  NO: C, 71.61; H, 9.87; N, 2.98. Found: C, 71.61; H, 9.69; N, 2.90. 
     EXAMPLE 5 
     (Linoleamide of Norfenfluramine from Crude Linoleic Acid) 
     A mixture of 36.7 g (0.1 mole) of norfenfluramine hydrochloride in chloroform was extracted with a 10% aqueous solution of sodium hydroxide. The chloroform layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 1 liter of dry pyridine, and 8.0 g (0.06 mole) of phosphorus trichloride was added dropwise with ice bath cooling and stirring. After stirring at room temperature for one hour, 14.0 g (0.05 mole) of linoleic acid containing in percentages by weight: 
     
         ______________________________________linoleic acid          65.5oleic acid             19.0linolenic acid         10.5palmitic acid          3.5myristic acid          0.5stearic acid           0.5misc. fatty acids      0.5                  100.0______________________________________ 
    
     was added. This solution was refluxed for 2 hours. Upon cooling, the solution was concentrated in vacuo. The residue was partitioned between chloroform and a 10% solution of sodium hydroxide. The chloroform layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in benzene and 75 l ml portions were collected from a magnesium silicate column, eluated with benzene followed by a 10% solution of acetone and benzene. The portion containing the product was concentrated in vacuo and distilled. B.P. 220°0.05 mm; Yield 26% theory. 
     Analysis found: C,71.94; H,9.15; N,2.84. 
     Analysis using high pressure liquid chromatography showed that the product was a mixture of fatty acid amides of norfenfluramine and that the predominant amide by a wide margin was the linoleamide of norfenfluramine. 
     According to the method of the invention the compounds of this invention, the norfenfluramine amides of Formula I, are administered orally to mammalian subjects which are suffering from hypercholesteremia or atherosclerosis. The compounds may be administered orally in the form of capsules, tablets, syrups, elixirs, or as admixtures to food. When the compounds are administered as capsules, tablets, elixirs and syrups, they should be given generally at meal time in daily amounts of 50 to 600 mg/kg, preferably 200 to 600 mg/kg. When the compounds are administered as admixtures to food, the weight percentage of the compound based on food will vary from 0.025 to 0.5 weight % and preferably is 0.1 to 0.2 weight %. Generally, subjects under these dosage regimens will show favorable bias to reduction in weight gain and the subject will have a tendency to become less obese. 
     Pharmacology 
     Triton-induced Hyperlipidemia Tests 
     Fasted, male Sprague-Dawley rats weighing 250-350 g were fed ad libitum a commercial lab chow with free access to water. The animals were fasted overnight and administered Triton-WR-1339 (produced by Ruger Chemical Company, Inc., Irvington, New Jersey) as described by Schurr et al.; Lipids 7 68(1972) except the procedure was modified to use the saphenous vein and divided doses of 70 mg/kg. The rats were anesthetized with sodium pentobarbital and terminally bled by heart puncture. Serum was stored at -20° C. until it was analyzed for total cholesterol and triglycerides. Comparison was also made with clofibrate. As shown in Table 1, fatty acid amides of norfenfluramine reduced serum triglycerides and serum cholesterol. 
     Dietary-induced Hyperlipemia Tests 
     General feeding experiments were conducted on rats to determine the effect of the amides of this invention on serum and liver lipids of animals fed a basal diet and a basal diet supplemented with cholesterol. In addition, the effect of these drugs on serum lipoproteins was studied as well as their effect on body weight, gross feed efficiency, liver weight, appetite and energy utilization with respect to their metabolic size. Male, Sprague-Dawley rats weighing 150-175 g. were housed in cages with raised wire floors in a room kept at a temperature of 24°-26° C. with a 12-hour day and 12-hour night cycle, fed ad libitum a semipurified diet consisting by weight % composition: vitamin-free casein, 20; glucose, 63; hydrogenated coconut oil, 10; GBI Vitamin Fortification Mixture, Cat. #40060 obtained from General Biochemical Company of Chargrin Falls, Ohio, 1; modified salt mix of Williams and Briggs, Cat. #170911 obtained from General Biochemical Company, 4; and cellulose, 2; and watered. The modified salt mix provided the following amounts in grams of elements per Kg. of diet: 
     
         ______________________________________calium               7.1chlorine             3.95copper               0.0059iodine               0.00067iron                 0.0287magnesium            0.528manganese            0.057phosphorus           4.55potassium            4.35sodium               2.40sulfur               0.73zinc                 0.135______________________________________ 
    
     The Vitamin Fortification Mix consisted of, in grams per Kg. of the mix: 
     
         ______________________________________p-aminobenzoic acid       11.0132ascorbic acid coated 97.5% pure                     101.6604biotin                    0.0441Vitamin B.sub.12, 0.12% in mannitol                     2.9736calcium pantothenate      6.6079choline dihydrogen citrate                     349.6916folic acid                0.1982innositol                 11.0132menadione (Vitamin K)     4.9559niacin                    9.9119pyridoxin HCl             2.2026riboflavin                2.2026thiamin HCl               2.2026dry Vitamin A palmitate   3.9648 (500,000 units/g)dry Vitamin D.sub.2       0.4405 (500,000 units/g)dry Vitamin E acetate     24.2291 (500,000 units/g)balance, diluent corn starch                     466.6878______________________________________ 
    
     Diets were supplemented with 0.5% cholic acid, 1% cholesterol, and drug at the expense of glucose. The experimental period was 18-21 days with body weight and food measured at specified intervals. Animals were fasted overnight and terminally bled by cardiac puncture. Blood was anti-coagulated with ethylenediamine tetracetic acid and plasma was separated by centrifugation, and stored at -20° C. Livers were excised, weighed, and stored at -20° C. All samples remained at this temperature until they were analyzed for total lipids, total cholesterol, triglycerides and phospholipids. Gross feed efficiency together with the effect of metabolic size on food intake and the effect of drug on energy utilization were determined. 
     
                                           Table 1__________________________________________________________________________Effect of Fatty Acid Amides of Norfenfluramine onSerum Triglycerides and Cholesterol in Triton-InducedHyperlipidemic Rats                  Serum    % Change                                 SerumTest             Dose, Triglycerides                           Triglyc-                                 Cholesterol                                          % ChangeGroup    Compound     mg/kg p.o                  mg/100 ml ± SD                           erides                                 mg/100 ml ± SD                                          Cholesterol__________________________________________________________________________    None (control)            None  588.2 ± 338.6                           0     231.0 ± 59.9                                            0I   Clofibrate   140   124.5 ±  7.8                           -79   173.0 ± 54.0                                          -24.0    Linoleic Amide (Ex. 1)            140   268.7 ±  69.6                           -54   209.0 ± 16.4                                          - 9.5    None (control)            None                 123.5 ± 13.4                                            0II  Clofibrate   140                   94.1 ± 13.6                                          -24    Linoleic &amp; mixed    acid amides (Ex. 5)            140                  101.9 ± 20.4                                          -18    None (control)            None  166.8 ±  82.0                           0     140.0 ± 20.0                                            0    Clofibrate   140   132.7 ±  64.5                           -20   109.3 ± 24.4                                          - 22III Linoleic &amp; mixed    acid amides (Ex. 5)            140    67.3 ±  19.1                           -60   109.0 ± 10.0                                          -22 &#34;           70    64.3 ±  33.9                           -62   109.7 ± 16.6                                          -22 &#34;           35.sup.(a)                  600.0 ± 214.7                           +260  189.0 ± 13.2                                          +28    None (control)            None  618.3 ± 302.2                           0     281.5 ± 40.3                                            0    Clofibrate   140   411.7 ± 118.0                           -34   213.0 ± 14.1                                          -24IV  Oleic acid amide (Ex.2)    of norfenfluramine            140   166.3 ±  37.2                           -73   173.3 ± 10.2                                          -39    Elaidic acid amide (Ex.3)    of norfenfluramine            140   260.0 ± 137.8                           -58   210.0 ± 47.8                                          -25    Stearic acid amide (Ex.4)    of norfenfluramine            140   160.0 ± 110.0                           -74   214.3 ± 91.6                                          -24__________________________________________________________________________ .sup.(a) anomalous result 
    
     Basal Diet 
     Results of testing the mixed amides of Example 5 and reference compounds in rats on a basal diet according to the foregoing procedure for dietary induced hyperlipemia are in Tables 2 and 3. Notably, the amides of this invention (Example 5) pronouncedly lowered food intake and feed efficiency, i.e., lower weight gain per unit of ingested food. 
     Basal Diet with Cholesterol 
     Results of testing the mixed amides of Example 5 an reference compounds in rats on a basal diet with added cholesterol according to the foregoing procedure for dietary induced hyperlipemia are in Tables 4 and 5. The mixed amides of Example 5 again produced pronounced reduction in feed efficiency but in addition lowered serum and liver cholesterol was observed. 
     Similarly obtained data in Table 6 using the pure linoleamide of norfenfluramine of Example 1 also demonstrate the effect on serum and liver lipids. 
     In other analyses, increased dosage amounts of the mixed amides of Example 5 produced decreasing amounts of high density lipoproteins (HDL), and continuing lowered amounts of low density lipoproteins (LDL), Table 7. 
     Toxicity Comparison 
     Motor activity of norfenfluramine and the amides of norfenfluramine of this invention were compared by determination of the activity in female, albino mice of the ICR strain by a modification of the method of Cook et al. in J. Pharmac. Exp. Ther. 113:11a (1955). Results suggest that the amides of norfenfluoramine have only mild effect on motor activity at 100 to 300 mg/kg, i.p. compared to strong effect noted for norfenfluramine at 6.5 mg/kg, i.p. No neurotoxicity was demonstrated for the amides of Example 5 in mice at dosages up to 300 mg/kg, i.p. and 1000 mg/kg, p.o., whereas tremors were observed with norfenfluramine at 40 mg/kg, i.p. and lethality at 100 mg/kg, i.p. 
     
                                           Table 2__________________________________________________________________________Effect on Liver Weight, Body Weight andFood Consumption of Rats Fed a Basal Semi-purified Diet                                               GrossTreatment    Dose.sup.a Liver wt, g ± S.D.                              Body wt, g ± S.D.                                        Food   Feed(c)      mg/kg/day          No. Rats               Total                   per 100 g body wt.                              Initial                                   Final                                        Consumed, g                                               Efficiency.sup.b__________________________________________________________________________None           6    5.7 ± .3                    2.7 ± .3                             158 ± 18                                   212 ± 22                                        309    .175Clofibrate .2%    209   6    9.2 ± .4                    4.4 ± .4                             155 ± 16                                   210 ± 21                                        306    .180Cholo-styramine, 3%    3120  6    5.8 ± .3                    2.7 ± .3                             151 ± 8                                   215 ± 13                                        316    .203Amides ofnorfenflur-amine (Ex. 5)  .1%     96   4    5.3 ± .8                    2.8 ± .2                             176 ± 21                                   190 ± 28                                        241    .058  .2%    204   6    7.0 ± .2                    3.4 ± .7                             171 ±  15                                   205 ± 22                                        304    .112  .5%    490   4    5.9 ± .6                    2.8 ± .1                             185 ± 16                                   208 ± 24                                        276    .083α-methylbenzyl-linoleamide .2%  (d)    182   6    6.7 ± .8                    2.9 ± .3                             158 ± 20                                   226 ± 30                                        331    .210__________________________________________________________________________ .sup.a Based on percentage drug in diet and mean daily food consumed. .sup.b Gross weight gain in grams/total food consumed in grams. .sup.c Weight % of additive in food .sup.d Prior art compound U.S. Pat. Nos. 3,621,043 and 3,728,459 
    
     
                                           Table 3__________________________________________________________________________Effect on the Mean Concentration of Serum and Liver Lipidsof Rats fed a Basal Semi-purified diet    Lipids    Serum mg/100 ml ± S.D.                          Liver mg/g ± S.D.Treatment (b)    Total   Cholesterol                   Triglycerides                          Total   Cholesterol                                        Triglycerides__________________________________________________________________________None     139.80 ± 22.57            69.67 ± 14.15                   30.67 ±  2.89                          46.86 ± 7.43                                  3.06 ± .18                                        4.39 ± 1.65Clofibrate,.2%    143.70 ± 22.42            89.83 ±  8.77                   31.83 ±  7.08                          51.21 ± 7.89                                  2.63 ± .09                                        1.78 ±  .43Cholestyramine 3.%     116.60 ± 23.16            69.20 ± 10.55                   25.80 ±  6.38                          39.32 ± 5.95                                  2.87 ± .33                                        4.88 ± 2.54Amides of nor-fenfluramine(Ex. 5) .1%     153.30 ± 20.10            84.00 ± 10.58                   35.33 ±  7.02                          30.71 ± 2.88                                  3.55 ± .55                                        3.42 ± 2.60 .2%     191.00 ± 49.80            79.33 ± 10.39                   75.33 ± 34.60                          31.97 ± 2.49                                  3.22 ± .40                                        4.00 ±  2.10 .5%     175.50 ±  9.40            86.00 ±  14.99                   70.00 ± 17.51                          34.51 ± 4.06                                  4.10 ± .27                                        6.82 ±  .46α-methylbenzyl-linoleamide (a) .2%     199.80 ± 60.9            77.50 ±  3.91                   72.33 ± 29.92                          40.05 ± 11.37                                  3.34 ± .24                                        4.85 ± 2.71__________________________________________________________________________  (a) Prior art compound U.S. Pat. Nos. 3,621,032 and 3,728,459  (b) Weight % of additive in food 
    
     
                                           Table 4__________________________________________________________________________Effect on Food Consumption and Feed Efficiencyof Rats Fed a Basal Semi-purified Diet Supplemented with Cholesterol               Liver wt, g ± S.D.       Gross         Dose.sup.a  Per 100 g                          Body wt, g ± S.D.                                    Food   FeedTreatment.sup.d    No. Rats         mg/kg/day               Total body wt.                          Initial                               Final                                    Consumed, g                                           Efficiency.sup.b__________________________________________________________________________None     6          7.5 ±  .6                     3.6 ± 2                          132 ± 4                               208 ± 13                                    321    .237Clofibrate, .2%    6    198   10.4 ± 2.6                     4.9 ± 1.2                          135 ± 5                               208 ± 16                                    340    .215Chole-styramine, 3%    6    2930  6.1 ± .5                     2.9 ± .2                          132 ± 13                               208 ± 18                                    336    .226Amides ofnorfenflur-amine (Ex. 5) .1%     6     91   5.9 ±  .5                     3.4 ± .2                          138 ± 6                               177 ± 15                                    288    .135 .2%     6    194   6.1 ±  .3                     3.2 ± .1                          148 ± 9                               190 ±  7                                    328    .128 .5%     6    466   5.7 ±  .4                     3.3 ± .1                          148 ± 12                               172 ± 11                                    298    .081α-methylbenzyl-linoleamide.sup.c .2%     4    199   7.1 ± 1.3                     3.7 ± .2                          137 ± 8                               192 ± 25                                    311    .177__________________________________________________________________________ .sup.a Based on percentage drug in diet and mean daily food consumed. .sup.b Gross weight gain in gross/total food consumed in grams. .sup.c Prior art compound U.S. pat. nos. 3,621,043 and 3,728,459 .sup.d Weight % of additive in food. 
    
     
                                           Table 5__________________________________________________________________________Effect on Serum and Liver Lipids of RatsFed a Basal Semi-purified Diet Supplemented with Cholesterol    Lipids    Serum, mg/100 ml ± S.D.                             Liver, mg/g ± S.D.Treatment.sup.b    Total    Cholesterol                     Triglycerides                             Total   Cholesterol                                             Triglycerides__________________________________________________________________________None     635.67 ± 73.03             272.67 ± 44.19                     253.83 ± 67.69                             120.00 ± 23.22                                     25.37 ± 6.51                                             12.45 ± 10.10Clofibrate,.2%    430.33 ± 119.37.sup.a             235.00 ± 68.27                     126.50 ± 47.21.sup.a                             93.83 ± 12.06.sup.a                                     14.17  ± 9.10.sup.a                                             7.83 ± 2.22Chole-styramine, 3%    242.83 ± 70.05.sup.a              93.67 ± 17.50.sup.a                     180.00 ± 82.19                             76.67 ±  8.09.sup.a                                     6.15 ± 1.37.sup.a                                             11.13  ± 4.11Amides of nor-fenfluramine(Ex.5) .1%     375.67 ± 69.11.sup.a             166.17 ± 44.58.sup.a                     176.00 ± 33.92.sup.a                             83.83 ±  7.96.sup.a                                     4.80 ± 3.42.sup.a                                             7.33 ±  .79 .2%     266.33 ± 40.27.sup.a             141.33 ±  28.08.sup.a                     184.67 ± 44.59                             78.83 ± 12.83.sup.a                                     2.55 ± 2.65.sup.a                                             6.50 ±  .97 .5%     286.67 ± 58.03.sup.a             163.00 ± 23.24.sup.a                     299.50 ± 51.88                             75.33 ± 12.94.sup.a                                     1.50 ±  .50.sup.a                                             7.07 ±  .86α-methylbenzyl-linoleamide.sup.b .2%     453.25 ± 90.58.sup.a             197.75 ± 23.24                     262.50 ± 51.88                             84.00 ± 14.26.sup.a                                     8.33 ± 1.37.sup.a                                             4.35 ± 2.88__________________________________________________________________________ .sup.a p&lt;.05 by Student t-test. .sup.b Prior art compound U.S. Pat. Nos. 3,621,043 and 3,728,459 .sup.c Weight % of additive in food. 
    
     
                                           Table 6__________________________________________________________________________Effect on Linoleamide of Norfenfluramine onSerum and Liver Lipids in Rats Fed aHypercholesteremic Diet (a)(b)   Serum Lipids   Liver Lipids   mg/100 ml.     mg/gTreatment     Trigly-             Phospho-   Trigly-                            Phospho-(d)     Cholesterol         cerides             lipids                  Cholesterol                        cerides                            Lipids__________________________________________________________________________None    454   105 97.5 57.32 30.69                            23.98   ± 121         ± 37             ± 32.6                  ± 4.06                        ± 14.66                            ± 5.44Linoleaamide ofnorfenfluramine(Ex. 1) 0.2%   212 (c)         156(c)             105.4                  7.15(c)                        5.59(c)                            24.1   ± 30         ± 62             ± 18.4                  ± 0.73                        ± 3.67                            + 8.75__________________________________________________________________________ (a) ± values are standard deviation of 10 animals per group. (b) Semi-purified diet supplemented with 1% cholesterol and 0.5% cholic acid at expense of glucose. (c) p&lt;.05 as determined by Student&#39;s t-test.  (d) Weight % of additive in food. 
    
     
                       Table 7______________________________________Effect on Serum Lipoproteins of RatsFed a Semi-purified Diet Supplemented with Cholesterol    No.   Percentage Composition.sup.aTreatment.sup.c      bands   VLDL     LDL   HDL   Albumin______________________________________None       6       37.58    45.94  2.52 13.93Clofibrate, .2%      8       25.76    42.56  9.03 22.63Chole-styramine, 3%      7       17.00    35.07 16.15 31.77Linoleamideof norfenflur-amine (Ex. 5) .1%       6       36.92    11.29 20.07 31.69 .2%       6       23.65    15.42 12.11 42.81 .5%       4       35.78    16.98  2.76 40.46α-methylbenzyl-linoleamide, .2%.sup.b      7       36.19    18.51 29.62 15.65______________________________________ .sup.a VLDL, very low density lipoproteins; LDL, low density lipoproteins and HDL, high density lipoproteins as determined on a Beckman-Gilford spectrophotometer. .sup.b Prior art compound U.S. Pats. 3,621,043 and 3,728,459. .sup.c Weight % of additive in food. 
    
     The LD 50  of the amides of norfenfluramine determined by a method adapted from Finney Statistical Methods in Biological Assay, Hafner Pub. Co., New York, 2nd Ed. (1964), was found to be greater than 10,000 mg/kg, p.o. The KD 50  of norfenfluramine by the same method was 137 mg/kg. The therapeutic index of the amides of norfenfluramine appeared very favorable compared to norfenfluramine and no adverse reactions of the amides on serum glucose, microsomal enzymes or monoamine oxidase were observed. 
     Synthesis of β Sterol and Nonsaponifiable Substances 
     The effect of the mixed amides of Example 5 and reference compounds on β Sterol synthesis was determined by a modified procedure of Hill and Dvornik Arch. Biochem. Biophys. 114 (1966), 88. Male Sprague-Dawley rates weighing 127-175 g. were freely provided a basal semi-purified diet and water. The rats were housed in cages with raised wire floors in a room kept at a temperature of 24°-26° C. with a 12-hour day-12-hour night cycle. The cycle was reversed so the night cycle corresponded to the working day to take advantage of the circadian rhythm that favors cholesterol synthesis. The test period was five days and 20 μCi sodium acetate-1- 14  C (Sp. act. 56 mCi/m mole) administered intraperitoneally. Animals were sacrificed under carbon dioxide and the distal 10 cm of the ileum as well as the median and left liver lobes excised and homogenized. Subsequently, the β Sterols were isolated as the digitonide and the radioactivity determined in a Packard Tricarb Liquid Scintillation Spectrometer Model 3385 using 0.5% 2,5 diphenyloxazole and 8% naphthalene in a solvent mixture of 40% toluene, 40% dioxane and 20% absolute ethanol. Data for the effect of the mixed amides of Example 5 on the synthesis of nonsaponifiable substances and β Sterols as determined by the Digitonide method are shown in Table 8. Results indicate that at doses of 140 mg/kg, p.o. the amides of this invention reduced sterol synthesis from control values by 48% in the liver and 15% in the ileum. A prior art compound, α-methylbenzyllinoleamide at 140 mg/kg, p.o. had no effect on cholesterol synthesis in either tissue. 
     
                                           Table 8__________________________________________________________________________β-Sterol Synthesis. Incorporation ofAcetate-1-.sup.14 C Into Nonsaponifiable andDigitonin Precipitate Sterols       Dose    Acetate-1-.sup.14 C incorporated    No.       mg/kg   n moles/g tissue ± S.D.Compound rats       p.o.           Tissue               Non-saponifiable                        Digitonide__________________________________________________________________________None     15     Liver               4.123 ± 1.718                        3.028 ± 1.072    15     Ileum               7.841 ± 2.467                        6.752 ± 1.248Clofibrate    10 140 Liver               2.943 ± 1.707                        1.588 ± 1.216    10     Ileum               6.774 ± 1.447                        6.098 ±  .909Cholestyra-    10 660 Liver               14.869 ± 4.027                        15.456 ± 2.710mine            Ileum               13.533 ± 3.904                        12.085 ± 1.430Linoleic andmixed acidamides (Ex.5)of norfen-fluramine     4 140 Liver               2.077 ± 1.246                        1.581 ± 1.158     4     Ileum               7.022 ± 2.125                        5.731 ± 1.499α-methylbenzyllinoleamide,(a)       4 140 Liver               4.533 ± 3.131                        3.882 ± 2.887     4     Ileum               7.648 ± 1.664                        5.947 ±  .654__________________________________________________________________________ .sup.(a)  prior art compound U.S. patents 3,621,043 and 3,728,459 
    
     Formulation and Administration 
     The cholesterol-lowering anti-obesity agents of this invention may be orally administered, usually the amount administered is 0.5 to 10 g, per day, preferably 0.25 to 2.5 g per day and the administration may be continued for several months. The cholesterol-lowering agent may be in any suitable form which is conventional for oral administration. Thus, it may be encased in a capsule, or it may be in liquid form such as a slurry, in a tablet form or in a powder form. In preparing the agents in these various forms, the active compound may be mixed with a liquid carrier such as an edible oil. Mixtures of two or more of the agents of this invention may be used in any of the foregoing described dosage forms. 
     Tablet Preparation 
     A granulation is prepared of 
     
         ______________________________________              Parts by wt.______________________________________Lactose              74Starch               26Water sufficient to granulate______________________________________ 
    
     The granulation is dried and screened. 
     
         ______________________________________              Parts by wt.______________________________________Amide of norfenfluramine(structural Formula I)                100Lactose granulation above                145Magnesium stearate    5______________________________________ 
    
     are mixed together and compressed into tablets weighing 250 mg and containing 100 g of the active ingredient per dose unit. 
     Slurry Dosage Form 
     An elixir is prepared containing per liter 
     
         ______________________________________Linoleamide of norfenfluramine(structural Formula I) 10.0 gEthyl alcohol          150.0 mlGlycerin               350.0 mlSorbitol (70% solution)                  350.0 mlBenzoic acid           1.0 gSodium saccharin       0.3 gColoring agent (FD and C Red No. 2)                  0.02 gImitation raspberry flavor                  0.2 mlSpice vanilla          0.02 mlDistilled water        q.s. to 1,000 ml______________________________________ 
    
     The active ingredient of Formula I is added to about two-thirds of the ethanol and all of the glycerin and sorbitol are added and the mixture thoroughly triturated. The saccharin and coloring agent are dissolved in a small amount of the water and coloring agent dissolved therein. The aqueous solution is then added to the alcohol solution and the balance of the water is added to bring the volume to 1 liter and after mixing and filtering an elixir is obtained containing 10 mg of the active ingredient per ml. A unit dose of 15 ml (1 tablespoon) thus contains 150 mg of active ingredient. 
     Any of the linoleamides of this invention or a mixture thereof may be used to prepare either the tableted form or the elixir form. The active ingredient can be suitably varied within the range of 50 to 400 mg and preferably 50 to 200 mg per dosage unit. In addition, other therapeutic agents may be added to these formulations if desired. 
     Powders are prepared with various conditioners added, such as starches, gums, etc., for mixing with human or animal food. 
     Various changes and modifications in the procedures for preparing these hypocholesteremic amides of norfenfluramine and incorporating the same into therapeutic compositions will occur to those skilled in the art, and to the extent that such changes and modifications are embraced by the appended claims, it is to be understood that they constitute part of this invention.