CA1080254A - Fatty acid amides of norfenfluramine - Google Patents

Abstract

Abstract of the Disclosure Novel amides of norfenfluramine having the formula

Description

108Vf~4 The present invention relates to novel fatty acid amides of norfenfluramine which are cholesterol-lowering agents having beneficial side effects. More particularly, the invention is concerned wîth the long chain fatty acid amides of norfenflur-amine which have dual action in reducing elevated cholesterol levels in mammalian subjects on a high cholesterol diet by inter-fering 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 character-ized by clogging of blood vessels, is due in part from deposition of excess lipids from the blood stream, primarily chlolesterol and tri-glycerides which circulate through the body conjugated with proteins as lipoproteins, cholesterol appearing to be the larger threatO
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, ~.

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by voluntary dietary restriction of food generally, by administration of anorectic drugs which lLmit 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 ~unction 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 ~-methylbenzylamines and anilines having cholesterol-lowering activity ascribed thereto are disclosed in U. S. Patents 3,621,043 and 3,728,459, ~-methylbenzyl linoleamide being of particular interest.

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Obesity is often closely associated with atherosclerosis and may be caused by the same root anomaly in the chemistry of in-j dividual mammalian sub;ects.
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.
j Thus the compounds of the present invention have mul-tiple 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, a-methyl-benzylamides, and function (2) the lowering of liver and serum cholesterol, is more pronounced m 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 in two ways, i.e., by ~1) reducing appetite, and ~2) reducing feed efficiency. While it has been stated in United States Patent 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, ~-methylbenzyl linoleamide, did suppress gain in body weight of rats which seemed to be caused by reduced feed intake. As set forth hereinbelow, it ,.

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will be seen that in ad~ition 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 carrier~ 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 amlde compounds.
SummarY of the Invention The present invention provides novel amides of norfenflur-amine and compositions and methods for lowering elevated serum cholesterol levels in mammalian subjects }ed an hypercholesteremic diet. The compounds act in multiplicity of ways to lower serum liver cholesterol and are ideally suited for combating athero-sclerosis 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 , - 5 -',, ,:

1o8()zs4 are, therefore, effective in controlling obesity in hyper-cholesteremia 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 - CH2-CH-I-C-R Formula , CF3 wherein R is an alkyl or alkenyl radical having 12 to 22 carbon , atoms, or a mixture of two or more such compounds.

Thus, this invention provides a process for the prepara-tion of a compound having the formula:

wherein R is an alkyl or alkenyl radical having 12 to 22 carbon atoms, , or a mixture of two or more such compounds, which comprises either (a) acylating norfenfluramine of the formula:-with a saturated or unsaturated fatty acid having 13 to 23 carbon atoms or a mixtura of such acids, or with an acylating derivative thereof; or ~ (b) reacting norfenfluramine with a phosphorus trihalide `` 20 to form the corresponding phospha70 compound and reacting this with :

~ - 6 -~08()Z54 a saturated or unsaturated fatty acid haying 13 to 23 carbon atoms or a mixture of two or more of said acids.
Thus the amides of norfenfluramine of this invention, are prepared by any of the known processes for preparation of acid amides, i.e.:-~ 1) Reaction of norfenfluramine in dry pyridine with phos-phorus trihalide to form the phosphazo compound followed by reaction with the fatty acid or a mixture of fatty acids, which is the pre-ferred method.
C2) Reaction of norfenfluramine with fatty acid halide or mixture of fatty acid halides;
C3) 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 100-300C.;

(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 ex-change resin.
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i The acids used in the preparation of the amides of this invention may be of any origin, but usually the acids will originate ~rom any of various natural fats and oils,specifi-cally vegetable oils such as the tall oils, linseed oil, hemp-seed oil, safflower oil, soybean oil, sun~lower 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 provlde compositions and methods for lowering blood serum cholesterol in mammalian subjects for the purpose of combating hypercholes-teremia and atherosclerosis. A still further object is to provide a method of combating obesity associated with atheros-clerosis 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.

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1C~8VZ54 Example 1 (Linoleamide of norfenfluramine) N-[l-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 5 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 phos trichloride was added drop-wise 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 two 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); ~0~ of theory.
Analysis: calculated for C28H42F3~0: C~72.2~; H,9.09; N,3.01 Found: C,72.~7; H, 9 . o8; ~,2.97 Example 2 (Oleamide of norfenfluramine) ~-[l-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 ~08VZS~

15.0 g. (0.11 mole) of phosphorus trichloride was added drop-wise while stirring, with ice bath cooling. After stirring at room temperature for one hour, 50.0 g. of pure oleic acid (0.18 mole) was added and the solution was refluxed for 15 hours.
Upon coolingJ 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.o g.
(0.09 mole); 50% of theory.
Analysis: Calculated for C2aH44F3~O: C,71.91; H~9.48; N,3.03 Found: C,71.90; H,9.43; ~,2.98 Example 3 (Elaidicamide of norfenfluramine) N-~l-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. ~30-235/0.1 mm Hg;
Analysis: Calculated for C28H44F3NO: C,71.91; H,9.48; ~,3.00 Found: C,71.ô3; H,9.40: ~,2.99 ~'~

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' Example 4 (stearamide of norfenfluramine) N-[l-methyl-2~(3-trifuluoromethylphenyl)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.74-76C.
Analysis: Calculated for C2~H4~F9N0: 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 hydro-chloride in chloroform was extracted with a 10~ aqueous solu-tion 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 8.0 g (0.06 mole) of phosphorus trichloride was added dro~wise with ice bath cooling and stlrring. After stirring at room temperature ~` 20 for one hour, 14.0 g (0.05 mole) of linoleic acid containing in percentages ~y weight:
linoleic acid65.5 oleic acid 19.0 linolenic acid10.5 palmitic acid3.5 myristic acid0.5 stearic acid 0.5 misc. fatty acids O.S
100. 0 30 was added. This solution was refluxed for t~o 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, 108025~

filtered, and concentrated in VaCUQ. The residue was dissolved in benzene and 75 ml portions were collected from a magnesiu~
silicate column, elùated with benzene followed by a 10% solu-tion of acetone and benzene. The portion containing the prod-, ~ uct was concentrated in vacuo and distilled. B.P. 22Q/O.OS
mm;. Yield 26% theory.
Analy.sis 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 norfenflur-- 10 amine and that the predominant amide by a wide margin was the linoleamide of norfenfluramine.
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According to the method of the invention the compounds of this invention, the norfenfluramine amides of Formula IJar~ -administered orally to mammalian subjects which are suffering ' 15 from hypercholesteremia or atherosclerosis. The compounds may be administered orally in the form of capsules, tablets, syrups, - elixirs, or as admixtures to food. ~hen the compounds are ad-ministered as capsules, tablets, elix~rs and syrups, they should b~ given generally at meal time in daily amounts o~ 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 ten-dency to become less obese.

Pharmacolog~
Triton-induced hyperli~idemia tests. Fasted, male Sprague-Dawley rats weighing 250-350 g were fed ad libitum a co~mercial lab chow with free access to water. The animals were fasted , overnight and administered Triton~WR-133g (produced by Ruger ~ r~

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108VZ5~ ( Chemical Company, Inc., Irvington, New Jersey) as described by Schurr et al; ~ 68(1972) except the proced~re was modified to use the saphenous vein and divided doses of 70 mg ~g. The rats were anesthetized with sodium pentobarbital and terminally bled by heart puncture. Serum was stored at -20C. until it . was analyzed for total cholesterol and triglycerides. Comparisonwas 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 efficiencyJ liver weight, appetite and energy utilization with respect to their metabolic size. Male, Sprague-Dawley ra~s weighing 150-175 g. were housed in cages with raised wire floors in a room kept at a temperature of 24-26C. with a 12-hour day and 12-hQur night cycle, fed ad libitum a semipurified diet consisting by weight % composition: vitamin-free casein, 20;
glucose, 63; hydrogenated coconut oil, 10; GBI Vitamin Forti-fication Mixture, Cat.#40060 obtained from General Biochemical Company of chargrin Falls, Ohio, l; 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.

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calcium 7.1 chlorine 3. 95 copper 0. 0059 iodine 0.000O7 iron 0.0287 magnesium 0. 528 manganese 0.057 phosphorus 4.55 potassium 4.35 sodium 2. 40 sulfur 0.73 zinc 0.1~5 The Vitamin Fortification Mix consisted of, in grams per Kg. of the mix:
p-aminobenzoic acid 11.0132 ascorbic acid coated 97.5,~ pure 101.6604 biotin 0. 0441 Vitamin Blz, 0.12% in mannitol 2-9736 calcium pantothenate6.6079 choline dihydrogen citrate 349.6916 folic acid 0.1982 innositol 11. 01~2 menadione (Vitamin K)4.9559 niacin 9.9119 pyridoxin HCl 2.2026 riboflavin 2.2026 thiamin EICl 2.2026 dry Vitamin A palmitate3.9648 (500,000 units/g) dry Vitamin D2 445 (500JOOO units/g) dry Vitamin E acetate24.2291 (500,000 units/g) balance, diluent cornstarch 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 ethylene-diamine tetracetic acid and plasma was separated by centrifugation, and stored at -20 C. Livers were excised, weighed, and stored at -20C. All samples remained at this temperature un-til 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.

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sasal 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. 3 lower weight gain per unit of ingested f~od.
Basal diet wlth cholesterol. Results of testing the mixed amides of Example 5 and 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 f norfenfluramine of Example 1 also demonstrate the effect on serum and liver lipids.
In other analyses, increased dosage amounts of the mixed amides of Exam~le 5 produced decreasing amounts of high de~sity 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 norfenfluramine have only mild effect on motor activity at 100 to 300 mg ~ g, i.p. compared to strong effect noted for ~08025~
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 ~ g, i.p. and 1000 mg ~gJ p.o., whereas tremors were observed with norfenfluramine at ~0 mg ~g, i.p. and lethality at 100 mg ~g, i.p.

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10~30254 Table 7 E~fect on Serum Lipoproteins of Rats Fed a Semi-purified Diet Supplemented with Cholesterol Treatment No. ~
(c) ba VLDL LDL HDL Albumin None 6 37.58 45.942.52 13.93 Cloflbrate, .2% 8 25.7642.56 9.03 22.63 Chole-styramine, 3% 7 17.0035.07 16.15 31.77 Linoleamide of norfenflur-amine (Ex. 5) .1% 6 36.~211.29 20.07 31.69 .2% 6 23.6515.42 12.11 42.81 .5% 4 35.7816.98 2.76 40.46 a-methylbenzyl-linoleamide,.2% 7 36.19 18.5129.62 15.65 (b) a = VLDL, very low density lipoproteins; LDL, low density lipoproteins;
and HDL, high density lipoproteins as determined on a Beckman-Gilford spectrophotometer.
b = Prior art compound U.S. patents 3,621,043 and 3,728,459.
c = Weight % of additive in food.

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The LD50 of the amides of norfenfluramine determined by a method adap~ed from Finney Statistical Methods in siological Assay, Hafner Pub. Co., Ne~ ~ork, 2nd Ed. (1964), was found to be greater than 10,000 mg ~ g, p.o. The KD50 of norfenfluramine by the same method was 137 mg ~g. 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 ~ Sterol and ~onsaponifiable Substances The effect of the mixed amides of Example 5 and reference compounds on ~ Sterol synthesis was determined by a modified procedure of Eill and Dvornik Arch. Biochem. Biophys. 114 (1966), 88. Male Sprague-Dawley rats 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. wlth a 12-hour day-12-hour night cycle.
The cycle was reversed so the night cycle corres30nded to the working day to take advantage of the circadian rhythm that favors ¦ 20 cholesterol synthesis. The test period was five days and 20 luCi sodium acetate-1-l4C (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 ~ Sterols were lsolated 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.

lO~V25~

Data for the effect of the mixed amides of Example 5 on the synthesis of nonsaponiflable substances and ~ 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, -methylbenzyllinoleamide at 140 mg/kg, p.o. had no effect on cholesterol synthesis in either tissue.
Table 8 ~-Sterol Synthesis. Incorporation of Acetate -1- C Into Nonsaponifiable and ! Digitonin Precipitate Sterols DoseAcetate-1-14C incorporated No. mg/kgn moles/g tissue + S.D.
Compound rats p.o. TissueNon-saponifiable Digitonide None 15 Liver4.123 + 1.7183.028 + 1.072 Ileum7.841 + 2.4676.752 + 1.248 Clofibrate 10 140 Liver2.943 + 1.7071.588 + 1 216 Ileum6.774 + 1.4476.098 + 909 Cholestyramine 10 660 Liver 14.869 + 4.027 15.456 + 2.710 Ileum13.533 + 3.90412.085 + 1.430 Linoleic and mixed acid amides (Ex. 5) of norfen-fluramine 4 140 Liver2.077 + 1.2461.581 + 1.158 4 Ileum7.022 + 2.1255.731 + 1.499 ~-methylbenzyl linoleamide, (a) 4 140 Liver4.533 + 3.1313.882 + 2 887 4 Ileum7.648 + 1.6645.947 + 654 (a) prior art compound U.S. patents 3,621,043 and 3,728,459 - 25 _ ~08V'~5~

Formulation and ~dministration The cholesterol-lowering anti-obesity agents of this in-vention may be orally administered, usually the amount adminls-tered 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 fonm 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.

I Tablet Preparation .. ~ , A granulation is prepared of Parts by wt.
Lactose 74 Starch 26 Water sufficient to granulate The granulation is dried and screened.
Parts by wt.
Amide of norfenfluramine (structural Formula I)100 Lactose granulation above 145 Magnesium stearate 5 are mixed together and compressed into tablets weighing 250 mg nd containing 100 g of the active ingredient per dose unit.

_26-. ~

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Slurry Dosage Form An elixir is prepared containing per liter Linoleamide of norfenfluramine/O,o (structural Formula I) 100.0 ~
Ethyl alcohol 150.0 ml Glycerin 350.0 ml Sorbitol (70~ solution) 350.0 ml Benzoic acid 1.0 g Sodium saccharin 0.3 g Coloring agent (FD and C Red No. 2) 0.02 g Imitation raspberry flavor 0.2 ml Spice vanilla 0.02 ml Distilled water q.s. to 1, oao 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 trituxated. The saccharin and I 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 i 20 added to bring the volume to 1 liter and after mixing and fil-tering an elixir is obtained containing ~ mg of the active ingredient per ml. A unit dose of 15 ml (1 tablespoon) thus I 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 suita~ly 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.

.

Claims (21)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound having the formula:

I

wherein R is an alkyl or alkenyl radical having 12 to 22 carbon atoms, or a mixture of two or more such compounds, which comprises either;
(a) acylating norfenfluramine of the formula:- II

with a saturated or unsaturated fatty acid having 13 to 23 carbon atoms or a mixture of such acids, or with an acylating derivative thereof; or (b) reacting norfenfluramine with a phosphorus trihalide to form the corresponding phosphazo compound and reacting this with a saturated or un-saturated fatty acid having 13 to 23 carbon atoms or a mixture of two or more of said acids.

2. A process according to claim 1(a) in which the preparation of the phosphazo compound is carried out in dry pyridine.

3. A process according to claim 1(a) in which the acylation is effected by reaction with a fatty acid halide or a mixture of fatty acid halides.

4. A process according to claim 1(a) in which the acylation is effected by reaction with a fatty acid or mixture of fatty acids by heating alone at 100-300°C or by reaction in the presence of a di-substituted carbodiimide.

5. A process according to claim 1(a) in which the acylation is effected by dehydrating a mixture of norfenfluramine with a fatty acid or a mixture of fatty acids.

6. A process according to claim l in which R is cis, cis CH3(CH2)4CH=CH CH2CH=CH(CH2)7-.

7, A process according to claim 1(b) in which N-[1-methyl-2(3-trifluoromethylphenyl)ethyl]octadeca-9,12-dienamide(cis-cis) is prepared by reacting norfenfluramine with phosphorus trichloride in the presence of pyridine and reacting the intermediate phosphazo compound so produced with linoleic acid.

8. A process according to claim 1 in which R is cis-CH3(CH2)7CH=
CH(CH2)7-.

9. A process according to claim 1(b) in which cis-N-[1-methyl-2-(3-trifluoromethylphenyl)ethyl]octadec-9-enamide is prepared by reacting norfenfluramine with phosphorus trichloride in the presence of pyridine and reacting the intermediate phosphazo compound so produced with oleic acid.

10. A process according to claim 1 in which R is trans-CH3(CH2)7 CH=
CH(CH2)7-.

11. A process according to claim 1(b) in which trans-N-[1-methyl-2-(3-trifluoromethylphenyl)ethyl]octadec-9-enamide is prepared by reacting norfenfluramine with phosphorus trichloride in the presence of pyridine and reacting the intermediate phosphazo compound so produced with elaidic acid.

12. A process according to claim 1 in which R is CH3(CH2)16-.

13. A process according to claim 1(b) in which N-[1-methyl-2-(3-trifluoromethylphenyl)ethyl]octadecanamide is prepared by reacting norfen-fluramine with phosphorus trichloride in the presence of pyridine and reacting the intermediate phosphazo compound so produced with stearic acid.

14. A process according to claim 1(b) in which norfenfluramine is reacted with phosphorus trichloride in the presence of pyridine and the in-termediate phosphazo compound so produced is reacted with a mixture contain-ing in percentages by weight:
linoleic acid 65.5 oleic acid 19.0 linolenic acid 10.5 palmitic acid 3.5 myristic acid 0.5 stearic acid 0.5 miscellaneous fatty acids 0.5

15. A compound selected from the fatty acid amides of norfenfluramine having effective cholesterol-lowering activity in mammals of the formula wherein R is an alkyl or alkenyl radical having 12 to 22 carbon atoms of a mixture of two or more such compounds whenever prepared by the process of claim 1 or 2 or by an obvious chemical equivalent thereof.

16. N-[1-methyl-2-(3-trifluoromethylphenyl)-ethyl]octadeca-9,12-dien-amide cis-cis isomer whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

17. Cis N-[1-methyl-2-(3-trifluoromethylphenyl)ethyl]octadec-9-enamide whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

18. Trans N-[1-methyl-2-(3-trifluoromethyl-phenyl)ethyl]octadec-9-enamide whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

19. N-[1-methyl-2-(3-trifluoromethyl-phenyl)ethyl]octadecanamide whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

20. A mixture of fatty acid amides of norfenfluramine having effec-tive cholesterol-lowering activity in mammals whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.

21. A process according to claim 5 in which the dehydrating agent is sulfuric acid or p-phenolsulphonic acid or a cation exchange resin.