DE2704744A1 - FATTY ACID AMIDES FROM NORFENFLURAMINE AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

The invention relates to new fatty acid mids of Norfenf lurc.mine (^ -Methyl-m-CtrifluoromethylJ-phenathylamine), the cholesterol-lowering agents with beneficial effects are. In particular, the invention relates to the long-chain fatty acid araids from Norfenfluremine, which have a double Effect on lowering elevated cholesterol levels in individuals or mammals at high levels Cholesterol diet by impairing or hindering cholesterol absorption and cholesterol synthesis in the

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Over and have a complementary activity in terms of reducing weight gain, being the pier reduction in weight gain partly due to decreased appetite and partly due to decreased food efficiency from ingested food. The choiesterin-depressing agents according to of the invention are ideal for combating the diseases atherosclerosis and Kypercholesteremia without harmful side effects and to combat obesity in persons or mammals afflicted with these diseases are suitable.

Atherosclerosis, a form of arteriosclerosis that is characterized by clogging of the blood vessels partly due to the deposition of an excess of lipids from the bloodstream, mainly cholesterol and triglycerides, that circulate through the body linked to proteins called lipoproteins, the cholesterol being the bigger threat seems to be. A decrease in the concentration of lipids in the blood appears to be desirable To be a means of combating atherosclerosis and related heart disease. Levels of lipids in the blood can depending on one of the methods mentioned below or by a combination of different methods from the primary type of hyperlipemia limiting lipid uptake through food choices, through voluntary dietary restriction of food in general, through the administration of anorectic (appetite suppressing) Medicines that restrict food intake in general, or through the use of medicines, known as therapeutic hyperlipidemic agents are decreased. When using an anti-hyperlipidemic By means it can generally be said that no single drug is completely effective in terms of Lowering of all classes of serum lipids and that no drug is equally effective in lowering it of cholesterol and triglycerides. To the-

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accordingly there is a need for effective remedial drugs to combat atherosclerosis.

•*O

Antihyperlipidenic agents are believed to have an effect on them one or the other way of lowering serum cholesterol as follows:

(1) Inhibition of the synthesis of cholesterol in the liver and / or in the ilium (Kruinmdarin),

(2) inhibiting the absorption of dietary cholesterol,

(3) Promoting excretion through increased catabolism of cholesterol from circulating lipids and from extrahepatic tissue.

The association of atherosclerosis with high serum cholesterol levels has directed the treatment of this disease to agents that lower serum cholesterol. Cholestyramine (polystyrene trimethylbenzylanimonium chloride ) and clofibrate (ethyl p-chlorophenoxyisobutyrate) act selectively in terms of lowering cholesterol, primarily through impairment or disturbance of its alimentary absorption or its synthesis. .

Other known compounds, the long chain fatty acid amides of certain "* methylbenzylamines and anilines which are ascribed cholesterol-lowering activity are described in U.S. Patents 3,621,043 and 3,728,459, where the ^ C-methylbenzyllinoleamide of particular Interest is.

Obesity is often closely related to atherosclerosis connected and may be due to the same basic anomaly in the

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Chemistry of individuals or mammals.

The invention is based on the unexpected knowledge

established that certain norfenfluramine ' fatty acid amicles act to lower cholesterol not only by decreasing its absorption but also its synthesis, and that food efficacy as well as appetite are decreased to bring about a decrease in weight gain.

Thus, the compounds according to the invention have multiple functions in terms of controlling lipid levels in the blood serum, as follows:

(1) appetite suppressant, which decreases cholesterol intake,

(2) decrease in cholesterol absorption, and

(3) decrease in cholesterol synthesis in the liver.

One of these functions, (3), the reduction of cholesterol synthesis in the liver, is not characteristic of the prior art cC -methylbenzylamides, and the function (2), the reduction of liver and serum cholesterol, is more pronounced for compounds according to the invention in the hypercholesteremic diet. In addition, the compounds differ from the known amide compounds in that the amides according to the invention reduce weight gain in a twofold (double) manner, ie (1) by decreasing appetite and (2) by decreasing food efficiency. While US Pat. No. 3,621,043 stated that the known compounds do not affect appetite, the Journal of Atherosclerosis Research, Vol. 9, pages *) (a-methyl-m- (trifluoromethyl) phenethylamine

of the formula chj

ι ^

-CH ₂ -CH-NH ₂ /

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65 to 71 (19δ9) reported that a known compound (oc-methylbenzyllinoleamide) the increase in body weight suppressed by rats what appears to be caused by decreased food intake. V / ie below discussed, it can be seen that in addition to appetite suppression, the compounds according to the invention degrade food efficiency, a feature common to the known compounds tested is not apparent.

Another distinction from the amides of the prior art is the greater reduction in value the low density lipid carrier in blood serum. There was a decrease with a decrease in lipid carriers of high density with increasing concentration when using compounds according to the invention.

The compounds according to the invention are therefore more suitable for controlling lipid levels in blood serum and have beneficial side effects in combating obesity, which amide compounds do not of the prior art.

The invention provides novel amides of norfenfluramine and compositions for lowering elevated serum cholesterol levels in mammalian subjects fed a hypercholesteremic diet. The compounds act in multiple ways with regard to the lowering of serum and liver cholesterol and are ideally suited for combating the ether oskis of the people below them. In addition, the compounds retain some of the anorectic activity of staramamine, ie norfenfluramine, without any of the undesirable side effects.

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reactions accompanying the administration of norfenfluramine. In the same V, ^r else affect the amides of Norfenfluraminedie utilization of administered food, so as to reduce the expected weight gain. So join in addition to the lowering of Cholestsrins dia effects of anorexia (loss of appetite) and the reduced food utilization, a reduction in weight gain without any perceptible V / MPACT the Y. ^r ohlbefinden of persons or other entities to bring about and appetite only mild to affect. Therefore, they are effective in combating obesity in persons and subjects afflicted with hypercholesteremia. Metabolic studies show that the blood level of norfenflur ~ amine in fatty acid amides is low when one considers the amount of drug given.

The compounds according to the invention have the general formula

CH ₃

\\ I II

\\ CH ₂ -CH-NCR

H CF ₃

in which R consists of saturated and unsaturated alkyl radicals Consists of 12 to 22 carbon atoms.

In the manufacture of aer amides from NorfenfluramiiE according to The invention can use any of the known methods for the production of acid amides are used, such as

(1) Reaction of norfenfluramine in dry pyridine with Phosphorus trihalide to make the phosphazo compound

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form, with subsequent reaction with the fatty acid or a mixture of fatty acids, v / as the preferred Procedure is.

(2) Reaction of Ilorfenfluramine with fatty acid halide or a mixture of fatty acid halides,

(3) Conversion of fatty acids or a mixture of fatty acids, horffluramines and suitable disubstituted ones Carbodiimide,

(A) Reaction of fatty acid or a mixture of fatty acids with norfenfluramine at 100 to 300 ° C, and

(5) catalytic dehydration of fatty acid or mixtures of fatty acids and norfenfluramines over a dehydrating agent like sulfuric acid, p-phenolsulfonic acid or the like., Or a cation exchange resin.

The acids used in the preparation of the amides according to the invention can be of any origin, usually however, the acids are derived from any natural fats and oils, particularly vegetable oils, such as tall oils, linseed oil, hempseed oil, safflower oil, soybean oil, Sunflower oil, rice husk oil, corn oil, 3aunwollseedöl, 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 invention to provide effective agents for reducing blood serum lipids and liver lipid levels Humans and mammals, especially cholesterol

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create. The invention also aims to provide compositions to lower blood serum cholesterol in people and mammals deliver to Kypercholesteremia and Fight atherosclerosis.

Another purpose of the invention is to provide medicines to combat obesity that associated with atherosclerosis in many patients.

The invention is explained in more detail below with reference to examples, which the production and the physical Show constants of the preferred amides of formula I.

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Example 1 (Linolear.:id of ITc rf enf luranine)

N- ₍ / 'I - :: ethyl-2- (3-trifluoromethylphenyl) eth?' - l7octadeca-9 .12-dienanide (cis-cis)

A mixture of 61.56 g (0.18 mol) of torfenfluraniine hydrochloride in chloroform was extracted with a 10% aqueous solution of hatric hydroxide. The chloroform layer was dried with sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in one liter of dry pyridine, and 15.0 g (0.11 mol) of phosphorus trichloride were added dropwise with cooling using an ice bath and added with stirring. After stirring for one hour at room temperature, 50.0 g of pure linoleic acid (0.18 µl) were added. This solution was refluxed for 2 hours. After 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 hydroxide sulfate, filtered, concentrated in vacuo and distilled. Bp 225-230 ° / 0.1 nnKg; the yield was 44.0 g (0.09 hol); 50 ^ of theory.
Analysis for C ₂₈ H ₄₂ P ₅ ITO:

Calculated: C 72.23 H 9.09 K 3.01 Found: C 72.37 H 9.08 IT 2.97

Example 2

(Oleamide from! Peat enf luranine ) N- ^ I-methyl-2- (3-trifluoromethylphenja) ethyl7octadec-9-

enaaid-cis-isorier

A mixture of 61.56 g (0.18 LIoI) of!

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- w - / I

hydrochloric in chloroform was extracted with a 10xigen IIatriurr * hydroxide solution. The chloroform layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 1 liter of dry pyridine, and 15.0 g (0.11 LIoI) of phosphorus trichloride were added with stirring and cooling by means of a bath. For one hour: stirring at room temperature, 50.0 g of pure oleic acid (0.13 LIoI) are added, and the solution was refluxed for 15 hours. After cooling, the solution was concentrated under vacuum 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. Bp 230-235 / 0.1 m ^ Hg; the yield was 42> 0 g (0.09 oil); 50fo of the theory.

Analysis for C ₂₈ H ₄₄ F-HO:

Calculated: C 71.91 H 9.48 N 3.03 Found: C 71.90 H 9.43 II 2.98

Example 3 (elaidic acid amide from! Torfeniluxamine)

N- ^ TI.iethyl-2- (3-trifluoromethyl-phenyl) -ethyl7octadec-9- enamido-trans-isonic

Following the procedure of Example 2 except that 50.0 g (0.18 LIoI) of elaidic acid was used in place of the oleic acid, the above compound was obtained in 15% yield. Kp 230 - 235 ° / 0.1 inKg.

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^H 44 - U- , 91 - H 9 , 48 II 3.00 C. Ah , 83 H 9 , 40 Π 2.99 Analysis for C-g C. P ₅ IiO: Calculated: 71 71

Example 4

(Stearamide from Horfenfluranine) N- / I-L; exhyl-2- (3-trifluoroethylphenyl) ethyi7octadecanaiaid

According to the procedure of Example 2, with the modification that oleic acid was replaced by 50.0 g (0.18 LIoI) of stearic acid and that the concentrated indrücksxand was not crystallized from ithylacetat instead of distilled, the above-mentioned compound was obtained in a yield of 29 ^{° C} / * received; ρ 74 _ 76 ⁰ C

Analysis for C ₀₃ H- ^ F ₇ -NO:

Calculated: C 71.61 H 9.87 U 2.98 Found: C 71.61 H 9.69 N 2.90

Example 5 (Linoleanide from Ilorf enf luramine from crude linoleic acid)

A mixture of 36.7 g (0.1 LIoI) of liorfenflurainine 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 a dry iridine, and 8.0 g (0.06 hol) of phosphorus tricloride were added dropwise with cooling by means of 2 ± s-

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. 270Λ74Α

/ η

added v / ater and with stirring. ! laugh for an hour? .watch at room temperature, 14.0 g (0.05 mol) of linoleum

acid that Weight-fo Linoleic acid 65.5 Oleic acid 19.0 Linolenic acid 10.5 Pal:.: Itic acid 3.5 I. Iyristic acid 0.5 Stearic acid 0.5 various fatty acids 0.5

100.0

contained, admitted. This solution was refluxed for two hours after cooling the solution was concentrated under vacuum. The residue was partitioned between chloroform and a 10% sodium hydroxide solution divided up. The chloroform layer was dried with sodium sulfate, filtered and concentrated in vacuo. The remainder was dissolved in benzene and 75 ml aliquots were collected on a magnesium silicate column, with benzene and then with a 10% solution of acetone and benzene eluted. The portion containing the product was concentrated under vacuum and distilled. Kp 220 ° / 0.05 mmng; the yield was 26 / j of theory.

Analysis:

Found: C 71.94 H 9.15 N 2.84

The analysis using high pressure liquid chromatography showed that the product was a hiss from fatty acid anides of! peat fluranine, and that that predominant amide mainly from Lir.oleamid (linoleic acid amide) des Horffluranine consisted of.

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The compounds according to the invention, the IIfenfluranineanide of the formula I, can in particular be administered to humans and mammals suffering from Kypercholesterenia or atherosclerosis. The compounds can be administered orally in the porin of capsules, tablets, syrups, elixirs or as admixtures to food, ', ienr ,. If the compounds are administered as capsules, tablets, elixirs and syrups, they should generally be given at meals in daily amounts of 50 to 600 mg / kg, preferably 200 to 600 mg / kg. When the compounds are administered as admixtures to foodstuffs, the weight percentage of the compound, based on the foodstuff, varies from 0.025 to 0.5% by weight, preferably from 0.1 to 0.2% by weight. - ^. In general, humans and mammals at these dosages show a beneficial tendency to decrease weight gain and decrease obesity.

Pharmacology Triton-induced hyperlipidecia tests

Caged male Sprague-Dawley rats with a Weight of 250 to 350 g were taken ad libitum with commercially available laboratory chow with free access to V / ater fed. The animals were caged from laughing and given iriton-WR-1339 (manufactured by Ruger Chemical Company, In ^. Irvington, ITew Jersey) as of Schurr et al. described in "Lipids" 2 68 (1972), administered, with the modification that the saphenous vein was taken and divided doses of 70 mg / kg were used. They were anesthetized with sodium pentobarbital and bled out by means of a core puncture. The serum was at

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- 2o C g until it reaches total cholesterol and triglycerides were analyzed. There was also a comparison employed with clofibrate. As shown in Table I, the norfenfluramine fatty acid amides decreased serum triglycerides and serum cholesterol.

Diet-induced Ky ^ eripami tests

General feeding experiments on rats were carried out carried out-to the effect of the amides according to the invention on serum and liver lipids from animals fed a basic diet and a basic diet supplemented with cholesterol were to determine. Also, the effect of these drugs on serum lipoproteins and their effect on the Body weight, gross feeding efficiency, liver weight, Appetite and energy utilization examined in terms of their metabolic size. Male Sprague-Dawley rats with a weight of 150 to 175 g were placed in cages with a raised wire floor in a room next to a Temperature was maintained at 24 to 26 ° C for a 12 hour period Daily and a 12-hour night rhythm and fed ad libitum with a semi-purified diet, had the following composition:

Weight? O.

vitamin-free casein 2o

Glucose 63

hydrogenated coconut oil io

GBI Vitamin Fortification Mixture, Cat. No. 4oo6o by the General Biochemical Company, Chargrin Falls, Ohio, USA 1

modified salt mixture from Williams and Briggs, Cat. No. 17o91i from General Biochemical Company 4

Cellulose 2

and watered. The modified salt mixture provided the following amounts of elements in g / kg.

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Calcium 7.1 chlorine 3.95 copper 0.0059 iodine 0.00067 iron 0.0287 magnesium 0.528 LJangan 0.0527 phosphorus 4.55 potassium 4.35 liatrium 2.40 sulfur 0.73 zinc 0.135

The vitamin fortification mixture (vitamin fortification liix) consisted in g / kg of the line:

p-aminobenzoic acid 11.0132

Ascorbic acid, coated 97.5 ^ 101.6604

Biotin ^pure 0.0441

Vitamin B ₁₂ , $ 0.12 in mannitol 2.9736

Calcium pantothenate 6.6079

Choline Dihydrogen Citrate 349.6916

Poly acid 0.1982

Innosite 11.0132

Lienadione (Vitamin K) 4.9559

Hiacin 9.9119

Pyridoxine HCL 2.2026

Riboflavin 2.2026

Thiamine HOL 2.2026

dry vitamin A palmitate 3.9648 (500,000 units / g)

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dry vitamin D ~

(500,000 units / s) 0.4405

dry vitamin Σ acetate 24.2291

(500,000 lines / g)
2est, thinning lais starch 466.6873

The diets were supplemented with 0.5ij cholic acid, 1 ^ ί cholesterol and drugs at the expense of glucose. The test period was 16 to 21 days, with body weight and food being measured at specific time intervals. The animals were locked up, laughs, and bled to death with a candle puncture. The blood was coagulated with anti-Athylendiamintetraessigsäure and the plasma was separated by centrifugation and stored at - 2O ⁰ C. The liver was excised, weighed, and stored at - 20 ⁰ C. All samples were kept at this temperature until they were analyzed for total lipids, total cholesterol, triglycerides and phospholipids. The gross feed efficiency was determined together with the effect of the metabolic variable on food intake and the effect of the drug on energy utilization.

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Table I.

Effect of fatty acid amides of norfenfluramine on serum triglycerides and cholesterol in triton-induced hyperli-

pldemi rats

group ο link η dose Serum triglycerides + ml + SD % Change Serum cholesterol ml + SD % Change O no control) mg / kg p.o. . mg / loo + tion tri- mg / loo tion -22 Cs> Clofibrate + glycerlcle Chole ISJ oleic acid amide (Ex. 2) 338.6 + 59.9 sterol -22 I. ">. no control) of Norfenfluramine no 538.2 7.8 O 231, ο i 54, ο O -22 O Clofibrate lilaidinsaureamld 14o 124.5 69.6 -79 173, ο - 16.4 -24, ο +28 ^ III Linoleic acid amide (Bap. 3) from Norfen- 14o 268.7 -54 2o9, o - 9.5 C- (Ex. 1) fluramine + 13.4 -24 no control) Stearic acid amide no 123.5 i 13.6 O Clofibrate j (Ex. 4) from Norfen- .14 ο + 94.1 -24 ' -39 Linoleic acid c & ge fluramine + 2o, 4 mixed acidic amides 14o lol, 9 -ίο ν * IV (Ex. 5) - 82, ο + 2o, o I. -XS ^ no control) no 166.8 + 64.5 O 14o, o + 24.4 Clofibrate 14o 132.7 - -2o Io9.3 Linolsiiuro & ge + 19.1 + lo, o mixed acidic amides 14o 67.3 t 33.9 -6 ο Io9, o + 16.6 (Ex. 5) 7o 64.3 * 214.7 -62 Io9.7 - 13.2 35 (a) 6oo, o 3o2.2 + 26o 189, ο + 4o, 3 no 618.3 118, ο O 281.5 t 14.1 14o 411.7 -34 213, ο + 37.2 £ lo, 2 14o 166.3 -7 3 173.3 I. 137.8 Hh 47.8 14o 26o, o -58. 21o, o Ho, ο - 91.6 14o 16o, o -74 214.3

abnormal prehistory

Grur.ddi'lt

The results of the prufunj of the gerischten Anide von Example 5 and the reference connections in liatten for a Basic diet jeniii3 the procedure described above for diet-induced eyperlipemia are shown in Tables 2 and 3 specified. Üeiaerkensv / erterv / eise lowered the anide of the Invention (Example 5) food intake and putterv / irksaakeit Considerable, i.e. lower weight gain per unit taken.

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Basic diet no cholesterol

The results of the examination of the mixed anide of Example 5 and the reference compounds in rats A basic diet with added cholesterol is a little prominent procedure described for diet-induced hyperlipemia are shown in Tables 4 and 5. The mixed amides of Example 5 produced wiaderuu a significant reduction in puttering health, but it does also became low serum and liver cholesterol. observed.

See similar ',', 'data obtained in table 6 using the pure linoleanide from Norfenfluranine of Example 1 also show the effect on serum and liver lipids.

In other analyzes, the increased doses generated mixed amides of Example 5 decreasing!.! tightness of lipoproteins high density (HDL) and further decreasing amounts of low density lipoproteins (LDL), see table

Toxizitätsver _f ~ facilitated

The motor activity of! Torfenfiuramine and the Amides of üfenfiuramine according to the invention have been made by Determination of the activity in female albino mice of the ICR-Stanaes by modification of the Liethode / on Cook i.a. in J. Pharmac. Exp. Ther. 113: 11a (1955) Compared. The results indicate that the amides of ITfenflurane are only a weak effect on motor activity at a dose of 100 to 300 mg / kg, i. p., ha-

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μ.

ben compared to the potent effect seen with norfenfluranine at a dose of 6.5 mg / kg, i.p. was established. In lice, at doses of 3OC mg / kg, i.p. and 1000 ng / kg, p.o. , no ileurotocicity in the amides of Example 5 » while at a dose of 40 jng / kg, i.p., with Korfenfluramine Tremors and at a dose of 100 mg / kg i.p. the iodine entered.

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Table II

Effects on liver weight, body weight and food consumption of rats (fed with semi-purified basic diet)

treatment
(O

No

dose
mg / kg / day

ο
co
oo clofibrate o.2%

¹⁰ Cho Ie-

^ styramine, 3%

u> amides of

- * Norfenfluramide (Ex. 5)
oil%

o, 5%

oc -Methylbenzyllinoleamid o, 2%
(d)

2o9
312o

96

2o4
49o

182

Number of liver weights, g + SD body weight, g - SD rats Total per 100 g body weight beginning end

6th
6th

4th
6th
4th

5.7 ± o, 3 9.2 ± o, 4

5.8 ± o, 3

5.3

7, ojo, 2

5,9-o, 6

6,7-o, 8

2.7 - o.3 4.4 - o.4

2.7 - o, 3

2.8 I o, 2 3.4 J o, 7 2.3 - o, l

2.9 I o.3 176 2 21
171 J 15
185 * 16

158-2o

158 - 18 212 ± 22 155 - 16 2I0-2I

151 - 8 215 ^ 3

Food consumption. G

3o9 3o6

316

19οχ28 2ο5χ22 2o8-24

226 * 3o

Gross, feed b

v / ineffective.

o, 175 o, 18o Xa I

o, 2o3 _k ,

241 o, o58 3o4 o, 112 276 o, o83

331

o, 21o

a * based on% pharmaceuticals in the diet and average daily food consumption

b * Gross weight increase in g, total food consumption in g

c * »Percentage by weight of additive in food

d »Connection according to US Pat. No. 3,621,043 and US Pat. No. 3,728,459 ISJ O

Table III

Effect on the mean concentration of serum and liver lipids in rats (fed with a semi-purified basic diet)

Lipids

Serum mg / 100 ml + SD

Treatment (b)
no

Clofibrate, 0.2%

_o Cholestyramines

co 3%

<** Amides from North

^ fenfluramii ^ e

__ (Ex. 5) '"-0, I *

ο o, 2%

OC -Methylbenzyl linoleamide (a) o, 2%

total

__________________ Cholenter

138.8o-22.57 69.67 * 14.15

143.7o ± 22.42 89.83- 8.77

116.6o-23.16 69.2o-lo, 55

153.3o ± 2o, lo 84, οοχ1ο, 58 191, ooj49.8o 79.33jlo, 39 175.5o- 9.4o 86.00-14.99

Triglycerides 3o, 67-2.89

31.83 ^ 7, o8 25.8- 6.38

35.33 | 7, o2 75.33 | 34.6o 7o, ΟΟ-17.51 Liver mq / q + SD

total

rholcnterin

77.5-3.91 72.33-29.92 46, R6i 7.43 -3.06-0.13 51.2li 7.89 2.63 ^ 0.09 39.32 ± 5.95 2.87 ^, 33

3o, 7lJ 2.88 3.55jo, 55 31.97j 2.49 3.22jo, 4o 34,51-4, o6 4, lo-o, 27

40.05 ^ 11.37 3.34 ^ 0.24

Triqlycorlde 4.39 to 1.65

1.78 - o.43 4.88 - 2.54

3.42 J 2.6o 4, oo - 2, Io 6.82 - o, 46

4.85-2.71

(a) = compound according to US Pat. No. 3,621,043 and US Pat. No. 3,728

(b) = weight percent of the additive in the food

Table IV

Effect on food consumption and feed effectiveness Rats (fed with a semi-purified basic diet supplemented with

Cholesterol)

Dose treatment number

(d) rats mq / kg / day

No 6

Clofibrate, 0.2% 6,198

^ aCholestyramine,

O 3% 6 293o

⁰⁰ amides of

^ Norfenflur-

N _n . amine (ex. 5)

_ »O, l% 6 91

O o, 2% 6 194

<-> o, 5% 6 466

oC methyl

benzyllinole-

amide (c) o, 2% 4,199

Liver weight, g - SD

per loo g total body weight

7.5 - o, 6

3.6 -

lo.4-2.6 4.9 ± 1.2

6.1 - o.5 2.9 ± o.2

5.9 J o, 5 3.4 ± o, 2 6.1 2 o, 3 3.2 J o, l 5.7 - o, 4 3.3 - o, l

7.1 - 1.3 3.7 - o, 2

Body weight,
Anfana g - SD
end Food
consumed. Gross
feed b
σ effective 132 - 4 2o8 ± 13 321 o, 237 135 - 5 2o8 ± 16 34 ο o, 215 132 ί 13 2oO ± 18 336 o.226

6th
9

138 y

148 ±
143 ί 12

137 ±

177 ^ 15 19θχ 7 172-11

192 ^ 25

288 o, 135 323 o, 128 298 o, o31

311

o, 177

a «= based on% drugs in the diet and average daily feed consumption

b = gross weight increase / gross total food increase in η

c = compound according to US Pat. No. 3,621,043 and US Pat. No. 3,728,4

d ^β percent by weight of the additive in food

CD

Table V

Effect on serum and liver lipids of rats (fed with a semi-purified basic diet with

Cholesterol)

Treatment (b) total
no

Clofibrate, 0.2%
Cholestyramines,

Lipids

Serum, mg / 100 ml - SD Cholesterol triglycerido

635.67 * 73.03 272.67 * 44.19 253, Γ. 3-67.69 430.13 * 119.37 235, oo * 68.27 126.5o * 47.21 *

3% 242.83 * 7o, o5 ^a 93.67 * 17.5o ^a 18o, oo * 32.19

Liver, mg / g - SD

total

Cholesterol triglycerides

12o, oo * 23.22 25.37 * 0.51 93.83 * 12, o6 ^a 14.17 * 9, lo ^a

76.67 * 8, o9 ^a

6.15 * 1.37 ^a

12.45-lo, lo 7.83 * 2.22

11.13 ¹ 4.11

ro Amides from Kor- 5) O, fenfluramine O (E.g. O, UJ -1% , 2% .5%

«. -Methylbenzyllinoleamide (b) o, 2%

375.67 *: i9, ll ^a 166, 17 * 44, 53 ^a 176, oo * 33.92 ^a 266.33 * 4o, 27 ^a 141.33 * 28, o8 ^a 184.67 * 44.59 286, 67 * 58, o3 ^a 163, oo * 23.24 ^a 299.5o * 51.80

453.25 * 9o, 58 ^a 197.75 * 23.24 262.5o * 51.88 «3.83 * 7.96 ^a

78.83 * 12.83 ^a
75.33 * 12.94 ^a

4.80 * 3.42 ^a

2.55 * 2.65 ^a 1.5o-o.5o ^a

84, oo * 14.26 ^a 8.33 * 1.37 ^a

7.33 * o.79

6.5o * o, 97 7, o7 * o, R6

4.35-2.88

a = ρ <o, o5 by Student's t-test b ■ Compound according to US Pat. No. 3,621,043 and US Pat. No. 3 7 28 c = percent by weight of the additive in foods

Table VI

Effect of linoleamide from norfenfluramine on serum and liver lipids in rats (fed on a hypercholesteremic diet) (a)

(b)

Serum lipids mg / 100 ml Liver lipids mg / g

Treatment (d)

O ι ■.

<*> None

_o Linoleamide from approx norfenfluramine
- * (Ex. 1) o.2%

cholesterol

. 454
- 121

212 (c)
3o

Tri-glycerides

₊ lo5 - 37

156 (C) 62

Phospholipids

97.5-32.6

Io 5.4 i 18.4

cholesterol

57.32-4, o6

. 7.15 (C) - o.73

Triglycerides

3o, 69-14.66

. 5.59 (C) - 3.67

Phospholioids

₊ 23.98 ¹ 5.44

24.1

a * values are standard deviations of Io animals per group

b ■ semi-purified diet supplemented with 1% cholesterol and 0.5% cholic acid at the expense of glucose

c ■ ρ <o, o5 determined according to Student's t-test

d = weight percent of the additive in food

TM -

$ 3

Table VII

Effect on serum lipoproteins from rats (fed with a semi-purified diet supplemented with cholesterol)

Percentage Composition (a)

Treatment (c) number
Tapes VLDL LD , 94 HDL albumin no 6th 37.53 45 , 56 2.52 13.93 Clofibrate 0.2% 8th 25.76 42 , 07 9, o3 22.63 Cholestyraraine
3% 7th 17, oo 35 , 29 16.15 31.77 Linoleamide from
Norfenf luramine
(Bs? .5) o, l% 6th 36.92 11 , 42 2o, o7 31.69 o, 2% 6th 23.65 15th , 98 12.11 42.81 o, 5% 4th 35.78 16 2.76 4o, 46

oc-methylbenzyllinoleamide (b) o, 2%

36.19 18.51 29.62

15.65

(a) = VLDL = very low density lipoproteins; LDL = Lioonroteins

low density; HDL = high density ion proteins, determined with a Beckman-Gilford spectrophotoneter.

(b) = V ^ binding according to US Pat. No. 3,621,043 and US Pat. No. 3,728,459

(c) = weight percent of the additive in food

7 0 9 8 3 2/1031

27047AA

a "

The LD-Q - '.,' Ert the amide of llorfenfluranir.e, fcestinates according to a method according to Finney Statistical Ilethods in Biological Assay, Hafner Pub. Co., New York, 2nd edition (1964) was greater than 10,000 mg / l: ^, -vo. The KD ₅₀ - er τ of ITfenfluranine was 137 mg / kg according to the same method. The therapeutic index of the amides of Ilorfenfluramine appeared to be very favorable in comparison with Ilorfenfluranir.e, and no adverse reactions of the amides to serum glucose, IlikrosoLial enzymes or ilonoamine oxidase were observed.

Synthesis of ß-bterir. and non-saponifiable substances

The effect of the mixed amides of the example and the reference compounds in the ß-sterol synthesis was determined by a modified method, according to Hill and Dvornik Arch . £ iophys. 114 (1966) 88. Determined. Male Sprague-Davrley rats weighing 127-175 g freely had a semi-purified basic diet and './asser. Which had been housed in cages with raised wire floors in a room which was maintained at a temperature of 24 to 26 ⁰ G, with a 12 hour day and 12 hour Nachtrhythnus. The rhythm was reversed so that the night cycle corresponded to the working day in order to take advantage of the circadian rhythm that promotes cholesterol synthesis. The test period was 5 days and 20 / uci sodium acetate-1- ^ C (Sp. Act. 56 mci / m mol) was administered intraperitoneally. Animals were sacrificed under carbon dioxide and the distal 10 cm of the ilium and the median and left lobes of the liver were excised and homogenized. The β-terins were then isolated as digitonide, and the radioactivity was measured in a "Packard Triearb Liquid Scintillation Spectrometer" Model 3365

♦ (circadian rhythm)

709832/1031

using G, 5 / S 2,5-Dipher; vloxa3ol and S? j naphthalene in a solvent mixture of 40) j toluene, 40 / »dioxane and 20 / absolute .ethanol ester.

709832/1031

Information on the effect of the mixed amides from Example 5 on the synthesis of unsaponifiable substances and 3-3terines, as determined by means of the digitonide-ethone, is given in Table 8. The results show that at doses of 140 mg / kg, ρ.ο., the aids of the invention lowered sterile synthesis from control values in 4-3 % in the liver and 15% in the ilium. A prior art compound, c * -Lethylbenzyllinoleanide, at a dose of 140 mg / kg po, had no effect on the cholesterol hypothesis in either.

709832/1031

BATH ORIGINAL

Table "III

ß-sterol synthesis. Incorporation of

14 Acetate -1- C in non-saponifiable and with

Digitonin precipitated sterols

Acetate-1- ¹⁴ C incorporated η mol / g QewebG -SD

link

No

Clofibrate

Cholestyramines

Linoleic acid and
mixed acid amides (ex. 5)
of Norfenfluramine

ot-methylbenzyllinoleamide
(a)

number
Rats dose
mg / kg
ο.ο. tissue 15th
15th liver
Iliun Io
Io 14o liver
Ilium Io 66o liver
Ilium

4th
4th

4th
4th

14o

14o

Liver Ilium

Liver Ilium

non-saponifiable digitoniol + 1 , 718 3 , O2sjl, o72 4th , 123 - 2 , 467 6th , 752-1.2 ^ 13 7th , 341 + 1 , 7o7 1 , 583 ± 1.216 2 , 943 1 , 447 6th , O93-0, 9o9 6th , 774

14.369 J 4, o27 13.533-3.9o4

2, o77 J l _f 246 7, o22 - 2.125

4.533 J 3.131 7.643-1.664

15.456 ^ 2.710 12, o85-l, 43o

5.731 ^ 1.459

, χ, 5.947Ϊ _Ο , 654

(a) A compound according to US-PS 3 6 21 3 o4 and 3,728,459

709832/1031 COPY

ORIGINAL fN

and administration

The cholesterol lowering anti-fatty drugs according to the invention can be administered orally; gewchnlich the amount administered is 0.5 to 13 5 ': e Ta; - :, preferably 0.25 to 2.5 g per day, and the administration may be multiple i.Ion £ .te continued for v / ground. The cholesterol reducing agent can be in any suitable form that is conventional for oral administration, i.e. it can be enclosed in a capsule or in liquid form, e.g. as a slurry, tablet or powder form. In making the compositions in these various forms, the active compound may be mixed with a liquid carrier such as an edible ul. Mixtures of two or more of the agents according to the invention can be used in any of the administration forms described above.

Tablet production

A granulation is made from

Parts by weight

Lactose 74

Strength 26

Water, enough for
the granulation

The granulation is dried and sieved.

Parts by weight

Amide from Horffluramine (Structural formula I) 100

Lactose Granulation 145

(as above) magnesium atearate , 5

are mixed and compressed into the form of tablets weighing 250 mg and 100 g of the active ingredient

709832/1031

COPY
ORIGINAL INSPECTED

per unit dose included.

Administration; in the form of a slurry

An elixir is made that contains per liter:

Linoleamide from norfenfluramine

(Structural formula I). 100.0 3

Ethyl alcohol 150.0 ml

Glycerin 350.0 ml

Sorbitol (70; Sige solution) 350.0 ml

Benzoic acid 1.0 g

Sodium cacharine 0.3 g

Colorants (FD and C Red ITo. 2) 0.02 g

artificial kimbesr flavor 0.2 ml

Spiced vanilla 0.02 ml distilled './water remainder to 1000 ml

The active ingredient of formula I is added to about two thirds of the ethanol, all of the glycerin and sorbitol are added and the mixture becomes thorough triturated. The saccharin and the coloring agent are grounded in a small, narrow water and the coloring agent dissolved therein solved. The aqueous solution is then added to the alcohol solution and it becomes that for a volume of one liter necessary V / water rest admitters; after mixing and filtering an elixir is obtained which contains 20 mg of the act j '/ en component / ml contains. One unit of a dose of 15 ml (one tablespoon) therefore contains 150 n ;; · of the active ingredient,

All linoleamides of the invention or Liischun-

709832/1031

27047U

These are used for the production of tablets or slixirs. The active component can be in suitable ./eise within the range of 50 "to 400 mg and preferably between 50 and 200 mg per unit dose can be varied. Also, others can be therapeutic Means added to these jorials if desired will.

The powder fora is made with the addition of various Conditioning agents such as starches, rubbers, etc. for the Mixture with educational materials for the LIenchen and for Animals made.

709832/1031

Claims (10)

1. Fatty acid amides of norfenfluramine the general formula CHs H 0 jT \ ^{! j jl (I)} tf y CH ₂ -CIl-NCR CF ₃ in which R consists of saturated and unsaturated alkyl radicals with 12 to 22 carbon atoms. 2. N- / I-Methy1-2- (3-trifluoromethylphenyl) -ethyl7octadeca-9 »12-dienamide-cis-cis-isomer. 3. N- / I-methyl-2- (3-trifluoromethylphenyl) ethyl-7octadec-9-enamide cis isomer. 4. N- / T-Methy1-2- (3-trifluoromethylphenyl) ethyl7octadec-9-enamido-trans-isomer. 5. N- / I-methyl-2- (3-trifluoromethylphenyl) ethyI7octadecanamide. 6. Mixture of fatty acid amides from norfenfluramine, in which the amides have the formula CH, H 0 f V-CH ₂ -CH-NCR CF, have, where R consists of saturated and unsaturated alkyl radicals having 12 to 22 carbon atoms. *) (a-methyl-m- (trifluoromethyl) phenethylamine the formula ",. ) F ₃ C 709832/1031 ORIGINAL INSPECTED 7. Mixture according to claim 6, characterized in that the predominant fatty acid amide from the linoleamide (Linoleic acid amide) consists of Uorfenfluramine. 8. A process for the preparation of fatty acid amides from norfenfluramine, characterized in that one in per se known way to a solution of norfenfluramine in dry pyridine phosphorus trichloride with stirring and cooling with an ice bath and then the solution with a fatty acid with 12 to 22 carbon atoms in the alkyl group or a mixture of such fatty acids is added and heated. 9. Medicinal product, consisting of a compound according to one of claims 1 to 7 and conventional carriers. 10 . Use of fatty acid amides or mixtures of fatty acid amides according to one of Claims 1 to 7 for combating atherosclerosis and obesity in humans and mammals. 709832/1031