Note: Descriptions are shown in the official language in which they were submitted.
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,
-- 2 --
~.
( (~ AHR-302-CIP
lO~V~S~
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.
- 3 -
1~)8VZS~
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
,.
-- 4 -
,. .
1080Z54
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:
CH2-CN-N-C-R
CF3
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:-
CH2-CH-NH2 II
CF3
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.
.
,;
.,
- 6a -
108()~5~
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.
- 7 -
.
AHR-~02-CIP
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
-- 8 --
~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
~'~
_ g _
~ .
'
1080Z54
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,
--I0 -
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.
.
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~
-11 -
. . .
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.
-12-
( (
~080Z5
of diet:
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
-13-
1080Z54
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.
~ -14-
1080~Z5
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108025~
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
-16-
~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.
108~254
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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.
- 23 -
~o~zs~
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.
-24-
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
14
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.
-27-
.
