COMPOSE PHARMACEUTIQUE CONTENANT DU P-ALCANOYLTOLUENE

PHARMACEUTICAL COMPOSITION CONTAINING P-ALKANOYLTOLUENE

Abrégé anglais

IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS
Abstract of the Disclosure
p-Alkanoyltoluene derivatives, useful as hypo-
lipidemic, anti-diabetic and anti-obesity agents.

Revendications

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A pharmaceutical composition comprising an
effective amount of a compound of formula I,
<IMG> I
in which R1 signifies hydrogen, fluorine, chlorine
or straight chain alkoxy of 1 to 4
carbon atoms, and
R2 and R3, which may be the same or dif-
ferent, each signifies methyl or ethyl,
in association with a pharmaceutically acceptable dil-
uent or carrier.
2. A pharmaceutical composition according to
Claim 1, in which the quantity of the compound of form-
ula I in relation to the quantity of the composition as
a whole is such that a unit dosage of the composition
contains from 20 to 1250 mg of the compound of formula I.
3. A pharmaceutical composition according to
Claim 1, in which, in the compound of formula I, R2 and
R3 each signify methyl.
4. A pharmaceutical composition according to Claim
1, 2 or 3, in which the compound of formula I is p-
pivaloyltoluene.
5. A pharmaceutical composition according to Claim 1,
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in the form of an integral solid final dosage form, con-
taining from 20 to 1250 mg of the compound of formula I.
6. A pharmaceutical composition according to
Claim 5, in which the integral solid final dosage form
is a tablet.
7. A pharmaceutical composition according to
Claim 5, in which the intergral solid final dosage form
is a capsule.
8. A pharmaceutical composition according to claim
5, 6 or 7, in which the integral solid final dosage form
has a total weight of from 80 to 6000 mg.
9. A pharmaceutical composition according to claim
5, 6 or 7, in which the integral solid final dosage form
has a total weight of from 200 to 3000 mg.
10. A pharmaceutical composition according to claim 1,
in the form of a liquid final dosage form, in which the
concentration of the compound of formula I is such that a
unit dosage of the liquid final dosage form contains
from 20 to 1250 mg of the compound of formula I.
11. A pharmaceutical composition according to
Claim 10, in which the liquid final dosage form is an
oral dosage form.
12. A pharmaceutical composition according to
Claim 11, in which the oral dosage form is an
emulsion or suspension.
13. A pharmaceutical composition according to
Claim 5 which includes at least one of a sweetening agent,
a flavouring agent, a colouring agent and a preserving
agent.

14. A pharmaceutical composition according to
Claim 10, in the form of a sterile injectable emulsion,
dispersion or suspension.
15. A pharmaceutical composition according to
claim 10, 11 or 12 in which the liquid final dosage
form contains from 0.5 to 90% by weight of the compound
of formula I.
16. A pharmaceutical composition according to
Claim 10, 11 or 12, in which the liquid final dosage form
contains from 3 to 50% by weight of the compound of
formula I.
17. A pharmaceutical composition according to
Claim 1, 2 or 3 in the form of a dispersible powder or a
liquid concentrate.
16

Description

CANADA
Case 600-6629
1041~0~ `
IMPROVE.`~:NTS IN OR PELATI~G TO ORGANIC CO~'POUNDS
This invention relates to ~-alkanoyltoluene
derivatives.
More particularly, this invention relates to
compounds of formula I,
CH3
1 ~ I
C=O
CH -C-R2
R3
in ~hich Rl signifies hydrogen, fluorine, chlorine
or straight chain alkoxy of 1 to 4
carbon atoms, and
R2 and R3, which may be the same or dif-
ferent, each signifies methyl or ethyl.
:.
The compounds of formula I are kncwn or may be
prepared in conventional manner from available materials.
The present invention is based on the discovery
that the compounds of formula I possess pharmacological
activity. In particular, they possess anti-obesity
activity as lndicated by preventing an increase in blood
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sugar levels in male Wistar rats. The rats, in groups
of 4,are given an initial dose of 200 mg/kg of the test
compound orally, a ter having fasted for 16 hours.
One hour later the rats are given, in a first test
series, 2 g/kg of maltose load and, in a second test
series, 200 mg/kg of starch load. Fifteen minutes
later (in the case of maltose load) and 30 minutes
later (in the case of starch load), the rats are
anesthetised with 120 mg/kg of sodium hexobarbital
- 10 after ~hich blood is collected via cardiac puncture.
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The blood samples are placed in an autoanalyser cup
containing 0.1 ml of heparin (1000 units per ml).
The heparinised blood is used to determlne the blood
sugar level ~ith an autoanalyser. The blood sugar
content is compared to the control group ~Jhich received
0.5% carboxymethyl cellulose and is run concurrently.
The blood sugar levels are calculated and compared to
the control.
The compounds are therefore indicated for use as
anti-obesity agents. ~n indicated suitable daily dosage
is from 75 to 1500 mg, suitably given in divided dosages
of about 20 to 750 mg, t~Jo to four times daily, or in
retard form.

~ANADA
1~4 i~ 0~ _ 3 _ 600-6629
The compounds of formula I also possess anti-
diabetic activity and are indicated for use in the
treatment of juvenile dia~etes. This activity is indic-
ated by lowering of blood glucose in 6-8 week old male
Royal ~art mice weighing 30 to 35 g. The mice, in
groups of 5, are given 200 mg/kg of the test compound
orally,after having fasted for 16 hours. ~inety min-
utes later, the mice are given, orally, 2 g/kg of a
~lucose challenge. 25 minutes later,the mice are anes-
thetised with 85 mg/~g of sodium hexobarbital and, 5minutes later, blood is collected via cardiac puncture.
The blood samples are placed in an autoanalyser cup
containing 0.025 ~.L of heparin (1000 units/ml) and the
samples are capped, sh~ken and stored in ice. ~he
glucose content is determine~ by the autoanalyser
potassium ferric-cyanide N-2b n~ethod and are compared
with a control group, which receives,orally,0.5% carboxy-
methyl cellulose vehicle and is run concurrently.
An indicated daily dosage for this usage is the
same as described above for anti-obesity usage.
The compounds also possess hypolipidemic, in part-
lcular hyperlipoproteinemic, activity, as indicated by
the fall in cholesterol and triglyceride levels in

C~NADA
600-6629
male albino ~istar rats weighing 110-130 g initially.
The rats are maintained on drug-free laboratory chow
diet for seven days and then divided into groups of 8
to 10 animals. Each group,-~ith the exception of the
S control,is then siven, orally, 30 mg/Xg per diem of
the corpound for six àays. At the end of this period,
the animals are anesthetised ~ith sodium hexobarbital
and bled from the carotid arteries. Serum or plasma
samples are collected, and 1.0 ml samples of the serum
are added to 9.0 ml of redistilled isopropanol. T~JO
autoanalyser cupsful of a mixture of zeolite-copper
hydroxide znd Lloydds reagent (~essler, G., and Lederer,
H., 196~, Technicon Syrposium, Mediad Inc., New York
[345-347])are added, and the mixture is shaken for 1
hour. Cholesterol and triglyceride levels are deter-
mined simultaneously on the sar;e sample by Technicon
N-24 A (cholesterol) and N-78 (triglyceride)
methodology. The mean total s~rum cholesterol levels
are then computed and hypocholesterolemic activity is
expressed as the fall in cholesterol levels as a per-
centage of the control level. The change in serum
triglyceride levels induced by the drug is computed
as a percentage of the control triglyceride levels.
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- 5 - 6~0-6629
The compounds are therefore indicated for use as
hypolipidemic, in particular hyperlipoproteinemic,
agents. An indicated suitable daily dosage is from
75 to 2500 mg, suitably administered in divided dosages
of from about 20 to 1250 r~g, two to four times daily,
or in retard form.
The present invention accordingly provides a
pharmaceutical composition comprising a compound of
formula I, stated above, in acsociation with a
pharmaceutically acceptable diluent or carrier.
The invention also provides a process for the
production of such pharmaceutical compos-tions, which
comprises working up a compound of formula I, stated
above, in a state of puritv sufficient for pharma-
¦ 15 ceutical acceptability, with a pharmaceutically
acceptable diluent or carrier.
In the corpositions of the invention, preferably
the quar.tity of the compound of formula I in relation
to the quantity of the composition as a whole is such
that a unit dosage of the composition contains from
20 to 1250 mg of the compound of formula I.
As used herein, the term "unit dosage" refers
` both to solid and liquid dosage forms and means gener~
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C~NADA
~ O ~ - 6 - 600-6629
ally that quantity of the composition in the final
dosage form in question (i.e. the compositions as
administered), which is appropriate for ad~inistration
of the required dosage of active ingredient.
The compositions of the invention may already be
in the final form ready for acministration, for example,
in the form of integral solid dosage forms, such as
tablets and capsules, in particular soft gelatine cap-
sules. Alternatively, the compositions may be in
liquid dosage forms, such as emulsions and suspensions
or in the for~ of a liquid suitable for parenteral use,
such as a suspensicn, dispersion or, in particular,
emulsion,e.g. a sterile injectable liquid such as an
aqueous emulsion. In the case of integral, solid
lS dosage forms, the term "unit dosage" si~ply means the
weight of one such form and this, of course, may vary
depending, for example, on the form in ques~ion.
Liquid ~inal dosage forms contain the active ingredient
in such a concentraticn that a "unit dosase" of the
liquid form, e.g. a teaspoonful, contains the required
dosage of active ingredient. Again, this concentration ;
may vary ~lithin fairly ~ide limits.
Although it is, as indicated, difficult to general-
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C~NADA
~ O9 _ 7 _ 600-6629
ise, integral solid dosage forms may suitably have a
total weight of from 80mg to 6000 mg, preferably
from 200 to 3000 mg, while liquid final dosage forms
may suitably contain from 0.5 to 90~, preferably from
3 to 50% by weight of the active ingredient.
The composition of the invention may also be in a
form requiring further wor~ing up to obtain the final
dos&ge form. They may thus, for example, be in
the form of dispersible powders or liquid concen-
trates. In this case, an appropriate quantity ofthe composition, for example a teaspoonful, is generally
j dispersed in or dilu.ed .ith an appropriate quantity of
water, for exa~ple, a glass thereof, to obtain a "unit
dosage" of the final dosage form. The concentration of
active ingredient in that "uni. dosage" will then suit--
ably fall within the preferred concentrations given
above for the liquid final dosage form of the compos-
itions of the invention.
The compositions of the invention may be prepared
according to any method ~no-:m in the art for the
manufacture of pharmaceutical compositions, and such
compositiors may contain one or ~ore conventional adju-
vants, such as sweetening agents, flavouring agents,
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O ~ C~NA~A
- 8 - 600-6629
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colourins agents and preserving agents, in order to
provide an elegamt and palatable preparation. Tablets
- may contain the active ingredient in ad~ixture with
conventional pharmaceutical excipients, e.g. inert
diluents,such as calcium phosphate, calcium sulphate
dihydrate, lactose and talc, yranulating and disinteg-
rating agents, e.g. starch and alginic acid, binding
a~ents, e.g. starch, gelatin, polyvinyl pyrrolidone and
acacia, and lubricating agents, e.g. magnesium stearate,
stearic acid and talc. The ta~lets may be uncoated or
coated by kno~n techniques to delay disintegration and
adsorption in the gastro-intestinal tract and thereby
provide a sustair.ed action over a longer period.
Simil~rly, suspensions or emulsions may contain
the active inaredient in admixture with any of the
conventional excipier.ts utilised for the preparation
of such corpositions, e.g., suspending agents
(methylcellulose, tragacanth and sodium alginate),
~etting agents (lecithin, polyoxyethylene stearate and
polyoxyethylene sorbitan monooleate) and preservatives
(ethyl-~-hydroxy-benzoate). Capsules may contain the
active inyxedient admixed with an inert liguid
or solid diluent, e.g. calcium carbonate, calcium
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9 0~ CANADA
- 9 - 600-6629
phosphate or kaolin. Soft gelatine capsules may
contain the active ingredient in admixture with con-
ventional pharmaceutical excipients, e.g. inert car-
riers, e.g. vegetable oils, (soy oil, corn oil, etc.),
polyethylene glycol derivatives or mineral oils.
The preferred compounas Or formula I are those in
which R2 and R3 are each methyl, particularly ~-pivaloyl~
toluene.
The following Examples illustrate the invention.

C~.NADA
~ 0 ~ - 10 - 600-6G29
EX~lPL~ 1:
A representative formulation suitable for oral
administration is a capsule prepared by standard
encapsula~ing techniques which contains the follo~ling
and is indicated for ac7rinistration of 2 to 4 times a
day in the treatment of obesity, diabetes, or lipidemia.
(m~.)
Ingredient caPsule
~-pivaloyl toluene 100
lactose 300
Total 400 mg.
EXA~PLE 2:
The follotiin~ corposition may he formulated t7itn
the indicated arount of in~recients using conventional
techniques. The oral licuid suspension is indicated
for admlnistration 2 to 4 times a day, in the treatment
of obesity, dizbetes or lipidemia.
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C~NADA
- 11 - 600-6629
In~redient (mg.)
oral
liquid
suspension
- 5 ~-pivaloyl toluene 100
sodium carboxy methylcellulose 12.5
U.S .P .
magnesium aluminium silicate 47.5
flavour q.s.
colour q.s.
methyl paraben, U.S.P. 4.5
propyl paraben, V.S.P. -- ~ 1.0
polysorbate 80 (e.g., ~ee 0),
U.S.P. 5
sorbitol solution, 70~, U.S.P. 2,500
buffer agent tc adjust pH for q.s.
desired stability
ater q.s. to
5 ml
EX~MPLE 3:
The follo~ing compositions may be formulated
using standard tabletting or encapsulatir.g techniques
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C~NA~h
- 12 - 600-6629
and are indicated for adr;~inistration 2 to 4 times a
day in the treatment of obesity, diabetes or lipidemia.
In~redient Weiqht (ma) Soft gelatine
Tablet Capsule Capsule
~-pivaloyl toluene 100 100 100
polyvinylpyrrolidone 15 - -
lactose 282.5 346
corn starch 25
talcum 15
colloidal 50 50
silicon dioxide
magnesiur. stearate 2.5 - -
steaxic acid - 4
soy bean oil - - 300
Total 500 mg 500 mg 400 n~g
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EX~PLE 4:
The follo~7ing compositions r.ay be formulated with
the indicated amounts of ingredients using conventional
- techniques. The injectable emulsion is indicated for
administration once or twice a day and the oral liquid
suspension 2 to 4 times a day, in the treatment of
obesity, diabetes or lipidemia.
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O~ CANADA
- 13 - 600-6629
i
Weight (mg.)
Inqredient Sterile inject- Oral liquid
able emulsion suspension
~-pivaloyl toluene 200 100
sodium carboxymethyl- 12.5
cellulose USP
polyvinyl pyrrolidone 5
henzyl alcohol 0.01
sodiu~ chloriae to be adjusted
to an isotonic
concentration
flavour - q.s
: colour - q.s
,. methyl paraben, USP - 4.5
propyl parabcn, USP - 1.0
Polysorbate ~0 (e.g. 1 5
~een@980) USP
Sorhitol solution, 70% USP - 2500
buffer acJent to adjust
pH for desired stability q.s q.s
water for injection, q.s to
q.s. to 1 ml. 5 ml.
EX~PLE 5:
The active ingredient in the ~ormulations of
25. ~xamples 1 to 4 may be replaced by 2-chloro-4-pivaloyl-
toluene or 2-methox.y-4-pivaloyltoluene, to obtain
~ormulations for similar use.
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