COMPOSES ORGANIQUES

ORGANIC COMPOUNDS

Abrégé anglais

Abstract of the Disclosure
Novel hypolipidemic compositions are described
comprising compounds of formula I,
Image I

in which W is Image or Image
R1 is t-butyl, isopropyl, isobutyl or
isopentyl
and R2 is hydrogen or methoxy
provided that 1) R2 is methoxy when R1 is isobutyl,
2) R2 is hydrogen when R1 is other
than isobutyl, and
3) W is Image when R1 is other than
t-butyl,
in association with a pharmaceutically acceptable diluent
or carrier.

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

Image I

in which W is Image or Image
R1 is t-butyl, isopropyl, isobutyl or
isopentyl
and R2 is hydrogen or methoxy
provided that 1) R2 is methoxy when R1 is isobutyl,
2) R2 is hydrogen when R1 is other
than isobutyl, and
3) W is Image when R1 is other
than t-butyl,
in association with a pharmaceutically acceptable diluent
or carrier.
2. A process for the production of a pharmaceutical
composition according to Claim 1, comprising working up
a compound of formula I, stated in Claim 1, in a state of
purity sufficient for pharmaceutical acceptability, with
a pharmaceutically acceptable diluent or carrier.
3. A pharmaceutical composition according to Claim 1,
in unit dosage form, containing from 50 to 1500 mg of
compound of formula I per unit dosage.

11


4. A pharmaceutical composition according to Claim 1
in the form of tablets or capsules each containing from
50 to 1500 mg of compound of formula I.
5. A pharmaceutical composition according to any
one of Claims 1, 3 or 4, in which the compound of formula I
is 4-phenoxy-pivalophenone.
6. A pharmaceutical composition according to Claim 1
in the form of a syrup, elixir, suspension or solution.
7. A pharmaceutical composition according to Claim 1
in the form of a sterile injectable solution, suspension,
dispersion or emulsion.
8. A liquid pharmaceutical composition according to
any one of Claims 1, 6 or 7, containing from 3 to 50% by
weight of the active ingredient.
9. A pharmaceutical composition according to Claim 1,
in the form of a dispersible powder, granules or a liquid
concentrate.
10. A pharmaceutical composition according to any
one of Claims 6, 7 or 9, in which the compound of formula I
is 4-phenoxy-pivalophenone.

12

Description

1~48934
AL~YL PHENOXY-PHENYL KETONES

This invention relates to phenoxy phenyl derivatives.
More particularly, the invention relates to pharma-
ceutlcal compositions comprising compounds of formula I,



R2 ~ ~ W - Rl I


ln which W is ~ C = O or ~CHOH
Rl ls t-butyl, lsopropyl, isobutyl or
lsopentyl
and R2 is hydrogen or methoxy
provided that 1) R2 is methoxy when Rl is isobutyl,
2) R2 is hydrogen when Rl is other
than isobutyl, and
3) W ls > C ~ O when Rl is other
than t-butyl,
in association with a pharmaceutically acceptable diluent
or carrier.


The compound 4-phenoxy-pivalophenone has been
previously disclosed in the literature by D.S. Tarbell
et al., J.A.C.S. 65, 2169-74 (1943). The compound a-tert.-
butyl-~-phenoxy benzyl alcohol has been also previously




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~;~ "'

CANADA
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~ 048934
described by B. W. Farnum et al.~ Proc. N. Dak. Acad.
Sci. _ , 78-81 (1966). The compound 2-methyl-4'-phenoxy-
propiophenone has been described by Buu Hoi et al.
J.C.S. 1954, 1034-38. In addition, the compound
4'-methoxy-4-phenoxyisovalerophenone has been described
by Petit and Buu-Hoi,J. Org. Chem. 26, 3~34 (1961).
Furthermore, the compound 4-methyl-4'-phenoxy-valeroDhenone
- has been described by Tomita and Watanabe~J. Pharm. Soc.
Japan _ , 1198-~203 (1951). To our knowledge, no
pharmacological activity has heretofore been associated
with any of these compounds.
The present invention is based on the discovery
that the compounds of formula I possess pharmacoloqical
activity. In particular, they are indicated for use as
hypolipidemic agents, in particular, hypolipoproteinemia
agents as indicated for example, by lowering chole~terol
and triglyceride blood serum levels in tests on a grGup
of white rats which are given typically 30-250 milligrams
per kilogram of body weight per diem of the compound
2~ orally, for 6 days, followed by extraction, wi.h
isopropanol, of ser~n or plasma after anaesthetizing
the rats with sodium hexobarbital, and then noting the
cholesterol and triglyceride contents as compared to
those of a control group. The cholesterol and triglyceride


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contents are determined by the methods of Lofland,
Anal. Biochem. 9, 393, (1964) and G. Kessler and H. Lederer,
Technicon Symposium, Mediad Inc., New York, pages
345-347, (1965), respectively.
As stated, the compounds of formula I are therefore
indicated for use as hypolipidemic agents and, in
particular, as hypolipoproteinemia agents. An indicated
suitable daily dosage is from 200 to 3,000 mg, suitably
administered in divided dosages of from 50 to 1,500 mg
two to four times daily, or in retard form.
According to the present invention, ihere is
provided a pharmaceutical composition comprising a
compound of formula I, stated above, in association with
a pharmaceutically acceptable diluent or carrier.
lS The invention also provides a process for the
production of such pharmaceutical compositions, ~hich
comprises working up a compound of formula I, stated
above, in a state of purity sufficient for pharmaceutical
acceptability, with a phat~aceutically acceptable
2n diluent or carrier.
In the compositions of the invention, preferably
the quantity 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
50 to 1,500 mg of the compound of formula I.

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1~41~934
As used herein, the term "unit dosage" refers
both to solid and liquid dosaye forms and means generally
that quantity of the composition in the final dosage
form in question (i.e. the compositions as admini~tered),
which is appropriate for administration of the required
dosage of active ingredient.
The compositions of the invention may already
be in the final form ready for administration, for
example, in the form of integral solid dosage forms,
such as tablets and capsules. Alternatively, the
compositi~ns may be in liquid dosage forms, such as
syrups, elixirs, suspensions and solutions or in the
form of a liquid suitable for parenteral use, such as
a solution suspension, dispersion, emulsion and the like,
e.g. a sterile injectable liquid such as an aqueous
suspension or solution. In the case of integral, solld
dosage forms, the term "unit dosage" simply means the
weight of one such form and this, of course, may vary
depending, for ex~mple, on the form in question. Liquid
final dosage forms contain the active ingredient in
such a concentration that a "unit dosagel' of the liquid
form, e.g. a teaspoonful, contains the required dosage
of active ingredient. Rgain, this concentration may
vary wi~hin fairly wid~ limits.


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Although it is, as indicated, difficult to
generalise, integral solid dosage forms may suitably
have a total weight of from 60 m~ to 2,000 mg, preferakly
from 100 to 1,000 mg, while liquia final dosage forms may
suitably contain from 0.5 to 90 %, preferably from 3 to
50 ~ by weight of the active ingredient.
The compositions of the invention may also be
in a form requiring further working up to obtain the
final dosage form. They may thus, for example, be
in the form of dispersible powders, granules or liquid
concentrates. In this case, an appropriate quantity Gf
the composition, for example a teaspoonful, is generally
dissolved or dispersed in or diluted with an appropriate
quantity of water, for example, a glass thereof, to
1~ obtain a "unit dosayP" of the final dosage form. The
concentration of active ingredient in that "Ullit dosage"
will then suitably fall within the preferred concentration~
given above for the li~uid final dosage form of the
compositions of the invention.
The compositions of the invention may ~e
prepared according to any method known in the art for
the manufacture of pharmaceutical compositions, and
such cormpos~tions may contain one or more conventional
adjuvants, such as sweeteniny agents, flavouring agents,

1048934
colouring agents and preserving agents, in order to
provide an elegant and palatable preparation. Tablets
may contain the active lngredient ln admlxture wlth
conventlonal pharmaceutical excipients, e.g., inert
dlluents such as calcium phosphate, calcium sulphate
dihydrate, lactose and talc, granulating and disintegrating
agents, e.g. starch and alginic acid, binding agents,
e.g. starch, gelatin, polyvinyl pyrrolidone and acacia,
and lubricating agents, e.g., magnesium stearate,
stearic acid and talc. The tablets may be uncoated or coated
by known techniques to delay disinteg.ation and
adsorption in the yastro-intestiIIal tract and thereby
provide a sustainecl action over a longer period.
Similarly, suspensions, syrups and elixirs may contain
the active ingredient in admixture with any of the
conventional excipients utilized for the preparation
of such compositions, e.g., suspending a~ents
(methylcellulcse, tragacanth and sodium alginate),
~etting ~gents (lecithin, polyoxyethylene stearate and
polyoxyethylene sorbitan monooleate) and preservatives
(ethyl-~-hydroxy-benæoate). Capsules may contain the
active ingredient alone or admixed with an inert liquid
or solid diluent, e.g. calcium carbor.ate, calcium
phosphate, kaolin, peanut oil, sesame oil and corn oil.
The following examples illustrate the invention:




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1~48934
- EX~MPLE 1:
__ .
Tablets
_ _ _ __ ~ _
Tablets sultable for oral administrat~on which
contaln the following ingredients may be prepared by
convent~onal tabletting techniques. Such tablets are
indicated for use in treating lipidemia, particularly
hypolipoproteinemia, at a dosage of one tablet two to
four times a day.
Ingredients l~eight
Compound of formula I, e.g.
4-phenoxy-pivalophenone 50
Tragacanth 10
Lactose 197.5
Corn Starch 25
Talcum 15
Magnesium stearate 2.5
EX~,~IPLE 2:
-
Capsules suitable for oral administration which
contain the follcwing ingredients a~e prepared in
conventional manner. Such capsules are indicated for
use in trcating lipidemia, particularly hypolipoprotein~mia,
at a dosage o~ one capsu]e 2 to 4 times per day.


1~48934

Liguid Filled Ca~sules Weight (mg)
__ ____~________ _____ ...
Compound of formula I, e.g.

4-phenoxy-pivalophenone 100

Peanut or sesame oil 120

Dry Filled Ca~sules
Ingredients ~eicJht (mg)

Compound of formula I, e.g.

4-phenoxy-pivalophenone ~ 100

Inert solid diluent

(starch, lactose, kaolin) 200

EX~MPLE 3:

Sterile Sus~ens~on for In2ection and Oral Ii~uid

Suspens-on
._ ~
The follo~Jing pharmaceutical compositions are
formulated ~ith the i.ndicated amount of active agent
usln~ conventioJl21 techniques. The injectable suspension
and the ora]. liquid suspc-nsion represen~ oxmulations
indicated for use as unit doses in the treatment of
lipidcmia, particularly hypolipoproteinemia. The
injectabl~ suspension is indicated as suit~ble for
admini.s.ration once or t~ice a day ~hereas the oral

liquid suspension is indicated as suitable for
adminlstration 2 to 4 times per day.




, ., ~

~4 89 3 4
Welght (mg)
sterlle oral
Ingredients injectableliqu~d
suspensionsuspension
-
Compound of formula I, e.g.
4-phenoxy-pivalophenone 200 100
Sodium carboxy methyl-
cellulose U.S.P. 1.25 12.5
Methylcellulose 0.4 ---
Polyvinylpyrrolldone 5 ---
Lecithin 3 ~--
Benz~1 alcohol 0.01 --
Magnesium aluminium silicate --- ~7.5
~lavour --- q.s.
Colour ~ .s.
Methyl paraben V.S.P. --- 4,5
Propyl paraben U.S.P. --- 1.0
Polysorhate 80 (e.g.
T~reen 80) U.S.P. --- 5
Sorbitol solution 70% U.S.P. --- 2,500
Buffer agent to adjust pH
for desired stability q.s. q.s.
~later for injection, q.s. to ~ ml.
q.s. to 1 ~1.




_ ~ _


. ~
, , j ~ , .. .

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EXA~IPLE 4:
The compositions of Examples 1, 2 and 3 may be
reformulated using, in place of 4-phenoxy-pivalophenore,
any one of the compounds:
~-t.butyl-~-phenoxy benzyl alcohol
2-methyl-4'-phenoxypropiophenone
4'-methoxy-4-phenoxyisovale~ophenone
4-methyl-4'-phenoxyvalerophenone.