CA1048934A - Organic compounds - Google Patents

Abstract

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

in which W is or 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

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 ~;~ "' CANADA

~ 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 CA~Dh ~ 3 ~ 600-6583 10~8g34 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.

CANADA
~ 4 ~ 600-6583 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.

~ANhD~

- 5 - 600-6583 ~4~934 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, 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:

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 ~ , .. .

1~48~?34 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.

Claims (10)

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

I

in which W is or 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 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.

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.