DE2653407A1 - Compsns. contg. 2-alpha:hydroxybenzyl-azetidine - with anti-lipogenic and anorexigenic activity - Google Patents

Abstract

A pharmaceutical compsn. contains 2-(alpha-hydroxy-benzyl)-acetidine (I) or its acid addn. salts as active ingredient. The compsns. have antilipogenic and anorexigenic activity and are suitable for treating fatty degeneration in mammals. The antilipogenic effect causes a reduction in the amt. of body fat and therefore in the body wt. There are no side effects like those produced by amphetamide and other sympathomimetics with anorexigenic activity (isomnia, nervousness, tachycardia etc.). The compsns. reduce the conversion of carbohydrates into fats ED50 of (I) is 0.2-30 mg/kg. (I) is relatively non-toxic.

Description

Pharmaceutical preparation

The invention relates to pharmaceutical preparations and their manufacture.

The preparations according to the invention are characterized in that they contain a pharmaceutically effective amount of 2- (a-hydroxybenzyl) azetidine, or an acid addition salt thereof.

The formula above includes 4 isomers: (+) -threo-2- (a-hydroxybenzyl) -azetidine; (-) -threo-2 - (α-hydroxybenzyl) azetidine; (+) - erythro-2 - («- hydroxybenzyl) azetidine; and (-) -erythro-2 - (α-hydroxybenzyl) azetidine.

Of course, both the different racemates (or their acid addition salts) as well as the individual isomers (or their acid addition salts) can be used in the preparations mentioned above.

2 - («- Hydroxybenzyl) azetidine is a well-known compound.

It is described in Belgian patent specification no. 834928.

So far it was not known that the connection (resp.

their isomers) and their acid addition salts pharmaceutically active are.

As already mentioned, preparations, the acid addition salts, are also included des 2- (a-hydroxybenzyl) azetidine or its isomers. As acids can both organic, such as maleic acid, phthalic acid, succinic acid, tartaric acid, citric acid, Malic acid and cinnamic acid, as well as inorganic ones such as sulfuric acid, hydrochloric acid, Hydrobromic acid, phosphoric acid and nitric acid, find use.

The preparations according to the invention show antilipogenic and anorexogenic Effects and are useful for treating obesity in mammals. Through the Antilipogenic effect is the amount of body fat and therefore also the body weight reduced.

It is known to have amphetamine and other sympathomimetics anorexogenic Have effects, but also exert an influence on the central nervous system which turns out to be an undesirable side effect. This influence includes nervousness, Over excitability syndrome, insomnia, euphoria and habituation. amphetamine May also have effects on the vessels of the heart, causing palpitations, tachycardia and increase in blood pressure can occur.

By the mode of action of the preparations according to the invention are such undesirable side effects do not exist. Si cause the The conversion of carbohydrates into fat is reduced.

The preparations according to the invention can, in addition to 2- (a-hydroxybenzyl) azetidine, also contain other active compounds.

The preparations are administered orally and as carriers should be used for this particular connection and for the Administration form is most advantageous. The carrier substances must not be chemical Enter into reactions with the active substance. The preparations can be in the form of Tablets, capsules, syrups, elixirs, suspensions, etc., including preparations find application with prolonged effectiveness.

Laboratory tests show that the effective amount of 2- (a-Hydroxybenzyl) -azetidins (ED50) apparently in a range between 0.2 and 30 mg / kg body weight.

The amount to be administered would therefore be between about 15 and 2000 mg per 70 kg per day. The minimum dose is around 0.6-3.5 mg / kg. the Compounds are relatively little .toxisch, whereby a high therapeutic efficiency given is.

The daily dose is advantageously reduced to smaller amounts. divided, which are preferably taken before or with meals. The exact dosage depends of course on the age and weight of the patient.

The 2- (a-hydroxybenzyl) azetidine can be prepared by processes which are known for making similar compounds. In this context reference is again made to Belgian patent specification no. 834928.

However, the compound can also be produced by a simple hydrogenation of l-benzhydryl -2 - (α-hydroxybenzyl) azetidine can be obtained.

If the racemate is used here, one naturally also obtains a Racemate of 2- (a-hydroxybenzyl) acetidine. The racemate can be prepared by standard methods known in the art be broken down into the individual isomers. But are used in the above-mentioned hydrogenation If the various l-benzhydryl isomers are used, one gets naturally directly the corresponding 2- (a-hydroxybenzyl) -azetidine isomer. The following example illustrates the preparation of the active compound (s): 42 g threo-1-benzhydryl-2 - (α-Hydroxybenzyl) -azetidine hydrochloride and 3.7 g of 20% palladium hydroxide on charcoal in 600 ml of absolute ethanol with hydrogen under pressure of 4 atmospheres in a Parr apparatus. The catalyst is filtered off and the solvent evaporated.

The residue consisting of a mixture of solid and oily substance is treated with ether. The precipitate is filtered off and washed with ether and recrystallized from a mixture of methanol and ethyl acetate. You get so pure threo-2 - (a-hydroxybenzyl) azetidine hydrochloride. Melting point 1720 - 173 0C.

If you use the free base in the process described above, the free base of the desired end product is of course also obtained. If the erythro isomer is used as the starting compound, the erythro isomer is obtained of the end product.

threo-2- (a-hydroxybenzyl) -azetidine (free base): m.p. 1140 - 1170C. (Recrystallized from hexane or methanol / ethyl acetate).

erythro -2- (a-hydroxybenzyl) azetidine: free base: melting point: 1080-109.50C HCl salt: Melting point: 1550-155.50C (recrystallized from hexane or methanol / ethyl acetate).

Using the different methods in the above procedure optical isomers as starting materials, the corresponding optical isomer is obtained the end connection.

Examples of preparations 1. Tablets Coated tablets mq / tablet HCl salt of threo-2- (a-hydroxybenzyl) -acetidine 30 Lactose 78 Dicalcium phosphate 50 sodium lauryl sulfate 12 polyvinylpyrrolidone 12 water (60 ml / 1000 tablets) corn starch 24 dry sodium lauryl sulfate 2.5 magnesium stearate 2.5 tablet weight 211.0 mg Production of threo -2 - (a -hydroxybenzyl) -azetidine hydrochloride is mixed with lactose, dicalcium phosphate and sodium lauryl sulfate. The mixture is sieved through a No. 60 sieve (U.S. Standard) and washed with an aqueous Granulated solution of polyvinylpyrrolidone. If necessary, add water, to get a paste. Then the corn starch is added and mixed further, until a uniform granulate is achieved. This is passed through a No. 20 sieve (U.S. Standard) sieved and dried in a mold at 1000C for 12-14 hours. To sieving again (No. 16 sieve; U.S. Standard), the additional dry Add the sodium lauryl sulfate and the magnesium stearate and press the mixture into tablets.

Coating The cores obtained above are treated with varnish and talc, to prevent moisture absorption.

Then the various coating layers are applied until the tablets have received a nice, smooth surface. Then be the tablets coated with the desired color and polished.

2. Capsules mv / capsule erythro-2- (a-hydroxybenzyl) -azetidine 85 sodium lauryl sulfate 25 lactose 40 magnesium stearate 90 240 Manufacture The first three Components are mixed and the mixture passed through a No. 80 sieve (U.S. Standard) sifted. Then the magnesium stearate is mixed in and the mixture is put into capsules filled.

Claims (4)

PATENTANS PRUECHE 1? Pharmaceutical preparations, characterized in that that they are as active compound 2- (a-hydroxybenzyl) azetidine or an acid addition salt of which included. 2. Preparations according to claim 1, characterized in that one the (+) or (-) - erythro-2- (a-hydroxybenzyl) -azetidine, the (+) or (-) - threo-2- (a-hydroxybenzyl) -azetidine or the corresponding racemates or mixtures or acid addition salts thereof Isomers, racemates or mixtures are used. 3. Process for the production of pharmaceutical preparations, thereby characterized in that one compounds according to claim 1 or 2 in one for therapeutic Administration brings appropriate form. 4. The method according to claim 3, characterized in that the active Compound is mixed with suitable carriers.