NO133802B - - Google Patents

Description

The present invention relates to an analogous method for the preparation of therapeutically effective vitamin A acid amides of the general formula where R and each means an alkyl group with 1-10 carbon atoms optionally substituted with a lower alkoxy group or a di-lower alkylamino group,

a hydroxy-lower alkyl group, or a phenyl or benzyl group,

where R additionally means hydrogen.

The term "alkyl group" means both straight-chain and branched hydrocarbon groups with 1-10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert.butyl, pentyl, hexyl, heptyl, n-decyl and the like. the term "hydroxy-lower alkyl group" means hydroxy-lower alkyl groups with 1-4 carbon atoms, such as e.g. a hydroxyethyl group:. The term "lower alkoxy group" means straight-chain or branched alkoxy groups with 1-4 carbon atoms, e.g. methoxy, ethoxy etc. the term "lower alkylamino group" means alkylamino groups of 1-4 carbon atoms, e.g. methylamino, ethylamino, etc.

The method according to the invention is characterized by reacting the vitamin A acid or a functional derivative thereof with an amine of the general formula,

where R and R^ have. the above meanings.

As the amine of formula II, the use of ethylamine is preferred,

As functional derivatives of vitamin A acid can especially

mention is made of the vitamin A acid halides, preferably chloride, as well as vitamin A acid esters.

It is appropriate to carry out the reaction in an inert organic solvent, such as e.g. ether, and at a temperature from approx. room temperature to the reflux temperature of the reaction mixture. It is also appropriate to carry out the reaction in an inert gas atmosphere, e.g. in a nitrogen atmosphere.

The new vitamin A acid amides can be used

for topical and systemic therapy of precancer and carcinoma, as well as for systemic and topical prophylaxis of carcinoma.

They can be used as such or in combination with cystostatic agents as well as with radiation therapy. In addition, they can be used for topical and systemic therapy of acne, psoriasis and other accompanying dermatological conditions with increased or pathologically variable cornification as well as eczema. They can also be used for affections of the mucous membrane which are caused by inflammatory or degenerative or metaplastic pre-changes. Vitamin A acid ethylamide can be mentioned as preferred vitamin A acid amide.

The toxicity studies carried out on mice and rats gave the following results with regard to acute toxicity:

The substituted vitamin A acid amides obtained with the method according to the invention have a pronounced epithelial protective effect (shown according to Boguth et al. Int. Z. Vitaminf. 1960, 31, 6), and in contrast to free vitamin A acid and the unsubstituted amide no skin irritation and no so-called A- hy per vi t ami nose-.

The following experiments were carried out:

Experiment 1 is aimed at a comparison of the epithelial-protective effect of the substituted amides of the vitamin A acid, which are produced according to the present invention, vitamin A acid and vitamin A acid amide, and

experiment 2 is aimed at a comparison of the skin irritation effect and the A hypervitaminosis side effects for the substituted amides of vitamin A acid which are produced according to the present invention, vitamin A acid and vitamin A acid amide.

For sock 1

Here, the aforementioned method of Boguth et al., Int. Z. Vitaminf. _31, 6 (1960) used and castrated female rats were pre-treated with a mixture of 1 meg oestradiol benzoate and 250 meg testosterone propionate in 0.1 ml sesame oil, until clean, cell-like cells appeared in the vaginal secretion. Then, the doses of vitamin A active compounds were administered in logarithmic steps by a factor of 1.2. The value for the epithelial protective effect was determined for each compound

as the dose required to give only approx. 50% scale-like cells in the secretion.

The results of this trial are reproduced in table 1.

As can be seen from the results of this experiment, the substituted amides of vitamin A acid, which are prepared according to the present invention, have epithelial protective effects which are comparable to the effects of vitamin A acid and vitamin A acid amide.

Attempt 2

Skin irritation and A-hypervitaminosis tests were carried out.

The skin irritation tests were carried out as follows:

Half the skin on the back of a guinea pig was shaved off. A 1% solution of the sample preparation dissolved in acetone was applied 8 times over the course of 10 days to 3 exposed skin.

The reaction was read on it. day using a scale from 0 to 4 to determine the degree as follows: 4 = strongest reaction with scabbing, redness and severe crusting 3 = strong reaction with scabbing, redness and some crusting 2 = moderate scabbing, no redness, no crusting

1 = weak scab

0 = no reaction.

The hypervitaminosis tests were performed with mice weighing 25-27 g receiving 10 i.p. administrations of the test substance suspended in arachis oil over the course of 14 days. The following symptoms were assessed: loss of weight, scabies, loss of hair and broken bones. They were assessed on a scale from 0 to 4 as follows:

1. Loss of weight: >10 g = 4

7-9 g = 3

4-6 g = 2

1-3 g = 1

< 1 g = 0-

2. Scabies: very strong = 4_

strong = 3

moderate = 2

weak =«1

none = 0

3. Loss of hair: very severe = 4

strong = 3

moderate = 2

weak = 1

nothing =0

4. Bone fractures: Number of extremities with fractured bones: 0 to 4

The lowest daily dose that produces hypervitaminosis in the 14-day test with mice was indicated in the tables. The condition of the animals resulting in a total of at least 3 points was considered as hypervitaminosis. The indication >400 was entered in the table if 400 mg/kg did not cause any hypervitaminosis. It is possible that much higher doses of these preparations can be used without causing any hypervitaminosis.

The results of this trial are set out in table 2.

As can be seen from the results of this experiment, the substituted amides of vitamin A acid, which are produced according to the present invention, have almost no skin irritation and almost no A hypervitaminosis in comparison with vitamin A acid and vitamin A acid amide.

The compounds, which are produced according to the method, can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations.

The preparations used for systemic use can be prepared by adding to a compound of the general formula I as active ingredient a non-toxic, inert solid or liquid carrier that is common in such preparations.

The agents can be administered enterally or parenterally. For enteral administration, e.g. funds in the form of

tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. Agents in the form of infusion or injection solutions are suitable for parenteral administration.

The dosage when administering the compound can vary according to the area of application and the needs of the individual patient.

The foitaiitiels according to the method can be administered in amounts up to 1000 mg daily in one or more doses.

A preferred form of administration is capsules with a content

from approx. 20 mg to approx. 200 mg of active substance. Suitable forms are capsules of hard or soft gelatin, methylcellulose or of another suitable material, which are easily dissolved in the digestive system.

The preparations may contain inert or medically active additives. Tablets or granules can e.g. contain a number of binders, fillers, carriers or diluents. Liquid substances can e.g. available in the form of a sterile and water-miscible solution. In addition to the active substance, capsules may also contain a filler or thickener. In addition, they may contain flavor-enhancing additives, as well as the usual preservatives, stabilizers, humectants or emulsifiers. Furthermore, they may contain salts to change the osmotic pressure, buffers or other additives.

The carriers and diluents mentioned above can be organic or inorganic substances, e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. A prerequisite is that the excipients used in the preparation of the preparations are non-toxic.

For topical application, the manufactured products can be suitably used in the form of ointments, tinctures, creams, solutions, "lotions", sprays, suspensions and the like. Ointments, creams and solutions are preferred. These preparations used for topical application can be prepared by adding to the manufactured products, which serve as active ingredients,

adds non-toxic inerts, for the topical treatment

suitable solid or liquid carriers common in such preparations.

It is appropriate for topical application to use 1 to approx. 10%, preferably approx. 2 to approx. 5% solutions,

and approx. 1 to approx. 10%, preferably approx. 2 to approx. 5% ointment or cream.

The manufactured products can also be used together with an antioxidant. Of these, in particular tocopherol, N-methyl-Y-tocopheramine, as well as butylated hydroxyanisole, butylated hydroxytoluene or ethoxyquinoline, come into consideration.

EXAMPLE 1

60 parts by weight of ethylamine and 300 parts by volume of absolute ether are stirred under ice-cooling in a nitrogen atmosphere, and to this the acid chloride of 30 parts by weight of vitamin A acid in 100 parts by volume of absolute ether is added dropwise for 30 minutes. You stir for 4 hours at room temperature, and then you stir for 2 hours under reflux. The mixture is cooled, diluted with 100 parts by volume of ether

and wash 4 times with lOO parts by volume of water each time. The ether solution is dried over sodium sulphate, the solvent is evaporated and the residue is crystallized in a benzene-hexane mixture. The vitamin A acid ethylamide is obtained with a m.p. at 137 - 138°C; X . = 347 mn, E }% 1540.

max ~' limb

EXAMPLE 2

Analogously to example 1, the following substituted vitamin A acid amides can be prepared:

EXAMPLE 3

Analogous to example 1, the vitamin A acid diethylamide is prepared.

In order to purify this substance, it is chromatographed using 600 g of aluminum oxide (activity III neutral) and using hexane, whereby, after isolating a preliminary fraction, the pure amide is obtained together with hexane. After removing the solvent, the vitamin A acid diethylamide is obtained in the form of an oil. Ama:k.s 340 mp E lcm 1300.

EXAMPLE 4

Analogous to examples 1 and 3, the following substituted vitamin A acid amides can be prepared: vitamin A acid di-n-butylamide

A 337 mt E*% 985

max r 1 cm

- vitamin A-acid-di-n-decylamide

A. 337 mu e}% 775

max n 1 cm

Claims (1)

Analogous process for the preparation of therapeutically active vitamin A acid amides of the general formula where R and R each mean an alkyl group with 1-1 carbon atoms optionally substituted with a lower alkoxy group or lower alkylamino group, a hydroxy lower alkyl group, or a phenyl or benzyl group, whereby R additionally means hydrogen, characterized by that one reacts vitamin A acid or a functional derivative thereof with an amine of the general formula, where R and R^ have the meanings indicated above.