NO140270B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPHUTICALLY ACTIVE TRIAMCINOLONACETONIDE-4,4`-METHYLENE-BIS- (3-METHOXY-2-NAFTHOATE) - Google Patents

Description

The present invention relates to an analogue method for the production of therapeutically active triamcinolone acetonide-4,41-methylene-bis-(3-methoxy-2-naphtha).

It is well known that triamcinolone acetonide or 9a-fluoro-lip,21-dihydroxy-16a,17a-isopropylidene-dioxy-1,^--pregna-diene-3,20-dione has found special use in dermatology. The compound shows significant effectiveness in the treatment of derraatosis, eczema, neurodermatitis, impetigo, psoriasis, pruritis and other related diseases. However, with long-term topical treatment over large areas, especially in children where there are skin lesions, a large number of secondary reactions may occur due to percutaneous absorption of the corticoid.

Triamcinolone acetonide is a fluorinated derivative of prednisone, where the fluorine atom in the 9a position of the corticosteroid ring system increases the activity of the glucocorticoid and reduces the effect on the metabolism of electrolytes.

In British patent document 1,332,058 and German publication document 2,149,470, it is described how the unwanted side effects of prednisone can be reduced or avoided by reacting this with an acid (or especially with the acid chloride) to form an ester that has reduced or no absorption compared to prednisone. Said ester has the desired anti-inflammatory properties of prednisone but can be administered without side effects due to absorption when administered orally or topically, e.g. intramuscularly or intravenously. The acid with which prednisone reacts is 4,4'-methylene-bis-{3-methoxy-2-naphthoic) acid.

Production of the acid is described in a Spanish patent document

385,254.

The present invention relates to an analogous method for the production of therapeutically active triamcinolone acetonide-4,4<1->methylene-bis-(3-methoxy-2-naphthoate), which method is characterized by the fact that 4,4<1->methylene-bis -(3-methoxy-2-naphthoic acid)

in a manner known per se is converted into a reactive derivative thereof, after which the reactive derivative obtained is reacted with triamcinolone acetonide.

When producing the naphthoate, the acid is preferably reacted with a halogenating agent such as thionyl chloride, forming two acid-halide groups on the molecule, i.e.

where X is preferably chlorine. This reaction is carried out in an anhydrous medium.

The acid halide thus obtained is then reacted with triamcinolone acetonide in the presence of an agent for binding the acid formed during the reaction, so that a final product corresponding to the formula is obtained:

where R is the radical of triamcinolone acetonide.

An organic base can be used as an acid-binding agent. A particularly suitable compound is pyridine, which acts both as a base and as a solvent for the reaction.

The following example illustrates the invention:

Example 15 gr. ^,■+'-methylene-bis(3-methoxy-2-naphthoic) acid was mixed with 55 ral of thionyl chloride. The mixture was heated on a water bath for two hours, after which excess thionylclofid ; was distilled from until a solid residue was obtained, which was purified by recrystallization from anhydrous benzene.

h,k'-methylene-bis(3-methoxy-2-naphthoinyl chloride) was obtained as a yellow solid.

Melting point: 170 - 173°C

Dividend : 95$

Elemental analysis:

Calculated: C = 66.23$ H = h. 02% Cl = l5. 6h%

Found: C = 66.80$ H = h. 10% Cl = 15.66$

10 gr. of the acid chloride was treated with 19.2 gr. triamcinolone acetonide in 150 ml of pyridine. The mixture was heated for 3 hours at 90°C and the resulting solution was added to 3 L of water. The product was obtained by filtration and washed with water. It was then vacuum dried at between h0°C and 50°C and triamcinolone acetonide h,*+' -methylene-bis(3-methoxy-2-naphthoate) was obtained in 90% yield.

After recrystallization from a mixture of acetone and water, the product was found to have the following properties: Melting point : 220°C (decomposition) Elemental analysis :

Calculated: C = 69.5$ H = 6.25$ F = 3.08$

Found: C = 70.18$ H = 6.29$ F = 3.0h%

Various pre-clinical tests showed that the product was neither absorbed orally nor topically (even over large areas of skin). In particular, it was found that oral administration of the product did not alter the urinary excretion rate of 17-ketosteroids, sodium or potassium ions, which values were significantly altered when related corticoids were administered.

Other measurements showed that the product produced according to the invention has the same anti-inflammatory activity as triamcinolone acetonide and was approx. 200 times more active than prednisone.

The compound may be administered in any suitable form together with a pharmaceutically acceptable carrier, for topical administration it may suitably be at a concentration of 0.3% in a cream or ointment. When the cream is administered three times daily on the affected areas, the main factual total cure was reported in 100$ of cases of various dermatological diseases, e.g. contact dermatitis and related allergies, eczema of physical, chemical and medical origin, folding eczema and household eczema, impetigo, psoriasis and erythema, without the risk of secondary disorders caused by absorption.

Lack of absorption provides a further advantage to the compound, namely that there is no danger of overdose when applied to the skin or mucous membranes, or even from tight dressings.

Biological examination.

A comparative study has been carried out using the method described by A. Jarret in Lawrence and R. Bacharach: Evaluation of Drug Activities; Pharmacometrics, New York Acad. Press, Vol II, page 649, 1964. This method is suitable for simple comparison of corticoid strength.

The investigation included flupamesone, i.e. the triamcilonone-acetonide-4,4'-methylene-bis-(3-methoxy-2-naphthoate) rmepason produced according to the invention, i.e. the compound prednisone-4,4'-methylene-bis- (3-methoxy-2-naphthoate which is known from German publication 2,149,470, as well as six further commonly known topically usable corticoids.

Method.

The method involves applying a daily dose of corticoid cream to uniform groups of mice for 18 days in a row. On the 19th day, the animals are euthanized and their tail skin is dried and prepared for histological assessment.

The skin sections are stained with hematoxylin-eosin and the character of the epithelium is observed. The thickness of the epithelium is compared (using a micrometer scale in the optical microscope) with the thickness of the epithelium in mice treated with the carrier substance alone (cream base layer) or with other reference corticoids. The determination of the thickness is made at the scalar area of the tail and the average of several readings is used for the numerical comparison.

In the experiment, 8 corticoid creams were used, designed for clinical use. These creams were applied daily for 18 days to the tails of female albino mice of the Swiss strain with a body weight of 25-30 g. Eight groups of 9 animals in each group were used. A control group of untreated animals served as a reference.

Results.

The 8 creams induced a reduction in the thickness of the tail epidermis. Application of triamcinolone acetonide, fluocortolone, fluocinolone acetonide, mepason and flupameson caused a fall in the mitotic activity compared to the untreated animals. The flupameson cream induced a reduction in the thickness of the epidermis to a greater extent than all the other corticoids examined.

The results obtained are shown in table 1.

Average thickness of the tail's epidermis in y .

Each value is the average of 15 readings for 9 mice per treatment, i.e. 135 provisions per treatment.

W Antimitotic index in relation to a 5% hydrocortisone preparation (100).

Judgment.

According to the results obtained, prednisone and mepasone have the same antimitotic index (120 and 121 respectively). In contrast, triamcinolone acetonide has an index of 240 compared to 300 for flupameson.

It thus appears that the esterification of triamcinolone acetonide with 4,4'-methylene-bis-(3-methoxy-2-naphthoic acid) to form flupamesone gives an unexpected increase in the antimitotic index (from 240 to 300), while the esterification of prednisone with the same acid during the formation of mepason does not give any increase of this index (from 120 to 121).

The properties of the flupameson produced according to the invention

is thus surprising on the basis of the properties of the known compounds prednisone and mepason.

Several authors have determined that the antimitotic effect of topical corticoids is related to their therapeutic effect. In addition, it has been shown in a double-blind study that flupameson is better than triamcinolone acetonide in clinical use. The flupamesone produced according to the invention is thus a drug that has a significantly better therapeutic effect than the hitherto known, related drugs.

Claims (1)

Analogous method for the production of therapeutically active triamcinolone acetonide-4,4'-methylene-bis-(3-methoxy-2-naphthoate) characterized in that 4,4'-methylene-bis-(3-methoxy-2-naphthoic acid) on in a manner known per se is converted into a reactive derivative thereof, after which the reactive derivative obtained is reacted with triamcinolone acetonide.