FI74953B - FOERFARANDE FOER FRAMSTAELLNING AV PHARMACOLOGISKT VAERDEFULLT LYCINSALT AV / (1-BENZYL-1H-INDAZOL-3-YL) OXY / AETTIKSYRA. - Google Patents

Description

1 74953

The process for the preparation of the pharmacologically valuable lysine salt of [(1-benzyl-1H-indazol-3-yl) oxyacetic acid -

The invention relates to a process for the preparation of a pharmacologically valuable lysine salt of [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid of the formula CH2-NH2 CH2.

I COOH

CH2C6H5

The process is characterized in that equal molar amounts of [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid and lysine are dissolved by heating in a solvent, preferably ethanol, acetone or mixtures thereof with water, from which salt the salt crystallizes on cooling, and that it is separated and obtained in hydrate or anhydrous form.

Italian publication 1,043,762, which corresponds to U.S. Patent Publication, describes [(1H-indazol-3-yloxy] alkanoic acids having interesting pharmacological properties, in particular [(1-benzyl-1H-indazol-3-yl) oxyacetic acid (bendazane) local anti-inflammatory agent.

2 74953 [(1H-indazol-3-yl) oxy] alkanoic acids, in particular [(1-Benzyl-1H-indazol-3-yl) oxyacetic acid, are only slightly absorbed, including as salts with alkali, alkaline earth metals or organic bases, such as morpholine, diethanolamine, piperazine, triethanolamine, diisopropylamine, hydroxyethylmorpholine. In all cases, blood concentrations of bendazane are found to be too low or variable to be used systemically.

Silvestrini, Catanese, and Lisciani have reported in the Proceedings of an International Symposium on Inflammation Biochemistry and Drug Interaction that Excerpta Medica International Congress Series No. 188 (1968) has shown that mean serum concentrations in humans have been found to be only 8 ug / ml after 8 days of treatment. after daily doses of 150 to 900 mg.

It has now been found that the lysine salt of [(1-benzyl-1H-indazol-3-yl) oxyacetic acid (bendazane) is better absorbed. As shown in Table I, the mean serum concentration was found to be 30 pg / ml in 6 volunteers 2 hours after administration of lysine salt as a single oral dose of 500 mg, corresponding to about 300 mg of [(1-benzyl-1H-indazol-3-yl) ) oxy] acetic acid; when 300 mg of [(1-benzyl-1H-indazol-3-yl) oxy] -acetic acid or bendazane is administered under the same conditions, the blood concentration is 8 μg / ml.

3 74953 + i "+ l"

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Cataract is an eye disease in which the lens, a convex organ located between the anterior cavities of the eye and the vitreous, becomes cloudy. The function of the lens is to focus light rays on the retina, where they are detected and from where they are transmitted to the brain as visual impulses. Cataracts are thus associated with impaired vision, which in the most severe cases leads to blindness.

The lens is surrounded by a collagen-containing flexible housing containing fibrous cells whose main component is a homogeneous, transparent protein gel that has the same function as glass in spectacles. As you age or due to many other factors, the fibers in your lens become cloudy and lose their transparency. Until recently, these changes have been considered irreversible. It was generally believed that the only possible treatment for cataracts was surgical removal of the lens, after which the lens was replaced with external or internal artificial lenses placed behind the eye.

It has now surprisingly been found that by orally administering a therapeutic amount of the concomitant bendazan-lysine salt, the development of cataracts not only slows down but in fact also kills recovery.

The bendazan-lysine salt can be used in the treatment of cataracts, especially in pharmaceutical compositions or forms for oral administration that can be applied topically to the eye: The compositions should, of course, deliver an effective concentration of bendazane to the tissue.

Investigation of anti-cataract activity in humans

The first trial was performed in 20 patients with different types of cataracts (cortical, corticonuclear, posterior subcapsular). The patients ’medical history showed that 5,74953 of their cataracts progressed rapidly. The experiment included vision examination, refraction test, and slit-lamp test; the researcher was asked to report the overall assessment. These assessments were performed before the start of treatment, after 4 weeks, and again at the end of treatment when treatment was continued. The lysine salt of bendazane was administered at 1500 mg (equivalent to 911.5 mg bendazane) divided into three daily administrations with meals. The median duration of treatment was 50.4 days, with ranges ranging from 28 to 86 days. The study group included 11 women and 13 men with a mean age of 59.5 (47–74). The effects of treatment are summarized in Table 2; the values obtained for each patient are instead shown in Table 3. For practical reasons, the results are reported as follows: improved (+), no change (0), deteriorated (-).

TABLE 2

Summary of the results of the first experiment in which cataracts were treated with the lysine salt of bendazane

Slit lamp

Light and / or through- Total

Arviointi_Näkö_taitto_valaisu_arvostelu

Improved (+) 18 10 14 18

No change (0) 6 13 10 5

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z (—ii — I 04 04 04 04 04 8 74953 In this experiment, the lysine salt of bendazane caused improvement in many patients (10 to 18, depending on the method of assessment), whereas only one patient experienced deterioration. Relatively poor results were obtained in 5 patients, one of whom was diabetic.

The experiments were repeated as a double-blind experiment comparing the lysine salt of bendazane to placebo. There were a total of 35 patients; 19 were treated with placebo and 16 with the lysine salt of bendazane using the same experimental procedures except that the treatment period was always 4 weeks. The results are summarized in Tables 4 and 5.

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o ·· vo r- 'co on o z κι η ιλ r ^ \ <r 74953 These studies prove without a doubt that the lysine salt of bendazane L has a healing effect on cataracts.

Four patients received eye drops containing 0.25% of the lysine salt of bendazane. Eye drops were used three times a day for one month. Cataracts were also clearly reversed in this group of patients.

In order to obtain a salt of bendazane with lysine, equal molar amounts of t (1-benzyl-1H-indazol-3-yl) oxyacetic acid and amino acid are heated, preferably in ethanol or water-acetone, and the salt crystallizes on cooling as the dihydrate.

The salt thus obtained can be used as it is or after it has been dried under vacuum to constant weight. In various pharmaceutical forms, both the dihydrate and the anhydrous salts with either of the two optically active forms of lysine and the salt with racemic lysine can be used.

When the present compound is used, it is administered orally in suitable formulations, i. together with pharmaceutical excipients commonly used in the preparation of compositions for oral administration. Single doses are between 0.3 g and 1 g and are given 2-3 times a day.

For oral administration, conventional pharmaceutical compositions such as tablets and capsules may be used; a unit dose of both a tablet and a capsule may contain 500 mg of active ingredient.

The following examples illustrate the preparation of the accompanying salt.

14

Example 1 74953 [(1-Benzyl-1H-indazol-3-yl) oxy / acetic acid salt with L. lysine.

12 g (0.042 mol) of 1- (1-benzyl-1H-indazol-3-yl) oxy] acetic acid and 6.2 (0.042 mol) of L-lysine were dissolved in 100 ml of 95% ethanol by heating. Small amounts of the impurity were removed by filtering the mixture while hot and the mixture was allowed to stand overnight at room temperature. The crystalline product was filtered and recrystallized from 95% ethanol. Initially, 15 g of salt was obtained (yield 75.9%). More product was obtained from the mother liquor.

The compound contains one molecule of [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid, one molecule of L. lysine and two molecules of water of crystallization; the compound has a melting point of 178-181 ° C, whereby water is lost during heating.

Example 2

The salt obtained according to Example 1 was dried under vacuum (5-10 Torr) at 105 ° C to constant weight. In this form, it has a melting point of 178-181 ° C (decomposes).

Claims (1)

Process for the preparation of a pharmacologically valuable [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid lysine salt of the formula CH2-NH2 ch2 DOCHoCOOH CH2 I COOH CH2C6H5 characterized in that equal molar amounts of [(1-Bent -syl-1H-indazol-3-yl) oxyacetic acid and lysine are dissolved by heating in a solvent, preferably ethanol, acetone or mixtures thereof with water, from which the salt crystallizes on cooling, and that it is separated and obtained in hydrate or anhydrous form. For the preparation of pharmacologically active lycins from [(1-benzyl-1H-indazol-3-yl) oxylethyl] in the form of CH2-NH2 CH2 och2cooh ch2 f CH-NH2 I COOH CH2C6H5