HU187633B - Process for producing lysine salt of /-1-benzyl-1h-indazol-3-y1/-oxy-acetic acid - Google Patents

Abstract

The present invention relates to a lysine salt of [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid of formula (II) having anti-inflammatory activity. In the process of the invention, equimolar amounts of [(1-benzylH-indazol-3-yl) oxy] acetic acid and lysine are dissolved by heating in a mixture of ethanol or acetone in water, the solution is filtered hot, and the salt crystallized upon standing. recrystallization from ethanol and the resulting hydrate is dried under vacuum, if desired. -1-

Description

The present invention relates to a process for the preparation of [(1-benzyl-1H-indazol-3-yloxy) -acetic acid lysine salt of formula (II) having interesting pharmacological properties.

Italian Patent 1,043,762, U.S. Patent 3,470,194 and Italian Patent Application No. 15,267 of April 21, 1967 disclose various valuable compounds of Formula I.

In particular, [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid (bendazac) has proved to be very interesting as a topical anti-inflammatory agent and has been used in medicine for this activity.

[(1H-Indazol-3-yl) -oxy] -alkanoic acids, in particular [(1-benzyl-1H-indazol-3-yl) -oxy] -acetic acid, are only slightly absorbed, even alkaline earth metal salts. or with organic bases such as morpholine, diethanolamine, piperazine, triethanolamine, diisopropylamine, hydroxyethylmorpholine. The concentration of bendazac in the blood is very low and in any case unpredictable to be used for treatment.

As reported by Silvestrini, Catanese and Lisciani in Proceedings of an International Symposium on Inflammation Biochemistry and Drug Interaction, Excerpta Medica International Congress Series no. 188, (1968): average human serum concentration after 8 days of treatment - daily doses: 150-200 mg at only 8 pg / ml.

However, the literature does not mention at all the bendazac-lysine salt and its preparation, nor does it, of course, describe it as a physical constant. The compound of the invention is thus novel.

It has been found that the lysine salt of [(1-benzyl-1H-indazol-1-yl) oxy] acetic acid (bendazac) has a significantly improved absorption property. As shown in Table _1.5 , after a single oral dose of 500 mg of lysine salt, corresponding to about 300 mg of [(1-benzyl-1H-indazol-3-yl) oxyacetic acid, six volunteers were administered 2 hours after administration. average blood serum concentration measured candidate _Q tion was 36.7 pg / ml; under the same conditions, serum concentrations of 11.7 pg / ml were added after administration of 300 mg [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid or bendazac.

Use of bendazac lysine salt is significantly higher levels of blood concentrations of ₅ m makes it possible, as in the case of bendazac and brought results that drastically changed the potential use of the drug.

Cataract is a disease in which the ophthalmic lens, which is a bioconvex body wedged between the outer chambers and the vitreous humor, becomes opaque. The function of the lens is to focus the light rays on the retina, where they are captured and transmitted in the form of visual impulses to the brain. Thus, cataracts are associated with a decrease in visual capacity, which in the most severe cases leads to blindness.

The backbone is surrounded by collagen elastic capsules containing fiber cells; their main component is a homogeneous translucent protein gel; It has the same function as glass in artificial lenses. As you grow older or due to a variety of factors, lens fibers become cloudy and lose their transparency. So far, these changes have been considered irreversible. It was generally believed that the only possible cure for cataract is surgical removal of the lens. Spreadsheet

Λ hendazac. or the lysine salt of hendazac,> .: serum concentrations in man, after single oral administration

Compound No Weight in kg Dose in mg 1 hour Concentration in pg / ml 2 hours 4 hours 8 hours 50 6 15 12 8 70 7 10 8 5 bendazac 80 60 300 2 5 9 16 7 6 4 4 ? 50 8 9 9 5 40 3 II 10 4 X ± 5.2 ± 11.7 ± 8.7 ± 5.0 ± NEITHER 0.94 1.26 0.88 0.63 60 15 56 25 10 s. 55 500 20 32 16 8 bendazac 80 (corresponds to approx 18 37 18 9 lysine salt 75 300 mg for acid) 23 46 30 16 60 20 27 10 5 45 15 22 11 5 X 18.5 ± 36.7 ± I8,3 ± 8.8 ± NEITHER 1.28 5:13 3:21 1.66

which is then replaced by an external lens or an artificial lens implanted in the eye.

Surprisingly, it has been found that the oral administration of a therapeutic amount of lysine salt of bendazac according to the method of the invention not only inhibits the development but also the development of cataract.

The lysine salt of bendazac (II) is used in the treatment of cataract, especially in the form of pharmaceutical compositions for oral or ocular administration, which, of course, provide an effective tissue concentration of bendazac. Study of cataract activity in humans:

The first experiment was carried out in twenty patients with different types of cataracts (cortical, corticonuclear, posterior sub capsular). Patient history has shown that cataracts have developed rapidly. The experiment included testing of vision, reflexion, and slit-lamp testing; the investigator was asked to express his general judgment. These tests were performed before treatment four weeks later and again at the end of treatment if repeated. Bendazac lysine salt at 1500 mg (corresponding to 911.5 mg bendazac) was divided into meals three times daily. The average duration of treatment was 50.4 days; the lower limit is 28; the upper limit was 86 days. The study group consisted of 11 women and 13 men; their mean age was 59.5 years (47-74). The effects of the treatment are summarized in Table II. are shown in a table; values for each patient are shown in Table III. is shown in Table. For practical purposes, the results are expressed as: improvement (+); no change (0); deterioration (-).

In this experiment, bendazac li / .in salt caused improvement in a large number of patients (10, 18; depending on the evaluation method), while only one patient showed deterioration. There were relatively poor results in five patients, one of whom was diabetic.

The experiments were repeated under double-blind conditions, comparing the lysine salt of bendazac with that of placebo. A total of 35 patients were examined; 19 were treated with placebo and 16 treated with lysine salt of bendazac, using the same experimental methods except that the treatment duration was always 4 weeks. The results are a

ARC. cs Table V summarizes:

II. Spreadsheet

Summary of the results of the first experiment on the effect of bendazac lysine salt on cataract

Evaluation Seeing refraction Slit Lamp and Cut) transzilluin »General perception improvement (+) 18 10 14 IS no change (0) 6 13 10 5 aggravation (-) - 1 1

Table 111.

Details of Patients in the First Experiment on the Effect of Bendazac Lysine Salt on the Treatment of Cataracts

Row- song Name Disease No Gray cataract type Treatment days number Seeing refraction slit lamp General. judge sub- 0 1 V.C. 47 E 63 + + capsular *) NEITHER. 51 E cortical 28 + + + THE- 3 1. Λ. 53 E korlilális 78 + + + ~ f 4 Ε. Λ. 55 56 M kortilális kortiko- 33 84 + + 0 + + 5 n. m. M + + + nuclear 6 D. Λ. P. 58 M kortiko- nuclear 72 + + 0 f 7 Λ. M. 63 E cortical 79 + + 0 -t- X Λ. G. 65 M .szub- capsular 35 0 - 0

187,633

III. Table (continued)

Row- song Name Disease No Gray cataract type Treatment days number Seeing refraction slit lamp General. judgment Comment 9 T.D. 66 M sub- capsular 34 + 0 + + 10 1. C. 66 F sub- capsular 33 + + + + II C.M. 67 F sub- capsular 65 + 0 + + 12 C L. 67 M cortical 54 + + 0 + ll T.A. 68 M cortical 31 + + 0 + 14 1. C. 68 F kortiko- nuclear 61 + + + + 15 P.A. 69 M cortical 36 0 0 + 0 16 1. G. 69 M sub- kapszyláris 86 + 0 + + 17 C.R. 73 F cortical 49 + + + + 18 1, G. 73 M sub- capsular 73 0 + + + 19 A.C. 51 M sub- capsular 54 + 0 0 0 20 E.A. 73 F kortiko- nuclear 29 + + 0 + 21 FLAX 58 M sub- capsular 35 0 0 0 0 diabetes 22 1. G. 74 F kortiko- nuclear 72 0 0 0 0 diabetes 23 1. E. 50 F sub- capsular 29 0 4 · 0 0 diabetes 24 E.F. 63 F sub- capsular 29 0 0 +  + diabetes

ARC. Spreadsheet

Summary of the results of a second experiment using bendazac in the treatment of cataracts using the double-blind method

Cases number No Cataract type Treatment For him- carbuncle Seeing Refrak- tion Gap- lamp Átvilá- dilutions of general judgment 19 12 N cortical 13 (+) 1 1 1 7 F corticuclear 6 placebo (0) 6 12 2 1 2 (-) 12 6 9 6 16 16 14 N cortical 13 bendazac (+) 10 9 10 4 II 2 F corticuclear 3 lysine salt (0) 6 7 2 2 3 (-) - - 1 - 2

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Table V.

Details of individual patients in the second experiment using hendazac on cataracts using the double-blind method

Cases number Name No Gray cataract type Treatment Lá'ás refraction slit lamp Background Check general judgment 1 P.A. F kortiko- nuclear placebo - 0 - 4 L. G. C. M cortical placebo + + 0 + 0 Μ. M. F kortiko- nuclear placebo - - - - 8 F.P. I. 0. F cortical bendazac L 0 0 0 9 F nuclear placebo - - - 0 Μ. M. F kortiko- nuclear bendazac L. + 0 + + + 11 S.M. F cortical placebo 0 0 0 12 C.P. M cortical placebo - 0 - 13 L.V. F cortical bendazac L + 0 + + 14 S.K. M cortical placebo - 0 - - 15 F.F. F cortical bendazac L 0 0 0 0 0 16 G.A. F kortiko- nuclear bendazac L 0 0 - - 17 P.E. F cortical bendazac L + + + + 18 C.G. F kortiko- nuclear placebo - 0 - - - 19 A.R. F cortical bendazac L + + + + 20 T.D. M kortiko- nuclear placebo - - - 21 C.L. M cortical placebo - 0 - 22 C. I. F cortical placebo - 0 - - - 23 C. I. F cortical placebo - 0 - - - 24 C.L. F cortical bendazac L 0 + + + 25 A.A. F cortical placebo 0 0 - - - 26 V.F. M cortical placebo - 0 - 27 D.S.E. F cortical bendazac L + + + + 28 F.C. M cortical placebo 0 0 0 0 0 29 M.R. F cortical bendazac L 0 + + + + 30 M.A. M kortiko- nuclear bendazac L + 0 0 0 0 31 T.A, F cortical placebo 0 - - - - 32 L.C. F cortical placebo 0 0 - - - 33 D.A.L. F cortical bendazac L + + + + + 34 C.A. F cortical placebo 0 - - - 35 E.D. F cortical bendazac L + + + + 36 P.A. F cortical bendazac L 0 0 - - 37 C.M. F cortical placebo - 0 - - 38 A.M. M cortical bendazac L + + + + • 39 V.P. F kortiko- nuclear placebo - - - 40 P.E. F cortical bendazac L + + + +

These studies undoubtedly prove that the L-lysine salt of bendazac has a curative effect on cataracts. Finally, eye drops containing 0.25% bendazac lysine salt were administered to 4 armor patients. The eye drops were instilled three times a day for one month. In this group of patients, cataract rebound was also observed.

The lysine salt of bendazac may be prepared by heating, preferably in ethanol, or in a water / acetone mixture using equimolar amounts of [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid and amino acid. The salt crystallizes in the dihydrate form upon cooling.

The salt thus obtained can be used immediately or dried under vacuum to constant weight. Both the dihydrate and the anhydrous salt of an optically active form of lysine as well as the racemic

187,633 salts of lysine can be used in a variety of pharmaceutical forms.

In practice, the active ingredient of the invention may be administered orally in a conventional formulation; namely, pharmaceutical excipients commonly used in the preparation of oral formulations. Single doses of 0.3 to 1 g should be taken 2-3 times daily.

Acceptable pharmaceutical formulations, such as tablets and capsules, may be used for oral administration; the amount of active ingredient in both tablets and capsules may be 500 mg.

The excipients used in the preparation of these compositions are well known in the pharmaceutical industry. Typical additives for the preparation of tablets include release agents such as corn starch and lubricants such as magnesium stearate; in the manufacture of capsules, standard gelatin capsules may be used which contain either the active ingredient alone or mixed with a diluent. Typical and used formulations are described below:

A) Tablets

Each tablet contains:

bendazac L-lysine salt hydrate 500.0 mg cellulose 91.5 mg corn starch 75.0 mg formalin-casein 30.0 mg polyvinylpyrrolidone 20.0 mg silica 7.5 mg magnesium stearate 6.0 mg hydroxypropyl cellulose 3.0 mg talc 1.5 mg B) Hard gelatin capsule Each capsule contains: bendazac L-lysine salt hydrate 500.0 mg corn starch 75.0 mg lactose 75.0 mg magnesium stearate 4.5 mg C) Granules Each dose (in paper cover) contains: bendazac L-lysine salt hydrate 0.5 g sucrose 4.85 g orange aroma 0.15 g D) Syrup 100 ml contains: bendazac L-lysine salt hydrate 5.0 g sucrose 66.0 g ethyl p-hydroxybenzoate 0, I5g Sodium benzoate 0.5 g Raspberry flavor 0.5 g filled with distilled water To 100 ml

E) 1% eye drops

100 ml contains:

bendazac L-lysine salt hydrate 1.00 g hydroxypropylmethyl cellulose 0.50 g sodium dihydrogen phosphate (1 crystal water) 0.018 g disodium hydrogen phosphate (12 crystal water) 0.19 g rock salt 0, 68 g of thimerosal is filled with 0.001 g of water for injections per 100 ml

F) 0.5% eye drops bendazac L-lysine salt hydrate 0.50 g hydroxypropyl methylcellulose 0.500 g sodium dihydrogen phosphate (1 molecule of water) 0.018 g disodium hydrogen phosphate (12 water) ) 0.19 g table salt 0.74 g thimerosal filled with 0.001 g water for injections per 100 ml

The following examples, which do not limit the scope of the invention, are provided for the preparation of the salt of the invention.

Example 1 [(1-Benzyl-1H-indazole-3-H) -oxy] -acetic acid

The L-lysine salt was dissolved in g (0.042 mol) [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid and 6.2 g (0.042 mol) of L-lysine in 100 ml of 95% ethanol, during heating. The mixture was then filtered hot to remove a small amount of impurity and allowed to stand at room temperature overnight. The crystalline product is filtered off and recrystallized from 95% ethanol to give 15 g of salt (75.9% yield), but more material can be recovered from the mother liquor. The composition is one molecule of {(1-benzyl-1H-indazole). 3-yl) oxy] acetic acid, one molecule of L-lysine and two molecules of crystalline water, m.p. 178-181 ° C, losing water during heating.

Example 2

The salt prepared according to Example I was dried under reduced pressure (5-10 torr) at 105 ° C to constant weight: in this form it had a melting point of 178-181 ° C with decomposition.

Claims (2)

A process for the preparation of a lysine salt of [(1-benzyl-1H-indazol-3-yl) -oxy] -acetic acid of formula (II), characterized in that [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid and Equimolar amounts of l-6,187,633 lysine are dissolved in ethanol or acetone with water while heating, the solution is warm filtered, the salt which crystallizes on standing, is recrystallized from ethanol and dried under vacuum, if desired. A process for the preparation of a pharmaceutical composition for the treatment of cataract, characterized in that the lysine salt of the [1- (1-benzyl-1H-indazol-3-yl) -oxy] -acetic acid of the formula II prepared according to claim I with pharmaceutically acceptable additives. when mixed in a conventional dosage form, it is conveniently formulated into tablets, capsules, granules, syrups, eye drops. I page drawing Published by the National Office of Inventions Responsible for publishing: Zoltán Himer, Head of Department Picking the Essentials for Printing Industry (N7? (> (, 7 tW)) 88-0643 - Dabasi Printing House, Budapest - Dabas Chief Executive Officer: Csaba Bálint Director