DD201892A5 - PROCESS FOR PREPARING THE LYSINE SALT OF ((1-BENZYL-1H-INDAZOLE-3-YL) OXY) ACETIC ACID - Google Patents

Abstract

The invention relates to a novel salt of (& 1-benzyl-1H-indiazol-3-yloxy) acetic acid & or Bendazac & with lysine. After oral administration of this compound to humans, Bendazac concentrations found in the blood are higher and more reproducible than those concentrations achieved after Bendazac was administered as such. This discovery extends the tehrapeutic application of Bendazac to an unprecedented extent. In fact, while Bendazac has so far only been used in the treatment of respiratory conditions, the new Bendazac salt mentioned above allows oral administration to the therapeutic treatment of cataracts. The salt is obtained by heating equimolar amounts of acid with lysine in a solvent, crystallizing and separating.

Description

Z S / U 4 J Ο AP C 07 D / 237 043 / β

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Process for the preparation of a lysine salt of / p-benzyl

Field of application of the invention

The invention relates to a preparation process of the lysine salt of ZXi-benzyl-1H-indazol-3-yl) oxy-7-acetic acid <> This salt can be used in medicine in particular for the treatment of cataracts »

Well-known technical solutions

In IT-PS 1 043 762, corresponding to US-PS 3 470 194, and IT patent application 15267, a number of compounds are claimed which are of the general Pormei

χ ^ f ^^ , _ ^ --- OCH ₂ COOH

In particular, / Ii-benzyl-1H-indazol-3-yl) oxy-7-acetic acid (Bendazac) has been found to be highly effective as an anti-inflammatory agent to be applied locally, because of its effectiveness in the art Medicine introduced and applied ..

The Z (1H-indazol-3-yl) oxyalkanoic acids, specifically TiTi-benzyl-1H-indazol-3-yl) oxy, 7-acetic acid, are only weakly absorbed, even if they are used as a salt with alkali metal or potassium Alkaline earth metals or with organic bases such as morpholine, di-e.thanolamine, piperazine, Trietha

9-1 iDiH

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nolamin, diisopropylamine, hydroxyethylmorpholine "In each Pall, Bendazac blood levels were found to be too low or inconsistent to allow systemic use of the drug.

As reported by Silvestrini, Catanese and Lisciani in "Proceedings of an International Symposium on Inflammatory Biochemistry and Drug Interaction" Excerpta Medica International Congress Series Ho. 188 (1968) vairde, the mean serum concentration in humans after eight days of treatment with doses of daily 150 .. "900 mg was found, only 8 / ug / ml."

Cataract is an eye disease associated with lens opacification - the lens is a biconvex body located between the anterior chamber of the eye and the vitreous humor. The function of the lens is to focus light rays on the retina, where "the light rays are perceived and transmitted to the brain in the form of visual impulses". The cataract is thus accompanied by a diminution of vision, in more severe cases to blindness leads"

The lens is surrounded by a collagenous elastic capsule containing fibrous cells, the main component of which is a homogeneous transparent protein gel that functions like the lens of an artificial lens. * With increasing age or due to a number of different factors, the lens fibers become cloudy and lose their transparency "Until recently, these changes were considered to be irreversible." It was generally assumed that the only possible cure for cataracts in the

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surgical removal of the lens and its replacement by an external or internal artificial lens implanted behind the eye »

Object of the invention

It is the object of the invention to develop a new preparation for the healing of cataracts, which does not necessitate a surgical intervention.

The object of the invention is to provide a preparation process of the lysine salt of _J / Ji-benzyl-1H-indazole-3-yl) oxy-7-acetic acid.

According to the invention, therefore, the lysine salt of / (1-benzyl-1H-indazole-3-vinyl) is obtained by dissolving equimolar amounts of (II-benzyl-1H-indozol-3-yl) -oxy-7-acetic acid and lysine by heating in a solvent, usually in ethanol, acetone or mixtures thereof with water, crystallizing the salt with cooling and then separating it into hydrate or anhydrous form.

It has been found that ^ 1 ~ benzyl-1H-indasol-3-yl) oxyacetic acid (3endazac) has better absorption as a salt with lysine. from Table I, the mean serum concentration found in 6 volunteers was 2 hours after oral administration of 500 mg of the lysine salt, corresponding to about 300 mg / Ti-benzyl-1H-indazole-3-yl) -oxy-7-acetic acid

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30 μg / ml; under the same conditions, the blood concentration determined with 300 mg / {i-benzyl-1H-indazol-3-yl) -osy_7-acetic acid or bendazac is 8 μg / ml »

The availability of a Bendazac salt (d * h * lysine salt) which is capable of producing higher concentrations in the blood compared to exclusive Bendazac use has given results which dramatically modify the potential uses of the drug.

Oral administration of a therapeutic amount of Bendazae lysine salt not only delays the development of cataract, but actually causes the cat to decline

The invention describes the use of bendazac-lysine salt of the formula

OCH ₂ COOH

CH ₂

CH ₀ I ^άCH ₂

CH-KH

COOH

for the treatment of cataract, especially in the form of pharmaceutical compositions for oral administration or for local administration to the eye; Of course, the compositions should ensure a sufficiently effective Bendazac concentration of the tissue *

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TABLE I

Serum concentrations in humans following oral administration of Bendazac as such or in the form of Bendazac lysine salt

Compound - mass dose concentrations in μg / ml poor in kg in mg

i h

2 h

4 · h

bendazac

male.

female.

300

6 7 2

5 8

15 10

16

11

12 8 7

10

5 4

4 5 4

5 ± 5, 2 + 11 .7 + ' S, 7 ± 5, 0 + Standard error 0 94 1 , 26 O ₅ 88 O, 63

with lysine

male · 60 500 15 56 25 10 55 (Equivalent * 20 32 16 8th 80 about 300 18 37 18 9 Acid) Female ·: 75 23 46 30 16 60 20 27 10 5 45 15 22 11 5

X +

standard error

18.5 + 36.7 + 18.3 + 8.8 + 1.28 5.13 3.21 1.66

^ ^ For investigation

A first experiment was performed on 20 patients with different types of cataracts (cortical, corticonuclear, posteriorly subcapsular). "The medical history of the patients indicated that their cataracts rapidly worsened"

included an examination of vision * a revision test and a slit light test p the examiner was required to give an overall assessment. These evaluations were performed before the start of treatment * four weeks later and with prolonged treatment after the end of the treatment «Bendazac-lysine» salt was given in a daily dose of 1,500 mg (equivalent to 911f5 mg Bendazac) in three dietary portions The mean duration of treatment was 50-4 days (28-86 days). The test group consisted of 11 women and 13 men with a mean age of 59-5 years (47 × 74 years). The treatment results are shown in Table 2 j: the values obtained for each individual patient are given in Table 3. * For practical reasons, the results are expressed as follows: (+) f no change [O) f deterioration (-) · '

TABLE 2

Summary of results obtained in the first experiment with the lysine salt of Bendazac in cataracts

Assessment of Vision Refraction Sporadic General

and / or mybe-transillum judgment »

Improvement (+) 18 10 14 18 no offense. _Q. change ^ * 6 13 10 , 5 Bad news -. - 1

BELLE 3 47 Results obtained with the lysine salt of Bendazac patients subcapsular Days visual Re fr «, in gray Ur- gerer part kung e im ι ar am 51st Kind of "gray stars" cortical 63 0 SpaTfU u / o. trans + first expe single - 53 W cortical 28 + 11 Name Al ter 55 W cortical 78 + + + V..C 56 W kortikonuklear 33 + * S, E • P. 58 m kortikonuklear 84 + 0 + IVA 63 m cortical 72 + + + + F.A. ;. it m subcapsular 79  ί- 0 + D ₉ M 66 W subcapsular 35 0 - 0 - THERE- 66 ra subcapsular 34 + - 0 0 AT THE 67 m subcapsular 33 + + + + A _e G »67 la » kertikal 65 + 0 + ' ⁺ I «D 68- W. cortical 54  f + +  ¥ A.G 68 ra kortikonuklear 31 + 0 + , C .M 69 m cortical 61 • ί- + 0 CL V 69 W subcapsular 35 0 0 + 0 T.A. V 73 m cortical 86 + 0 + Z.C 73 ra subcapsular 49 + + + + P.A , 51 W subcapsular 73 G + * > A »G * 73 m kortikonuklear 54  j 0 + 0 ' CR UN "58 m subcapsular 29 + + 0 + . I .S _β 74 W kortikonuklear 35 0 G 0 0 diabe ! UC V 50 m subcapsular 72 0 0 0 0 'CA »63 subcapsular 29 0 + 0 0 IiP W 29 * 0 0 L F.G m -f > LeE I- E _e F

In this experiment, the lysine salt of Bendazac caused an improvement in a large number of patients (10 "" 18, depending on the assessment method) _4, while only one patient showed worsening. Relatively weak results were obtained in 5 patients, one of whom was diabetic ",

The experiments were repeated under double blind conditions comparing the lysine salt of Bendazac with a placebo. A total of 35 patients was included; 19 were treated with the placebo and 16 with the lysine salt of Bendazac using the same experimental methods except that the treatment duration was in each case four weeks * The results are summarized in Tables 4 and 5.

TABLE_4

Summary of the results obtained in the second experiment using the double-blind method to study the efficacy of Bendazac in cataracts

FeTb Closed Startup type Handle. Be Seh- Refr, "Spalt- Trans" Gewerin, leucn- illustate te mina-

part,

12 w cortical 13 (+)

¹⁹ 7m kort ^ nuclear · ₆ ^pla2ebo (0)

2 9

14 w kortikfal 13 Benda- (+) 10 9 10 16 zac-Ly

2 m corto-nukJL 3 sin »(0) 6 7 2

salt (-) - - 'l

4 2

ELLE 5

zelpatienten results from the second experiment ·; - using

Double-blind method was used to investigate the efficacy of Bendazac in uem Star

Surname

Start type treatment

Rope «» "" Reverm .. frak.

Slit lamp ιrana illura. ijösauit ~ beurtlg 0 4 0 4 ⁺ 0 + + 0 0 0 4 ·

P .A. W \ N kort.nuk , placebo L - 0 L.GC. m W cortical placebo + M.M W W kort.nuk * Placebo L M F. P. cortical bendazac " 0 0 L.O. vtf m kort.nuk _e placebo M.M. W W kort.nuk , bendazac L + 0 S. M. W cortical placebo 0 0 CP. m cortical placebo L - 0 L.V. W cortical bendazac L 4 0 S.R. m cortical placebo L 0 F. F. W cortical bendazac 0 0 CA. W kort.nuk , bendazac L 0 0 P.E. W cortical bendazac .. + + CG _e W kort, nuk β placebo . * - 0 A ₉ R ₄ , W cortical bendazac 4th + T .D .. m kort.nuk , placebo L '' - CL. m cortical placebo - 0 CI * cortical placebo ~ * _ 0 CL. W cortical bendazac L 0 4 A.A. W cortical placebo 0 0 V _e F, m cortical placebo L ". 0 D .S .E. cortical bendazac L + F .C. m cortical placebo ·. 0 0 M. R. W kortiakl Bendazyc 0 4 M.Ä " ro cort _e nuk , bendazac L 4 0 kortikai placebo .. 0 L .C. W cortical placebo L 0 0 THERE. IU w cortical bendazac L 4 · 4 G.A.- cortical placebo ... 0 - E .D ♦. cortical bendazac L ψ + P.A. cortical bendazac 0 0 CM. cortical placebo L 0 AT THE. cortical bendazac + 4 · V. P. cort »nuk ". placebo - P.E. cortical bendazac + +

4 · 0 4 · 0

These investigations confirm beyond doubt ;; the administration of Bendazac L. lysine salt has a cataract healing effect.

In conclusion, 4 patients were given eye drops containing 0.25 % Bendazac lysine salt. "The eye drops were instilled three times daily for one month. A clear decrease in cataract was also observed in this patient group.

The bendazac lysine salt is recovered by heating equimolar amounts of ε (1-benzyl-1H-indazol-3-yl) oxyacetic acid and the amino acid, preferably in ethanol or water-acetone. Upon cooling, the salt crystallizes as a dihydrate.

The salt thus obtained can be used as such, but it can also be used after it has been dried under vacuum to constant mass. It is possible to use in various pharmaceutical forms both the dihydrate and the anhydrous salts with one of the two optically active lysine residues as well as the salt with racemic lysine.

The compound of the invention is used orally in the form of conventional formulations, viz. In association with pharmaceutical excipients. as commonly used in the preparation of compositions for oral administration. "Single doses between θ3 g and 1.g are to be administered 2 to 3 times a day.

As conventional pharmaceutical compositions for oral administration, for example, tablets and capsules may be used; the single dose for both a tablet and a capsule may be 500 mg active ingredient «

The excipients used in the preparation of these compositions are the excipients known in the art of the pharmacist in the manufacture of tablets

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Among the typical excipients include the decomposing substances such as corn starch and lubricants such as magnesium stearate; in the manufacture of capsules, standard gelatin capsules containing the active ingredient alone or in admixture with a diluent may be used.

In the following typical and contemporary formulations are listed «

Ai tablets

Each tablet contains (in mg):

Bendazac L. lysine salt hydrate 500.0

Cellulose 91.5

Corn starch 75.0

Formalin casein 30.0

Polyvinylpyrrolidone 20.0

Silicon dioxide 7.5

Magnesium stearate 6.0

Hydrorxpropyl cellulose 3 »Q

Talc 1.5 ·

^B: hard gelatin capsules

Each capsule contains (in mg) ϊ

Bendazac-L-Lysil salt hydrate 500.0

Corn starch '75.0

Lactose '75 _} 0

Magnesium Stearate 4 _S 5

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C: granules

Each Binzeldosis (in paper envelope) contains (in g):

Bendazac L. - lysine salt hydrate 0.5

Sucrose '4> 85

Orange flavor. 0.15

D: ' syrup

100 ml contain:

Bendazac-L-Lysilsalzhydrat 5 * 0 g

Sucrose 66.0 g

Ethyl p-hydroxybenzoate 0.15 g

sodium benzoate. 0.5 g

Raspberry flavor 0.5 g distilled water to 100 ml

E: 1% eye drop

100 ml contain:

Bendazac-L-Lysilsalzhydrat 1.00 g

Hydroxypropylmethyl cellulose 0.500 g

H ₂ HaPO ₄ .H ₂ O 0.018 g

HKa ₂ PO ₄ .12 H ₂ O 0.190 g

UaCl 0.680 g

Thimerosal 0.001 g

Water for injections up to 100 ml

F: 0.5% Au dropwise

Bendazac-L-Lysilsalzhydrat 0.50 g

Hydroxypropylmethyl cellulose 0.500 g

H ₂ NaPO ₄₀ H ₂ O 0.018 g

HUa ₂ PO ₄ .12H ₂ O 0.190 g

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NaCl thimerosal

0.740 g 0.001 g

Water for injections up to 100 ml

The following non-limiting examples illustrate the preparation of the salt of the invention *

Execution ia 1 1

Salt of r (1-benzyl-1H-indazol-3-yl) oxy / acetic acid with L ^ -lysine, 12 g (0 * 042 mol) of f (1-benzyl-1H-indasol-3-yl) oxy] Acetic acid and 6> 2 g (0.042 mol) of L _e . lysime were dissolved by heating in 100 mL of 95% ethanol. * The mixture was filtered while warm to remove the very small amounts of impurities, then the mixture remained Room temperature overnight. The crystalline product was filtered and recrystallized from 95% ethanol; initially, 15 g of salt was recovered (75; 9 % yield), while the mother liquor yielded more product. * The compound consists of one molecule of F (l-8enzyl-H-indazol-3-yl) oxy-acetic acid, one molecule of L-lysine and two molecules Kristallisationswasseri. the compound shows a melting point at 178 ° C * 181 ° C with water loss during the Er. heat _e

The salt obtained according to Example 1 was dried under vacuum (5 ». * 10 Torr) at 105 ° C to constant mass; in this form it shows a melting point at 178 ... 181 ° C with decomposition *

Claims (3)

13 · 4 · 1982 AP C 07 D / 237 043 / β 60 334 12 Invention claim 1. A process for the preparation of a lysine salt of
/ Ji-benzyl-1H-indazol-3-yl) oxo-7-acetic acid, characterized in that equimolar amounts of / X 1-benzyl-1H-indazol-3-yl) oxy-7-acetic acid and lysine by heating in a
Solvent - usually in ethanol ^ acetone or mixtures thereof with water - are dissolved and crystallized from the salt with cooling and then separated and recovered in a hydrate form » 2. Method according to item 1, characterized in that said lysine salt is separated and recovered in an anhydrous form. 3 method according to item 1 or 2, characterized by
that it is a salt of / (1-benzyl-1H-indasol-3-yl) oxy-7-acetic acid with L-lysine