IE52514B1 - (1-benzyl-1h-indazol-3-yl)oxy)acetic acid salt with lysine - Google Patents

Description

In the following: Italian Patent No. 1,043,762 granted on February 29, 1980 and entitled Acidi E(lH-indazol-3il)ossi] acetioi e processo per la loro preparazione, corresponding to U.S. Patent No. 3,470,194 granted on Sept. 30, 1969 and Italian Patent Application No. 15267, filed on April 21, 1967, also pending and entitled Acidi [ (lH-indazol-3-il)ossi] alcanoici e processo per la loro preparazione it is claimed a series of compounds belonging to the general formula and possessing interesting pharmacological properties. Particularly E(l-benzyl-lH-indazol-3-yl)oxy] acetic acid (bendazac) was found to be very interesting as a local anti-inflammatory agent and it was introduced in medicine and used for this activity.

The E(lH-indazol-3-yl)oxy] alkanoic acids particularly E(l-benzyl-lH-indazol-3-yl)oxy] acetic acid, are only slightly absorbed, even as a salt with alkaline, alkaline52514 - 3 earth metals or with organic bases such as morpholine, diethanolamine, piperazine, triethanolamine, diisopropylamine, hydroxyethylmorpholine. The bendazac blood concentrations are found in any case to be too low or erratic to permit the systemic use of the drug.

As reported by Silvestrini, Catanese and Lisciani· in Proceedings of an International symposium on Inflammation Biochemistry and Drug Interaction Exoerpta Medica International Congress Series No. 188 (1968) - the mean serum concentration found in man after an 8-day treatment with daily doses from 150 to 900 mg is only 8 pg/ml.

It has now been found that [(l-benzyl-lH-indazol-3-yl)oxy] acetic acid (bendazac) as a salt with the lysine has a better absorption. As shown in Table I, after a single oral administration of 500 mg of the lysine salt, corresponding to about 300 mg of [(l-benzyl-lH-indazol-3yl)-oxy] acetic acid, the mean serum concentration found in 6 volunteers, two hours after . administration, is 30 jag/ml; under the same conditions, the blood concentration obtained with 300 mg C(l-benzyl-lH-indazol-3-yl)-oxyJ acetic acid or bendazac is 8 pg/ml.

The availability of a bendazac salt (i.e. lysine salt) capable of producing higher blood concentrations than those previously obtained with bendazac gave results which dramatically modify the drug's possible uses.

Serum concentrations in man after a single oral administration of bendazac as such or bendazac r“i € σ» a c •r| β •d +> td +> β Φ U β u σ> s β •rl Φ CO O Q cn a: β •rl +J •r| φ c •rt n >1 (H fi +J •rl β £ □ 0 +J u. e (0 0 co a £ ¢0 00 in M* in ’φ 5.0+ KO o +1 00 r* co £ CM a KO ok o • • r-i 00 o +1 KO CM • • ,fi in o OK KO O' rl rH rd H rl H H γ4 + 1 CM OK KO CM m co CO • • m o o o ro o o o ο o © If) f* CO φ ΙΛ *o id N Φ Ό β Φ Or +1 i X + | vo oo a co o\ Φ in in in vo co ri +1 id ω ci oo <*> + 1 o C* H io ci r» in CM Ci TABLE I COtrtd 0 0 p O © o • ω o > in •d P Ό •d u (ύ o vo in in o co in c* o vo 04c •d >1 id Λ u •P (tf ♦d N £ m •n •P Π H +1 «3 XI CO w co - 6 Cataract is a disease of the eye involving opacification of the lens, a bioconvex body interposed between the anterior chambers and the vitreous body of the eye. The lens has the function of focusing the light rays on the retina where they are perceived and transmitted to the brain in the form of visual impulses. Cataract is, therefore, accompanied by a decrease in visual capacity, which in the more severe cases leads to blindness.

The lens is surrounded by a collagenous elastic capsule containing fiber cells whose main component is a homogeneous, transparent protein gel which has the same function as the glass in an artificial lens. With increasing age, or due to a variety of different factors, the lens fibers become opaque and loose their transparency. Until recently these changes were considered irreversible. It was generally believed that the only possible cure for cataract was surgical removal of the lens which was then substituted with external or internal artificial lens implanted behind the eye.

It has now surprisingly been found, according to the present invention that the orally administration of a therapeutic amount of bendazac lysine salt, not only delays cataract development but also actually causes regression. - 7 The present invention provides the use of bendazac lysine salt having the formula : 0CH2C00H CH2C6H5 CH2-NH2 I ch2 I ch2 I ch2 I ch-nh2 I COOH for the treatment of cataract, especially in the form of 10 pharmaceutical compositions for oral administration or for administration topically to the eye: the compositions should, of course, provide effective tissue concentration of the bendazac.

Study of the anti-cataract activity in humans A first experiment was conducted on 20 patients with different types of cataract (cortical, corticonuclear, posterior subcapsular). The patients' medical history showed that their cataract was rapidly progressing. The experiment included an examination of vision, refraction and slit-lamp test; the investigator was asked to express an overall judgement. These evaluations were performed before the beginning of treatment, after 4 weeks and again at the end of treatment when prolonged. The lysine salt - 8 of bendazac was administered at the dose of 1500 mg (corresponding to 911.5 mg of bendazac) divided into three daily administrations during meals. The average duration of treatment was 50.4 days with time limits from 28 to 86 days. The study group consisted of 11 females and 13 males with an average age of 59.5 (47 - 74). The effects of treatment are summarized in Table 2; the values obtained in each patient are illustrated instead in Table 3. For practical purposes the results are expressed as: improvement (+), no change (0), worsening (-).

TABLE 2 Summary of the results obtained in the first experiment conducted with the lysine salt of bendazac in cataract Evaluation vision Refraction SIit-lamp and/or Transilium Overall Judgement Improvement (+ ) 18 10 14 18 io change (0) 6 13 10 5 worsening (-) ** 1 1 each patient, used in the first experiment, conducted with the lysine salt of bendazac φ Q Note H H (0 Φ + + + + + k 4J Φ fl > Φ o ε k •H • 1 o 0) c +J ft c •H + + + + + ε Ό /0 E id c k 3 (0 H id k H I 0 ιϋ o + + + o k c ik 0 Φ •H OS k a 0 + + + + + •H (0 > ω +1 id +J co co 00 co >1 0 c VO CM f> co 00 id M Φ a •P b k id H 9 ik rd a (0 id (d id 0 k Q & u u 0 0 (d (d Ή •rl •rf Φ u P •P P P H Π. 4J JS k k k k 0 S 3 0 0 0 0 3 Eh υ W u U 0 a 3 X Φ ft fa ft 2 2 co Φ ik <*) in kO $ in in m m Φ E υ w 4 4 2 a s> co H fa ft tn Φ • (a id 0 rk CM m ..to- «ί- 10 a 0) +> 0) rt ♦H Ό + + + + 00 o TABLE 3 contd + + o + o + + + o o + + O + O + + o + + + + + + o + + o + + O cm at in Si* co in 1—) i—1 m io & in r* co co co 10 in co IO co GO •rt* in CO u •H -P μ a U rt i4 3 μ rt w rt μ rt H 3 h rt H 3 1 h μ rt H rt μ rt H rt μ rt H 3 H 0 3 μ rt iH rt rt o 05 05 05 rt rt 0 μ rt 05 rt 03 05 C a u ft ft Ω. ft u u u rt a o< u H* I S' rt rt rt rt •H •H Φ •rl rt •H rt rt • rt +) o o □ u -p +> P i-H P u •P u o +> u μ 43 X) 43 43 μ μ μ 0 μ Λ μ 9 μ 0 3 s rt 3 0 0 0 g 0 rt 0 rt rt 0 3 0 a 0 . 05 05 u u u fi u 05 u 01 05 0 Q E E s Pm Pm E s Pm E E Pm s s Pm s GO co in 10 10 r- Γ* co GO 01 σι co co i-4 CO co in Ό 10 IO 10 iO IP 10 IO 10 0 I*· r* in in ft s 0 Q u s J 4 □ 0 ft 0 □ »< 2! ffl a H H H ό u H H ft j ό j j 0 hl o rH CM CO in IO r* CO σι o «—j 10 go σι rH Ή r-4 i-H rH l-t r-1 i-H r“l rd CM CM TABLE 3 contd μ μ (0 it 0 id id □ a 0 a m W a u< • (0 It) P 0 0 μ Λ £ 0 a 0 υ to (0 tl s O co r» in VO 6 w fa H j u Cl tn Tf Cl £U £L, - 12 In this experiment the lysine salt of bendazac produced an improvement in a high number of patients (10 - 18, depending on the evaluation method), whereas only 1 patient showed a worsening effect. Relatively poor results were obtained in 5 patients, one of whom was a diabetic.

The experiments were repeated under double blind conditions comparing the lysine salt of bendazac with placebo. A total of 35 patients were used; 19 were treated with placebo and 16 with lysine salt of bendazac, using the same experimental methods except that the duration of treatment was always 4 weeks. The results were summarized in Tables 4 and 5.

TABLE 4 Summary of the results obtained in the second experiment conducted with the double blind method to study the activity of bendazac in cataract.

Table Overall Judgement r-4 (N 16 11 co CM β 0 1 •H 4J •H W kJ β I r-4 10 CM 1 β •ri KJ £ β Eh t—1 g. s KJ H o CM r4 +) 1 Ci <31 rP Ή r4 to β 0 •H 4J u r—1 CM 10 σι 1 kJ r-t P m Φ K c 0 *h VO CM o 10 I (Q r4 r4 > β 0 — + O 1 + O I 3 *—* r4 kJ ft +J β 0 □ Φ g β Φ •P 0 nj C •H P 0) β ω t—1 ft 0 >1 β Bi co i-4 m CO CO I—} 10 r4 co Ψ4 4J □ r4 β 0 P r4 β 0 P o KJ υ □ β 0 0 β H 0) •H •H +J P H •P P H ft >1 +J μ P U P P 0 kJ 0 0 β 0 0 β Eh U U υ β □ u β X ft ft S 0) cm sf CM CO I—J r4 to QJ • 0) 10 0 ιΰ is U (-4 r4 - 14 Table +> β φ r—1 Β Φ Φ I 4- O k tn +1 Φ Ό 0 Φ k > 3 Ο Φ Ό Φ +J +J Φ 0 1 β 0 •Η 0 Η 4J 3 β •Η Φ Ό •Η Φ β β bendazac β •Η 0 Φ ε D k 3 Εη ι—1 β Φ ε •Η 1 +J •rl ί= Ο k ΨΙ 0 «—1 φ Φ Ά X Φ ω Γ-1 > +J Ό β η •Η > •Η ο Φ k β ο + o α Ρ 0 Φ ik 0 φ Φ •Η ω ¢4 +J the Φ A +> β used in > Ό 3 +J φ Visio ι + o -1 0 +> d +) β Ό +J β u φ 0 φ 0 π 0 Φ 0 »β ε d d d N d +J Φ +> Φ φ φ Φ Φ Φ φ 0 υ 0 ‘0 a a € φ φ φ φ β φ Ό β k t—1 Φ r—I g a a a d a φ φ Γ-Ι +> I r4 33 ο 0 k Φ 0 k Φ 0 k c Φ ο φ ο Φ ϋ υ Φ U o Φ 0 k ♦rl Φ •rl •r| Φ •rl •H Φ φ Φ Μ ι—I +J 4J r—1 +» P ι—1 φ £ fa +J k 0 k k 0 k k 0 3 >1 Φ 0 3 0 0 3 0 Q 3 •Η φ 0 Ό Β V 0 β υ U β u O C +J φ Q the Sex fa g a fa fa Λe +J •Η & Φ ε υ Ό g fa 6 φ • • • a fa g. fa d tk 0 φ φ • φ 0 φ a 0 1—1 VO co σκ - 15 + OI + IOI + 000000 + 0+ i oo + oo TABLE S contd oi + ioo+i + i 1 iooi XI J J J >-l E S SB ω ό > j w fa fa o W o ό Pi Q »4 ό H ό h4 0 A.A. • > o r-1 id r—i 04 id cn id id in id •d N K CD id o CM id CM ω CM ’t CM m CM vO CM - 16 + O + OI 1 + 1 + I 1 + 1 + o + oi i + + o + oi i + i + i i + + + 0 + 010+1+00 + i + TABLE 5 contd + 00 + 00 + 0 + 0 I + I + +1 J iJ >4 J j ►4 Hl 0 υ ϋ 0 0 u 0 0 (0 0 (0 (0 0 0 (0 0 <0 (0 0 10 0 10 N 33 N N Λ N Λ N M ΰ N N rt Φ <0 (0 ¢) Φ 10 4) rd «0 0) 10 Φ Ό u Ό Ό u 0 Ό 0 Ό Ό 0 Ό o *0 CJ (0 c S <0 10 c 10 C C <0 a 10 fi Q) 0) Φ H in l4 V (3) r—I □ i-4 0) Λ ft Λ Λ ft ft n ft a ft μ rP . ' • (-4 □ r4 f4 r4 r4 1-4 r—1 1-4 r4 0 i-4 10 10 (0 a 10 10 (0 10 10 10 10 10 3 <0 0 u a c U υ 0 υ U U U U fi 0 •H •H •H •H •H •H ♦H Ή •H •H Ή • *H p p p p P P P +1 P P P P P P p p p p P P P P P P P P P P o o 0 0 0 0 0 0 0 0 0 0 0 0 O υ U U o u u U 0 u O U u a ft s ft 2 fa ft ft ft ft ft ft 2 ft ft W >4 UlcSojeCliU'i’iofiESftiW Qft22Hr4QOHftOft r^fflffiOi-if'if'iM'invor-oowo - 17 These studies confirm without doubt that the administration of bendazac L. Lysine salt has a healing effect on cataract.

Finally eye drops containing 0.25% of the lysine salt of bendazac were administered to 4 patients. Eye drops were instilled 3 times daily for one month. Even in this group of patients a clear-cut regression of the cataract was observed.

In order to obtain the bendazac salt with the lysine the preparation is performed by heating, preferably in ethanol or water-acetone, equimolecular quantities of [(l-benzyl-lH-indazol-3-yl)oxy] acetic acid and the aminoacid. The salt crystallizes on cooling as a bihydrate.

The so-obtained salt can be used as such or after drying under vacuum to constant weight. Both the bihydrate and the anhydrous salts with one of two optically active forms of lysine, as well, as the salt with racemic lysine can be employed in different pharmaceutical forms.

In use, the compound of the invention is administered orally in conventional formulations, namely in association with pharmaceutical excipients generally used for the production of compositions for oral administration. Singles doses between 0.3 g and 1 g have to be - 18 administered 2-3 times a day.

Conventional pharmaceutical compositions for oral administration may be used such as tablets and capsules; the unit dose for both tablet and capsule of active ingredient may be 500 mg.

The carriers used in the preparation of these compositions are the excipients known in the pharmacist art. In the preparation of tablets, typical excipients include disintegrating agents, e.g. maize starch and lubricant agents, e.g. magnesium stearate; in the preparation of capsules, standard gelatin capsules may be used containing the active ingredient alone or admixed with a diluent.

Typical and actual formulations are shown below A: Tablets 15 Each tablet contains: Bendazac L. lysine salt hydrate mg 500.0 cellulose II 91.5 maize starch II 75.0 formalin-casein II 30.0 20 polyvinyl pyrrolidone II 20.0 silicon dioxide . II 7.5 magnesium stearate II 6.0 hydroxy propyl cellulose II 3.0 talc 1.5 - 19 Bs Hard gelatine capsules Each capsule contains: Bendazac L lysine salt hydrate mg 500.0 Maize starch II 75.0 5 lactose II 75.0 magnesium stearate II 4.5 C: Granules Each simple dose (in paper envelope) contains: bendazac L. lysine salt hydrate g 0.5 10 saccarose II 4,85 orange flavour II 0,15 D: syr«p 100 ml contain: bendazac L lysine salt hydrate g 5.0 15 saccarose II 66.0 ethyl p-hydroxybenzoate It 0.15 sodium benzoate II 0.5 raspberry flavour II 0.5 distilled water to 100 ml - 20 E: 1¾ eye drops 100 ml contain: bendazac L lysine salt hydrate hydroxy propyl-methyl-cellulose H2NaPO4.H2O HNa2PO4.12H2O NaCl thimerosal water for injections to 100 ml g 1.00 g 0.500 g 0.018 g 0.190 g 0.680 g 0.001 F: 0.5% eye drops bendazac L lysine salt hydrate hydroxy-propyl-methyl cellulose H2Na P04.H20 HNa2P04.12H20 NaCl thimerosal water for injections to 100 ml g 0.50 g 0.500 g 0.018 g 0.190 g 0.740 g 0.001 The following non-restrictive examples illustrate the preparation of the salt which is the matter of the present invention. - 21 Example 1 Salt of [(l-benzyl-lH-indazol-3-yl)oxy] acetic acid with L. lysine. g (0.042 mol) of [(l-benzyl-lH-indazol-3-yl)oxy] acetic acid and 6.2 g (0.042 mol) of L. lysine were dissolved in 100 ml of 95% ethanol by heating. The mixture was filtered warm in order to remove the very small amounts of impurities and it was then left to stand overnight at room temperature. The crystalline product was filtered and recrystallized from 95% ethanol: 15 g of the salt were first obtained (yield 75,9%) while the mother-liquor yielded more product. The compound consists of one molecule of C(1-benzyl-lH-indazol-e-yl)oxy] acetic acid, one of L. lysine and two of crystallization15 water; the same shows melting point 178-81θΟ with loss of water during heating.

Example 2 The salt obtained according to the Example 1 was dried under vacuum (5-10 Torr.) at 105°C to constant weight: in such a form it shows melting point 178-81° with decomposition.

Claims (13)

What we claim is

1. A salt of C(l-benzyl-lH-indazol-3-yl)oxy] acetic acid with lysine.

2. A salt of [ (l-benzyl-lH-indazol-3-yl)oxy] acetic

3. A salt according to claim 2 in which the said salt contains crystallization water.

4. A salt according to claim 2 in which the said salt is anhydrous.

5. A medicament for use in the treatment of cataract. 5 acid with L. lysine.

6. A process according to claim 5 in which the said lysine salt is separated and obtained in a anhydrous form. 20

7. A therapeutic composition useful in the treatment of cataract, in an acceptable pharmaceutical - 23 carrier and containing bendazac lysine salt in a form suitable to obtain effective tissue concentrations.

8. Use of bendazac lysine 3alt for the preparation of

9. Use as claimed in claim 8 wherein the medicament is administered by the oral route at a daily dose of 300 - 1000 mg eventually divided in 2 or more daily administrations.

10. 10. A compound substantially as hereinbefore described with reference to the examples. 10 5. A process for preparing the salt of claim 1 consisting in that equimolecular quantities of [ (l-benzyl-lH-indazol-3-yl)oxy] acetic acid and lysine are dissolved by heating in a solvent, usually in ethanol, acetone or their mixtures with 15 water from which the salt crystallizes on cooling and then separated and obtained in a hydrate form.

11. A salt substantially as hereinbefore described with reference to the examples.

12. A process substantially as hereinbefore described 15 with reference to the examples.

13. A composition substantially as hereinbefore described with reference to the examples.