JPH01175934A - Anti-glaucoma agent - Google Patents

Abstract

PURPOSE: To obtain an antiglaucoma agent showing no irritating action and no allergic reaction when locally applied to an eye, containing hexahydrodibenzo[a,f]quinoline or its salt. CONSTITUTION: This antiglaucoma agent is obtained by mixing a compound of the formula (R1 and R2 are each H, CH, or CH3 CO3 R3 and R4 are each H or OH; R5 to R7 are each H, OH or CH3 OH; X is a halogen) or its physiologically permissible salt such as S-2,3-dihydroxy-9,10,11trimethoxy-5,8,13,13a- tetrahydro-6H-dibenzo(a,f)quinolizine hydrochloride in a racemic modification or an optically active state as an active ingredient with an ophthalmological additive. The compound will not cause important change in arterial pressure and chronotropic cardiac function in the case of an normotensive animal.

Description

[Detailed description of the invention] The present invention relates to an anti-glaucoma agent used in ophthalmological treatment.

It is known that the most used preparations for the treatment of glaucoma are pilocarpine, epinephrine, and timolol. However, these preparations exhibit a good therapeutic effect as well as a number of side effects.For example, pilocarpine causes miosis, contraction of the muscles around the eyes, hyperemia of the conjunctiva and allergic reactions of the eye.
11, 12]. Epinephrine has a small instantaneous effect on intraocular pressure, causing tachycardia, mydriasis, and hyperemia [8,10].Topically administered timolol can cause bradycardia, hypotension, and bronchospasm, especially in patients with asthma and bronchitis. It exhibits side effects such as central nervous system syndrome, depression and drowsiness [4,7,9,15], thus limiting its widespread use in medical practice.

The object of the present invention is to provide an anti-glaucoma agent which does not cause significant changes in arterial pressure and chronotropic cardiac function in normotensive animals and which does not exhibit irritating effects and allergic reactions when administered topically to the eye. It provides:

This object is achieved by using the following physiologically tolerated salts of hexahydrodibenzo(a,f)quinolidines of the general formula I in racemic or optionally optically active form as anti-glaucoma agents.

In the formula, R1 and R2 are H, CH3, CH3CO,
R3 and R4 are H, OH, R5°R6 and R7 are H, OH, CH30, and X is CI.

Synthetic or plant source hexahydrodibenzo (a.

f) Some quinolidines have a momentary hypotensive effect [13]
It is known to exhibit , anticholinesterase action [1], and depressive action [6] on the central nervous system. Additionally, some of these exhibit bile duct antibacterial [3], anti-inflammatory, and anti-ulcer effects [5].

However, 1. There are no data on the antiglaucoma activity of hexahydrodibenzo(a,f)quinolidine for use as a medicament in the treatment of glaucoma; the most antiglaucoma active of this series of salts is s-/-/-2 ,3-
Dihydroxy-9,10,11-trimethoxy-5,8
,13,13a-tetrahydro-0H-dibenzo(a,
f) Quinolidine hydrochloride-1a. Its manufacturing method and physiochemical properties are listed under Bulgarian Inventor Certificate No. 3235.
3 [2].

The advantages of the compounds of general formula I according to the invention are as follows.

-They do not cause bronchospasm or bradycardia with systematic local administration compared to timolol.

◆These have only a slight momentary hypotensive effect.

・These do not show irritating effects when administered locally to the eye.

-They do not produce miosis, hyperemia or allergic reactions when administered locally to the eye.

The compound of the general formula I can be used in the treatment of glaucoma in the form of an ophthalmic solution [eye drops], which is expressed as an aqueous solution of the active ingredient and auxiliary pharmaceutical substances. The ophthalmic solution containing 0.25-0.5% of Ia is sterile, benzalconic chloride,
It can contain antibacterial agents like phenylmercury nitrate and thimerosal. Thiourea, thioglycerin, ascorbic acid or sodium metabisulfite can be used as antioxidants. This ophthalmic solution can be prepared by known technical methods.

The ophthalmic solution of the invention is administered in therapeutic doses of 2 to 3 drops 2 to 4 times a day.

In order to better understand the present invention, an example will be described next.

Example 1 s-/-/-2,3-dihydroxy-9,10,11-
trimethoxy-5,8,13,13a-tetrahydro=
BH-dibenzo(a,r)quinolidine hydrochloride,
50g sodium metabisulfite 4g EDTA disodium salt
2g benzalconic chloride 1g glycerin 470g water for injection
After boiling freshly distilled water for injection to 10,1' for 20-30 minutes, it was saturated with pure nitrogen with bubbling and cooled to 40-50 °C. Sodium metabisulfite is sequentially added to this saturated water of about 8 liters.

The disodium salt of EDTA, compound Ia, and benzalconic chloride were dissolved with continuous saturation with nitrogen. The product solution was leaked through a minipore type filter with a 0.22μ membrane. Ampoule filling was performed by double nitrogen gasification.

Example 2 Eye Study The study was conducted on the eyes of normotensive rabbits without anesthesia. In a series of experiments, intraocular pressure was measured with a Schietz tonometer and mmHg on the Leydhecker scale.
However, in other experiments, it was measured using a muffler tip tonometer. Comparative experiments were conducted with Compound Ia and Timolol administered topically to the eye in the form of a 0.5% aqueous solution.
Ia was satisfactorily reduced and the intraocular pressure measured with a Schietz tonometer was highest at 60-120 minutes, but a comparison with that of timolol showed that there was no important difference in its effectiveness. See Figure 1].

Compound 1a was tested in the form of an ophthalmic solution [eye drops] - 0.5% aqueous solution. Administer in this form of treatment.

A comparative study conducted on a non-anesthetized "Bister" type capsule that reduced intraocular pressure measured with a muffler-knot tonometer [Figure 2] showed that Compound 1a, unlike timolol, was administered locally. [See Table 1].

Example 3 Effects on the Cardiovascular System Compound 1a administered intravenously at doses of 0.1 or 0.5 or 1 or 2 or 3 or 516/kg reduces arterial pressure in anesthetized cats and rabbits. In particular, the hypotensive effect of low doses was slight and instantaneous. 0.2
At the dose of 51S/kg, it was 22% in 10 minutes [
See Table 2].

Table 2 0.1 13 8 0.25 22 10 0.5 25 24 3 42 Pharmaceutical analysis of over 60 mesoieters and other test substances showed that in the background of compound 1a [dose 3
is/kg] Effects of dopamine and isobrenaline on arterial pressure and occlusion of the carotid artery
n of aa, carotes communis
It was shown that the pressor effect of norepinephrine decreased, but the pressor effect of norepinephrine increased. This is mesoieta
Presynaptic drugs that promote the release of noradrenaline [
preslnapHc], probably related to the stimulation of beta receptors [Table 3], the hypotensive effect of compound 1a is significantly suppressed in the background of intravenously administered propranolol-1-1,54/kg.

Pharmaceutical studies performed on unanesthetized rabbits show that Compound 1a has a short-lived positive chronotropic effect that is much smaller than isobrenaline, but does not produce statistically significant changes in cardiac chronotropy [ Figure 3], and unlike timolol, compound 1a does not produce statistically significant changes in cardiac chronotropic effects [Table 4].

Table 3 Dopamine 2ON/kg 2 -13.6
-8.3 Dopamine 4ON/kg 2 -2
3.0 -4.2 Isobrenaline 1.5 g 3
-30.5 -8.8 noradrenaline 3Ar/kg
1.5 +21.0 +46.0 norepinephrine aug/kg 3.0 +17.0 +33.0
Histamine 5#/kg 5 -52.0-2
3.0 carotes [aa, carotesl occlusion 2
-40.0 communisl
5-53.0 Example 4 Investigation of local tolerance The local tolerance of Compound 1a in the form of eye drops [0.5% aqueous solution] was tested by method 2.

a) The method of Marzulli and Simon, as confirmed and carried out by Marzulli and Lagras, in this experiment the weight of 3200-400
Twelve white rabbits of both sexes weighing 0 g were tested in two groups of 6 animals each.6 The first group was treated with eye drops, while the second group was treated only with the eye drop vehicle. - Sample 0.11 was applied to the conjunctival recess in the eye, while the other eye was used as a control.
Local ocular reactions were determined after treatment in Section 1. 24th. No. 48. Measurements were taken at the 72nd hour and on the 7th day. The standard system assumed by the cited authors was applied. That is, for the cornea, 0 to 4. 0 to 2 for the iris. 0 to 3 for conjunctiva. Regarding hyperemia, no local irritation was observed in the force recordings of both groups 0-41. cornea.

All three factors of the iris and conjunctiva were examined. The obtained results showed that Compound 1a was well tolerated and its application in medical practice was also effective against irritant blepharitis and conjunctivitis.

It is shown that there is no risk of developing toxic damage to the iris and the whole eye.

b) McDonald's method, this test is based on an average weight of 370
Twelve white rabbits of equal numbers of males and females weighing 0 g were divided into two groups of 6 rabbits. The first group was treated with eye drops, while the second group was treated only with the vehicle.

- In the eye, apply 0.05 iu of the test sample to the conjunctival recess 3 times a day.
One local ocular reaction after instillation over 5 days was in the cornea, iris,
Recordings were made daily before each treatment of the conjunctiva and then compared to the control untreated eye of each rabbit.

No changes were observed in the three factors studied when recording in triplicate for 5 days of treatment.6 References: I Berezhlnskaja, V., E., A.
Ieslnskaja-Pharmacol, it
okiko+, 31.1968. p, 19B.

2 1vanov, C,, N, 1vanov e
tal, Inventor's Certificate BG32353 3 Am1n, A,, T, 5ubbajah-C
an, J. Microbiol.

15(9), 1989.9.10B7-10784
Arrata, M., -0cular pharm
acology oftimol drops,
London Acad, Press, 19805
1kram, L, Planta Med, 2g
(4) 1975. p, 353-6 Jaaahar
a, J., T., Konoshiia-Chew, Pha.
rm.

Bull, 24(8), 1976, p, 1902-1
9127 Katz l-1nvest, O
phthalmol, Vls, Sc1. ．． 15
゜197B, p, 489-492 8 Katz 1-Ann, Ophthal
mol, 10. 1978. p, 8479
KosIlan, M.-JAMA, 241, 197
9. p, 2301-230310 Leydheck
er, M.-Klin, Monatsbl.

Augenheik, 171. 1977, p.
538-54711 0keda, A et al.
-Duodeclm, 95.1979. p. 111
2 5chiffer, H, -Merck 5har
p Dohme Intern-197B, p, 4
9-52 13 shimamoto, ni, -Nlppon
Iakugaku Zasshi, 53°1957.
1), 75-80 14 Velludo et al, -Lucr
Arle present, Conf.

Na11. Farm, Bucharest, 1958
．． p, 851-35415 Zimmermann,
T, -〇phthalmo1. Vis, Sci,...
1B.

1977, p, 687-688゜

[Brief explanation of the drawing]

1 to 3 are graphs showing the effects of the present invention. Applicant's representative Patent attorney Takehiko SuzueChanges in intraocularpre
sSure 0 Inventor Dobrynka Genche Burga IJ
Country of Africa, Ba Gentjevat, B.Sofia, Nis Andonov Kenstry 114 Knee-4

Claims (3)

[Claims] (1) Hexahydrodibenzo (
a, f) An anti-glaucoma agent comprising quinolidine or a physiologically tolerated salt thereof in admixture with an ophthalmological additive. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I In the formula, R_1 and R_2 are H, CH_3, CH_3CO
, R_3 and R_4 are H, OH, R_5,
R_6 and R_7 are H, OH, CH_3O, and X is halogen. (2) s-/-/-2,3-dihydroxy-9,10,11-trimethoxy-5,8,13,1 as an active ingredient
3a-Tetrahydro-6H-dibenzo(a,f)quinolidine hydrochloride [R_1=R_2=R_3=R_4
=H, R_5=R_6=R_7=CH_3O] and a suitable pharmaceutical carrier. (3) The anti-glaucoma agent according to claim 1, which is used in the form of a 0.5% ophthalmic solution.