EP0483252A1

EP0483252A1 - Tetrahydrobenzothiazole derivatives for treating diseases of the eye

Info

Publication number: EP0483252A1
Application number: EP90911576A
Authority: EP
Inventors: Joachim Leonard; Christian Schilling
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim GmbH
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim GmbH
Priority date: 1989-07-18
Filing date: 1990-07-14
Publication date: 1992-05-06
Also published as: DE3923689A1; KR927003051A; HU9200150D0; WO1991001136A1; DD298395A5; CA2063988A1; HUT60922A; AU6149690A

Abstract

Les composés connus de formule (I) (définition de R1 et R2 selon la description) peuvent être employés sous forme de préparations courantes pour le traitement des maladies de l'oeil, en particulier pour diminuer la pression intraoculaire et augmenter la sensibilité visuelle aux contrastes.The known compounds of formula (I) (definition of R1 and R2 according to the description) can be used in the form of current preparations for the treatment of diseases of the eye, in particular for reducing intraocular pressure and increasing visual sensitivity to contrasts. .

Description

Tetrahydrobenzthiazole derivatives for the treatment of eye diseases.

The invention relates to the use of tetrahydrobenzthiazole derivatives of the formula I given below in the treatment of eye diseases, in particular for lowering the intraocular pressure (IOP) or glaucoma treatment and for increasing the visual contrast sensitivity (VKE).

The compounds which can be used according to the invention correspond to the general formula I:

in the R, a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkenyl or alkynyl group each with 3 to 6

Carbon atoms or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, where the phenyl nucleus can in each case be substituted by 1 or 2 fluorine, chlorine or bromine atoms,

R "is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group each having 3 to 6

Carbon atoms or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, where the phenyl nucleus can be substituted by 1 or 2 fluorine, chlorine or bromine atoms, mean their enantiomers and the respective

Acid addition salts. The invention relates to the use of tetrahydrobenzthiazole derivatives of the formula I given below in the treatment of eye diseases, in particular for lowering the intraocular pressure (IOP) or glaucoma treatment and for increasing the visual contrast sensitivity (VKE).

in which R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6

R_ is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group each having 3 to 6

Acid addition salts. Preference is given to the compounds in which NKR is in the 5- or 6-position, especially those compounds which are of the formula l

correspond in which R is C ₂ -C -.-- alkyl, allyl or propargyl.

Examples of compounds that can be used in accordance with the present invention are:

1) 2, 6-diamino-4, 5,6, 7-tetrahydro-benzothiazole-dihydrobromide

Melting point:> 315 ° C, melting point of the base: 233-236 ° C

2) 2, 6-diamino, 5,6, 7-tetrahydro-benzothiazole-dihy rochloride

Melting point:> 315 ° C (decomposition)

3) 6-Amino-2-methylamino-4,5,6,7-tetrahydrobenzthiazole hydrobromide Melting point: 262-263 ° C

4) 2-Amino-6-methylamino-4,5,6,7-tetrahydro-benzothiazole-dihydrobromide Melting point: 312-313 ° C (decomposition) 5) 6-Amino-2-ethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride

Melting point: 155-158 ° C

6) 2-Amino-6-ethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride

Melting point: 296-297 ° C

7) 2-Amino-6-n-propylamino-4,5,6,7-tetrahydro-benzothiazole-dihydrochloride Melting point: 286-288 ° C

8) (-) - 2-Amino-6-n-propylamino, 5,6,7-tetrahydrobenzothiazole dihydrochloride

Melting point: 270-272 ° C

@ 20 ₌ _56 ° (c = 1, methanol) D

9) (+) - 2-Amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride

Melting point: 270-272 ° C

@ ²⁰ = + 56 ° (c = 1, methanol) D

10) 2-amino-6-isopropylamino-4, 5,6, 7-tetrahydro-benzothiazole-dihydrochloride Melting point: 295-296 ° C (decomposition)

11) 2-Amino-6-n-butylamino-4, 5,6, 7-tetrahydrobenzothiazole dihydrochloride Melting point: 254-256 ° C

12) 2-Amino-6-isobutylamino-4,5,6,7-tetrahydro-benzothiazole-dihydrochloride Melting point: 268 ° C. (decomposition) 13) 2-amino-6-n-pentylamino, 5,6, 7-tetrahydrobenzehiazole semifumarate

Melting point:> 270 ° C

14) 2-Amino-6-n-hexylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride Melting point: 272-274 ° C

15) 2-Allylamino-6-amino-4,5,6,7-tetrahydro-benzothiazole oxalate

Melting point: 164-165 ° C (decomposition)

16) 6-Allylamino-2-amino-4,5,6,7-tetrahydro-benzothiazole-dihydrochloride Melting point: 282-283 ° C (decomposition)

17) 2-Allylamino-6-ethylamino-4,5 _/ 6,7-tetrahydro-benzothiazole dihydrochloride

Melting point: 218-220 ° C (decomposition)

18) 2-Amino-6-propargylamino-4,5,6,7-tetrahydro-benzothiazole-dihydrochloride Melting point: 268-270 ° C (decomposition)

19) 2-Amino-6-cyclopentylamino-4,5,6,7-tetrahydro-benzothiazole dioxalate

Melting point: 212-213 ° C

20) 2-Amino-6-cyclohexylamino-4,5,6,7-tetrahydrobenzthiazole dihydrochloride

Melting point: 288-290 ° C

21) 2-Amino-6- [N- (2-phenylethyl) amino] -4,5,6,7-tetrahydro-benzothiazole dihydrochloride Melting point: 289-291 ° C 22) 2-Amino-6- [N- (4-chlorobenzyl) amino] -4, 5,6,7-tetrahydro-benzothiazole

Melting point: 146 ° C

23) 2-Amino-6- [N- (2-chlorobenzyl) amino] -4, 5,6,7-tetrahydro-benzothiazole dihydrochloride Melting point:> 280 ° C (decomposition)

24) 6-Ethylamino-2-methylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride

Melting point:> 260 ° C;

25) 2-Benzylamino-6-ethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride

Melting point: 242-245 ° C

26) 6-Ethylamino-2-n-propylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride

Melting point: 267-268 ° C

27) 2- (4-chloro-benzylamino) -6-ethylamino-4, 5,6,7-tetrahydro-benzothiazole dihydrochloride Melting point:> 260 ° C

28) 2- (2-chloro-benzylamino) -6-ethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Melting point: 251-253 ° C

29) 2- (3,4-dichlorobenzylamino) -6-ethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Melting point:> 260 ° C

30) 6-Ethylamino-2- [N- (2-phenyl-ethyl) -amino] -4,5,6,7-tetrahydrobenzothiazole dihydrochloride hemihydrate Melting point: 248-251 ° C 31) 6-Amino-2-n-propylamino-4,5,6,7-tetrahydrobenzthiazole dihydrobromide

32) 6-Amino-2-benzylamino-, 5,6,7-tetrahydro-benzothiazole-dihydrobromide

33) 6-Amino-2- [N- (2-phenyl-ethyl) amino] -4,5, 6,7-tetrahydro-benzothiazole dihydrobromide

The compounds of formula I are known from European patent application 85 116 016.8 (publication no. 0186 087). Numerous therapeutic applications of the compounds are also specified in the application mentioned, but there is no indication of the surprisingly found effects on the eye.

Several agents have been proposed for glaucoma treatment; however, they have disadvantages, some of them considerable.

In healthy volunteers, 1.25 mg bromocriptine significantly reduced the IOP in a single dose. However, bromocriptine has an unfavorable side effect profile with nausea, vomiting, constipation and psychomotor disorders.

Increase 200 mg L-Dopa and 50 mg benserazide; -. in healthy people the visual contrast sensitivity. However, extrapyramidal dyskinesias must be expected.

0.1 mg lisuride increases the visual contrast sensitivity and decreases the IOP in healthy young women with premenstrual symptoms. However, a significant deterioration in the Responsiveness to be accepted.

Even in low doses, the compounds which can be used according to the invention bring about a lowering of the IOP and an improvement in the RLO without there being any undesirable side effects.

For example, with a single oral dose of 0.2 mg (-) - 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole (compound 8), the contrast sensitivity of the eye was significantly increased in healthy subjects. No disturbing influence on the reactivity was observed; there were no significant effects on motor variables such as reaction time, motor speed and accuracy (ipsimodal and crossmodal reaction time, tapping). The sedative effects, which were detectable in the EEG and the state of health, were slight and did not reach the statistical significance limit. Overall, there was only a slight sedative trend.

Compound 8, which is given here by way of example, is thus effective in a much lower concentration than bromocriptine and L-dopa and in a concentration comparable to that of lisuride on the intraocular pressure and the visual sensitivity to contrast and has considerably fewer side effects than the comparative preparations.

In comparison to preparations of the clonidine type, which act on the intraocular pressure via alpha-2-adrenergic receptors and whose peripheral blood pressure lowering is undesirable in the case of CNS pathological indications, or of the pilocarpine type, which reduce the intraocular pressure via a permanent contraction of the ciliary muscle Compounds which can be used according to the invention in lower doses, without lowering peripheral blood pressure and sedative effect and without causing temporary myopia, increase the intraocular pressure and increase the contrast sensitivity of the eye.

The compounds of the formula I are used in conventional pharmaceutical preparations. Preferred preparations are those which are applied topically to the eye, e.g. Eye drops, ointments or gels. The dosage is relatively uncritical because of the few side effects. The single dose, which can be administered several times a day, is - depending on the active ingredient and the severity of the symptoms to be treated - between 0.05 mg and 5 mg. For connection 8, e.g. in the form of eye drops, a dose of 0.1 to 0.5 mg applied.

The auxiliaries and excipients customary for these purposes are used to formulate the compounds of the formula I to give the customary pharmaceutical preparations. When preparing the eye drops, care must be taken to set a suitable pH value (in the range 6.5 to 7.5) and to a suitable osmotic pressure (approximately corresponding to a physiological saline solution).

Dragees for oral use can be obtained according to the following example:

Draσees

Composition: 1 coated tablet contains:

Active substance 0.5 mg

Milk sugar 33.5 mg

Corn starch 10.0 mg

Gelatin 1.0 mg

Magnesium stearate 0.5 mσ

50_ mg

production method

The mixture of the active substance with milk sugar and corn starch is granulated with a 10% gelatin solution through a sieve with a mesh size of 1 mm, dried at 40 ° C. and rubbed again through the sieve above. The granules obtained in this way are mixed with magnesium stearate and pressed to dragee cores. Manufacturing should be done in darkened rooms.

Core weight: 50 mg

Stamp: 5 mm, domed.

The dragee cores thus obtained are coated according to known methods with an envelope consisting essentially of sugar and talc. The finished coated tablets are polished with the help of beeswax.

Drage weight: 100 mg Clinical findings:

Randomized placebo-controlled, double-blind, single-use study of 0.1, 0.2 and 0.3 mg (p.o.) of compound 8 as hydrochloride in 12 healthy volunteers:

From 0.2 mg, the contrast sensitivity is significantly increased for up to 8 hours.

Claims

1. Use of compounds of the general formula

in the

R, a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkenyl or alkynyl group each with 3 to 6 carbon atoms or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, the phenyl nucleus each having 1 or 2 fluorine, chlorine or bromine atoms can be substituted

R _{2 represents} a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms or a phenylalkyl group having 1 to 3 carbon atoms in the alkyl part, the phenyl nucleus being represented by 1 or 2 Fluorine, chlorine or bromine atoms can be substituted, mean their enantiomers and the respective

Acid addition salts in the manufacture of medicines for the treatment of eye diseases.

2. Use of compounds of the formula I, their enantiomers or the respective acid addition salts for the preparation of medicaments for the treatment of glaucoma and for increasing the contrast sensitivity of the eyes.

3. Use according to claim 1, characterized in that those compounds are used as compounds of formula I in which H ₂ is in the 5- or 6-position.

4. Use according to claim 1 or 2, characterized in that NHR. stands for NH ".

5. Use according to claim 1, 2, 3 or 4, characterized in that used as the compound of formula I (-) - 2-amino-6-n-propylamino-, 5,6,7-tetrahydro-benzothiazole or its acid addition salts become.

6. Medicament for the treatment of eye diseases, characterized by a content of a compound of the general formula

in the R. is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkenyl or alkynyl group each with 3 to 6 carbon atoms or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, the phenyl nucleus each having 1 or 2 fluorine, chlorine or bromine atoms can be substituted

R "is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms or a phenylalkyl group having 1 to 3 carbon atoms in the alkyl part, the phenyl nucleus being represented by 1 or 2 Fluorine, chlorine or bromine atoms can be substituted,

mean their enantiomers or the respective acid addition salts in addition to conventional auxiliaries and / or carriers.

7. Medicament according to claim 6, characterized in that the active ingredient of the formula I (-) - 2-amino-6-n-propylamino-, 5,6,7-tetrahydro-benzothiazole or its acid addition salts are used.

8. medicines for the treatment of glaucoma and to increase the contrast sensitivity of the eyes, characterized by a content of a compound of formula I, its enantiomersπ cc r of the respective acid addition salts, in addition to conventional auxiliaries and / or carriers.

9. Medicament according to claim 6, 7 or 8 for the treatment of glaucoma and for increasing the contrast sensitivity of the eyes, characterized by a content of (-) - 2-amino-6-n-propylamino-, 5,6,7- tetrahydrobenzthiazole or its acid addition salts.