DE3923689A1 - NEW USE OF TETRAHYDROBENZTHIAZOL DERIVATIVES AS DRUGS - Google Patents

Abstract

The known compounds of formula (I), where R1 and R2 have the meanings given in the description, can be used in the form of conventional preparations for treating diseases of the eye, in particular to reduce the intraocular pressure and to increase the visual contrast sensitivity.

Description

The invention relates to the use of Tetrahydrobenzothiazole derivatives of the below Formula I in the treatment of eye diseases, especially for lowering and increasing the visual Contrast sensitivity (RLO).

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

in the
R₁ is a hydrogen atom, an alkyl group having 1 to 6 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, wherein the phenyl nucleus in each case substituted by 1 or 2 fluorine, chlorine or bromine atoms can be,
R₂ 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, wherein the phenyl nucleus is represented by 1 or 2 fluoro , Chlorine or bromine atoms may be substituted, mean
their enantiomers and the respective acid addition salts.

Preference is given to the compounds in which NHR₂ itself located in the 5- or 6-position, especially those compounds that are of the formula

correspond, in the R₂ for C₂-C₅-alkyl, allyl or propargyl stands.

As compounds according to the present invention can be used as examples are listed as examples:

• 1) 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole dihydrobromide
  Melting point: <315 ° C
  Melting point of the base: 233-236 ° C
• 2) 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride
  Melting point: <315 ° C (decomposition)
• 3) 6-Amino-2-methylamino-4,5,6,7-tetrahydrobenzothiazole hydrobromide
  Melting point: 262-263 ° C
• 4) 2-amino-6-methylamino-4,5,6,7-tetrahydrobenzothiazole hydrobromide
  Melting point: 312-313 ° C (decomposition)
• 5) 6-Amino-2-ethylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride
  Melting point: 155-158 ° C
• 6) 2-Amino-6-ethylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride
  Melting point: 296-297 ° C
• 7) 2-Amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride d
  Melting point: 286-288 ° C
• 8) (-) - 2-Amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride
  Melting point: 270-272 ° C @ = - 56 ° (c = 1, methanol)
• 9) (+) - 2-amino-6-n-propylamino-4,5,6,7-tetrahydro-benzthiazole-dihydro-chloride
  Melting point: 270-272 ° C @ = + 56 ° (c = 1, methanol)
• 10) 2-Amino-6-isopropylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloro-id
  Melting point: 295-296 ° C (decomposition)
• 11) 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride d
  Melting point: 254-256 ° C
• 12) 2-amino-6-isobutylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride d
  Melting point: 268 ° C (decomposition)
• 13) 2-amino-6-n-pentylamino-4,5,6,7-tetrahydrobenzothiazole 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-tetrahydrobenzothiazole oxalate
  Melting point: 164-165 ° C (decomposition)
• 16) 6-Allylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride
  Melting point: 282-283 ° C (decomposition)
• 17) 2-Allylamino-6-ethylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride
  Melting point: 218-220 ° C (decomposition)
• 18) 2-Amino-6-propargylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride id
  Melting point: 168-270 ° 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-tetrahydrobenzothiazole dihydrochloride
  Melting point: 288-290 ° C
• 21) 2-Amino-6- [N- (2-phenylethyl) amino] -4,5,6,7-tetrahydrobenzothiazole dihydrochloride
  Melting point: 289-291 ° C
• 22) 2-Amino-6- [N- (4-chloro-benzyl) amino] -4,5,6,7-tetrahydro-benzothiazole
  Melting point: 146 ° C
• 23) 2-Amino-6- [N- (2-chloro-benzyl) amino] -4,5,6,7-tetrahydro-benzothiazole dihydrochloride
  Melting point: <280 ° C (decomposition)
• 24) 6-ethylamino-2-methylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride
  Melting point: <260 ° C
• 25) 2-Benzylamino-6-ethylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride
  Melting point: 242-245 ° C
• 26) 6-ethylamino-2-n-propylamino-4,5,6,7-tetrahydrobenzothiazole 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-dichloro-benzylamino) -6-ethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride
  Melting point: <260 ° C
• 30) 6-Ethylamino-2- [N- (2-phenylethyl) amino] -4,5,6,7-tetrahydrobenzothiazole dihydrochloride hemihydrate
  Melting point: 248-251 ° C
• 31) 6-amino-2-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrobromide
• 32) 6-Amino-2-benzylamino-4,5,6,7-tetrahydrobenzothiazole dihydrobromide
• 33) 6-Amino-2- [N- (2-phenylethyl) amino] -4,5,6,7-tetrahydrobenzothiazole-d-ihydrobromide

The compounds of the formula I are from the European Patent Application 85 116 016.8 (Publication no. 01 86 087) known. In the aforementioned application are also numerous therapeutic applications of the Compounds indicated, but there is no indication on the now surprisingly found effects on Eye.

For glaucoma treatment are several drugs been proposed; However, they point - in part considerable - disadvantages.

1.25 mg bromocriptine decreased in healthy volunteers in a single dose of IOP significantly. Bromocriptine has an unfavorable Side effects profile with nausea, vomiting, Constipation and psychomotor disorders.

200 mg L-Dropa and 50 mg benserazide increase in healthy people the visual contrast sensitivity. However, it must with extrapyramidal dyskinesia.

0.1 mg Lisurid increases in healthy young women premenstrual symptoms the visual Contrast sensitivity and reduces the IOP. there However, a significant deterioration of the  Reaction behavior can be accepted.

The compounds which can be used according to the invention effect even in low doses lowering the IOP and an improvement of the RLO, without disturbing Side effects occur.

For example, a single oral dose of 0.2 mg (-) - 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole (Compound 8) on the healthy the Contrast sensitivity of the eye significantly increased. There was no disturbing influence of the To observe reactivity; significant effects on motor variables such as reaction time, motor Speed and accuracy (ipsimodal and crossmodal reaction time, tapping) did not occur. The sedative effects seen in the EEG and the Sensitivity were detectable, were easy and did not reach the statistical significance limit. Overall, only a slight sedative trend identify.

The compound 8 exemplified here is thus in much lower concentration than bromocriptine and L-Dopa and in comparable concentration as Lisurid on the intraocular pressure and the visual Contrast sensitivity is effective and essential lower side effects than the comparator products.

In comparison to preparations of the clonidine type, the over Alpha-2 adrenergic receptors on intraocular pressure and their peripheral blood pressure decreases CNS pathological indications are undesirable, or of the pilocarpine type, which has a permanent contraction of the Ciliarismuskels lower the intraocular pressure, lower the  in accordance with the invention lower dosages, without peripheral Lowering blood pressure and sedative effects and without to cause transient myopia Intraocular pressure and increase the contrast sensitivity of the Eye.

The application of the compounds of formula I is carried out in usual galenic preparations. Preferred are such preparations that are applied topically on the eye be, for. For example, eye drops, ointments or gels. The Dosage is - because of the small side effects - relatively uncritical. The single dose, the can be administered several times a day, is - ever the active substance and the severity of the symptoms to be treated - between 0.05 mg and 5 mg. For compound 8 becomes preferably, for. In the form of eye drops, a dose from 0.1 to 0.5 mg.

For the formulation of the compounds of formula I. the usual galenic preparations are the for these purposes customary excipients and carriers used. In the preparation of the eye drops must the setting of a suitable pH (in the range 6.5 to 7.5) and to a suitable osmotic pressure (about according to a physiological Saline).

Drag'es for oral use can according to the following example:

Drag'es Composition: 1 drag core contains: @ active substance 0.5 mg lactose 33.5 mg corn starch 10.0 mg gelatin 1.0 mg magnesium stearate  0.5 mg 50 mg

production method

The mixture of the active substance with lactose and corn starch is granulated with a 10% gelatin solution through a sieve of 1 mm mesh size, dried at 40 ° C and rubbed again through the above sieve. The granules thus obtained are mixed with magnesium stearate and pressed into drag cores. The production should be made in darkened rooms.
Core weight: 50 mg
Stamp: 5 mm, arched.
The Drag'ekerne thus obtained are coated by known methods with a shell consisting essentially of sugar and talc. The finished Drag'es are polished using beeswax.
Drag'e weight: 100 mg
Clinical findings:
Randomized double-blind, placebo-controlled study of 0.1, 0.2 and 0.3 mg (po) of compound 8 as hydrochloride in 12 healthy volunteers:
From 0.2 mg contrast sensitivity is significantly increased for up to 8 hours.

Claims (9)

1. Use of compounds of the general formula in the
R₁ is a hydrogen atom, an alkyl group having 1 to 6 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, wherein the phenyl nucleus in each case substituted by 1 or 2 fluorine, chlorine or bromine atoms can be,
R₂ 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, wherein the phenyl nucleus is represented by 1 or 2 fluorine , Chlorine or bromine atoms may 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 production of Medicines for glaucoma treatment and for Increase in contrast sensitivity of eyes. 3. Use according to claim 1, characterized characterized in that as compounds of the formula I such compounds are used in which NHR₂ is in the 5- or 6-position. 4. Use according to claim 1 or 2, characterized characterized in that NHR₁ is NH₂. 5. Use according to claim 1, 2, 3 or 4, characterized characterized in that as the compound of formula I (-) - 2-amino-6-n-propylamino-4,5,6,7-tetrahydro-benzthiazole or its acid addition salts to be used. 6. Medicaments for the treatment of eye diseases, characterized by a content of a compound of the general formula in the
R₁ is a hydrogen atom, an alkyl group having 1 to 6 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, wherein the phenyl nucleus in each case substituted by 1 or 2 fluorine, chlorine or bromine atoms can be,
R₂ 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, wherein the phenyl nucleus is represented by 1 or 2 fluoro , Chlorine or bromine atoms may be substituted, mean
their enantiomers or the respective acid addition salts in addition to customary auxiliaries and / or carriers. 7. Medicament according to claim 6, characterized characterized in that as active ingredient of the formula I. (-) - 2-amino-6-n-propylamino-4,5,6,7-tetrahydro-benzthiazole or its acid addition salts to be used. 8. Medicines for the treatment of glaucoma and to increase the contrast sensitivity of the eyes,  characterized by a content of one Compound of formula I, their enantiomers or the respective acid addition salts, in addition customary auxiliaries and / or carriers. 9. Medicament according to claim 6, 7 or 8 for the Treatment of glaucoma and increase of Contrast sensitivity of the eyes, characterized by a content of (-) - 2-amino-6-n- propylamino-4,5,6,7-tetrahydrobenzothiazole or its acid addition salts.