WO1992014465A1 - Use of annulated tetrahydropyridinacetic acid derivates for treating neurological diseases - Google Patents

Abstract

A compound having general formula (I) or its pharaceutically acceptable salts with an anorganic or organic acid, are used for treating neurological diseases. In general formula (I), A stands for a benzo, thieno or indolo residue; U and V represent each hydrogen or, when A stands for an indolo residue, they represent together a link; whereas R?4 and R6¿ stand for independent groups or form together a group having formula (a).

Description

USE OF ANELLELED TETRAHYDROPYRIDINIC ACID DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL DISEASES

The invention relates to the use of fused tetrahydropyridine acetic acid derivatives for the treatment of neurological diseases.

German patent application P 38 27 727.1 describes fused tetrahydropyridine acetic acid derivatives as compounds with cardioprotective activity.

The present invention relates to

 Use of these compounds for the treatment of neurological diseases.

The invention relates to the use of a compound of the general formula I,

worin

wherein

A represents a benzo, thieno or indolo radical;

R is hydrogen, (C ₁ -C ₄ ) alkyl, halogen (F, Cl,

Br, J), hydroxy, (C ₁ -C ₄ ) alkoxy, amino, methylthio, methanesulfonyloxy or

Methanesulfonamido, or two adjacent substituents R together are -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-; m represents 1, 2 or 3 when A is a benzo or indole radical and 1 or 2 when A is a thieno radical; R ^{5 is} hydrogen, (C ₁ -C ₁₀ ) alkyl, phenyl,

Phenyl (C ₁ -C ₅ ) alkyl, (C ₁ -C ₄ ) alkoxy or

-NHCOX (where X is (C ₁ -C ₅ alkyl); R ^{4 is} hydrogen or (C ₁ -C ₄ ) alkyl; R ^{6 is} hydroxy, (C ₁ -C ₄ ) alkoxy or one

-NR ⁷ R ⁸ group means, or R ⁴ and R ⁶ together the group

bedeuten; wobei, wenn R ⁶ die -NR⁷R⁸-Gruppe bedeutet,

mean; where when R ^{6 represents} the -NR ⁷ R ⁸ group,

in this

R ⁷ and R ^{8 are} independent of one another

 (a) hydrogen,

 (b) branched or unbranched aikenyl having 3 to 6 carbon atoms,

(c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or (d) mean branched or unbranched alkyl having 1-12 carbon atoms, where the alkyl can be substituted by

 Hydroxy,

(C ₁ -C ₄ ) alkoxy,

Di (C ₁ -C ₄ ) alkylamino,

 Furyl,

 Pyridyl,

 Pyrrolidinyl,

 Morpholino,

 Indolyl,

 Nitrilo,

 Thienyl,

 Phenyl or phenyl, one or more times by hydroxy, methoxy or fluorine

is substituted; or R ^{7 is} hydrogen and R ^{8 is} phenyl,

Fluorophenyl, pyridyl or N-benzylpiperidyl; or R ⁷ and R ⁸ together with the

 Nitrogen atom to which they are attached

 Pyrrolidinyl

 Piperidinyl

 Morpholinyl or

 Piperazinyl mean, the

 Piperazinyl ring optionally by methyl, unsubstituted phenyl, mono- or

Di (C ₁ -C ₄ ) alkoxyρhenyl, pyrimidinyl or

Phenyl (C ₁ -C ₄ ) alkyl may be N-substituted; and when R ⁴ and R ⁶ together form the group

bedeuten, darin

mean in it

R ⁸ (a) hydrogen,

 (b) branched or unbranched aikenyl having 3 to 6 carbon atoms,

(c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or

(d) denotes branched or unbranched alkyl having 1-12 carbon atoms, where the alkyl can be substituted by hydroxy,

(C ₁ -C ₄ ) alkoxy,

Di (C ₁ -C ₄ ) alkylamino,

 Furyl,

 Pyridyl,

 Pyrrolidinyl,

 Morpholino,

 Indolyl,

 Nitrilo,

 Thienyl,

 Phenyl or phenyl, one or more times by hydroxy, methoxy or fluorine

 is substituted;

(e) phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl and R ^{9 represents} hydrogen or (C ₁ -C ₃ ) alkyl;

U and V each represent hydrogen or

 U and V together mean a bond if

(a) A is an indole radical, R, m and R ^{5 are} as defined above,

R ^{4 represents} (C ₁ -C ₄ ) alkyl; R ^{6 is} hydroxy, (C ₁ -C ₄ ) alkoxy or a

-NR ⁷ R ⁸ group, the -NR ⁷ R ⁸ group being as defined above; and if

(b) A is an indole residue,

R and m are as defined above, R ^{4 is} hydrogen,

R ^{5 is} hydrogen, (C ₁ -C ₁₀ ) alkyl,

Phenyl (C ₁ -C ₅ ) alkyl,

(C ₁ -C ₄ ) alkoxy or -NHCOX (where X

(C ₁ -C ₅ ) alkyl) means

R ^{6 is} hydroxy, (C ₁ -C ₄ ) alkoxy or a

-NR ⁷ R ⁸ group, the -NR ⁷ R ⁸ group being as defined above; or their pharmaceutically acceptable salt with an inorganic or organic acid for the treatment of neurological diseases.

The use of a compound of the general formula Ia is preferred

worin

wherein

A represents a benzo, thieno or indolo radical;

R denotes hydrogen, (C ₁ -C ₄ ) alkyl, halogen (F, Cl, Br, J), hydroxy, (C ₁ -C ₄ ) alkoxy, amino, methylthio, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R together - Are O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-; m means 1, 2 or 3 when A is a benzo- or

Is indole and 1 or 2 when A is thieno; R ^{4 represents} hydrogen or (C ₁ -C ₄ ) alkyl; R ^{5 is} hydrogen, (C ₁ -C ₁₀ ) alkyl, phenyl,

Phenyl (C ₁ -C ₅ ) alkyl, (C ₁ -C ₄ ) alkoxy or

-NHCOX (where X is (C ₁ -C ₅ ) alkyl); R ^{8 is} hydroxy, (C ₁ -C ₄ ) alkoxy or a

-NR ⁷ R ⁸ group means in which R ⁷ and R ⁸ independently of one another

 (a) hydrogen,

 (b) branched or unbranched aikenyl having 3 to 6 carbon atoms,

 (c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or

 (d) mean branched or unbranched alkyl having 1-12 carbon atoms, where the alkyl can be substituted by

 Hydroxy,

(C ₁ -C ₄ ) alkoxy,

Di (C ₁ -C ₄ ) alkylamino,

 Furyl,

 Pyridyl,

 Pyrrolidinyl,

 Morpholino,

 Indolyl,

 Nitrilo,

 Thienyl,

 Phenyl or phenyl, one or more times by hydroxy, methoxy or fluorine

 is substituted;

or R ^{7 is} hydrogen and R ^{8 is} phenyl,

Fluorophenyl, pyridyl or N-benzylpiperidyl; or R ⁷ and R ⁸ together with the

 Nitrogen atom to which they are attached

 Pyrrolidinyl

 Piperidinyl

Morpholinyl or Piperazinyl mean, the

Piperazinyl ring can optionally be N-substituted by methyl, unsubstituted phenyl, mono- or di (C ₁ -C ₄ ) alkoxyphenyl, pyrimidinyl or phenyl (C ₁ -C ₄ ) alkyl; or their pharmaceutically acceptable salt with an inorganic or organic acid for the treatment of neurological diseases.

The invention further relates to the use of a compound of the general formula Ib

worin

wherein

A means an indole residue and

a) R, m and R ^{5 are} as defined above,

(C ₁ -C ₄ ) alkyl;

Hydroxy, (C ₁ -C ₄ ) alkoxy or a

-NR ⁷ R ⁸ group means, the

-NR ⁷ R ⁸ group is as defined above; and b) R and m are as defined above,

R ^{4 represents} hydrogen,

R ^{5 is} hydrogen, (C ₁ -C ₁₀ ) alkyl,

Phenyl (C ₁ -C ₅ ) alkyl,

(C ₁ -C ₄ ) alkoxy or -NHCOX (where X

(C ₁ -C ₅ ) alkyl) means

R ^{6 is} hydroxy, (C ₁ -C ₄ ) alkoxy or a

-NR ⁷ R ⁸ group means, the

-NR ⁷ R ⁸ group is as defined above; or their pharmaceutically acceptable salt with an inorganic or organic acid for the treatment of neurological diseases.

The invention further relates to the use of a compound of the general formula Ic,

wherein A, R, m, R ⁵ , R ⁸ and R ⁹ as for the

general formula I are defined, or their

pharmaceutically acceptable salt with a

inorganic or organic acid for the treatment of neurological diseases.

The formulas I, Ia, Ib and Ic described above are to be understood as meaning that they are also the possible isomers

Include structures. Especially to be highlighted be that the compounds of general formula Ib, in which R ^{4 is} hydrogen, also in the structure of general formula Id or Ie

can be present. The above definition of the general formula Ib also includes the compounds of the general formula Id in which R ^{4 is} hydrogen or

(C ₁ -C ₄ ) alkyl.

The use of a compound of the general formula Ia in which A is a benzo radical, in particular a compound in the

-) R is hydrogen, hydroxy, (C ₁ -C ₄ ) alkoxy or

Is methylthio, preferably is methoxy; especially where R is methoxy and m 2 and the substituents R are in positions 6 and 7; -) R ^{4 is} hydrogen or methyl;

-) R ^{5 is} hydrogen, (C ₁ -C ₅ ) alkyl, phenyl,

Is phenyl (C ₁ -C ₅ ) alkyl or (C ₁ -C ₄ ) alkoxy

preferably R ^{5 is} hydrogen, (C ₁ -C ₅ ) alkyl,

 Phenyl, phenethyl or methoxy is preferred

C ₄ or C ₅ alkyl 'or phenethyl; -) R ^{6 is} hydroxy or ethoxy, or

-) R ^{6 is} an NR ⁷ R ⁸ group, wherein

-) R ⁷ and R ^{8 are} (C ₁ -C ₅ ) alkyl, or

-) R ^{7 is} hydrogen and R ^{8 is} aikenyl or alkynyl with 3 carbon atoms, preferably

-CH ₂ CH = CH ₂ ; or

-) R ^{7 is} hydrogen and R ^{8 is} alkyl with 1-8

 Carbon atoms; or

-) R ⁷ hydrogen and R ⁸ alkyl with 1 to 3

Is carbon atoms and the alkyl can be substituted by hydroxy, methoxy, dimethylamino, furyl, pyridyl, pyrrolidinyl, morpholino, phenyl or penyl which is 1 to 3 times substituted by hydroxy or methoxy; or -) R ⁷ and R ⁸ together with the nitrogen atom

 that they are bound, mean pyrrolidinyl, morpholino or piperazinyl.

It should also be emphasized the use of a compound of the general formula Ia in which A is a thieno radical and R is hydrogen. Of these compounds, those are preferred in which -) R ^{4 is} hydrogen or methyl; and / or -) R ^{5 is} phenyl or phenethyl; and or

E -) R ^{6 is} a -NR ⁷ R ⁸ group in which

-) R ^{7 is} hydrogen, methyl or ethyl and R ⁸

 Methyl or ethyl by morpholino or

Thienyl can be substituted; or -) R ⁷ and R ⁸ together with the nitrogen atom

 that they are bound, are morpholino.

It should also be emphasized the use of a compound of the general formula Ib and

 in particular Ia, in which A is an indole radical, and

R ^{4 is} hydrogen and / or R ^{5 is} hydrogen or

Phenyl and / or R ⁶ (C ₁ or C ₂ ) alkoxy or

R ^{6 is} the -NR ⁷ R ⁸ group in which R ⁷

Hydrogen and R ⁸ unsubstituted

Is (C ₁ -C ₄ ) alkyl or (C ₁ or C ₂ ) alkyl,

 which can be substituted as defined above.

Also to be emphasized is the use of compounds of the general formula Ic, in which A is a benzo radical and

-) R is hydrogen, hydroxy, (C ₁ -C ₄ ) alkoxy or

 Is methylthio, preferably methoxy, especially where R is methoxy and m 2 and the substituents R are in positions 6 and 7;

-) R ^{5 is} hydrogen, (C ₁ -C ₅ ) alkyl, phenyl,

Is phenyl (C ₁ -C ₅ ) alkyl or (C ₁ -C ₄ ) alkoxy,

preferably -) R ^{5 is} hydrogen, (C ₁ -C ₅ ) alkyl, phenyl,

Is phenethyl or methoxy, preferably C ₄ - or

C ₅ alkyl or phenethyl;

-) R ⁸ aikenyl or alkynyl with 3 carbon atoms, preferably -CH ₂ CH = CH ₂ , or

-) R ⁸ alkyl with 1-8 (preferably 1-5)

 Carbon atoms; or

-) R ^{8 is} alkyl with 1 to 3 carbon atoms and

 the alkyl can be substituted by hydroxy, methoxy, dimethylamino, furyl pyridyl,

 Pyrrolidinyl, morpholino, phenyl or penyl which is 1 to 3 times substituted by hydroxy or methoxy.

The use of is also preferred

Compounds of the general formula Ic, in which A is a thieno radical and R is hydrogen and -) R ^{5 is} phenyl or phenethyl, and / or

-) R ^{8 is} methyl or ethyl, which is replaced by morpholino

 or thienyl may be substituted.

Of the compounds of the general formula Ic, those in which R ^{9 is} hydrogen are particularly noteworthy.

Examples of compounds of general formula I are summarized in the following tables.

(A): amorphous isoimer mixture

Compound No. isomer mixture

229 50:50

 231 70:30

 233 40:60

 234 90:10

 235 60:40

236 70:30

Die durch die allgemeine Formel I beschriebenen

Those described by general formula I.

As mentioned at the beginning, compounds have valuable therapeutic properties both as bases and in the form of their salts. In particular, these substances have a clear neuroprotective effect. As already mentioned at the beginning, the subject of the present invention is the use of the compounds mentioned as a neuroprotective agent. The compounds are used to treat

degenerative and necrotic diseases of the brain beneficial. Preventive treatment of patients at risk from such diseases is also possible. As demonstrated by the experiments described below, the action of the compounds is not based on one

Improvement of blood flow to the tissues. The substances bend the pathophysiologically significant intracellular

Ca ²⁺ overload before and directly attack the

Neuron cells. The Ca ²⁺ overload obviously plays a key role in the pathogenesis of a variety of neurodegenerative diseases: in epilepsy (EJ

SPECKMANN et al., ARZNEIM. RESEARCH. 39: 149-156, 1989)

M. ALZHEIMER (Lit.M.P. MATSON, ADV.EXP.MED.BIOL. 268:

211-220, 1990) (and R.A. NIXON, ANN. N.Y. ACAD. SCI, 568:

198-208, 1989) and stroke (Lit. W. YOUNG, CENTR

NERVE. SYST. TRAUMA 3: 235-250, 1986; YES. ZIVIN and Choi,

SCIENTIFIC AMERICAN 36-41, July 1991. The compounds are thus for a novel treatment of epilepsy and the

Alzheimer's disease suitable, and especially in the

Treating patients who have had a stroke or are at risk of having a stroke.

The following test results show the

surprising effect of the compounds. in the

 Hypoxia tolerance tests have become the general compounds

Formula I or its salts as effective

When testing the viability of animals in a closed chamber (hypoxia tolerance test), which with a gas mixture consisting of 96.5% nitrogen and

3.5% oxygen was flowed through, those with the

Compounds of the general formula I pretreated animals showed a statistically highly significantly greater survivability than control animals or animals pretreated with diltiazem, nifedipine or verapamil. The brain-protective effect tested with this method was often already pronounced at a dose of 5 mg / kg po.

Test results are given below for the following compounds:

Die folgenden Untersuchungen an isolierten Zellkulturen zeigen die Wirkung der untersuchten Verbindungen.

The following investigations on isolated cell cultures show the effect of the examined compounds.

Furthermore, it can be concluded from these test results that the compounds of general formula I for those mentioned in this patent application

Treatments can be used.

On isolated corticals and hippocampals

Neuronal cells from fetal rat brains (preparation according to HW Müller and W. Seifert, Proc. Natl. Acad. Sei. USA 81: 1248-1252, 1984; J. Neurosci. Res. 8: 195-204, 1982; and Müller and Seifert in "Methods for Serum Free Culture of Neuronal and Lymphoid Cells," p. 67-77, AR Liss Inc., 150 Fifth Ave., New York, NY 10011, 1984) became the direct neural attack of the

investigated compounds demonstrated. In FURA ₂ - loaded single cells, the

Concentration-time curves (calcium transient) of the cytoplasmic [Ca ²⁺ ] registered (method:

modified according to J.A. Connor, Proc. Natl. Acad. Be.

83: 6179-6183, 1986). Both after mechanical lesion and after excitatory amino acids (E.A.A., e.g. glutamate, kainate, quisqualate and NMDA), there was a strong increase in the cytoplasmic

 Calcium levels provoked by

 Compounds of general formula I was inhibitable.

The mechanism of action of this inhibition has been demonstrated both on neuronal cell cultures and on human neutrophilic granulocytes and HL 60 cells and

Platelets examined. It could be shown that the investigated compounds inhibit the transmembrane calcium influx into the cells which is caused by

Receptor agonists (eg EAA, the chemotactic peptide fMLP, leukotrienes, PAF, endothelin, etc.) stimulated becomes. This influx, described by TJ Hallam and TJ Rink (Tips 10: 8-10, 1989) as "receptor mediated Ca ²⁺ entry (RMCE)", is characterized by classic

Calcium antagonists cannot be inhibited. Classic calcium channel blockers can leukocyte and

Do not prevent platelet activation as these cells do not have voltage-dependent Ca ²⁺ channels.

The blocking of the transmembrane calcium influx was possible electrophysiologically (voltage clamp technique)

HL60 cells and neuron cells are confirmed.

The test results are summarized in the following table. % H =% inhibition of the transmembrane Ca ²⁺ current, which is determined by a uniform (10 ^-5 M) concentration of

Test substances is effected. The is inhibited

 Stimulation effect of 30μM kainate on the

intracellular [Ca ²⁺ ] in corical neuron cells.

D

Aus diesen Versuchsergebnissen kann geschlossen werden, daß für die Herstellung neuroprotektiver Mittel

From these test results it can be concluded that for the production of neuroprotective agents

(In particular for agents for the treatment or prevention of epilepsy, Alzheimer's disease and stroke) the use of compounds of the general formula I is advantageous, in which

A is a benzo radical;

R is hydrogen, hydroxy, methoxy or methylthio

means or two adjacent substituents R together are -O-CH ₂ -O-; m represents 1, 2 or 3; R ^{4 represents} hydrogen or methyl; R ^{5 is} hydrogen, (C ₁ -C ₅ ) alkyl, phenyl,

Phenyl (C ₁ -C ₅ ) alkyl or (C ₁ -C ₄ ) alkoxy; R ⁶ (C ₁ -C ₄ ) alkoxy or an -NR ⁷ R ⁸ group

means, wherein when R ^{6 represents} the -NR ⁷ R ⁸ group, therein a) R ⁷ and R ⁸ independently of one another

(C ₁ -C ₄ ) are alkyl or b) R ^{7 is} hydrogen and R ^{8 is} aikenyl or alkynyl

 with 3 carbon atoms or alkyl with 1-8

Is carbon atoms or substituted alkyl having 1 to 3 carbon atoms, this alkyl being substituted by hydroxy, methoxy, Dimethylamino, furyl, pyridyl, pyrrolidinyl,

Morpholino, phenyl or penyl which is 1 to 3 times substituted by hydroxy or methoxy, or R ^{8 is} phenyl or fluorophenyl, or c) R ⁷ and R ⁸ together with the nitrogen atom

 that they are bound, pyrrolidinyl, morpholino or

Piperazinyl mean.

In this area of the invention, the use of a compound in the is particularly preferred

 A is a benzo radical;

m is 2 and the two substituents R in the

 Positions 6 and 7 are, where the two R are independently methoxy, methylthio or

Is hydrogen;

R ^{4 represents} hydrogen or methyl;

R ⁵ (C ₂ -C ₅ ) alkyl or phenyl (C ₁ -C ₅ ) alkyl

 means;

R ^{6 represents} ethoxy or an NR ⁷ R ⁸ group, where

when R ^{6 represents} the NR ⁷ R ⁸ group, therein

a) R ⁷ and R ⁸ independently of one another

(C ₂ -C ₅ ) alkyl or

b) R ^{7 is} hydrogen and R ^{8 is} alkyl with 4-8

 Is carbon atoms or substituted alkyl having 1, 2 or 3 carbon atoms, this alkyl being substituted by hydroxy, dimethylamino, furyl, phenyl or

Is dimethoxyphenyl or R ^{8 is} phenyl or fluorophenyl; respectively the

 Using a connection

wherein A is a benzo radical, m is 2 and the two substituents R in the

 Positions 6 and 7 are, either either R being methoxy or one

 Substituent R methylthio and the other

Is hydrogen, R ^{4 is} hydrogen or methyl, R ^{5 is} (C ₂ -C ₈ ) alkyl or phenethyl,

R ^{6 is} ethoxy or the group NR ⁷ R ⁸ , wherein

a) R ⁷ and R ⁸ independently of one another

Are (C ₂ -C ₄ ) alkyl or

b) R ^{7 is} hydrogen and R ⁸

(C ₄ -C ₈ ) alkyl, phenyl, fluorophenyl or substituted (C ₁ -C ₃ ) alkyl by

 Phenyl, dimethoxyphenyl, furyl, dimethylamino or hydroxy is substituted;

or the use of a compound in which R ^{4 is} hydrogen

R ^{5 is} C ₄ or C ₅ alkyl or phenethyl, R ^{6 is} ethoxy or the group NR ⁷ R ⁸ , wherein

a) R ⁷ and R ^{8 are} butyl or

b) R ^{7 is} hydrogen and R ^{8 is} phenyl,

Is fluorophenyl, C ₁ - or C ₂ alkylphenyl (in which the phenyl can be substituted by 2 methoxy groups) or (C ₅ -C ₈ ) alkyl; or the use of a compound in which R ^{6 is} hydrogen, R ^{5 is} C ₄ - or C ₅ -alkyl or phenethyl,

R ^{6 is} ethoxy or the group NR ⁷ R ⁸ , wherein

a) R ⁷ and R ^{8 are} butyl or

b) R ^{7 is} hydrogen and R ^{8 is} phenyl,

is p-fluorophenyl, benzyl, phenethyl or alkyl of 5 to 8 carbon atoms; in particular the use of a compound in which R ^{4 is} hydrogen,

R ^{5 is} butyl or phenethyl,

R ^{6 is} the NR7R8 group, wherein

a) R ⁷ and R ^{8 are} butyl or

b) R ^{7 is} hydrogen and R ^{8 is} phenyl,

 Phenethyl or alkyl with 5 to 8

 Is carbon atoms.

The use of a compound of the range described above is particularly preferred, wherein m is 2, both substituents R are methoxy and are in positions 6 and 7, in particular such a compound in which R ^{6 is} the NR7R8 group, in which R ⁷

Hydrogen and R ⁸ -CH (CH ₃ ) (CH ₂ ) ₃ CH (CH ₃ ) ₂

is.

The use of a compound of the general formula is particularly preferred

worin R⁵ (CH₂)₃CH₃ ist und R⁶ Ethoxy oder -NH(CH₂)₄CH₃ ist und die

wherein R ^{5 is} (CH ₂ ) ₃ CH ₃ and R ^{6 is} ethoxy or -NH (CH ₂ ) ₄ CH ₃ and the

 Use of a compound of the general formula

worin R⁵ (CH₂)₃ CH₃ ist und R⁶ NHCH(CH₃) (CH₂)₃CH(CH₃)₂ oder

wherein R ^{5 is} (CH ₂ ) ₃ CH ₃ and R ⁶ NHCH (CH ₃ ) (CH ₂ ) ₃ CH (CH ₃ ) ₂ or

 is

or R ⁵

 is

or

R ^{5 is} C ₆ H ₅ (CH ₂ ) ₂ and

R ⁶ N [(CH ₂ ) ₃ CH ₃ ] ₂ ,

NHCH (CH ₃ ) (CH ₂ ) ₃ CH (CH ₃ ) ₂ ,

NH (CH ₂ ) ₂ C ₆ H ₅ or

NHC ₆ -H ₅ .

The alkyl groups mentioned in the definitions above can be either straight-chain or branched.

The active ingredients are suitable for use in pharmaceuticals for oral or parenteral administration. The main forms of medicine used are tablets,

Dragees, ampoules and juice preparations. The

Single dose to these dosage forms is between 1.0 and 200 mg, preferably 20 and 50 mg per 75 kg

Body weight. Depending on the severity of the case, 1 to 3 single doses should generally be administered daily.

Some of the compounds covered by the general definition of formula I in which A is a benzo- or

Indolorest is known, some of which are known as

Tranquilizers have been described:

 Eur. J. Med. Chem.- Chim. Ther, 14 (1), 77-89

 Heterocycles, 3 (2), 179-82

 Synthesis (5), 474-7

J. Med. Pharm. Chem. 2, 505-17 (1961)

EP 2 18 57

US 3 021331

US 3,081,306

Compounds which are structurally close to the compounds of the general formula Ib are in the

European patent applications EP-A-288 048 and

EP-A-251 194. As has already been mentioned at the beginning, these are

Compounds of the general formula I and their salts have been described in German patent application P 38 27 727.1 as cardioprotective compounds.

The preparation of the compounds of the general

Formula I can be carried out by processes known per se. A compound of the formula Ia in which A, R, m, R ⁴ ,

R ⁵ and R ^{6 are} as defined above, can be made by the corresponding compound of

general formula II or the tautomer

reduziert wird. In der Verbindung der Formel II sind A, R, m, R ⁴, R⁵ und R⁶ wie in der gewünschten

is reduced. In the compound of formula II, A, R, m, R ⁴ , R ⁵ and R ^{6 are} as in the desired one

 Compound of formula Ia defined. (The compounds of the formula II are therefore compounds in which A is benzo,

Thieno or Indolo is.)

This method is preferably applied to compounds of the formula II in which R ^{4 is} hydrogen.

For the preparation of a compound of formula Ia in which R ^{4 is} (C ₁ -C ₄ ) alkyl, one of the following can be used

Find variants application: a) a compound of the formula Ia in which R ⁴

 Is hydrogen is N-alkylated;

b) a compound of formula II in R ⁴

 Hydrogen is quaternary in it

 Ammonium salt transferred (e.g. by reacting with

(C ₁ -C ₄ ) alkyl iodide) and then to

Compound of the formula Ia (in which R ₄

(C ₁ -C ₄ ) alkyl is reduced).

Complex metal hydrides (such as, for example, are suitable for the reduction of the compounds of the formula II

Sodium boranate, sodium cyanoborohydride, optionally in combination with a noble metal catalyst) or catalytically activated hydrogen.

The reduction is preferably carried out in a solvent such as, for example, methanol or ethanol at room temperature or, if appropriate, at elevated temperatures

Temperature to the reflux temperature of the

Reaction mixture.

Some of the compounds of the general formula Ia (shown below as formula If) can be prepared by reducing a corresponding compound of the general formula V

worin A einen Benzo-, Thieno- oder Indolorest bedeutet;

wherein A represents a benzo, thieno or indolo radical;

R is hydrogen, (C ₁ -C ₄ ) alkyl, halogen (F, Cl, Br,

J), hydroxy, (C ₁ -C ₄ ) alkoxy, amino, methylthio, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R together are -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O- ; m means 1, 2 or 3 when A is a benzo- or

Is indole and 1 or 2 when A is thieno; R ^{9 represents} hydrogen or (C ₁ -C ₄ ) alkyl;

R ^{5 is} hydrogen, (C ₁ -C ₁₀ ) alkyl, phenyl,

Phenyl (C ₁ -C ₅ ) alkyl, (C ₁ -C ₄ ) alkoxy or

-NHCOX (where X is (C ₁ -C ₅ ) alkyl); R ⁸ (a) hydrogen,

 (b) branched or unbranched aikenyl having 3 to 6 carbon atoms,

 (c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or

(d) means branched or unbranched alkyl having 1-12 carbon atoms, where the alkyl can be substituted by

Hydroxy,

(C ₁ -C ₄ ) alkoxy,

Di (C ₁ -C ₄ ) alkylamino,

 Furyl,

 Pyridyl,

 Pyrrolidinyl,

 Morpholino,

 Indolyl,

 Nitrilo,

 Thienyl,

 Phenyl or phenyl which is substituted one or more times by hydroxyl, methoxy or fluorine;

 (e) phenyl, fluorophenyl, pyridyl or

 N-benzylpiperidyl; means.

The reduction can be carried out with NaBH ₄ in glacial acetic acid, possibly with the addition of a solvent (based on C. Djerassi, HJ Monteiro, A. Walser, LH Durham J. Am. Chem. Soc. 88, (1966) 1792). For this purpose, a compound of general formula Ic is dissolved in glacial acetic acid and with cooling and stirring

in portions with an excess of sodium boranate.

The reaction time is very largely determined by the length of the radical R ⁵ and is between 1 and 15 hours at room temperature. The response times take in order

R ⁵ = H <CH ₃ - <C ₂ H ₅ <C ₄ H ₉ <C ₅ H ₁₁ ....

to. From R ⁸ they are not or only in

insignificantly affected. The reaction temperature is largely uncritical and can be between 5 ° C and the boiling point of

Reaction mixture lie. For safety reasons, the implementation is ice cooling in one

Temperature range between 5 ° C and room temperature.

In addition to glacial acetic acid, the

occurs simultaneously as a reactant, mixtures of

Glacial acetic acid and a suitable, inert solvent are used, for example THF, dioxane, ethanol etc. The reaction in glacial acetic acid is preferred.

Preferred execution of the reduction:

The starting compounds (Ic) are dissolved in glacial acetic acid. While stirring and cooling to 5 ° C., the finely powdered NaBH ₄ (4 × 10-fold excess) is introduced in portions. When the reaction has ended, water is carefully added, the mixture is made alkaline with dilute NaOH and extracted with CH ₂ Cl ₂ . The

organic phase is washed with water, over

Na ₂ SO ₄ dried and concentrated. The residue

is, if necessary after cleaning via a

Silica gel column (eluent: CH ₂ Cl ₂ / MeOH 100: 10) for

Brought crystallization.

The compounds of the formula Ia obtained in this way can be subjected to one or more of the following aftertreatments: A compound of the general formula Ia in which R ^{6 is} hydroxy or (C ₁ -C ₄ ) alkoxy can be converted into the corresponding amide in which

R ^{6 is} the group NR ⁷ R ⁸ . The

 Starting compound, (if necessary after

prior protection of the basic ring nitrogen and / or activation of the carboxy or

 Ester group) with the corresponding amine

NHR ⁷ R ⁸ (III) implemented.

Examples of reactive carboxylic acid derivatives are: acid halides,

Acid azides or mixed acid anhydrides (e.g. with an aromatic or aliphatic

Carboxylic acid, alkyl carbonic acid or

Dialkylphosphoric acid, etc.), also acid amides (e.g. with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, etc.) or active esters (e.g. cyanomethyl, methoxymethyl, vinyl, propargyl or

p-nitrophenyl ester, etc.) or esters with

Dimethylhydroxylamine, 1-hydroxysuccinimide,

Dicyclohexylurea etc., the active imidazolides are preferred.

The amide formation is generally carried out in an inert solvent such as dioxane, acetonitrile, dimethylformamide or a mixture of one or more of these solvents, if appropriate in the presence of an organic or inorganic base as an acid scavenger. However, it is also possible to carry out the reaction in excess of the amine without a solvent. The reaction temperature can, depending on

Starting materials used vary within wide limits and between about 0 ° C and

Boiling temperature of the reaction mixture. A compound of general formula Ia in which

R ^{4 is} hydrogen, can be converted by N-alkylation into the corresponding compound of the formula Ia, in which R ⁴ (C ₁ -C ₄ ) alkyl

is.

In principle, all known alkylating agents are suitable for N-alkylation insofar as they have sufficient reactivity, e.g. active alkyl esters, such as dialkyl sulfate,

Toluenesulfonic acid alkyl ester or

Alkyl fluorosulfonates or alkyl halides, such as alkyl bromides or alkyl iodides. The reaction takes place at temperatures up to the boiling point of the reaction mixture. Alkyl stands for

(C ₁ -C ₄ ) alkyl.

 The aminoalkylation can also follow

Leuckart gelding (Ber. Dtsch. Chem. Ges. 18th

 (1985), 2341) or Eschweiler-Clarke (Teilheimer 2, (1948) No. 352; 4. (1950) No. 378). In general, the substance with an approximately 30% aldehyde solution is preferred

Formalin solution treated in the presence of formic acid at reflux temperature. The time varies between 3 and 18 hours. This

The reaction is particularly suitable for compounds (I) in which R ^{6 is} not NH ₂ or NHR ⁸ . c) A compound of the formula Ia in which R ⁶

Hydroxy is, can be converted into the corresponding ester (R ⁶ = (C ₁ -C ₄ ) alkoxy). d) A compound of the formula Ia in which R ⁶

(C ₁ -C ₄ ) alkoxy or NR ⁷ R ⁸ can be hydrolyzed to the corresponding free acid. e) The diastereomer separation is partially successful

 spontaneously by crystallization or by

 Apply the usual methods of

 Racemate separation, e.g. Column chromatography. f) The free base of the general formula Ia is converted into its acid addition salts in a manner known per se.

Acids suitable for salt formation are

 for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, maleic acid,

 Fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, cinnamic acid, ascorbic acid or methanesulfonic acid.

The compounds of the formula II or Ib can be prepared by processes known per se, preferably by that in the German

Patent application P 37 18 570.5 described method. In the presence of a condensing agent, a

Malonic acid diamide of the general formula IV,

in der R, m, R⁵ und R⁶ wie oben definiert sind und Ar Phenyl, 2- oder 3-Indolyl oder 2- oder 3-Thienyl bedeutet, zu den entsprechenden Verbindungen II bzw. Ib cyclisiert werden.

in which R, m, R ⁵ and R ^{6 are} as defined above and Ar is phenyl, 2- or 3-indolyl or 2- or 3-thienyl, are cyclized to the corresponding compounds II and Ib.

Here are A, m, R, R ⁵ and R ⁶ as above for the

Compounds IV defined, R ⁴ is hydrogen or (C ₁ -C ₄ ) alkyl.

The execution of the method is discussed in more detail below. If the reaction is e.g. with a

Mixture of phosphorus pentoxide and

(C ₁ -C ₄ ) alkylsulfonic acid, in addition to the corresponding compounds II and Ib in which R ^{4 is} hydrogen, the analogous compounds in which R ^{4 is} (C ₁ -C ₄ ) alkyl are also obtained.

Strong Lewis acids, such as e.g. Phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride,

Phosphorus pentoxide, titanium tetrachloride, boron trifluoride,

Tin tetrachloride, but also inorganic acids, e.g. Polyphosphoric acid, sulfuric acid, fluorosulfonic acid and hydrofluoric acid, or mixtures of

Condensing agents such as a mixture of

Phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (C ₁ -C ₄ )

Alkylsulfonic acid, for example with a P ₂ O ₅ content of approx. 10 percent by weight.

If a compound IV in the presence of the mixture of

Phosphorus pentoxide and (C ₁ -C ₄ ) alkyl sulfonic acid

cyclized, one obtains, as mentioned above, in addition to the corresponding compounds II and Ib, in which R ^{4 is} hydrogen, the analogues

Compounds II and Ib in which R ^{4 is} (C ₁ -C ₄ ) alkyl. This method variant is preferably used

Running methanesulfonic acid.

The cyclization can be carried out in the presence or absence of a solvent. All inert solvents are suitable, provided they are one

have sufficient solubility for the reactants and a sufficiently high boiling point

e.g. benzene, alkylbenzenes (e.g. toluene, xylene), chlorobenzenes, chloroform, acetonitrile, decalin. A preferred variant of the method is the condensing agent, for example phosphorus oxychloride in acetonitrile or a

(C ₁ -C ₄ ) alkyl sulfonic acid / phosphorus pentoxide mixture to be used without the addition of solvents.

The cyclization is preferably carried out with

Phosphorus oxychloride in acetonitrile or in difficult cases with a mixture of phosphorus pentoxide and (C ₁ -C ₄ ) alkyl sulfonic acid (preferably methanesulfonic acid). Implementation can be done within a large

Temperature range, preferably with heating or heating to 50 ° C to about the boiling point of

Reaction mixture can be carried out.

The required reaction time depends on

Starting compound IV between 2 and 15 hours.

The tautomers of general formulas II and Ib, wherein R ^{4 is} hydrogen, can be separated according to known methods, such as by column chromatography.

The compounds of general formula Ic can be prepared by a corresponding

Compound of the general formula Ia, in which R ⁴

Is hydrogen and R ^{6 represents} the group -NHR ⁸ and R, m, R ⁵ and R ⁸ as in the desired one

Compound of formula Ic are defined, reacted with an aldehyde of the general formula R ⁹ CHO (VI).

R ^{9 represents} hydrogen or (C ₁ -C ₃ ) alkyl. The

 Implementation is expedient with a 30%

 Aldehyde solution at elevated temperature. The reaction with formalin solution is preferably carried out in the presence of

Formic acid run at reflux temperature.

 The compounds of the general formulas Ib and Ic can be subjected to aftertreatments which are analogous to the aftertreatments described for the compounds of the general formula Ia.

 Compounds of the general formula II, in which R

(C ₁ -C ₄ ) alkyl means can also be prepared

be by a compound of formula II in which

R 4 is hydrogen, is converted into its quaternary ammonium salt (for example by reaction with (C ₁ -C ₄ ) alkyl iodide) and then with a base (for example

Alkali) is treated. example 1

 2- (1,2,3,4-tetrahydro-6-methylmerkapto-1-isoquinolinyl) - N- (1-pentyl) hexanamide.

2.5 g of 2- (3,4-dihydro-6-methylmerkapto-1-isoquinolinyl) -N- (l-pentyl) hexanamide are dissolved in 100 ml of methanol

in portions with 0.5 g NaBH. added and stirred for 3 hours at room temperature. After the reaction, excess NaBH. decomposed, the solvent removed in vacuo, the residue partitioned between CH ₂ Cl ₂ and water. After drying the organic phase over anhydrous sodium sulfate, the mixture is evaporated and the residue is made up of ethyl acetate / petroleum ether

crystallized.

Mp 95 ° C

Example 2

 2- (1,2,3,4-Tetrahydro-6-methylmerkapto-1-isoquinolinyl) hexanoic acid ethyl ester hydrochloride.

20 g of ethyl 2- (3,4-dihydro-6-methylmerkapto-1-isoquinolinyl) -hexanoate are added in portions in 200 ml of boiling ethanol with 5.2 g of solid NaBH ₄ and stirred at boiling temperature for 2 hours. After

Working up the reaction mixture will

Hydrochloride formed and from ethanol / ether

crystallized.

Mp 123 ° C Example 3

 Ethyl 2- (1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl) hexanoate hydrochloride

60 g of ethyl 2- (3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl) -hexanoate are dissolved in 600 ml of ethanol with the addition of 17 g of concentrated HCl in the presence of 6 g of PtO_ at 20 ° C. and 5 bar with hydrogen catalytically hydrogenated. After removing the catalyst, the reaction solution is concentrated and the product is crystallized by adding ether.

Mp 141-145 ° C

Example 4

 2- (1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-methyl-1-isoquinoliny1) -hexanoic acid hydrochloride

A mixture of 12 g of 2- (1,2,3,4-tetrahydro-6,7-di-methoxy-1-isoquinolinyl) hexanoic acid ethyl ester, 33 g of formalin (30%) and 16 g of formic acid (98%)

Heated to boiling for 1 hour. After evaporation of the reaction mixture is made alkaline with semi-saturated sodium carbonate solution, extracted with CH ₂ Cl ₂ , the

organic phase washed with water, dried over Na ₂ SO ₄ and evaporated in vacuo. The

The reaction product is purified on Al ₂ O ₃ activity level III (eluent CCl ₄ ) and into the hydrochloride

transferred.

Mp 156-157 ° C (ethanol / ether) Example 5

 2- (1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methyl-1-isoquinolinyl) hexanoic acid hydrochloride

15.5 g of ethyl 2- (1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl) hexanoate are concentrated in 100 ml. Hydrochloric acid heated to boiling for 1.5 hours. After the reaction is largely concentrated in vacuo and a diastereomer by adding acetone

Crystallization brought (mp. 180-183 ° C), the second diastereomer remains in the mother liquor.

Example 6

 2- (1,2,3,4-tetrahydro-6-methylmerkapto-1-isoquinolinyl) N- (1-pentyl) hexanamide

3 g of ethyl 2- (1,2,3,4-tetrahydro-6-methylmerkapto-1-isoquinolinyl) hexanoate are heated to boiling in 50 ml of n-pentylamine for about 14 hours. After the reaction has ended (TLC control), excess amine is removed in vacuo, the residue is taken up in CH ₂ Cl ₂ and shaken out several times with water, and the organic phase is dried over anhydrous Na_S0.

dried, evaporated and the residue purified on silica gel (eluent CH ₂ Cl ₂ / MeOH = 100: 3).

Mp 95 ° C

Example 7

2- (1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methyl-1-isoquinolinyl) hexane-N- [2- (2,4-dimethoxyphenyl) ethyl] amide 2.58 g of 2- (1,2,3,4-tetra-hydro-6,7-dimethoxy-2-N-methyl-1-isoquinolinyl) hexanoic acid are dissolved in 50 ml of anhydrous DMF with 3.2 g N, N'-carbonyldiimidazole

Stirred for 4 hours at room temperature. Then 3 ml of 3,4-dimethoxyphenylethylamine are added and, after standing for 15 hours, worked up at room temperature. This implementation takes place without structural changes. If an isomer is used as the starting material, the corresponding isomer of the end compound is obtained.

Diastereomer 1: mp 94-96 ° C (ethyl acetate / ligroin)

Diastereomer 2: mp. 75-78 ° C (ethyl acetate / ligroin)

Example 8

 2- (1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl) hexane-N- (2-phenylethyl) amide hydrochloride a) 2- [1,2,3,4- Tetrahydro-6,7-dimethoxy-2-N- (9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl] hexanoic acid.

In a mixture of 10.8 g of 2- (1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl) -hexanoic acid, 70 ml of aqueous sodium carbonate solution (10%) and 35 ml of dioxane at 0 ° C a solution of 9.1 g over 30 minutes

 9-fluorenylmethyloxycarbonyl chloride in 55 ml of dioxane was added dropwise. After stirring at 0 ° C. for 1 hour, the mixture is left to stand at room temperature for 15 hours, poured onto 1000 ml of ice water and extracted 3 times with each

100 ml ether. The aqueous phase is brought to pH = 2, the solid white precipitate is filtered off with suction and, after dissolving in CHCl ₃ / MeOH (1: 1), crystallized by adding petroleum ether.

Mp 169-172 ° C. b) 2- [1,2,3,4-tetrahydro-6,7-dimethoxy-2-N- (9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl] hexane-N- (2-phenylethyl) amide

2.65 g of 2- [l, 2,3,4-tetrahydro-6,7-dimethoxy-2-N- (9-fluorenyl-methyloxycarbonyl) -1-isoquinolinyl] -hexanoic acid are dissolved in 15 ml of anhydrous DMF with 1 g

 N, N'-carbonyldiimidazole reacted. After 1 hour, use an equivalent amount

 2-phenylethylamine added; after further

It is worked up for 15 hours at room temperature, over silica gel (eluent CHCl ₂ / MeOH = 100: 2)

 cleaned and made from acetic ester / petroleum ether

 crystallized.

 Mp 168-170 ° C. c) 1.5 g of 2- [1,2,3,4-tetrahydro-6,7-dimethoxy-2-N- (9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl] hexane N- (2-phenylethyl) - amide in 30 ml of a

 Mixture of trifluoroacetic acid and anisole (1%) stirred for 15 hours at room temperature. After this

Removing the solvent, the residue is partitioned between CH ₂ Cl ₂ and a 10% sodium carbonate solution, the organic phase with water

washed, dried over Na ₂ SO ₄ , concentrated,

 the hydrochloride formed and crystallized from ethanol / ether.

Mp 154-156 ° C.

Example 9

 2- (1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-isoquinolinyl-butyric acid ethyl ester hydrochloride a) 2- (3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl ) - ethyl butyric acid methoiodide.

0.35 g of 2- (3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl) butyric acid ethyl ester and 1 ml of methyl iodide are mixed in 10 ml of a

 Ethanol / nitromethane mixture (1: 1) heated to 60 ° C for 1.5 h. After complete implementation

(TLC control) is evaporated in vacuo and the residue is crystallized from ethanol / petroleum ether. Mp 183-185 ° C. b) 0.5 g of ethyl 2- (3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl) -butyrate are stirred in 5 ml of ethanol at room temperature with 0.1 g of NaBH _{4 for} 3 hours. When the reaction has ended (TLC control), the mixture is worked up in the customary manner and the hydrochloride is formed.

 Mp 164-166 ° C

Example 10

2- (1H-1,2,3,4-tetrahydropyrido [3,4-b] indol-1-yl) -N- (2-morpholinoethyl) acetamide hydrochloride a) 2- (1H-3,4- Dihydropyrido [3,4-b] indol-1-yl) -N- (2-morpholinoethyl) acetamide 15 g of 2- (3-indolyl) ethylaminocarbonylacetic acid-N- (2-morpholinoethyl) amide and 45 ml of POCl ₃ are heated in 250 ml of an acetonitrile-benzene mixture (1: 1) at 40-45 ° C. for 5 hours. After removing the solvent and excess POCl ₃ , the residue between ice water and

Chloroform distributed, over Al ₂ O ₃ (eluent:

CH ₂ Cl ₂ / MeOH = 100: 3) cleaned and out

Crystallized ethyl acetate / ether with the addition of Ligroin 55-75 ° C. The product thus obtained is reduced analogously to Example 1, the product isolated and into the

Hydrochloride (title compound) transferred.

Mp 262-265 ° C

Examples of pharmaceutical preparations: a) coated tablets

 1 coated tablet contains:

 Active ingredient of the general formula I 30.0 mg

Milk sugar 100.0 mg

Corn starch 75.0 mg

Gelatin 3.0 mg

Magnesium stearate 2.0 mg

210.0 mg

Manufacturing

 The mixture of the active substance with milk sugar and

Corn starch is made with a 10% aqueous solution

Granulated gelatin solution through a sieve with a mesh size of 1 mm, dried at 40 ° C. and forced through a sieve again. The granules obtained in this way are mixed with

Magnesium stearate mixed and pressed. The so

Cores obtained are coated in the usual way with a shell, which is by means of an aqueous

Suspension of sugar, titanium dioxide, talc and gum arabic is applied. The finished coated tablets are polished with beeswax.

b) tablets

 Active ingredient of the general formula I 30.0 mg

Milk sugar 100.0 mg

Corn starch 70.0 mg soluble starch 7.0 mg

Magnesium stearate 3.0 mg

210.0 mg Manufacturing

 Active ingredient and magnesium stearate are combined with a

granulated aqueous solution of the soluble starch, the granules dried and intimately with milk sugar and

Cornstarch mixed. The mixture then becomes

Tablets of 210 mg weight pressed.

c) capsules

 Active ingredient of the general formula I 20.0 mg

Milk sugar 230.0 mg

Corn starch 40.0 mg

Talc 10.0 mg

300.0 mg

Manufacturing

 The active ingredient, milk sugar and corn starch are first mixed in a mixer and then in one

 Shredder blended. The mixture is added to the mixer again, thoroughly mixed with the talc and mechanically in hard gelatin capsules

bottled.

Claims

Claims: 1. Use of a compound of general formula I,

wherein A represents a benzo, thieno or indolo radical; R is hydrogen, (C ₁ -C ₄ ) alkyl, halogen (F, Cl, Br, J), hydroxy, (C ₁ -C ₄ ) alkoxy, amino, methylthio, methanesulfonyloxy or  Methanesulfonamido means, or two adjacent substituents R together Are -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-; m means 1, 2 or 3 when A is a benzo- or  Is indole and 1 or 2 when A is thieno; R ^{5 is} hydrogen, (C ₁ -C ₁₀ ) alkyl, phenyl, Phenyl (C ₁ -C ₅ ) alkyl, (C ₁ -C ₄ ) alkoxy or -NHCOX (where X is (C ₁ -C ₅ ) alkyl); R ^{4 represents} hydrogen or (C ₁ -C ₄ ) alkyl; R ^{6 is} hydroxy, (C ₁ -C ₄ ) alkoxy or a -NR ⁷ R ⁸ group means or R ⁴ and R ⁶ together form the group

mean; where when R ^{6 represents} the -NR ⁷ R ⁸ group, in this R ⁷ and R ^{8 are} independent of one another  (a) hydrogen,  (b) branched or unbranched aikenyl having 3 to 6 carbon atoms,  (c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or  (d) mean branched or unbranched alkyl having 1-12 carbon atoms, where the alkyl can be substituted by  Hydroxy, (C ₁ -C ₄ ) alkoxy, Di (C ₁ -C ₄ ) alkylamino,  Furyl,  Pyridyl,  Pyrrolidinyl,  Morpholino,  Indolyl,  Nitrilo,  Thienyl, Phenyl or phenyl which is substituted one or more times by hydroxyl, methoxy or fluorine; or R ^{7 is} hydrogen and R ^{8 is} phenyl, Fluorophenyl, pyridyl or N-benzylpiperidyl; or R ⁷ and R ⁸ together with the  Nitrogen atom to which they are attached  Pyrrolidinyl  Piperidinyl  Morpholinyl or  Piperazinyl mean, the  Piperazinyl ring optionally by methyl, unsubstituted phenyl, mono- or Di (C ₁ -C ₄ ) alkoxyphenyl, pyrimidinyl or Phenyl (C ₁ -C ₄ ) alkyl may be N-substituted; and when R ⁴ and R ⁶ together form the group

mean in it  R (a) hydrogen,  (b) branched or unbranched aikenyl having 3 to 6 carbon atoms, (c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or (d) denotes branched or unbranched alkyl having 1-12 carbon atoms, where the alkyl can be substituted by hydroxy, (C ₁ -C ₄ ) alkoxy, Di (C ₁ -C ₄ ) alkylamino, Furyl, Pyridyl,  Pyrrolidinyl,  Morpholino,  Indolyl,  Nitrilo,  Thienyl,  Phenyl or phenyl, one or more times by hydroxy, methoxy or fluorine  is substituted;  (e) denotes phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl and R ^{9 represents} hydrogen or (C ₁ -C ₃ ) alkyl; U and V each represent hydrogen or  U and V together mean a bond if (a) A is an indole radical, R, m and R ^{5 are} as defined above. R ^{4 represents} (C ₁ -C ₄ ) alkyl; R ^{6 is} hydroxy, (C ₁ -C ₄ ) alkoxy or a -NR ⁷ R ⁸ group means, the -NR ⁷ R ⁸ group is as defined above; and if (b) A is an indole residue,  R and m are as defined above, R ^{4 represents} hydrogen, R ^{5 is} hydrogen, (C ₁ -C ₁₀ ) alkyl, Phenyl (C ₁ -C ₅ ) alkyl, (C ₁ -C ₄ ) alkoxy or -NHCOX (where X (C ₁ -C ₅ ) alkyl) means R ^{6 is} hydroxy, (C ₁ -C ₄ ) alkoxy or a -NR ⁷ R ⁸ group, the -NR ⁷ R ⁸ group being as defined above; or their pharmaceutically acceptable salt with an inorganic or organic acid for the treatment of neurological diseases. 2. Use of a compound according to claim 1, in which R ^{4 is} hydrogen or (C ₁ -C ₄ ) alkyl; R ^{6 is} hydroxy, (C ₁ -C ₄ ) alkoxy or a -NR ⁷ R ⁸ group means, wherein the -NR ⁷ R ⁸ group is as defined in claim 1. 3. Use of a compound according to claim 2 wherein A is a benzo radical; R represents hydrogen, hydroxy, methoxy or methylthio, or two adjacent substituents R together are -O-CH ₂ -O-; m represents 1, 2 or 3; R ^{4 represents} hydrogen or methyl; R ^{5 is} hydrogen, (C ₁ -C ₅ ) alkyl, phenyl, Phenyl (C ₁ -C ₅ ) alkyl or Is (C ₁ -C ₄ ) alkoxy; R ^{6 represents} (C ₁ -C ₄ ) alkoxy or an -NR ⁷ R ⁸ group, wherein when R ^{6 represents} the -NR ⁷ R ⁸ group therein a) R ⁷ and R ⁸ independently of one another (C ₁ -C ₅ ) are alkyl or b) R ^{7 is} hydrogen and R ^{8 is} aikenyl or Alkynyl having 3 carbon atoms or alkyl having 1-8 carbon atoms or substituted alkyl having 1 to 3 carbon atoms, this alkyl being substituted by hydroxy, methoxy, dimethylamino, furyl, pyridyl, pyrrolidinyl, morpholino, phenyl or penyl which is substituted 1 to 3 times is by hydroxy or methoxy, or R ^{8 is} phenyl or fluorophenyl, or c) R ⁷ and R ⁸ together with the nitrogen atom to which they are attached mean pyrrolidinyl, morpholino or piperazinyl. 4. Use of a compound according to claim 3, in the A is a benzo radical;  m is 2 and the two substituents R in the  Are positions 6 and 7, where the two R's independently of one another are methoxy, methylthio or hydrogen; R ^{4 represents} hydrogen or methyl; R ⁵ (C ₂ -C ₅ ) alkyl or phenyl (C ₁ -C ₅ ) alkyl  means; R ^{6 represents} ethoxy or an NR7R8 group, where when R ^{6 is} the NR ⁷ R ⁸ group  means in it a) R ⁷ and R ⁸ independently of one another (C ₂ -C ₅ ) alkyl or b) R ^{7 is} hydrogen and R ^{8 is} alkyl with  4-8 carbon atoms or substituted alkyl having 1, 2 or 3 carbon atoms, this alkyl being substituted by hydroxy, dimethylamino, furyl, Phenyl or dimethoxyphenyl or R ⁸  Is phenyl or fluorophenyl. 5. Use of a compound according to claim 4  wherein A is a benzo radical, m is 2 and the two substituents R in the  Positions 6 and 7 are, either both R being methoxy or one R being methylthio and the other Is hydrogen, R ^{4 is} hydrogen or methyl. R ^{5 is} (C ₂ -C ₅ ) alkyl or phenethyl, R ^{6 is} ethoxy or the group NR ⁷ R ⁸ , wherein a) R ⁷ and R ⁸ independently of one another (C ₁ -C ₄ ) alkyl or b) R ^{7 is} hydrogen and R ⁸ (C ₄ -C ₈ ) alkyl, phenyl, fluorophenyl or substituted (C ₁ -C ₄ ) alkyl which is substituted by phenyl, dimethoxyphenyl, furyl, Dimethylamino or hydroxy is substituted. 6. Use of a compound according to claim 5, wherein R ^{4 is} hydrogen R ^{5 is} C ₄ or C ₅ alkyl or phenethyl, R ^{6 is} ethoxy or the group NR ⁷ R ⁸ , wherein a) R ⁷ and R ^{8 are} butyl or b) R ^{7 is} hydrogen and R ^{8 is} phenyl, Fluorophenyl, C ₁ - or C ₂ alkylphenyl (in which the phenyl can be substituted by 2 methoxy groups) or (C ₅ -C ₈ ) alkyl. 7. Use of a compound according to claim 6, wherein R ^{4 is} hydrogen, R ^{5 is} C ₄ or C ₅ alkyl or phenethyl, R ^{6 is} ethoxy or the group NR ⁷ R ⁸ , wherein a) R ⁷ and R ^{8 are} butyl or b) R ^{7 is} hydrogen and R ^{8 is} phenyl,  is p-fluorophenyl, benzyl, phenethyl or alkyl of 5 to 8 carbon atoms. 8. Use of a compound according to claim 7, wherein R ^{4 is} hydrogen, R ^{5 is} butyl or phenethyl, R ^{6 is} the NR ⁷ R ⁸ group, wherein a) R ⁷ and R ^{8 are} butyl or b) R ^{7 is} hydrogen and R ^{8 is} phenyl,  Phenethyl or alkyl with 5 to 8  Is carbon atoms. 9. Use a connection according to one of the  Claims 5 to 8, wherein m is 2, both  R are methoxy and are in positions 6 and 7. 10. Use a connection according to one of the Claims 5 to 9, wherein R 6 is the NR ⁷ R ⁸ group, wherein R 7 is hydrogen and R8 -CH (CH ₃ ) (CH ₂ ) ₃ CH (CH ₃ ) ₂ . 11. Use of a compound of the general formula

according to claim 5, wherein R ^{5 is} (CH ₂ ) ₃ CH ₃ and R ^{6 is} ethoxy or -N (H) (CH ₂ ) ₄ CH ₃ . 12. Use of a compound of the general formula

according to claim 5, wherein R ^{5 is} (CH ₂ ) ₃ CH ₃ and R ⁶ NHCH (CH ₃ ) (CH ₂ ) ₃ CH (CH ₃ ) ₂ or  is

 or R ⁵

 is or R ^{5 is} C ₆ H ₅ (CH ₂ ) ₂ and R ⁶ N [(CH ₂ ) ₃ CH ₃ ] ₂ , NHCH (CH ₃ ) (CH ₂ ) ₃ CH (CH ₃ ) ₂ , NH (CH ₂ ) ₂ C ₆ H ₅ or Is NHC ₆ H ₅ . 13. Use of a compound according to claim 2, in which A is a thieno radical and R is hydrogen. 14. Use of a compound according to claim 13, in which R ^{4 is} hydrogen or methyl. 15. Use of a compound according to claim 13 or 18, in which R ^{5 is} phenyl or phenethyl. 16. Use of a connection according to one of the  Claims 13 to 15, in which R is a -NR ⁷ R ⁸ group. 17. Use of a compound according to claim 16, m R ^{7 is} hydrogen, methyl or ethyl and R ^{8 is} methyl or ethyl, which may be substituted by morpholino or thienyl. 18. Use of a compound according to claim 16, in which R ⁷ and R ⁸ together with the nitrogen atom to which they are attached are morpholino. 19. Use of a compound according to claim 2, in which A is an indole radical. 20. Use of a compound according to claim 19, in which R ^{4 is} hydrogen and / or R5 is hydrogen or Phenyl and / or R ⁶ (C ₁ or C ₂ ) alkoxy or is the -NR ⁷ R ⁸ group. 21. Use of a compound according to claim 20, in which R ^{6 is} the -NR ⁷ R ⁸ group, in which R ⁷ Hydrogen and R ⁸ unsubstituted Is (C ₁ -C ₄ ) alkyl or (C ₁ or C ₂ ) alkyl, which is substituted as defined in claim 1. 22. Use of a connection according to one of the  Claims 19 to 21, wherein U and V each represent hydrogen. 23. Use of a compound according to claim 19, in which U and V together represent a bond, R ⁵ Is hydrogen and R ^{6 is} the group -NHCH ₂ CH (CH ₃ ) ₂ or.

24. Use of a compound according to claim 1, in which R ⁴ and R ⁶ together form the group

mean and A, R, m, R ⁵ , R ⁸ , R ⁹ as in  Claim 1 are defined and U and V each  Means hydrogen. 25. Use of a compound according to claim 24, in which A, R, m, R ⁵ and R ⁸ as in one of the  Claims 3, 13, 15 and 17 are defined. 26. Use of a compound according to claim 24 or 25, in which R ^{9 is} hydrogen.