CZ387898A3 - ANTI-NEURODEGENERATIVELY ACTIVE SALTS OF 10-AMINOALIPHATILDIBENZ[b,f]OXEPINE, PROCESS OF THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION CONTAINING THEREOF - Google Patents

Abstract

Acid addition salts of 10-aminoaliphatyl-dibenz[b,f]oxepines of formula (I), wherein alk signifies a divalent, aliphatic radical, R represents an amino group, either unsubstituted or mono- or di-substituted by monovalent aliphatic and/or araliphatic radicals, or disubstituted by divalent aliphatic or araliphatic radicals, and R1, R2, R3 and R4, independently of one another, denote hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with organic carboxylic acids, may be employed as anti-neurodegenerative active ingredients for medicaments. The invention also relates to new compounds of formula (I) in free form.

Description

Antineurodegenerative active salts of 10-aminoalkynyl dibenz [b, f] oxepine, process for their preparation and composition containing them

Technical field

The present invention relates to the use of the acid addition salts of 10-aminoalkynyl dibenz [b, f] oxepines of the general formula I

176611 / KB

Wi-Fi ’

where alk is a divalent, aliphatic residue,

R is an amino group which is either unsubstituted or mono- or disubstituted with a monovalent aliphatic and / or arylaliphatic residue, or disubstituted with a divalent aliphatic, arylaliphatic or heteroarylaliphatic residue, and

R _x, R _2, R ₃ and R ₄ are, independently, hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with organic carboxylic acids, which are antineurodegeneratives active ingredient of a medicament or used to prepare them as well as the novel acid addition salts of the compounds of formula I with organic carboxylic acids per se, their preparation process and pharmaceutical compositions containing them.

· · · * * * * * * * * * * * * *

SUMMARY OF THE INVENTION

Novel acid addition salts of compounds of formula I are, for example, acid addition salts of 10-aminoalkyldibenz [b, f] oxepines of formula I wherein a1) R is other than methylamino, dimethylamino, lam'-methylpiperazino and Ν '- (2-hydroxyethyl) piperazino, or at least one of the radicals R _{1 Z} R ₂ and R ₄ is other than hydrogen, or R ₃ is different from hydrogen and 8-methoxy, or R is different from dimethylamino and diethylamino or at least one of the radicals R _1; R ₂ and R ₄ are other than hydrogen or R ₃ is other than 8-chloro, or R is other than pyrrolidine or at least one of R ₃ , R ₂ and R ₄ is other than hydrogen when alk is methylene _b ) R is other than methylamino or at least one of R _1, R ₂ and R ₄ is other than hydrogen or R ₃ is other than 6-methyl, or R is other than diethylamino, at least one of R 1 and R ₂ R ₂ and R ₄ is other than hydrogen, or R ₃ is different from 7-methyl or at least one of the radicals R _2, R ₃ and R ₄ is other than hydrogen, or R ₄ is other than 3-methyl, if alk is ethylene, cl) R is other than methylamino and dimethylamino, or at least one radical R _1, R ₂ , R ₃ and R ₄ is other than hydrogen when alk is ethylidene, and d 1) R is other than dimethylamino or at least one of R ₂ and R ₄ is other than hydrogen or R _x is other than a hydrogen atom, a 3-chloro group and 3-trifluoromethyl, or R ₃ is different from hydrogen, 8-Cl and 8-trifluoromethyl, or R is different from diethylamino or at least one R _HR R ₂ , R ₃ and R ₄ is other than hydrogen, or R is other than piperidine, R ₂ , R ₃ and R ₄ are other than atom

9 99 99 9 · 99

9 9 9999

9 9 9 99 99 999

9999 9 999 999 99 99 hydrogen, or R _x is other than 1-bromo or R _{x /} R ₂ and R ₄ is other than hydrogen and R _{3 is} other than 9-bromo when alk is propylene, in each case with with the exception of N- (dibenzo [b, f] oxepin-10-ylmethyl-N-methyl-Nprop-2-ynylamine) hydrogen oxalate, preferably one in which a ethylidene lower alkylalkyl lower a2) alk is other than a methylene group when R is an amino group, a dialkylamino group-containing or a nitrogen atom bonded alkyleneamino, oxa, azaalkylenaminoskupinu, Ν'alkylazaalkylenaminoskupinu-lower alkyl, or N-N'hydroxyalkylazaalkylenaminoskupinu alkanoyloxyalkylazaalkylenaminoskupinu having 5-7 ring members, and R _*, R _2, R ₃ and R ₄ represent hydrogen, lower alkyl, lower alkoxy, bromine or chlorine, and b2) alk is other than ethylene, 1,2- and 1,3-propylene 1,2-, 1,3- and 1,4-butylene and 1,3- (2-methyl) propylene when R is a lower alkyl-dialkylamino group, a pyrrolidine group, a piperidine group, a lower alkyl-N-alkylpiperidinyl group a group:, piperazine, N ¹ -methylpiperazine, N'-formylpiperazino,, '- (2hydroxyethyl) piperazine, Ν' - (2-acetoxyethyl) piperazine or Ν '- [2- (2-hydroxyethoxy) ethyl ] piperazine, R ₁ and R ₃ are hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and R ₂ and R ₄ are hydrogen, and c2) alk is other than ethylene when R is methylamino, R _x and R ₃ are hydrogen, hydroxyl, lower alkyl or lower alkoxy and R ₂ and R ₄ are hydrogen.

• ·

Monovalent aliphatic radicals are, for example, a lower alkyl group, a lower alkenyl group or a lower alkynyl group which is unsubstituted or substituted with an optionally esterified or amidated carboxyl group, a cyano group, an optionally etherified or esterified hydroxyl group or an aliphatic substituted amino group such as a lower alkyl group, carboxyalkyl a lower alkyl group, an alkoxycarbonylalkyl group containing a lower alkoxy group and a lower alkyl group, a carbamoylalkyl group containing a lower alkyl group, a cyanoalkyl group containing a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group containing a lower alkoxy group and a lower alkyl group, alkanoyloxyalkyl a lower alkanoyl group and a lower alkyl group lower alkyl, dialkylaminoalkyl lower alkyl, lower alkylene lower alkylene, lower alkenyl, lower alkenyl hydroxyalkenyl, lower alkoxy lower alkenyl, alkanoyloxyalkenyl a lower alkanoyl and lower alkenyl group, a dialkylaminoalkenyl group containing lower alkyl and lower alkenyl groups, a lower alkynyl group, a hydroxyalkynyl group containing a lower alkynyl group, an alkoxyalkynyl group containing a lower alkoxy group and a lower alkynyl group, an alkanoyloxyalkynyl group containing a lower alkanoyl group; lower alkynyl or dialkylaminoalkynyl containing lower alkyl groups and lower alkynyl.

• · · · β ···· · ··· ··· ·· ··

Arylaliphatic radicals are, for example, a phenylalkyl group having a lower alkyl group which is unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group and / or a lower alkyl group optionally esterified by a carboxyl group.

Amino groups mono- or disubstituted by a monovalent aliphatic or arylaliphatic group are, for example, a lower alkylamino group; lower alkyl, phenylalkylamino, phenyl (carboxyalkyl) amino, phenyl (alkoxycarbonylalkyl) amino containing lower alkoxy and lower alkyl or phenylalkylalkylamino containing lower alkyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, and / or trifluoromethyl; a lower alkyl hydroxyalkylamino group, a lower alkyl carboxyalkylamino group, a lower alkoxycarbonylalkylamino group, a lower alkyl carbamoylalkylamino group, a lower alkyl cyanoalkylamino group, a lower alkoxyalkoxy alkoxyalkylamino group, and a lower alkyl alkoxyalkoxy group; and lower alkyl, lower-alkylaminoalkylamino, lower-alkyl-lower alkylaminoalkylamino, lower-alkylene-lower alkylene-aminoalkylamino, lower-alkenylamino, lower-alkenyl-hydroxyalkenylamino, lower-alkoxy-alkenylamino and lower-alkenyloxy a lower alkanoyl-containing alkanoyloxyalkenylamino group; and

Lower alkenyl, dialkylaminoalkenylamino containing lower alkyl and lower alkenyl, lower alkynylamino, hydroxyalkylamino containing lower alkynyl, alkoxyalkynylamino containing lower alkoxy and lower alkynyl, alkylaminoalkylamino lower-alkanoyl and loweralkynyl, lower-dialkylaminoalkylamino and lower-lower alkynyl, lower-dialkylamino, di-hydroxyalkyl) amino, lower-alkyl hydroxyalkylalkylamino, lower-alkoxy-di (alkoxyalkyl) amino and lower alkyl, alkoxyalkylalkylamino containing lower alkoxy and lower alkyl, alkanoyloxy lower alkanoyl and lower alkyl γ-alkylamino, lower alkanoyloxyalkylalkylamino and lower alkyl groups, lower alkylaminoalkylaminoalkyl lower alkyl groups, dialkylaminoalkyl lower alkyl groups, alkenyl groups, lower alkenylamino lower alkyl groups and lower alkenylalkylamino groups , lower alkenyl and lower alkyl hydroxyalkenylalkylamino, lower alkoxy and lower alkenyl di (alkoxy-alkenyl) amino, lower alkoxyalkenylalkylamino, lower alkenyl and lower alkyl, alkanoyloxyalkenylalkylamino and lower alkanoyl, lower alkyl, dialkylaminoalkenes lower alkyl and lower alkenyl-alkylamino, lower alkynyl and lower alkyl-alkylamino, this group, lower alkoxyalkylamino-lower-alkylamino; a lower alkynyl group and a lower alkyl group, an alkanoyloxyalkynylalkylamino group containing a lower alkanoyl group, a lower alkynyl group and a lower alkyl group, or a dialkylaminoalkynyl alkylamino group containing a lower alkyl group and a lower alkynyl group.

Divalent aliphatic radicals of alk are, for example, lower alkylidene groups, as an amino component disubstituted by a divalent aliphatic radical, lower alkylene, lower alkenylene or lower alkadienylene, which is either unsubstituted or substituted with an optionally esterified or amidated carboxyl or cyano group; an azaalkylene group containing a lower alkylene group or an oxa- or thiaalkylene group having a lower alkylene group which is either unsubstituted or substituted by a lower alkyl group, a lower alkanoyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group containing a lower alkoxy group and a lower alkyl group; a phenyl group which is unsubstituted or substituted by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group; as a 3- or 4-azaalkylene group containing a lower alkylene group which is either unsubstituted or Ν'-substituted by a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group containing a lower alkoxy group and a lower alkyl group, a phenyl group, a halophenyl group or lower alkoxyphenyl or lower alkanoyl; A lower alkylene group containing 3 or 4-oxaalkylene or optionally a lower alkylene group containing an oxidized 3- or 4-thiaalkylene group.

Amino groups disubstituted by divalent aliphatic radicals are, for example, a 3- to 8-membered lower alkylene amino, lower alkenylene amino or lower alkadienylene amino group which is either unsubstituted or substituted with an optionally esterified or amidated carboxyl group such as carboxyl, lower alkoxycarbonyl or carbamoyl; 3- or 4-azaalkylene amino having a lower alkylene group which is either unsubstituted or N ¹ -substituted by a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group containing a lower alkoxy group and a lower alkyl group, a phenyl group which is unsubstituted or substituted lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, or lower alkanoyl; 3- or 4-oxaalkyleneamino containing lower alkylene or optionally S-oxidized 3- or 4-thiaalkyleneamino containing lower alkylene, such as in particular pyrrolidine, pyrrolino (2,5-dihydropyrrol-1-yl), pyrrolo (pyrrol-1) -yl), piperidino, loweralkyl-lower alkylpiperidine, carboxypiperidine, lower alkoxycarbonylpiperidine, carbamoylpiperidine, cyanopiperidine, tetrahydropyridine, such as 1,2,5,6-tetrahydropyridine or 1,2,3,4 -tetrahydropyridine, dihydropyridine, such as 1,2-dihydropyridine, hexamethyleneimino, heptamethyleneimino, piperazine, piper'-phenyl-, N'-chlorophenyl- or N'-alkoxyphenylpiperazine containing lower alkoxy, N ¹ -alkylpiperazine containing a lower alkyl group, Ν'-

······ · · · · 00 ·· · 0 0 · · 0 0 0 ·

Hydroxyalkylpiperazine containing lower alkyl, N'-alkoxyalkylpiperazine containing lower alkoxy and lower alkyl, N'alkanoylpiperazine containing lower alkanoyl, morpholino, thiomorpholino, S- oxothiomorpholino or S, S-dioxothiomorpholino.

A divalent arylaliphatic radical is, for example, a phenylalkylene group containing a lower alkylene group, a phenyl (cyano) alkylene group having a lower alkylene group, a phenylalkylalkylene group having a lower alkyl group and a lower alkylene group, a Ν'-phenylazaalkylene group containing a lower alkylene group or Ν'-phenyl-alkylazaalkylene a lower alkyl group and a lower alkylene group which is either unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group with a group.

Amino groups substituted with a divalent arylaliphatic radical are, for example, a 3- to 8-membered phenylalkyleneamino group containing a lower alkylene group, an N'-phenylazaalkylene group containing a lower alkylene group or a Ν'-phenyl-alkylazaalkyleneamino group containing a lower alkyl group and a lower alkylene group which is on a phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group such as a phenylpiperidine group optionally substituted as indicated, such as a 4-phenylpiperidine group, a phenyl (cyano) piperidine group such as 4-cyano-4- a phenylpiperidine group, a phenylalkylpiperidine group having a lower alkyl group such as a benzylpiperidine group, a iper'-phenylpiperazine group or an N'-phenylalkylpiperazine group having a lower alkyl group such as a Ν'-benzylpiperazine group .

···· ·

Amino groups disubstituted by a divalent heteroarylaliphatic group are, for example, a N ¹ -heteroarylazaalkyleneamino group containing a lower alkylene group, wherein the heteroaryl group is a pyridyl group, a pyrimidinyl group or a triazinyl group bound, for example, by a carbon atom such as Ν'-pyridyl-, Ν'-pyrimidinyl- a triazinylpiperazine group.

Above and below, lower moieties and compounds are, for example, those containing up to and including 7 carbon atoms, preferably up to and including 4 carbon atoms (C atoms).

Di (hydroxyalkyl) amino containing lower alkyl is, for example, N, N-di (hydroxyalkyl) amino having 2 to 4 carbon atoms in the alkyl moiety, such as N, N-di (2-hydroxyethyl) amino or N, N-di (3-hydroxypropyl) amino.

A di (alkoxyalkenyl) amino group having a lower alkoxy group and a lower alkenyl group is, for example, N, Ndi (alkoxyalkenyl) amino having 1 to 4 carbon atoms in the alkoxy moiety and 2 to 4 carbon atoms in the alkenyl moiety such as N, N-di ( 4-methoxy-but-2-enyl) amino.

Di (alkoxyalkyl) amino having a lower alkoxy group and a lower alkyl group is, for example, N, N-di (alkoxyalkyl) amino having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety such as N, Ndi (2 -methoxyethyl) amino, N, N-di (2-ethoxyethyl) amino or N, N-di (3-methoxypropyl) amino.

Lower alkenyl-containing dialkenylamino is, for example, Ν, Ν-dialkenylamino having 2 to 4 carbon atoms in the alkenyl moieties, such as N, N-diallylamino or N-methallyl-N-allylamino.

·· ·· ♦ ·

A lower alkyl dialkylamino group is, for example, a Ν, Ν-dialkylamino group having 1 to 4 carbon atoms in the alkyl moiety, such as dimethylamino, diethylamino, ethylmethylamino, dipropylamino, methylpropylamino, ethylpropylamino, dibutylamino or butylmethylamino.

Dialkylaminoalkenylalkylamino having lower alkyl groups and lower alkenyl groups is, for example, N (dialkylaminoalkenyl) -N-alkylamino having 1 to 4 carbon atoms in each alkyl moiety and 2 to 4 carbon atoms in the alkenyl moiety such as N- (4-dimethylaminobut-2). (phenyl) -N-methylamino.

Dialkylaminoalkenylamino having lower alkyl groups and lower alkenyl is, for example, N (dialkylaminoalkenyl) amino having 1 to 4 carbon atoms in the alkyl moieties and 2 to 4 carbon atoms in the alkenyl moiety such as N- (4-dimethylaminobut-2-enyl) amino .

For example, a dialkylaminoalkylamino group having a lower alkyl group and a lower alkynyl group is an N (dialkylaminoalkynyl) amino group having from 1 to 4 carbon atoms in the alkyl moieties and a C2-4 alkynyl moiety such as N- (4-dimethylaminobut-2-ynyl) amino .

Dialkylaminoalkylalkylamino having lower alkyl groups is, for example, N- (dialkylaminoalkyl) -N-alkylamino having 1 to 4 carbon atoms in the first alkyl moiety, 2 to 4 carbon atoms in the second alkyl moiety and 1 to 4 carbon atoms in the third alkyl moiety such as N - (2-dimethylaminoethyl) -N-methylamino, N- (2-dimethylaminoethyl) -N-ethylamino, N- (3-dimethylaminopropyl) -N-methylamino or N (4-dimethylaminobutyl) -N-methylamino.

• 9 99 9 9 ···· · ..........

A lower alkyl-dialkylaminoalkylamino group is, for example, N- (dialkylaminoalkyl) amino having 1 to 4 carbon atoms in the first alkyl moiety and 2 to 4 carbon atoms in the second alkyl moiety, such as N- (2-dimethylaminoethyl) amino, N- (2-dimethylaminoethyl) amino, N- (3-dimethylaminopropyl) amino or N- (4-dimethylaminobutyl) amino.

For example, a halogen atom is a halogen atom with an atomic number up to and including 35, such as a chlorine atom or a bromine atom.

Hydroxyalkenylalkylamino having a lower alkenyl group and a lower alkyl group is, for example, N (hydroxyalkenyl) -N-alkylamino having 2 to 4 carbon atoms in the 1-phenyl portion and 1 to 4 carbon atoms in the alkyl portion, such as N- (4-hydroxybut-2-enyl) -N-methylamino.

A lower alkenyl-hydroxyalkenylamino group is, for example, a hydroxyalkenylamino group having 2 to 4 carbon atoms in the alkenyl moiety, such as 4-hydroxybut-2-enylamino.

A hydroxyalkynylamino group containing a lower alkynyl group is, for example, a hydroxyalkynylamino group having 2 to 4 carbon atoms in the alkynyl moiety, such as a 4-hydroxybut-2-ylamino group.

A hydroxyalkylalkylamino group of a lower alkyl group is, for example, N- (hydroxyalkyl) -N-alkylamino having 2 to 4 carbon atoms in the first alkyl moiety and 1 to 4 carbon atoms in the second alkyl moiety, such as N- (2-hydroxyethyl) -Nmethylamino, N- (3-hydroxypropyl) -N-methylamino or N- (4-hydroxybutyl) -N-methylamino.

A lower alkyl hydroxyalkylamino group is, for example, a hydroxyalkylamino group containing an alkyl moiety

4 4 4

4444 • 4 * • · 4 44

4 4 • 44

4444 to 4 carbon atoms, such as 2-hydroxyethylamino, 3-hydroxypropylamino or 4-hydroxybutylamino.

A lower alkyl β-hydroxyalkylpiperazino group is, for example, an N ¹ - (hydroxyalkyl) piperazino group having 1 to 4 carbon atoms in the alkyl moiety, such as N '(2-hydroxyethyl) piperazino or β' - (3-hydroxypropyl) piperazino.

N'-alkanoylpiperazino containing lower alkanoyl is, for example, N ¹ -alkanoylpiperazino having 1 to 7 carbon atoms in the alkanoyl moiety, such as Ν'-acetylpiperazino.

A Ν'-alkoxyalkylpiperazino group having a lower alkoxy group and a lower alkyl group is, for example, a Ν '- (alkoxyalkyl) piperazino group having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety such as Ν' - (2-methoxyethyl) piperazino or Ν '- (3-methoxypropyl) piperazino.

N'-alkylpiperazino containing lower alkyl is, for example, N'-alkylpiperazino having 1 to 4 carbon atoms in the alkyl moiety, such as N'-methylpiperazino, N'-ethylpiperazino, N'-propylpiperazino or N'-butylpiperazino.

Alkanoyloxyalkenylalkylamino having lower alkanoyl, lower alkenyl and lower alkyl is, for example, N- (alkanoyloxyalkenyl) -N- (alkyl) amino having 1 to 7 carbon atoms in the alkanoyl moiety, 2 to 4 carbon atoms in the alkenyl moiety and 1 to 7 alkyl moieties. 4 carbon atoms such as N- (4-acetoxybut-2-enyl) -N-methylamino.

Alkanoyloxyalkenylamino having a lower alkanoyl group and a lower alkenyl group is, for example, N- (alkanoyl) -4- (oxyanenyl) oxyalkenyl. ) an amino group containing 1 to 7 carbon atoms in the alkanoyl moiety and 2 to 4 carbon atoms in the alkenyl moiety, such as

N- (4-acetoxybut-2-enyl) amino.

Alkanoyloxyalkynylalkylamino having a lower alkanoyl group, a lower alkynyl group and a lower alkyl group is, for example, N- (alkanoyloxyalkynyl) -N- (alkyl) amino having 1 to 7 carbon atoms in the alkanoyl moiety, 2 to 4 carbon atoms in the alkynyl moiety and 1 alkyl moiety. up to 4 carbon atoms such as N- (4-acetoxybut-2-ynyl) -N-methylamino.

Alkanoyloxyalkynylamino having a lower alkanoyl group and a lower alkynyl group is, for example, N (alkanoyloxyalkynyl) amino having 1 to 7 carbon atoms in the alkanoyl moiety and 2 to 4 carbon atoms in the alkynyl moiety, such as N- (4-acetoxybut-2-ynyl) amino.

Alkanoyloxyalkylalkylamino having lower alkanoyl and lower alkyl groups is, for example, N (alkanoyloxyalkyl) -N- (alkyl) amino having 1 to 7 carbon atoms in the alkanoyl moiety, 2 to 4 carbon atoms in the first alkyl moiety and 1 to 4 carbon atoms in the alkyl moiety. such as N- (2-acetoxyethyl) -N-methylamino, N- (2-acetoxyethyl) Nethylamino, N- (3-acetoxypropyl) -N-methylamino or N- (4-acetoxybutyl) -N-methylamino.

Alkanoyloxyalkylamino having a lower alkanoyl group and a lower alkyl group is, for example, N- (alkanoyloxyalkyl) amino having 1 to 7 carbon atoms in the alkanoyl moiety and 2 to 4 carbon atoms in the alkyl moiety, such as N- (2acetoxyethyl) amino, N- (3- acetoxypropyl) amino or N- (4-acetoxybutyl) amino.

Alkenylalkylamino having a lower alkenyl group and a lower alkyl group is, for example, N- (alkenyl) -N- (alkyl).

an amino group containing 2 to 7 carbon atoms in the alkenyl moiety and 1 to 4 carbon atoms in the alkyl moiety, in particular N- (alkenyl) -N (alkyl) amino having 2 to 4 carbon atoms in the alkenyl moiety and 1 to 4 carbon atoms in the alkyl moiety such as Nvinyl-N-methylamino-N-allyl-N-methylamino, N-allyl-Nethylamino, N-but-2-enyl-N-methylamino or Nbut-3-enyl-N-methylamino.

Alkenylamino having a lower alkenyl group is, for example, N- (alkenyl) amino having 2 to 7 carbon atoms in the alkenyl moiety, especially N- (alkenyl) amino having 2 to 4 carbon atoms in the alkenyl moiety such as vinylamino, allylamino, but-2- enylamino or N-but-3-enylamino, especially allylamino.

Alkynylalkylamino having a lower alkynyl group and a lower alkyl group is, for example, N- (alkynyl) -N- (alkyl) amino having 2 to 4 carbon atoms in the alkynyl moiety and 1 to 4 carbon atoms in the alkyl moiety such as N-propargyl-Nmethylamino, N-but-2-ynyl-N-methylamino or N-but-3-ynyl-N-methylamino.

Lower alkynylamino is, for example, N- (alkynyl) amino having 2 to 7 carbon atoms, especially N- (alkynyl) amino having 2 to 4 carbon atoms, such as propargylamino, but-2-ynylamino or N-but-3-ylamino, especially propargylamino.

Lower alkoxy is, for example, C 1 -C 7 alkoxy, preferably C 1 -C 4 alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but may also be isobutyloxy, butoxy, secondary butyloxy, butyloxy, butoxy, up to 7 carbon atoms such as pentyloxy, hexyloxy or heptyloxy.

• ·

Alkoxyalkenylalkylamino having a lower alkoxy group, a lower alkenyl group and a lower alkyl group is, for example, N- (alkoxyalkenyl) NN- (alkyl) amino having 1 to 4 carbon atoms in the alkoxy moiety, 2 to 4 carbon atoms in the alkenyl moiety and 1 to 4 alkyl moieties. 4 carbon atoms such as N- (4-methoxybut-2-enyl) -N- (methylamino, N- (4-methoxybut-2-enyl) -N-ethylamino or N- (4-ethoxybut-2enyl) -N-methylamino .

Alkoxyalkenylamino having a lower alkoxy group and a lower alkenyl group is, for example, N (alkoxyalkenyl) amino having up to 4 carbon atoms in the alkoxy moiety and 2-4 carbon atoms in the alkenyl moiety, such as N- (4-methoxybut-2-enyl) amino or N - (4-ethoxybut-2enyl) amino.

Alkoxyalkynylalkylamino having a lower alkoxy group, a lower alkynyl group and a lower alkyl group is, for example, N- (alkoxyalkynyl) -N- (alkyl) amino having 1 to 4 carbon atoms in the alkoxy moiety, 2 to 4 carbon atoms in the alkynyl moiety and 1 in the alkyl moiety up to 4 carbon atoms such as N- (4-methoxybut-2-ynyl) -N-methylamino, N- (4-methoxybut-2-ynyl) -N-ethylamino or N- (4-methoxybut-2-ynyl) -N -methylamino.

Alkoxyalkylamino comprising lower alkoxy and lower alkynyl is, for example, N- (alkoxyalkynyl) amino having 1 to 4 carbon atoms in the alkoxy moiety and 2 to 4 carbon atoms in the alkynyl moiety such as N- (4-methoxybut-2-ynyl) amino , N- (4-ethoxybut-2-ynyl) amino or N- (4-propyloxybut-2-ynyl) amino.

Alkoxyalkylamino having a lower alkoxy group and a lower alkyl group is, for example, alkoxyalkylamino having 1 to 4 carbon atoms in the alkoxy moiety and 2 to 4 carbon atoms in the alkyl moiety, such as 2-methoxyethylamino,

2-ethoxyethylamino, 2-propyloxyethylamino, 3methoxypropylamino, 3-ethoxypropylamino, 4methoxybutylamino, 2-isopropyloxyethylamino or 2-butyloxyethylamino.

Alkoxyalkylalkylamino having a lower alkoxy group and lower alkyl groups is, for example, N- (alkoxyalkyl) N (alkyl) amino having 1 to 4 carbon atoms in the alkoxy moiety, 2 to 4 carbon atoms in the first alkyl moiety and 1 to 4 carbon atoms in the second alkyl moiety. such as N- (2-methoxyethyl) -N-methylamino, N- (2-ethoxyethyl) -N-methylamino, N- (2-propyloxyethyl) -N-methylamino, N- (3-methoxypropyl) -N-methylamino, N- (3- ethoxypropyl) -N-methylamino or N- (4-methoxybutyl) -N-methylamino.

Lower alkyl is, for example, C 1 -C 7 alkyl, preferably C 1 -C 4 alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, but can also be isobutyl, a secondary butyl group, a tertiary butyl group or an alkyl group containing 5 to 7 carbon atoms, such as a pentyl group, a hexyl group or a heptyl group.

Lower alkylamino is, for example, C 1 -C 7 alkylamino, preferably C 1 -C 4 alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino or butylamino, but may also be isobutyl amino, butylamino, butylamino, secondary butylamino, C 5 to 7 carbon atoms such as pentylamino, hexylamino or heptylamino, and in particular methylamino or propylamino.

• ·

4 · · 4 · 44 • 4 4 4 444444 4

..... ...... **

Alkylaminoalkylamino having lower alkyl groups is, for example, N- (alkylaminoalkyl) amino having 1 to 4 carbon atoms in the first alkyl moiety and 2 to 4 carbon atoms in the second alkyl moiety, such as N- (2-methylaminoethyl) amino, N- (1- methylaminoethyl) amino, N- (3-methylaminopropyl) amino, N- (4-methylaminobutyl) amino, N- (2-ethylaminoethyl) amino, N- (1-ethylaminoethyl) amino, N- (3-ethylaminopropyl) amino or N - (4-ethylaminobutyl) amino.

Alkyleneaminoalkylamino having a lower alkylene group and a lower alkyl group is, for example, a 3- to 8-membered alkylenaminoalkylamino group having 2 to 4 carbon atoms in the alkyl moiety, such as 2-pyrrolidinethylamino, 2-piperidinethylamino, 2-dimethylpiperidinethylamino, 3-hexamethylenimino, 3-hexamethylenimino piperidinopropylamino, 3-dimethylpiperidinopropylamino or 3-hexamethyleneiminopropylamino.

A lower alkylidene group is, for example, an alkylidene group having 1 to 4 carbon atoms, such as a methylene group or an ethylidene group.

Phenyl (carboxyalkyl) amino containing lower alkyl is, for example, 1-carboxy-o-phenylalkylamino having 2 to 4 carbon atoms in the alkyl moiety, such as 1-carboxy-2-phenylethyl or 1-carboxy-3-phenylpropyl.

Phenyl (alkoxycarbonylalkyl) amino having a lower alkoxy group and a lower alkyl group is, for example, 1alkoxycarbonyl-co-phenylalkylamino having 1 to 4 carbon atoms in the alkoxy moiety and 2 to 4 carbon atoms in the alkyl moiety such as 1-methoxycarbonyl-2-phenylethyl, 1-ethoxycarbonyl-2-phenylethyl, 1-methoxycarbonyl-3-phenylpropyl or 1-ethoxycarbonyl-3-phenylpropyl.

Phenylalkylalkylamino having lower alkyl groups is, for example, N- (phenylalkyl) -N- (alkyl) amino having 1 to 4 carbon atoms in the first alkyl moiety and 1 to 4 carbon atoms in the second alkyl moiety, such as N-benzyl-Nmethylamino, N- (2-phenylethyl) -N-methylamino;

N- (4-phenylbutyl) -N-methylamino.

Phenylalkylamino having a lower alkyl group is, for example, phenylalkylamino having 1 to 4 carbon atoms in the alkyl moiety, such as benzylamino, 1- or 2-phenylethylamino, 3-phenylpropylamino or 4-phenylbutylamino.

Phenylalkylalkylene amino having a lower alkyl group and a lower alkylene group is, for example, a phenylalkylpyrrolidino group having 1 to 4 carbon atoms in the alkyl moiety which is either unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl such as 2- or 3-benzylpyrrolidino; phenylalkylpiperidino having 1 to 4 carbon atoms in the alkyl moiety such as 2-, 3- or 4-benzylpiperidino, further phenylalkylhexahydroazepino having 1 to 4 carbon atoms in the alkyl moiety such as 2-, 3- or 4-benzylhexahydroazepino, phenylalkylaziridino moieties 1-4 carbon atoms such as 2-benzylaziridino or phenylalkylazetidino having 1 to 4 carbon atoms in the alkyl portion such as 2- or 3-benzylazetidino.

An N-phenylalkylazaalkyleneamino group containing a lower alkyl group and a lower alkylene group is, for example, an N'-phenylalkylimidazolidino group containing in the alkyl moiety 1

Up to 4 carbon atoms which are either unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, such as Ν'-benzylimidazolidino, phenylalkylpiperazino having 1 to 4 carbon atoms in the alkyl moiety such as N'benzylpiperazino, or phenylalkylhexahydro-1,3-diazepino having 1 to 4 carbon atoms in the alkyl moiety such as N ¹ -benzylhexyl 1,3-diazepino, phenylalkyl-1,3-diazetidino having up to 4 carbon atoms in the alkyl moiety such as Ν'-benzyl-1,3-diazetidino, or phenylalkylpyridazino having 1 to 4 carbon atoms in the alkyl moiety such as Ν ' -benzylpyridazino.

The acid addition salts of the compounds of formula I with organic carboxylic acids are, for example, pharmaceutically usable acid addition salts with pharmaceutically usable or optionally hydroxylated lower alkanoic acids, for example acetic acid, propionic acid, pivalic acid, glycolic acid, pyroacemic acid, lactic acid or gluconic acid, with optionally hydroxylated, aminated and / or oxosubstituted alkanedicarboxylic acids, for example, oxalic acid, malonic acid, succinic acid, glutamic acid, aspartic acid, tartaric acid or malic acid, optionally hydroxylated and / or oxosubstituted alkanetricarboxylic acids containing e.g. citric acid or aconitic acid, optionally hydroxylated and / or oxosubstituted lower alkene dicarboxylic acids, e.g. for example fumaric acid, maleic acid or itaconic acid, optionally hydroxylated and / or oxosubstituted lower alkindicarboxylic acids, for example acetylenedicarboxylic acid, further with aromatic, heteroaromatic or arylaliphatic acids.

acid carboxylic acids such as benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid.

The portions of the compounds of formula I which have been proposed for use in the present invention are already known. GB Patent No. 1,080,979 suggested compounds of formula I wherein alk is methylene or ethylidene and R is amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, Ν '-methylpiperazino, Ν' - (2-hydroxyethyl) piperazino, Ν '- (2-acetoxyethyl) piperazino, Ν' - (2-pivolyloxyethyl) piperazino or Ν'-methylhompiperazino, and R _1Z R ₂ , R ₃ and R ₄ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group and / or a halogen atom, as adrenolytic and centrally depressants, such as sedatives and narcotically active drug ingredients.

The present invention is based on the surprising finding that compounds of formula I when administered to recently born rats in the experimental procedure of Ansari et al., J. Neuroscience 13, 4042-4053 (1993) at doses of approximately

0.1 mg / kg s.c. and less, have a marked protective effect on facial motor neurons from apoptotic cytolysis, and when administered to fully developed rats in the experimental procedure of Golowitz and Paterson, Soc. Neurose. Abstr. 20, 246, 113.2 (1994) at 0.275 mg / kg s.c. and lower doses of 4 days, have a marked protective effect on hypocampal pyramid cells from cytolysis by administration of kainic acid ([2S- (2α, 3β, 4β)] - 2-carboxy-4- (1-methylethenyl) -3-pyrrolidinacetic acid).

Similarly, compounds of Formula I protect mesencephalic, dopaminergic neurons in culture at about 10 to 8 molar concentrations from MPP + -induced apoptotic cytolysis.

Further, when administered to mice at 0.14 mg / kg p.o. at a lower dose of 20 days, they exhibit a marked protective effect on thyrosine hydroxylase nigral neurons prior to cytolysis by administration of MPTP.

Thus, the compounds of formula I and their pharmaceutically usable salts, in addition to their already known adrenolytic and centrally attenuating utility, are particularly useful for the prophylaxis and treatment of neurodegenerative disorders, particularly those in which apoptotic cytolysis, such as cerebral ischemia, Alzheimer's disease, Huntington and Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, various types of glaucoma, retinal degeneration, especially retinide pigmentosis, as well as general or diabetic peripheral neuropathy.

In particular, the invention relates to the use of acid addition salts of compounds of formula I wherein alk is lower alkylidene,

R is amino, lower alkylamino; lower alkyl-phenylalkylamino, phenyl-carboxyalkyl-amino, lower-alkoxycarbonylalkyl-amino-lower-alkyl or lower-alkyl-phenylalkylalkylamino, which is either unsubstituted or substituted by lower-alkyl, lower-alkoxy, halogen and / or trifluoromethyl; a lower alkyl hydroxyalkylamino group, a lower alkyl carboxyalkylamino group, a lower alkoxycarbonyl23 lower alkyl group, a lower alkyl carbamoylalkylamino group, a lower alkyl cyanoalkylamino group, a lower alkoxyalkoxy alkoxy group, and a lower alkyloxyalkoxy group; and lower alkyl, lower-alkylamino-alkylamino, lower-alkyl-alkylaminoalkylamino, lower-alkylene-lower alkylene-amino-alkylamino, lower-alkenyl-lower alkenylamino, lower-alkenyl-lower-alkoxyalkenylamino-lower-alkoxy lower alkanoyl and lower alkenyl, dialkylaminoalkenylamino of lower alkyl and lower alkenyl, lower alkynylamino, hydroxyalkylamino of lower alkynyl, alkoxyalkylamino of lower alkoxy and lower alkynyl, lower alkanoyl and lower alkynyl, dialkylaminoalkylamino comprising lower alkyl and lower alkynyl, dialkylamino containing lower alkyl, di (hydroxyalkyl) amino containing lower alkyl, hydroxyalkylalkylamino containing lower alkyl, di (alkoxyalkyl) amino containing lower alkoxy and lower alkyl, alkoxyalkylalkylamino containing lower alkoxy and lower alkyl groups, alkanoyloxyalkylamino group containing lower alkanoyl group and lower alkyl group, alkanoyloxyalkylalkylamino group containing lower alkanoyl group and lower alkyl groups, dialkylamino containing alkylamino group containing alkylamino group lower alkyl groups, dialkylaminoalkylalkylamino group containing lower alkyl groups, dialkenylamino group containing lower alkenyl groups, alkenylalkylamino group containing lower alkenyl group and lower alkyl group, hydroxyalkenylalkylamino group containing lower alkenyl group and lower alkyl group, di (alkoxyalkenyl) amino group containing lower alkoxy group and lower alkenyl group and lower alkoxy group alkoxyalkenylalkylamino containing lower alkoxy, lower alkenyl and lower alkyl, alkanoylox lower alkanoyl, lower alkenyl and lower alkyl yalkenylalkylamino, lower alkyl and lower alkenyl dialkylaminoalkenylalkylamino, lower alkynyl and lower alkyl alkynylalkylamino, lower alkoxyalkyloxy and lower alkyloxyalkylamino, lower alkanoyl, lower alkynyl and lower alkyl, dialkylamino-alkynylalkylamino comprising lower alkyl groups, lower alkynyl; 3- to 8-membered lower alkyleneamino, lower alkenyleneamino or lower alkadienyleneamino, which is either unsubstituted or substituted by carboxyl, lower alkoxycarbonyl or carbamoyl or cyano; a cyano (phenyl) alkylene amino group having a lower alkylene group which is either unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group; A 3- or 4-azaalkylene amino group having a lower alkylene group which is either unsubstituted or N-substituted by a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group containing a lower alkyl group

0 «0000 • 0 0 ·· ·· 0 0 ··

0 0 0 · 0 00

An alkoxy group and a lower alkyl group, a pyridinyl group, a pyrimidinyl group, a triazinyl group or a lower alkanoyl group; A 3- or 4-oxaalkyleneamino group containing a lower alkylene group, optionally an S-oxidized 3- or 4-thiaalkyleneamino group containing a lower alkylene group; or a Ν'-phenylazaalkyleneamino group containing a lower alkylene group or a Ν'-benzylazaalkyleneamino group having a lower alkylene group which is either unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group, and

R _HR R _2, R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with a pharmaceutically acceptable, optionally hydroxylated lower alkanoic acid, for example acetic acid, propionic acid, acid pyroacemic, pivalic, glycolic, lactic or gluconic acid, with optionally hydroxylated, aminated and / or oxosubstituted alkanedicarboxylic acids, for example malonic acid, aspartic acid, malic acid, optionally with oxalic acid, succinic acid, glutamic acid, tartaric acid or hydroxylic acid and / or oxosubstituted alkanetricarboxylic acids containing a lower alkane moiety, for example citric acid or aconitic acid, optionally hydroxylated and / or oxosubstituted lower alkene dicarboxylic acids, e.g. ad fumaric acid, maleic acid or itaconic acid, optionally hydroxylated and / or oxosubstituted lower alkindicarboxylic acids, for example acetylenedicarboxylic acid, further with aromatic, heteroaromatic or • 0 000 · • 0 0 0 • 0 0 0 0 0

0 0

Arylaliphatic carboxylic acids such as benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid, as antineurodegeneratively active pharmaceutical ingredients, or for the preparation thereof, as well as acid addition salts of the novel compounds of formula I, as such as defined above, preferably those wherein alk is methylene or ethylidene and R is other than amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino, pyrrolidino; , morpholino, N'-methylpiperazino, N '- (2-hydroxyethyl) piperazino, N' - (2-acetoxyethyl) piperazino, N ^1- (2-pivaloyloxyethyl) piperazino and Ν'-methylhomopiperazino, provided that R _x and R ₃ hydrogen, lower alkyl, lower alkoxy or halogen and R ₂ and R ₄ are hydrogen, with the above-mentioned acids, as well as their preparation process.

More particularly, the present invention relates to the use of acid addition salts of compounds of formula I wherein alk is methylene or ethylidene,

R is amino, lower alkylamino; lower alkyl-phenylalkylamino, phenyl-carboxyalkyl-amino, lower-alkyl (alkoxycarbonylalkyl) -amino or lower-alkyl-phenylalkylalkylamino which is either unsubstituted or substituted by lower-alkyl, lower-alkoxy,

a halogen atom and / or a trifluoromethyl group; lower alkyl hydroxyalkylamino, lower alkoxyalkylamino and lower alkyl alkoxy, lower alkanoyloxyalkylamino and lower alkyl, lower alkyl alkylaminoalkylamino, lower alkyl dialkylaminoalkylamino, lower alkylene alkylamino and lower alkylamino; lower alkenylamino, hydroxyalkenylamino having a lower alkenyl group, alkoxyalkenylamino having a lower alkoxy group and a lower alkenyl group, alkanoyloxyalkenylamino group having a lower alkanoyl group and a lower alkenyl group, dialkylaminoalkenylamino group having a lower alkyl group and a lower alkenyl group, lower alkynylamino group, a lower alkynylamino group vinyl, lower alkoxyalkylamino and lower alkynyl, lower alkanoyloxyalkylamino and lower alkynyl, loweralkylaminoalkylaminoalkylamino, loweralkylalkylaminoalkylamino, loweralkylalkylaminoalkylaminoalkylamino lower alkyl groups, di (alkoxyalkyl) amino groups containing lower alkoxy and lower alkyl groups, lower alkoxyalkylalkylamino groups containing lower alkoxy and lower alkyl groups, lower alkanoyloxyalkylamino groups and lower alkyl groups, lower alkanoyloxyalkylalkylamino groups and lower alkyl aminoalkyl groups, containing lower alkyl a lower alkyl group, a dialkylaminoalkylalkylamino group;

9 ·

• ·

998 9 * · · «· *

9 99 9 9 9 9 · 9 · 99

9 9 999 9

9 9 9 ·

999 999 99 99 lower alkenyl-lower-dialkenylamino, lower alkenyl-lower-alkenylalkylamino, lower-alkenyl-lower-alkenyl-hydroxyalkylamino, lower-alkoxy-lower-alkenyl-amino, lower-alkenyl-lower-alkoxy, lower-alkenyl-lower-alkoxy lower alkenyl and lower alkyl, alkanoyloxyalkenylalkylamino containing lower alkanoyl, lower alkenyl and lower alkyl, dialkylaminoalkenylalkylamino of lower alkyl and lower alkenyl, alkynylalkylamino of lower alkynyl and lower alkyl, alkoxyalkynylalkylamino lower alkynyl and lower alkyl, alka noyloxyalkynylalkylamino having a lower alkanoyl group, a lower alkynyl group and a lower alkyl group, a dialkylaminoalkynylalkylamino group having a lower alkyl group and a lower alkynyl group, a 3- to 8-membered lower alkylene amino group; A 3- or 4-azaalkyleneamino group having a lower alkylene group which is either unsubstituted or N-substituted by a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group having a lower alkoxy group and a lower alkyl group or a lower alkanoyl group; 3 or a 4-oxaalkyleneamino group containing a lower alkylene group or optionally an S-oxidized 3- or 4-thiaalkyleneamino group containing a lower alkylene group, and

R _{1 Z} R _2, R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with a pharmaceutically acceptable, optionally hydroxylated lower alkanoic acid, for example acetic acid, • · · · 4 4 4 4 4 4 0 4 4 4 4 4 glycolic, propionic acid , lactic acid or pivalic acid, with optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acids, for example oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, pyroacemic acid or malic acid, further aromatic, heteroaromatic or arylaliphatic carboxylic acids such as benzoic acid, nicotinic acid or mandelic acid such as antineurodegeneratively of the active ingredients of the medicaments, or for their preparation, as well as the acid addition salts of the novel compounds of formula I as defined above, preferably those wherein R is other than amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino , dimethylamino, diethylamino, dipropylamino, pyrrolidino, piperidino, hexahydroazepino, morpholino, N'-methylpiperazino, Ν '- (2hydroxyethyl) piperazino, Ν' - (2-acetoxyethyl) piperazioethyl) piperazino methylhomopiperazino when R @ ₁ and R @ ₃ are hydrogen, lower alkyl, lower alkoxy or halogen and R @ ₂ and R @ ₄ are hydrogen, with the above acids, as well as a process for their preparation.

In particular, the present invention relates to the use of acid addition salts of compounds of formula I wherein alk is lower alkylidene,

R is amino, lower alkylamino, cyanoalkylamino containing lower alkyl; and lower alkyl-phenylalkylamino, phenyl 44 4444 4 4 · 4

4 44 · / 4444 · · 44 ·· · 4 4 4 ······ 4 4 4 4 4

(Carboxyalkyl) lower alkyl group, phenyl (alkoxycarbonylalkyl) lower alkoxy group and lower alkyl group or lower alkyl phenylalkylalkylamino group which is either unsubstituted or substituted with lower alkyl, lower alkoxy, halogen and / or trifluoromethyl; lower alkynylamino, dialkylamino containing lower alkyl groups, 3- to 8-membered lower alkylene amino or cyano (phenyl) alkylene amino containing lower alkylene, 3- to 8-membered lower alkenylene amino; A 3- or 4-azaalkylene amino group having a lower alkenylene group which is either unsubstituted or N-substituted by a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group containing a lower alkoxy group and a lower alkyl group or a lower alkanoyl group; A 3- or 4-oxaalkyleneamino group containing a lower alkylene group, optionally an S-oxidized 3- or 4thiaalkyleneamino group containing a lower alkylene group, or a 3- to 8-membered N'-pyrimidinylazaalkyleneamino group containing a lower alkylene group; lower alkylene-containing phenylalkylene, lower alkylene-phenyl (cyano) alkylene, lower alkylene-za'-phenylazaalkyleneamino or lower alkylene-N'-benzylazaalkyleneamino which is either unsubstituted or substituted on the phenyl group by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, and

R _x, R _2, R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, • · "" · · · malonic acid, aspartic acid, glutamic acid, tartaric acid or with pharmaceutically usable and optionally hydroxylated lower alkanoic acids, for example acetic acid, propionic acid, pivalic acid, glycolic acid, pyroacemic acid, lactic acid or gluconic acid, optionally hydroxylated, aminated and / or oxosubstituted lower alkanedicarboxylic acids, for example oxalic acid, acid succinic, malic acid, optionally hydroxylated and / or oxosubstituted lower alkanetricarboxylic acids, for example citric acid or aconitic acid, optionally hydroxylated and / or oxosubstituted lower alkene dicarboxylic acids, for example fumaric acid, maleic acid or itaconic acid, optionally hydroxylated and / or oxosubstituted lower alkindicarboxylic acids, for example acetylenedicarboxylic acid, further, aromatic, heteroaromatic or arylaliphatic carboxylic acids, such as benzoic acid, salicylic acid, phthalic acid, phenylacetic acid , cinnamic acid or nicotinic acid, as antineurodegenerative active ingredients of the medicaments, or substances for their preparation, as well as acid addition salts of the novel compounds of formula I as defined above, preferably those wherein alk is methylene or ethylidene and R is other than amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino, dipropylamino, py pyrrolidino, piperidino, hexahydroazepino, morpholino, Ν'-methylpiperazino, Ν '- (2-hydroxyethyl) piperazino, Ν' - (232 «4 4 4) 4 '(acetoxyethyl) piperazino, Ν' - (2-pivaloyloxyethyl) piperazino and N ¹ -methylhomopiperazino when R ₃ and R ₃ are hydrogen, lower alkyl, lower alkoxy or halogen and R ₂ and R ₄ are a hydrogen atom with the above-mentioned acids, as well as a process for their preparation.

In particular, the invention relates to the use of acid addition salts of compounds of formula I wherein alk is a methylene group,

R is C 1 -C 4 alkylamino, such as methylamino, ethylamino, propylamino or butylamino, C 1 -C 4 cyanoalkylamino, such as cyanomethylamino; phenylalkylamino having 1 to 4 carbon atoms in the alkyl moiety, phenylalkylalkylamino having 1 to 4 carbon atoms in each alkyl moiety, phenyl- (1-carboxyalkyl) amino having 1 to 4 carbon atoms in the alkyl moiety or phenyl- (1-alkoxycarbonylalkylamino) moiety each alkyl moiety of from 1 to 4 carbon atoms and in the alkoxy moiety of from 1 to 4 carbon atoms which is either unsubstituted or substituted by a C1-C4 alkyl group such as a methyl group, a C1-C4 alkoxy group such as a methoxy group a halogen atom of up to and including 35, such as chlorine or bromine, and / or trifluoromethyl, such as benzylamino, phenethylamino, N-benzyl-N-methylamino, 2-phenyl-1-carboxyethylamino, 2-phenyl-1- ethoxycarbonylethylamino or N-benzyl-N-methylamino, alkenylamino containing 2 to 2 7 carbon atoms such as allylamino, methallylamino or but-2-enylamino33

C 2 -C 7 alkynylamino, such as propargylamino or but-2-ylamino, N-alkenyl-N-alkylamino containing in the alkenyl moiety 2; up to 7 carbon atoms and in the alkyl portion 1 to 4 carbon atoms such as N-allyl-N-methylamino, N-allyl-N-ethylamino, Nmethallyl-N-methylamino or N-but-2-enyl-N-methylamino, N -alkynyl-N-alkylamino having 2 to 7 carbon atoms in the alkynyl moiety and 1 to 4 carbon atoms in the alkyl moiety, such as N-propargyl-N-methylamino, N-propargyl-N-ethylamino or N-but-2-ynyl-N -methylamino, dialkylamino having 1 to 4 carbon atoms in each alkyl moiety, such as dimethylamino, diethylamino, N-methyl-N-propylamino or N-butyl-N-methylamino, pyrrolidino, piperidino, 1,2,3,6-tetrahydropyridino; 4-cyano-4-phenylpiperidino which is either unsubstituted or substituted by C1-C4alkyl, such as methyl, C1-C4alkoxy, such as methoxy, with a halogen atom of up to and including 35, such as is chlorine or bromine and / or trifluoromethyl; such as 4-cyano-4-phenylpiperidino, morpholino, piperazino, Ν'-alkylpiperazino having 1 to 4 carbon atoms in the alkyl moiety, such as Ν'-methylpiperazino, Ν '- (hydroxyalkyl) piperazino having 2 to 4 carbon atoms in the alkyl moiety, such as Ν '- (2-hydroxyethyl) piperazino, Ν'-pyrimidinylpiperazino; or Ν'-phenylpiperazino or Ν'-phenylalkylpiperazino having 1 to 4 carbon atoms in the alkyl moiety, which is either unsubstituted or substituted by a alkyl group having 1 to 4 carbon atoms such as a methyl group, an alkoxy group having 1 to 4 carbon atoms such as a halogen atom having an atomic number up to and including 35, such as a chlorine atom or a bromine atom and / or

9 * trifluoromethyl; such as N'-phenylpiperazino, Ν '(4-chlorophenyl) piperazino, Ν' - (4-methoxyphenyl) piperazino or N ¹ -benzylpiperazino, and

R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, C 1 -C 4 alkyl, such as methyl, C 1 -C 4 alkoxy, such as methoxy, halogen with atomic number up to 35 inclusive, such as chlorine or bromine, or trifluoromethyl, with pharmaceutically usable and optionally hydroxylated alkanoic acids containing 1 to 7 carbon atoms, for example acetic acid, propionic acid, pivalic acid, glycolic acid, pyroacemic acid, lactic acid or acid gluconic, optionally hydroxylated, aminated and / or oxosubstituted alkanedicarboxylic acids containing 2 to 7 carbon atoms, for example with oxalic acid, malonic acid, succinic acid, glutamic acid, aspartic acid, tartaric acid or malic acid, optionally hydroxylated and / or oxosubstituted C 4 -C 7 alkanetricarboxylic acids, for example citric acid or aconitic acid, optionally hydroxylated and / or oxosubstituted C 4 -C 7 alkenedicarboxylic acids, for example fumaric acid, maleic acid or itaconic acid, optionally hydroxylic and / or oxosubstituted C 4 -C 7 alkindicarboxylic acids, for example acetylendicarboxylic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid; · ·· 6 «•» »· ·· * • * 9« * · * ·· · »· '·· · ^1' · ·· '* · as anti-neurodegenerative active ingredients for medicaments or substances for their preparation, as well as acid addition salts of the novel compounds of the formula I such as those as defined above, preferably those wherein R is other than amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino, dipropylamino, pyrrolidino, piperidino, piperidino, piperidino, piperidino, piperidino, piperidino, piperidino, piperidino, piperidino, piperidino, piperidino, piperidino, piperidino, '- (2-hydroxyethyl) piperazino, N' - (2-acetoxyethyl) piperazino, 'Ν' - (2-pivaloyloxyethyl) piperazino and Ν'-methyl-homopiperazino when R _x and R ₃ are hydrogen, lower alkyl , lower alkoxy or halogen, and R ₂ and R ₄ are hydrogen, with the above acids, as well as a process for their preparation.

The present invention preferably relates to the use of acid addition salts of compounds of formula I wherein alk is a methylene group,

R is C 1 -C 4 alkylamino, such as methylamino, ethylamino, propylamino or butylamino; phenylalkylamino having 1 to 4 carbon atoms in the alkyl moiety, phenylalkylalkylamino having 1 to 4 carbon atoms in each alkyl moiety, phenyl- (1-carboxyalkyl) amino having 1 to 4 carbon atoms in the alkyl moiety or phenyl- (1-alkoxycarbonylalkylamino) moiety C 1 -C 4 alkoxy and in C 1 -C 4 alkyl which is either unsubstituted or substituted by C 1 -C 4 alkyl, such as methyl, C 1 -C 4 alkoxy, such as

methoxy, halogen with atomic number up to and including 35, such as chlorine or bromine, and / or trifluoromethyl; such as benzylamino, phenethylamino, N-benzyl-N-methylamino, 2-phenyl-1-carboxyethylamino, 2-phenyl-1-ethoxycarbonylethylamino or N-benzyl-N-methylamino, alkenylamino having 2 to 7 carbon atoms such as allylamino; but-2-enylamino, C 2 -C 7 alkynylamino, such as propargylamino or but-2-ylamino, Nalkenyl-N-alkylamino having 2 to 7 carbon atoms and C 1-4 alkyl, such as N-allyl-N-methylamino, N-allyl-N-ethylamino, Nmethallyl-N-methylamino or N-but-2-enyl-N-methylamino, N-alkynyl-N-alkylamino containing 2 to 7 carbon atoms in the alkynyl moiety and in the alkyl moiety of 1 to 4 carbon atoms such as N-propargyl-N-methylamino, N-propargyl-N-ethylamino or N-but-2-ynyl-N-methylamino, dialkylamino containing each alkyl moiety having from 1 to 4 carbon atoms such as dimethylamino, diethylamino, N-methyl-N-propylamino or N-butyl-N-methylamino, pyrrolidino, piperidino, morpholino, piperazino, Ν'-alkylpiperazo to 1-alkyl such as Ν'-methylpiperazino, Ν '- (hydroxyalkyl) piperazino having 2 to 4 carbon atoms in the alkyl moiety, such as Ν' - (2-hydroxyethyl) piperazino, and

R _{@ 1} , R _{@ 2} , R @ ₃ and R _{@ 4} are each independently hydrogen, C1 -C4 alkyl, such as methyl, C1 -C4 alkoxy, such as methoxy, halogen atoms of up to 35 carbon atoms including, such as chlorine or bromine, or trifluoromethyl, 4 propionic, pyroacetic acid, acetic acid, pivalic acid, glycolic acid, lactic acid , oxalic acid, succinic acid, tartaric acid or malic acid, citric acid, fumaric acid, maleic acid, benzoic acid, mandelic acid or nicotinic acid, as antineurodegenerative active ingredients or substances for their preparation, as well as acid addition salts of the novel compounds of formula (I) as defined above, preferably such ch, wherein R is different from amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino, dipropylamino, pyrrolidino, piperidino, hexahydroazepino, morpholino, N'-methylpiperazino, N ¹ - (2-hydroxyethyl) piperazino, N '- (2acetoxyethyl) piperazino, Ν' - (2-pivaloyloxyethyl) piperazino, and N ¹ -methylhomopiperazino when R _x and R ₃ are hydrogen, lower alkyl, lower alkoxy or halogen and R ₂ and R ₄ are both a hydrogen atom with the above acids, as well as a process for their preparation.

The present invention preferably relates to acid addition salts of compounds of formula I wherein alk is a methylene group,

R is C 2 -C 7 alkenylamino, such as allylamino, methallylamino or but-2enylamino, C 2 -C 7 alkynylamino, such as propargylamino or but-2-ynyl38 amino, N-alkenyl-N-alkylamino in the alkenyl moiety 2 to 7 carbon atoms and 1 to 4 carbon atoms in the alkyl moiety such as N-allyl-N-methylamino, N-allyl-Nethylamino, N-methallyl-N-methylamino or Nbut-2-enyl-N-methylamino, N -alkynyl-N-alkylamino having 2 to 7 carbon atoms in the alkynyl moiety and 1 to 4 carbon atoms in the alkyl moiety such as N-propargyl-N-methylamino, N-propargyl-N-ethylamino or N-but-2inyl-N -methylamino; or a phenylalkylamino group having from 1 to 4 carbon atoms in the alkyl moiety which is either unsubstituted or substituted by a alkyl group having 1 to 4 carbon atoms such as a methyl group, 4 carbon atoms such as an alkoxy group containing 1 to methoxy, including a halogen atom such as chlorine or bromine, and / or trifluoromethyl; such as benzylamino or phenethylamino, and

R _{@ 1} , R _{@ 2} , R @ ₃ and R _{@ 4} are each independently hydrogen, C1 -C4 alkyl, such as methyl, C1 -C4 alkoxy, such as methoxy, halogen atoms of up to 35 carbon atoms including, such as chlorine or bromine, or trifluoromethyl, with an atomic number of up to 35 with pharmaceutically acceptable, optionally hydroxylated, C1 -C7 alkanoic acids, e.g. acetic acid, propionic acid, pivalic acid, glycolic acid, pyroacemic acid , lactic acid or gluconic acid, optionally hydroxylated, aminated and / or oxosubstituted alkanedicarboxylic acids containing 2 to 7 carbon atoms, for example with oxalic acid, malonic acid, succinic acid, glutamic acid, aspartic acid, tartaric acid or acid.

fefe ·· · 4 · β

Malic, optionally hydroxylated and / or oxosubstituted alkanetricarboxylic acids containing 4 to 7 carbon atoms, for example with citric acid or aconitic acid, optionally hydroxylated and / or oxosubstituted alkenedicarboxylic acids containing 4 to 7 carbon atoms, such as fumaric acid, maleic acid or itaconic acid, optionally hydroxylated and / or oxosubstituted C 4 -C 7 alkindicarboxylic acids, for example acetylendicarboxylic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid, processes for their preparation and their use as antineurodegeneratively active drug ingredients or as agents for their preparation.

In particular, the present invention relates to acid addition salts of compounds of formula I wherein alk is a methylene group,

R is C 2 -C 7 alkenylamino, such as allylamino, methallylamino or but-2enylamino, C 2 -C 7 alkynylamino, such as propargylamino or but-2-alkylamino, N-alkenyl-N-alkylamino containing 2 to 7 carbon atoms and 1-4 carbon atoms in the alkyl moiety, such as N-allyl-N-methylamino, N-allyl-Nethylamino, N-methallyl-N-methylamino or Nbut-2-enyl-N-methylamino, N-alkynyl- N-alkylamino having 2 to 7 carbon atoms in the alkynyl moiety and 1 to 4 carbon atoms in the alkyl moiety, such as N-propargyl-N-methylamino, N-propargyl-N-ethylamino or Nbut-2-ynyl-N-methylamino; · · Fc ·

Fc fcfc fcfc · fcfcfc fc fcfc

R _HR R _2, R ₃ and R ₄ are hydrogen, alkyl having 1 to 4 carbon atoms such as methyl, alkoxy having 1 to 4 carbon atoms, such as methoxy, halogen with an atomic number up to and including 35, such as is a chlorine or bromine atom and / or a trifluoromethyl group with pharmaceutically acceptable, optionally hydroxylated, C1 -C7 alkanoic acids, for example acetic acid, propionic acid, pivalic acid, glycolic acid, pyroacemic acid, lactic acid or gluconic acid, optionally hydroxylated, aminated and / or oxosubstituted C 2 -C 2 alkanedicarboxylic acids, for example with oxalic acid, malonic acid, succinic acid, glutamic acid, aspartic acid, tartaric acid or malic acid, optionally hydroxylated and / or oxosubstituted alkantric acid arboxylic acids such as citric acid or aconitic acid, optionally hydroxylated and / or oxosubstituted alkene dicarboxylic acids containing 4 to 7 carbon atoms, such as fumaric acid, maleic acid or itaconic acid, optionally hydroxylated and / or oxosubstituted alkindicarboxylic acids containing 4 to 7 carbon atoms carbon, for example acetylendicarboxylic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid, processes for their preparation and their use.

The present invention most preferably relates to acid addition salts of compounds of formula I wherein

0000 • 0 0 * 0 00 0 0 0

0 0 0 00 00 000 0 0 · 0 · 00

0000 0 00 «000 0 · 00 41 alk is a methylene group,

R is C 2 -C 7 alkenylamino, such as allylamino, methallylamino or but-2enylamino, C 2 -C 7 alkynylamino, such as propargylamino or but-2-ylamino, N-alkenyl-N-alkylamino containing 2 up to 7 carbon atoms and in the alkyl portion 1 to 4 carbon atoms such as N-allyl-N-methylamino, N-allyl-Nethylamino, N-methallyl-N-methylamino or Nbut-2-enyl-N-methylamino, or N -alkynyl-N-alkylamino having 2 to 7 carbon atoms in the alkynyl moiety and 1 to 4 carbon atoms in the alkyl moiety, such as N-propargyl-N-methylamino, N-propargyl-N-ethylamino or Nbut-2-vinyl-N-methylamino and

R ₃ and R ₃ are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or trifluoromethyl; and

R _2, R ₄ are hydrogen, with glycolic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid pyroacemic acid, malic acid, benzoic acid, nicotinic acid or mandelic acid, the method their preparation and use.

In particular, the present invention relates to acid addition salts of the compounds of formula I exemplified.

A process for the preparation of acid addition salts of the compounds of formula (I) is characterized in that:

in free form, it reacts with at least the quantitative amount of the organic carboxylic acid required to form the salt and isolating the desired salt.

The reaction of the compounds of the formula I with organic carboxylic acids is carried out in a conventional manner, for example in an organic solvent which is preferably miscible with water, in particular lower alcohols such as methanol, ethanol, propanol or isopropanol, or in a cycloaliphatic ether which is miscible. with water, such as dioxane, if necessary with heating, for example to a temperature of 50 ° C to 110 ° C, using a conventional processing method.

The compounds of the formula I in free form which serve as starting materials for the abovementioned salts are obtained, for example, from a) a compound of the formula II

(II) (III) y R wherein one of X and Y is a reactive, esterified hydroxyl group and the other is an optionally temporarily protected amino group, and R, R _{1 (} R ₂ , R ₃ and R ₄ are as hereinbefore defined and optionally a temporary group the amino protecting group is cleaved off again, or

wherein alk 'is a lower alkylidene group which is substituted with an oxo group or an optionally esterified hydroxyl group, the alk group is reduced to the corresponding alk group by replacing the oxygen group, the salt obtained according to the method is converted into the free compound and, if necessary, the compound which is obtained by the process is converted to another compound of formula I.

The reactive, esterified hydroxyl group in the starting material of formula II or III according to process variant a) is, for example, a hydroxyl group which is esterified with a hydrohalic acid or an organic sulfonic acid such as halogen, for example chlorine, bromine or iodine; benzenesulfonyloxy optionally substituted with lower alkyl, halogen and / or nitro such as benzenesulfonyloxy, p-bromobenzenesulfonyloxy or p-toluenesulfonyloxy, or lower alkanesulfonyloxy such as methanesulfonyloxy.

The reaction of the compounds of formulas II and III is carried out in a conventional manner, for example in the presence of a basic condensing agent such as a tertiary or sterically hindered binary organic nitrogen base such as a lower alkyl-containing trialkylamine or a hindered dialkylamine containing lower alkyl groups such as triethylamine or heteroaromatic bases such as pyridine or dimethylaminopyridine, with -výhodou in an organic solvent such as toluene, • fl flfl flflflfl · flfl flfl flflflfl • fl · · · · · · • flfl fl flflflfl * · · · • flfl flflfl

......... * .....

if necessary, with cooling or heating, for example at a temperature in the range of 0 to 80 ° C.

The amino protecting groups may be those customary for the temporary protection of primary amino groups, especially solvolytically cleavable amino protecting groups. They are, for example, acyl groups derived from carboxylic acids or carbonic acid semi-esters such as, for example, an optionally halogenated lower alkanoyl group such as formyl, acetyl or pivaloyl, a polyhalogenoalkanoyl group containing a lower alkanoyl group such as trifluoroacetyl, lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, or tertiary butyloxycarbonyl, or an optionally substituted lower alkoxycarbonyl group such as benzyloxycarbonyl, silyl groups such as trialkylsilyl, for example lower alkylsilyl, for example.

The cleavage of these amino protecting groups is carried out in a conventional manner, for example by reaction with a solvolyzing agent such as water in the presence of an acid, for example an aqueous mineral acid such as hydrohalic acid or an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide solution, in particular acids such as methanesulfonic acid in halogenated hydrocarbons such as dichloromethane, or in particular for cleavage of the formyl group, suitable silyl compounds such as trialkylsilyl containing a lower alkyl group such as trimethylsilyl bromide, or disilazane such as hexamethyldisilazane.

• ·· 99 9 9 · · ^· *

The starting materials of formulas II and III are known to be prepared in an analogous manner to the compounds of formulas II and III.

or may be prepared known

Thus, compounds of formula II wherein alk is methylene and X is reactive hydroxyl are obtained, for example, by compounds of formulas V and VI

(VI), wherein X represents a halogen atom and X ₂ represents a hydrogen atom or a hydroxyl group which are condensed together in a known manner, the process preferably being carried out at a temperature of 100 to 180 ° C and starting from a compound of formula V wherein X ₂ is a hydroxyl group and X ₂ is, for example, a chlorine atom, the process is preferably carried out in the presence of copper / copper (I) iodide and when starting from compounds of formula V wherein X ₂ is a hydrogen atom and X ₂ is a fluorine atom in the presence of potassium carbonate in dimethylacetamide to give the compound of formula VII

-C (= P) -X ₁ is hydroxymethyl in conventional manner, for example by reacting a light metal such as lithium aluminum hydride in tetrahydrofuran, the hydroxymethyl group is converted in conventional manner to methyl halide, for example by heating with hydrohalic acids, especially hydrobromic acid, halogen Reduce with a dihydride

0000 is replaced in a conventional manner by a cyano group, for example by reaction with an alkali metal cyanide such as sodium cyanide in ethanol to give a compound of formula VIII.

0 • 0

0 ··· 0 • 0 ··

0 0 4 • 0 * 0

0 · 0 0 4

0 00

(VIII) which is reacted with a dialkyl ester of a lower alkyl group, for example oxalate, in a conventional manner, for example in the presence of an alkali metal alkanolate such as sodium methoxide, treated to form the acid,

the carboxyl group is conventionally reduced to a hydroxymethyl group, for example by reaction with a haloformic acid ester such as isobutyl chloroformate in the presence of a nitrogenous base such as N-methylmorpholine, preferably in an ether solvent such as dimethoxymethane followed by a light metal dihydride such as sodium borohydride in water to give a compound of formula X ch ₂ OH

(X) o

ft 4 4 4 4

4

4 ·· 44 • 4 4 *

No. 4,444,444 which is reacted with an agent that introduces a group X, such as a hydrohalogenic acid or a sulfonyl halide, such as methanesulfonyl chloride.

Higher homologues of compounds of formula II wherein alk is ethylene, propylene, etc. or ethylidene, propylidene, etc. can be obtained, for example, by extension in the acid step of formula IX in a conventional manner, or the carboxyl group is converted in conventional manner to the desired 1-oxoalkyl group.

Compounds of formula (II) wherein X is optionally protected amino may be obtained in a conventional manner, for example from reactive esters of formula (II) wherein X is a reactive esterified hydroxyl group obtained as described above by reaction with ammonia in a conventional manner, e.g. a saturated solution of ammonia in methanol and, if necessary, subsequent introduction of an amino protecting group.

In the starting materials of formula (IV) according to process variant b), the esterified hydroxyl group is, for example, an esterified hydroxyl group which is derived from a carboxylic acid or a carbonic acid semi-ester such as an optionally halogenated alkanoyloxy group, for example a lower alkanoyloxy group such as formyloxy, acetyloxy or pivaloyloxy alkoxycarbonyloxy such as methoxycarbonyloxy, ethoxycarbonyloxy, isopropyloxycarbonyloxy or tertiary butyloxycarbonyloxy, or an optionally substituted phenylalkoxycarbonyloxy group such as benzyloxy.

The reduction of compounds of formula IV is carried out in a conventional manner, for example by reaction with a light metal dihydride such as lithium aluminum hydride in tetrahydrofuran.

ΦΦ φφφφ

33 ·· φ ft ··

Φ 9 I • * ♦

The starting materials of the formula IV, in which alk is a ωoxoalkyl group containing a lower alkyl group bonded to the R group in the ω position, can be obtained, for example, from the corresponding acids of formula IX or their homologs by reaction with an amine of formula III protected amino, for example by reaction with an acidic halogenating agent such as oxalyl chloride in the presence of dimethylformamide. From these compounds, the corresponding compounds of formula IV, wherein alk 'is a lower alkylidene group substituted with an optionally esterified hydroxyl group, may be prepared by partial reduction and, if necessary, esterification. Starting where alk is lower alkyl (ω-1) ω, compounds of formula IV, an oxoalkyl group containing a bond to the R group at, for example, from the corresponding methyl ketones by halogenation, for example with N-bromo or N-chlorosuccinimide, and subsequent by reaction with an amine of formula III, wherein Y is an optionally temporarily protected amino group.

The compounds obtainable by this process can be converted in a conventional manner to the compounds of formula I.

In compounds of formula I wherein R is unsubstituted amino, the amino group may be conveniently substituted by one or two identical or different monovalent aliphatic or arylaliphatic or one divalent radical. Similarly, in compounds of formula I wherein R is an amino group that is substituted with a monovalent aliphatic or arylaliphatic moiety, an additional monovalent aliphatic or arylaliphatic moiety may be introduced.

The salts obtained can be converted into the free compounds in a known manner, for example by reaction with a base such as an alkali metal hydroxide, a metal carbonate or a metal bicarbonate

or other salt-forming bases mentioned above, or with an acid such as a mineral acid, for example hydrochloric acid or another salt-forming acid mentioned above.

The acid addition salts of the compounds of formula (I) may also be prepared in the form of hydrates or may contain the solvent used in the crystallization.

The novel starting materials which have been developed in particular for the preparation of the compounds according to the invention, in particular the selection of the starting materials leading to the compounds of the general formula I designated initially as preferred compounds, their preparation and their use as intermediates, form an object of the present invention.

This relates to compounds of formula I wherein R is an amino group which is monosubstituted with an optionally esterified or amidated lower alkyl group, a lower alkyl group cyanoalkyl or a lower alkyl phenylalkyl group which is unsubstituted or substituted on the phenyl group alkyl, lower alkoxy, halogen and / or trifluoromethyl and in the lower alkyl group is substituted with an optionally esterified carboxyl group; or an amino group which is disubstituted by a lower alkylene group, a lower alkenylene group or a lower alkadienylene group which is either unsubstituted or substituted by an optionally esterified or amidated carboxyl or cyano group or a phenylalkylene group containing a lower alkylene group, a phenyl (cyano) alkylene group containing a lower alkylene group , a lower alkyl and lower alkylene phenylakylalkylene group, a Ν'-phenylazaalkylene group having a lower alkylene group, or a Ν 4444 ·· 44

4 4 44 44 4 4 4 4 4 4 44 444 444 444 44 4 4 * 4 * 4 4 4 ₅₀ Phenylalkylazaalkylene group containing lower an alkyl group and a lower alkylene group which is unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group; in free form.

Another preferred object of the present invention are compounds of formula I

where alk is a lower alkylidene group,

R is an amino group monosubstituted with a lower alkyl group or a lower alkyl phenylalkyl group which is either unsubstituted on the phenyl group or substituted with a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group and a lower alkyl group optionally esterified with a carboxyl group ; or an amino group disubstituted by a lower alkylene group, a lower alkenylene group or a lower alkadienylene group or a phenylalkylene group containing a lower alkylene group, a cyano (phenyl) alkylene group having a lower alkylene group, a phenylalkylalkylene group having a lower alkyl group and a lower alkylene group, N'phenylazaalkylene group containing a lower an alkylene group or a Ν'-phenylalkylazaalkylene group having a lower alkyl group and a lower alkylene group which is unsubstituted or substituted by a phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group, and

R ₁ , R ₂ , R ₃ and R ₄ , independently of one another, are hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, in free form.

The invention preferably relates to compounds of formula I wherein alk is a lower alkylidene group,

R is a lower alkyl-containing cyanoalkylamino group, a 3- to 8-membered lower alkylene amino group, a 3- to 8-membered lower alkadienylene amino group, a 3- to 8-membered pyrimidinylazaalkyleneamino group containing a lower alkylene group; 3- to 8-membered phenyl (carboxyalkyl) amino-lower alkyl group, phenyl (alkoxycarbonylalkyl) amino-lower alkoxy group and mzsi lower alkyl, cyano (phenyl) alkylamino alkyl group, N ¹ -phenylazaalkyleneamino lower alkyl group or N a lower alkylene benzylazaalkyleneamino group which is either unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group; or 1,2,3,6-tetrahydropyridino, and

R ₁ , R ₂ , R ₃ and R ₄ , independently of one another, are hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, in free form, process for their preparation, pharmaceutical composition containing them and their use as active ingredients for pharmaceuticals.

In particular, the present invention relates to compounds of formula I wherein alk is a methylene group,

R is cyanoalkylamino having 1 to 4 carbon atoms in the alkyl moiety, such as cyanomethylamino; phenyl- (1 · · · t * ··· ♦... I _: .,

.... ». Carboxyalkyl) amino group containing from 1 to 4 carbon atoms in the alkyl moiety or phenyl- (1-alkoxycarbonylalkylamino group containing from 1 to 4 carbon atoms in the alkoxy moiety and from 1 to 4 carbon atoms in the alkyl moiety either unsubstituted or substituted with C 1 -C 4 alkyl, such as methyl, C 1 -C 4 alkoxy, such as methoxy, with a halogen atom of up to and including 35, such as chlorine or bromine, and / or trifluoromethyl, such as is 2-phenyl-1-carboxyethylamino or 2-phenyl-1-ethoxycarbonylethylamino; phenylalkylpyrrolidino having 1 to 4 carbon atoms in the alkyl moiety which is unsubstituted or substituted by C1 -C4 alkyl such as methyl, alkoxy containing 1; up to 4 carbon atoms, such as methoxy, with ato halogen a number of up to and including 35 and / or a trifluoromethyl group such as a benzylpyrrolidino group; 4-cyano-4-phenylpiperidino or phenylalkylpiperidino having 1 to 4 carbon atoms in the alkyl moiety, which is either unsubstituted or substituted by C1-C4 alkyl, such as methyl, C1-C4 alkoxy, such as methoxy a halogen atom having an atomic number up to and including 35, such as a chlorine or bromine atom and / or a trifluoromethyl group such as benzylpiperidino, 1,2,3,6-tetrahydropyridino, N'pyrimidinylpiperazino; or phenylpiperazino or phenylalkylpiperazino having 1 to 4 carbon atoms in the alkyl moiety, which is either unsubstituted or substituted by a alkyl group having 1 to 4 carbon atoms such as a methyl group, an alkoxy group having 1 to 4 carbon atoms such as methoxy, a halogen atom with an atomic atom a number up to and including 35, such as a chlorine atom or a bromine atom

I i .. a group such as

3θ

N

53 and / or trifluoromethyl benzylpiperazino, and

R ₁ , R ₂ , R ₃ and R ₄ are independently hydrogen, C 1 -C 4 alkyl, such as methyl, C 1 -C 4 alkoxy, such as methoxy, halogen atom having an atomic number up to and including 35, such as a bromine or chlorine atom or a trifluoromethyl group, in free form, a process for their preparation, pharmaceutical compositions containing them and their use as active pharmaceutical ingredients.

In particular, the present invention relates to compounds of formula I wherein alk is a methylene group,

R is a phenyl- (1-alkoxycarbonylalkylamino group having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, such as 2-phenyl-1-ethoxycarbonylethylamino, which is either unsubstituted or substituted with C1-4 alkyl) a carbon atom such as a methyl group having an alkoxy group having 1 to 4 carbon atoms such as a methoxy group, a halogen atom having an atomic number up to and including 3, such as a chlorine atom or a bromine atom and / or a trifluoromethyl group, and

R _x, R _2, R ₃ and R ₄ are independently hydrogen, an alkyl group comprises from 1 to 4 carbon atoms such as methyl, alkoxy having 1 to 4 carbon atoms, such as methoxy, halogen with an atomic number up to and including 35, such as a chlorine or bromine atom or a trifluoromethyl group, in free form, a process for their preparation, a pharmaceutical composition containing them and their use as active pharmaceutical ingredients.

ί · «e e * *

In particular, the present invention relates to 2 - [(dibenzo [b, f] oxepin-10-ylmethyl) amino] -3-phenylpropionic acid ethyl ester;

1- (dibenzo [b, f] oxepin-10-ylmethyl) -1,2,3,6-tetrahydropyridine;

1- (dibenzo [b, f] oxepin-10-ylmethyl) -4-phenylpiperidine-4-carbonitrile;

1- (dibenzo [b, f] oxepin-10-ylmethyl) -4- (4-chlorophenyl) piperazine;

(dibenzo [b, f] oxepin-10-ylmethylamino) acetonitrile;

1- (dibenzo [b, f] oxepin-10-ylmethyl) -4- (4-methoxyphenyl) piperazine;

2- [4- (dibenzo [b, f] oxepin-10-ylmethyl) -piperazin-1-yl) pyrimidine and / or

1-Benzyl-4-dibenzo [b, f] oxepin-10-ylmethylpiperazine, processes for their preparation, pharmaceutical compositions containing them and their use as active ingredients of medicaments.

Another preferred object of the present invention are pharmaceutical compositions comprising the salts of the compounds of the formula I according to the invention with organic carboxylic acids or the novel compounds of the formula I or their pharmaceutically acceptable salts as active ingredients, as well as a process for their preparation.

The pharmaceutical compositions of the present invention are intended for internal, such as oral, also rectal and paremteral administration to warm-blooded animals, wherein the pharmacologically active ingredient occurs therein alone or with a pharmaceutically acceptable carrier. The daily dose of the active ingredient depends on the age and condition of the patient as well as the route of administration.

fcfc fcfc. · I *:: · ···· ¹ ......

The novel pharmaceutical compositions contain, for example, 10% to 80%, preferably 20 to 60%, of the active ingredient. The pharmaceutical compositions of the present invention for enteral or parenteral administration are, for example, single doses such as dragees, tablets, capsules or suppositories, as well as ampoules. These compositions are prepared in a manner known per se, for example by means of conventional mixing, granulating, dragee-forming, dissolving or lyophilizing processes. Pharmaceutical compositions for oral administration can thus be obtained by mixing the active ingredient with a solid carrier, optionally granulating the resulting mixture and processing the mixture or granules into tablets or dragees, if necessary, after the addition of suitable additives.

Suitable carriers are fillers such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose compositions and / or calcium phosphates, for example calcium phosphate or dibasic calcium phosphate, binders such as starch paste such as corn, wheat, rice or potato starch, gelatin , tracacanth, methylcellulose and / or polyvinylpyrrolidone, if necessary disintegrating agents such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts such as sodium alginate. The additives are in particular mobile phases, mobile phase regulators and lubricants, for example silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate and / or polyethylene glycol. Dragees are prepared with coatings that are resistant to gastric juices, if appropriate. They are prepared from concentrated solutions of sugars, optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or a coating solution in a suitable organic solvent or solvent mixture, or for preparing gastric juice resistant coatings, from solutions of the respective cellulose. Compositions such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the tablets and dragee coatings, for example, to identify or characterize different amounts of the active ingredient.

Other orally useful pharmaceutical compositions are hard gelatin capsules, also soft, sealed capsules containing gelatin and a plasticizer such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of a granulate, for example mixed with a filler such as lactose, a binder such as starch and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid, such as fatty oils, paraffin oil or liquid polyethylene glycols, similarly stabilizers may be added.

Suppositories may be, for example, rectally administrable pharmaceutical compositions. They contain a mixture of the active ingredient, with a rosehip base. Suppository bases can be, for example, natural or artificial triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. In addition, rectal capsules or gelatin containing a mixture of the active ingredient and the base may be used. The base may be, for example, liquid triglyceride, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration by infusion and / or injection, solutions of the active ingredient in water-soluble form, for example, water-soluble salts, as well as suspensions of the active ingredient, such as suitable oily suspensions, where appropriate lipophilic solvent or vehicle such as fatty oils, sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous suspensions containing viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally also stabilizers.

0

00 0 0 i · 0

0 0 0 ··· · ·

0 fe

0 0 0

00 0 * »

00

The dosage of the active ingredient depends on the species of warm-blooded animal, age and condition as well as the route of administration. Under normal conditions, an approximate dose of 10 mg to 500 mg is orally administered to a patient weighing 75 kg per day.

The following examples serve to illustrate the present invention; temperatures are given in degrees Celsius and pressures in kPa (mbar).

DETAILED DESCRIPTION OF THE INVENTION

Example 1

N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynylammonium maleate

The compound is prepared from N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynylamine by reaction with maleic acid. Recrystallization is carried out from hot methanol. The title compound is N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynylamine hydrogen maleate;

Melting point: 158-159 ° C;

Elemental analysis: C 70.73% (70.58); H, 5.35% (5.41); N 3.50% (3.58);

@ 1 H-NMR (200 MHz, CDCl3): 2.84 (s, 3H); 3.31 (t, 1H);

H); 3.99 (m, 2 H); 4.42 (s, 2 H); 6.25 (s, 2H, maleic acid); 7.15-7.60 (m, 9H).

The starting material can be prepared as follows:

a) N- (dibenzo [b, f] oxepin-10-ylmethyl-N-methyl-N-prop-2-ynylamine)

N-methyl-N-propargylamine (4.5 g, 65 mmol) was dissolved in benzene (75 mL) and methanol (25 mL). A solution of 10-bromomethyl-dibenz [b, f] oxepine (7.0 g, mmol) in benzene (25 mL) was added dropwise at 0 ° C over 0.5 h. When the addition was complete, stirring was continued at 40-50 ° C for an additional 0.5 hour. The solution was poured into water and then extracted with 5% methanesulfonic acid solution. The pH of the acidic aqueous layer was adjusted to basic with concentrated ammonia solution and extracted with diethyl ether. The ether layer was dried over sodium sulfate and concentrated by evaporation. Crystallization of the residue from petroleum ether gave N- (dibenzo [b, f] oxepin-10-ylmethyl-N-methyl-N-prop-2-ynylamine) (5.3 g, 77%).

Melting point: 66-67 ° C.

Example 2

N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynylammonium fumarate

The compound was prepared from N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynylamine by reaction with fumaric acid in methanol in an analogous manner to that described in Example 1. The product was recrystallized from petroleum ether. The title compound is N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynylamine hydrogen fumarate;

Melting point: 118 ° C (dec.);

Elemental analysis: C 70.25% (70.58); H, 5.33% (5.41); N 3.52% (3.58);

@ 1 H-NMR (200 MHz, CDCl3): 2.50 (s, 3H); 2.90 (t, IH); 3.59 (d, 2 H); 3.93 (s, 2 H); 6.72 (s, 2H, fumaric acid); 7.00 (s, 1H); 7.10-7.41 (m, 7H); 7.56 (dd, IH).

Example 3

N-benzyl-N- (dibenzo [b. F] oxepin-10-ylmethyl) -N-methylammonium maleate

The compound was prepared from N-benzyl-N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methylamine by reaction with maleic acid in hot methanol in an analogous manner to that described in Example 2. The title compound was obtained as N-benzyl-N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methylamine hydrogen maleate;

Melting point: 161-162 ° C;

@ ¹ H-NMR (200 MHz, CDCl3): 2.81 (s, 3H); 4.38 (s,

2H); 4.40 (s broad, 2H); 6.25 (s, 2H, maleic acid);

7.15-7.55 (m, 9H).

For example, the starting material is prepared as follows:

a) N-benzyl-N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methylamine

A solution of 1.0 g (3.48 mmol) of 10-bromomethyldibenzo [b, f] oxepine in 6.5 mL of methanol was treated with a solution of 1.02 mL (8 mmol) of N-benzyl-N-methylamine in 10 mL of toluene and stirred 4 hours at room temperature. After evaporation of the solvent, flash chromatography on silica gel was eluted directly with hexane / ethyl acetate (9: 1). 1.01 g (89%) of crystalline N-benzyl-N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methylamine are obtained;

1 H-NMR (200 MHz, CDCl 3): 2.28 (s, 3H); 3.53 (s,

2H); 3.60 (s, 2 H); 6.90 (s, 1H); 7.05-7.45 (m, 8H);

MS: 327 (M &^lt; ⁺ &^gt;); 236, 208, 207M;

TLC (silica gel, hexane / ethyl acetate (9: 1)): _Rf = 0.14

Example 4

2 - [(dibenzo [b, f] oxepin-10-ylmethyl) -ammonio] -3-phenylpropionic acid ethyl ester maleate

The compound was prepared from the free base (2 [(dibenzo [b, f] oxepin-10-ylmethyl) amino] -3-phenylpropionic acid ethyl ester) with maleic acid in hot methanol. The title compound is obtained as 2 [(dibenzo (b, f) oxepin-10-ylmethyl) amino] -3-phenylpropionic acid ethyl maleate;

Melting point: 140-141 ° C;

@ 1 H-NMR (200 MHz, CDCl3): 1.01 (t, 3H); 3.00-3.30 (m, 2 H); 4.08 (q, 2H); 4.20 (m, 1H); 4.32 (d, 2 H); 6.25 (s, 2H, maleic acid); 7.10-7.50 (m, 9H); optical rotation (c = 1.0, methanol) _{:? D} = + 4.9 °.

The starting material is prepared as follows:

(a) 2 - [(Dibenzo [b, f] oxepin-10-ylmethyl) amino] -3-phenylpropionic acid ethyl ester

The compound was prepared analogously to Example 3a from 10-bromomethyl-dibenz [b, f] oxepine and L-phenylalanine ethyl ester. 2 - [(Dibenzo [b, f] oxepin-10-ylmethyl) amino] -3-phenylpropionic acid ethyl ester was prepared as a yellow oil;

¹ H-NMR (200 MHz, CDCl 3): 1.20 (t, 3H); 1.76 (broad s, 1H, NH); 2.97 (m, 2 H); 3.65 (m, 2 H); 3.90 (dd, IH); 4.14 (q, 2H); 6.75 (s, 1 H); 7.02-7.35 (m, 13H);

Mass spectroscopy: 3 99. (M ⁺ ); 308, 207;

Thin layer chromatography (silica gel, hexane / ethyl acetate (9: 1)): Rf = 0.16

Example 5

-benzyl-4-dibenzo [b, f] oxepin-10-ylmethylpiperazinium dimaleinate

The compound was prepared from 0.5 mmol of 1-benzyl-4-dibenzo [b, f] oxepin-10-ylmethylpiperazine with 2 equivalents of maleic acid in 10 mL of chloroform / methanol (1: 1). The mixture is allowed to stand overnight and the title compound is obtained as 1-benzyl-4-dibenzo [b, f-oxepin-10-ylmethyl-piperazine dihydrogen maleate, is obtaind as white crystals in 66% yield;

Mp 207-209 ° C;

¹ H-NMR (200 MHz, CDCl 3): 2.80-3.10 (m broad, about 8H); 3.76 (s broad, 2H); 4.19 (s broad, 2H); 6.13 (s, 4H, 2x maleic acid); 6.97 (s, 1H); 7.14-7.65 (m, 13H);

ES-MS: 383 (M ⁺ +1).

The starting material is prepared as follows:

1-Benzyl-4-dibenzo [b, f] oxepin-10-ylmethylpiperazine

1.27 ml (8.0 mmol) of N-benzylpiperazine was slowly sprayed onto a solution of 1.0 g (3.48 mmol) of 10-bromomethyldibenzo [b, f] oxepine in 7 ml of methanol and 7 ml of toluene. The solution was stirred at room temperature for 16 hours, the solvent was evaporated, the residue was taken up in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, the organic layer was dried over magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography eluting with dichloromethane methanol (39: 1). 1.42 g of 1-dibenzo [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydropyridine are obtained as a yellowish oil;

¹ H-NMR (200 MHz, CDCl 3): 2.45 (m broad, about 4H);

2.61 (broad m, 4H); 3.50 (s, 4H); 6.83 (s, 1H); 7.03-7.35 (m,

12H); 7.60 (dd, 1H);

* ·

ES-MS: 383 (M ⁺ +1).

Example 6

-benzyl-4-dibenzo [b, f] oxepin-10-ylmethylpiperazini umdi fumarate

The compound was prepared from 0.5 mmol of 1-benzyl-4-dibenzo [b, f] oxepin-10-ylmethylpiperazine free base with 2 equivalents of fumaric acid in 10 mL of chloroform / methanol (1: 1). The mixture was allowed to stand overnight to give the title compound as 1-benzyl-4-dibenzo [b, f] oxepin-10-ylmethyl-piperazine dihydrogen fumarate as white crystals in 80% yield;

Melting point: 227-229 ° C, ¹ H-NMR (200 MHz, perdeuterodimethylsulfoxide): 2.40-2.60 (m broad, about 8H); 3.51 (m, 4H); 6.62 (s, 4H, 2x fumaric acid); 6.90 (s, 1 H); 7.10-7.40 (m, 12H); 7.63 (dd, IH);

ES-MS: 383 (M ⁺ +1).

Example 7 1-Dibenz [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydro-pyridinium maleate

The compound was prepared from 1-dibenzo [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydropyridine free base with 1 equivalent of maleic acid in hot methanol. The mixture was allowed to stand overnight to give the title compound as 1-dibenzo [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydropyridine hydrogen maleate, in 70% yield as light beige crystals;

Melting point: 188-191 ° C;

¹ H-NMR (200 MHz, CDCl 3): 2.50 (m, 2H); 3.45 (m,

2H); 3.80 (m, 2 H); 4.57 (s, 2 H); 5.76 (m, IH); 6.00 (t, 1H);

6.29 (s, 2H, maleic acid); 7.19-7.69 (m, 9H);

Μ · *

ES-MS: 290 (M ⁺ +1), 207.

Elemental analysis: C: 70.61% (calculated: 71.10%); H: 5.72% (5.72%); N: 3.32% (3.45%).

The starting material is prepared as follows:

a) 1-dibenzo [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydropyridine

1,45 ml (16,0 mmol) of 1,2,5,6-tetrahydropyridine is slowly sprayed into a solution of 2.0 g (6.96 mmol) of 10-bromomethyl-dibenzothi [f] oxepine in 15 ml of methanol and 15 ml of toluene . The solution was stirred at room temperature for 16 hours, the solvent was evaporated and the residue was purified by silica gel chromatography eluting with hexane / ethyl acetate (9: 1). This gave 1.59 g (79%) of the title compound as an orange oil;

1 H-NMR (200 MHz, CDCl 3): 2.13 (m, 2H); 2.65 (t,

2H); 3.05 (m, 2 H); 3.57 (m, 2 H); 5.69 (m, 2 H); 6.87 (s, 1H);

7.00-7.30 (m, 7H); 7.58 (dd, 1H);

ES-MS: 285, 287 (M, weak); 207 (M-Br).

Example 8

1-Dibenzo [b, f] oxepin-10-yl-1,2,3,6-tetrahydropyridinium fumarate

The compound was prepared from 1-dibenzo [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydropyridine free base with 1 equivalent of fumaric acid in hot methanol. The mixture was allowed to stand overnight to give pale beige crystals in 50% yield;

mp: 168-171 ° C. 1 H-NMR (200 MHz, CDCl 3): 2.45 (m, 2H); 3.38 (m, 2 H); 3.78 (m, 2 H); 4.43 (s, 2 H); 5.73 (m, 1H); 5.95 (m, 1H); 6.71 (s, 2H, fumaric acid); 7.18-7.65 (m. 9H);

• · ·· · ·

ES-MS: 290 (M ⁺ +1), 207.

Elemental analysis: C: 71.12% (calculated: 71.10%); H: 5.73% (5.72%); N: 3.38% (3.45%).

Example 9

1-Dibenzo [b, f] oxepin-10-yl-1,2,3,6-tetrahydropyridinium succinate

The compound was prepared from 1-dibenzo [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydropyridine free base with 1 equivalent of succinic acid in hot methanol. The mixture was allowed to stand overnight to give pale beige crystals in 40% yield;

mp 133-135 ° C. ^* H-NMR (200 MHz, CD OD): 2.33 (m, 2H); 2.57 (s,

4H, succinic acid); 3.10 (t, 2 H); 3.45 (m, 2 H); 4.15 (s,

2H); 5.70 (m, IH); 5.89 (m, IH); 7.10-7.65 (m. 9H);

ES-MS: 290 (M ⁺ +1), 207.

Elemental analysis: C: 70.83% (calculated: 70.75%); H: 6.18% (6.18%); N: 3.43% (3.44%).

Example 10

-dibenzo [b, f] oxepin-10-ylmethyl-4-phenylpiperidinium-4-carbonitrile maleate

The compound was prepared from 0.5 mmol of 1dibenzo [b, f] oxepin-10-ylmethyl-4-phenylpiperidine-4-carbonitrile free base with 1 equivalent of maleic acid in 10 mL of 1: 1 chloroform / methanol. After evaporation of the chloroform / methanol mixture and crystallization from ethanol / diethyl ether, the title compound is obtained as 1-dibenzo [b, f] oxepin-10-ylmethyl-4-phenylpiperidine-4-carbonitrile hydrogen maleate as white crystals in 94% yield. %;

• 4 ♦ «4 * • f ·· · 4 · · · ·

4,444 ·

4 4 4

44 · 4 · · * melting point: 202-203 ° C;

¹ H-NMR (200 MHz, CDCl 3): 2.45 (m, 4H); 3.35 (m,

2H); 3.78 (m, 2 H); 4.63 (s, 2 H); 6.28 (s, 2H, maleic acid); 6.97 (s, 1H); 7.20-7.70 (m, 14H);

ES-MS: 393 (M ⁺ +1).

The starting material is prepared as follows:

(a) 1-dibenzo [b, f] oxepin-10-ylmethyl-4-phenylpiperidine-4-carbonitrile

1.36 ml (9.74 mmol) of triethylamine, then 1.78 ml (8.0 mmol) of 4-cyano-4-phenylpiperidine hydrochloride are slowly sprayed onto a solution of 1.0 g (3.48 mmol) of 10-bromomethyl -dibenzo [b, f] oxepine in 7 mL of methanol and 7 mL of toluene. The solution is stirred at room temperature for 16 hours, the solvent is evaporated, the residue is taken up in dichloromethane, washed with saturated sodium bicarbonate solution, the organic layer is dried over magnesium sulphate, the solvent is evaporated and the residue is purified by silica gel chromatography (dichloromethane). After evaporation of chloroform and methanol, the residue was crystallized from ethanol / diethyl ether to give 0.93 g (68%) of the title compound as a light foam.

¹ H-NMR (200 MHz, CDCl 3): 2.10 (m, 4H); 2.58 (m,

2H); 3.29 (m, 2 H); 3.62 (d, 2 H); 6.89 (s, 1H); 7.05-7.60 (m,

13H);

ES-MS: 393 (M ⁺ +1).

Example 11

-benzo [b, f] oxepin-10-ylmethyl-4-phenylpiperidinium-4-carbonitrile fumarate

0 ···· · ·

0 «0 · 0 · 0

0 ··· ·

0 0

The compound was prepared from 0.5 mmol of 1dibenzo [b, f] oxepin-10-ylmethyl-4-phenylpiperidine-4-carbonitrile free base with 1 equivalent of fumaric acid in 10 mL of chloroform / methanol (1: 1). Evaporation of the chloroform / methanol mixture and crystallization from ethanol / diethyl ether gave the title compound as 1-dibenzo [b, f] oxepin-10-ylmethyl-4-phenylpiperidine-4-carbonitrile hydrogen fumarate as white crystals in 75% yield. .

Mp 232-234 ° C;

¹ H-NMR (200 MHz, CDCl 3): 1.90-3.70 (m broad, about 10H); 6.71 (s, 2H, fumaric acid); 6.99 (s, 1H); 7.10-7.70 (m, 13H);

ES-MS: 393 (M ⁺ +1).

Example 12

1-Dibenzo [b, f] oxepin-10-ylmethyl-4- (4-chlorophenyl) piperazinium maleate

The compound was prepared from 0.5 mmol of 1dibenzo [b, f] oxepin-10-ylmethyl-4- (4-chlorophenyl) piperazine free base with 1 equivalent of maleic acid in 10 mL of 1: 1 chloroform / methanol. Evaporation of the chloroform / methanol mixture and crystallization from ethanol / diethyl ether gave the title compound as 1-chloro-4-dibenzo [b, f] oxepin-10-ylmethylpiperazine maleate as white crystals in 84% yield.

Melting point: 180-183 ° C;

NMR (200 MHz, CDCl 3): 2.40-2.60 (m, 8H); 4.52 (s, 2 H); 6.28 (s, 2H, maleic acid); 6.99 (m, 2H); 7,207.70 (m, 11H);

ES-MS: 403 (M ⁺ +1).

The starting material is prepared as follows:

a) 1-Dibenzo [b, f] oxepin-10-ylmethyl-4- (4-chlorophenyl) piperazine

2.43 ml (17.4 mmol) of triethylamine, after 2.16 g (8.0 mmol) of 1- (4-chlorophenyl) piperazine dihydrochloride, was slowly added to a solution of 1.0 g (3.48 mmol) of 10- bromomethyldibenzo [b, f] oxepine in 7 mL of methanol and 7 mL of toluene. The solution was stirred at room temperature for 16 hours, the solvent was evaporated, dichloromethane was added, washed with saturated sodium bicarbonate solution, the organic layer was dried over magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography (dichloromethane). This afforded 0.46 g (33%) of the title compound as an adhesive = beige foam.

¹ H-NMR (200 MHz, CDCl 3): 2.70 (m, 4H); 3.15 (m,

4H); 3.58 (s, 2 H); 6.80-6.90 (m, 3H); 7.05-7.35 (m, 9H); 7.60 (dd, IH);

ES-MS: 403 (M ⁺ +1).

Example 13

-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-chlorophenyl) piperazinium fumarate

The compound was prepared from 0.5 mmol of 1dibenzo [b, f] oxepin-10-ylmethyl-4- (4-chlorophenyl) piperazine free base with 1 equivalent of fumaric acid in 10 mL of 1: 1 chloroform / methanol. Evaporation of the chloroform / methanol solvent and crystallization from ethanol / diethyl ether gave the title compound as 1-chloro-4-dibenzo [b, f] oxepin-10-ylmethylpiperazine fumarate as white crystals in 58% yield;

·· · »··

mp 195-198 ° C;

1 H-NMR (200 MHz, CDCl 3): 2.40-3.60 (m broad, 10H); 6.62 (s, 2H, fumaric acid); 7.10 (m. 2H);

7.20-7.40 (m, 10H); 7.67 (dd, IH);

ES-MS: 403 (M ⁺ +1).

Example 14

-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-chlorophenyl) piperazinium fumarate

The compound was prepared from 0.5 mmol of (dibenzo [b, f] oxepin-10-ylmethylmethylamino) acetonitrile free base with 1 equivalent of maleic acid in 10 mL of 1: 1 chloroform / methanol. After evaporation of the chloroform / methanol mixture and crystallization from ethanol / diethyl ether, the title compound is obtained as hydrogen maleate (dibenzo [b, f] oxepin-10-ylmethylmethylamino) acetonitrile as white crystals in 61% yield;

mp 137-139 ° C;

@ 1 H-NMR (200 MHz, CDCl3): 2.28 (s, 3H);

3.63 (s, 2 H); 3.75 (s, 2 H); 6.27 (s, 2H, maleic acid); 6.95 (s, 1 H); 7.12-7.42 (m, 7H); 7.55 (dd, IH);

ES-MS: 277 (M ⁺ +1).

The starting material is prepared as follows:

a) (dibenzo [b, f] oxepin-10-ylmethylmethylamino) acetonitrile

1.36 ml (9.74 mmol) of triethylamine, then 0.85 g (8.0 mmol) of methylaminoacetonitrile hydrochloride, are slowly added to a solution of 1.0 g (3.48 mmol) of 10-bromomethyldibenzo [b, f] oxepine in 7 ml of methanol and 7 ml of toluene. The solution is stirred for 16 hours at room temperature, then the solvent is evaporated, the residue is taken up in dichloromethane, washed with saturated sodium bicarbonate solution, the organic layer is dried over magnesium sulphate, the solvent is evaporated and the residue is chromatographed silica gel (dichloromethane). 0.96 g (100%) of (dibenzo [b, f] oxepin-10-ylmethylmethylamino) acetonitrile was obtained as a beige oil;

1 H-NMR (200 MHz, CDCl 3): 2.49 (s, 3H); 3.59 (s,

2H); 3.66 (s, 2 H); 6.92 (s, 1H); 7.05-7.5 (m. 8H);

ES-MS: 277 (M ⁺ +1).

Example 15 (dibenzo [b, f] oxepin-10-ylmethylmethylammonio) acetonitrile fumarate

The compound was prepared from 0.5 mmol of (dibenzo [b, f] oxepin-10-ylmethylmethylamino) acetonitrile free base with 1 equivalent of fumaric acid in 10 mL of 1: 1 chloroform / methanol. Evaporation of the chloroform / methanol mixture and crystallization from ethanol / diethyl ether gave the title compound as hydrogen fumarate (dibenzo [b, f] oxepin-10-ylmethylmethylamino) acetonitrile as white crystals in a yield of 57%;

mp: 100-105 ° C;

¹ H-NMR (200 MHz, CDCl 3): 2.45 (s, 3H); 3.69 (s,

2H); 3.71 (s, 2 H); 6.78 (s, 2H, fumaric acid); 6.95 (s,

1H); 7.12-7.42 (m, 7H); 7.55 (dd, 1H);

ES-MS: 277 (M ⁺ +1).

Example 16

2- (4-dibenzo [b, f] oxepin-10-ylmethylpiperazin-1-yl) maleate

The compound was prepared from 0.5 mmol of 2- (4-dibenzo [b, f] oxepin-10-ylmethyl-piperazin-1-yl) -pyrimidine free base with 1

5 · «·«. «

· · 44 ♦ · 4 4

4 44

4 4 4 4

4 4

44 equivalents of maleic acid in 10 mL of chloroform / methanol (1: 1). The title compound, 2- (4-dibenzo [b, f] oxepin-10-ylmethyl-piperazin-1-yl) -pyrimidine maleate, was obtained as white crystals in 41% yield;

mp: 199-204 ° C;

@ 1 H-NMR (200 MHz, CDCl3): 2.40-4.20 (m br, 10H), 6.12 (s, 2H, maleic acid); 6.69 (t, 1 H); 7.10-7.70 (m, 10H); 8.40 (d, 1H);

ES-MS: 371 (M ⁺ +1).

The starting material is prepared as follows:

a) 2- (4-Dibenzo [b, f] oxepin-10-ylmethylpiperazin-1-yl) pyrimidine

2.43 ml (17.4 mmol) of triethylamine, then 1.9 g (8.0 mmol) of 1- (2-pyrimidyl) piperazine dihydrochloride, are slowly added to a solution of 1.0 g (3.48 mmol) of 10- bromomethyl-dibenzo [b, f] oxepine in 7 mL of methanol and 7 mL of toluene. The solution was stirred at room temperature for 16 hours, the solvent was evaporated, the residue was taken up in dichloromethane, washed with saturated sodium bicarbonate solution, the organic layer was dried over magnesium sulfate and the residue was purified by silica gel chromatography (dichloromethane / methanol 39: 1). 0.62 g (48%) of 2- (4-dibenzo [b, f] oxepin-10-ylmethylpiperazin-1-yl) pyrimidine was obtained as a light brown oil;

¹ H-NMR (200 MHz, CDCl 3): 2.61 (t, 4H); 3.53 (s,

2H); 3.82 (t, 4H); 6.46 (m, IH); 6.89 (s, 1 H); 7.03-7.35 (m,

7H); 7.65 (m, IH); 8.29 (dd, 2 H);

ES-MS: 371 (M ⁺ +1).

• fc ····

Example 17

2- (4-dibenzo [b, f] oxepin-10-ylmethylpiperazin-1-yl) pyrimidine umfumará fcfcfcfc · fcfcfcfcfcfcfcfcfcfcfcfcfc fcfcfc ·· fcfc

The compound was prepared from 0.5 mmol of free base (2- (4-dibenzo [b, f] oxepin-10-ylmethyl-piperazin-1-yl) -pyrimidine) with 1 equivalent of fumaric acid in 10 mL of chloroform / methanol (1: 1). the compound, 2- (4-dibenzo [b, f] oxepin-10-ylmethyl-piperazin-1-yl) -pyrimidine fumarate, was obtained as white crystals in 58% yield;

mp 234-237 ° C;

¹ H-NMR (200 MHz, CDCl 3): 2.51 (m, 4H);

3.57 (s, 2 H); 3.71 (m, 4H); 6.71 (m, 1H); 6.72 (s, 2H, fumaric acid); 6.92 (s, 1 H); 7.10-7.40 (m, 5H); 7.67 (dd, 1H); 8.32 (d, IH);

ES-MS: 371 (M ⁺ +1).

Example 18

-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazinium maleate

The compound was prepared from 0.5 mmol of 1dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazine free base with 1 equivalent of maleic acid in 10 mL of 1: 1 chloroform / methanol. The title compound, 1-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazine maleate, was obtained as white crystals in 29% yield;

mp: 193-194 ° C;

@ 1 H-NMR (200 MHz, CDCl3): 2.40-4.20 (m br, 10H); 6.10 (s, 2H, maleic acid); 6.80-7.75 (m, 13H);

»444

44 • * * 4 • 4 · 4

4 · 4 · 9

4 4

ES-MS: 399 (M ⁺ +1).

The starting material is prepared as follows:

a) 1-Dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazine

2.43 ml (17.4 mmol) of triethylamine, then 2.12 g (8.0 mmol) of 1- (p-methoxyphenyl) piperazine dihydrochloride, are slowly added to a solution of 1.0 g (3.48 mmol) of 10- bromomethyl-dibenzo [b, f] oxepine in 7 mL of methanol and 7 mL of toluene. The solution was stirred at room temperature for 16 hours, the solvent was evaporated, the residue was taken up in dichloromethane, washed with saturated sodium bicarbonate solution, the organic layer was dried over magnesium sulfate and the residue was purified by silica gel chromatography (dichloromethane / methanol 39: 1). 19.0 g (14%) of 1-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazine are obtained in the form of pale beige crystals;

¹ H-NMR (200 MHz, CDCl 3): 2.71 (m, 4H); 3.10 (m,

4H); 3.58 (s, 2 H); 3.75 (s, 3H) 6.78-6.92 (m, 5H); 7.05-7.35 (m, 7H); 7.65 (m, 1H);

ES-MS: 399 (M ⁺ +1).

Example 19

-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazinium fumarate

The compound was prepared from 0.5 mmol of 1dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazine free base with 1 equivalent of fumaric acid in 10 mL of 1: 1 chloroform / methanol. The title compound, 1-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazine fumarate, is obtained as white crystals;

·························

m.p .: 176-179 ° C;

¹ H-NMR (200 MHz, CDCl 3): 2.40-4.20 (m br, 10H); 6.72 (s, 2H, maleic acid); 6.70-7.70 (m, 13H);

ES-MS: 399 (M ⁺ +1).

Example 20

Tablets containing 50 mg each of N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynyl ammonium fumarate can be prepared as follows:

Ingredients (10,000 tablets) Active ingredient 500.0 g lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (highly disoerged) 20.0 g ethanol qs

The active ingredient is mixed with lactose and 292 g of potato starch, moistened with an ethanolic gelatin solution and granulated through a sieve. After drying, the remaining potato starch, magnesium stearate, talc and silica are added and the mixture is compressed into 145.0 mg tablets containing 50.0 mg of active ingredient. If necessary, the tablets may be provided with a partial notch for dose adjustment.

··························

Example 21

A sterile, filtered, aqueous solution of gelatin with 20% cyclodextrins as a dissolving agent, each containing 3 mg of N (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynylammonium fumarate as the active ingredient, heating is mixed under aseptic conditions with a sterile gelatin solution containing phenol as a preservative such that 1.0 ml of the solution has the following composition:

active ingredient gelatin phenol dest. water with 20% cyclodextrins as solvent.

mg

150.0 mg

4,7 mg

1.0 ml

Example 22

For the preparation of a sterile dry substance for injection, each containing 5 mg of N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-Nprop-2 -inylammonium oxalate, 5 mg of one of the compounds of the formula I mentioned above Examples, as active ingredient, are dissolved in 1 ml of an aqueous solution of 20 mg of mannitol and 20% cyclodextrins as a dissolution agent. The solution is sterile filtered and filled into a 2 ml ampoule under aseptic conditions, deep-frozen and lyophilized. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of saline. The solution is applied intramuscularly or intravenously. The composition may also be filled into two-chamber injection ampoules.

Example 23

The following procedure may be used to prepare 10,000 film-coated tablets, each containing 100 mg of N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynyl ammonium fumarate:

• · • ·

1000 g

680 g

200 g g

G

250 g

q.s.

corn starch and active ingredient corn starch colloidal silica magnesium stearate stearic acid sodium starch starch water

The mixture of the active ingredient, 50 mg of corn starch and colloidal silicic acid is processed into a wet mass with a starch paste containing 250 g of corn starch and 2.2 kg of demineralized water. This mass is passed through a 3 mm sieve and dried for 30 minutes at 45 ° C on a bed of the fluid bed dryer. The dried granulate is passed through a 1 mm sieve, mixed with a pre-sieved (1 mm sieve) 330 g corn starch, magnesium stearate, stearic acid and sodium starch glycolate and compressed into slightly rounded tablets.

Example 24

Further, pharmaceutical compositions containing the compounds of Examples 1 to 19 can be prepared in an analogous manner to those described in Examples 20-23.

Claims (23)

PATENT CLAIMS An acid addition salt of 10-aminoaliphatic dibenz [b, f] oxepines of the general formula I wherein alk represents a divalent, aliphatic residue, R is an amino group which is either unsubstituted or mono- or disubstituted with a monovalent aliphatic and / or arylaliphatic residue, or disubstituted with a divalent aliphatic, arylaliphatic or heteroarylaliphatic residue, and R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, provided that: a) R is different from methylamino, dimethylamino, Ν'-methylpiperazino and Ν '- (2-hydroxyethyl) piperazino, or at least one of the radicals R _{1 Z} R ₂ and R ₄ is other than hydrogen, or R ₃ is other than hydrogen and 8-methoxy, or R is other than dimethylamino and diethylamino, or at least one of R ₁ , R ₂ and R ₄ is other than hydrogen or R ₃ is other than 8-chloro, or R is other than pyrrolidine or at least one of the radicals R _{L R} R _2, R ₃ or R ₄ is other than hydrogen, if alk is methylene, I 9 9 9 9 9 9 9999 9 9 · · · »····· • W · · 9 9 9 9999 9 999 999 99 99 b) R is different from methylamino or at least one of the radicals R _{1 Z} R ₂ and R ₄ is other than hydrogen, or R ₃ is other than a β-methyl group, or R is different from diethylamino, at least one of the radicals R _HR R ₂ and R ₄ is other than hydrogen or R ₃ is other than 7-methyl or at least one of R ₂ , R ₃ and R ₄ is other than hydrogen or R _x is other than 3-methyl when alk is ethylene group, c) R is different from methylamino and dimethylamino or at least one R _{1 Z} R _2, R ₃ and R ₄ is other than hydrogen, if alk signifies ethylidene, and d) R is other than dimethylamino or at least one of R ₂ and R ₄ is other than hydrogen or R _x is other than hydrogen, 3-chloro and 3-trifluoromethyl, or R ₃ is other than hydrogen, 8 -chloro and 8-trifluoromethyl, or R is other than diethylamino or at least one R _{1 (} R ₂ , R ₃ and R ₄ is other than hydrogen, or R is other than piperidine, at least one of R ₂ , R ₃ and R ₄ is other than hydrogen, or R _x is other than 1bromskupina or R ₂ and R ₄ is other than hydrogen and R _x 1bromskupina other than and R ₃ is other than hydrogen, or R _x is different than hydrogen and R ₃ is other than 9-bromo group can, if alk signifies propylene, with an organic carboxylic acid, with the exception of the hydrogen oxalate of N- (dibenzo [b, f] oxepin-LO-ylmethyl-N-methyl-N-prop 2inylamine. An acid addition salt of a compound of formula I according to claim 1, wherein alk is a lower alkylidene group, R is amino, lower alkylamino; and lower alkyl-phenylalkylamino, phenyl-carboxyalkyl-amino, lower-alkoxycarbonylalkyl-amino-lower-alkyl or lower-alkyl-phenylalkylalkylamino, which is either unsubstituted or substituted by lower-alkyl, lower-alkoxy, a halogen atom and / or a trifluoromethyl group; a lower alkyl hydroxyalkylamino group, a lower alkyl carboxyalkylamino group, a lower alkoxycarbonylalkylamino group, a lower alkylcarbamoylalkylamino group, a lower alkoxyalkylamino group, a lower alkyl group, an alkanoyloxyalkylamino group and a lower alkyl group, lower alkyl alkylamino, dialkylaminoalkylamino lower alkyl, lower alkylene amino lower alkyl, lower alkenylamino, lower alkenyl hydroxyalkenylamino, lower alkoxy lower alkenyl and lower alkenyl lower alkenyl, alkanoyl and lower alkenyl, dialkylaminoalkenylamino having lower alkyl and lower alkenyl groups, lower alkynylamino, hydroxyalkylamino having lower alkynyl, alkoxyalkylamino having lower alkoxy and lower alkynyl, alkanoyloxyalkylamino having lower alkanoyl and lower alkanoyl and loweralkynylamino lower alkyl groups and lower alkynyl groups, dialkylamino groups containing lower alkyl groups, di (hydroxyalkyl) amino groups containing lower alkyl groups, hydroxyalkylalkylamino groups containing lower alkyl groups, di (alkoxyalkyl) amino groups containing lower alkoxy groups and lower alkyl groups, alkoxyalkyl- alkylamino containing lower alkoxy and lower alkyl groups, alkanoyloxyal lower alkanoyl and lower alkyl-amino, lower alkanoyloxyalkylalkylamino and lower-alkyl, lower-alkyl-dialkylaminoalkylamino, lower-alkyl-dialkylaminoalkylamino, lower-alkenyl-lower-alkenyl-alkylamino and alkenylalkyenylamino lower alkenyl and lower alkyl, di (alkoxyalkenyl) amino containing lower alkoxy and lower alkenyl, alkoxyalkenylalkylamino containing lower alkoxy, lower alkenyl and lower alkyl, alkanoyloxyalkenylalkylamino containing lower alkanoyl, lower alkenyl and lower alkyl, dialkylaminoalk lower alkyl and lower alkenyl-lower alkylamino, lower alkynyl and lower-alkynylamino, lower-alkoxy-lower alkylamino, lower-alkynylamino and lower-alkanoyloxyalkylamino, lower-alkynyl and lower-alkylamino a dialkylaminoalkynylalkylamino group containing lower alkyl groups and lower alkynyl group; respectively a 3- to 8-membered lower alkyleneamino, lower alkenyleneamino or lower alkadienyleneamino group which is either unsubstituted or substituted by carboxy, lower alkoxycarbonyl or carbamoyl or cyano; a cyano (phenyl) alkylene amino group containing a lower alkylene group which is either unsubstituted or substituted at the lower phenyl group • β ·· «·« 9 9 9 9 9 9 9 9 98 9 9 9999 9 9 9 9 9 9 999 9 9 9 9 9 9 9 9 9999 4 999 9 9 9 99 99 alkyl, lower alkoxy, halogen and / or trifluoromethyl; 3- or 4-aza-lower alkylene amino which is either unsubstituted or N-substituted by lower alkyl, hydroxyalkyl containing lower alkyl, alkoxyalkyl containing lower alkoxy and lower alkyl, pyridinyl, pyrimidinyl, triazinyl or lower alkanoyl; A 3- or 4-oxaalkyleneamino group containing a lower alkylene group, optionally an S-oxidized 3 or 4-thiaalkyleneamino group containing a lower alkylene group; or a N ¹ -phenylazaalkyleneamino group containing a lower alkylene group or a Ν'-benzylazaalkyleneamino group having a lower alkylene group which is either unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group, and R _{1 Z} R _2, R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with the proviso that R is other than an amino group which is either unsubstituted or mono- or di-substituted by lower alkyl; pyrrolidino, piperidino, morpholino, Ν'methylpiperazino, Ν '- (2-hydroxyethyl) piperazino, Ν' (2-acetoxyethyl) piperazino, Ν '- (2-pivaloyloxyethyl) piperazino and N'-methylhompiperazino, or when alkenyl is methyl or ethylidene group, and R _{1 Z} R _2, R ₃ and R ₄ are hydrogen, lower alkyl, lower alkoxy and / or halogen, with a pharmaceutically applicable, optionally hydroxylated lower alkanoic acid, optionally hydroxylated, aminated • · · · • « • ♦ ·.: ..: and / or an oxosubstituted lower alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, with the exception of oxenoxalate N (dibenzo [n] dibenzoate) -10-ylmethyl-N-methyl-N-prop-2-ynylamine. An acid addition salt of a compound of formula I according to claim 1, wherein alk is a methylene group or an ethylidene group, R is amino, lower alkylamino; lower alkyl, phenylalkylamino, phenyl (carboxyalkyl) amino, phenyl (alkoxycarbonylalkyl) amino containing lower alkoxy and lower alkyl or phenylalkylalkylamino containing lower alkyl which is either unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl; a lower alkyl hydroxyalkylamino group, a lower alkoxyalkylamino group and a lower alkyl alkanoyloxyalkylamino group containing a lower alkanoyloxy group and a lower alkyl group, a lower alkyl group alkylaminoalkylamino group, a lower alkyl group containing an alkylene amino group, an alkylene amino group containing a lower alkyl group, lower alkenylamino, hydroxyalkenylamino containing lower alkenyl, alkoxyalkenylamino containing lower alkoxy and lower alkenyl, alkanoyloxyalkenylamino containing lower alkanoyl and lower alkenyl, dialkylaminoalkenylamino> · 4 4 4 4 4 4 • 44 4 4 containing lower alkyl and lower alkenyl, lower alkynylamino, lower alkynyl hydroxyalkylamino, lower alkoxyalkylamino and lower alkynyl, lower alkanoyloxyalkylamino and lower alkynyl, lower alkylaminoalkynylamino lower alkyl, dialkylamino containing lower alkyl, di (hydroxyalkyl) amino containing lower alkyl, hydroxyalkylalkylamino containing lower alkyl, di (alkoxyalkyl) amino containing lower alkoxy and lower alkyl, alkoxyalkyl-alkylamino containing lower alkyl, and lower alkoxy, alkanoyloxyalkylamino containing lower alkanoyl and lower alkyl coupler, lower alkanoyloxyalkylalkylamino group containing lower alkanoyl and lower alkyl groups, dialkylaminoalkylamino group containing lower alkyl groups, dialkylaminoalkylalkylamino group containing lower alkyl groups, dialkenylamino group containing lower alkenyl groups and lower alkyl group containing lower alkenyl and lower alkyl groups, hydroxyalkylamino group lower, di (alkoxyalkenyl) alkoxy and lower alkenyl, lower alkoxyalkenylalkylamino containing lower alkoxy, lower alkenyl and lower alkyl, lower alkanoyloxyalkenylalkylamino, lower alkenyl and lower alkyl, dialkylaminoalkenylalkylamino lower alkyl and lower alkyl a lower alkynyl alkylamino group containing a lower alkynyl group and a lower alkyl group, a lower alkoxyalkylamino alkylamino group, a lower alkynyl group 4 ··· • 4 4 44 4 · 4444 • 4 4 4 9 9 ·· 4 · 4 4 4 9 44 · 4 · 4 · 4 4 · 4444 4444 444 44 44 and a lower alkyl group, a lower alkanoyloxyalkylaminoalkylamino group, a lower alkynyl group and a lower alkyl group, a dialkylaminoalkynylalkylamino group having a lower alkyl group and a lower alkynyl group, a 3- to 8-membered lower alkylene amino group; A 3- or 4-azaalkylene amino group having a lower alkylene group which is either unsubstituted or N-substituted by a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group containing a lower alkoxy group or a lower alkyl group or a lower alkanoyl group; A 3- or 4-oxaalkyleneamino group containing a lower alkylene group or an optionally S-oxidized 3- or 4-thiaalkyleneamino group containing a lower alkylene group, and R _{1 Z} R _2, R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with pharmaceutically applicable, optionally hydroxylated lower alkanoic acid, optionally hydroxylated and / or oxo-substituted lower alkane acid , fumaric acid, maleic acid, tartaric acid, citric acid, pyroacemic acid, malic acid, further with an aromatic, heteroaromatic or arylaliphatic carboxylic acid. An acid addition salt of a compound of formula I according to claim 1, wherein alk is a lower alkylidene group, R is amino, lower alkylamino, cyanoalkylamino containing lower alkyl; a lower alkyl phenylalkylamino group, a lower alkyl phenyl (carboxyalkyl) amino group, 4 4 44 4 4 4 4 444 44 44 phenyl (alkoxycarbonylalkyl) amino group containing a lower alkoxy group and a lower alkyl group or phenylalkylalkylamino group containing a lower alkyl group, which is optionally unsubstituted; or 4 4 4 4 4 44 44 substituted with lower alkyl, lower alkoxy, halogen and / or trifluoromethyl; lower alkynylamino, dialkylamino containing lower alkyl groups, 3- to 8-membered lower alkylene amino or cyano (phenyl) alkylene amino containing lower alkylene, 3- to 8-membered lower alkenylene amino; A 3- or 4-azaalkylene amino group having a lower alkylene group which is either unsubstituted or N-substituted by a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group having a lower alkoxy group and a lower alkyl group or a lower alkanoyl group; A 3- or 4-oxaalkyleneamino group containing a lower alkylene group, optionally an S-oxidized 3- or 4thiaalkyleneamino group containing a lower alkylene group, or a 3- to 8-membered Ν'-pyrimidinylazaalkyleneamino group containing a lower alkylene group, respectively; lower alkylene-containing phenylalkylene, lower alkylene-phenyl (cyano) alkylene, lower alkylene-N'-phenylazaalkylenamino or lower alkylene-Ν'-benzylazaalkyleneamino which is either unsubstituted or substituted on the phenyl group by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, and R _{1 Z} R _2, R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with pharmaceutically applicable, optionally hydroxylated lower alkanoic acid, optionally hydroxylated, aminated • · 0 «00 0 0 0 0 • 0 0 0 00 0 0 0 0 0 0 And / or an oxosubstituted lower alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, further with an aromatic or aromatic, heteroaromatic or heteroaromatic . An acid addition salt of a compound of formula I according to claim 1, wherein alk is a methylene group, R is C 1 -C 4 alkylamino, C 1 -C 4 cyanoalkylamino, C 1 -C 4 phenylalkylamino, C 1 -C 4 phenylalkylalkylamino, phenyl (1-carboxyalkyl) amino (C 1 -C 4) -alkyl or phenyl- (1-alkoxycarbonylalkylamino) (C 1 -C 4) and (C 1 -C 4) alkyl which is unsubstituted or substituted by (C 1 -C 4) alkyl, such as is methyl, C1-C4alkoxy, halogen of atomic number up to and including 35 and / or trifluoromethyl, alkenylamino of 2 to 7 carbon atoms, alkynylamino of 2 to 7 carbon atoms, N-alkenyl-N-alkylamino containing in the alkenyl moiety 2 up to 7 carbon atoms and 1 to 4 carbon atoms in the alkyl moiety, N-alkynyl-N-alkylamino having 2 to 7 carbon atoms in the alkynyl moiety and 1 to 4 carbon atoms in the alkyl moiety; carbon atoms, pyrrolidino, piperidino, 1,2,3,6-tetrahydropyridino; 4-cyano-4-phenylpiperidino which is either unsubstituted 99 9999 99 99 9 9 9 9 9 9 9 9 9 9 98 9 9 9999 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9999 9 999 ··· 99 99 or substituted by an alkyl group having 1 to 4 carbon atoms in the alkyl moiety, an alkoxy group having 1 to 4 carbon atoms, a halogen atom having an atomic number up to and including 35 and / or trifluoromethyl; morpholino, piperazino, Ν'-alkylpiperazino having 1 to 4 carbon atoms in the alkyl moiety, Ν '- (hydroxyalkyl) piperazino having 2 to 4 carbon atoms in the alkyl moiety, N'pyrimidinylpiperazino; or Ν'-phenylpiperazino or Ν'-phenylalkylpiperazino having 1 to 4 carbon atoms in the alkyl moiety, which is either unsubstituted or substituted by a alkyl group having 1 to 4 carbon atoms, a alkoxy group having 1 to 4 carbon atoms, a halogen atom having an atomic number up to 35 including and / or trifluoromethyl, and R _x, R _2, R ₃ and R ₄ are independently hydrogen, alkyl of 1-4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogen with an atomic number up to and including 35 or trifluoromethyl, with pharmaceutically applicable , optionally hydroxylated alkanoic acid containing 1 to 7 carbon atoms, optionally hydroxylated, aminated and / or oxosubstituted alkanedicarboxylic acid containing 2 to 7 carbon atoms, optionally hydroxylated and / or oxosubstituted alkantricarboxylic acid containing 4 to 7 carbon atoms, optionally hydroxylated and / or oxosubstituted a C 4 -C 7 alkenedicarboxylic acid, optionally a hydroxy and / or an oxosubstituted C 4 -C 7 alkindicarboxylic acid, further with benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid. ·· ···· • 0 00 * · 0 · · 0 0 0 0 0 0 * · 0 An acid addition salt of a compound of formula I according to claim 1 1 wherein alk is a methylene group, R is C 1 -C 4 alkylamino; phenylalkylamino having 1 to 4 carbon atoms in the alkyl moiety, phenylalkylalkylamino having 1 to 4 carbon atoms in each alkyl moiety, phenyl- (1-carboxyalkyl) amino having 1 to 4 carbon atoms in the alkyl moiety or phenyl- (1-alkoxycarbonylalkylamino) moiety (C 1 -C 4) alkoxy moieties and C 1 -C 4 alkyl moieties which are either unsubstituted or substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen atoms up to and including 35; and / or C 2 -C 7 alkenylamino, C 2 -C 7 alkynylamino, N-alkenyl-N-C 2 -C 7 alkylamino and C 1 -C 4 alkyl, N-alkynyl- N-alkylamino having 2 to 7 carbon atoms in the alkynyl moiety; (C 1 -C 4) alkyl moieties, (C 1 -C 4) dialkylamino, pyrrolidino, piperidino, morpholino, piperazino, N'-alkyl (C 1 -C 4) alkyl, or N '- (hydroxyalkyl) piperazino having 2 to 4 carbon atoms in the alkyl moiety, and R _{@ 1} , R _{@ 2} , R @ ₃ and R _{@ 4} are each independently hydrogen, C1 -C4 alkyl, C1 -C4 alkoxy, halogen having atomic numbers up to and including 35, or trifluoromethyl with acetic acid , propionic acid, pivalic acid, glycolic acid, pyroacemic acid, ·· ···· 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 ₈₈ ............... lactic acid, oxalic acid, succinic acid, tartaric acid or malic acid, citric acid, fumaric acid, maleic acid, benzoic acid, mandelic acid or nicotinic acid. An acid addition salt of a compound of formula I, wherein alk is a methylene group, R is a C 2 -C 7 alkenylamino group, a C 2 -C 7 alkynylamino group, a N-alkenyl N-alkylamino group having 2 to 7 carbon atoms in the alkenyl moiety, and a C 1 -C 4 alkyl moiety, an N-alkynyl-Nalkylamino group in the alkynyl moiety 2 to 7 carbon atoms and 1 to 4 carbon atoms in the alkyl moiety; or a phenylalkylamino group having 1 to 4 carbon atoms in the alkyl moiety which is either unsubstituted or substituted by a alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom having an atomic number up to and including 35 and / or trifluoromethyl; R _x, R _2, R ₃ and R ₄ are independently hydrogen, alkyl of 1-4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogen with an atomic number up to and including 35 and / or trifluoromethyl group, a pharmaceutically usable, optionally hydroxylated alkanoic acid having 1 to 7 carbon atoms, optionally a hydroxylated, aminated and / or oxosubstituted alkanedicarboxylic acid having 2 to 7 carbon atoms, an optionally hydroxylated and / or an oxosubstituted alkantricarboxylic acid 4 to 7 carbon atoms, optionally hydroxylated and / or oxosubstituted alkene dicarboxylic acid containing 4 to 7 carbon atoms, optionally hydroxylated, optionally hydroxylated This and / or an oxosubstituted alkindicarboxylic acid containing 4 to 7 carbon atoms, with ben acid zoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid. An acid addition salt of a compound of formula I according to claim 1, wherein alk is a methylene group, R is C 2 -C 7 alkenylamino, C 2 -C 7 alkynylamino, C 2 -C 7 alkenyl-N-alkylamino and C 1 -C 4 -alkyl, or N-alkynyl N-alkylamino in the alkynyl moiety a C 2 -C 7 moiety and a C 1 -C 4 alkyl moiety; R _{1 Z} R _2, R ₃ and R ₄ are hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogen with an atomic number up to and including 35 and / or trifluoromethyl, with pharmaceutically applicable, optionally hydroxylated alkanoic acid having 1 to 7 carbon atoms, optionally hydroxylated, aminated and / or oxosubstituted alkanedicarboxylic acid having 2 to 7 carbon atoms, optionally hydroxylated and / or oxosubstituted alkanetricarboxylic acid having 4 to 7 carbon atoms, optionally hydroxylated and / or oxosubstituted alkenedicarboxylic acid containing 4 to 7 carbon atoms, optionally hydroxylated and / or oxosubstituted alkindicarboxylic acid containing 4 to 7 carbon atoms, for example with acetylenedicarboxylic acid, benzoic acid, salicylic acid, phthalic acid, ··· · tt ·· 9 9 9 9 9 9 9 9 99 9 9 9 9 9999999 9 9 9 9 9 9 9999 9 999 999 99 99 Phenylacetic acid, cinnamic acid or nicotinic acid. mandelic acid An acid addition salt of a compound of formula I according to claim 1, wherein alk is a methylene group, R is C 2 -C 7 alkenylamino, C 2 -C 7 alkynylamino, C 2 -C 7 alkenyl-N-alkylamino and C 1 -C 4 -alkyl, or N-alkynyl N-alkylamino in the alkynyl moiety parts of 2 to 7 carbon atoms and in the alkyl part of 1 to 4 carbon atoms, R _x and R ₃ are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or trifluoromethyl; and R ₂ , R ₄ are hydrogen, with glycolic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, pyroacemic acid, malic acid, benzoic acid, nicotinic acid or mandelic acid. An acid addition salt selected from the group consisting of N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynylammonium maleate, N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methyl-N-prop-2-ynylammonium fumarate, N-benzyl-N- (dibenzo [b, f] oxepin-10-ylmethyl) -N-methylammonium maleate, 9 9 99 9 9 99 99 9 9 9 9 9 9 9 9 9 99 9 9 9 9 9 9 999 9 9 9 9 9 9 9 9 · ·· * 9 999 999 99 99 2 - [(dibenzo [b, f] oxepin-10-ylmethyl) -ammonio] -3-phenylpropionic acid ethyl ester maleate 1-dibenzo [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydropyridinium maleate, 1-dibenzo [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydropyridinium fumarate, 1-dibenzo [b, f] oxepin-10-ylmethyl-1,2,3,6-tetrahydropyridinium succinate, 1-benzyl-4-dibenzo [b, f] oxepin-10-ylmethylpiperazinium dimaleate, 1-benzyl-4- dibenzo [b, f] oxepin-10-ylmethylpiperazinium difumarate, 1-dibenzo [b, f] oxepin-10-ylmethyl-4-phenylpiperidinium-4-carbonitrile maleate, 1-dibenzo [b, f] oxepin-10-ylmethyl-4-phenylpiperidinium-4-carbonitrile fumarate, 1-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-chlorophenyl) piperazinium maleate, 1-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-chlorophenyl) piperazinium fumarate, (dibenzo [b, f] oxepin-10-ylmethylmethylammonio) acetonitrile maleate, (dibenzo [b, f] oxepin-10ylmethylmethylammonio) acetonitrile fumarate , 2- (4-dibenzo [b, f] oxepin-10-ylmethylpiperazin-1-yl) pyrimidinium maleate, fcfc · fcfc ··· · fcfcfc · · · · · · · 2- (4-dibenzo [b, f] oxepin-10-ylmethylpiperazin-1-yl) pyrimidinium fumarate, 1-dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazinium maleate, or 1-Dibenzo [b, f] oxepin-10-ylmethyl-4- (4-methoxyphenyl) piperazinium fumarate. A compound of formula I wherein alk is a lower alkylidene group, R is an amino group monosubstituted with a lower alkyl group or a lower alkyl phenylalkyl group which is either unsubstituted on the phenyl group or substituted with a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group and a lower alkyl group optionally esterified with a carboxyl group ; or on an amino group disubstituted by lower alkylene, lower alkenylene or lower alkadienylene or a phenylakylene group containing a lower alkylene group, a cyano (phenyl) alkylene group having a lower alkylene group, a phenylalkylalkylene group having a lower alkyl group and a lower alkylene group, N'phenylazaalkylene group a lower alkylene group or a Ν'-phenylalkylazaalkylene group containing a lower alkyl group and a lower alkylene group which is either unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group, and R _1, R ₂ , R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, in free form. The compound of claim 11, wherein alk is a lower alkylidene group, R is cyanoalkylamino having 1 to 4 carbon atoms in the alkyl moiety; phenyl- (1-carboxyalkyl) amino having 1 to 4 carbon atoms in the alkyl moiety, phenyl- (1-alkoxycarbonylalkylamino having 1 to 4 carbon atoms in the alkoxy moiety and 1-4 carbon atoms in the alkyl moiety, 4-cyano-4-phenylpiperidino, phenylalkylpiperidino) (C1-C4) -alkyl, phenyl-C1-C4-phenylalkylpiperazino, phenyl-piperazino or (C1-C4) -phenyl-alkylpiperazino, which is either unsubstituted or substituted by C1-C4alkyl, alkoxy having 1 to 4 carbon atoms, a halogen atom having an atomic number of up to and including 35 and / or a trifluoromethyl group, a 1,2,3,6-tetrahydropyridino group or a Ν'-pyrimidinylpiperazino group, and R _HR R _2, R ₃ and R ₄ are independently hydrogen, alkyl of 1-4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogen with an atomic number up to and including 35 or trifluoromethyl, inve free form. The compound of claim 11, selected from the group consisting of 2 - [(dibenzo [b, f] oxepin-10-ylmethyl) amino] -3-phenylpropionic acid ethyl ester; 1- (dibenzo [b, f] oxepin-10-ylmethyl) -1,2,3,6-tetrahydropyridine; 1- (dibenzo [b, f] oxepin-10-ylmethyl) -4-phenylpiperidine-4-carbonitrile; 1- (dibenzo (b, f) oxepin-10-ylmethyl) -4- (4-chlorophenyl) piperazine; (dibenzo (b, f) oxepin-10-ylmethylamino) acetonitrile; 1- (dibenzo [b, f] oxepin-10-ylmethyl) -4- (4-methoxyphenyl) piperazine; 2- [4- (dibenzo [b, f] oxepin-10-ylmethyl) -piperazin-1-yl] pyrimidine and 1-benzyl-4-dibenzo [b, f] oxepin-10-ylmethylpiperazine. A compound according to any one of claims 1 to 13 for the treatment of human or animal. A pharmaceutical composition comprising an acid addition salt according to any one of claims 1 to 10 or a compound according to any one of claims 11 to 13, as well as conventional pharmaceutical additives and carriers. 16. A process for the preparation of acid addition salts of compounds of formula (I) wherein alk is a divalent, aliphatic radical, and 4 .alpha.-4 .alpha.-4 .alpha. «· ··· ·· ·· '95 R is an amino group which is either unsubstituted or mono- or disubstituted with a monovalent aliphatic and / or arylaliphatic residue, or disubstituted with a divalent aliphatic, arylaliphatic or heteroarylaliphatic residue, and R _HR R _2, R ₃ and R ₄ are, independently, hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with the proviso that (a) R is other than methylamino, dimethylamino, Ν'-methylpiperazino and N '- (2-hydroxyethyl) piperazino, or at least one of R _1, R ₂ and R ₄ is other than hydrogen or R ₃ is other than hydrogen and 8-methoxy gr on, or R is different from dimethylamino and diethylamino or at least one of the radicals R _{1 Z} R ₂ and R ₄ is other than hydrogen, or R ₃ is other than 8-chloro, or R is different from pyrrolidino or at least one of the radicals R _{1 Z} R _2, R ₃ or R ₄ is other than hydrogen, if alk is methylene, b) R is different from methylamino or at least one of the radicals R _{L R} R ₂ and R ₄ is other than hydrogen, or R ₃ is other than 6-methyl, or R is different from diethylamino, at least one of the radicals R _HR R ₂ and R ₄ is other than hydrogen or R ₃ is other than 7-methyl or at least one of R ₂ , R ₃ and R ₄ is other than hydrogen or R _x is other than 3-methyl, when alk is ethylene, c) R is different from methylamino and dimethylamino or at least one R _{1 Z} R _2, R ₃ and R ₄ is other than hydrogen, if alk signifies ethylidene, and d) R is other than dimethylamino or at least one of the radicals R ₂ and R ₄ is other than hydrogen or R _x is other than hydrogen, 3-chloro and 3-trifluoromethyl, or R _{3 is} feefefe Is other than a hydrogen atom, an 8-chloro group and an 8-trifluoromethyl group, or R is other than a diethylamino group or at least one R ₁ group ₍ R ₂ , R ₃ and R ₄ is other than hydrogen, or R is other than piperidine, at least one of R ₂ , R ₃ and R ₄ is other than hydrogen, or R _x is other than 1-bromo, or R ₂ and R ₄ are other than atom hydrogen and R ₂ other than 1-bromo and R ₃ is other than hydrogen or R _x is other than hydrogen and R ₃ is other than 9-bromo when alk is propylene with an organic carboxylic acid, with the exception of N- ( dibenzo [b, f] oxepin-10-ylmethyl-N-methyl-N-prop-2-ylamine, characterized in that the compound of formula (I) in free form is reacted with at least a quantitative amount of the organic carboxylic acid required to form the salt and isolating the desired salt. 17. A method of treating neurodegenerative disorders in which apoptotic cytolysis plays a role, such as cerebral ischemia, Alzheimer's disease, Huntington's and Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, various types of glaucoma, retinal degenenation, particularly retinida pigmentosis, as well as general or diabetic peripheral neuropathy, characterized in that a therapeutically effective amount of an acid addition salt of 10-aminoaliphatic-dibenz [b, f] oxepine of formula I R alk Γ O) where alk is a divalent, aliphatic residue, R is an amino group which is either unsubstituted or mono- or di-substituted with a monovalent aliphatic and / or arylaliphatic residue, or disubstituted with a divalent aliphatic, arylaliphatic or heteroarylaliphatic residue, and R _{1 Z} R _2, R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with an organic carboxylic acid, with the exception of the hydrogen oxalate of N- (dibenzo [b, f] oxepin-10 -ylmethyl-N-methyl-N-prop-2-ylamine, or a compound according to claims 11, is administered to warm-blooded persons or animals in need of such treatment. Use of an acid addition salt of 10-aminoalkyldibenz [b, f] oxepine of the general formula I wherein alk represents a divalent, aliphatic residue, (I) R is an amino group which is either unsubstituted or mono- or di-substituted with a monovalent aliphatic and / or arylaliphatic group, or disubstituted with a divalent aliphatic, arylaliphatic or heteroarylaliphatic group, and R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with an organic carboxylic acid except for N (dibenzo [b, f] oxepin-10- ylmethyl-N-methyl-N-prop-2-ynylamine as an antineurodegenerative drug or for the preparation of such a drug. Use of an acid addition salt of a compound of formula I according to claim 18, wherein alk is a lower alkylidene group, R is amino, lower alkylamino; and lower-alkyl-phenylalkylamino, phenyl-carboxyalkyl-amino, lower-alkoxycarbonylalkyl-amino, or lower-alkyl-phenylalkylalkylamino, which is either unsubstituted or substituted by lower-alkyl, lower-alkoxy, a halogen atom and / or a trifluoromethyl group; a lower alkyl hydroxyalkylamino group, a lower alkyl carboxyalkylamino group, a lower alkoxycarbonylalkylamino group, a lower alkylcarbamoylalkylamino group, a lower alkoxyalkylamino group, a lower alkyl group, an alkanoyloxyalkylamino group and a lower alkyl group, alkylamino contains alkynylaminoalkylamino, alkyleneaminoalkyl99 ivv> mzsi Containing lower alkyl, lower lower alkylene and lower alkyl, lower alkenylamino, hydroxyalkenylamino lower alkenyl, alkoxyalkenylamino lower alkoxy and lower alkenyl, alkanoyloxyalkenylamino lower alkenylamino and lower alkenylamino; lower alkyl and lower alkenyl, lower alkynylamino, hydroxyalkylamino lower alkyl, lower alkoxyalkylamino and lower alkynyl, lower alkanoyloxyalkylamino and lower alkynyl, lower alkyl and lower alkylamino alkynylamino, alkyl groups, di (hydroxyalkyl) amino group containing lower alkyl groups, hydroxyalkylalkylamino group containing lower alkyl groups, di (alkoxyalkyl) amino group containing lower alkoxy group and lower alkyl group, alkoxyalkyl-alkylamino group containing lower alkoxy group and lower alkyl groups, alkanoyloxyalkylamino group containing lower alkanoyl group and alkanoyl and lower alkyl lower alkyl containing lower groups, dialkylaminoalkylamino group containing lower alkyl groups, dialkylaminoalkylamino group containing lower alkenyl groups, alkenylalkylamino group containing lower alkenylalkylamino group, a lower alkenyl group and a lower alkyl group, di (alkoxyl) yalkenyl) amino group containing a lower alkoxy group and a lower alkenyl group ·· · ·· · * 9 9 9 9 9 9 · · · · 9 9 9 9 9999999 9 9 · · 9 9 9 9999 9 ··· ··· ·· ·· 100, lower alkoxyalkenylalkylamino comprising lower alkoxy, lower alkenyl and lower alkyl, alkanoyloxyalkenylalkylamino comprising lower alkanoyl, lower alkenyl and lower alkyl, dialkylaminoalkenylalkylamino comprising lower alkyl and lower alkenyl, alkynylalkylamino and lower alkynyl alkylamino; lower alkoxyalkylamino, lower alkynyl and lower alkyl, lower alkanoyloxyalkylaminoalkylamino, lower alkynyl and lower alkyl, lower alkyl and lower alkynyl alkylaminoalkylamino; respectively a 3- to 8-membered lower alkyleneamino group which is either unsubstituted or substituted by a carboxyl, lower alkoxycarbonyl or carbamoyl or cyano group, a 3- to 8-membered lower alkenyleneamino group, a lower alkenyleneamino group or a lower alkadienyleneamino group; 3- or 4-azaalkylene amino having a lower alkylene group which is either unsubstituted or N-substituted by a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group having a lower alkoxy group and a lower alkyl group, a pyridinyl group, a pyrimidinyl group, a triazinyl group or a lower alkanoyl group a group; A 3- or 4-oxaalkyleneamino group, optionally an S-oxidized 3- or 4-thiaalkyleneamino group containing a lower alkylene group; or a N'-phenylazaalkyleneamino group containing a lower alkylene group or a Ν'-benrylazaalkyleneamino group containing a lower alkylene group which is either unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group, and 101 R _{1 Z} R _2, R and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with pharmaceutically applicable, optionally hydroxylated lower alkanoic acid, optionally hydroxylated, aminated and / or oxo-substituted lower alkane acid , optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, further with an aromatic, heteroaromatic or arylaliphatic carboxylic acid for such a medicament as an antineurodegenerative. Use of an acid addition salt of a compound of formula I according to claim 18, wherein alk is a methylene group or an ethylidene group, R is amino, lower alkylamino; lower alkyl-phenylalkylamino, phenyl (carboxyalkyl) lower-alkyl, lower-alkoxycarbonylalkyl) lower-alkyl or lower-alkyl phenylalkylalkylamino, which is either unsubstituted or substituted by lower-alkoxy, trifluoromethyl ; lower alkyl hydroxyalkylamino, lower alkoxyalkylamino lower alkyl, lower alkanoyloxyalkylamino lower alkyl, lower alkyl lower alkyl alkylaminoalkylamino, dialkyl lower alkyl halogen and / or 102 Lower alkyl aminoalkylamino, lower alkylene aminoalkylamino and lower alkyl, lower alkenylamino, hydroxyalkenylamino containing 102 alkenyl, lower alkoxyalkenylamino having lower alkoxy and lower alkenyl, lower alkanoyloxyalkenylamino having lower alkanoyl and lower alkenyl, dialkylaminoalkenylamino having lower alkyl and lower alkenyl, lower alkynylamino, hydroxyalkylamino having lower alkynyl and alkoxyalkylamino a lower alkanoyl and a lower alkynyl group, a dialkylaminoalkylamino group containing a lower alkanoyl group and a lower alkynyl group; lower alkyl and lower alkynyl, dialkylamino containing lower alkyl groups, di (hydroxyalkyl) amino containing lower alkyl groups, hydroxyalkylalkylamino group containing lower alkyl groups, di (alkoxyalkyl) amino group containing lower alkoxy and lower alkyl groups, alkoxyalkylalkylamino group containing lower alkoxy groups and lower alkyl, lower alkanoyloxyalkylamino and lower alkyl, lower alkanoyloxyalkylalkylamino and lower alkyl, lower alkyl dialkylaminoalkylamino, lower alkyl lower alkylamino, lower alkenyl alkylamino and lower alkenyl alkylamino; alkyl, hydroxyalkenylal a lower alkenyl and lower alkyl cylamino group, a di (alkoxyalkenyl) lower alkoxy and lower alkenyl amino group, alkoxyalkenylalkyl44 4 · 4 · • 4 44 • 4 4 44 44 4 4 4 · 4 4 4 44 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4444 4,444 444 44 44 103 amino group containing lower alkoxy, lower alkenyl and lower alkyl groups, alkanoyloxyalkenylalkylamino group containing lower alkanoyl group, lower alkenyl group and lower alkyl group, dialkylaminoalkenylalkylamino group containing lower alkyl groups and lower alkenyl groups, alkynylalkylamino group containing lower alkylamino group and lower alkylalkylamino group, comprising lower alkoxy, lower alkynyl and lower alkyl, lower alkanoyloxyalkylaminoalkylamino, lower alkynyl and lower alkyl, dialkylaminoalkynylalkylamino of lower alkyl, lower alkynyl and lower alkyl, 3- to 8-membered lower alkyleneamino; A 3- or 4-azaalkylene amino group having a lower alkylene group which is either unsubstituted or N-substituted with a lower alkyl group, a hydroxyalkyl group having a lower alkyl group, an alkoxyalkyl group having a lower alkoxy group and a lower alkyl group or a lower alkanoyl group; A 3- or 4-oxaalkyleneamino group containing a lower alkylene group or optionally an S-oxidized 3- or 4-thiaalkyleneamino group containing a lower alkylene group, and R _x, R _2, R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with pharmaceutically applicable, optionally hydroxylated lower alkanoic acid, optionally hydroxylated and / or oxo-substituted lower alkane acid , fumaric acid, maleic acid, tartaric acid, citric acid, pyroacemic acid, malic acid, further with an aromatic, heteroaromatic or arylaliphatic carboxylic acid, »··· 104 as an antineurodegenerative drug or for the preparation of such a drug. Use of an acid addition salt of an compound of formula I according to claim 18, wherein alk is a lower alkylidene group, R is amino, lower alkylamino, cyanoalkylamino containing lower alkyl; lower alkyl-phenylalkylamino, phenyl-carboxyalkyl-amino, lower-alkoxycarbonylalkyl-amino-lower-alkyl or lower-alkyl-phenylalkylalkylamino, which is either unsubstituted or substituted by lower-alkyl, lower-alkoxy, halogen and / or trifluoromethyl; lower alkynylamino, dialkylamino containing lower alkyl groups, 3- to 8-membered lower alkyleneamino or cyano (phenyl) alkylene amino containing lower alkyl, 3- to 8-membered lower alkenyleneamino; A 3- or 4-azaalkylene amino group having a lower alkylene group which is either unsubstituted or N-substituted by a lower alkyl group, a hydroxyalkyl group containing a lower alkyl group, an alkoxyalkyl group having a lower alkoxy group and a lower alkyl group or a lower alkanoyl group; A 3- or 4-oxaalkyleneamino group containing a lower alkylene group, optionally an S-oxidized 3- or 4thiaalkyleneamino group containing a lower alkylene group, or a 3- to 8-membered N'-pyrimidinylazaalkyleneamino group containing a lower alkylene group; a lower alkylene-containing phenylalkylene group, a lower alkylene-containing phenyl (cyano) alkylene group, a N'-phenylazaalkyleneamino group containing a lower alkylene group BBBBBB · ** · * ΒΒΒΒ Β Β Β Β ΒΒ ΒΒΒΒ · Β Β · · · ΒΒ ΒΒΒΒΒΒΒ Β Β Β ΒΒΒΒΒΒΒ ΒΒΒ Β Β Β ΒΒΒ ΒΒ Β ΒΒΒ ΒΒΒ ΒΒ ΒΒ 105 an alkylene group or a Ν'-benzylazaalkyleneamino group containing a lower alkylene group which is either unsubstituted or substituted on the phenyl group by a lower alkyl group, a lower alkoxy group, a halogen atom and / or a trifluoromethyl group, and R _x, R _2, R ₃ and R ₄ are independently hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, with pharmaceutically applicable, optionally hydroxylated lower alkanoic acid, optionally hydroxylated, aminated and / or oxo-substituted lower an alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanetricarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, optionally hydroxylated and / or oxosubstituted lower alkanedicarboxylic acid, further with an aromatic, heteroaromatic or arylaodiphatic carboxylic acid, pharmaceuticals. Use of an acid addition salt of a compound of formula I according to claim 18, wherein alk is a methylene group, R is (C 1 -C 4) alkylamino, (C 1 -C 4) cyanoalkylamino, (C 1 -C 4) phenylalkylamino, (C 1 -C 4) phenylalkylalkylamino, phenyl (1-carboxyalkyl) amino (C 1 -C 4) -alkyl or phenyl- (1-alkoxycarbonylalkylamino) (C 1 -C 4) -alkoxy and (C 1 -C 4) alkyl which is either unsubstituted or 4 4 44 4 4 43 4 · 44 4 44 4 4 ·· · 4 · 4 4 · 4 4 4 4 4 4 ···· · ··· 44 · 4 106 substituted with C 1 -C 4 alkyl, such as methyl, C 1 -C 4 alkoxy, halogen with atomic number up to and including 35 and / or trifluoromethyl; (C 2 -C 7) alkenylamino, (C 2 -C 7) alkynylamino, (C 2 -C 7) alkenyl-N-alkylamino, (C 1 -C 4) -alkyl, (N-alkynyl-N-alkylamino) in the alkynyl moiety of 2 to 7 carbon atoms and in the alkyl moiety of 1 to 7 carbon atoms 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl moiety, pyrrolidino, piperidino, 1,2,3,6-tetrahydropyridino; A 4-cyano-4-phenylpiperidino group which is either unsubstituted or substituted by a C1-C4 alkyl group, a C1-C4 alkoxy group, a halogen atom having an atomic number up to and including 35 and / or trifluoromethyl; morpholino, piperazino, Ν'-alkylpiperazino having 1 to 4 carbon atoms in the alkyl moiety, N '- (hydroxyalkyl) piperazino having 2 to 4 carbon atoms in the alkyl moiety, N'pyrimidinylpiperazino; or N'-phenylpiperazino or Ν'-phenylalkylpiperazino containing from 1 to 4 carbon atoms in the alkyl moiety, which is either unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, a halogen atom having an atomic number of up to 35 including and / or trifluoromethyl, and R _{1 Z} R _2, R ₃ and R ₄ are independently hydrogen, alkyl of 1-4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogen with an atomic number up to and including 35 or trifluoromethyl, 5 a pharmaceutically usable or hydroxylated alkanoic acid having 1 to 7 carbon atoms, optionally this; to · to to to ··· ··· ··· ··· 107 hydroxylated, aminated and / or oxosubstituted alkanedicarboxylic acid having 2 to 7 carbon atoms, optionally hydroxylated and / or oxosubstituted alkanetricarboxylic acid having 4 to 7 carbon atoms, optionally hydroxylated and / or oxosubstituted alkenedicarboxylic acid having 4 to 7 carbon atoms, optionally hydroxylated and and / or an oxo-substituted C 4 -C 7 alkindicarboxylic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid as an antineurodegenerative drug or for the preparation of such a drug. Use of an acid addition salt of a compound of formula I according to claim 18, wherein R is C 1 -C 4 alkylamino; phenylalkylamino having 1 to 4 carbon atoms in the alkyl moiety, phenylalkylalkylamino having 1 to 4 carbon atoms in each alkyl moiety, phenyl- (1-carboxyalkyl) amino having 1 to 4 carbon atoms in the alkyl moiety or phenyl- (1-alkoxycarbonylalkylamino group containing 1 to 4 carbon atoms) (C 1 -C 4) alkoxy moieties and C 1 -C 4 alkyl moieties which are either unsubstituted or substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen atoms up to and including 35; and / or C 2 -C 7 alkenylamino, C 2 -C 7 alkynylamino, N-alkenyl-N-C 2 -C 7 alkylamino and C 1 -C 4 alkyl, N-alkynyl- N-alkylamino having 2 to 7 carbon atoms in the alkynyl moiety; alkyl moieties of 1 to 4 atoms 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9999 9 999 999 99 99 108 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl moiety, pyrrolidino, piperidino, morpholino, piperazino, N'-alkylpiperazino of 1 to 4 carbon atoms, or N '(hydroxyalkyl) piperazino of 2 to 4 alkyl groups 4 carbon atoms, and R _{@ 1} , R _{@ 2} , R @ ₃ and R _{@ 4} are each independently hydrogen, C1 -C4 alkyl, C1 -C4 alkoxy, halogen having atomic numbers up to and including 35, or trifluoromethyl, with a pharmaceutically acceptable , optionally hydroxylated alkanoic acid having 1 to 7 carbon atoms, optionally hydroxylated, aminated and / or oxosubstituted alkanedicarboxylic acid having 2 to 7 carbon atoms, optionally hydroxylated and / or oxosubstituted alkanetricarboxylic acid having 4 to 7 carbon atoms, aconitic acid, optionally hydroxylated and and / or an oxosubstituted C 4 -C 7 alkenedicarboxylic acid, optionally a hydroxylated and / or an oxosubstituted C 4 -C 7 alkindicarboxylic acid, further with benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid as an antineurodegenerative drug, or for the preparation of such a drug.